Abstracts of the Internistendagen 2001

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Abstacts of the Internistendagen 2001 I. Oral Presentations Research 1. Colonisation density, topographic localisation and anti CagA antibody tires of Helicobacter pylori. M. Twisk medical student, J. Kusters[ PhD, A.G. Balk* MD, R.J.L.F. Loffeld MD PhD. Departments of Internal Medicine and Pathology*, de Heel Zaans Medisch Centrum Zaandam; Department of Microbiology Free[ University Amsterdam. Introduction: It is reported that the density of cagA1 H. pylori strains is higher than that of cagA2 strains. No data is present about the density and topographic localisation of H. pylori and its relation to height of IgG antibody titre against CagA. Aim of the study: To explore the correlation of height of the IgG antibody titre against CagA, the bacterial density, and the topographic localisation. Material and Methods: Biopsy specimens were taken from consecutive patients for detection of H. pylori. A serum sample was taken for determination of IgG anti CagA antibodies (sens 94.4% and spec 92.5%). Biopsy specimens were stained according to the modified Giemsa stain in order to assess density of H. pylori semiquantitative at high power magnification (grade I: sporadic presence of bacteria; grade II; clusters of bacteria present; grade III: bacteria covering at least half of the mucosal surface; and grade IV: the entire mucosal surface covered with bacteria). Topographic localisation was assessed: score A: H. pylori lying closely attached to the mucosa; score B: H. pylori lying attached to the mucosa and in the mucus; and score C: H. pylori lying solely in the mucus. Results: 293 consecutive H. pylori-positive patients were included (124 X, 169 C, mean age 52.6 years, range 12–87). CagA antibodies were present in 154 (52.5%) of the patients. There was no statistical significant difference in colonisation density and cagA status: gradeI 23(14%), gradeII 78(50.6%0, 1 gradeIII 42(27.5%) and grade IV 11(7.2%) in the cagA and 29(21.2%), 57(40.8%), 38(27%), and 15(11%) in the cagA2 respectively. If patients using PPI’s were excluded from analysis no changes occurred in the relation of bacterial density and cagA status of H. pylori. No difference in topographic localisation between cagA1 and cagA2 H. pylori was present. Mean Anti CagA titre in patients with grade I bacterial density was 0.84; in grade II 0.84; in grade III 0.89; and in patients with grade IV 0.73 (p 5 ns). After exclusion of patients receiving pre-treatment with PPI no significant changes were noticed.

Conclusions: It is concluded that there is no correlation of height of antibody titres against CagA, bacterial colonisation density and topographic localisation with respect to cagA1 and cagA2 H. pylori strains. 2. A comparative study of endoscopic duodenal and jejunal biopsies in suspected celiac disease. W.J. Thijs, J. van Baarlen, N. van Bentem, G.H. van Olffen and J.J. Kolkman. Department of Gastroenterology and Pathology, Medisch Spectrum Twente, Postbus 50000 7500 KA, Enschede, the Netherlands. Tel.: 053 4872412, fax: 053 -4873085, e-mail: w.thijs@ castel.nl Introduction: The diagnosis Celiac Disease (CD) is based on histological evaluation of a small bowel biopsy. With a Crosby capsule it was possible to obtain large biopsies with excellent orientation. However, this procedure has several disadvantages (radiation necessity, patient discomfort, failure and complications). Most physicians therefore rely on normal sized biopsies from the distal duodenum using an endoscope. Frequently, these biopsies are too small or poorly oriented to enable optimal diagnosis. We investigated whether large and oriented jejunal biopsies can be obtained endoscopically. Methods: In patients suspected of CD (mainly diarrhea and weight loss) we performed an upper endoscopy using a colonoscope with large working channel enabling passage of a largecapacity forceps, after sedation with midazolam. Four jejunal and 4 duodenal biopsies were obtained under direct vision. The biopsies were carefully oriented on a strip paper. Histopathological evaluation and histomorphometry using a CD3 marker were performed. In the first 30 patients we confirmed that the colonoscope was positioned beyond Treitz’ ligament by fluoroscopy. The complications and failures to reach the jejunum were recorded. Results: In a 2-year period we investigated 145 patients. No major complications occurred, although 3 patients experienced moderate pain despite midazolam. The jejunum was reached in 141 / 145 patients (97%); reasons for failure were inability to advance the forceps (n 5 1), esophageal stenosis (n 5 1) and uncorrectable looping in the stomach (n 5 2). Histopathology revealed a mean biopsy size of 5 mm, with adequate to excellent orientation in all, enabling assessment of crypts and villous anatomy as well as crypt / villus ratio. Marsh I–II lesions were found in 55 (38%) and Marsh III in 15 patients (10%). Duodenal

0300-2977 / 01 / $ – see front matter  2001 Published by Elsevier Science B.V. PII: S0300-2977( 01 )00100-0

Internistendagen 2001 and jejunal biopsies were concordant in 53 / 55 (96%) patients with Marsh I–II and in 10 / 10 patients with Marsh III. In 2 patients duodenal biopsies were normal, but jejunum showed Marsh I–II. Conclusions: The use of large-capacity forceps and orientation of biopsies on strip paper allowed excellent histopathological examination in all patients. Using a colonoscope, the jejunum can be reached in almost all patients. Duodenal biopsies were sufficient to diagnose CD in virtually all patients. Thus, jejunal biopsies should be considered only in case of very high clinical suspicion despite normal duodenal biopsies. 3. Lipid mobilisation and oxidation induced by a growth hormone bolus in obese and normal weight women. M. Buijs 1 , 2 1 2 1 ¨ J.Burggraaf , J. Langendonk , R. Schoemaker , M. Frolich , A.Cohen 2 , J. Romijn 3 , A. Meinders 1 , H. Pijl 1 . Department of General Internal Medicine 1 , Centre for Human Drug Research 2 , and Department of Endocrinology 3 , Leiden University Medical Centre, C1 -R39, P.O Box 9600, 2300 RC Leiden, The Netherlands, Phone: 1 31 71 526 4470, Fax: 1 31 71 524 8140, e-mail: m.m.buijs@ lumc.nl Introduction: Obesity is associated with very low 24-hour growth hormone (GH) concentrations. The physiological consequences of these low levels are unclear. As GH has lipolytic effects, an impaired GH release may perpetuate the obese state. On the other hand, obese children attain final heights within the normal range, suggesting that obese humans are more sensitive to the bio-action of GH. Aim of the study: We aimed to determine whole body lipolysis and GH sensitivity with respect to its lipolytic effects in obese (OB) and normal weight (NW) women. Materials and Methods: An iv. bolus of rhGH (200–300 mU) or NaCl 0.9% was administered in randomised order to eight NW (body mass index (BMI): 22.261.6 kg / m 2 ) and eight OB (BMI: 32.162.6 kg / m 2 ) postmenopausal women. Lipolysis was measured by infusion of D5-glycerol. The glycerol rate of appearance (R a ) was modelled as a function of plasma GH concentrations to describe adipose tissue sensitivity. Results: Similar plasma GH peaks ( | 20 mU / L) were reached by GH injection in both groups. Mean plasma GH levels were significantly lower in OB vs. NW women during saline conditions (NW: 2.0861.18 mU / L, OB: 0.7460.52 mU / L, p 5 0.023). Basal whole body glycerol R a was significantly greater in OB than in NW women (NW: 12268.9 mmol / min, OB-NW: 26.5612.2 mmol / min, 95%CI 5 2.1 / 50.9). Adipose tissue sensitivity per unit GH effect concentration was not different in both groups (NW: 12.165.5, OB-NW: 4.864.9, 95%CI 5 2 4.9 / 14.5). Conclusion: These results suggest that obesity is associated with reduced plasma GH levels while adipose tissue sensitivity to GH bio-action is similar in NW and OB women, indicating that obese individuals are functionally GH deficient. 4. Effects of peritoneal dialysis with an overnight icodextrin dwell on parameters of glucose and lipid metabolism. S.J.H. Bredie 1 , F.H. Bosch 1 , P.N.M. Demacker 2 , A.F.H. Stalenhoef 2 , R van Leusen 1 Department of General Internal Medicine, Rijnstate Hospital of Arnhem 1 , Department of General Internal Medicine,

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University Medical Centre of Nijmegen 2 , P.O. Box 9101, 6500 HB Nijmegen, Tel.: 024 -3618819, Fax: 024 -3541734, e-mail: S.Bredie@ azn.nl Introduction: Patients on continuous ambulatory peritoneal dialysis (CAPD) frequently show atherogenic lipid profiles with elevated plasma total cholesterol (TC) and triglyceride (TG) levels and decreased high-density lipoprotein (HDL-C) levels. These lipid abnormalities are associated with elevated plasma glucose and insulin concentrations, in CAPD probably influenced by enhanced peritoneal glucose uptake from high glucose containing dialysis solutions. Aim of the study: Examine whether a reduction of the daily glucose load by overnight replacement with a less-absorbed glucose polymer icodextrin, would have favourable effects on lipid profiles. Material and Methods: In a crossover study with two subsequent periods of six weeks, the participants were randomly assigned to receive an overnight dwell with either standard glucose solution or with a 7.5% icodextrin containing solution. Only patients stable on CAPD and without recent peritonitis, manifest diabetes mellitus or primary hyperlipidemia were included. Results: 21 of 22 included patients (age 50.3611.8 years and BMI 25.762.5 kg / m2) finished the study protocol. After the nocturnal icodextrin dwells, a reduction of total cholesterol (TC) (5.4360.85 to 4.8660.70 mmol / l, p , 0.001) and low density lipoprotein (LDL) cholesterol (3.3860.87 to 2.9360.73 mmol / l, p 5 0.001) was observed. Also high density lipoprotein (HDL) cholesterol (0.9560.27 to 0.9060.24, p 5 0.029) was reduced, but the TC to HDL ratio remained similar. Plasma free fatty acids and triglyceride levels tended to decrease (0.1760.10 to 0.1360.08 mmol / l, p 5 0.06 and 2.1461.96 to 1.9261.03 mmol / l, respectively). The effects on lipids were not accompanied by a decrease of fasting plasma glucose (5.7661.29 to 5.8660.80 mmol / l) or insulin levels (19.5614.4 to 20.3613.0). Evaluation of LDL subfraction profiles after ultracentrifugation showed a more buoyant LDL subfraction profile with less dense LDL particles in 6 patients after icodextrin, whereas in 14 patients no changes after icodextrin were observed. Conclusion: These results suggest a beneficial effect on lipid profiles of non diabetic CAPD patients by application of an overnight dwell with icodextrin. 5. The early course of D-dimer activity following pulmonary artery embolisation. J.J. Mager, R.E.G. Schutgens, P. Zanen, F.J.L.M. Haas, C.J.J. Westermann, D.H. Biesma. Departments of Pulmonology, Internal Medicine and Clinical Chemistry, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands, Tel.: 1 31.30.6099111, Fax: 1 31.30.6056357, email: schutgensvos@ hetnet.nl Background Normal D-dimer concentrations are increasingly used to rule out acute venous thromboembolic processes. There is, however, little information about the lag time between initiation of thrombosis and increase in D-dimer activity and about the extend and duration of D-dimer elevation in patients during the first hours of a thrombotic event. We measured D-dimer concentrations during the first hours after pulmonary artery embolisation in

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patients with pulmonary arteriovenous malformations due to Rendu-Osler-Weber disease. Method We studied D-dimer concentration before and during a 8-hour time period after embolisation in 13 patients; the control group consisted of 14 patients who underwent a diagnostic right or left heart catheterisation without embolisation. We also investigated the extent of D-dimer activity in relation to the total volume of the parts of the pulmonary arteries that were embolised, to the improvement in pO2 and to the reduction in shunt fraction. Findings The patient group had significantly increased D-dimer levels at t 5 2, 4 and 8 hours after the procedure as compared to baseline values ( p 5 0.001, p 5 0.016 and p 5 0.001 respectively). The control group had no significant increase in D-dimer levels as compared to baseline. There was a significant difference between the patient and the control group ( p 5 0.047). We found a correlation between the D-dimer activity and the calculated volume of the embolised pulmonary arteries (R2 5 0.74). No correlation was found between D-dimer activity and the increase in pO2 or reduction in shunt fraction. Interpretation There is no relevant lag time between the increase in D-dimer activity and pulmonary embolisation in patients with pulmonary arteriovenous malformations. D-dimer activity may be suitable to predict the extent of thrombus formation. 6. Monocyte activation and subsequent acute phase response (APR) during super-flux hemodialysis (HD): long-term results. 1 2 1 A. van Tellingen , M.P.C. Grooteman , M.J. Nube´ , M.G. 2 1 1 1 Vervloet , M. Schoorl , P.C.M. Bartels , M. Schoorl , T. van der Ploeg 3 , 1 Medical Centre Alkmaar, 2 Academic Hospital VU, 3 Universitiy of Professional Education Hogeschool Alkmaar, Wilhelminalaan 12, 1815 JD Alkmaar, Tel.: 072 -5484444, Fax: 072 -5482159, e-mail: avantellingen@ worldmail.nl Introduction: Recently, concern has been raised about the long-term consequences of non-sterile dialysate and the concomitant use of dialyzers with superior permeability in clinical HD. Aim of the study: This prospective study was designed to investigate the magnitude of the APR in chronic HD patients in the long-term, comparing various dialyzers with both standard and filtered dialysate. Materials and Methods: Besides the quality of the dialysate (CFU / ml, LPS in EU / ml), plasma concentrations of interleukin-6 (IL-6), C-reactive protein (CRP), pre-albumin and lipoprotein (a) [Lp(a)] were measured in 37 patients undergoing HD for 12 weeks with two of the following dialyzers: high-flux polysulfon (PS: F 60), super-flux PS (F 500S), super-flux cellulosic tri-acetate (CTA: Tricea 150G) or super-flux CTA with filtered dialysate (Tricea 150G f ), resulting in 72 periods in which measurements were obtained. Blood samples, collected at the start of the study and after 12 weeks, were drawn from the afferent line before dialysis (t 0 ). As for IL-6, samples were also drawn from the efferent line 180 min (t 180 ) after the start of HD. Results: During high-flux dialysis IL-6 remained stable (t 0 3.864.6 pg / ml, t 180 3.765.3 pg / ml, p 5 0.52), whereas IL-6 decreased significantly during super-flux dialysis (t 0 3.665.0 pg / ml, t 180 2.863.8 pg / ml, p 5 0.001). In contrast, IL-6 did not change after HD for 12 weeks. More over, as for CRP, pre-

albumin and Lp(a), marked fluctuations were not observed in the long-term. A strong positive correlation was found between IL-6 and CRP (r 5 0.84, p , 0.001), whereas negative correlations were found between IL-6 and pre-albumin (r 5 2 0.24, p 5 0.038), respectively CRP and pre-albumin (r 5 2 0.28, p 5 0.015). Multivariate analysis revealed that IL-6 was the only significant predictor of CRP accounting for 70.4% of its variance ( p , 0.001). Conclusion: The quality of the dialysate did not contribute to cytokine release or to the production of acute phase proteins during super-flux HD in the long-term. Efforts should be undertaken to clarify other possible underlying mechanisms responsible for the chronic inflammatory state in clinical HD. 7. Diagnosis of familial combined hyperlipidemia (FCH) based on lipid phenotype expression in 32 families: results of a 5 years follow-up study. M. Veerkamp, J. de Graaf, S. Bredie, J. Hendriks 1 , A. Stalenhoef. Dept. General Internal Medicine and Medical Statistics 1 , University Medical Center Nijmegen, Postbox 9101, 6500 HB Nijmegen, The Netherlands, Tel.: 024 -3618819, Fax: 024 -3541734, e-mail: m.veerkamp@ aig.azn.nl Introduction: FCH is the most common lipid disorder, characterized by hypercholesterolemia and / or hypertriglyceridemia and associated with premature cardiovascular disease. Aim of the study: (1) to evaluate the variability in lipid phenotype expression over a 5 years period; (2) to study factors affecting the lipid phenotype expression. Materials and Methods: FCH was defined by internationally accepted criteria including the presence of elevated plasma total cholesterol and / or triglyceride levels above the 90th percentile for age and gender and the presence of premature atherosclerosis in first degree relatives. In total 32 families, including 307 subjects, were studied in both 1994 and 1999. Data and blood samples were collected after an overnight fast and four weeks withdrawal of lipid-lowering medication. Results: In 1994, 93 of the 307 subjects (30%) were affected (FCH), whereas 214 subjects (70%) were normolipidemic (NL). In 1999 the diagnosis FCH was consistent in only 69 of the 93 subjects (74%). So, 26% of the subjects with FCH in 1994 showed a normolipidemic pattern in 1999. Furthermore, 185 of the 214 subjects (86%) remained normolipidemic and 14% of the non-affected relatives in 1994 developed the FCH phenotype in 1999. In total 83 of the 307 subjects (27%) showed a switch in lipid phenotype. The mean change in cholesterol and triglyceride level to switch from phenotype was 1.1060.66 mmol / l and 1.4861.14 mmol / l respectively. Multiple regression analysis showed that gender (odds ratio 2.06 (CI 95% 1.11–3.93, p 5 0.02) and BMI (odds ratio 1.13 (CI 95% 1.05–1.23, p , 0.001) significantly contributed to the variability in lipid phenotype expression. Conclusion: This is the first long term follow-up study of a large cohort of FCH families showing that the diagnosis FCH, based on total cholesterol and triglyceride levels, is consistent in only 74% of the subjects over a 5 years period. Our results emphasize the need for re-evaluation of the diagnostic criteria for FCH. Other traits are frequently associated with FCH, although not considered as criteria for diagnosis. These include the presence

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Internistendagen 2001 of small dense LDL, elevated levels of apoB and insulin resistance. The contribution of these traits to improve the diagnostic criteria for FCH will be evaluated. 8. Impaired NO dependent vasodilation in patients with type 2 diabetes is restored by folate. R.W. van Etten 1, 2 , E.S. Stroes 1 , M.L. Honing 1 , M.C. Verhaar 1 , E.J.P. de Koning 1 , C.A.J.M. Gaillard 1, 2 , T.J. Rabelink 1 . Dept. of Vascular Medicine and Diabetes, University Medical Center, Utrecht, The Netherlands. Dept. of Internal Medicine, Eemland Hospital, Amersfoort, The Netherlands. Address: UMC Utrecht, Room number: G.02.402, Tel.: 030 -2507570, e-mail: r.w.vanetten@ azu.nl Introduction: Cardiovascular disease is the principal cause of morbidity and mortality in patients with type 2 diabetes. Endothelial dysfunction predicts outcome in cardiovascular compromised patients. Patients with type 2 diabetes are characterized by endothelial dysfunction. Hyperglycemia, the hallmark in diabetes, causes oxygen radical stress and has also been associated with uncoupling of endothelial nitric oxide synthase (eNOS), both leading to decreased nitric oxide (NO) availability. We recently demonstrated that folate reverses eNOS uncoupling. Methods: Using forearm plethysmography, we evaluated the effect of 5-methyltetrahydrofolate (5-MTHF, the active form of folic acid) on forearm vasomotion in 23 patients with type 2 diabetes and 21 control subjects, matched for age, gender, blood pressure, BMI and smoking habits. Serotonin was infused as agonist for endothelium-dependent, NO-mediated vasodilation, bradykinin for endothelium-dependent, hyperpolarizing factor-mediated vasodilation and sodium nitroprusside for endotheliumindependent, NO-mediated vasodilation. Results are expressed as percent increase of the ratio of forearm blood flow of the measurement arm (M) and control (C) arm (M / C%). Results: Serotonin-induced vasodilation was significantly blunted (53630 vs. 102666 M / C%, p , 0.005), bradykinininduced vasodilation was unaltered (4296247 vs. 5166232 M / C%, NS) and nitroprusside-induced vasodilation was mildly reduced (2756146 vs. 3916203 M / C%, P , 0.05) in patients with type 2 diabetes compared to control subjects. 5-MTHF significantly improved endothelium dependent, NO mediated vasodilation (from 53630 to 88659 M / C%, p , 0.05) whereas bradykinin mediated and endothelium-independent vasodilation remained unaltered during 5-MTHF co-infusion in patients with type 2 diabetes. 5-MTHF had no effect on vasomotion in control subjects. Conclusion: These data imply that folic acid can be used to enhance cardiovascular protection by improving NO status in patients with type 2 diabetes. 9. Theophylline improves impaired hormonal and symptom responses to hypoglycemia in type 1 diabetic patients with hypoglycemia unawareness. B.E. de Galan 1 , C.J.J. Tack 1 , C.J.W. Pasman 2 , J.A. Lutterman 1 , P. Smits 1,3 Departments of Medicine 1 , Clinical Neurophysiology 2 , and Pharmacology-Toxicology 3 , University Medical Center St Radboud, PO Box 9101, 6500 HB, Nijmegen. Tel.: 024 -3613889, Fax: 024 -3541734, e-mail: b.degalan@ aig.azn.nl

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Introduction: Currently, the most widely used method to alleviate hypoglycemia unawareness in type 1 diabetic patients is relaxation of metabolic control. However, compromising glycemic control is undesirable when longterm diabetic risk reduction is being sought. From a pharmacological point of view, the adenosine-receptor antagonist theophylline might be beneficial in the management of hypoglycemia unawareness, because theophylline is a central stimulant and it augments release of catecholamines. Aim of the study: To investigate the effects of theophylline on responses to and awareness of hypoglycemia. Patients and Methods: In a placebo controlled double-blind randomised fashion, infusions of theophylline (2.8 mg ? kg 21 bolus, followed by 0.5 mg ? kg 21 ? hr 21 continuously) or placebo were administered to 15 type 1 diabetic patients with hypoglycaemia unawareness and 15 age-, sex-, and BMI-matched controls. Subsequently, hyperinsulinemic (60 mU ? m 22 ? min 21 ) stepped hypoglycemic (5.0–3.5–2.5 mM) glucose clamps were performed. A brachial artery was cannulated for blood sampling and hemodynamic monitoring. Measurements included counterregulatory hormones, symptoms, hemodynamic parameters, and sweat detection using a dew point electrode. Additionally, middle cerebral artery velocities (VMCA ) using transcranial doppler were monitored as an estimate of cerebral blood flow. Results: When compared to placebo, theophylline enhanced hypoglycemia-induced responses of plasma adrenaline, noradrenaline, and cortisol levels in diabetic patients (P for all , 0.001) and controls (P for all , 0.05). In both groups, theophylline caused heart rate responses to double (P , 0.05) and sweat production to start at | 0.3 mM higher glucose levels (P , 0.01); symptom scores in diabetic patients approached those in controls. Theophylline decreased VMCA in both groups (P , 0.001), but significantly more in diabetic patients (P 5 0.03), and prevented the hypoglycemia-induced increase that occurred during the placebo studies. Conclusion: Theophylline induces an early and sustained promoting effect on metabolic and symptom responses to hypoglycaemia, possibly related to the reduction in cerebral blood flow. Theophylline thus contributes to recovery from and allows earlier perception of hypoglycaemia in diabetic patients with hypoglycemia unawareness. 10. Acromegaly: results of treatment at the Leiden University Medical Center between 1977 to 2001. N.R. Biermasz, H. van Dulken, A.M. Pereira Arias, J.W.A. Smit, J.A. Romijn and F. Roelfsema. Leids Universitair Medisch Centrum, Albinusdreef 2, 2333 AA, Leiden. Tel 071 5263082 Fax: 071 5248136, e-mail: nrbiermasz@ lumc.nl Introduction: Transsphenoidal surgery is the treatment of choice for patients with acromegaly. Other treatment modalities include radiotherapy and medical treatment with somatostatinanaloga, dopaminergica and in trials GH-receptor antagonists. Aim of the study: Evaluation of treatment results for acromegaly in the Leiden University Medical Center focusing on the late outcome of surgery, the results of postoperative radiotherapy and possible predictors for recurrence of disease. Material and Methods: 148 patients underwent surgery for acromegaly between 1977 and 2000 (21% microadenoma, 60%

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noninvasive macroadenoma and 19% invasive adenoma). All operations were performed by a single neurosurgeon (HvD). Criteria for remission were normalization of suppressed GH concentration (GH , 1 mU / L for the IFMA-assay and , 2.5 mU / L for the previously used RIA), a serum GH concentration , 5 mU / L and a normal IGF-I concentration for age. Results: Immediately postoperatively, serum GH concentration decreased from 90.668.9 to 10.261.8 mU / L and serum IGF-I concentration from 57.462.6 to 29.962 nmol / L (IGF SDscore from 7.360.5 to 2.0360.36). Mean postoperative glucose-suppressed GH was 4.7560.9 mU / L. A serum GH , 5 mU / L was achieved in 64% of patients, a normalized GH suppression in 68% and a normal IGF-I in 56%. Direct postoperative remission was associated with preoperative serum GH and tumor size, but not with year of surgery. In 59 patients with early postoperative remission followed for at least 10 years (range 10 –22 yr) postoperatively, 5 out of 27 patients (19%) developed recurrence of disease. However, after a mean follow-up of 16 years, 78% of patients have a serum GH concentration , 5 mU / L, 73% a normal glucose- suppressed GH and 74% a normal IGF-I without the need of other treatment. In 36 patients with postoperative active disease, radiotherapy was effective in normalizing serum IGF-I levels in 60% after 5 years, 74% after 10 years and 84% after 15 years. A ‘‘safe’’ serum GH concentration ( , 5 mU / L) is furthermore achieved in 75% (5 yr), in 76% (10 yr) and 87% (15 yr) (n 5 40). The incidence of hypopituitarism after radiotherapy increased with time, and after 10 years more than 50% required replacement therapy. Conclusion: Early postoperative remission rate was 68%. In the other patients, debulking of adenoma mass led to remarkable reduction of GH hypersecretion and clinical improvement. This remission rate is favorable compared to other series. Our late follow-up results with a recurrence rate higher than previously described, emphasize the necessity of long-term follow-up. 11. Increased TNF-a production ex vivo is associated with elevated CRP and fibrinogen levels in hypertriglyceridemia. reversal upon lipid-lowering therapy by bezafibrate. I.J.A.M. Jonkers 1 , M.F.M. Mohrschladt 1 , F.H.A.F. de Man 1 , A van der Laarse 1 and A.H.M. Smelt 1 . Leiden University Medical Center 1 , Albinusdreef 2, 2300 RC Leiden. Tel.: 071 -5264654; Fax: 071 5248159, e-mail: IJAMJonkers@ lumc.nl Introduction: Earlier we demonstrated that hypertriglyceridemia (HTG) is associated with a pro-inflammatory cytokine profile (increased TNF-a production ex vivo) compared to normolipidemic controls. We hypothesize that this TNF-a production ex vivo induces an increase in both CRP and fibrinogen levels in HTG, which might subsequently contribute to the increased risk for cardiovascular disease in HTG. Aim of the study: To compare TNF-a production ex vivo, CRP and fibrinogen levels between HTG patients and controls. Secondary, the effects of lipid-lowering therapy by bezafibrate were studied on TNF-a production ex vivo, CRP and fibrinogen levels. Materials and Methods: 18 patients with endogenous HTG without cardiovascular disease and 20 age- and sex-matched healthy volunteers participated in this study. A double-blind placebo-controlled cross-over study was designed for the HTG

patients to determine whether they differed from controls regarding CRP and fibrinogen levels and to assess whether bezafibrate affected these parameters. In addition, in a subset of this population (13 HTG patients and 19 controls) TNF-a production was measured ex vivo using whole blood stimulation with cumulative doses of LPS. Results are expressed as medians (IQR). Results: HTG patients had 12 fold higher TG levels than controls ( p , 0.001). In addition, both CRP and fibrinogen levels were significantly higher in HTG patients than in controls (CRP 2.2 (1.0–5.8) vs. 0.9 (0.4–2.4) mg / L, p 5 0.02 and fibrinogen 3.4 (2.8–3.8) vs. 2.6 (2.5–3.2) g / L, p , 0.001; respectively).TNF-a production was significantly higher in HTG patients than in controls ( p , 0.001). Bezafibrate therapy resulted in a reduction in serum TG and both CRP and fibrinogen levels (262%, p , 0.001; 2 44% p 5 0.05 and 2 20%, p , 0.001; respectively). In addition, bezafibrate therapy reduced TNF-a production ( p 5 0.019). Change in TNF-a production (at LPS 100 pg / mL) correlated with both change in CRP levels and change in fibrinogen levels (r 5 0.731 and r 5 0.721, both p , 0.01;respectively), but not with change in lipids. Conclusion: HTG is associated with the presence of increased levels of CRP, fibrinogen and TNF-a production ex vivo, which may contribute to the increased risk for cardiovascular disease in HTG. Bezafibrate has, besides its lipid-lowering capacities, beneficial anti-inflammatory effects, as represented by bezafibrate-induced reductions in TNF-a production, CRP and fibrinogen levels. 12. Postoperative iron utilisation and ferrokinetics. C.E. van Iperen 1 , J.J.M. Marx 2 , A van de Wiel 1 . Departments of Internal Medicine, 1 Eemland Hospital Amersfoort,2 University Hospital Utrecht, The Netherlands Introduction: Anemia is not uncommon after major surgery and is related both to blood loss and the inflammatory response induced by the procedure. Recovery of hemoglobin concentration goes slowly and iron is relatively ineffective. This may be caused by a blunted responsiveness of the bone marrow in the postoperative period. Aim of the study: To evaluate incorporation of plasma iron by red cell precursors during the first days after surgery Methods: Five patients scheduled for elective total hip surgery received 50 kBq 59 Fe ferric citrate bound to endogenous transferrin intravenously within one week after surgery. Results: Median half life time of the injected iron was 54 minutes (range: 49–65) which is reduced compared to healthy volunteers (83 min.). Plasma iron turnover was normal (111 mmol / l blood / day, range: 79–134). Red cell iron uptake 12–14 days after the injection was increased (99%, range: 92–100) compared to healthy volunteers (81%) and rapid shown by a median marrow transit time (MMT) of 2.3 (range: 1.3–2.5) days (normal value: 3.5 days). Conclusion: Red cell iron utilization is rapid and almost complete after surgery. Ineffectiveness of oral iron treatment and impaired increase in erythropoiesis found after surgery can therefore not be attributed to defective iron incorporation in the erythron but must be due to decreased iron absorption and impaired release of iron from the macrophage system and hepatocytes during the inflammatory period after surgery.

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Internistendagen 2001 13. Proinflammatory but not antiinflammatory cytokines, are upregulated in patients with chronic renal failure undergoing peritoneal dialysis. M.G.E.C. Hilkens, M.G. Netea, A.A.M.J. Hollander, J.L.J. Janssen, M.I. Koolen. Bosch Medicentrum, Department of Internal Medicine, Nieuwstraat 34, 5200 ME ‘ s-Hertogenbosch, Tel.: 073 -6162000, Fax: 073 -6162257 Introduction: Patients with chronic renal failure often manifest anorexia, weight loss and atherosclerosis, in which proinflammatory processes are though to play a central role. The proinflammatory cytokines tumor necrosis factor-a (TNF) and interleukin-1b (IL-1) are important mediators in the pathogenesis of these complications. In contrast, the antiinflammatory cytokines IL-6 and IL-10 counteract the biological effects of TNF and IL-1, and may play a protective role. Aim of the study: To assess the circulating concentrations of pro- and antiinflammatory cytokines in patients with chronic renal failure undergoing peritoneal dialysis (PD). Materials and Methods: Heparin plasma was collected from ten patients with chronic renal failure treated with PD at 3, 6 and 12 months after the start of PD, as well as 10 healthy volunteers as a control group. TNF and IL-1 concentrations were determined by specific radioimmunoassays, whereas IL-6 and IL-10 levels were measured by commercial ELISA kits (Pelikine, CLB, Amsterdam). Results: TNF plasma concentrations 3 months after the start of PD were significantly higher in the patients compared to the controls (223 1 21 vs. 94 1 22 pg / ml, p , 0.02). Similar high TNF concentrations were measured after 6 and 12 months of PD, but no significant differences with the levels at 3 months were found (not shown). IL-1 plasma concentrations were similar in the PD patients at 3 months (62 1 12 pg / ml), 6 and 12 months (not shown), vs. the healthy volunteers (55 1 18 pg / ml, p . 0.05). In contrast to the proinflammatory cytokines, the circulating concentrations of the antiinflammatory cytokines IL-6 and IL-10 were below the detection limit of the assays in both patients and controls ( , 3 pg / ml and , 5 pg / ml, respectively). Conclusion: Circulating concentrations of the TNF are elevated in patients with PD, compared to healthy controls, whereas IL-1 levels are only marginally increased. In contrast, the levels of the antiinflammatory cytokines IL-6 and IL-10 are not upregulated in PD patients. This bias towards a proinflammatory status may be involved in the pathogenesis of cachexia and proinflammatory complications in patients with chronic renal failure undergoing PD, and therapeutic strategies aimed to restore the pro- / antiinflammatory cytokine balance may prove to be beneficial. 14. Rapid progression of albumin excretion is a risk indicator for cardiovascular mortality in microalbuminuric type 2 DM patients. A.M.E. Spoelstra – de Man, MD 1 ; C.B. Brouwer, MD 1 ; C.D.A. Stehouwer, MD 2 ; Y.M. Smulders, MD 1 . 1 Department of Internal Medicine, Onze Lieve Vrouwe Gasthuis, 1 e Oosterparkstraat 279, 1091 HA Amsterdam, Tel.: 020 -5993503, Fax: 020 5993523, e-mail: apspoel@ xs4 all.nl, 2 Free University Hospital Amsterdam. Introduction: In patients with type 2 DM, microalbuminuria is associated with an increase in predominantly cardiovascular mortality. Considerable inter-individual variability in the rate of

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progression of microalbuminuria exists. The prognostic significance of rate of progression of microalbuminuria with regard to cardiovascular and renal clinical endpoints is unknown. Aim of the study: To study the prognostic significance of rate of progression of microalbuminuria for cardiovascular and renal clinical endpoints. Materials and Methods: In a previous prospective cohort study, progression of microalbuminuria (expressed as mean yearly change in albumin to creatinine ratio) was assessed in 58 patients. During a median follow up period of 7 years (range 6–9) after progression of microalbuminuria was determined, we registered as primary endpoints: all-cause and coronary heart disease mortality, and as secondary endpoints: fatal and nonfatal coronary heart disease, peripheral vascular disease, ischaemic stroke, retinopathy, macroalbuminuria, and change in serum creatinine. Results: Seven subjects had died, 5 from coronary heart disease. Cox regression analysis identified progression of microalbuminuria as a significant predictor of all-cause (hazard ratio, hr 5 1.46 per point increase in albumin to creatinine ratio per year) and coronary heart disease mortality (hr 5 2.32), and macroalbuminuria (hr 5 1.79). Adjustment for multiple cardiovascular risk factors did not affect these results. Identical analyses for baseline level of microalbuminuria did not show significant hazard ratios. In addition, progression of microalbuminuria was significantly related to change in serum creatinine (Spearman’s rank correlation analysis: r 5 0.29; p 5 0.04). Conclusion: In patients with type 2 diabetes mellitus and microalbuminuria, the rate of progression of microalbuminuria appears to be a powerful independent predictor of both all-cause and coronary heart disease mortality. 15. Effective and safe practical diagnosis of deep vein thrombosis in 811 patients referred to non-academic teaching hospitals; the Pradia study. Ton E. 1 , Tick L.W. 1 , Voorthuizen van T. 2 , Hovens M.M.C. 3 , Leeuwenburgh I. 3 , Lobatto S. 2 , Stijnen P.J. 3 , Heul van der C. 4 , Huisman P.M. 2 , Kramer M.H.H. 1 , Huisman M.V. 5 Eemland Ziekenhuis 1 , Postbus 1502, 3800 BM, Amersfoort, Tel.: 033 -4222444, Fax: 033 -4222695, e-mail: L.Tick@ zkh-eemland.nl; Ziekenhuis Hilversum 2 ; Amphia Ziekenhuis 3 , Breda; St. Elisabeth Ziekenhuis 4 , Tilburg; Leids Universitair Medisch Centrum 5 , Leiden Introduction: The clinical diagnosis of deep vein thrombosis (DVT) is unreliable. Aim of the study: We assessed the efficacy and safety of the combination of a standardised clinical probability test (CPT) according to Wells (Lancet 1997), compression ultrasonography (CUS) and D-dimer in patients with clinically suspected DVT in a non-academic setting. The CPT was performed by the attending physician at the first-aid prior to any following diagnostic test. Results: 811 consecutive patients with suspected DVT participated in the study. We excluded 110 patients (anticoagulant use, suspected pulmonary embolism (PE), DVT within previous 6 months or refusal). At three months follow-up no death due to VTE was observed. A low CPT was established in 280 (35%) of the 811 patients of whom 30 (11%) patients had a positive initial CUS. During 3 months follow up of the patients with low CPT and normal CUS, 4 patients developed DVT and 1 patient PE

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(2.0%, 95%CI 0.7%–4.6%). A non-low CPT was determined in 531 (65%) patients of whom 300 patients (56%) had a positive CUS. In the 231 patients with non-low CPT and normal CUS, D-dimer (Simply RED  ) was abnormal in 83 patients; all these patients had a second CUS at day eight performed, which got abnormal in 9 patients. Two of the 64 patients with serial normal CUS developed DVT at follow-up (3.1%, 95%CI 0.4%–10.8%). None of the patients with a non-low CPT, normal CUS and normal D-dimer developed DVT within three months (upper 95%CI 2.6%). Conclusion: The combination of a standardised CPT, CUS and D-dimer is practical and safe to rule out DVT in patients seen in non-academic teaching hospitals. The low incidence of VTE (2%) in three months follow up in the low CPT group with a normal CUS is considered acceptable and well within range of results from other studies. In addition, no DVT was seen in three months follow up of patients with a non-low CPT, normal CUS and normal D-dimer. Finally, by this practical approach it was possible to reduce the need for repeated CUS testing at day eight by 83%.

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17. Double infection of the stomach with Helicobacter pylori and non-Helicobacter pylori bacteria: A cause for the development of atrophic gastritis during acid-suppressive therapy? S. Sanduleanu 1 , D. Jonkers 1 , A. de Bruine 2 , W. Hameeteman 1 , R.W. 1 1 ¨ Stockbrugger . Departments of Gastroenterology /Hepatology , and Pathology 2 , University Hospital Maastricht, The Netherlands. Current evidence indicates an accelerated development of atrophic body gastritis in H.pylori-infected patients treated with acid inhibitory medication. The pathogenetic mechanism is still unclear. Chronic hypochlorhydria predisposes to gastric colonization by non-H.pylori species. This study tested the hypothesis that the double gastric infection with H.pylori and non-H.pylori bacteria may induce an enhanced inflammatory response, thereby promoting the development of atrophic gastritis. Methods: A consecutive series of 150 patients on continuous medium-term (6 weeks to 1 year) or long-term (longer than 1 year) acid inhibition with either proton pump inhibitors (PPIs, n 5 113) or histamine 2 -receptor antagonists (H 2 RAs, n 5 37) for gastro-oesophageal reflux disease, and 76 subjects without acid inhibition (control group) was investigated. Gastric biopsy specimens were examined for detection of H.pylori by immunohistochemistry (IMM), of non-H.pylori flora by modified Giemsa (according to morphology, location, and negative IMM on the same position), and for classification of gastritis (Sydney system). Serum samples were analyzed for pro-inflammatory cytokines, specifically interleukin (IL)-1b, IL-6 and IL-8 (ELISA). Results: Patients on acid suppression with either PPIs or H 2 RAs had similar rates of H.pylori infection as non-treated controls, but were more likely to be infected with non-H.pylori bacteria (61.1% and 59.5% versus 28.9%, P , 0.0001 and P , 0.002, respectively). Logistic regression analysis identified infection with H.pylori as independent risk factor of atrophic body gastritis (OR, 95%CI, 11.7 [1.4–97.8], P 5 0.022). Furthermore, double infection with

H.pylori and non-H.pylori bacteria was associated with higher risk of atrophic body gastritis (OR, 20.4 [2.5–168.6], P 5 0.005), compared to the risk by either type of infection alone. This effect was synergistic (relative excess risk due to interaction 5 3.26; synergy index 5 1.26). In addition, double infection with both types of bacteria was associated with the highest levels of IL-1b, IL-6 and IL-8 compared to those in subjects with either type of infection alone (P , 0.05 for all cytokines). Conclusions: (1) In H.pylori-infected patients treated long-term with acid inhibition, the super- infection with non-H.pylori bacteria may cause an enhanced inflammatory response, explaining their increased risk of developing atrophic body gastritis. (2) H.pylori ‘‘test-and-treat’’ strategy should therefore be considered prior to the start of long-term gastric acid inhibition to prevent the potential pathogenetic effect of a double bacterial infection. 18. Follow-up of COPD patients on home mechanical ventilation (HMV). E. Westermann, M. Kampelmacher, L. van Ewijkvan den Bosch, L. Verwey-van den Oudenrijn, R. van Kesteren, Centre for Home Mechanical Ventilation, University Medical Centre Utrecht, HP C02.410, Heidelberglaan 100, 3584 CX Utrecht, Tel.: 030 -2508865, Fax: 030 -2505440, e-mail: E.Westermann@ digd.azu.nl The effectiveness of HMV in COPD patients is still uncertain. To evaluate the efficacy and feasibility of HMV we retrospectively studied all COPD patients who were referred to our centre since 1984. Out of a total of 131 patients (mean age (6SD) 6269 years, FEV1 pred. 38616%, FEV1 / VC 47618%, PCO 2 9.262.7 kPa) 36 patients (28%) were diagnosed as having COPD only, while the remaining 95 patients had adipositas (36%), sleep apnea syndrome (25%), thorax deformities (14%) or neuromuscular diseases (5%) as well. HMV was never started in 29 patients because of alternative therapeutic options (16 patients), sufficient recovery (10) or premature death (3). Before starting HMV 62 patients (48%) used long-term oxygen therapy with a flowrate of 1.260.7 l / min. Of the 102 patients who started HMV, 21 used invasive HMV (iHMV) by means of a tracheostomy and 81 non-invasive HMV (niHMV) with nasal masks. After 19 (3–275) days 96 patients (78 niHMV and 18 iHMV) were discharged to their home (93%), a nursing home (6%) or a rehabilitation centre (1%), leaving 6 patients in whom initiation of HMV could not be completed due to noncompliance (5) or death (1). Long-term oxygen was used by 73 (76%) of these 96 patients. The percentage of patients using oxygen increased from 44% before admission to 83% at discharge, respectively, from 51% to 74% in the iHMV and niHMV groups. After a mean period of 42630 and 4776415 days, respectively 4 patients on iHMV could be managed with niHMV while 4 patients on niHMV had to be switched to iHMV due to insufficient effectiveness of niHMV. On 1-1-2000 the 96 HMV patients were ventilated for 2.1 (0.1–11.8) years (iHMV 2.9 (0.2–11.8); niHMV 2.0 (0.1–9.9)). The estimated time needed for iHMV and niHMV related care was 3.665.3 respectively 1.562.8 h / d. The total number of both medical and nursing consultations amounted to 19.764.2 and 9.166.5 per patient per year for iHMV and niHMV patients, respectively. Hospital admis-

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Internistendagen 2001 sions amounted to 0.961.6 per patient per year (iHMV 1.762.3; niHMV 0.761.3). A total of 31 patients (33%) quitted HMV: 27 died (10 patients using iHMV and 17 niHMV) and 4 chose to discontinue HMV. It is concluded that a considerable number of patients (22%) referred to our centre did not require HMV. Although mortality was substantial, particularly in iHMV patients, HMV may prolong survival in COPD patients with chronic respiratory insufficiency. HMV was, above all, feasible in the home setting of these patients. 19. Value of various laboratory parameters for diagnosing iron deficiency in hospitalised patients with microcytic or normocytic anemia. J.C. Kuenen 1, * , A. van Tellingen 1 , W. de Kieviet 2 , H van Tinteren 3, MLK Kooi 3, WLE Vasmel 1 . Departments of 1 Internal Medicine and 2 Clinical Chemistry, Sint LucasAndreas Hospital, Amsterdam; 3 Comprehensive Cancer Centre, Amsterdam, The Netherlands. * Corresponding author: J.C. Kuenen, Department of Internal Medicine, Sint Lucas-Andreas Ziekenhuis, Jan Tooropstraat 164, 1061 AE Amsterdam, The Netherlands; telephone number: 1 31 -(0)20 -5108911, fax number: 1 31 -(0)20 -6838771, e-mail: postbus@ mjvdmeulen.demon.nl Introduction: Patients on a general, internal ward form an heterogeneous population in which various factors complicate the diagnostic evaluation of anaemia. Diagnosing iron deficient or sufficient erythropoiesis has important clinical implications. The real value of newer parameters, such as zinc protoporphyrin (ZPP), plasma transferrin receptor (PtrfR), PtrfR / ferritin ratio for the individual patient in this population is not clear. Aim of the study: We have performed a prospective study to determine the predictive value of these parameters and ferritin, for diagnosing iron deficiency anaemia (IDA) in hospitalised patients with microcytic or normocytic anaemia. A standard questionnaire was used to obtain relevant patient characteristics. Based upon this questionnaire, the clinician has been asked to estimate ‘a priori’ whether the patient suffers from IDA. Also, the reticulocyte response upon 10 days iron therapy was measured. As the golden standard a bone marrow examination was performed in all patients. Inclusion criteria were as follows: Hb , 8.2 mmol / l (men), , 7.0 mmol / l (women) and MCV , 96 fl. Patients with known haematologic disease, bone marrow suppression by chemotherapy or radiotherapy and supplementation of iron less than 7 days before entry were excluded. Results: In 62 patients a bone marrow examination was obtained. Depleted iron stores were found in 24 patients, whereas in 33 patients RES showed no iron deficiency. In 5 patients insufficient material was obtained for iron staining. We found that the reticulocyte response on iron supplementation correlated well with the iron-status of the bone marrow. Univariate analysis showed that ferritin, PtrfR / log ferritin, ZPP, PtrfR, have good predictive values for differentiating IDA from non-IDA in this population. Interestingly, multivariate analysis revealed that ferritin was the only significant, independent predictor of IDA, with a cut-off point of 30 . g / l (sensitivity 79.2%, specificity 96.9%). Conclusions: The results of this study indicate that in this representative group of patients ferritin is the most predictive value for diagnosing IDA. The low sensitivity and specificity of

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Zpp, PtrfR and PtrfR / ferritin ratio render them insufficient to be used as a single ‘best’ test for the identification IDA in a non-selected group of anaemic patients. 20. Acarbose improves glycaemic control and insulin sensitivity in obese type 2 diabetes patients with secondary failure on sulphonylureas. P.J.W.S. Vrijlandt 1 , J. Huisman 2 , Groningen 1 University Hospital, Department of Internal Medicine , Medisch 2 Spectrum Twente, Enschede , P.O. Box 30.001, 9700 RB Groningen, The Netherlands, Tel.: 1 31 50 3616161, Fax: 1 31 50 361 9069, e-mail: P. J.W.S.Vrijlandt@ int.azg.nl. Introduction: In previous studies, the glucosidase inhibitor acarbose has been found effective as a single agent in the treatment of type 2 diabetes mellitus. Aim of the study: To show an additional effect of acarbose to sulphonylureas and gain insight in the mechanism of the improvement. Materials and Methods: In a single centre, double-blind randomised controlled trial, 73 patients with type 2 diabetes and overweight (body-mass index . 27 kg / m 2 ), who were failing on therapy with diet and sulphonylureas (HbA 1c . 7.5%) were treated with acarbose (100 mg tid) or placebo during 24 weeks. We used hyperinsulinaemic euglycaemic clamps to determine insulin sensitivity in a substudy. Results: HbA 1c was the primary efficacy parameter. At the end of the study, the HbA 1c level for the acarbose group was 8.7% compared to 9.7% in the placebo group ( p 5 0.0006). Also the secondary efficacy parameters (fasting blood glucose, 1-hour postprandial glucose and 1-hour post-prandial insulin) differed significantly at the end of the study. Median fasting insulin levels were not influenced by acarbose. Insulin sensitivity, as determined by M / I values from the hyperinsulinaemic euglycaemic clamps, decreased in the placebo group (n 5 10) but increased in the acarbose group (n 5 7) (20,129 vs. 1 0,094 mmol m 22 min – 1 L mU 21 ; p 5 0.047). Conclusion: Compared to placebo, acarbose was efficacious in lowering HbA 1c levels in obese type 2 diabetes subjects failing on diet and sulphonylureas with a simultaneous improvement in insulin sensitivity. 21. Collagenous colitis; diagnosis and medical treatment. P. Honkoop 1 , R.J.Th. Ouwendijk 1 , R.W.M. Giard 2 and D.J. Bac 1 . Department of Internal Medicine, Ikazia Hospital Rotterdam 1 and Department of Pathology MCRZ-St Clara Rotterdam 2 . Montessoriweg 1 3083 AN Rotterdam, tel: 010 -2975136, fax: 010 4859959, e-mail: djbac@ worldonline.nl Collagenous colitis is recently recognized as another form of inflammatory bowel disease. The disease is characterised by chronic watery diarrhoea without specific endoscopic abnormalities. Histology shows a subepithelial collagen band in biopsy specimens. We routinely performed biopsies during colonoscopy if no abnormalities were found and the indication for endoscopy was chronic diarrhoea. In several studies the incidence is estimated 1-2 / 100.000 population or 6 / 1000 colonoscopy’s performed. Between 01-1995 and 01-2000 we identified 14 cases, 9 females (64%), histology showed a thickened collagen band exceeding 10

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mm and an increased mixed inflammatory cell infiltrate in the lamina propria. The median duration of complains at the time of diagnosis was 14 weeks (min-max, 1–300). Median stool frequency was 5 (1–10) times a day with a weight loss of 5 (0–8) kg. Initially 5 patients were treated with fibers, 4 with antibiotics and 3 with 5-ASA, one was treated with hydrocortisone because of a history of ulcerative colitis, and one was not treated at all. A second therapeutic course was needed in 8 patients, 4 received 5-ASA, one in combination with hydrocortisone, two budesonide, one received antibiotic therapy and one cholestyramine. Of these 8 patients 4 received antibiotic therapy, as first line therapy. Only one patient needed third therapeutic intervention with hydrocortisone. Totally five out of 14 patients were treated with steroids (two hydrocortisone, three budesonide). Response to steroids was seen in a two weeks period. After a median follow-up of 75 (3–258) weeks 6 out of 14 patients were perfectly well with fibers (2 of them on demand), two patients were still treated with 5-ASA, one because of CU and one was lost to follow-up while using 5-ASA. Conclusion: Collagenous colitis is an underdiagnosed cause of chronic diarrhoea. In patients with chronic diarrhoea and normal colonoscopy routine biopsies are advocated. Most of the patients with collagenous colitis will respond to fiber therapy. For patients not responding to fibers, budesonide seems to be efficient and effective as second line treatment. 22. Inadequate delivery of enteral tube feeding in the ICU. I. Purmer, L. Flierman, L. Bos, D.J. Versluis. Department of Intensive Care and The Nutritional Support Team, Medical Centre Haaglanden, Post-box 432, 2501 CK The Hague, The Netherlands, tel:070 -3302000, Fax:070 -3809459, e-mail: d.versluis@ mchaaglanden.nl Introduction: Enteral nutrition is a key component of the management of critically ill patients. To achieve early and complete enteral tube feeding, the nutritional requirements need to be assessed adequately, but also a thorough understanding of factors that may interfere with the delivery of enteral tube feeding is required. Aim of the study: To evaluate those factors that impact on the delivery of enteral tube feeding. Materials and Methods: Patients newly admitted to the ICU who were placed on enteral tube feeding and were otherwise to receive nothing orally, were included. The caloric goals were determined using the Harris-Benedict formula predicting resting energy expenditure added with extra calories depending on the clinical severity of disease. An adequate delivery of daily calories was defined by at least 90% intake of the calculated caloric requirements. All patients were placed on continuous infusion of enteral tube feeding. Results: Twenty consecutive patients were evaluated for a total of 158 days of enteral nutrition. In only 39% of the days the patients met their calculated caloric requirements as defined. On 40% of the days patients received less than 75% of the calories needed. In addition the causes of cessation of the enteral feeding were evaluated. The most cited reasons were diagnostic procedures, endoscopic evaluation, surgical procedures, start up

periods of feeding, starting mechanical ventilation and routine nursing procedures together leading to cessation of infusion in 51% of the study days. Tube displacement or occlusion, gastrointestinal intolerance (vomiting, diarrhoea) and high residual volume as cause for discontinuation of enteral tube feeding occurred in 10% of the days. Conclusion: There was an inadequate delivery of enteral tube feeding on the ICU due to a frequent and often inappropriate cessation of tube feeding, although the ordering of the caloric requirements was supervised by a dietician. The prolonged discontinuation of enteral tube feeding before and after procedures in 51% of the study days was judged to be at least in part avoidable. To optimise enteral tube feeding on an ICU the development of strict infusion protocols is needed. 23. Feasibility study of paclitaxel (Taxol  ), gemcitabine, and cisplatin for patients with advanced ovarian cancer. J. van den Bosch 1 , K. Hoekman 1 , R.H.M. Verheyen 2 , H.M. Pinedo 1 . Dpt of Medical Oncology 1 , Dpt of Gynaecologic Oncology 2 , Academical Hospital Vrije Universiteit, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands, Tel.: 1 31 -20 -4444300, Fax: 1 31 20 -4444355, e-mail: jbosch65@ hotmail.com Background: Platinum-based chemotherapy, following debulking surgery, has become the cornerstone in the treatment of advanced ovarian cancer, while the introduction of the taxanes has been a major contribution in the treatment of these patients, both in first as in second line. Gemcitabine has been shown to induce anti-tumour responses in second-line treatment of ovarian cancer and is non-crossresistant with cisplatin. For these reasons we performed a phase II study to explore potential synergistic effects of these three agents in the treatment of patients with advanced ovarian cancer, both in primary as in recurrent disease. Patients and Methods: Treatment consisted of paclitaxel 150 mg / m 2 and cisplatin 75 mg / m 2 on day 1, and gemcitabine 800 mg / m 2 on day 1 and 8, followed by G-CSF sc. from days 2 to 7. Treatment was repeated every three weeks. Patients had histologically verified epithelial ovarian cancer, FIGO stages IIb, IIc, III, IV or recurrent disease, measurable disease, age between 18 and 70 years, performance status # 2, and no brain metastases or demonstrated resistance against cisplatin. The planned number of TGC cycles was 6, with a maximum of 9, starting within 4 weeks after surgery or with a minimal inter-treatment interval of 4 weeks for previously treated patients. Results: 18 Patients were treated, with a median age of 51 years. FIGO stages III and IV were present in 61%. 16 Patients had prior surgery, 5 had prior chemotherapy. 11 Patients completed 6 or more cycles. Treatment was prematurely stopped because of hypersensitivity reactions (11%), progressive disease, or nephrotoxicity. No grade IV toxicity was seen. Grade III toxicity consisted of anaemia (7%), leucopenia (27%), thrombocytopenia (27%), nausea / vomiting (13%), and neurotoxicity (13%). 12 out of 15 patients had a normalisation of the CA-125 within 4 cycles of TGC. The response rate was 73%, with 60% complete responses. Stable disease was present in 13% (one with recurrent disease). Progressive disease was present in 2 patients (13%), one of who had recurrent disease. Median response duration was $ 8 months.

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Internistendagen 2001 Conclusion: The combination of paclitaxel, gemcitabine, and cisplatin is feasible in the treatment of advanced ovarian cancer, both in primary as in recurrent disease. 24. Effects of dopamine and norepinephrine on myocardial oxygen expenditure and cardiac output in septic humans with an arterial pressure clamp. W.T. Jellema 1,2 , K.H. Wesseling 4 , J. van Goudoever 4 , M.J. Lubbers 3 , N. Westerhof 5 and J.J. van Lieshout 1,2 . 1 Cardiovascular Research Institute Amsterdam, Departments of 2 Internal Medicine and 3 Surgery, Academic Medical Center, 4 TNO-BioMedical Instrumentation, Netherlands Organization for Applied Scientific Research, and 5 Institute for Cardiovascular Research, Laboratory for Physiology, Vrije Universiteit, Amsterdam, The Netherlands. Introduction: In septic humans with preload optimised by volume expansion, left ventricular (LV) afterload and myocardial contractility are the two determinants of stroke volume amenable for further manipulation. Dopamine and norepinephrine affect cardiac contractility and thus cardiac output. In addition they increase systemic vascular resistance and produce non-equivocal levels of arterial pressure. The result is that these agents affect LV afterload and myocardial energy expenditure differently. Aim of the study: To test the hypothesis that in critically ill patients treated with catecholamines the ratio of the diastolic to systolic aortic pressure time index (DPTI / SPTI) as an established surrogate of the balance of myocardial oxygen supply and demand can be optimized with maximization of cardiac output. Materials and Methods: In eleven critically ill mechanically ventilated patients the separate effects of dopamine and norepinephrine (cross-over design) on DPTI / SPTI ratio, cardiac index (CI; ventilatory phase-controlled quadruple thermodilution), cardiac pressure work index (PWI), heart rate (HR), systemic vascular resistance (SVRl) and systemic oxygen consumption (VO2; Fick principle) were assessed with arterial pressure clamped within 10 mmHg. The aortic pressure pulse was reconstructed from radial pressure using a generalized transfer function based on an inverted aortic-to-radial model. The DPTI as an estimate of cardiac oxygen supply was calculated from the area under the diastolic part of the constructed aortic pressure curve defined as the period between the pressure wave incisura and the next systolic upstroke. The SPTI as an indicator of cardiac oxygen demand was obtained from the remaining part of the aortic pressure curve. Results: MAP was clamped within 8 mmHg from baseline values in 10 of the 11 crossovers (91%), and within 5 mmHg in 8 crossovers (73%). With norepinephrine vs. dopamine, HR (9066 to 10067 beats / min) and CI (4.260.5 to 5.060.6 l.min 21 .m 22 ) were larger ( p , 0.001). Pulmonary artery, wedge and right atrial pressures, VO2 (149646 vs. 150667 ml.min.m 22 ) and arterial blood lactate level (2.160.5 vs. 1.560.5 mmol.l 21 ) did not change. With dopamine the SVRI was lower (15576228 vs. 19296278 dyn.s.cm 25 .m 22 ; p , 0.001) but the PWI tended to increase 8% (N.S.) and the DPTI to SPTI ratio declined 10% (1.1860.28 to 1.0760.25 mmHg.s; p , 0.05). Conclusions: In septic patients the heart has become less able to recruit the Frank-Starling mechanism in the face of an increasing afterload and under those conditions a rise in cardiac

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output is attained preferably at the lowest possible myocardial oxygen consumption. The data of this study indicate that a) in critically ill patients maximization of CO is attained with dopamine at a suboptimal balance of cardiac oxygen supply and demand, and b) SVRI as main clinical parameter of LV afterload does not reflect the metabolic load to the heart. 25. Early impairment of endothelial function by hyperglycemia; restoration by vitamin C. R.W. van Etten 1, 2 , E.J.P. de Koning 1 , C.A.J.M. Gaillard 1, 2 , T.J. Rabelink 1 . Dept. of Vascular Medicine and Diabetes, University Medical Center, Utrecht, The Netherlands, Dept. of Internal Medicine, Eemland Hospital, Amersfoort, The Netherlands, Address: UMC Utrecht, Room number: G.02.402, Tel.: 030 -2507570, e-mail: r.w.vanetten@ azu.nl Introduction: Endothelial dysfunction is an early marker of cardiovascular disease and predicts outcome in cardiovascular compromised patients. Patients with diabetes mellitus are characterized by endothelial dysfunction. It is unknown to what extent risk factors in diabetes such as hyperglycemia and dyslipidemia contribute to this vascular dysfunction. Recently we were not able to show a beneficial effect of aggressive lipid lowering on endothelium dependent vasodilation in type 2 diabetes patients, suggesting other mechanisms. Hyperglycemia causes oxygen radical stress and has also been associated with uncoupling of endothelial nitric oxide synthase (eNOS), both leading to decreased nitric oxide (NO) availability. Therefore we examined the effect of hyperglycemia on endothelial function and the role of hyperglycemia-induced oxygen radicals by using the potent antioxidant vitamin C. Methods: Using plethysmography, we evaluated the effect of local forearm hyperglycemia (15 mmol / l) on forearm vasomotion in 8 healthy, non-smoking males. Subsequently vitamin C (24 mg / min) was co-infused intra-arterially. To exclude potential effects of insulin on vasomotion, octreotide (7.5 ng / kg / min) was i.v. infused simultaneously. Serotonin was infused as agonist for endothelium-dependent, NO-mediated vasodilation and sodium nitroprusside for endothelium-independent, NO-mediated vasodilation. Results are expressed as percent increase of the ratio of forearm blood flow of the measurement arm (M) and control (C) arm (M / C%). Results: Serotonin-induced vasodilation during normoglycemia at baseline was 102617 M / C%. This was significantly blunted after 1 and 6 hours hyperglycemia (58634 M / C%, p , 0.01and 49625 M / C%, p , 0.0005 at 1 and 6 hours hyperglycemia respectively). Nitroprusside-induced vasodilation was unaffected by glucose infusion (3946211, 3536102 and 4046143 M / C% at baseline, 1 and 6 hours hyperglycemia respectively, NS). Vitamin C restored hyperglycemia-induced impairment of endothelium dependent vasodilation (from 49625 to 89624 M / C% at 6 hours hyperglycemia vs. hyperglycemia plus vitamin C respectively, p , 0.01). Vitamin C had no effect on endothelium-independent vasodilation. Conclusion: Hyperglycemia per se causes endothelial dysfunction in healthy subjects. Vitamin C restores this phenomenon, suggesting enhanced formation of oxygen radicals by hyperglycemia. These data suggest that hyperglycemia is an important factor for endothelial dysfunction in diabetes mellitus.

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26. Potential involvement OF TRAIL / DR4-mediated apoptosis in the development of colorectal cancer. J.J. Koornstra 1,2 , S. de Jong 1 , F.E.M. Rijcken 2,3 , H. Hollema 3 , E.G.E de Vries 1 , J.H. Kleibeuker 2 . Departments of Medical Oncology 1 , Gastroenterology 2 , Pathology 3 , University Hospital Groningen, PO Box 30001, 9700 RB Groningen, tel: 050 -3616161, e-mail: j.j.koornstra@ int.azg.nl. Introduction: Most colorectal carcinomas develop from preexisting adenomas, a concept known as the adenoma-carcinoma sequence. The balance between proliferation and apoptosis in the epithelial cell compartment, maintained in normal colonic mucosa, is disturbed in colorectal cancer. In the adenoma-carcinoma sequence, a progressive increase is seen not only in proliferative activity but also in frequency of apoptosis, possibly to delete cells with sustained DNA damage. Insight in mechanisms of apoptosis might provide possibilities to modify the sequence of events. Three major apoptosis-inducing cytokines have been identified: tumor necrosis factor alpha (TNF-a), Fas ligand and TRAIL (TNF-related apoptosis-inducing ligand). TRAIL can bind to apoptosis-inducing death receptors DR4 and DR5 and apoptosisinhibiting receptors DcR1 and DcR2. Since the importance of TNF-a- and Fas ligand-mediated apoptosis in colorectal cancer development seems limited, we considered the possibility that increased apoptosis during the adenoma-carcinoma sequence might be paralleled by increased expression of one of the apoptosis-inducing TRAIL receptors. Aim of the study: To investigate the expression of TRAIL receptor DR4 in colorectal adenomas and carcinomas and determine the relationship with levels of apoptosis and proliferation. Materials and Methods: Paraffin-embedded sections of normal mucosa (n 5 5), colorectal adenomas (n 5 77), carcinomas (n 5 23) and normal mucosa in or adjacent to adenoma or carcinoma (n 5 100) were studied. DR4 expression, levels of apoptosis (cytokeratin 18 antibody) and proliferation (Ki-67 antibody) were determined by immunohistochemistry. Results: The intensity and extent of DR4 staining was increased in 76 / 77 adenomas and 20 / 23 carcinomas compared to normal mucosa. The mean percentage of positively staining epithelial cells was higher in carcinomas than adenomas (93.3% vs. 38.6%, p , 0.0001). The levels of apoptosis ( p , 0.001) and proliferation ( p , 0.001) were higher in carcinomas than in adenomas. The extent of DR4 expression was positively correlated to the level of apoptosis (r 5 0.49; p , 0.05), whereas no correlation was found with proliferative activity. Conclusion: DR4 expression appears to increase during the adenoma-carcinoma sequence, in association with the frequency of apoptosis. These data suggest that TRAIL / DR4-mediated apoptosis is involved in colorectal cancer development. 27. Major mutation of the hyper-IgD and periodic fever syndrome originates from one common ancestor 400 years ago – truly Dutch type periodic fever? A. Simon 1 , E. Mariman 2 , J.W.M. van der Meer 1 , J.P.H. Drenth 3 , Departments of General Internal Medicine 1 , Human Genetics 2 and Gastroenterology 3 , UMC St. Radboud, P.O. Box 9101, 6500 HB, Nijmegen, tel: 024 -3614763, fax: 024 -3541734, e-mail: a.simon@ worldonline.nl Introduction: Hyper-IgD and periodic fever syndrome (HIDS)

is an autosomal recessively inherited disorder characterized by recurrent attacks of fever, lymphadenopathy and abdominal distress. HIDS is caused by mutations in the gene encoding for mevalonate kinase (MVK). Patients are generally compound heterozygote for two missense mutations. HIDS is most commonly associated with the V377I allele followed by the I268T allele and in half of the patients the genotype consists of these 2 mutations. Almost all HIDS patients described so far originate from Europe, with a clear geographical clustering of cases in the Netherlands. Aim of the study: To determine whether the geographical clustering and the high prevalence of the V377I mutation could be explained by a founder effect. Patients, materials and methods: Haplotype analysis was performed in 14 families with one or more affected siblings (68 persons; 7 families from the Netherlands, 2 from France and the United Kingdom and from Spain, Italy and Czechia each 1 family) and in 4 patients homozygous for the V377I mutation. This yielded 19 alleles containing the V377I mutation and 25 control alleles containing a wild type MVK gene. Five markers surrounding the MVK gene were analyzed: D12S1605, D12S1339, D12S1645, D12S234 and D12S1583. Exact distance of markers from the MVK gene was determined by BLAST search for the three markers D12S1339 (33,5 kb), D12S1645 (4,5 kb) and D12S234 (39,8 kb). We calculated linkage disequilibrium (d) for these 5 markers on the V377I allele, and, for the two gene-flanking markers D12S1645 and D12S234, the number of generations since the common origin. A generational interval of 30 years was presumed. Results: The 19 alleles with V377I mutation were in linkage disequilibrium for four of five markers tested: D12S1339 (d 5 0.68), D12S1645 (d 5 0.93), D12S234 (d 5 0.61) and D12S1583 (d 5 0.51). The shared V377I mutation-related haplotype could be dated back 11–14 generations, which would indicate that it arose around the year 1600. We suggest that genetic drift caused the high frequency of this mutation. Conclusion: The most prevalent missense mutation in HIDS, V377I, originates from one common allele, dating back 400 years, most probably of Dutch origin. 28. Effect of atorvastatin vs. simvastatin on the low density lipoprotein subfraction profile and oxidizability in relation to intima media thickness in patients with familial hypercholesterolemia. The effect of Atorvastatin vs. Simvastatin on Atherosclerosis Progression (ASAP) study. T.J. Smilde 1a , S. van Wissen 2 , J. de Graaf 1 , J.J.P. Kastelein 2 , A.F.H. Stalenhoef 1 , From the Department of Internal Medicine Bosch Medical Center’ sHertogenbosch 1 a Department of Medicine, Division of General Internal Medicine, University Medical Center Nijmegen 1 , and Department of Vascular Medicine, Academic Medical Center Amsterdam 2 , The Netherlands. Address: BMC, P.O. Box 90153, 5200 ME ’ s-Hertogenbosch. Tel 073 -6162446, Fax 073 -6162257, e-mail: t.smilde@ worldonline.nl Introduction: Familial hypercholesterolemia (FH) is an inherited disorder, characterised by accelerated atherosclerosis due to elevated plasma low density lipoprotein (LDL) levels. LDL-C reduction is essential to reduce cardiovascular disease (CVD) risk

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in patients with FH. In addition changes in composition of LDL particles are potentially important, because LDL heterogenicity has also been linked to CVD. Carotid intima media thickness (IMT) is an independent predictor of CVD and becomes increasingly important in intervention studies. Aim: To investigate the contribution of changes in lipoprotein profile and oxidizability to the effect on change in IMT during treatment in patients with FH. Materials and Methods: In a double-blind, randomised trial of 325 patients with FH, the effect of high dose atorvastatin (80 mg) (A) vs. conventional dose simvastatin (40 mg) (S) on LDL subfraction profile (n 5 289), LDL-oxidizability (n 5 121), and progression of atherosclerosis (IMT) (n 5 325) was evaluated. Results: Mean LDL-C at baseline was 8.00 and 8.33 mmol / L in the A and S group resp. High dose A reduced total cholesterol, LDL-C and triglycerides significantly more than conventional dose S (41.8 vs. 33.6 and 50.5 vs. 41.2 and 29.2 vs.17.6%), A vs. S ( p , 0.002). At baseline, all FH patients showed an intermediate LDL subfraction profile, with LDL2 as the predominant subfraction. Both A and S decreased the cholesterol content in all LDL subfractions. A strong negative correlation was found between triglyceride level and a dense LDL subfraction profile, (r 5 2 0.64). Both A and S reduced the resistance to oxidation slightly (S vs. A n.s.). In contrast, the LDL oxidation rate and maximum amount of dienes formed during oxidation was reduced more by A compared with S ( p , 0.05). High dose A resulted after two years of treatment in a regression of the carotid IMT of 0.031 mm, whereas mainly progression was observed in the S group ( 1 0.036) (A vs. S p 5 0.0001). The IMT at baseline correlated significantly with triglycerides and small dense LDL3 subfraction. Age, baseline IMT and treatment explained most of the variation in change in IMT (R2 5 0.32). However, in a subgroup (n 5 121) the change in triglycerides and amount of dienes formed during oxidation contributed to the effect on change in IMT (R2 5 0.12). Conclusion: Serum triglycerides are associated with an increased IMT at baseline even in patients with specifically high LDL-C levels. The change in triglycerides and dienes formation contribute at least in part to the effect on change in IMT during treatment.

Aim of the study: To analyze the incidence of HLA loss or downregulation in patients with acute myeloid leukemia (AML) or acute lymphoid leukemia (ALL) Materials and Methods: We analyzed 397 acute myeloid leukemia (AML) and 186 acute lymphoid leukemia (ALL) patients who were serologically HLA typed. Typing was based on complement mediated cytotoxic reactions using polyclonal antibodies. Subgroups were distinguished based on increasing numbers of leukemic blasts present during typing (0%, 1–20%, 21– 50%, . 50% blasts). In case of HLA Class I downregulation or loss, further analysis was performed using flow cytometry and monoclonal antibodies (MoAbs). In addition, flow cytometry was used to study whether altered HLA expression was present in case of progression or relapse of the disease. Phytohemagglutinin (PHA) stimulated T cells were used as positive controls. To test the reversibility in two cases in which HLA loss was observed, leukemic cells were cultured in the presence of a- or g- interferon and T cell recognition using HLA specific T cell clones (CTL) was analyzed. Results: HLA downregulation was found in 2% of the AML and ALL samples without malignant cells whereas this was 8–15% in the groups with blasts ( p 5 0.05 for ALL and p 5 , 0.001 for AML). In 15 cases of downregulation or loss, leukemic cells and control PHA stimulated lymphoid cells were further analyzed using HLA-antigen-specific monoclonal antibodies and flow cytometry. In 4 / 6 ALL and 4 / 9 AML patients downregulation or complete loss (2 cases) could be confirmed. To analyze whether allelic loss was associated with progression of the leukemia, we tested 12 AML and 13 ALL patients during relapse using flow cytometry. In 1 / 12 AML patients and 1 / 13 ALL patients allelic loss during relapse was found. In two patients this downregulation or loss corresponded to impaired T cell mediated lysis using HLA specific CTL but after culture in the presence of a- or g- interferon, HLA expression and CTL recognition was restored. Conclusion: We conclude that downregulation of HLA Class I expression at the allelic level in AML and ALL is infrequent but functionally relevant. Moreover, downregulation was reversible and T cell recognition could be restored after culture in the presence of a- or g- interferon.

29. Loss or downregulation of HLA class I expression at the allelic level in acute leukemia is infrequent and can be restored. Rolf E. Brouwer 1 , Pim van der Heiden 1 , Ieke M.Th 2 2 2 2 Schreuder , Arend Mulder , G. Datema , J. Anholt , Roel Willemze 1 , Frans H.J. Claas 2 , J.H. Frederik Falkenburg 1 . Laboratory of Experimental Hematology, Department of Hematology 1 and Department of Immunohematology and Blood Transfusion 2 , Leiden University Medical Center, Leiden, The Netherlands, Department of Hematology Leiden University Medical Center, C2 -R, P.O. Box 9600, 2300 RC Leiden, The Netherlands, Tel.: 31 -71 -5262271, Fax: 31 -71 -5266755, e-mail: rbrouwer@ lumc.nl Introduction: Expression of HLA molecules is essential for T-cell mediated recognition. Downregulation of HLA expression may play a role in tumor escape as has been shown in several solid tumors. In hematological malignancies it is not clear whether this mechanism play an important role.

30. The use of D-dimer concentration and a clinical decision rule in the diagnostic work up of patients with suspected pulmonary embolism; a prospective management study. 1 1 1 ¨ 2. M.J.H.A. Kruip , M.J. Slob , C. van der Heul , H.R. Buller Department of internal medicine, St. Elisabeth Hospital, Tilburg 1 , Department of Vascular Medicine, Academic Medical Center, Amsterdam 2 . Adress: Hilvarenbeekseweg 60, 5011 LC, Tilburg, Tel.: 013 -5391313, Fax: 013 -5352515, e-mail: kruip86@ zonnet.nl. ivonne.brancart@ gtkoningshof.goldentulip.nl Introduction: Diagnosing or excluding pulmonary embolism (PE) is difficult when only the medical history and physical examination are available. Only approximately a quarter of the patients presenting with signs and symptoms suggestive of PE actually has the disease. A method to select patients who are unlikely to have PE before further diagnostic procedures are performed, is wanted. Various studies have shown that a normal

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D-dimer concentration can exclude PE accurately in most patients. Also, a clinical decision rule is available that is able to categorise the patients likelihood for PE as low, moderate or high. Aim of the study: The aim of the present prospective management study in a large teaching hospital was to evaluate the utility and safety of a new strategy in excluding PE in patients with a low clinical probability of PE and a normal D-dimer concentration. Materials and Methods: All patients suspected of PE, above the age of 16 years, were asked to participate. After inclusion the clinical decision rule (CDR), as described by Wells et al., was scored. Patients with a low clinical probability of PE and a normal D-dimer concentration ( , 500 ng / ml, Vidas-ELISA) were considered not to have PE and further diagnostic testing for PE and anticoagulant therapy was withheld. Patients with a low clinical probability of PE and an elevated D-dimer concentration or with a moderate or high clinical probability underwent compression ultrasonography (CUS). When there was a deep venous thrombosis the diagnosis of PE was certain. If the CUS was normal, a pulmonary angiography was performed. All patients were followed-up for 3 months. Results: From January 1998 to May 2000 a total of 251 consecutive patients were seen with suspected PE. Seventeen patients (6.7%) were excluded because of refusal or inability to give consent (n 5 5), contraindication to pulmonary angiography (n 5 2) and in 10 patients the D-dimer concentration was not obtained. Of the remaining 234 patients 26% (n 5 60) had the combination of a low clinical probability of PE and a normal D-dimer concentration. During the 3-month follow up period none of these patients died and 3 patients had recurrent complaints of PE. In these 3 patients PE was excluded (normal pulmonary angiography (n 5 2), normal perfusion scan (n 5 1)). PE was present in 22% (n 5 52) of the study population; 27 had a positive CUS and 25 an abnormal pulmonary angiography. Conclusion: The combination of a low clinical probability of PE and a normal D-dimer concentration appears to be a safe method to exclude pulmonary embolism, with a high clinical utility (26% of the presenting patients) and readily accepted by clinicians. 31. Aenzyme-supplementation therapy for Fabry disease: first possible treatment? G.E. Linthorst 1 , J.M.F.G. Aerts 2 , D.K. Bosman 3 , H.S.A. Heymans 3 and C.E.M. Hollak 1 * *. Departments of Internal Medicine /Clinical Haematology, Biochemistry and Pediatrics /Emma Kinderziekenhuis, Academic Medical Center, Amsterdam, e-mail: G.E.Linthorst@ amc.uva.nl ** on behalf of the International Fabry study-team. Introduction: Fabry disease is an X-linked lysosomal storage disorder caused by the deficiency of the enzyme a-Galactosidase A. This results in accumulation of glycosphingolipids (especially GL-3) in many cell types, but predominantly in the endothelium. At childhood the disorder is characterized by painful episodes in the extremities (acroparesthesia) and teleangiectasia on the skin (angiokeratoma). Later in life patients develop progressive renal failure, cerebral infarctions and restrictive cardiac hypertrophy. Only symptomatic treatment is currently available. Enzyme augmentation by infusion of recombinant aGal (rhaGAL) is the first

treatment modality that aims to restore the underlying enzyme deficiency. The safety and efficacy of rhaGAL (Genzyme corp, MA USA) in patients with Fabry disease was investigated. Methods: A multicenter, randomised, double-blind, placebocontrolled trial was performed in 58 Fabry-patients. Patients with a kreatinin-level below 195 mmol / l were included and randomised to receive 11 infusions of placebo or 1.0 mg / kg rhaGAL once every 2 weeks. Clearance of GL-3 accumulation in the capillary endothelium of the kidney was the primary endpoint. Other assessments included GL-3 accumulation in cardiac and skin tissue, renal function, evaluation of pain and quality of life. Upon completion all patients continued in an open-label extension trial. Results: All patients completed the study and there were no severe side-effects of the drug. Twenty out of the 29 rhaGAL treated patients met the primary endpoint. (absence of storagematerial in the capillary endothelium, p , 0.0001), where as the placebo-group showed no reduction. Both skin and cardiac tissue showed the same results ( p , 0.001). No clinical benefit could be shown in this short period of time with regards to pain, quality of life, or renal function in the treated group. The infusions were generally well tolerated. rhaGAL treated patients showed mild reactions during infusion, which were probably related to the development of antibodies against rhaGAL occurring in 24 out 29 patients. In the extension trial 42 / 43 evaluated patients reached the primary endpoint after 12 or 6 months (originally receiving enzyme or placebo), respectively. Also the other tissues showed clearance of accumulated GL-3. Levels of antibodies showed a trend towards decline. Conclusion: Enzyme supplementation therapy can effectively clear tissue storage material in patients with Fabry disease. Further studies are needed to evaluate the clinical benefit with this type of therapy is required. Studies concerning the prevalence and symptoms of Fabry patients in the Netherlands are currently being performed. 32. The effect of aggressive versus standard doses of atorvastatin on diabetic dyslipidemia; the Diabetes Atorvastatin Lipid Intervention study (The DALI study). F.V. van Venrooij a,d , M.A. van de Ree b , D.W. Erkelens a , I. Berk-Planken c , R.P. Stolk d , on behalf of the DALI study group. a Dept. of Vascular Medicine, University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands. Tel.: 030 -2509388, Fax: 030 -2518328, e-mail: f.vanvenrooij@ digd.azu.nl, b Dept. of General Internal Medicine, Leiden University Medical Center, The Netherlands, c Dept. of Internal Medicine, Erasmus Medical Center Rotterdam, The Netherlands, d Julius Center for Patient Oriented Research, University Medical Center Utrecht, The Netherlands. Introduction: Dyslipidemia constitutes an important modifiable risk factor contributing to angiopathy in type 2 diabetes mellitus. Aim of the study: The DALI study is a double-blind, randomized, placebo-controlled, multicenter study in which aggressive lipid lowering by atorvastatin 80 mg (A80) was compared to standard 10 mg atorvastatin (A10) and placebo (P) in type 2 diabetic patients for a period of 6 months. The primary endpoint was the change in fasting triglyceride (TG) level. Materials and Methods: Type 2 diabetes patients, HbA1c # 10%, without manifest coronary artery disease, aged 45–75 years,

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Internistendagen 2001 total cholesterol between 4.0–8.0 mmol / L and fasting TG between 1.5–6.0 mmol / L were eligible for the study. Results: The entry criteria were met by 217 patients of whom 197 patients completed the follow-up. In patients using A10 and A80, TG levels were significantly lowered to 1.8460.86 (225%) and 1.7861.21 (235%) mmol / L respectively vs. 2.8861.68 ( 1 10%) in the P-group. The difference in TG lowering between the two intervention groups was not statistically significant. Significant dose-dependent reductions in A10 and A80 were shown for total cholesterol (30% and 39%), LDL-c (41% and 52%) and apoB (31% and 40%). HDL-c significantly increased with atorvastatin treatment (6%) for both dosages. LDL particle size and lipoprotein lipase activity did not differ at 6 months. No differences between A10, A80 and P were found in adverse events or safety parameters. Conclusion: Atorvastatin 10 mg is effective and safe in patients with type 2 diabetes and dyslipidemia. Increase of dosage to atorvastatin 80 mg can be safely done to achieve a further reduction in LDL-c. 33. Thalidomide in the treatment of chemotherapy refractory multiple myeloma: a follow up. H.H. Helgason 1 , K.L. Wu 1 , B.S. Hylkema 1 , D.J. Richel 1, 3 , W.M. Smit 1 , M.R. de Groot 1 , C. Neef 2 , M.R. Schaafsma. 1 Department of Internal medicine and 2 Department of Pharmacy, Medisch Spectrum Twente, Enschede, The Netherlands, Tel.: 0534872000, Fax: 0534873085, e-mail: hhhfg@ wxs.nl. 3 Present address AMC, Amsterdam. Introduction: Thalidomide was in 1961 withdrawn from the market because of its teratogenic effect. Renewed interest in thalidomide has developed because of its anti-tumour activity in chemotherapy refractory multiple myeloma (MM). The precise mechanism of thalidomide action is not known. Thalidomide has an anti-angiogenic activity but also an immunomodulating effect. Aim of the study: To assess the effectivity of action of thalidomide in the treatment of refractory multiple myeloma. Materials and Methods: Between May 1999 and December 2000 we treated 25 patients (pts) (12 males and 13 females, median age 67.3 range 50–82), with progressive and chemotherapy refractory MM, with thalidomide (mean b2 microglobulin 7.96 mg / l (median 5.0), range 2.0–40). Thalidomide was administered orally in a dose escalating schedule of 200 mg / day, with an increase by 200 mg according to tolerance, every14 days, to a max. of 800 mg / day. Mean follow-up 7 months, range 1 week–17 months. Results: Complete response (CR), defined as 100% reduction in M protein and normalisation of bone marrow, was seen in 3 pts, all within 10 weeks from the start of thalidomide. One pt. with a follow up 17 months, had reappearance of polyclonal immunoglobulins. Major response (MR) or . 75% reduction in M protein was seen in 1 pt. Partial response (PR) or . 50% reduction in M protein or plasmacytoom (n 5 2) was seen in 8 pts. Stable disease (SD) or . 25% reduction in M protein was seen in 3 pts. Six pts did not respond. Four pts were not evaluable; 2 pts deceased within 2 weeks and 2 pts stopped thalidomide within 1 month because of adverse effects. Of the 12 pts (48%) who were responsive (PR or more), 4 pts had a relapse (mean 9.6 months, range 5.5–12, all PR), 3 pts deceased without relapse (infection,

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renal insufficiency) but 5 pts are still in remission (range 5.75–17 months). The cumulative probability of survival at 12 months was 46% for the whole group, only 22% fore the none-responders but 54% for the responders. Adverse effects were seen in most pts (grade I, II, III); constipation, fatigue, sensory polyneuropathy or dizziness but 2 pts stopped thalidomide because of dizziness and several pts had to lower the thalidomide dose. Conclusion: Thalidomide is an effective drug in the treatment of chemotherapy refractory multiple myeloma, 48% showed a PR or more. The cumulative probability of survival at 12 months was 46%. The dose related adverse effects are considerable. 34. Does the beneficial effect of HRT on endothelial function depend on lipid changes? Marlies E. Ossewaarde 1 , Michiel L. Bots 1 , Yvonne T. van der Schouw 1 , Miriam J.J. de Kleijn 1 , Hanneke W. Wilmink 2 , Annette A. A. Bak 1 , Juan Planellas 3 , Jan-Dirk Banga 2 , Diederick E. Grobbee 1 . Julius Center for General Practice and Patient Oriented Research 1 , Dept. of Internal Medicine 2 , University Medical Center Utrecht, Utrecht; Organon NV, Oss 3 ; Heidelberglaan 100, 3584 CX Utrecht, Tel.: 030 -2509354, Fax: 030 -2505485, e-mail: M.E.Ossewaarde@ jc.azu.nl Introduction: Most of the evidence regarding the cardioprotective effect of estrogens concentrates on effects on lipid profile. However, evidence supporting beneficial effects of estrogens on endothelial function is accumulating. Yet, lipid lowering in itself has also been shown to be associated with improved endothelial function. Aim of the study: To determine whether the improvement in endothelium-dependent flow-mediated dilatation (FMD) of the brachial artery observed in women treated for 3 months with conjugated equine estrogens and medroxyprogesterone acetate (CEE 1 MPA) can be attributed to direct arterial effects of CEE 1 MPA or to changes in lipid profile. Materials and Methods: A single-center, randomized, double blind, placebo-controlled trial was performed. 70 healthy postmenopausal women, aged 50–65 years were treated during 3 months with 0.625 mg conjugated equine estrogens combined with 2.5 mg medroxyprogesterone acetate or placebo. At baseline and after 3 months of intervention, endothelial function was assessed using FMD and nitroglycerin-induced dilatation (NTG) and serum lipids were measured. A multiple linear regression model was used to determine the intermediary effects of serum lipids. Results: Compared to placebo, 3 months treatment with CEE 1 MPA was associated with a significant improvement in FMD of 2.5% (95%CI:0.2%;4.7%), a significant 13% decrease in total cholesterol (95%CI: 2 18%; 2 8%), 23% decrease in low density lipoprotein (LDL-cholesterol) (95%CI: 2 23%; 2 15%) and 13% decrease in lipoprotein(a) (Lp(a)) (95%CI: 2 26%;0.02% (analysis of logLp(a): p 5 0.012). Sequential adjustment for changes in serum lipids did not materially change the observed association of CEE 1 MPA and FMD. However, adjustment for change in Lp(a) decreased our estimate for 3 month FMD (2.5%) to 1.6%. CEE 1 MPA was not related to NTG, with or without adjustment for change in lipids. Conclusion: The improvement in endothelial function in

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women treated for 3 months with CEE 1 MPA appears not to depend on changes in serum lipids, except Lp(a). Beneficial effects of CEE 1 MPA on the arterial wall and Lp(a) changes may play a role in the improvement of endothelial function. 35. Beta-lactam induced bacterial filaments in a murine thigh model: a study of cytokine-patterns and morphology after a 1 1 1 second dose of antibiotics. J. Buijs , A. Dofferhoff , J. Mouton , 2 1 J. van der Meer , Canisius-Wilhelmina Ziekenhuis . UMC St. Radboud 2 , Weg door Jonkerbos 100, Nijmegen, Tel.: 024 3658740, Fax: 024 -3658738, e-mail: jacqbuijs@ hotmail.com Introduction: In gram-negative bacteria, beta-lactam-antibiotics like ceftazidime may induce formation of filaments, i.e. large strands of bacteria that are capable of dividing but not septating. Previous in vitro studies demonstrated excessive endotoxin release after filament lysis. Aim of the study: to study the in vivo consequences of this phenomenon by exposing ceftazidime-induced bacterial filaments to a second dose of antibiotics. We hypothesized, that this might provoke excessive endotoxin-release from the filament cell wall, leading to production of pro-inflammatory cytokines such as TNF-alpha and IL-6 and negative effects on the host. Animals and Methods: Twenty-two neutropenic Swiss mice were challenged with a dose of 1.60 3 10 7 and 0.73 3 10 7 E.coli ATCC 25922 in the left thigh muscle. Two hours after inoculation, ceftazidime 20 mg / kg (peak level 200 3 MIC) was given intravenously in the tail vein to induce bacterial filament-formation. Four hours later, a second dose of ceftazidime 20 mg / kg or tobramycin 20 mg / kg or saline for control was given. After 0.5 and 1 hours, mice were sacrificed for morphology studies, bacterial cell-counts (CFU’s) in muscle, liver and spleen, and plasma was collected to measure TNF and IL-6 concentrations. Results: Compared to controls, filaments were shorter in the tobramycin-group, but longer in the ceftazidime-group. Half an hour after the second dose of ceftazidime, IL-6 levels were significant elevated compared to controls ( p , 0.05), despite lower CFU’s of E.coli in thigh muscle in these mice. One hour after the second dose, IL-6 concentrations were still higher in the treated mice. In the groups treated with tobramycin, IL-6 levels also appeared higher, but statistically not significant ( p 5 0.30). TNF was below the detection limit of 0.20 ng / ml in most mice, with no significant difference between groups. Conclusion: Challenge of bacterial filaments with a second gift of antibiotics, particularly ceftazidime, may provoke significant elevations of pro-inflammatory cytokines such as IL-6. Our invivo data support the hypothesis that bacterial filaments may lead to excessive endotoxin-liberation from the cell-wall. Therefore, antibiotic-induced filament-formation by Gram-negative bacteria is an undesirable effect of antibiotic therapy, and therapeutic strategies should aim at preventing this phenomenon. 36. Risk factors for thromboembolic complications in inflammatory bowel disease: the role of hyperhomocysteinaemia. Bas = van Tuyl*, Bas Oldenburg*, Rene´ van der Griend , Jacob C. [ Koningsberger*, Rob Fijnheer and Gerard P. vanBergeHenegouwen*. Departments of * Gastroenterology and [ Hematology, University Medical Center, Utrecht, the

Netherlands=, Department of Internal Medicine, Diakonessenhuis, Utrecht. Current adress: St Antonius Hospital, Department of Internal Medicine, Koekoekslaan 1, 3435 CM Nieuwegein, 030 6092088, Sactuyl@ knmg.nl Introduction: Inflammatory bowel disease (IBD) is associated with an increased risk for thromboembolic events. Hyperhomocysteinaemia, an established risk factor for arterial, as well as venous thrombosis, is reportedly more prevalent in IBD patients although a clear correlation with a history of thrombosis in these patients has not been found. Aim of the study: To examine the relationship of hyperhomocysteinaemia and thrombosis in IBD patients and to assess the value of this factor in addition to other known prothrombotic abnormalities. Materials and Methods: IBD patients with a history of thrombosis (n 5 22) and sex, age and diagnosis-matched IBD controls (n 5 23) were studied. Homocysteine (tHcy) was assessed before and after methionine loading. Plasma levels of protein C, protein S, antithrombin III, fibrinogen and the presence of anticardiolipin and antiphospholipid antibodies were determined and genetic testing for the factor V Leiden and the prothrombin mutation was performed. Results: Fasting homocysteine levels in IBD patients with a history of arterial or venous thrombosis tended to be higher than in IBD controls, although significance was not reached. The increase in homocysteine levels after methionine loading was significantly higher in IBD patients in the arterial thrombosis group than in IBD controls (40.9617.7 vs. 27.269.9:mol / l, p , 0.05). The factor V Leiden mutation was found in 20% of the patients with a history of venous thrombosis, compared with 0% in the IBD control group ( p 5 0.05). The prevalence of other risk factors for thrombosis was not higher in IBD patients with thrombosis. At least one risk factor was found in 46% of the IBD patients with a history of thrombosis. This percentage increased to 64% if tHcy was determined (NS). Conclusion: There is an association between hyperhomocysteinaemia and a history of arterial thrombosis in IBD patients. In 64% of IBD patients with a history of thromboembolism at least one prothrombotic risk factor is detected. If tHcy is not assessed, risk factors are only found in 46% of the cases. 37. Four-year follow-up of patients with chronic fatigue. H.J.F. van Hoogstraten 1 , J. van der Meulen 2 . 1 Department of Medicine, University Hospital Rotterdam, 2 Albert Schweitzer Hospital, location Dordwijk, P.O. Box 306, 3300 AH Dordrecht, Tel.: 078 6523333, Fax: 078 6523377, e-mail: b.vanhoogstraten@ planet.nl Objective: To determine prognostic characteristics of patients with fatigue of more than 1 year referred to an internist. Methods: In 1994–1995, all patients referred with chronic fatigue (CF) were asked about the presence of the 11 minor case definition criteria for chronic fatigue syndrome (CFS) as described by the Centers for Disease Control. To exclude secondary chronic fatigue (sCF) appropriate examinations were performed. If no cause was found, patients were advised to seek cognitive-behavioral therapy (CBT). In 2000, all patients were asked about treatment for CFS by others and to complete the shortened fatigue questionnaire (SFQ).

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Internistendagen 2001 Results: 43 patients were included (31 female) with a mean age of 41 years at presentation (range 15–81; standard deviation (SD) 15). Patients with sCF (n 5 7) were significantly ( p , 0.05, nonparametric tests) older (mean 62 years, SD 16), their complaints existed significantly shorter (1 year) and they had significantly less minor criteria (mean 07, SD 0.8), as compared to the CFS patients (mean age 37 years, SD 11.4; mean duration 4.9 years, SD 5.2; mean minor criteria 2.9, SD 1). Six sCF patients and 34 CFS patients responded. The sCF patients had a significantly lower SFQ-score (mean 7.3, SD 8.2) as compared to CFS patients (mean 21, SD 7.7). Seven CFS patients reported that a cause for CF, mostly a non-physical one, was found. They were not significantly (n.s.) older (mean 39 years, SD 12.3); they had a shorter history (mean 2.0 year, SD 2.2, n.s.), less minor criteria (mean 2.4, SD 1.1, n.s.) and a significantly lower SFQ-score (mean 12.4, SD 7.5) than those who reported that still no cause was found (mean age 36 years, SD 11.3; mean duration 5.6 years, SD 5.5; mean minor criteria 3.0, SD 0.9; mean SFQ-score 23, SD 6.2). No difference in SFQ-score was found between patients who received CBT (n 5 13) and those who had not received CBT. Patients who had visited alternative practitioners (n 5 12) had a significantly higher SFQ-score. Conclusion: In 15% of the patients with CF a cause was found. These patients were older, had a shorter history and less minor criteria than CFS patients. After 4 years, approximately 15% of the CFS patients reported that a cause was found and they showed moderate improvement. Poor prognostic characteristics were young age, long duration of complaints and the presence of more than 3 minor criteria. CBT had no beneficial effects. Alternative therapies seemed to be detrimental. 38. TSH-R mRNA expression in orbital tissue of Graves’ ophthalmopathy (GO) patients is related to disease activity and to Th1 and proinflammatory cytokines. I.M.M.J. Wakelkamp, O. Bakker, W.M. Wiersinga, M.F. Prummel, Department of Endocrinology & Metabolism, F5 -171, Academic Medical Centre,Meibergdreef 9, 1105 AZ Amsterdam, e-mail: I.M.M. J.Wakelkamp@ amc.uva.nl Introduction: The inflammatory process in GO is only very partially characterized. It is postulated that orbital fibroblasts (OF) are the key target of the autoimmune attack and that cytokines produced by infiltrating lymphocytes stimulate OF proliferation and glycosaminoglycan production. This is supported by in vitro studies on OF cultures. However, which cytokines are present in the orbit during the active phase of GO is unknown. At some stage in their differentiation, OF in culture express the TSH-R, the prime antigen in Graves’ disease. The aim of this study was to determine the orbital expression of cytokines in relation to the TSH-R in active as opposed to inactive GO. Methods: Orbital fat and connective tissues were obtained during decompressive surgery from both active, untreated (n 5 6) and inactive (n 5 11) GO patients. We performed quantitative Real Time PCR using the LightCycler instrument and published primer sequences to measure the cytokine and TSH-R mRNA’s. Results are expressed as the ratio of unknown to b-actin mRNA. Results: 1. Cytokines: In active patients median (range) mRNA levels of proinflammatory cytokines were higher than in inactive

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patients: IL-1 b (median / range 445 / 153–877 vs. 0 / 0–455, p 5 0.002), IL-6 (1583 / 968–18825 vs. 559 / 0–7181, p 5 0.012), IL-8 (1422 / 38–7579 vs. 32 / 0–1081, p 5 0.044) and IL-10 (145 / 58– 318 vs. 27 / 0–189, p 5 0.003). There was also a trend towards higher Th1 in active GO: IL-2 (37 / 0–158 vs. 0 / 0–68, p 5 0.039), IFN g (20 / 0–79 vs. 0 / 0–16, p 5 0.092) and IL-12 (2.3 / 0–14.8 vs. 0 / 0–1.6, p 5 0.10). Th2 cytokine expression was similar in both groups. 2. TSH-R was almost exclusively found in active patients (5 / 6 [83%] vs. 1 / 11 [9%]) with a median mRNA level of 4, range 0–24 vs. 0, 0–9, p 5 0.016. Conclusions: (1) The TSH-R mRNA is observed in the active stage but lost in the inactive stage of GO. (2) The orbital cytokine profile in active GO is clearly distinct from the pattern in inactive disease, and consists mainly of proinflammatory and Th1 cytokines. These findings suggest that the TSH-R is causally involved in the pathogenesis of GO. The observed cytokine profile might be relevant in selecting specific immunomodulatory treatment modalities. 39. Two years of Penicillin prophylaxis is sufficient to prevent carditis in post-streptococcal reactive arthritis (PSRA). P.W. Kamphuisen 1 , A.J.L. de Jong 2 , and M.Janssen 2 . Depts. of 1 Internal Medicine and 2 Rheumatology, Rijnstate Hospital, Arnhem, The Netherlands. Address: Dept. Internal Medicine, Rijnstate Hospital, P.O. Box 9555, 6800 TA, Arnhem. e-mail: pkamphuisen@ rijnstate.nl Introduction: Post-streptococcal reactive arthritis (PSRA) is a syndrome following throat infection with b-haemolytic streptococci of Lancefield group A. This disease seems to be distinct from acute rheumatic fever (ARF) since it occurs mainly in middleaged subjects, may not be accompanied by carditis, and has a high association with erythema nodosum. The most feared complication of ARF is carditis, and after the first attack a minimum of five years with penicillin prophylaxis is advised. After an episode of PSRA, also five years of penicillin prophylaxis is advised in order to prevent carditis. In the present study we have investigated whether prophylaxis of two years in PSRA patients is adequate and necessary to prevent carditis. Methods: Between September 1994 and September 1999, 42 patients with clinically and serologically confirmed PSRA were prospectively followed. Mean age (SD) was 49 years (range 19–74), with 26 females and 16 males. None of the patients had a history of ARF or carditis. 36 of the 42 patients received prophylaxis, benzylpenicillin 1.2 million units once a month. A recurrence of PSRA was defined as arthritis secondary to a serologically (AST . 200 U / ml, anti-DNase B . 200 U / ml) or cultured proven infection with b-haemolytic streptococci. Signs of carditis were detected clinically, by electrocardiograph, or when necessary by echocardiography. Results: The mean duration of penicillin prophylaxis was 21 months (range 2–48), and the mean follow-up after stopping prophylaxis was 20 months (range 1–59). 4 patients still have prophylaxis. Recurrent PSRA occurred in 3 of the 36 patients (8%) after stopping prophylaxis, and in none of the 6 patients without prophylaxis. One event occurred 5 years after stopping prophylaxis, the second after two years. The third recurrence occurred in a female patient who deliberately stopped prophylaxis after two months. None of the patients had signs of carditis.

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Discussion: This study shows that two years prophylaxis (instead of five years) with penicillin is sufficient to prevent carditis, but is not sufficient to prevent recurrence of PSRA. It is not clear whether PSRA is a benign disorder in which carditis rarely occurs. If so, penicillin prophylaxis would be unnecessary in these patients. 40. Arterial wall properties in pts with chronic renal failure and pts on renal replacement therapy. C.J.A.M. Konings, P.L. Rensma[, R. Dammers, L. Kornet, J.P. Kooman, L.M.A.B. van Bortel, A. Hoeks, U. Gladziwa*, K.M.L. Leunissen. University of Maastricht and [ St.Elisabeth Hospital Tilburg, the Netherlands. * University of Witten, Germany. It is well known that abnormalities of the arterial system are commonly present in HD pts and even were found to be related to mortality. However, few studies have focused on arterial wall properties in pts with earlier stages of renal insufficiency and in pts on peritoneal dialysis (PD). In this study, we assessed and compared arterial distensibility coefficient (DC) and compliance coefficient (CC) as a marker of arteriosclerosis, and intima-media thickness (IMT) of the carotid artery, as a surrogate marker of atherosclerosis in 18 HD pts (mean age 59.9612.2), 36 PD pts (57.169.6 yrs), 30 pts with CRF (59.7614.4 yrs; mean creatinine clearance (Ccl) 33.6616.7 [10–82] ml / min, and 16 age matched normotensive controls (57.264.6 yrs) without diabetes or symptomatic atherosclerotic disease. DC, CC, IMT and arterial diameter (DIAM) were assessed by an automated vessel wall detection system (Walltrack; Pie-Medical). Statistics: Kruskal-Wallis and Mann-Whitney test (see table).

II. Oral Presentations Case Reports 41. IgA mediated immune hemolytic anemia. W.H. van Houtum 1 , F.P.W. Tegelaers 2 , L.H. Siegenbeek van Heukelom 3 , Medical Center Alkmaar, department of Internal Medicine 1,3 , department of Biochemistry and Hematology 2 Wilhelminalaan 12, 1815 JD Alkmaar, phone 072 -5484444, houtum@ worldonline.nl Case: A 21-year-old man was referred to our clinic for having red coloured urine for two days. He reported no trauma nor did he use any medication. His medical history revealed nodular sclerosis Hodgkin’s disease (stage IIa) 2 years ago for which he was succesfully treated with chemotherapy (MOPP/ABV times 12). Physical examination revealed a slight jaundice, but no enlarged lymphnodes or hepatosplenomegaly were found. Urinalysis showed hemoglobinuria without the presence or erythrocytes. Further blood analysis revealed a hemolytic anemia with a hemoglobin of 4.6 mmol / l and a MCV of 92.3 fl. Total bilirubin was 86.6 mmol / l, direct bilirubin 5.0 mmol / l, LDH 1272 U / l, haptoglobin , 0.1 g / l and reticulocytes 87‰. Given the negative result of a polyspecific direct Coombs’ test a non-immune hemolytic anemia was suspected. Genetic causes of hemolysis were discarded, because it was assumed these would have appeared during previous chemotherapy. The patient did not have any vascular implants and no fragmentocytes were identified on a peripheral blood smear, therefore eliminating a microangiopathic origine of the hemolysis. A negative Ham’s test made the diagnosis paroxysmal nocturnal hemoglobinuria less likely. CMV, EBV, HIV and Mycoplasma serology was found negative. Because of continued hemolytic activity further hematological tests were

Results:

DC(10 23 / kPa)

CC(mm 2 / kPa)IMT (mm)

Controls CRF HD PD

16.664.9 12.667.5* 11.667.6*[ 14.766.2

0.6760,20 0.5760.19[ 0.6360.38 0.7660.33

6636171 5896115 6226115 5856121

DIAM

MAP (mmHg)

71536508 799261183* 851461297* 826261134*

109617 104618 104617

* p , 0.05 compared to controls [p , 0.05 compared to PD @ p 5 0.06 compared to PD. In CRF pts, DC was related to Ccl (r 5 0.41, p , 0.05). Multiregression analysis showed than in CRF pts, only age and Ccl were predictors of DC (t 5 2 6.3 and 2.6, p , 0.025), whereas duration of renal disease was not. Conclusion: In patients with CRF and HD pts, DC is significantly reduced compared to controls, whereas in PD pts DC did not differ signicant from controls. In pts with CRF, a significant relation was found between Ccl and DC, suggesting that arteriosclerotic changes develop gradually during the course of renal insufficiency. Surprisingly, arterial wall properties appeared to be less pathological in PD pts compared to HD and CRF pts. No difference in IMT was observed between renal pts and controls, suggesting that according to this marker, atherosclerosis is not increased per se in renal pts. These data suggest that other pathophysiological mechanisms like an increased vascular calcification may play an important role in the vascular disease of renal pts.

performed. Monospecific direct antiglobulin test was negative with anti-IgG, anti-IgM and anti complement reagents, but strongly positive with anti-IgA. The warm IgA class auto-antibodies were identified as anti-e. Since the patient had a history of a lymphoreticular malignancy a possible recurrence of the Hodgkin’s disease was suspected. However, a chest X-ray, ultrasound examination of the abdomen and a galliumscan were normal. Bone marrow cytology did not show any malignant or leucemic cells. Therefore, an idiopathic IgA mediated immune hemolytic anemia was diagnosed and treatment with 80 mg prednison was instituted. A normal hemoglobin level was achieved within 2 months of treatment. Conclusion: This case reports shows a possible pitfall in the analysis of a hemolytic anemia. When a hemolytic anemia with a negative direct Coombs? test is encountered and no specific origin is found, monospecific antiglobulin tests should be performed. A polyspecific direct Coombs’ test (anti-IgG and anti-complement)

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Internistendagen 2001 fails to detect a solely IgA or IgM mediated immune hemolytic anemia. 42. Pneumomediastinum and pneumopericardium complicat1 ing laparoscopic inguinal hernia repair. J.M. van der Klooster , 1 A.F. Grootendorst , Afdeling Intensive Care Geneeskunde, 1 Medisch Centrum Rijnmond-Zuid , Olympiaweg 350, 3078 HT Rotterdam, Tel.: 010 -2911911, Fax: 010 -2911083, e-mail: jmvanderklooster@ planet.nl Stabbing chest pain in the postoperative period is highly suggestive of pulmonary embolism. Subsequently, extensive diagnostic procedures are usually performed to exclude venous thrombosis, pulmonary embolism and myocardial infarction. However, other causes should also be considered especially if laparoscopic abdominal surgery has been performed. These include pneumoperitoneum, pneumothorax, pneumomediastinum, pneumopericardium and subcutaneous emphysema. A 27-year-old man developed stabbing chest pain, several hours after laparoscopic inguinal hernia repair. This procedure was performed without technical difficulties or operative complications. Despite prophylactic measurements his complaints were suggestive of pulmonary embolism. Doppler ultrasonography and pulmonary perfusion scan excluded venous thrombosis of the legs and pulmonary embolism respectively. However, follow-up chest radiography showed subcutaneous emphysema, minute air collections around the thoracic aorta and pericardium, suggesting pneumomediastinum. Treatment consisted of oxygen, analgesics and rest. The patient recovered completely within several days. A 38-year-old man developed crushing chest pain exacerbated by breathing deeply. Earlier that day, he had undergone laparoscopic inguinal hernia repair without surgical difficulties. Physical examination revealed extensive subcutaneous emphysema, abdominal tenderness and Hamman’s sign (a crunching sound in synchrony with the cardiac cycle, resembling a pericardial rub). Chest X-ray showed pneumoperitoneum, but also pneumopericardium and extensive subcutaneous emphysema. Treatment consisted of analgesics and rest. Doppler ultrasonography of the heart revealed no abnormalities one-day later. The patient was discharged without any complaints. If chest pain develops following laparoscopic abdominal surgery, pneumomediastinum and pneumopericardium should be considered first. Conventional chest radiography is usually sufficient to establish these diagnoses. However, since the abnormalities may be inconspicuous and may be easily overlooked, they should be actively searched for. Treatment is conservative and consists of analgesics and rest. The free air is readily absorbed within several days. 43. A woman with painful cramps of the upper limbs. M.A.A.J. van den Bosch 1 , S. Wittebol 1 , H. van Dijk 2 , M.H.H. Kramer 1 , Department of Internal Medicine 1 and Immunology 2 , Eemland Ziekenhuis, lokatie Lichtenberg, Postbus 1502, 3800 BM Amersfoort. Tel.: 033 -4222443, fax: 033 -4222695, e-mail: M.Kramer@ zkh-eemland.nl Introduction: The DiGeorge anomaly (DGA) arises due to a failure of migration of neural crest cells into the third and fourth

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pharyngeal pouches. Patients display a characteristic clinical syndrome. Case: A 29-year-old woman presented with painful cramps of the upper limbs. Her medical history included cleft palate, atrium septum defect, right descending aorta, growth retardation, recurrent pulmonary infections (S. aureus), and IgA deficiency with transient intravenous immunoglobulin suppletion during childhood. In the eighties she presented with muscle pain and fatigue and ‘‘fibromyalgia’’ and ‘‘viral myositis’’ was diagnosed. On examination, provocative repetitive movement of both hands resulted in a fit of cramp, which resolved after two hours. She presented subtle dysmorphic facial features: hypertelorism and small fish mouth. She was 1.55 meter tall and weighted 38.5 kilogram. Laboratory tests indicated decreased serum calcium (1.43 mmol / L), elevated phosphate (1.71 mmol / L), normal level of serum albumin, decreased magnesium (0.60 mmol / L), and decreased parathyroid hormone level (0.9 pmol / L), with normal 25 OH-Vit D and TSH levels. The differential diagnosis included primary autoimmune hypoparathyroidism, chronic granulomatous disease, polyglandular autoimmune syndrome, and DGA. Flowcytometry showed a decreased CD4 1 / CD8 1 ratio and an increased count of gd 1 T cells in peripheral blood. Granulomatous function test were normal. Fluorescence-in-situ-hybridisation detected a 22q11.2 deletion. Because of hypoparathyroidism, Tcell dysfunction, right descending aortic arch, atrium septum defect, facial dysmorphy, and deletion of 22q11.2, DGA was diagnosed. The patient was treated with vitamin D and calciumcarbonate, with clinical improvement within one week. Discussion: Approximately 90% of patients with DGA have microdeletions involving chromosome 22q11-2. Deletions in the same region are found in cases of velo-cardio-facial syndrome, and in some patients with isolated cardiac defects. The facies consists of hypertelorism, micrognathia, short philtrum, and low set posteriorly rotated ears with small pinnae. Cardiac defects are variable. Type B interrupted aortic arch is the most common, and is associated with DGA in 50 percent of cases. The parathyroid glands are usually affected since they are adherent to the thymus. Hypocalcemic tetany resulting from parathyroid hormone deficiency is one of the more common presenting symptoms of DGA. The parathyroid deficiency is often more pronounced than the thymic defect. Partial and complete forms of DGA are distinguished based upon the degree of immune dysfunction. Among these patients, T cell number and function are variable, and are presumably correlated with the amount of ectopic thymus tissue present. B cells and antibody production are generally normal. Conclusion: This patient, who remained undiagnosed for 29 years, indicates that manifestations of DGA may not be evident in infancy or during childhood. Physicians must consider the diagnosis in patients of any age with hypocalcaemic tetany, congenital heart disease and T-cell deficiency. 44. Polyuria, renal insufficiency and liver test abnormalities during pregnancy. K. Bevers, M. Jongen-Lavrencic, A.A.M.J. Hollander, Department of Internal Medicine, Bosch Medicentrum, P.O. Box 90153, 5200 ME, ’ s Hertogenbosch, The Netherlands, Tel.: ( 1 31) 73 6162000.

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Introduction: Diabetes insipidus is the condition of falling renal water reabsorption with diuresis of dilute urine (3–20 l / day). We present an uncommon form of transient diabetes insipidus during pregnancy. Case: A 31-year-old nullipara presented with polyuria (5 l / day) in the 33rd week of pregnancy. Her laboratory results showed glucose 5.0 mmol / l, thrombocytes 228 3 10 9 / l, urea 9.1 mmol / l, creatinine 173 mmol / l, sodium 133 mmol / l, bilirubin 35 mmol / l, AF 250 IU / l, gGT 115 IU / l, ASAT 139 IU / l, ALAT 268 IU / l and LDH 314 IU / l. A water restriction test showed low urine osmolality in relation to plasma osmolality. There was a maximal rise of urine osmolality to 330 mosmol / kg after water restriction and a further rise to 594 mosmol / kg after the administration of 1-desamino-8-D-arginine-vasopressine (dDAVP). Diabetes insipidus, renal insufficiency and liver test abnormalities resolved after a cesarean delivery. Discussion: Normoglycaemia and a persistent low ( , 500 mosm / kg) urine osmolality during water restriction excluded diabetes mellitus and primary polydipsia as a cause of polyuria. So, our patient suffered from diabetes insipidus. According to the results of the water restriction test we concluded that this was a partial central diabetes insipidus. In central diabetes insipidus the hypophysis produces insufficient amounts of antidiuretic hormone (ADH). During pregnancy the ADH deficit can be caused by vasopressinase which is produced by the placenta and results in an increased ADH catabolism. Diabetes insipidus can occur in women with preexisting subclinical diabetes insipidus or in women with higher than normal vasopressinase levels. In these patients, polyuria is resistant to native ADH but not to dDAVP, which is not degraded by vasopressinase. Hence, a water restriction test performed in these patients and in patients with central diabetes insipidus can have the same results. It is most likely that our patient either had a preexisting subclinical diabetes insipidus or a vasopressinase surplus. Microangiopathic hemolysis (like HELLP syndrome) as a cause of liver dysfunction and renal insufficiency during pregnancy could be excluded by the absence of hemolysis and low platelet count. Our patient could have an acute fatty liver of pregnancy. This syndrome can explain all her problems including transient central diabetes insipidus. Acute fatty liver of pregnancy can have substantial morbidity and mortality. The treatment of the syndrome is delivery. 45. Co-infection of HIV and hepatitis C; a therapeutic dilemma. M.A. Hoefnagels, R. van Leusen, R.A. de Vries, C. Richter. Department of Internal Medicine, Rijnstate Hospital, Arnhem, Wagnerlaan 55, postbus 9555, 6800 TA, 026 -3788888. e-mail: guido.diermen@ worldonline.nl Introduction: Human immunodeficiency virus (HIV) infection accelerates the natural course of hepatitis C, causing a more rapid progression to cirrhosis. On the other hand, co-infection with hepatitis C virus (HCV) is independently associated with HIV disease progression and survival, even in patients who receive potent antiretroviral therapy. The following case illustrates the difficulty to establish the best treatment strategy in an individual patient. Case history: A 40 year old female was referred to the outpatient clinic because of hepatitis C. Evaluation showed that

she also was suffering from very active HIV-infection reflected by a high value of HIV-RNA in plasma ( . 1.000.000 copies / ml) and profoundly decreased cellular immunity (CD4 cell count: 60 3 10 6 / l). Regarding HCV-infection she had an increased ALT of 77 U / l, a HCV-RNA value of 1.600.000 copies / ml, subtype 3A infection and minimal active hepatitis C with some fibrosis and no cirrhosis on liver biopsy. Ultrasonography showed an irregular pattern of the liver. Since it appeared that the immunodeficiency due to HIV-infection was most threatening, we decided to start with antiretroviral therapy. We didn’t give a protease inhibitor because of the risk of causing reactivation of hepatitis C and chose for 3 nucleoside analogues: zidovudine, lamivudine and abacavir. After 4 weeks of treatment she developed fatigue, nausea and jaundice. The laboratory tests showed increased bilirubin of 82 mmol / l and ALT of 381 U / l. Treatment was immediately stopped. Three weeks later, when ALT had decreased to 176 U / L treatment for hepatitis C was initiated consisting of interferon alpha (IFN) 6 MU od in combination with amantadine 100 mg bid in trial connection. After 8 weeks treatment was changed to IFN 3MU od with ribavirin. The ALT normalised within 4 weeks and the HCV-RNA became undetectable from week 8. IFN and ribavirin were stopped on week 24 due to unacceptable hair loss. In the meantime, treatment for HIV-infection was restarted on week 18 after start of the HCV-treatment. This time, protease inhibitors were part of the regimen not leading to any disturbances of the liver enzymes in the following weeks. Conclusion: Management of HIV/ HCV co-infection is complicated. We believe our patient developed deterioration of the chronic hepatitis due to reactivation hepatitis C; however, direct toxicity of the antiretroviral medication on the background of an active hepatitis C is possible as well. From this case and experience from others we conclude that it might be favourable to control HCV-infection first before starting antiretroviral therapy. 46. A rare cause of severe bleeding. R.S. van Rijn 1 , J.C.M. Meijers 2 , Ph.G. de Groot 1 , D.W. Erkelens 1 , L.F. Verdonck 1 . Departments of Haematology and Internal Medicine 1 , University Medical Center Utrecht, Utrecht and Department of Vascular Medicine 2 , Academic MedicalCenter, Amsterdam, The Netherlands. Tel.: 030 -2507230, fax: 030 -2511893, e-mail: L.F. Verdonck@ DIGD. AZU.nl A previously healthy 44-year-old woman was admitted to the hospital with a large intramuscular haematoma of the right leg, that had developed spontaneously. Six weeks before admission she experienced several bruises on arms and legs without antecedent trauma. There was no lymphadenopathy or hepatosplenomegaly. Haemogram and biochemical investigations were unremarkable, except for an elevated ESR (91 mm / 1 hr), and a normocytic anaemia (haemoglobin level 5.7 mmol / l). Clotting times were abnormal: activated partial thromboplastin time was 58 seconds (contro1: 33 sec), prothrombin time was 21.2 seconds (control: 12.6 sec), thrombin time was 20.1 seconds (control: 16.5 sec), and Simplate bleeding time was 10 minutes (normal 3–9 min). The fibrinogen level was 2.1 g / l and D-dimers were not elevated. Factor (F) II was 102%, FV 67%, FVII 77%, FVIII 91%, FIX 72%, FX 39%, FXI 79%, FXII 51%, FXIII 69%. The level of von Willebrand factor was normal. However, the plas-

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Internistendagen 2001 minogen level had significantly decreased (27%) as well as the level of the major physiological inhibitor of plasmin, a-2-antiplasmin (33%). Plasmin-antiplasmin complexes were . 5000 ng / ml, confirmative of the diagnosis of pathologic fibrinolysis as the cause of the bleeding tendency. Serum protein and immunoelectrophoresis revealed a paraproteinaemia of the type IgM-l. Urinalysis showed microalbuminuria (0.2 g / l), with free l light chains. Bone marrow aspirate and biopsy contained 4 – 6% plasma cells, which by immunophenotyping proved to be monoclonal. Congo red staining of the biopsy sample appeared green under polarized light, and primary amyloidosis was diagnosed. Therapy was initiated the day after admission and consisted of daily suppletion of fresh frozen plasma, after 3 days followed by inhibition of fibrinolysis with tranexamic acid, 1 gram 4 times daily. Within 2 weeks, clotting times, plasminogen and a-2antiplasmin levels normalized, together with an increase of FV and FX levels to 81% and 67% respectively. Treatment with tranexamic acid was continued and the patient was enrolled in the HOVON 41 study for AL amyloidosis, consisting of intensive treatment with chemotherapy followed by autologous stem cell transplantation. Conclusion: The severe clinical bleeding in our patient was caused by pathologic fibrinolysis, resulting from primary amyloidosis. The mechanisms for pathologic fibrinolysis are either increased levels of tissue-type plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA) or a deficiency of plasminogen activator inhibitors (PAIs). In our patient t-PA levels were normal and PAIs were increased. The u-PA level is currently being investigated. 47. A family with Job’s syndrome: recurrent infections, chronic eczema, elevated serum IgE and a distorted Th1 / Th2 balance. M.G. Netea 1,2 , P.M. Schneeberger 1 , E. de Vries 1 , J.W.M. van der Meer 2 , M.I. Koolen 1 . 1 Bosch MediCentrum, ‘ s-Hertogenbosch, and 2 University Medical Center St. Radboud, Nijmegen, Geert Grooteplein 8, Postbus 9101, 6500 HB Nijmegen, Tel.: 024 -3614763, Fax: 024 -3541734, e-mail: M.Netea@ aig.azn.nl Introduction: Job’s syndrome (or hyper IgE syndrome) is a rare immunodeficiency characterised by recurrent skin and respiratory tract infections, skeletal and dental abnormalities, chronic eczema, and elevated circulating IgE concentrations. Aim of the study: We describe a family consisting of four patients with Job’s syndrome (38, 37, 30 and 7 years old), and one possible patient (5 years old), in which we investigated both non-immunologic and immunologic features of the disease. Materials and Methods: Cytokine production capacity was measured in the patients and four healthy volunteers after stimulation of whole-blood at 378C with either lipopolysaccharide (10 ng / mL), heat-killed Staphylococcus aureus (10 6 CFU / mL) or a combination of interleukin (IL)-12 (1 ng / mL) and IL-18 (10 ng / mL). Tumor necrosis factor-a (TNFa) and IL-1b were measured after 24 h stimulation using specific radioimmunoassays, whereas interferon-g (IFNg) and IL-10 were determined after 48 h stimulation with a commercial ELISA kit. Results: All patients had severe recurrent skin abcesses, from which the same strain of S.aureus was isolated. All three adult patients had chronic candidiasis of the nail beds, and all patients

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had a history of recurrent otitis media and upper respiratory tract infections. The patients had chronic eczema since early childhood, and three of them had skeletal or dental abnormalities. The circulating levels of IgE ranged from 5000 to 16670 IU / mL. TNFa and IL-1b production did not differ between the patients and controls. In contrast, after stimulation with S. aureus, a pronounced imbalance towards a Th2 fenotype was found, with severely reduced IFNg/ IL-10 ratios in the Job’s syndrome patients: median 1.0 (range 0.3 to 7.6) vs. 13.0 (7.9 to 52) in the controls. Moreover, a significantly decreased responsiveness of lymphocytes from Job’s syndrome patients to stimulation with IL-18 / IL-12 was detected: IFN production 385 (37 to 760) pg / ml vs. 780 (53 to 2200) pg / ml in controls. Conclusion: Job’s syndrome is a rare disorder characterised by a multifaceted clinical picture with both non-immunologic and immunologic abnormalities. An imbalance in the Th1 / Th2 cytokine production may be involved in the pathogenesis of the recurrent infections (relatively low IFNg production) and / or chronic eczema (relatively high IL-10 production). 48. A rare cause of osteoporosis in a 60-year old female. A.J.M. Rennings, H. de Boer, L. Verschoor, Rijnstate Hospital, Arnhem, The Netherlands, Address: P.O. Box 9555, 6800 TA Arnhem, Tel.: 026 -3787750, fax: 026 -3786737, e-mail: arennings@ rijnstate.nl A 60-year old female was presented by the orthopaedic surgeon because of 2-year old backpain and a lumbar X-ray suggestive of severe osteoporosis. Her medical history revealed primary amenorrhea, hypertension, chronic obstructive pulmonary disease, depression, mamma augmentation and epilepsy after skull fracture. She was using antihypertensive and antiepileptic agents and aerosols. On examination her weight and length were 55 kg and 1.72 m respectively. Her mammae looked prepubertal. She had virtually no axillary hair and a P2 pubic hairstage. The vagina was narrow without a palpablel cervix. Diagnostic work up included osteoporosis analysis and evaluation of suspected hypogonadism. Laboratory results revealed the following: calcium 2.38 mmol / L (2.10–2.55), phosphorus 1.26 mmol / L (0.87–1.45), 25-hydroxy vitamine D 32 nmol / L (normal values 17.7–113.3), alkaline phosphatase 147 U / L (1–120), luteinizing hormone 0.5 U / L (normal values: for prepubertal males and females 0–1.0), folliclestimulating hormone 7.1 U / L (normal values: for males 2–7.5, for prepubertal males 1–7 and for postmenopausal females 30–120), estradiol 146 pmol / L (normal values: for prepubertal males and females and postmenopausal females , 100 and for males 100– 170), testosterone 0.6 nmol / L (normal values: for prepubertal males 0.7–2.8, for males 10–31 and for females 0.1–1.2), progesteron 2.3 nmol / L (normal values for: males 0.4–3.1 and for postmenopausal females 0.4–2.2). Further screening for pituitary hormone levels was normal. Dual energy X-ray absorptiometry revealed a T-score of 2 4.9 in the lumbar spine and 2 3.8 at the femoral neck. On transvaginal ultrasound no internal genitalia were visualised. Karyotyping showed genotype XY. In summary, there was proven severe osteoporosis caused by lifetime deficiency of gonadal steroids. The patient was chromosomally male, but she had a female phenotype. The absence of ¨ internal genitalia on ultrasound indicates regression of Mullerian ducts, which suggests there has been some testicular activity in

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early embryogenesis. This finding in combination with the hormonal status is compatible with testicular regression. The therapeutic consequence could be testosterone suppletion, but this is psychosocially not acceptable. Estrogen or selective estrogen receptor modulator therapy is optional. We started with calcium, biphosphonates and analgetics. 49. Ruptured massive liver cyst: a rare cause of acute abdomen in a haemodialysed patient with end-stage renal disease due to autosomal-dominant polycystic kidney disease. R.A. Carels, E.F.H. van Bommel, A.C.M. van Vliet. Dept. of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, tel: 078 -6541111, Fax: 078 -6542244, e-mail: r.a.carels@ dszh.nl Autosomal-dominant polycystic kidney disease (ADPKD) has multiple systemic manifestations. Although liver involvement is the most frequent extra-renal manifestation, serious complications due to liver cysts are very rare. We report the third case in the literature of acute abdomen due to haemoperitoneum because of rupture of a massive liver cyst in ADPKD. In December 1999 a 76-year-old man was admitted to the emergency department of our hospital with progressive abdominal pain. His medical history revealed end-stage renal disease due to ADPKD for which he received chronic haemodialysis from June 1999. He received chronic anticoagulation therapy because of a PTFE shunt in the left arm. Upon physical examination we saw a severely ill patient. His blood pressure was 75 / 50 mmHg, pulse rate 100 beats / minute, body temperature 378C. Abdominal inspection revealed no distension, bowel sounds were sparse and inactive. Severe tenderness was noted in the upper abdomen with diffuse rebounding pain. Relevant laboratory investigation showed: Hb 6.1 mmol / L; WBC 12.2 3 10 9 / L; Platelet count 195 3 10 9 / L; Lactate 1.70 mmol / L; INR 5.4. Blood gas analysis revealed no acidosis. X-ray examination of the abdomen showed no subdiaphragmal air. Computed tomography disclosed a large liver cyst of 9 cm diameter in the right lobe with suspected bleeding. Exploratory laparotomy revealed massive haemoperitoneum due to a ruptured giant liver cyst. Placing omentum over the ruptured cyst stopped the bleeding. After an eventful postoperative course the patient eventually died 5 weeks after admission. The literature upon hepatic complications in ADPKD patients on haemodialysis is discussed. The present case and previous observations suggest that massive liver cysts may be at significant risk of rupture and may cause life-threatening haemoperitoneum. Treatment options are discussed and the need for careful evaluation of chronic anticoagulation therapy in these patients is emphasised. 50. Disappearance of a MALT lymphoma of the urinary bladder after eradication therapy for Helicobacter pylori. J. van den Bosch 1 , W.B.J. Gerrits 1 , P. Blok 2 , R.F. Kropman 3 , and P.W. Wijermans 1 dpt of Haematology 1 , dpt of Pathology 2 , and dpt of Urology 3 , Leyenburg Hospital, The Hague, The Netherlands; Tel.: 1 31 -70 -3592556; Fax: 1 31 -703592108, e-mail: haematologie@ leyenburg-ziekenhuis.nl Introduction: Primary lymphomas of the urinary bladder are rare. Most are of low-grade malignancy. We report the first patient

whose MALT lymphoma of the urinary bladder disappeared after eradication therapy for Helicobacter pylori. Case report: A 62-year-old man presented with painless macroscopic haematuria. Physical examination was normal. An IVU revealed a staghorn calculus in the lower pole of the left kidney and a small stone in the distal left ureter. A CT scan of the abdomen revealed no abnormalities of the urinary bladder nor lymphadenopathy. Urine cultures and cytology were negative. Cystoscopy showed a reddish swollen urothelium at the right bladderbase. The right urethral orifice was involved in the lesion. Bladder biopsies were taken. Pathology findings showed Non Hodgkin lymphoma of the MALT type. The patient refused curative radiotherapy. Because of the known relationship of a gastric MALT lymphoma and Helicobacter pylori infection, HP serology was performed, which was positive. A gastroduodenoscopy showed a minor gastritis. The patient was treated with quadruple therapy. Thereafter the gastroscopy was normal. Biopsy specimens of the gastric mucosa were negative for HP at that time. Cystoscopy after eradication therapy only revealed little redness at the trigonum vesicae on the right side. Biopsies of the urinary bladder showed signs of follicular cystitis without any signs of a malignant lymphoma. Later on a percutaneous nefrolitholapaxy was performed with total removal of the lower pole kidney stone. Examination of the stone revealed that it was not caused by an infection. The patient is, three years later, without complaints and in a persistent complete remission. Discussion: The role of HP infection in the pathogenesis of gastric MALT lymphomas has been confirmed by clinical studies documenting a regression of these lymphomas after eradication of HP infection. Because our patient refused standard therapy, and because of the suggested relationship with HP, we also treated our patient for HP infection. After this quadruple therapy biopsies of the urinary bladder were negative for lymphoma. A thorough search at Medline learned that this is the first reported case in which a urinary bladder MALT lymphoma has been successfully treated with HP eradication therapy. 51. Familial ACTH-independent Cushing’s syndrome. W.H. van Houtum, J.M. Sepers, Medical Center Alkmaar, department of Internal Medicine, Wilhelminalaan 12, 1815 JD, Alkmaar, phone 072 -5484444, houtum@ worldonline.nl Case: The first patient (female, 51 years) presented with chronic fatigue, body-weight increase (5 kg in 1 year) and easy bruising. Her medical history showed a hypertensive cardiomyopathy for which she was taking atenolol, bumetanide and quinapril. Her physical examination was normal except for centripetal obesity. Her blood pressure was 140 / 90 mmHg. The urinary free-cortisol excretion was 398 nmol / 24 hours and the low-dose dexamethasone suppression test revealed a cortisol level of 630 nmol / l after two days suppression; the basal ACTH level was 0.7 ng / l. On an abdominal CT scan an adrenal adenoma was discovered on the left. The adrenal gland was surgically removed and the pathology report showed an adrenal adenoma. The second patient (female, 27 years) presented with dyspnoea with coughing

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and bloodstained frothing sputum. She also reported an increase in bodyweight (5 kg in 2 years), easy bruising and frequent headaches. On examination she had severe hypertension (220 / 150 mmHg) and showed signs of cardiac failure. She clearly demonstrated a moonface and reddish striae were found on the abdomen. Initial treatment was focussed on her left heart failure and hypertension. After she was stable, urinary free-cortisol excretion was measured (2541 nmol / 24 hours) and her low-dose dexamethasone suppression test revealed a cortisol level of 912 nmol / l after two days suppression. Basal ACTH level was 0.7 ng / l. She underwent an abdominal CT scan and again an adrenal adenoma was diagnosed, which was removed. Discussion: Surprisingly, the above mentioned patients are mother and daughter. Therefore, a possible genetic origin explaining the familial presentation of a cortisol producing adrenal adenoma was considered. A MEN I syndrome was considered highly unlikely as they usually present as a Cushing’s disease and is associated with pheochromocytomas and pancreatic tumours. Further DNA analysis of the MEN I gene (11p13) did not show any affected alleles. The macro- and microscopic aspect of the adrenal glands was not compatible with a bilateral micronodular dysplasia. Additionally, both patients did not have blue nevi, myxomas or pituitary adenomas, mostly seen in patients with the Carney complex. Another possible explanation may be epidemiological coincidence, but the incidence of adrenal adenomas is estimated to be 2 per million per year. In conclusion, the familial presentation is either due to chance or a not yet discovered genetic defect is present.

basis of peripheral pancytopenia, bone marrow findings and clinical symptoms. During life, no underlying disease was definitively proven. The patient developed multi-organ failure and died. Postmortem examination showed intravascular infiltration of lymphoma cells into various organs: gut, omentum, kidney, liver and lung. In a few small abdominal lymph nodes ( , 5 mm) tumor cells were diagnosed, but no localization was found in bone marrow or spleen. These lymphoma cells were of B-cell phenotype, confirming the diagnosis of angiotropic B-cell lymphoma. Discussion: HPS is connected with severe clinical conditions, such as various infections, malignancies, and malignant hystiocytic tumors. It is characterized by organomegaly, pyrexia, jaundice and pancytopenia. In particular, HPS is related with malignant lymphomas (lymphoma-associated HPS: LAHS). LAHS is mostly associated with mature T / NK-cell lymphomas. LAHS is thought to be caused by activation of latent Epstein-Barr virus (EBV). Subsequent hypercytokinemia is mediated in the development of this syndrome. Angiotropic B-cell lymphoma is histologically characterized by disseminated intravascular proliferation of tumor cells. Its clinical features are quite diverse due to the growth pattern of the lymphoma cells, including pyrexia, organomegaly, pancytopenia and lack of lymphadenopathy. The combination of LAHS with angiotropic B-cell lymphoma is thus far only described in patients from Asian descent (Br J Haematol 2000;111:826–34). Conclusion: We present the first Caucasian patient with haemophagocytic syndrome due to intravascular diffuse large B-cell lymphoma.

52. Haemophagocytosis associated with Intravascular Diffuse Large B-cell lymphoma: the first case in a Caucasian patient. G.J.A. ten Bosch 1 , L. Budel 2 , T. Bartelink 3 , M.H.H. Kramer 1 . Department of Internal Medicine 1 , Pathology 2 and Intensive Care 3 , Ziekenhuis Eemland, lokatie Lichtenberg, postbus 1502, 3800 BM Amersfoort. Tel.: 033 -4222443, fax: 033 -4222695, email: m.Kramer@ zkh-eemland.nl Introduction: Haemophagocytic syndrome (HPS) is characterized by fever, pancytopenia, icterus with organomegaly and is often associated with malignancy and, in particular, with malignant lymphoma with a T- or natural killer (NK)-cell phenotype. Case: A 40-year-old male was analyzed elsewhere because of fever of unknown origin, anemia and elevated concentration of lactate dehydrogenase (LDH). Six weeks before admission, he felt general malaise, and his weight decreased 6 kg. At presentation he was febrile and during his admission the temperature spiked daily to 39–408C. A physical examination revealed anemia in addition to enlarged liver and spleen. However, neither peripheral lymphadenopathy nor skin lesions were found. No focus of infection was found and all cultures remained negative. Vasculitis or other autoimmune related diseases were ruled out. Extensive radiologic studies didn’t show evidence for lymphadenopathy or a disseminated malignant disease. The patient was transferred to our Intensive Care because of respiratory insufficiency, where he was mechanically ventilated. Laboratory studies concealed pancytopenia, and a marked increase of LDH to 3455 IU / l (normal 230–450). Bone marrow examination revealed a hypercellular marrow with large numbers of phagocyting cells. No monoclonality was proven. The patient was diagnosed with HPS on the

53. An unusual cause of pleural fluid. E.M.G. Jacobs 1 , G. den Hartog 2 , F.J.J. van den Elshout 3 . Department of Internal Medicine 1 , Department of Gastro-enterology 2 , Department of Pulmonology 3 . Rijnstate Hospital, Arnhem, the Netherlands. Postbus 9555, 6800 TA Arnhem. Tel.: 026 -3788888. Fax: 026 3787878, e-mail: ejacobs@ rijnstate.nl A 66-year old man was referred because of persisting complaints of dyspnoe and cough following a right sided pleural pneumonia two months earlier. His sputum was white. During these last two months he lost 15 kilograms of weight. His medical history revealed a duodenal ulcer, operatively corrected and a selective vagotomia in the same session. Alcohol- and nicotinabusus. Medical examination showed a lean patient with diminished lung sounds left basal. His chest X-ray showed massive pleural fluid left sided and a rest of fluid with cavities on the right side, without obvious infiltrations. Laboratory results showed an hemoglobin of 9.1 mmol / l (8.4–10.8), leucocytes 11.9 mmol / l (3.9–10.6), ESR 80 mm / h (1–20), creatinine 69 mmol / l (70– 105), amylase 173 U / l (1–220), LD 241 U / l (1–450), albumin 24.5 g / l (35.0–50.0), CDT 2.0% (0.0–5.0) and arterial bloodgas analysis a pCO 2 of 4.0 kPa (4.7–6.4) and a pO 2 of 7.5 kPa (11.0–14.4). A pleural infection, or a malignancy was considered. Pleural fluid showed an LD of 3399 U / l and an amylase of 15664 U / l without malignant cells or bacteria (tbc included). After drainage of twice 1500 ml of pleural fluid, dyspnoe revealed. On CT scan no signs of malignancy were seen only a pseudocyst central in the corpus of the pancreas. A diagnostic ERCP showed no additional findings. Abdominal MRI showed the same cyst in the body of the pancreas and also distal from it a wide pancreatic

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duct with a large fistula to the medial part of the left pleural cavity and a second smaller fistula from the cyst to the same part of the pleural cavity. After pleural drainage and conservative management the dyspnoe complaints diminished just partially, the fistula’s decreased but still remained. A pancreatico-pleural fistula as a complication of chronic pancreatitis is rare. As described above, the presentation can be that of pleural fluid only, without signs of pancreatitis or elevated serum amylase. An elevated amylase in the pleural fluid is diagnostic. Treatment depends on the place of the fistula and the condition of the patient. Nonsurgical treatment of the chronic pancreatitis is the therapy of choice, and consists of fluid and electrolyte replacement, nutritional support and eradication of infection if present. Somatostatin, which suppresses pancreatic secretion and decreases the volume of fistula drainage, can be obtained. During the courses of therapy, a fistulogram should be obtained when the tract is well formed. In case of ductal obstuction between the site of the leak and the duodenum, pancreatic duct stenting can be helpful. Most of the fistulas, however, close spontaneously. In rare cases surgical treatment is necessary. 54. Lead poisoning due to herbal medicin. A.W.G. van der Velden, J.J.M. van Meyel. Department of Internal Medicine, Lucas Andreas Hospital, Amsterdam. Case: A 33 year-old man with an unremarkable medical history was admitted to our hospital with abdominal complaints: cramps in his abdomen, accompagnied by anorexia, nausea, vomiting and constipation. He lost 5 kg of weight. These complaints started after using a veganistic diet and taking Ayurvedic herbs: Amlaky Rasayana tablets twice daily, Maha jogradj gogulu 2–3 tablets daily and Brahmi capsules twice daily. In his job and environment were no risks for lead poisoning. Physical examination showed no abnormalities except a diffuse tenderness of the abdomen. Laboratory results showed a normal ESR, a normocytic anemia (Hb 6.8 mmol / l, MCV 83 fl) with basophilic stippling. Albumin and CRP were within the normal range. Because of the suspicion of porphyria we examined the urine for porphyrins. The results showed an elevated excretion of coproporphyrins and pentaporphyrins with normal excretion of hexa-, hepta- and uroporphyrins. Blood examination: remarkably elevated protoporphyrins and zincporphyrins, and a decreased ALA dehydratase. All these results pointed to lead poisoning and this was confirmed by a lead level of 2.0 mmol / l (taken after the worst complaints were resolved). Analysis of the Ayurvedic herbs revealed 6.2% pure lead in the Maha jogradj gogulu tablets. Discussion: Lead poisoning is a disease that is diagnosed in children and adults with occupational or environmental exposure. Another possible cause is ingesting contaminated herbs and food supplements. Lead has an inhibitory effect on many steps in the heme biosynthesis and acts especially on ALA dehydratase. Lead limits the intracellular delivery of iron to the site of ferrochelatase so that zinc protoporfyrins accumulates. Clinical manifestations with lead levels above 1.4–3.6 mmol / l are autonomic neuropathy causing abdominal pain and ileus,

motor neuropathy, gingival lead lines and occasionally renal dysfunction. More frequently complaints are insidious, non specific musculoskeletal and neuropsychiatric complaints. Laboratory findings indicating lead poisoning are a normocytic anemia, basophilic stippling, decreased ALA dehydratase activity in the blood, increased urine ALA in excess of urine PBG. Urinary coproporphyrins are increased and to a lesser extent also uroporphyrins. Therapy for lead poisoning exits of removal of the lead source and administration of chelators like EDTA intravenously for 5 days. Conclusion: The cause of the lead poisoning in our case is the use of the Ayurvedic herbs. After discontinuing all his complaints resolved in a several weeks, he gained weight and the anemia disappeared without chelation therapy. 55. Case report; category: endocrinology. Adrenal suppression after intra-articular glucocorticoid administration. S.A.C. van Tuyl, P.H.Th.J. Slee, St Antonius Ziekenhuis Nieuwegein, Koekoekslaan 1, 3435 CM Nieuwegein, tel 030 -6099111, sactuyl@ knmg.nl Oral or intravenous administration of corticosteroids may result in side effects. Local administration (by inhalation or intraarticularly) is advocated because of a higher safety profile resulting in less or no side effects. For inhaled corticosteroids literature advises to monitor for systemic effects, like adrenal suppression and growth retardation. After intra-articular administration of corticosteroids these clinical effects are very rarely described. We report on a patient who appeared to have adrenal suppression after one intra-articular injection with triamcinolonacetonide. A 37-year-old woman visited our outpatient’s clinic with symptoms suggestive for hypercortisolism. She complained of tiredness, weight gain and secondary amenorrhoea, which she developed in several months. Three months earlier she received 40 mg triamcilonacetonide in her shoulder because of pain. One month later she noticed, that her face became swollen, and she put on weight. On physical examination she had a moon face, buffalo hump and hirsutism. The RR was 120 / 85 mmHg. Laboratory examination demonstrated leukocytes 15.5 G / l with normal differentiation, potassium 3.3 mmol / l, cortisol , 28 nmol / l, ACTH , 2 pmol / l. The other values for electrolytes, renal function and endocrine tests were within normal limits. As ACTH and cortisol levels were both below the detection level, a secondary adrenocortical insufficiency was diagnosed. After 100 mg CRH ( 5 corticotropin releasing hormone) i.v. no increase of cortisol and ACTH was noticed. Only five months after the triamcinolonacetonide injection the cortisol was 430 nmol / l, ACTH 4 pmol / l. The CRH-response after i.v.injection was normalised: cortisol rose from 430 to 600 nmol / l. We also examined the bone mineral density: in the lumbar spine (L2-L4) BMD was 1,009 g / cm 2 , with a T-score of 2 1.59, in the left femoral neck 0.799 g / cm 2 , with a T-score of 2 1.51. These values confirm the diagnosis osteopenia; Radiology of the thoracolumbar spine showed flattening of the 12 th thoracic vertebra.

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Internistendagen 2001 Retrospectively this patient received two injections of triamcinolonacetonide in the shoulder 3 (40 mg) and 9 months (20 mg) before this episode. We assume hypercortisolism after intra-articular corticosteroid injection and possibly related osteopenia and followed by a long-lasting secondary adrenal suppression. This sequence suggests the possibility of a corticosteroid receptor hyperresponsiveness, for which we consider in vitro testing. The possibility of adrenal suppression even several months after an intra-articular corticosteroid injection should be kept in mind. 56. A spontaneous intramural oesophagus haematoma. J. Aalten, B.W.M. Spanier, J.L. Meijer, K. Bakker. Department of Internal Medicine, Spaarne Ziekenhuis Heemstede, The Netherlands. Case report: An 80 year old woman was admitted at the coronary care unit with severe complaints of acute retrosternal chest pain. She was known with stable angina pectoris for which she used aspirin 100 mg / day, a beta-blocker and nitrates. The pain commenced three hours post-prandially and was constant with intermittent cramps. During diner the patient did not choke and no fish was eaten. An hour after presentation she started vomiting and had two times haematemesis with approximately 100 cc of dark blood. Physical examination was unremarkable. Laboratory tests were within normal limits, especially a normal haemoglobin level and no coagulation disorders. Electrocardiography showed no signs of ischaemia. The chest X-ray was normal. Because of the haematemesis we performed an upper gastrointestinal endoscopy. This showed a blue longitudinal mass extending over the half of the oesophageal circumference from the gastro-oesophageal junction till 23 cm from the incisors. No active bleeding focus was seen. To exclude pathology of the aorta a CT-thorax and an MRI / MRA were performed. An intramural mass in the oesophagus wall was seen with no evidence of an aortic lesion or malignancy. The patient was treated with a proton pump inhibitor, a nothingby-mouth regimen and discontinuing of the aspirin. After ten days the patient was totally recovered and she could swallow normally. A control gastroscopy and a CT-thorax showed a complete regression of the haematoma. Conclusion: A diagnosis of a spontaneous intramural oesophageal haematoma was made, because of the absence of coagulation disorders, the absence of choking (e.g. sharp fish bones) and spontaneous regression of the lesion. This very rare diagnosis is especially associated with the use of aspirin, coagulation disorders and oesophageal hyperpressure. Most oesophageal haematomas resolve spontaneously. Spontaneous oesophagus haematoma is an important differential diagnosis in patients presenting with acute chest pain. Anticoagulation therapy and even surgery can be extremely harmful in this otherwise benign disease.

III. Endocrinology 57. Fasting induced responses in lipolysis and hormone profiles in normal weight and obese women. M. Buijs 1 , J.

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2 1 2 1 ¨ Burggraaf , C. Wijbrandts , R. Schoemaker , M. Frolich , A. 2 3 1 1 Cohen , J. Romijn , A. Meinders , H. Pijl , Department of General Internal Medicine 1 , Centre for Human Drug Research 2 , and Department of Endocrinology 3 , Leiden University Medical Centre, C1 -R39, P.O Box 9600, 2300 RC Leiden, The Netherlands, Phone: 1 31 71 526 4470, Fax: 1 31 71 524 8140, e-mail: m.m.buijs@ lumc.nl Introduction: During fasting adipose tissue becomes the most important source of energy. In normal weight (NW) subjects short-term fasting will increase whole body lipolytic rates, but in obese (OB) persons this increase is blunted through unknown mechanisms. Aim of this study: We determined whole body lipolytic rates and major factors regulating lipolysis in NW and OB women to gain insight into fasting induced metabolic responses. Methods: Eight OB (body mass index (BMI): 32.162.6 kg / 2 2 m ) and six NW (BMI: 22.761.5 kg / m ) postmenopausal women were studied from 12 to 20 h. of fasting. Lipolysis was measured by infusion of D5-glycerol. Results: Baseline whole body glycerol rate of appearance (R a ) was significantly greater in OB than in NW women (NW: 139632 mmol / min, OB: 184640 mmol / min, p 5 0.038). A significant correlation was found between lean body mass (LBM) and baseline glycerol R a (r 5 0.779, p 5 0.001). Continued fasting increased lipolysis in NW, but in obese women glycerol release did not change. Percent increase in whole body lipolysis was significantly higher in NW than in OB women (NW: 22.9% with 95%CI: 9.0 / 38.6; OB: 2 1.7% with 95%CI: 2 18.0 / 17.9; p 5 0.030). In both groups of subjects plasma insulin concentrations declined significantly with continued fasting and percent declines were the same in both groups (NW: 2 27.6% with 95%CI: 2 36.3 / 2 17.7, OB: 2 33.3% with 95%CI: 2 42.2 / 2 23.0, p . 0.05). At 20 h. of fasting, mean insulin levels were still higher ( p , 0.05). Catecholamine excretion in urine and plasma cortisol levels were similar in OB and NW women. The only apparent difference between OB and NW women was that NW women had significantly higher plasma GH levels (NW: 1.8160.98 mU / L; OB: 0.7460.52 mU / L; p 5 0.046). Conclusions: These results suggest that (1) blunted GH secretion may explain diminished increase in lipolysis observed in obesity during short-term fasting and (2) lipolytic rates appear to be strongly correlated with LBM in women.

58. Pergolide induced retroperitoneal fibrosis: a case report. I. van Stijn 1 , J.M. van der Klooster 1 , A.F. Grootendorst 1 , J.M.L. Stouthard 1 , MCRZ lokatie Clara 1 , Olympiaweg 350, 3078 HT Rotterdam. Tel.: 010 -2911911, fax: 010 -2911083, e-mail: ivanstijn@ hotmail.com. A 50-year old man was diagnosed with Parkinson’s disease in 1990 and treated with pergolide, levodopa / benserazide and selegiline. He presented with slowly progressive peripheral oedema on both legs and intermittent claudicatio. On physical examination patient appeared well, though with distinct features of parkinsonism. Central venous pressure was normal. No lymphadenopathy was found. Venous collaterals were found on the lower abdomen and upper legs. Non-pitting oedema extended from feet to upper legs, and progressed to the abdominal wall within weeks.

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Laboratory investigation showed an ESR 49 mm / hour and a mild normocytic anaemia. Renal function was not impaired. Ultrasound showed no signs of deep venous thrombosis. CT scanning revealed no pathologic lymph masses. To exclude a neurogical cause of the claudicatio, an MRI of the lumbar spine was performed. The spine was normal, but an arteriovenous malformation of the lumbo-sacral plexus was suspected. Subsequently, an angiography was performed. A partial thrombosis of both iliacal veins and of the inferior caval vein was seen. The aorta was narrowed and both iliacal arteries were partly stenosed. Revision of the CT scan of the abdomen revealed a retroperitoneal mass, consistent with retroperitoneal fibrosis, without involvement of the ureters. Study of the literature showed another seven cases of pergolideinduced retroperitoneal fibrosis, but none of the cases presented with intermittent claudicatio. Pergolide was discontinued, and steroid with anti-coagulant therapy was instituted. Within one month after starting therapy the oedema and claudicatio complaints gradually disappeared. Repeated CT-scanning of the abdomen showed complete disappearance of all abnormalities, and normalisation of laboratory findings. In conclusion, pergolide is associated with retroperitoneal fibrosis. Discontinuation of the drug and steroid therapy can result in complete resolution of both symptoms and radiological features. 59. Cushing’s syndrome caused by ectopical ACTH production in a 51-year-old woman with small cell lungcarcinoma. J.M. van den Akker, M. Koopman, H. De Boer, K. Kaasjager. Department of Internal Medicine, Rijnstate Hospital, Wagnerlaan 55, 6800 TA Arnhem, Tel.: 026 -3788888, Fax: 026 -3786737, e-mail: s.hoogendijk@ planet.nl. A 51-year-old woman visited the outpatient department with severe fatigue, extreme proximal muscle weakness of the legs and a weight gain of 20 kilograms in a few months. Physical examination showed an otherwise healthy but obese woman with a moon facies, a buffalo hump, mild hirsutism and high bloodpressure (180 / 100 mmHg). Laboratory examination revealed a low potassium (2.1 mmol / l), a metabolic alkalosis (pH 7.53; pCO2 5.6; bicarbonate 36 mmol / l), a bloodglucose level of 18 mmol / l, an elevated cortisol level at 2.00 pm of 1.63 mmol / l with an ACTH level of 275 ng / l. Urinary collections were incomplete. The association of a clinical picture of Cushing’s syndrome and severe hypokalemia strongly suggested ectopical ACTH or CRH production as the underlying cause. X-ray and CT-scan of the chest demonstrated a widened mediastinum with an enlarged left hilus, suspect for a central bronchuscarcinoma. Bronchoscopy was performed and the bronchial alveolair lavage showed a small cell lungcarcinoma. Gradualy she developed severe psychological disturbance. A CT-scan of the cerebrum was performed, revealing 4 intracerebral brain metastases. The hypokalemia, hyperglycemia, hypercortisolism and hypertension were treated with spironolacton, potassiumchloride, metformin, actrapid, ketoconazol and lisinopril. Cyclophosphamide / doxorubicine / etoposide (CDE) chemotherapy was started for the small cell lungcarcinoma.

This case clearly demonstrated an obvious Cushing’s syndrome preceding the diagnosis of small cell lungcarcinoma. 60. Hyperprolactinemia and abnormal function of the pituitary-gonadal axis caused by pituitary enlargement as a result ¨ of primary hypothyroidism. T.E.H. Romkens, J.L.J. Jansen, P.M. Netten. Department of Internal Medicine, Bosch Medicentrum, ‘ s-Hertogenbosch. A 25-year old, previously healthy woman presented at the out patient clinic of gynaecology with primary infertility since 1 year. Her menstruation cycle seemed regular, every five weeks. Beside weightgain of 12 kg in 3 years and some tiredness she had no complaints. Physical examination showed no abnormalities, thyroid was not enlarged. The laboratory results were: prolactine 1.25 (0.0 – 0.60 ) IE / l, FSH 5.1 IE / l, LH , 1.0 IE / l, 17-b-oestradiol 0.19 nmol / l, progesterone , 1.0 nmol / l and testosterone 0.4 (0.2 – 3.0 ) nmol / l, TSH 774 (normal: 0.15 – 6.0 ) mu / l, FT4 1.6 (11.0 – 23.0 ) pmol / l, T3 , 0.3 (1.30 – 2.70 ) nmol / l, cortisol 0.34 mmol / l (0.19 – 0.69 ). Because of these laboratory results the patient was refered to the department of internal medicine. Further laboratory examination showed a mild anaemia of 7.4 mmol / l (MCV 93 fl), leucocytosis (12.4 3 10 29 / l), and normal kidney and liver function tests. Autoantibodies to thyroglobulin were negative and to thyroid peroxidase positive; 1:100. The electrocardiogram showed very low voltages. Because of the elevated prolactine and reduced FSH and LH-levels a MRI-scan of the pituitary was made, which revealed a large pituitary mass (12 3 18 mm). No differentiation could be made between tumour and hyperplasia. Levothyroxine (LT4) replacement was started at a low dose (12.5 mgram), because of her abnormal ECG, and increased to 150 mgram in the following two months. Although the patient previously had minor complaints, she observed a major improvement in her well being. Three months after starting LT4 therapy a second MRI-scan of the pituitary was made, which showed a normal pituitary; the large pituitary mass was vanished. Laboratory examination during this period showed normal results: TSH 0.64 mu / l, FT4 22.6 pmol / l, T3 1.75 nmol / l, prolactine 0.4 IE / l, FSH 3.8 IE / l, and LH 5.7 IE / l. Approximately 81% of the patients with hypothyroidism have an enlarged volume of the sella turcica on skull X-ray. Thyrotroph cell hyperplasia is believed to be caused by a decrease in the negative feedback exerted by circulating thyroid hormones. With the MRI-scan it is possible to visualise the pituitary better, but it is still difficult to differentiate between tumour and hyperplasia. In case of primary hypothyroidism with abnormal levels of pituitary hormones and enlargement of the pituitary gland, levothyroxine replacement should be started, to differentiate between tumour and hyperplasia. 61. Oriental syndrome (hypokalemic thyroitoxic paralysis). M.E. Sleeswijk, M.D. Themmen, A.J.J. Woittiez. Department of Internal Medicine, Twenteborg Hospital, P.O. Box 7600, 7600 SZ Almelo, The Netherlands. Tel.: 0546 -833333; Fax: 0546 -833418, e-mail: msleeswijk@ hotmail.com A case with the so-called Oriental syndrome or hypokalemic thyroitoxic periodic paralysis (HTPP) History: A 30-year-old Asian man was presented with acute

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Internistendagen 2001 progressive onset of muscle weakness. There was neither a history of vomiting nor use of diuretics. At physical examination a conscious man was seen, with a blood pressure of 140 / 80 mmHg and a pulse of 82 BPM and a temperature of 37.88C. There was a tetraparesis with symmetrical reflexes and a normal sensory function. Laboratory investigation revealed a BUN 7.3 mmol / l,serum creatinin 63 mmol / l, plasma sodium 142 mmol / l potassium 2.7 mmol / l P 1.38 mmol / l, magnesium 0.77 mmol / l, calcium 2.4 mmol / l albumen 41 g / l and a normal pH (7.41) and bicarbonate. TSH was 0.03(0.2–4.2 mU / l) and FT4 68(10–25 pmol / l). Potassium was repleted (5 mmol / hr); after six hours the tetraparesis had disappeared completely. Hyperthyroidism was treated with thiamazol After three days our patient was discharged from our hospital without any complaints. Discussion: This patient was diagnosed with the so-called oriental syndrome or hypokalemic thyroitoxic periodic paralysis (HTPP). Oriental syndrome is a syndrome of thyroitoxicosis with hypokalemia, hypofosfatemia and hypomagnesemia induced paralysis. An attack of periodic paralysis tends to occur during the night. Proximal muscles of the lower extremities are preferentially affected The attacks predominantly occur in males of Asian descent in the presence of excessive thyroid hormones in serum. About 10% of Asian males, who develop hyperthyroidism also have HTPP. Conclusion: If a young male of Asian descent is initially seen with severe paralysis, HTPP should be considered as a cause of paralysis. 62. Effects of fish-oil vs. bezafibrate on lipid parameters and determinants of cholelithiasis in hypertriglyceridemia. I.J.A.M. Jonkers 1 , A.A.M. Masclee 2 , F. Stellaard 2 , F. Kuipers 2 , J.A. Gevers Leuven 1 , C.H.B.W. Lamers 1 , A.E. Meinders 1 and A.H.M. Smelt 1 . Academic Hospital Groningen 2 and Leiden University Medical Center 1 , Albinusdreef 2, 2300 RC Leiden. Tel.: 071 5264654; Fax: 071 -5248159, e-mail: IJAMJonkers@ lumc.nl Introduction: Clinical studies showed an increased incidence of gallstones upon fibrate therapy. Patients with hypertriglyceridemia (HTG) are at risk for gallstone disease. Since fibrates may further enhance the risk for gallstone disease in HTG, an alternative therapy may be preferable for lowering lipids in HTG. Aim of the study: To investigate whether fish-oil could be a therapeutic alternative for bezafibrate in HTG patients by comparing its effects on serum lipids and determinants of cholelithiasis (biliary lipid composition and gallbladder motility) to those of bezafibrate. Materials and Methods: 9 HTG patients participated in a randomized, cross-over study, consisting of three treatment periods: baseline (without medication), bezafibrate (400 mg once daily) and fish-oil (5 gm / day). At the end of the treatment periods, blood samples were taken for determination of lipids and cholecystokinin (CCK) levels, duodenal bile was collected during intravenous CCK infusion and postprandial gallbladder motility was assessed using ultrasonography. Regression analysis was

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performed to investigate the sensitivity of the gallbladder for CCK. Results: Both bezafibrate and fish-oil reduced serum triglycerides (268% and 2 51% vs. baseline respectively, both p , 0.01). In addition, bezafibrate reduced serum cholesterol (228% vs. baseline, p 5 0.04), whereas fish-oil only tended to reduce serum cholesterol levels (216%, p 5 0.10). In contrast to fish-oil, bezafibrate did adversely affect biliary lipid composition (molar ratio of cholesterol to bile acids 1 33% vs. both baseline and fish-oil, both p , 0.03). CCK levels did not differ between the three periods. However, postprandial gallbladder motility was improved by both bezafibrate and fish-oil (ejection fraction 1 71 and 1 43% vs. baseline for bezafibrate and fish-oil, respectively, both p , 0.03) due to an increased sensitivity of the gallbladder for CCK (both p , 0.001 vs. baseline). Conclusion: Bezafibrate (400 mg / day) seems to have stronger lipid-lowering capacities than fish-oil at a dose of 5 gm / day. Concerning determinants of cholelithiasis, fish-oil and bezafibrate both improved postprandial gallbladder motility, whereas bezafibrate, in contrast to fish-oil, caused an adverse biliary lipid composition. Based on these data, we suggest that fish-oil may be a therapeutic alternative for bezafibrate in HTG patients. 63. Health-related quality of life (HRQOL) in postmenopausal women with or without prevalent vertebral fractures. A.M. Oleksik 1, 2 , P. Lips 1 , M. Levi 2 , A. Dawson 3 , M.E. Minshall 3 , W. Shen 3 , C. Cooper 4 , J. Kanis 5 . 1 Department of Endocrinology, Academic Hospital Vrije Universiteit, Amsterdam, The Netherlands. 2 Departement of Internal Medicine, Academic Medical Center, University of Amsterdam, The Netherlands. 3 Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA. 4 Medical Research Centre, Academic Hospital, Southampton, UK. 5 University of Sheffield Medical School, Sheffield, UK. Address: Meibergdreef 9, Postbus 22660, 1100 DD Amsterdam, kamer F4 -222 Telefoon: 5669111 ( pager 58499) e-mail: a.m.oleksik@ amc.uva.nl Introduction: Fractures and subsequent morbidity determine the impact of established postmenopausal osteoporosis. Health-related quality of life (HRQOL) has become an important outcome criterion in the assessment and follow-up of osteoporotic patients. Aim of this study: To assess HRQOL in patients with or without prevalent vertebral fractures. Matherials and methods: As part of the baseline measurements of the MORE (Multiple Outcomes of Raloxifene Evaluation) study, HRQOL was assessed in 751 osteoporotic (BMD T-score # 2 2.5) women from Europe with or without vertebral fractures (VFX). This was done using the quality of life questionnaire of the European Foundation for Osteoporosis (QUALEFFO), Nottingham Health Profile (NHP) and the EQ-5D (former EuroQol). QUALEFFO contains questions in five domains: pain, physical function, social function, general health perception and mental function. Each domain score and QUALEFFO total scores are expressed on a 100 point scale, with 0 representing the best HRQOL. Results: In comparison to patients without VFX, those with VFX were older (66.265.9 vs. 68.866.3 year, p , 0.001), had higher prevalence of non-vertebral fractures (25% vs. 36%, p 5

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0.002), and higher QUALEFFO scores (worse HRQOL; total score: 26614 vs. 36617, p , 0.001). QUALEFFO scores increased with an increasing number of VFX, especially lumbar fractures ( p , 0.001). Patients with a single VFX already had a significant increase in QUALEFFO scores ( p , 0.05). Similar, though weaker, associations were observed for NHP and EQ-5D scores. Conclusion: This study confirms the hypothesis that HRQOL decreases for patients with prevalent VFX. In osteoporotic patients, QUALEFFO scores change in relation to the number of VFX. QUALEFFO is a suitable outcome measure for clinical studies in patients with postmenopausal osteoporosis. Part of this work has been published in the Journal of Bone and Mineral Research, 15:1384–1392, 2000. 64. An unusual cause of persistent vomiting. E.H. Hoogendoorn, B.M. Cools, Department of Internal Medicine, University Medical Centre St Radboud, Nijmegen, The Netherlands. Geert Grooteplein 8, Postbus 9101, 6500 HB, Nijmegen., Tel.: 024 3618819, Fax: 024 -3541734, email: E.Hoogendoorn@ aig.azn.nl A 32-year-old woman was referred to the outpatient clinic of our hospital because of persistent vomiting and abdominal pain. Following a course of prednison, given for pulmonary reasons, she had been vomiting for 10 days. Antacids and prokinetics prescribed by her general practitioner gave no relieve. Physical examination showed no abnormalities, except for a fall in blood pressure from 150 / 90 mmHg (with a pulse rate of 96 bpm) lying down to 130 / 76 mmHg (with a pulse rate of 104 bpm) while standing. Laboratory testing showed no electrolyte disorders and no signs of dehydration. Three days later she reported black stools and she was admitted to our hospital for observation. There were no signs of gastro-intestinal bleeding, and she refused gastroscopy. The only biochemical abnormality was a mild elevation of the aminotransferases. Pregnancy and hepatitis were ruled out. She was discharged without a diagnosis. Six days later she came to the emergency department, complaining of persistent vomiting, abdominal pain and weight loss of 7 kilograms. She appeared to have a sinustachycardia of 134 bpm, rising to 150 bpm while standing with a blood pressure of 132 / 84 mmHg lying down and 125 / 80 while standing. At laboratory evaluation there were again no signs of dehydration. Her liver tests results had normalized. An attempt was made for X-ray examination of her stomach, but this was impossible due to vomiting. Four days later on her next visit to the outpatient clinic she sat in the waiting room with a bucket because of continuous vomiting. Her pulse rate was 100 bpm. The were no abnormalities on physical examination. Because of her earlier tachycardia, her thyroid function was tested. Her TSH level was , 0.01 mE / l, and her free thyroxine level was . 75 pmol / l (normal range 8–17). The serum aminotransferase levels had increased to 5 times normal. She was admitted under the diagnosis thyrotoxicosis and treated with a beta-blocking agent and a anti-thyroid agent (propylthiouracil). Within 24 hours the vomiting had stopped and she was free of complaints, even though the free thyroxine level was still 50,7 pmol / l after five days of treatment. Scintigrafy of the thyroid gland was compatible with the diagnosis m. Graves.

Conclusion: persistent vomiting can be a symptom of thyrotoxicosis, even when other ’classical’ symptoms are absent. 65. Addison’s disease, alopecia and myasthenia gravis: incomplete polyglandular autoimmune syndrome type 2. I. van der Lee, S. Wittebol, M.H.H. Kramer, Eemland Ziekenhuis, lokatie Lichtenberg, Postbus 1502, 3800 BM Amersfoort. Tel.: 033 4222345, fax: 033 -4222695, e-mail: M.Kramer@ zkh-eemland.nl Introduction: About half of the patients with Addison’s disease do exert other autoimmune phenomena. Case: A 58-year-old woman was admitted because of vomiting. Her medical history started in 1967 with the diagnosis of Addison’s disease, which was substituted with lifelong oral glucoand mineralocorticoids. In 1997 she developed alopecia areata, with almost complete baldness. She gave birth to two sons, and had regular menses until she was 46. Three months before admission she developed weakness of the ocular and bulbar muscles. An electromyography was suggestive of myasthenia gravis; acetylcholine-receptor antibodies were present. No thymus was seen with CT scanning. Myasthenia gravis was diagnosed, but the patient refused medication. The family history was negative for endocrinopathy or autoimmune disease. On admission, she presented with an adrenal crisis and worsening of the myasthenia gravis, due to vomiting. The clinical coarse was complicated by an aspiration pneumonia due to the progressive bulbar palsy, leading to respiratory failure, for which intubation and mechanical ventilation was necessary. Treatment with antibiotics, hydrocortisone and neostigmin intravenously was started, at which she responded well. Although the patient had abdominal complaints, no abnormalities were found with ultrasound of the abdomen, esophago-gastro-duodenoscopy and colonoscopy. Testing for antibodies against gliadin and parietal cells was negative. The patient was dismissed in good clinical condition. Other autoimmune diseases, especially thyroid disease and diabetes mellitus, were excluded. Discussion: This patient suffered from three autoimmune diseases: Addison’s disease, myasthenia gravis and alopecia. This led to the diagnosis of incomplete Polyglandular Autoimmune Syndrome (PGAS) type II. Adrenal insufficiency is the initial manifestation in about 50 percent of patients, occurs simultaneously with autoimmune thyroid disease or diabetes mellitus in about 20 percent, and follows them in about 30 percent. Alopecia and pernicious anaemia are much less frequent than in the type I syndrome. Other nonendocrine autoimmune disorders, such as myasthenia gravis (as in our patient), vitiligo, thrombocytopenic ¨ purpura, Sjogren’s syndrome, rheumatoid arthritis and primary antiphospholipid syndrome occur occasionally, as does serositis with pericardial and / or pleural involvement. Approximately onehalf of cases are familial, and several modes of inheritance (autosomal recessive, autosomal dominant, and polygenic) have been reported. Women are affected 1.8 times more often than men. The age of onset ranges from childhood to late adulthood, with most cases occurring between age 20 and 40 years. Conclusion: Patients with autoimmune adrenal insufficiency as part of one of the PGAS are predominately female (70%), and should be closely monitored for the development of subsequent autoimmune disorders.

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Internistendagen 2001 66. Severe hypokalemia possibly due to a mineralocorticoid effect with renal potassium loss. J.H.M. Groeneveld, E.J. Buurke, Westeinde Ziekenhuis, Lijnbaan 32, 2512 VA, Den Haag, Tel.: 070 -3302000, Fax: 070 -3807160, e-mail: groeneveld@ wanadoo.nl. A 69-year-old woman was admitted to the hospital for progressive muscle weakness, cramps and aching that started three months ago. She could hardly stand and was unable to walk. She had pitting edema, like her mother, since adolescence that did not decline, unlike her mothers’, after the menopause at the age of 38. Furosemide had had no effect on the edema. She was unmarried and childless. Her intake had decreased considerably due to a depression. She used large doses of laxatives for chronic constipation, but no other medication nor licorice. On examination, her blood pressure was 150 / 70, her pulse was 70, jugular venous pressure appeared normal, but pretibial edema was present. No pubic or axillary hair was found. There were no signs of Cushing’s syndrome. Reflexes were low and she was paretic. Laboratory findings yielded a potassium of 1.1 mmol / l, a metabolic alkalosis with a bicarbonate of 33.5 mmol / l, an elevated creatine kinase of 3642 U / l. Sodium and creatinine were normal. Two years ago potassium was 3.8 and nine months ago 3.1 mmol / l. The ECG revealed a first-degree AV block, U-waves and STsegment abnormalities. The severe hypokalemia clearly caused her symptoms. After one week of oral potassium supplementation (in total around 60 gram), it became 4.4 mmol / l. She could walk and the ECG turned to normal. The supplementation was stopped and potassium fell in two weeks to 2.8 mmol / l. Three gram potassium daily raised it to normal values. Further analysis revealed a renal potassium loss (38–50 mmol / day) with a suppressed plasma renin and aldosterone. Serum cortisol was normal, but 24-h excretion was slightly elevated (191 nmol / l), which could be suppressed by dexamethasone. Aldosterone excretion was very low. Computed Tomography revealed diffuse, moderately enlarged adrenals without an adenoma. Spironolactone 100 mg daily without supplementation raised potassium to 3.4 mmol / l. Her legs became smaller and she lost 4 kilogram. The effect of 200 mg Spironolactone and glucocorticoid treatment has yet to be evaluated. Further steroid analyses should confirm our suspicion of a late-onset congenital adrenal hyperplasia resulting in a mineralocorticoid effect causing the edema, potassium loss and metabolic alkalosis. The extremely low level of potassium on admittance has, to our knowledge, not been described before. This case illustrates that a slow decline of potassium results in a attenuated clinical picture and allows a slow, oral supplementation. 67. Clinical experience with Sandostatin LAR in patients with acromegaly. C. Heijckmann, P. Menheere, J. Sels, B. Wolffenbuttel, University Hospital Maastricht, P. Debijelaan 25, 6229 HX Maastricht, Tel.: 043 -3877019, e-mail: caroline@ heesen.net Introduction: Patients with acromegaly, who are not cured after transsphenoidal adenomectomy, may be treated with external irradiation and / or octreotide injections. Recently, a long-acting

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formulation of octreotide (Sandostatin LAR ) has become available in clinical practice. Aim of the study: To assess the effects of treatment with long-acting octreotide in patients with acromegaly, who had persistent signs and symptoms of acromegaly despite transsphenoidal surgery. Materials and Methods: 18 patients with acromegaly despite transsphenoidal surgery with (n 5 7) or without irradiation (n 5 11). Twelve of them were already treated with regular octreotide for a period of 0.5–8 years in dosages of 3 3 50 to 3 3 300 mcg s.c. (median daily dose 300 mcg). All patients started with i.m. injections of 20 mg Sandostatin LAR every 4 weeks. Results: In the patients who started treatment with octreotide for the first time, mean serum IGF-1 levels (measured by IRMA, Nichols Diagnostics) decreased from 6346229 to 255688 ng / ml after 3 months, 271681 ng / ml after 1 year and 263697 ng / ml after 2 years (all p , 0.05), while random GH levels (DELFIA, Wallac) decreased from 6.6 (range 3.1–67.0) to 2.1 (0.5–3.1) mU / l after 2 years ( p , 0.05). In the 12 patients already treated with octreotide, mean IGF-1 also fell, from 3676193 to 3316195 ng / ml ( p 5 0.023) after 3 months, to 3426191 ng / ml after 1 year and 2776169 ng / ml ( p 5 0.002) after 2 years, while random GH levels decreased from 4.5 (1.1–46) mU / l at baseline to 2.1 (0.4–23.0) after 2 years ( p 5 0.003). So, the average decrease of IGF-1 was 10% after 3 months and 25% after 2 years. One patient had a decrease less than 5% (but her IGF-1 was normal, 193 ng / ml), one patient showed no response to both regular and long-acting Sandostatin (avg. IGF-1 755 ng / ml). No specific side-effects occurred. One patient chose to return to t.i.d. injection of regular octreotide because of slight worsening of her headache despite normal IGF-1 levels, all other patients favored continuation of the monthly injections. In 6 patients the dose had to be increased to 30–40 mg monthly because of the fact the IGF-1 levels still remained elevated. Conclusion: Sandostatin LAR may be considered a great improvement for the treatment of patients with (symptomatic) acromegaly. 68. I.V. Pamidronate compared with alendronate for treatment of postmenopausal osteoporosis. C. Heijckmann, J. Juttmann, St. Elisabeth hospital, Hilvarenbeekseweg 60, 5022 GC Tilburg, Tel.: 013 -5392520, e-mail: caroline@ heesen.net Introduction: Osteoporosis is a major health problem in postmenopausal women. There are several therapeutic and preventive options in the treatment for it. One of the options is treatment with bisphosphonates. These are analogs of inorganic pyrophosphate and very potent inhibitors of osteoclast mediated bone resorption in vitro and vivo. The most potent aminobisphosphonates have an amino side chain. These so-called amino-bisphosphonates can be given orally or intravenously and are till now hardly compared with each other, regarding BMD and fracture incidence. Aim of the study: In this study we compared the results of 126 postmenopausal women treated with alendronate orally (n 5 60) or pamidronate intravenously (n 5 66) in our clinic. Materials and Methods: Women aged 41–81 with a low bone density were treated with 60 mg pamidronate i.v. / month or 10 mg

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alendronate orally / day. 126 patients were treated for at least one year, 106 for 2 years, 57 for 3 years and 21 for 4 years. Mean age at onset of therapy was 6669.5 in the pamidronate group, compared to 60611.0 in the alendronate group. Once a year BMD was checked by dexa measurement and X-rays of the thoracaland lumbar spine were taken. Results: We found that the mean T-score increased from 2 3.57 to 2 2.84 SD after 3 years of treatment in the pamidronate group. The alendronate treated patients showed an increase of the T-score from 2 2.72 to 2 2.45 SD during the same observation period. From 50 patients treated at least 3 years X-rays of the lumbal spine were analysed (25 in both groups). At baseline 9 patients (36%) had one or more vertebral fractures in the pamidronate group compared to 7 patients (28%) in the alendronate group. After 3 years of treatment only 3 women in the pamidronate group and 2 in the alendronate group showed a deterioration of one or more vertebral fractures. In both groups there were no new fractures. Conclusion: We conclude that i.v. pamidronate is as good as alendronate orally in the treatment of postmenopausal women with osteoporosis, with regard to improvement of bone mineral density of the lumbar spine. No striking difference in fracture incidence was noticed between the two groups before and during treatment. Pamidronate i.v. is well tolerated, easy to administer and cheap. So It seems to be a good alternative for the more widely used oral bisphosphonates, certainly in those patients who devellop gastrointestinal complaints. 69. Asymptomatic hyperprolactinaemia. A. Kotsopoulos, H. de Boer, R. van Leusen, Rijnstate Hospital Arnhem, P.O. Box 9555, 6800 TA Arnhem, fax: 026 -3787878, e-mail: h.debeer@ planet.nl A 34 year old woman from Sudan was evaluated because of a frontal headache and possible diplopia of the right eye without loss of vision. She had a history of hyperprolactinemia diagnosed 4 years ago in Egypt and treated with bromocriptin for two months.The menses has always been regular and she never had galactorrhea. She had two healthy children. No medication where used. No abnormalities where found on physical examination except of obesitas (Quetelet index of 31.8). Laboratory tests revealed elevated serum prolactin levels 5464 mu / l (reference range 80–150 mu / l) with normal levels of TSH, free T4, LH, FSH, oestradiol, progesteron, cortisol and ACTH. Biochemical evidence of ovulation where obtained, serum progesteron ranged from 1.9 to 45.5 nmol / l during the menstrual cyclus. Subsequently chromatography preformed to screen for macroprolactinaemia. Serum prolactin consisted of 78.6% BIG-BIG prolactin (bbPRL), 17.5% BIG prolactin (bPRL) and 3.9% monometric prolactin (mPRL). Normally the major form is mPRL (85–95%) with less than 1% bbPRL [1]. Several cases of asymptomatic hyperprolactinaemia have been reported [2,3]. bbPRL is believed to be a complex of prolactin and IgG anti-prolactin antibody. Its clinical significance is incompletely understood. References [1] Okulonga A et al.: Macroprolactinaemia: validation and application of the polyethelene glucol precipitation test and

clinical cahracterization of the condition. Clin Endocrinol. 1999 Jul;51(1):119–26. [2] Larrea F et al.: Further evidence that big big prolactin is preferentially secreted in women with hyperprolactinaemia and normal ovarian function. Fertility and Sterility 1985;44:25–30. [3] Fraser I et al.: Detailed assessment of big big prolactin in women with hyperprolacitnaemia and normal ovarian function. J Clin Endocrin and Metab. 1989;69:585–92. 70. Reversible adrenocorticotropin deficiency due to autoimmune lymphocytic hypophysitis in a young woman. P.W. Kamphuisen, H.A.H. Kaasjager. Dept. of Internal Medicine, Rijnstate Hospital, Arnhem, The Netherlands. Address: Dept. Internal Medicine, Rijnstate Hospital, P.O. Box 9555, 6800 TA, Arnhem, e-mail: pkamphuisen@ rijnstate.nl Introduction: Lymphocytic hypophysitis is an inflammatory disorder of unknown etiology that occurs mainly in women during late pregnancy and the post-partum period. It is associated with Hashimoto’s thyroiditis, which suggests an autoimmune pathogenesis. The clinical presentation is variable depending on the degree of pituitary destruction. We present a young woman with severe hypotension, lethargy, and ventricular tachycardia, caused by lymphocytic hypophysitis. Case: A 34-year-old woman delivered her second child after an uneventful pregnancy and delivery. Three weeks later she had complaints of progressive fatigue and anorexia resulting in a 18 kg weight loss. At this time she had a raised FT4 level (34.3 pmol / l, N 11–25) and undetectable TSH ( , 0.01 mU / l, N 0.2–3.0). TPO antibodies were not measured. The hyperthyroidism resolved without treatment two months later (FT4 5.4 pmol / l, TSH 0.15 mU / l). Six weeks later the patient was hospitalized with hypotension and lethargy. Shortly after, ventricular tachycardia developed, which was terminated with electrical cardioversion. After this she was transferred to our hospital. Physical examination disclosed an apathetic and anorectic young woman. Blood pressure was 69 / 47 mmHg, pulse rate 94 bpm, respirations 15 / min, and temperature 38.28C. The thyroid gland was not enlarged, and neurologic examination showed no specific abnormalities. The remaining examination was normal. Initial laboratory evaluation demonstrated mild normocytic anemia of 6.0 mmol / l. Sodium level was 136 mmol / l, potassium 3.5 mmol /, creatinine 133 mmol / l, creatinine phosphokinase 204 U / l, glucose 4.1 mmol / l, and lactate 0.7 mmol / l. Further assessment showed secondary adrenal insufficiency by the finding of low cortisol (0.13 mmol / l, N 0.08–0.6) and ACTH ( , 10 ng / l, N 10–60) levels in an afternoon sample. Treatment with hydrocortisone was started, and the patient improved markedly. After improvement she declared that breastfeeding was not possible and that her menstrual cycle had not resumed yet. Further studies of the pituitary gland revealed secondary hypothyroidism (FT4 3.0, TSH 2.68, antithyroid antibodies negative), undetectable prolactin level ( , 10 mU / l, N 80–160), low growth hormone level (1 mU / l, N 0–26), and normal LH and FSH concentrations. Hydrocortisone doses were gradually tapered and levothyroxine 75 mg / day was started. One week later, diabetes insipidus was diagnosed, which was treated with desmopressine 100 mg td. Magnetic resonance scan

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Internistendagen 2001 (MRI) showed no pituitary enlargement and a normal pituitary stalk. Further course of the patient was uneventful. Discussion: Symptoms and laboratory values in this young woman are compatible with anterior (ACTH, TSH, GH) and posterior (diabetes insipidus) pituitary gland insuffiency. This case report illustrates that prompt recognition of this potentially fatal condition is important because of the availability of lifesaving treatment. 71. Bone mineral density in patients with inflammatory bowel disease; role of age, gender, disease duration, corticosteroids and immunosuppressive drugs. J.G. Oudenaarden, K.I.M. Kloppenborg, H.E. van der Wiel, G. Geldof. Departments of internal medicine and gastro-enterology, IJsselland Hospital Capelle a /d IJssel. P.O. Box 690. 2906 ZC Capeele a /d IJssel, Tel.: 010 2585165, fax: 010 -4586261, e-mail: kimklop@ hotmail.com Introduction: Patients with inflammatory bowel disease are at risk for developing osteoporosis. We performed a retrospective analysis of bone mineral density measurements in patients with inflammatory bowel disease, to elucidate whether there are specific risk factors for a decreased bone mineral density. Aim of the study: To assess the prevalence and risk factors for a decreased bone mineral density in patients with inflammatory bowel disease. Materials and Methods: We studied 76 consecutive patients with inflammatory bowel disease who had obtained a measurement of the bone mineral density. Data collected include sex, age, disease diagnosis, location and duration, nutritional status, operations, current and past use of corticosteroids, immunosuppressive drugs, salazopurines, vitamin D supplements, calcium supplements, the level of serum calcium, serum hydroxy-vitamin D and measurements of bone mineral density of the lumbar spine, the femoral neck and the femoral trochanter. The values of the BMD were expressed as a score of the mean of the normal values ( 5 Z score) for age and sex. Results are expressed as mean6SD. Results: Mean age6SD: 41.8615.4 years. Twenty-nine patients were male, 47 were females. Thirty patients had Crohn’s disease, 46 patients had ulcerative colitis. Thirty-one patients (41%) had a low BMD, defined as BMD with a Z score , 2 1 at least one region. Eighteen out of 29 males (62%) and 13 out of 47 (28%) females had a low BMD. The mean Z score of lumbar spine was significantly lower in male patients. The difference in BMD values between males and females were persistent in corresponding age groups. Among males significant more patients had colitis ulcerosa and a decreased 25-hydroxy vitamin D level during the course of disease. BMD of the lumbar spine was significantly lower in patients who had used oral corticosteroids. The mean Z score of the femoral trochanter was significantly lower in Crohn’s disease in comparison with ulcerative colitis. Conclusion: We conclude that men with inflammatory bowel disease are more at risk for a low bone mineral density than women. Patients using corticosteroids and patients using immunosuppressive drugs are more at risk for a decreased BMD. 72. Papillary carcinoma in struma ovarii. S. Festen, M.J. Boeree, R. Naudin ten Cate, T. van der Heyden, Th.F. Veneman. Department of Internal Medicine, Twenteborg Hospital, PO Box

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7600, 7600 SZ Almelo, The Netherlands. Tel.: 0546 -833333; Fax: 0546 -833418; e-mail: t.veneman@ twenteborg.nl Struma ovarii is defined as a teratoma of the ovary, totally or predominantly composed of thyroid tissue.Twenty percent of ovarian tumors are of germ cell origin, and 95% of these are cystic teratomas. Approximately 2.5% of cystic teratomas are struma ovarii. Thus, malignant struma ovarii is a rare form of ovarian cancer, and in particular the papillary form has only been described 4 times in the literature. A 51-year old female was admitted to our hospital because of severe chronic obstructive pulmonary disease. Several years earlier she had had an episode of postmenopausal vaginal blood loss, which reoccurred during her present admission. Physical examination revealed a palpable mass in the right lower abdomen. Laboratory evaluation showed ESR 15 mm / hr, leucocytes 10.2 3 e9 / l, TSH 0.01 mU / l, T3 1.9 nmol / l, fT4 11 pmol / l. A TRH-test appeared to be normal.Transvaginal ultrasound showed a normal uterus, and a mass in the left-lower posterior abdomen, originating from the left adnex. In the abdomen a small amout of ascites was detected. CT-scan showed a large multicystic lobed nodular process in the small pelvis, originating from the left adnex. A number of small lymphnodes were seen locally and para-aortal. Through laparotomy, bilateral ovariectomy was performed. The right ovary was enlarged with a nodular surface. Pathological examination revealed papillary thyroid carcinoma. Conclusion: The papillary form of malignant struma ovarii is exceptionally rare. There were no signs of hyperthyroidism, which is in accordance to the literature. Due to its rarity, there has been controversy about diagnosis and therapy. The diagnosis can be made if invasion or metastases can be detected, papillary type of tumor morphology, including immunohistochemical presence of thyroglobulin can be demonstrated, and ovarian stromal carcinoid as well as a primary thyroid tumor can both be excluded. Malignant struma ovarii seldom metastasizes, whereby the mode of spread is comparable to that of ovarian cancer. Surgery as well as radioactive iodine have been described as effective modes of therapy. In young patients with no metastases the former mode of therapy is preferred. 73. A patient with Sheehan’s syndrome diagnosed five years after severe postpartum bleeding. J.M. van der Klooster 1 , L.J.D.M. Schelfhout 1 , Afdeling Interne Geneeskunde, Medisch Centrum Rijnmond-Zuid 1 , Olympiaweg 350, 3078 HT Rotterdam, Tel.: 010 -2911911, Fax: 010 -2911083, e-mail: jmvanderklooster@ planet.nl Sheehan’s syndrome is defined as postpartum infarction of the pituitary gland following hypotension and shock due to obstetric haemorrhage. The enlarged pituitary gland of pregnancy may be more vulnerable to vasospasm and ischaemia. The extent of the pituitary necrosis will eventually determine the time of presentation and degree of hypopituitarism. Besides signs of hypothyroidism and adrenal insufficiency, Sheehan’s syndrome typically presents with failure to lactate postpartum and failure to menstruate subsequently. However, if hysterectomy has been performed for postpartum haemorrhage and hypovolaemic shock, these latter clinical symptoms may be easily overlooked.

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A 42-year-old woman was referred because of fatigue, apathy, anorexia and weight loss. She also complained of depressive thoughts, gradual loss of pubic hair and libido. Five years before, she was hospitalised for severe postpartum haemorrhage and hypovolaemic shock due to retention of the placenta, for which resection of the uterus was performed. Her medical history further consisted of hypothyroidism since one year, which was thought to be primary in origin and treated accordingly in an adjoining hospital. However, replacement therapy with thyroid hormone had not abolished her complaints. Recently, she had been treated for pneumonia by her general practitioner. Physical examination showed a woman in a malnourished condition (L: 1.51 m, W: 35 kg), with a blood pressure of 90 / 60 mm Hg and pulse rate 60 beats per minute. Loss of axillary and pubic hair and a ‘monkey-face’ appearance were noted. Laboratory examinations showed no abnormalities except for hypocortisolism (both spontaneous and after ACTH stimulation). Autoantibodies against thyroid and adrenal tissue were absent. Since panhypopituitarism was suspected, stimulation tests with the hypothalamic releasing hormones were performed (CRH, TRH, GHRH and GnRH). These showed blunted responses of ACTH, TSH, GH, LH, FSH and PRL release, thus proving the diagnosis of panhypopituitarism. The definitive diagnosis of Sheehan’s syndrome was confirmed after MRI of the brain, which showed a so-called ‘empty sella’ or complete pituitary necrosis. Treatment consisted of replacement therapy with hydrocortisone, thyroxin and estrogens. She recovered completely within several weeks. In women with signs of hypothyroidism or adrenal insufficiency, taking an accurate obstetric history is essential. Since failure to lactate and menstruate postpartum are easily overlooked, especially after hysterectomy, these symptoms should be actively asked for in order to establish the diagnosis of Sheehan’s syndrome.

IV. Diabetes mellitus 74. Impaired cardiovascular autonomic function in diabetic patients with neuropathy is related to an elevated urinary albumin excretion. J.D. Lefrandt 1 , E. Bosma 1,2 , J.H. van der Hoeven 3 , A.M. van Roon 1 , R.P.F. Dullaart 2 , R.O.B. Gans 1 , A.J. Smit 1 , K. Hoogenberg 2 , University Hospital Groningen, Depts. of General Internal Medicine 1 , Endocrinology 2 and Neurology 3 , Hanzeplein 1, 9713 GZ Groningen, The Netherlands. Tel 1 31503611369, Fax 1 31503619687, e-mail: jdlef@ knmg.nl Introduction: Foot ulceration in diabetic patients is associated with a high mortality. Distal peripheral neuropathy (DPN) and vascular disease play are important etiological factors. Elevated urinary albumin excretion (UAE), as a marker of widespread microvascular alterations, is highly prevalent in these patients. Accompanying cardiovascular autonomic neuropathy (CAN) may contribute to the high mortality rate. Power spectral analysis of heart rate variability (HRV) and measurement of baroreflex sensitivity (BRS) are advanced measures of CAN. Aim of the study: The primary aim was to assess whether HRV and BRS measurements are abnormal in diabetic patients carefully

selected for the presence of overt DPN. Furthermore, we evaluated whether an elevated UAE affects the association between neuropathy and cardiovascular autonomic function. Materials and Methods: Diabetic patients with DPN (DN, n 5 18) and without DPN (DC, n 5 18) and healthy controls (C, n 5 18) were matched for sex and age. Cardiac and peripheral arterial occlusive disease was excluded. (Cross-) spectral analysis was performed on 300 seconds heart rate (ECG) and blood pressure (Finapres) registrations to calculate HRV and BRS. Results: HRV (total power) was lower in DN (7.160.3 [mean6SEM]) compared to DC (8.960.3) and C (9.360.3 ln(ms 2 ), p , 0.001 for both). BRS was similarly impaired in DN (3.060.7) compared to DC (6.060.6) and C (6.761.1 ms / mmHg, p , 0.01 for both). The lower HRV and BRS in DN were limited to those patients who had concomitant elevated urinary albumin excretion (UAE) (HRV, 6.260.4 ln(ms 2 ) and BRS, 1.760.6 ms / mmHg, n 5 9) vs. normal UAE (HRV 8.060.4 ln(ms 2 ) and BRS 5.261.1 ms / mmHg, n 5 9, p , 0.01 for both). In a multivariate analysis, an elevated UAE was the main determinant of a lower HRV and BRS. Conclusion: HRV and BRS are impaired in diabetic patients with DPN if UAE is elevated. We propose the concept that abnormal cardiovascular autonomic function in diabetic patients with DPN is likely an expression of microvascular alterations rather than of neuropathy per se. 75. Increased capillary permeability and loss of sympathetic control of skin blood flow in diabetic patients with neuropathic foot ulceration. J.D. Lefrandt 1 , E. Bosma 1,2 , P.H.N. Oomen 1 , A.J. Smit 1 , K. Hoogenberg 2 , University Hospital Groningen, Depts. of General Internal Medicine 1 , Endocrinology 2 , Hanzeplein 1, 9713 GZ Groningen, The Netherlands. Tel 1 31503611369, Fax 1 31503619687, e-mail: jdlef@ knmg.nl Introduction: Structural and functional vascular abnormalities contribute to the development of neuropathic foot ulceration. Sodium fluorescence (NaF) leakage is a measure of capillary permeability. Aim of the study: To evaluate whether capillary permeability is increased in diabetic patients with peripheral neuropathy (NP). Materials and Methods: 18 diabetic patients with a history of neuropathic foot ulceration (NP 1 , age 5863 year), 20 diabetic patients without neuropathy (NP-, age 5262 year) and 16 healthy controls (C, age 6062 year) were measured. Arterial occlusive disease was excluded by ankle-arm indices, toe pressures and plethysmography. NaF leakage after a bolus injection was assessed by videodensidometry (large window method). NP was quantified by neurography. Spectral analysis of skin blood flow variability at the ankle (Laser Doppler) was measured in the 0.02–0.15 Hz frequency band (LF-BFV) represented vascular sympathetic function. Microalbuminuria (MA) was used a an indicator of microvascular damage. Skewed variables were log transformed for statistical analysis. Data as mean6SEM. Results: NaF leakage was increased (relative fluorescence intensity after 1 minute of 3365% (NP 1 ) vs. 1963% (NP-) and 1662% (C), t-test: p , 0.01 for both) and LF-BFV was diminished (5664 normalized units (NP 1 ) vs. 7664 (NP-) and 7764 (C), t-test: p , 0.001 for both) in the NP 1 group compared

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Internistendagen 2001 to NP- and C. NaF leakage was strongly related to LF-BPV (Peason’s r 5 2 0.53, p , 0.001). Linear regression showed that only LF-BFV independently contributed to the variance in NaF leakage, with no significant contributions of age, sex, blood pressure, diabetes duration, Hba1c and microalbuminuria. Conclusion: Capillary leakage is increased in diabetic patients with neuropathic foot ulceration. This abnormality may result from abnormal sympathetic control of skin vessels. 76. Treating hypertension in patients with type 2 diabetes mellitus in a specialist’s practice. A. Schrivers, J. Lambert, R. van Marwijk Kooy, Isala Klinieken locatie Sophia Ziekenhuis, Address: Dr van Heesweg 2 8025 AB Zwolle, Tel.: 038 -4247432, e-mail: schriver@ sophia.nl Introduction: Hypertension, which is highly prevalent in patients with type 2 diabetes mellitus (DM2), increases the already high risk of cardiovascular mortality and morbidity. Many studies have shown that tight bloodpressure control reduces cardiovascular complications. However, studies in the primary care setting, show that the goals for bloodpressure published in the new Dutch guidelines for family practice, are difficult to achieve. There are no studies that have focused on the specialist’s practice. Aim of the study: We determined whether the goals for adequate bloodpressure control according to Dutch guidelines (NHG), are met by the specialist. Materials and Methods: Between November 1999 and May 2000 we retrospectively examined the files of 508 patients with DM2, who visited the out-patient-clinic of two internists on a regular basis, for bloodpressure levels. According to the NHG guidelines target bloodpressure, was defined as a bloodpressure 5 150 / 85 mmHg in patients older than 50 years and in patients younger than 50 years with normo-albuminuria. In patients younger than 50 years with signs of diabetic nefropathy the target bloodpressure level was defined as 5 140 / 80 mmHg. Results: Information about the bloodpressure level was lacking in 65 of the 508 patients, they were excluded from further evaluation. Of the remaining 443 patients, 38.1% were men and 61.9% women. They had an average age of 66 years (range 28–99), an average BMI of 31.0 kg / m 2 and an average duration of diabetes of 12 years (range 1–49). The average HbA1c was 8.0%, 89.6% of the patients were using insulin. 150 patients (33.9%) had macrovascular complications. The average systolic bloodpressure level was 153.5 mmHg (SD 22.0), average diastolic bloodpressure level was 78.4 mmHg (SD 11.1). Fifty-two patients (11.7%) were normotensive. Fifteen patients were younger than 50 years and had signs of diabetic nefropathy (micro-or macroalbuminuria), 7 reached their target bloodpressure ( 5 140 / 80 mmHg), 10 used an ACE-inhibitor. The average bloodpressure of the remaining 376 patients was 156.8 / 78.8 mmHg (SD 21.5 / 11,.). The number of patients, in which the target bloodpressure of 150 / 85 mmHg was met, was 137 (36.4%). 44% of them used 3 or more anti-hypertensive prescriptions. Diuretics and ACE-inhibitors were the most prescribed drugs. Conclusion: Tight bloodpressure-control is achieved in 44.2% of the patients in the specialist’s practice. The mean bloodpressure level seems to be comparable with bloodpressure levels in the primary care setting.

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77. The long term effect of continuous subcutaneous insulin infusion on metabolic control in type 1 and type 2 diabetes. A.A.M. Zandbergen, R.J.Th. Ouwendijk, M.G.A. Baggen. Dept of Internal Medicine, Ikazia Hospital, Montessoriweg 1, 3083 AN Rotterdam, Tel.: 010 -2975000, Fax: 010 -4859959, e-mail: ikazint@ knmg.nl Introduction and aim of the study: So far continuous subcutaneous insulin infusion (CSII) therapy is mainly used in type 1 diabetes mellitus, and much less in type 2. Now that large prospective trials have shown that improvement of metabolic control reduces complications in type 1 (DCCT) as well as in type 2 diabetics (UKPDS), long term normoglycaemia should be a major treatment goal in both groups. We studied the role of CSII in this. Materials and Methods: A retrospective analysis was performed of all diabetics who started with CSII therapy in the period of 1995 to 1999 in our hospital. The statistical method used was the paired t test. Results: 40 patients were studied: 23 with type 1 diabetes (age 3267 years; diabetes duration 1869 years) and 17 with type 2 diabetes (age 47610 years; diabetes duration 1167 years). The average CSII treatment was 32 months (range 12–58) in the type 1 group, and 33 months (range 13–62) in the type 2 group. Before CSII was started all 40 patients were on intensified convential insulin therapy by multiple daily injection. The indications for switching to insulin pump therapy were poor glycemic control, often severe hypoglycemic events and uncontrollable fluctuations in blood glucoses. In the type 1 group HbA1c dropped from 9.260.4% 1 year prior to CSII to 7.960.2% ( p , 0.0001) after 1 year of CSII; after 3 years of CSII it still was 7.960.2% ( p 5 0.002). In the type 2 group HbA1c 1 year prior to CSII was 9.160.4% and decreased to 8.360.3% ( p 5 0.0009) after 1 year of CSII therapy. 3 years after CSII HbA1c was 8.060.3% ( p 5 0.03). No significant changes were found in the serum lipid profiles of both groups. None of the 40 patients stopped with the pump therapy during follow-up, and all experienced lifestyle benefits. Mean number of hospitalizations dropped from 0.5 / patient in the year prior to CSII to 0.08 / patient in the second year of CSII ( p 5 0.003). Conclusions: CSII improves long-term metabolic control and therapeutic satisfaction in patients with both type 1 and type 2 diabetes mellitus, who are on multiple daily insulin injection regime. 78. Additional basal insulin during lispro intensive therapy in a randomised multicentre crossover study. A.M.E. Stades 1 , J.B.L. Hoekstra 1 , I. van der Tweel 2 , C. van Bolhuis 3 , D.W. Erkelens 4 , F. Holleman 1 , STABILITY investigators group. Diakonessenhuis Utrecht 1 , Centre of Biostatistics 2 , Eli Lilly Nederland B.V.3 , University Medical Centre Utrecht 4 . Bosboomstraat 1, 3582 KE Utrecht, Tel.: 030 -2566566, Fax: 030 -2566606, e-mail: astades@ diakhuis.nl Introduction: In an intensive regimen with rapid-acting insulin lispro and once daily basal insulin at night, the waning basal insulinemia might cause increased predinner and evening glucose values. This study was performed to evaluate the glycemic control of patients with type 1 diabetes on insulin lispro intensive therapy with an additional lunchtime dose of basal insulin.

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Methods: The study was an 8-month randomised multicenter crossover trial. After a 2-month run-in period, subjects injected NPH insulin once (1 3 NPH) or twice (2 3 NPH) daily for 4 months in a randomised order. Patients were included if they had HbA1c-levels , 8.5%, and had used insulin lispro intensive therapy for . 3 months. Efficacy measures were HbA1c levels, 8-point glucose profiles, and hypoglycaemic events. The statistical analysis included a within-patient comparison for crossover trials. Results: Of 121 randomised patients 104 patients finished the trial. Three out of 17 subjects dropped out because of increased mild hypoglycaemia. The mean HbA1c levels during 1 3 NPH and 2 3 NPH were 7.2% (sd 5 0.94) and 7.1% (sd 5 0.93), respectively. The within-patient differences in HbA1c levels did not differ significantly (T-test, mean difference 5 0.07%, p 5 0.30, 95%CI 5 2 0.063–0.20). The predinner and 2-hours postdinner blood glucose values were significantly lower during 2 3 NPH, with a mean difference of 0.78 mM (T-test, p 5 0.003, 95%CI 5 0.28–1.3) and 0.64 mM (T-test, p 5 0.027, 95%CI 5 0.1–1.2), respectively. In the evening hours (18.00–24.00 hours), the frequency of mild and severe hypoglycemia increased significantly during 2 3 NPH with a median difference of 0.55 episodes / 30 days (range –3.4–5.5, Wilcoxon signed rank test, p 5 0.002) and of 6.6 episodes / patient year (range 2 6.9–26.0, Wilcoxon signed rank test, p 5 0.033), respectively. Conclusion: Equal HbA1c levels and increasing frequencies of hypoglycemia in the evening overshadow the slight improvement of the evening glucose profiles during a regimen with twice daily NPH insulin. Generalised use of an additional lunchtime injection of NPH insulin cannot be recommended to patients with type 1 diabetes using intensive insulin lispro therapy.

V. Haematology 79. Atypical presentation of non-Hodgkin lymphoma in a patient with rheumatoid arthritis, treated with anti-TNF-a. R.J.H. Koppers 1 , R.A. de Vries 1 , J.W.R. Meijer 2 , J.J. Mol 1 , C. Richter 1 . Depts of Internal Medicine 1 and Pathology 2 , Rijnstate Hospital, Arnhem, Tel.: 026 3786735, Fax: 026 3786737, e-mail: rdevries@ rijnstate.nl Introduction: Development of non-Hodgkin lymphoma (NHL) has been associated with (previous) anti-TNF-a therapy. The following case illustrates a remarkable presentation of NHL, in a patient treated with anti-TNF-a. Case: A 58 year old woman was admitted to our hospital because of fever, diarrhoea, desquamation of the skin and loss of hair. Medical history revealed seronegative rheumatoid arthritis, resistant to conventional therapy. She was treated with iv. antiTNF-a once a month since two years. During stay in hospital the diarrhoea resolved spontaneously. Further investigations (lab, cultures of urine and feces, ultrasound, and endoscopy) were normal, except blood culture which showed growth of staphylococcus aureus and treatment with flucloxacilline was started. After clinical improvement she was discharged. Two weeks later she was re-admitted with high fever, progressive desquamation of the skin, total baldness and an enlarged

lymph node in the right axilla. Laboratory tests: ESR 125 mm / h and Hb 6.0 mmol / l, otherwise no abnormalities. Viral serology and auto-immune factors were negative. Bon-marrow aspirate was normal. Repeated ultrasound revealed enlarged abdominal lymph nodes. Skin biopsy demonstrated chronic dermatitis. Excision biopsy of the axillar node showed histiocytic reactions and stimulation of T-cells, no lymphoma. Again staphylococcus aureus was found in blood cultures, and she was treated with flucloxacilline. At the beginning, improvement was seen, fever disappeared and there was regression of abdominal lymph nodes. However in the following weeks the patient deteriorated again and repeated ultrasound demonstrated enlarging abdominal lymph nodes. Diagnostic laparotomy was performed and histopathological examination of para-iliacal lymph nodes showed localisation of highly malignant, large-cell anaplastic lymphoma. Polychemotherapy was started. Discussion: The association of anti-TNF-a therapy and occurrence of NHL, with atypical presentation, in our patient is remarkable and noteworthy. Causal relationship, although not proven, is a real possibility. 80. Splenic rupture as presenting syndrome in a patient with idiopathic hypereosinophilic syndrome. M.J.J.H. Grootenboers, M.M.C. Hovens, Stijnen P.J., Department of Internal Medicine, Amphia hospital location Langendijk, Breda, The Netherlands Introduction: The idiopathic hypereosinophilic syndrome (IHS) is a leukoproliferative disorder characterized by overproduction of eosionophils, leading to eosinophilia and organ dysfunction. Organs most frequently involved are heart, lungs and the neurological system. We present a case in which a spontaneous splenic rupture was the first symptom of IHS. Case: A 63 year old male patient was admitted to the hospital because of sudden onset of shortness of breath and left-sided chest pains. Medical history was unremarkable. On physical examination, a mildly ill patient was noted with local tenderness of the left hemithorax and epigastrium. Laboratory data disclosed a leukocyte count of 10.4 3 10 9 with 17% eosinophils. Blood gas analysis showed a hypoxia with hypercapnia. Chest x-ray, electrocardiography and a compression ultrasound examination of the lower extremities did not point towards a specific diagnosis. The tentative diagnosis of pulmonary embolism was made and intravenous heparine was started. Over the next few hours, the patient developed severe abdominal pain and became hemodynamically unstable. Ultrasound imaging of the abdomen revealed free fluid and splenic rupture. A splenectomy was performed. Histopathologic examination of the ruptured spleen showed extensive infiltration of eosinophilic cells. The patient underwent further investigations. He had no history of asthma, allergies or parasitic infections. Stool cultures and examination for ova and parasites were negative. IgE level was normal. Screening for autoimmune antibodies was negative. A bone marrow biopsy was performed, showing normal hematopoiesis and an absolute rise of eosinophilic granulocytes (15%). Subtyping of lymfocytes was performed, showing no signs of leukemia or lymphoma. Echocardiography was normal. Because of persistent hypereosinophilia, exclusion of other causes of hypereosinophilia

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Internistendagen 2001 and clear prove of organ involvement, the diagnosis of idiopathic hypereosinophilic syndrome was made. After splenectomy, no other signs of organ dysfunction were found and the eosinophilia persisted. Clinically the patient was in perfect health. We decided ¨ treatment. therefore upon withholding steroıd Conclusion: IHS is defined according to three criteria: presence of blood eosinophilia for more than three months, exclusion of known causes of eosinophilia and evidence of organ dysfunction. Our patient illustrates a case of IHS presenting by a spontaneous rupture of the spleen. To our knowledge, this has been described only once before. 81. Occurrence of low grade Non Hodgkin lymphoma following Filgrastim therapy; a coincident? H.K.A. Knaapen, J.J. Mol, R. van Leusen, Rijnstate Hospital, P.O. Box 9555, 6800 TA Arnhem, The Netherlands, Tel.: 026 3786735, Fax: 026 3786737, e-mail: rvanleusen@ rijnstate.nl. Introduction: Filgrastim is a granulocyte colony stimulating factor (G-CSF) used to reduce neutropenia caused by chemotherapy or HIV-infection. Nowadays it is increasingly used to treat chronic idiopathic neutropenia. In this situation Filgrastim may be in use for many years which offers the possibility of unexpected longterm side effects. Case history: a 64-year-old man known with idiopathic neutropenia for 20 years presented himself with two pathologically enlarged inguinal lymph nodes. Ten months before presentation of the enlarged lymph nodes, Filgrastim therapy was started because of recurrent bacterial infections. Before therapy was started there where no signs of active malignant lymphoma e.g. anamnestic no complaints, no palpable lymph nodes, normal lactic dehydrogenase. Leukocyte count showed 1.5 3 10 9 / l with 10% neutrophils. Therapy was started with a weekly dose of 300 mg Filgrastim. There was a significant rise in leukocyte count to 5.2 3 10 9 / l with 73% neutrophils. Eventually after 8 month the dose was changed to 300 mg Filgrastim 2 times a week because of gradual decreasing leukocyte count. Ten months after starting therapy we discovered two pathologically enlarged inguinal lymph nodes during outclinic examination. Laboratory investigation at that point showed normal haemoglobin, leukocyte count, platelet count, electrolytes, kreatinine and liver function tests, including lactic dehydrogenase. Excision biopsy revealed a follicular center non Hodgkin lymphoma grade 1. CT scanning of chest and abdomen showed no other localisation. A bone marrow biopsy showed no signs of malignant invasion. Filgrastim therapy was stopped and the patient was treated with radiation therapy followed by significant reduction of the tumour localisation. Conclusion: Filgrastim is a hematopoietic cytokine, produced by recombinant DNA-technology. It is supposed to stimulate the proliferation, differentiation and activation of cells of the granulocyte lineage only. It also stimulates migration of pluripotential stem cells. A direct relation with the development of lymphoid malignancies seems to be unlikely. However in vitro G-CSF can promote the growth of some non-myeloid malignant cell lines. There are no published cases of the occurrence of Non Hodgkin lymfoma during or after therapy with G-CSF until now. This case

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report asks attention for a relation, maybe more than coincidental, between G-CSF and the development of malignant lymfoma. 82. Intravascular hemolysis by IgA red cell autoantibodies. 1 2 3 E.A.M. Beckers , C. van Guldener , M.A.M. Overbeeke , D.J. 1 1 van Rhenen . Bloodbank Rotterdam, Wytemaweg 10 3015 CN 2 Rotterdam, 010 -4263600, erik.beckers@ bloodrtd.nl; Department 3 of Internal Medicine, VU Medical Centre Amsterdam; CLB, Amsterdam. Introduction: Autoimmune hemolytic anemia (AIHA) is categorized as warm, cold or combined AIHA, according to the nature of the autoantibodies. The direct antiglobulin test (DAT) is essential in the diagnosis of AIHA. Immunoglobulin type IgG is detected in most cases of warm AIHA. Hemolysis in AIHA occurs mainly via extravascular mechanisms. We report a rare case of severe intravascular hemolysis of IgA-only sensitized red cells. Case report: A 66-year-old male was presented with a 6-weekshistory of progressive dyspnoe, after an influenza-like disease. A color change of his urine from normal to dark brown occurred in the last 2 weeks. He appeared pale and icteric. Apart from tachycardia (110 / min) and a systolic ejection murmur, physical examination was normal. Laboratory results: Hb 2.9 mmol / l, MCV 131 fl, bilirubin 103 mmol / l, 85% unconjugated, haptoglobin , 0.6 g / l, LD 4480 U / l. Reticulocytosis (550‰), erythroblastosis and sferocytosis were present. Macroscopically the serum appeared hemolytic. The patient had blood group type O, Rhesusphenotype CCDee (R1R1). The DAT was negative using the Diamed gel method. Aspecific agglutination reactions were observed in the serum. Because free circulating antibodies were not detected by the indirect antiglobulin test with anti-IgG and antiC3d using the bovine-albumin and polyethyleenglycol technique, these aspecific reactions were mistakenly considered to be caused by cold autoantibodies. The patient was transfused with multiple standard red cell concentrations. Because of ongoing hemolysis additional tests were performed at the CLB. The DAT test was negative with anti-IgG, anti-IgM and anti-complement reagents antiC3d and antiC3c. It appeared strongly positive with monospecific anti-IgA. IgA-autoantibodies with anti-e specificity as well as aspecific IgA-autoantibodies were isolated from the eluate and were present in the serum. The presence of IgA autoantibodies was detected by the indirect antiglobulin test with anti-IgA. The patient was transfused with multiple e-negative typed red cells and treated with high dose prednison (60 mg / day), which was stopped after three months. Two years after the diagnosis there are no signs of recurrent hemolysis. Discussion: Intravascular hemolysis requires complement activation and is rare in warm AIHA. IgA-coated red cells are hemolysed by adherence to Fc receptors of phagocytic cells, which occurs mainly in the spleen. Intravascular hemolysis of IgA-only sensitized red cells may be attributed to ‘reactive lysis’, involving C3-independent binding of C5b-9 complexes to bystander cells. The pathophysiologic mechanism of ‘reactive lysis’ offers the best explanation of the severe hemolysis in our patient. This case reports supports the recommendation that monospecific anti-IgA, in addition to polyspecific anti-human sera, anti-IgM or anti-C3, should be used for the diagnosis of autoimmune mediated hemolytic anemia.

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83. A family with the hereditary hyperferritinemia cataract syndrome. R.A. Reuters 1 , Dr. W.A. Bode 2 , Dr. H.R.A. Fischer 1 , Departments of internal medicine 1 and gastroenterology 2 , IJssellandziekenhuis, Prins Constantijnweg 2, Capelle a /d IJssel, tel: 010 -2585170, e-mail: breejen@ worldonline.nl Introduction: For many years serum ferritin has been considered to be a marker of iron overload. A few years ago a disorder of ferritin synthesis has been described resulting in hyperferritinemia without iron overload and bilateral cataract at very young age, an autosomal dominant inherited disease (HHCS). Several mutations of the L-ferritin gene on chromosome 19 were found to be responsible for overproduction of the L-ferritin subunit. Case: A 55-year old male was treated for ulcerative colitis in our outpatient-clinic. When further tests were done because of elevated liver enzymes, hyperferritinemia (ferritin:7500 mg / l) was found and the presumptive diagnosis of haemochromatosis was made. He was treated with phlebotomies, but soon he developed iron deficiency anemia. Further tests showed a normal transferrin saturation and no mutations in the HFE gene. Our patient was known with bilateral cataract since early childhood. A surgical extraction was performed at age 52. After further screening of his family we found out that his mother and his sister had been treated for bilateral cataract at young age. His sister has three daugthers, one of them had a surgical cataract extraction when she was 18 years old. Two of the three sons of that daughter developed bilateral cataract at very young age as well. All affected family members had hyperferritinemia (range 769-14320 mg / l), whereas all unaffected family members had normal ferritin levels. Discussion: Ferritin is an iron storage protein composed of 24 heavy (H) and light (L) subunits. The genes coding for these subunits have been found on chromosome 11 and 19 respectively. The synthesis of ferritin is regulated by the interaction of iron regulatory proteins (IRP) and the iron responsive element (IRE) in the L-ferritin gene. In 1995 the first mutation in the L-ferritin subunit gene leading to ferritin synthesis in the absence of iron overload was described. In patients with HHCS cataract might be caused by the high levels of ferritin in the lens fibers with increased influx of water into the cell. Conclusion: We present the first Dutch family with the hyperferritinemia cataract syndrome. The ferritin levels found in the affected members of this family are even higher than the levels found in the literature. Maybe a new mutation will be found in this family. Blood samples of affected family members are currently being analysed for genetic mutations.

84. Cutaneous mucormycosis; hit hard and quickly in an AML patient. M. Hadithi 1 , P.J. van Diest 2 , Ch.R. Leemans 3 and A.R. Jonkhof 1 . Departments of Haematology 1 , Pathology 2 and ENT 3 ; Academic Hospital Vrije Universiteit, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands; Tel.: 020 -444 -4444, Fax: 020 -444 0505, e-mail: m.hadithi@ azvu.nl Mucormycosis, caused by fungi of the order Mucorales (Zygomycetes) is an opportunistic fungal infection that appears to increase in frequency due to the marked rise in the number of immunocompromised patients.

Besides disseminated infection and fungemia, more often the fungus spreads locally to adjacent tissues by overcoming tissue barriers and crossing facial planes which can be overwhelming and fatal with an overall mortality rate of is 24%. Microbiological studies are rather unhelpful since the cultures frequently fail to identify a causative microorganism. The management should not append culture confirmation, as progression can occur within the course of few hours in patients who are severely immunocompromised. During chemotherapy-induced neutropenia, a patient with acute myeloid leukemia, developed spontaneously primary cutaneous mucormycosis on his lower right chin. A high index of clinical suspicion was essential for diagnosing this unusual infection, leading to rapid establishment of the diagnosis within a few hours through a biopsy followed by appropriate surgical debridement. Defects secondary to resection of infected tissue were restored with skin grafting. This procedure is associated with substantial rate of success as noticed on this patient who remained uninfected for more than 1 year since then. Consequently the patient could complete his chemotherapy courses due to lack of an appropriate donor for bone marrow transplantation. The patient is in remission till now. 85. Serum ferritin iron in haemochromatosis, b-thalassaemia major and liver damage. Correlation to the Body Iron Stores and Diagnostic Relevance. U. Guenther 1,2 , P. Nielsen 1 , H. Haak 2 , Universitaetskrankenhaus Eppendorf 1 , Hamburg, Germany, Diaconessenhuis Eindhoven 2 , Tel.: 040 -2335503, e-mail: ugunther@ freeler.nl Introduction: Serum ferritin is a valuable parameter in the diagnostic and follow up of iron deficiency as well as iron overload. However, increased serum ferritin is not only seen in iron overload. Secondary factors such as infection, inflammation, or the presence of a malignancy can increase serum ferritine values, too. The use of serum ferritin iron has recently been reinvestigated as a better predictor of iron stores. Aim of the study: To correlate serum ferritin iron with individual liver iron concentrations, which is the best available parameter of the total iron stores and to investigate the diagnostic relevance of this parameter. Materials and Methods: The iron content of serum ferritin was determined in more than 150 serum samples in patients with elevated serum ferritin levels and normal iron stores such as hepatopathies (n 5 39) or increased iron stores such as homozygote (n 5 27) and heterozygote haemochromatosis (n 5 11), and b-thalassaemia major (n 5 58). In 13 patients with homozygote haemochromatosis ferritin iron was analysed during phlebotomy treatment. A technique of ferritin immunoprecipitation was used followed by iron quantitation using atomic absorption spectroscopy. The results were correlated to individual liver iron concentrations, measured non-invasively by SQUID biomagnetometry. Results: A close correlation between serum concentration of ferritin protein and ferritin iron was found (r 5 0.92) in all groups of patients. However, the correlatoin between ferritin iron and individual liver iron concentration was poor with both haemochromatosis (r 5 0.63) and b-thalassaemia major patients (r 5

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Internistendagen 2001 0.57). The degree of ferritin iron saturation was about 4.5% in iron-loaded patients, which contrast to two recent studies but confirms older observations. During iron depletion no decrease in serum ferritin iron saturation was observed. In patients with liver cell damage, the ferritin iron saturation in serum was with 6.4% significantly higher than that found in groups with iron overload disease, probably indicating the release of intracellular iron-rich ferritin into the blood. For a typical patient with moderate liver siderose the amount of serum ferritin iron would account for about 5% of the total plasma iron. It can be speculated that this fraction may play a role in the recirculation of iron. Conclusion: In contrast to other statements in literature, we found the benefit of serum ferritin iron as an additional diagnostic parameter to be small in patients with iron overload disease. 86. Pericardial effusion preceding hematological manifestation of acute myeloid leukaemia by six weeks. A case report. V. Zwart, M.C. Legdeur. Medisch Spectrum Twente, P.O. Box 50000, 7500 KA, Enschede. Tel.: 053 -4872440, Fax: 053 -4873085, email: L.vd.Ende@ hetnet.nl A 47-year old man presented with fever, night sweats and a one-day history of chest pain and dyspnoe. Apart from a mild normocytic anaemia (7.1 mmol / L) no hematological abnormalities were found. His ECG was normal. A chest X-ray revealed a mild left-sided pleural effusion. Further evaluation by CT scan of the chest demonstrated a mild pericardial effusion. A diagnostic pericardiocentesis was not performed because of the small amount of fluid. Serology and microbiology tests to a wide variety of pathogens remained negative and no evidence of a connective tissue disease or malignancy was found. His clinical condition remained stable and he was evaluated further at the outpatient clinic. Six weeks after initial presentation he was re-admitted because of clinical deterioration. In addition, he had noted a lump on his skull and obtained a scleral infiltrate of the left eye. A chest X-ray demonstrated an enlarged heart with distended pulmonary vessels and pleural effusion seen previously. Echocardiography showed stable pericardial effusion but a strikingly thickened pericardium. The ECG showed ST-depressions in lead I, II V5 and V6 with T-wave inversions. There were no signs of impaired hemodynamic circulation or complaints of chest pain. Laboratory results showed gross hematological abnormalities with anaemia, thrombopenia and marked leukocytosis (127 3 10 g / L) of which 95% were blasts. Laboratory results two weeks earlier were normal apart from the mild anaemia noted previously. A bone marrow aspirate established the diagnosis of acute myeloid leukaemia FAB-M1. The ECG abnormalities were ascribed to leukostasis and the X-ray findings were interpreted as congestion caused by the thickened pericardium, although a leukemic infiltrate or leukostasis can not be ruled out. Hydroxyurea and induction chemotherapy with cytarabine and idarubicin were initiated resulting in a fast decline of leukocyte count. At day 12 after induction chemotherapy, the chest X-ray and ECG findings were normalised and echocardiography could no longer demonstrate pericardial effusion. Moreover, the lump on his skull and the scleral infiltrate had disappeared. Although no haematological signs of leukemia or peripheral blasts were seen at first presenta-

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tion, the pericardial effusion can be explained by infiltration with leukemic cells by exclusion of other causes and by the disappearance of this and other abnormalities after chemotherapy. The extramedullary presentation of acute leukaemia, as demonstrated by pericardial effusion in this case report, without haematological manifestations is rare. When pericardial effusion is seen in a previously healthy patient, the diagnosis of new onset leukemia should be considered. 87. Gelatinous transformation of the bone marrow in a patient with severe COPD. D.C.J.J. Bergmans, P.A.A. Pauwels, L.T. Vlasveld, Diaconessenhuis Eindhoven, Ds. Th. Fliednerstraat 1, 5631 BM, Eindhoven, Tel.: 040 -2335503, Fax: 040 -2450385, e-mail: dcjj.bergmans@ freeler.nl Gelatinous transformation of the bone marrow is a rare disorder of unknown pathogenesis, characterized by fat cell atrophy, focal loss of hematopoietic cells, and deposition of extracellular gelatinous substances. Gelatinous transformation typically occurs in cachectic patients losing weight in a short period of time due to malignancies, infection or malnutrition. A thin 64-year-old man with severe COPD presented with headache and dyspnea. He had no recent weightloss. Physical examination revealed no abnormalities besides pulmonary wheezing. Laboratory evaluation showed a macrocytic anemia (Hb 4.5 mmol / l, MCV 108 fl) with low reticulocyte count (17.7 3 10 9 / l). Thrombocyte count was 273 3 10 9 / l and the leucocyte count was 8.7 3 10 9 / l with a normal differential count. Serum folic acid and vitamin B12 levels were normal. Bone marrow aspirate was hypocellular and nondiagnostic. During admission the headache spontaneously subsided but dyspnea increased intermittently with chest pain. Pulmonary embolism was diagnosed and heparin therapy combined with acenocoumarol was started. A severe bleeding tendency developed with large soft tissue hematomas and an upper alimentary tract bleeding most likely from a small esophageal polyp. The thrombocyte count had rapidly dropped to , 10 3 10 9 / l due to a type I heparin-induced-thrombocytopenia. After discontinuation of anticoagulants the bleeding tendency subsided but thrombocytopenia and anemia persisted. Bone marrow aspiration yielded a dry tap. The bone marrow biopsy showed hypocellular marrow, secondary myelofibrosis, amorphous ground substance and fat cells of varying diameter. Gelatinous transformation of the bone marrow was diagnosed. Extensive analysis by repeated physical examination, laboratory- and microbiological tests combined with radiologic imaging revealed no underlying malignancy or infection. During the follow-up for one year now in the outpatients´ department the profound anemia and thrombocytopenia persisted. The body weight remained stable. Still no evidence for an underlying disease, besides COPD, has been found. This case report describes a patient with gelatinous transformation of the bone marrow causing macrocytic anemia. On admission thrombocyte count was normal but a heparin-induced thrombocytopenia developed with persistent thrombocytopenia probably due to the lack of megakaryocyte recovery. To the best of our knowledge, gelatinous transformation of the bone marrow has not been described in association with severe COPD.

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88. Agranulocytosis as a manifestation of vitamin B 12 deficiency. C. van Nieuwkoop, R.J.Th. Ouwendijk, M.G.A. Baggen. Department of Internal Medicine, Ikazia Hospital Rotterdam, Montessoriweg 1, 3083 AN Rotterdam, Tel.: 1 31 -10 -2975000; fax: 1 31 -10 -4859959, e-mail: ikazint@ knmg.nl Introduction: Acquired agranulocytosis is commonly seen as a side effect of drug therapy but will be seen with infection, hematological diseases, autoimmnune disorders and nutritional deficiencies as well. We report on a patient presenting with agranulocytosis caused by vitamin B 12 deficiency. Case: A 72-year old man was admitted for amputation of a necrotic toe after a recent femoro-popliteal bypass operation. His medical history revealed chronic obstructive pulmonary disease, pancreatitis, and cerebellar degeneration with combined degeneration of the spinal cord as complications of alcohol abuse. Postoperatively we investigated the patient because of acquired leukopenia. Laboratory tests were: hemoglobin 5.9 mmol / l (8.5–11.0 mmol / l), hematocrit 0.27 l / l (0.4–0.5 l / l), white blood cell count (WBC) 1.4 3 10 9 / l (4.0–10.0 3 10 9 / l) with 94% lymphocytes, granulocytes 0.19 3 10 9 / l (1.8–7.7 3 10 9 / l) and thrombocytes 230 3 10 9 / l (130–350 3 10 9 / l). The mean red cell volume was 78 fl (80–100 fl). Iron was 2.4 mmol / l (10.0–30.0 mmol / l), transferrin 19 mmol / l (22–44 mmol / l) and ferritin 282 mg / l (20–350 mg / l). Kidney function was reduced with creatinin 134 mmol / l (65–110 mmol / l) and urea 14.6 mmol / l (2.7–7.5 mmol / l). Liver function tests were normal. Serologic tests for conceivable underlying vasculitis were all negative. A bone marrow aspirate showed a normal erythropoiesis, lymphopoiesis and megakaryocytopoiesis but granulocytopoiesis was nearly absent. Prussian blue staining of this marrow aspirate confirmed an iron deficiency. We postulated that this agranulocytosis was presumably drug induced especially since patient used certain drugs including H 2 blockers and tranquilizers. Other diagnoses, as aplastic anemia, were considered but in the absence of specific treatment options we decided not to do any further diagnostic procedures at this point. The patient was managed supportive with stopping of all medicaments and frequent checks of WBC. Unfortunately, the leukopenia sustained with WBC levels below 1.0 3 10 9 / l and the patient developed a complicating pneumonia requiring assisted ventilation. After 14 days without any change in WBC we started injections with vitamin B 12 based on test results verifying a vitamin B 12 deficiency; 95 pmol / l ( . 150 pmol / l). A tremendous elevation of WBC followed; 3.3 3 10 9 / l the first day and 5.8 3 10 9 / l the second day after these injections. Hereafter a leukocytosis developed with recovery of patient’s pneumonia and necrotic foot specifically. Treatment with vitamin B 12 was continued and during follow up, WBC checks remained normal. The patient recovered completely without any further infectious events. Conclusion: Agranulocytosis is a serious disorder with barely specific treatment options besides treatment of an underlying disorder. Vitamin B 12 deficiency should always be considered as a gentle treatable cause. 89. When Scylla and Charybdis meet; multiple coagulation disorders can have an unexpected course. H.P.C.M. Heijmen 1 ,

L.Th. Vlasveld 1 , A.A.M. Ermens 2 . 1 Department of Internal Medicine, 2 Clinical Laboratory, Diaconessenhuis, Ds. Th. Fliednerstraat 1, 5631 BM, Eindhoven, Netherlands. A 55-year old male with severe Hemophilia A (Factor VIII , 1%), complicated by persistent Hepatitis C, was admitted for total-knee-prosthesis surgery because of symptomatic gonarthrosis. Four years before a left-sided hemisensible syndrome developed due to multiple lacunar infarctions (MRI-scan). Thrombophilic screening revealed signs of an antiphospholipid syndrome with a persistently positive anti-Cardiolipine-IgG and a moderate thrombocytopenia (60 3 10 9 / l). No other causes of thrombocytopenia seemed apparent. The megakaryocyte count was normal and autoantibodies against platelets were absent. A mildly enlarged spleen without signs of portal hypertension was noted on ultrasound. However, in view of a normal albumin and antithrombin III level, hepatic failure was considered unlikely. The patient was treated with acetylsalicyc acid (38 mg) and a strict regimen of prophylactic F VIII suppletion. Cardiac analysis showed moderate hypertension, mild left ventricular hypertrophy and a new left bundle branch block on the ECG without anginal complaints or signs of heart failure. A test dose Factor VIII was administered intravenously (bolus 50 IU / kg, followed by continuous infusion of 4 IU / kg / hr) resulting in a F VIII-level of 100%. However, activated partial thromboplastin time (APTT) did not normalize. Because the APTT could be corrected in vitro by incubation of patient plasma with an equal volume of normal plasma the presence of a lupuslike circulating anticoagulans was excluded. However a prolonged prothrombin time (PT) and deficiencies of Factor II, V and X with a lowered choline-esterase indicated hepatic failure despite normal albumin and fibrinogen levels. Pre-operatively acetylsalicyc acid was stopped and low molecular weight heparin in a prophylactic dose for thrombo-embolic events in antiphospholipid syndrome (Fraxiparine  1 dd 0.3 ml s.c.) was started. At the start of surgery the above mentioned regimen of F VIII, 2 units of fresh frozen plasma (FFP) and 1 unit of platelet suspension were administered. Total-knee-prosthesis-surgery was performed without any bleeding complication. One day postoperatively there was profound blood loss from the wound. Because of prolonged APTT and PT, 3 FFP’s and 2 units of platelet suspension were administered. Factor VIII infusion was continued and bleeding stopped. Unfortunately, during administration of FFP severe dyspnea and fever occurred, followed by respiratory failure and cardiac arrest. Cardiopulmonary resuscitation was unsuccessful. Autopsy revealed an acute posterior myocardial infarction caused by a single atherosclerotic obstruction in the right coronary artery without signs of general atherosclerosis. Therefore this hemophilic patient with hepatic failure died because of a complication of clotting instead of bleeding. 90. Acquired von Willebrand Syndromes: Clinical features, Etiology, Pathophysiology, Classification and Management. Jan Jacques Michiels 1,3 , Marc van der Planken 1 , Huub H.D.M. van Vliet 2 , Wilfried Schroyens 1 and Zwi Berneman 1 . Haemostasis Thrombosis Research and Vascular Medicine, Department of

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Internistendagen 2001 Haematology, University Hospital Antwerp 1 , Department of Haematology 2 , University Hospital Rotterdam and Goodheart Institute 3 , Hemostasis & Thrombosis Center, Rotterdam, The Netherlands. AvWS has been associated with several disorders due to various mechanisms (43, 44, 45). AvWS associated with hypothyroidism is of type I, results from decreased synthesis of factor VIII and von Willebrand factor (vWF), reponds to DDAVP and disappears after treatment with l-thyroxine. AvWS associated with SLE or IgG benign monoclonal gammapathy is of type II and caused by anti-vWF autoantibodies, usually IgG, which preferentially binds to the high molecular weight vWF.FVIII particles. This autoantibody-antigen IgG:vWF.FVIII-complex is rapidly cleared from the circulation resulting in low factor VIII and vWF parameters levels as could be documented by a poor response to DDAVP and vWF / FVIII concentrate. AvWS type II associated with SLE or IgG benign monoclonal gammapathy typically respond to highdose IV:Ig, which transiently corrects factor VIIIc and vWF levels lasting for a few weeks. AvWS associated with IgM monoclonal gammapathy does not respond to high-dose IV:Ig. Prednisone is effective in AvWS associated with SLE. Prednison and chemotherapy will not affect AvWS associated with IgG or IgM benign monoclonal gammapathy because the monoclonal protein persists to act as an anti-vWF autoantibody. Another immune mechanism is absorption of vWF to malignant cells and has been desribed in a few patients with various lymphoproliferative disorders or adrenal carcinoma. Treatment of the underlying disorder resolves the AvWS. Where AvWS is associated with myeloproliferative disorders and high platelet counts ( . 1500 3 10 9 / l), the mechanism is proteolytic degradation of vWF resulting in selective deficiency of vWF:Rcof and loss of high molecular weight vWF multimers (AvWS type II), but the values for vWF:Ag and factor VIII remain normal. Another mechanism has been described in young patients with Wilms tumour of the kidney. The multimeric sizing (MS) pattern in these subjects is consistent with type I or III vWD, with low levels of vWF:Ag, vWF:Rcof and FVIII:C. The causative agent is thought to be hyaluronic acid, which is secreted by the nephroblastoma cells (45). AvWS disappears after reduction of platelet count in thrombocythemia and after chemotherapy or resection of the Wilms tumour. Finally, drug-induced AvWS has been described in association with the use of valproic acid, ciprofloxacin, griseofulvine, tetracycline, thrombolytic agents, pesticides and hydroxyethyl starch and disappears after discontinuation of the drug. 91. Acquired von Willebrand Syndrome as the cause of spontaneous mucocutaneous bleeding symptoms in a child with Essential Thrombocythemia: effectiveness of platelet reduction by Anagrelide. J.J. Michiels, U. Budde, E. Signer, P. Imbach. Hemostasis Thrombosis Research, Goodheart Institute Rotterdam and Dept of Hematology University Hospital Antwerp, Coagulation Laboratory Hamburg, and Department of Pediatrics, Basler Kindersptital, University of Basel. A 9-year-old Caucasian boy presented in June 1994 with severe headache, attacks of migraine, aggressive behavior and minor bleeding symptoms. While on continuous low-dose aspirin 100 mg / day the cerebral symptoms did not recur, but spontaneous

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bleedings of recurrent epistaxis, bruises, hematomas and gum bleedings persisted throughout 1995. An iron deficiency anemic state developed in November 1995: Hb 5.7 mmol / l, ht 0.30, MCV 77 fl, leukocytes 8.6 and platelets 1946 3 10 9 / l, ferritine 6 mg / l. Essential Thrombocythemia was diagnosed. Coagulation screening revealed a prolonged bleeding time and deficiency of von Willebrand factor parameters. Von Willebrand factor antigen (vWF.Ag) was assayed by an ELISA. The binding of vWF to collagen (vWF.CBA) was measured according to the ELISA-based method of Brown and Bosac. Analysis of the vWF-multimeric pattern was performed and visualized in luminograms of low and medium resolution gels by the Coagulation Laboratory of Budde. At time of bleedings in November 1995 at platelet counts between 1500 and 2000 3 10 9 / l, Acquired von Willebrand Synrome (AvWS) type II was diagnosed: vWF.Ag (0.55 m / ml), vWF.CBA (0.29 m / ml), vWF Ag / CBA ratio (0.53) and loss of the high-molecular-weight vWF-multimers. A severe epistaxis lasting in November 1995 lasting for hours immediately stopped after substitution of 3000 umits Hemate P. Subsequent treatment with anagrelide resulted in the continuous relief of bleeding symptoms and correction of platelet count and all vWF parameters to normal with reappearance the large vWF multimers. While on longterm anagrelide the platelet count remained normal and AvWS did not recur.

VI. Oncology 92. Membranous glomerulonephritis as paraneoplastic manifestation of non small cell lung cancer. M.J. Wondergem, A.G. Balk*, R.J.L.F. Loffeld, A. van Bochove. Departments of Internal Medicine and Pathology*, De Heel Zaans Medisch Centrum, P.O. Box 210, 1500 EE Zaandam, Tel.: 075 -6502779, fax: 075 6502379, The Netherlands. A 51-year-old man, with unremarkable medical history, presented with progressive weight gain and generalized edema. Physical examination showed a blood pressure of 160 / 100 mmHg, orbital edema, and edema of the extremities and abdominal wall. In the right supra-clavicular fossa a firm non-tender mass was palpated. Laboratory studies showed a total serum protein of 42 g / l, albumin of 17.0 g / l, cholesterol of 13.5 mmol / l, creatinine of 114 micromol / l and an ESR of 72 mm / hr. Creatinine clearance was 76 ml / min. There was a proteinuria of 24.9 g / 24 hour, with microscopic haematuria. Histologic examination of a kidney biopsy specimen showed the classical manifestations of membranous glomerulonephritis with immune-complex deposits of IgG and C3 along the glomerular basal membrane. CT-scan of the thorax revealed a small tumor (1 cm) in the right lung, with pleural effusion, enlarged lymph nodes in the mediastinum and in the right supra-clavicular region. Histologic examination of the supraclavicular lymph node revealed metastases of non-small cell lung cancer. The final diagnosis was non-small cell lung cancer (T1 N3 M0), with a paraneoplastic nephrotic syndrome due to membranous glomerulonephritis. Therapy with diuretics and ACE-inhibitors was started and decreased proteinuria to 14–16 g / 24 hr. Because of the impaired renal function an alternative scheme of chemotherapy containing carboplatinum (500 mg) and gemcitabin

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(1250 mg / m2) was started. After the first course proteinuria further decreased to 8.5 g / 24 hr and the dose of diuretics and ACE-inhibition could be reduced. After six courses radiological evaluation showed only a minor response: the primary tumor and lymph nodes decreased in size. Although proteinuria persisted, peripheral edema remained in remission with continued use of diuretics and ACE-inhibitors. Nephrotic syndrome due to membranous glomerulonephritis is a well-known paraneoplastic phenomenon. It has been recommended to initiate a search for cancer in patients older than 40–50 years presenting with membranous glomerulonephritis. Successful treatment of lung carcinoma by resection, radiation and chemotherapy (in small cell lung cancer) with subsequent resolution of the nephrotic syndrome has been reported. To our knowledge, effect of chemotherapy on paraneoplastic nephrotic syndrome in non-small cell lung cancer was never described. Chemotherapy resulted in important reduction of proteinuria and, hence, adequate palliation. The presented case emphasizes the importance of a search for malignancy in the adult patient presenting with nephrotic syndrome based on membranous glomerulonephritis. By identifying the tumor, appropriate therapy can be selected and important palliation can be achieved. 93. Serum S100 is suitable for prediction and monitoring of response to chemo-immunotherapy in metastatic malignant melanoma. A.P. Hamberg 1,2 , J.M.G. Bonfrer 2 , C.M. Korse 2 , G.C. de Gast 2 . 1 Diakonessenhuis, Bosboomstraat 1, 3582 KE, Utrecht, Tel.: 030 -2566206, fax: 030 -2566738, e-mail: paulhamberg@ yahoo.com, 2 Antoni van Leeuwenhoekhuis, Amsterdam. Introduction: Serum markers suitable for predicting and monitoring response of treatment in patients with malignant melanoma (MM) may be useful in view of new treatment modalities. S100 has been shown to be an independent prognostic marker for survival of patients with MM. Aim of the study: To assess the applicability of S100 in monitoring and follow up of patients treated for metastatic MM with sequential chemo-immunotherapy. Materials and Methods: In 53 patients S100 and LDH levels were measured at regular intervals before, during and after treatment. The control group consisted of 19 patients with renal cell carcinoma (RCC) receiving similar immunotherapy. Results: S100 levels before treatment were predictive for the outcome. 70% of 34 patients with an initial S100 level below 1.0 mg / l had a response on treatment while on the contrary, 70% of 19 patients with levels of 1.0 mg / l or more experienced progressive disease (PD). If this stratification was applied to LDH no such significant difference was found. After treatment the median value of S100 in the response group was below the reference value of 0.16 mg / l. After treatment only 1 of 22 patients (4.5%) with PD had a S100 level below the reference value, but 55% of the patients with response had a normal S 100 after treatment. In the control group none of the patients had increased S100 levels before or after treatment. Remarkably a transient increase in serum S100 was found in several MM patients as well as in the RCC-controlgroup. This is probably due to dendritic cell activation.

Conclusion: S100 is a very useful assay to assist in the clinical response evaluation of patients treated for MM with chemoimmunotherapy. 94. Phenotypic and genetic characterization of different metastases in patients with unknown primary tumor. A.J. van de Wouw 1 , E.J.M. Speel 2 , S.R. Joosten-Achjanie 1 , H.F.P. Hillen 1 . 1 Department of Internal Medicine, University Hospital Maastricht, yesvandewouw@ wxs.nl; 2 Department of Molecular Cell Biology & Genetics, University of Maastricht. Introduction: Unknown primary tumor (UPT) is defined as a biopsy-confirmed malignancy in which the anatomical origin remains unidentified after a complete history and physical examination, routine laboratory tests and chest radiography. It has been postulated that UPTs are not only a clinical but also a biological entity. The hypothesis is that, though the primary originates from different organs, UPTs share common genetic aberrations, leading to early metastases and organ-independent homing of metastases. Aim of the study For further understanding and especially improving therapeutic opportunities we investigated phenotypic and genetic characterizations of UPT. Patient and Method We examined 23 biopsies from 5 patients with UPT on whom autopsy was performed. Biopsies were taken from 4 to 5 different sites of metastases in these patients. Five different loci, including D1S243 (1p36), D3S1100 (3p21), D9S1748 (9p21), TP53 (17p13) and AR (Xq12) were analyzed by microsatellite analysis. In addition, fluorescence in situ hybridization (FISH) was performed on paraffin sections using centromere 1 and 17-specific probes and in 3 patients a comparative genomic hybridization (CGH) profile of the UPT could be generated. Immunohistochemical staining was performed on paraffin sections using monoclonal antibodies against CD44v6, P53, TUNEL, VEGF and Ki67. Results Each set of UPT samples from different organs within one patient demonstrated a similar profile of LOH, retention of heterozygosity and immunohistochemical staining. Though similar, the results were not identical within the patients, we found in 1 or 2 organs a slightly different profile. This similarity indicates a single clonal origin of the metastases within one patient. Furthermore, FISH analysis revealed high copy numbers of centromeres 1 and 17 in all UPTs, illustrating an aneuploid DNA content that might be the result of multiple rounds of endoreplication. All UPTs within one patient showed the same range of copy numbers per nucleus, also suggestive of a common clonal origin. Immunohistochemistry markers were also suggestive for clonality only in few cases they differed from each other within a patient. These differences occurred in the same metastases as in which we found a different profile of LOH. Conclusion In conclusion, our data suggest a clonal relationship between all metastases of UPTs residing in different organs within one patient. 95. A single center dose finding study of doxorubicin and ifosfamide with G-CSF and peripheral stem cell transplantation for the treatment of advanced adult soft tissue sarcomas. J. van den Bosch, K. Hoekman, M.M. Fechter, C.J. van Groeningen, H.M. Pinedo. Dpt of Medical Oncology, Academical Hospital Vrije Universiteit, De Boelelaan 1171, 1081 HV Amsterdam, The

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Internistendagen 2001 Netherlands, Tel.: 1 31 -20 -4444300, Fax: 1 31 -20 -4444355, email: jbosch65@ hotmail.com Background: Doxorubicin and ifosfamide have been used in the treatment of advanced adult soft tissue sarcomas (ASTS), but results at standard doses have been disappointing compared to single agent treatment. There is evidence for a dose-response relationship for both drugs in this tumour type. The aim of our study was to define the maximum tolerable dose (MTD) using dose escalation first without haematological support, and then to further escalate the dose with the use of peripheral stem cell transplantation (PSCT) and G-CSF. Patients and Methods: Doxorubicin was given on day 1, starting at 90 mg / m 2 . Ifosfamide was given over 4 days, starting at 8 g / m 2 . Treatment was planned for three cycles. At each dose level the dose of doxorubicin was increased with 10 mg / m 2 and ifosfamide with 2 g / m 2 . Patients had a histologically proven diagnosis of advanced ASTS, measurable tumour lesions, age between 18 and 55 years, and a performance status # 2. Prior chemotherapy or concomitant radiotherapy of the lesions was not allowed. Results: Thirteen patients were treated, with a median age of 43 years. Eleven patients (85%) had prior surgery. Nine patients had metastases, predominantly in the lungs. At dose level 1 two patients were entered, at dose level 2 three, and at dose level 3 eight. The median treatment interval between cycles was 25 days, which didn’t alter with PSCT. The dose-limiting toxicity (DLT) at the third dose level was leucopenia for more than seven days. After support with G-CSF and PSCT the DLT remained leucopenia, together with encephalopathy. The median number of days of severe leuco / thrombocytopenia didn’t alter with PSCT. Four patients had a grade III encephalopathy, which was the non-haematological DLT. Overall response rate was 15%, with 2 partial responses and no complete responses. Four patients had stable disease. Median progression free survival was 11 months, median overall survival 20 months. The partial responders had no longer progression free and overall survival. Conclusion: High dose chemotherapy with doxorubicin and ifosfamide for the treatment of advanced ASTS is a toxic therapy, while even at the doses applied any suggestion for a higher response rate than reported for the individual drugs is lacking. 96. Feasibility study of escalating doses of ifosfamide plus mesna in patients with advanced or metastatic adult soft tissue sarcoma. J. van den Bosch, K. Hoekman, M.M. Fechter, C.J. van Groeningen, H.M. Pinedo. Dpt of Medical Oncology, Academical Hospital Vrije Universiteit, De Boelelaan 1171, 1081 HV Amsterdam, The Netherlands, Tel.: 1 31 -20 -4444300, Fax: 1 31 20 -4444355, e-mail: jbosch65@ hotmail.com Background: There is evidence that for ifosfamide a doseresponse relationship exists in the treatment of advanced adult soft tissue sarcomas (ASTS). The aims of this study were to determine the response rate and the duration of response in patients with advanced ASTS (both as first and second line treatment), and to define the side effects of high dose ifosfamide. Patients and Methods: Ifosfamide was given at a dose of 2.5 g / m 2 / day during 4 days. Prior to ifosfamide a bolus of mesna of

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200 mg / m 2 was given, while mesna was given at the same dose as ifosfamide during the continuous infusion and at a dose of 50% in 6 hours after the ifosfamide. If there was no grade III or IV toxicity and no delay of treatment, the dose was escalated with 0.5 g / m 2 / day. Treatment was scheduled every 3 weeks. Patients had a histologically proven diagnosis of advanced or metastatic ASTS, measurable tumour lesions, age between 18 and 75 years, and a performance status # 2. Prior treatment with doxorubicin was allowed. Neurological conditions or psychiatric disorders, which could interfere with evaluation of neurological toxicity, were not allowed. Results: 34 Patients were treated, with a median age of 48 years. 23 Patients (68%) had prior surgery. 19 Patients (56%) had metastases, predominantly in the lungs. A total of 115 courses were given, with a median of 4 per patient. 18 Patients had dose escalating according to the protocol; 4 patients received 3.5 g / m 2 / day and 2 patients 4.0 g / m 2 / day. Dose escalating was withheld because of grade III / IV leucopenia in 16 patients. 74% Of the patients had a grade III / IV leucopenia, 9% a grade III / IV thrombocytopenia. Grade III non-haematological toxicity consisted of central neurotoxicity (15%) and nephrotoxicity (6%). Overall response rate was 18%, with no complete responses. The response rate was 20% as first, and 11% as second line treatment. 10 Patients (29%) had stable disease. Median progression free survival was 5 months, median overall survival 17 months. Conclusion: Dose escalation of ifosfamide in the treatment of advanced ASTS is feasible in the minority of patients, with low response rates, both as first as second line treatment. 97. Second recurrence of adult Wilms’ tumour. A. Zandsteeg 1 , A.J. van de Wouw 1 , F. Bot 2 , P.Muus 3 , P.S. Hupperets 1 . 1 Department of Internal Medicine and 2 Department of Patholoy, University Hospital Maastricht. 3 Department of Hematology,University Medical Center St,. Radboud, Nijmegen. P. Debyelaan 25, Maastricht. Tel.: 043 -3877025, e-mail: yesvandewouw@ wxs.nl Adult Wilms’ tumour is an uncommon entity, with approximately 250 cases reported in world literature. Because of its rare occurrence it has been proven difficult to obtain distinct directives for diagnosis and treatment. In the previous treatment reviews it was recommended to treat adult Wilms’ tumour with a combined modality therapy, involving surgery, chemotherapy and radiation therapy. However, despite this intensive treatment, relapses tend to appear early, most frequently within 2 years. We report on a patient who was diagnosed with stage IV nephroblastoma at the age of 36-years and who enjoyed a prolonged complete remission following multimodal treatment for a first relapse of the disease. First line treatment consisted of combination chemotherapy (cyclophosphamide, doxorubicine, cisplatin and etoposide), followed by a right radical nephrectomy and adjuvant radiotherapy. As a result he remained free of disease for a period of 27 months before a pararectal relapse was diagnosed. The tumour was surgically removed and patient subsequently underwent an allogeneic bone marrow stem cell transplantation (conditioning: ifosfamide and melphalan). He was healthy without any sign of illness for a remarkable period of almost 12 years. Unfortunately then a rapidly progressive second relapse and pulmonary metastases were diag-

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nosed. Repeated combination chemotherapy (etoposide, ifosfamide, and cisplatinum) gave only a partial response. Also an infusion with lymphocytes from the original stem cell donor, given to hopefully induce a graft versus nephroblastoma effect, was without any response. Eventually, the patient deceased of progressive disease and pulmonary insufficiency. To the best of our knowledge a second remission of almost 12 years in adult nephroblastoma has not been described. Therefore we would like to emphasis on the possible role for allogeneic BMT in the treatment of recurrent adult nephroblastoma.

VII. Vascular medicine 98. Ruling out clinically suspected pulmonary embolism by assessment of clinical probability and d-dimer levels. M.G.L. ¨ Leclercq, J.G. Lutisan, M. van Marwijk Kooy and H.R. Buller. Internal medicine, Isala klinieken, Zwolle and Academisch Medisch Centrum, Amsterdam, The Netherlands, locatie Sophia, postbus 10400, 8000 GK Zwolle, Tel.: 0384245750, e-mail: jl@ jager-leclercq.demon.nl New diagnostic strategies have been investigated to simplify the diagnostic work-up for patients with suspected pulmonary embolism (PE). A combination of D-dimer test and clinically probability have been proposed as the first step in the diagnostic work-up. We performed a prospective management study in 200 consecutive in- and outpatients with suspected PE to investigate the safety and efficiency of excluding PE by a normal d-dimer combined with a low or moderate clinical probability. To simplify further diagnostic strategy we replaced ventilation lung scanning by chest X-ray. Plasma D-dimer levels were measured using a commercial assay (Tinaquant). Clinical probability was assessed by a standardised clinical model. Patients with an elevated D-dimer or high clinical probability underwent lung perfusion scan and chest X-ray. If non-diagnostic, a compression ultrasonography was performed followed by a pulmonary angiography in case of absence of deep vein trombosis (DVT). PE was excluded in case of a normal D-dimer combined with a low or moderate clinical probability; normal perfusion scan; absence of DVT and a normal result of the pulmonary angiography. Patients in whom venous tromboembolism was deemed absent were not given anticoagulants and were followed up for 3 months. Here we present the interim analysis of the first 150 patients. A normal D-dimer concentration ( , 500 ng / ml) in combination with a low or moderate clinical probability ruled out PE in 49 (33%) patients. Lung perfusion scan / chest X-ray was normal in 22 (22%), nondiagnostic in 49 (48%) and high in 30 (30%) of the remaining 101 patients. Compression ultrasonography was done in 40 (27%) patients and pulmonary angiography in 37 (25%) patients of the entire cohort. PE was diagnosed in 43 (29%) patients of the entire cohort. The prevalence of PE in the low clinical probability category was 25%, in the moderate category 29% and in the high category 39%. The 3-month tromboembolic risk in 107 patients not given anticoagulants, based on the results of the diagnostic protocol, was 0% (95% CI, 0.0–3.4%). Ruling out PE by a normal D-dimer with a low or moderate clinical probability seems a safe strategy. Replacement of the

ventilation scan by chest X-ray in the further diagnostic strategy is useful, leading to a high percentage of high probability Q / X results. However, these results should be confirmed in the larger study. The accuracy of the clinical probability assessment is disappointing. Excluding PE by D-dimer and clinical probability is mainly based on the result of the D-dimer test. 99. The risk of mortality in carriers of the hereditary hemochromatosis gene (HFE). M.O. van Aken, A.J.M. de Craen, B.T. Heijmans, P.E. Slagboom, J. Gussekloo, R.G.J. Westendorp. Leiden University Medical Center, Postbus 9600, 2300 RC Leiden, Tel.: 071 -5269111, e-mail: movaken@ lumc.nl. Introduction: Hemochromatosis is associated with homozygosity for the mutation Cys282Tyr in the hereditary hemochromatosis gene (HFE). The estimated population frequency for HFE heterozygosity is 10 to 15 percent and for HFE homozygosity it is 0.5%. Some, but not all HFE carriers have lifelong increased levels of serum ferritin and serum iron. Because iron is thought of as a determinant of atherosclerosis by promoting oxygen radical formation and lipid peroxidation, HFE homozygous and heterozygous subjects may be at risk for atherosclerotic events and mortality. Aim of the study: 1. Showing a depletion of HFE gene carriers in the oldest old, illustrating the increased mortality risk of the HFE gene during life. 2. Investigating the association of HFE gene carriership with mortality and cardiovascular disease in a prospective follow-up study. Materials and Methods: Within the Leiden 85-plus Study, a longitudinal population-based study of inhabitants of Leiden aged 85 and over, HFE-genotypes and serum ferritin levels were determined for 661 participants (187 men / 474 women). After the baseline measurements (1986–1988) all participants were followed for mortality and primary causes of death during a 10-years follow-up period. As a control group, the HFE-genotype was also determined in 248 young subjects, aged 18–40 years. Results: The prevalence of HFE heterozygosity was similar in old and young subjects (82 / 661 (12.4%) versus 30 / 248 (12.1%), p 5 0.9). The prevalence of HFE homozygosity among the oldest old was 0.2% (1 / 661), instead of 0.5% expected. During the 10-years follow-up period, the risk of mortality of all cause (Relative Risk 1.1, 95% confidence interval 0.9 to 1.4) and of cardiovascular causes (RR 1.0, 95% CI 0.7–1.5) was not increased in carriers of the HFE gene. Median serum ferritin levels were similar for HFE carriers and non-carriers (97 versus 87 mg / l, p 5 0.5). Conclusion: HFE homozygous subjects suffer an increased mortality risk, although some survive until very old age. HFE heterozygous subjects do not suffer an increased mortality risk. 100. Aggressive lipid lowering does not improve endothelium dependent vasodilation in patients with type 2 diabetes. R.W. van Etten 1, 2 , E.S. Stroes 1 , M.L. Honing 1 , M.C. Verhaar 1 , E.J.P. de Koning 1 , CA.J.M. Gaillard 1, 2 , T.J. Rabelink 1 . Dept. of Vascular Medicine and Diabetes, University Medical Center, Utrecht, The Netherlands. Dept. of Internal Medicine, Eemland Hospital,

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Internistendagen 2001 Amersfoort, The Netherlands. Address: UMC Utrecht, Room G.02.402, Tel.: 030 -2507570, e-mail: number: r.w.vanetten@ azu.nl Introduction: Cardiovascular disease is the most important cause of morbidity and mortality in patients with type 2 diabetes. Endothelial dysfunction predicts outcome in cardiovascular compromised patients. Patients with type 2 diabetes are characterized by endothelial dysfunction which may be caused by dyslipidemia. We have previously demonstrated that statin therapy restores endothelial function in hyperlipidemic patients. Methods: Using forearm plethysmography, we evaluated the effect of high dose HMG-Co-A reductase inhibition (atorvastatin 80 mg od for 4 weeks) on forearm vasomotion in 23 patients with type 2 diabetes and mild dyslipidemia (LDL . 4.0 mmol / l and / or TG . 1.8 mmol / l). Twenty-one baseline-control-subjects were matched for age, gender, BMI, blood pressure and smoking habits. Serotonin was infused as agonist for endothelium-dependent, nitric oxide (NO)-mediated vasodilation and sodium nitroprusside for endothelium-independent, NO-mediated vasodilation. Results are expressed as percent increase of the ratio of forearm blood flow of the measurement arm (M) and control (C) arm (M / C%). Results: Endothelium dependent vasodilation was significantly blunted (52630 vs. 102666 M / C%, p , 0.005) and endothelium independent vasodilation was modestly reduced (2756146 vs. 3916203 M / C%, P , 0.05) in patients with type 2 diabetes compared to control subjects. Despite significant reduction of total- and LDL-cholesterol and triglycerides (5.861.0 to 3.260.6 ( p , 0.0001), 4.161.1 to 1.860.7 ( p , 0.0001) and 2.261.3 to 1.460.5 ( p , 0.05) mmol / l respectively) by atorvastatin, no effect on endothelium dependent (59644 M / C%) and independent (2926202 M / C%) vasodilation was demonstrated. Conclusion: These data suggest that aggressive lipid lowering by atorvastatin has no effect on NO availability in the forearm resistance arteries in type 2 diabetic patients. Effects on non-NO mediated pathways may explain the benefit of statin therapy on cardiovascular events in this patient group. 101. Enalapril and losartan alone or in combination in patients with renovascular hypertension. M.E. Sleeswijk, A.E. Prins, A.J.J. Woittiez, Department of Internal Medicine Twenteborg Hospital, PO Box 7600, 7600 SZ Almelo, The Netherlands. Tel.: 0546 -833333; Fax: 0546 -833418; e-mail: msleeswijk@ hotmail.com Introduction: ACE-inhibtors have proven to be effective antihypertensive drugs in patients with renovascular hypertension. However, some patients doesn’t respond well under ACE-inhibition, maybe due to escape of A-II formation in the stenotic kidney. To date, no trials in patients with RVHT, comparing combination therapy of ACE-inhibitors and A-II antagonists have been reported. Aim of the study: to compare the antihypertensive efficacy and the effects on renal haemodynamics of enalapril and losartan, and the combination-therapy, in patients with renovascular hypertension (RVHT), associated with an unilateral renal artery stenosis (URAS). Design and Methods: 12 patients with a proven URAS ( . 50% lumen reduction) and positive renography (Tc MAG3 scan)

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entered a single blind, prospective, cross-over randomised trial. After 1week therapy-off patients were randomised for enalapril 20 mg bid or losartan 50 mg bid for 8 weeks. After 8 weeks cross-over therapy another 8 weeks with combination of both drugs followed. Primary endpoint was change in 24 hour ambulatory blood pressure (24 hr BP, Spacelabs). Secondary endpoints were renal hemodynamics (Inuline and Hippurate clearances) and humoral responses (renin, A-II and aldosterone). Results: Three patients did not complete the trial (due to angina pectoris and lungcancer) Losartan decreased 24 hrBP from 168 / 90 / 117 to 148 / 80 / 104 mmHg ( p , 0.05) and Enalapril decreased 24 hr BP to 155 / 87 / 111 mmHg ( p , 0.05,diff in drugs NS). GFR decreased on both drugs(NS), while RPF only decreased on losartan. Addition of either drug to monotherapy resulted in a 24 hr BP of 148 / 82 / 103 mmHg (NS, compared with monotherapy and no further change in renal haemodynamics) Conclusion: Enalapril and Losartan are equally effective in lowering BP in patients with RVHT, due to URAS. Both drugs are safe in terms of renal function. We did not find an additive effect of combination therapy, which is not in support with escape of A-II-formation in RVHT. 102. Arterial baroreflex and peripheral chemoreflex function after bilateral carotid body tumor resection. H.J.L.M. Timmers 1 , W. Wieling 2 , H.Th.M. Folgering 3 , J.M. Karemaker 4 , J.W.M. Lenders 1 . 1 Department of Internal Medicine, 3 Department of Pulmonary Disease: University Hospital Nijmegen, 2 Department of Internal Medicine, 4 Department of Physiology: Academic Medical Centre, Amsterdam, The Netherlands. Bilateral carotid body tumor surgery (CBTS) may result in baroreflex failure, producing severe, labile hyper- and hypotension. Whether CBTS affects chemoreceptor function is unknown. In carotid body denervated asthmatic patients, ventilatory response to hypoxia is absent. objective: To assess arterial baroreflex and peripheral chemoreflex function in non-selected CBTS patients. patients and methods: We examined 7 CBTS patients (2m:5f, mean6sd age: 53.4612.3 years) with a median interval between treatment and examination of 3.7 (range 1.3–20.6) years and 9 healthy controls (5m:4f, 50.769.8 years). Baroreflex sensitivity (BRS) was measured using phenylephrine. Standard cardiovascular reflex testing was performed to assess overall baroreflex integrity. Ventilatory response to hypoxia as a measure of peripheral chemoreceptor function was assessed. results: BRS was lower in CBTS patients (6.168.1 ms / mmHg) as compared to controls (14.865.8 ms / mmHg, p , 0.05). Normal responses to forced breathing, Valsalva’s maneuver, standing up, and cold face test suggested intact overall baroreflex integrity in all subjects. During ambulatory blood pressure measurements, 2 CBTS patients had excessive pressure variability without symptoms. In response to hypoxia under normocapnic or hypercapnic ( 1 1 kPa) conditions, controls showed an increase in ventilation of 0.2260.09 l / min / %SaO2 and 1.7161.38 l / min / %SaO2 respectively. In contrast, ventilation did not increase in CBTS patients (20.0260.37 l / min / %SaO2 and 0.0960.20 l / min / %SaO2 respectively, difference: p , 0.05). conclusion: Bilateral carotid body tumor resection may result in decreased baroreflex sensitivity, but does not necessarily elicit clinically relevant baroreflex failure. In addition, CBTS

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abolishes chemoreceptor reflex mediated ventilatory response to hypoxia. 103. Hyperinsulinemia contributes to impaired endotheliumdependent vasodilation in chronic hypertriglyceridemia. 1 1 1 I.J.A.M. Jonkers , A.H.M. Smelt , F.H.A.F. de Man , A. van der Laarse 1 , A.M. Kamper 1 , G.J. Blauw 1 . Leiden University Medical 1 Center , Albinusdreef 2, 2300 RC Leiden. Tel.: 071 -5264654; Fax: 071 -5248159, e-mail: IJAMJonkers@ lumc.nl Introduction: There is controversy regarding the relation between chronic hypertriglyceridemia (HTG) and endothelial dysfunction. Hyperinsulinemia is associated with endothelial dysfunction as well. Since HTG is often accompanied by hyperinsulinemia, we hypothesized that hyperinsulinemia and not HTG per se causes endothelial dysfunction in chronic HTG. Aim of the study: To compare endothelial function in patients with chronic hypertriglyceridemia with high and moderate hyperinsulinemia to that of normolipidemic controls. Materials and Methods: Eleven non-smoking, normotensive patients with endogeneous HTG participated in the study. Data of these patients were dichotomized around the median of serum insulin levels, resulting in the formation of 2 groups: a HTG group with high hyperinsulinemia (HTG-HHI) and a HTG group with moderate hyperinsulinemia (HTG-MHI). Both groups were compared to a control group, consisting of 16 normolipidemic, nonsmoking, normotensive individuals. Cumulative-dose infusions of serotonin and sodium nitroprusside were infused locally into the brachial artery to study endothelium-dependent and endotheliumindependent vasodilation, respectively. Results are expressed as median (IQR). Results: Age and body mass index were similar in all groups. Triglycerides levels were significantly lower in the control group than in both HTG groups (both p , 0.01), whereas no significant difference in serum triglycerides was noted between the HTGMHI and the HTG-HHI group (serum triglycerides 0.8 (0.7–1.2) vs. 8.7 (5.8–9.2) and 7.5 (6.6–12.9) mmol / L in controls, the HTG-MHI and the HTG-HHI group, respectively). Insulin levels were higher in the HTG-HHI group than in the HTG-MHI and control group (43.0 (35.0–52.5) vs. 20.0 (14.5–25.3) and 11.0 (7.8–12.0) mU / L, respectively, both p , 0.001). No significant differences were observed in serotonin-induced endothelial-dependent vasodilation between HTG-MHI and controls. In contrast, the response to serotonin was attenuated in the HTG-HHI group compared to the control group (low and high dose by respectively 2 60 and 2 49%, both p , 0.01), and tended to be lower than in the HTG-MHI group as well (243%, p 5 0.068 and 2 31%, p 5 0.100 respectively). No significant differences were observed in nitroprusside-induced endothelium-independent vasodilation between the three groups. Conclusion: These findings suggest that endothelial dysfunction in chronic HTG is determined by hyperinsulinemia and not by triglycerides concentrations per se. 104. Long distance travelling increases risk of pulmonary embolism. ten Wolde M., Quak E., Prins M.H., Kraaijenhagen ¨ R.A., Buller H.R., on behalf of the ANTELOPE-Study Group. Department of Vascular Medicine, Academic Medical Centre,

Meibergdreef 9, 1105 AZ Amsterdam, Tel.: 020 -5667050, Fax: 020 -6968833, e-mail: m.tenwolde@ amc.uva.nl The relationship between travelling and venous thrombosis is debated. Previous studies revealed a correlation between the two, which was recently refuted by a prospective study. This study showed no correlation between deep venous thrombosis and travelling. We studied the relationship between pulmonary embolism (PE) and travelling. So far, no solid methodological study about the relationship between travelling and this potentially fatal manifestation of venous thromboembolism (VTE) has been reported. We prospectively studied consecutive patients suspected of PE. The diagnosis of PE was confirmed or refuted according to the outcome of a diagnostic management strategy, using a clinical estimate, a D-dimer test, ventilation perfusion (V/ Q) lung scintigraphy, serial ultrasonography of the legs, spiral computer tomography (CT) and 3 months of clinical follow-up. Cases were considered to be patients with PE confirmed by a high-probability scintigram, a non-high probability scintigram in combination with a positive ultrasonogram or abnormal spiral CT. The patients in whom PE was rejected served as controls. In both groups the travel history – defined as non-stop travelling for at least three hours in the previous four weeks – was compared. From May 1999 until August 2000, 813 patients were included. PE was confirmed in 198 patients (24%). Fourteen patients with PE had been travelling (7.1%), while in the control group 44 patients had a recent travel history. An odds-ratio (OR) – adjusted for cancer, surgery, thrombophilia, previous venous thromboembolism and a positive family history – of 0.7 (95% CI: 0.3–1.7) was found. When the means of transport were studied separately an adjusted OR of 1.1 (95% CI: 0.3–3.3) was found for air travel, whereas the adjusted OR of travelling by other types of transport was 0.5 (95%CI; 0.1–2.01). Interestingly, the OR increases when the duration of travelling becomes longer: the OR was 1.0 (95% CI: 0.04–2.7), 1.5 (95% CI: 0.5–4.3) and 1.8 (95% CI: 0.6–5.2) for travelling for more than 4, 6 and 8 hours respectively. We conclude that although median travelling for 4 hours does not relate to an increase risk of PE, it appears that long distance travelling may be associated with an enhanced risk of PE. 105. Systemic and renal effects of exogenous angiotensin II: blocking perspective of candesartan cilexetil as compared to losartan and placebo. J. Willemsen 1 , C. Gaillard 1 , T. Rabelink 2 . 1 Eemland Hospital Amersfoort, Departments of Internal Medicine, 2 University Hospital Utrecht, Netherlands. Eemland Hospital, Postbus 1502, 3800 BM Amersfoort, Tel.: 033 -4222444, fax: 033 -4222695, e-mail: jmrwillemsen@ hetnet.nl Introduction: Candesartan cilexetil is reported to have superior and insurmoutable AT 1-receptor blocking perspective as compared to other angiotensin II antagonists. This may be of utmost importance, since angiotensin II is a powerful vasoconstrictor and plays a major role in regulating vascular tone and renal vascular resistance. Aim of the study: The purpose of this study was to determine the blocking perspective of candesartan cilexetil as compared to losartan and placebo during angiotensin II infusion, by measuring bloodpressure and renal haemodynamics. Design and Methods: A randomized, double blind, crossover

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Internistendagen 2001 study, in which thirteen patients were selected with mild to moderate essential hypertension. The patients received after three weeks placebo run-in, either candesartan cilexetil 16 mg, losartan 50 mg or placebo once daily for four weeks. After each period 24 hours ABPM and urine sampling were carried out. Three clearance-studies were performed 24 hours post dose during baseline and cumulative infusion dose of angiotensin II (1, 3, 10 and 30 ng / kg / min). Results: Candesartan cilexetil reduced the 24 hours ABPM more (141 / 87 mmHg) than losartan (146 / 89 mmHg). Candesartan cilexetil and losartan attenuated but did not abolish the angiotensin II induced response on ERPF and RVR. The magnitude of this effect was greater with candesartan cilexetil. During cumulative infusion dose of angiotensin II the GFR decreased clearly with losartan and placebo. This angiotensin II induced decrease did not appear in the candesartan treated group (see table).

Placebo Losartan Candesartan cilexetil

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rFVIIa as a single intravenous bolus dose or placebo during the operation. The volume of peri-operative blood loss was assessed by measurement of blood-volume in suction containers, weighed swabs and drains. Perioperative transfusion requirement was monitored as well. To evaluate safety, physical examination, blood sample analysis and electrocardiography were performed daily up to 10 days post-operatively and ultrasonography of the legs was performed pre- and post-operatively. The data presented are based on the results of an interim analysis by an independent committee. Results: Thirty-six patients were enrolled in the study. The mean volume of blood loss was 2450 (6350) in placebo-treated patients. Treatment with recombinant FVIIa resulted in mean blood loss of 1400 ml (6190), a reduction of 45% ( p 5 0.007). Six out of ten placebo-treated patients (60%) required at least one red cell transfusion, compared to 3 / 8 (38%) patients that were treated with rFVIIa at a dose of 20 mg / kg. Treatment with rFVIIa

24 hABPM

MmHg

ml / min

baseline

Angiotensin II ng / kg / min

1

3

10

30

SBP DBP SBP DBP SBP DBP

152 94 146 89 141 87

GFR ERPF GFR ERPF GFR ERPF

117 516 119 543 116 537

GFR % ERPF% GFR% ERPF% GFR% ERPF%

29 2 16 26 26 4 0

2 10 2 29 2 11 2 21 26 2 15

2 12 2 37 2 12 2 26 1 2 17

2 12 2 38 28 2 31 21 2 28

Conclusion: The present study demonstrates that candesartan cilexetil 16 mg is more effective in lowering 24 hours ambulatory bloodpressure than losartan. Interestingly the constrictor actions of angiotensin II on renal haemodynamics, particularly GFR, are attenuated more effectively with candesartan cilexetil than with losartan. Through which mechanism this occurs remains to be established. 106. Reduction of perioperative blood loss and transfusion requirement in patients undergoing transabdominal retropubic prostatectomy by administration of recombinant activated factor VII. P.W. Friederich, Ch.P. Henny, E.J. Messelink, D. Breederveld, M.G.F. Geerdink, M. Spataro, K.H. Kurth, ¨ H.R. Buller, M. Levi. Departments of Vascular Medicine, Internal Medicine, Anesthesiology and Urology, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands. Tel.: 020 -5669111, Fax. 020 -6968833, e-mail: P.w.Friederich@ amc.uva.nl Introduction: Transabdominal retropubic prostatectomy is associated with significant peri-operative blood loss, often requiring blood transfusion. Several studies have indicated that systemic administration of recombinant activated factor VII (rFVIIa, NovoSeven) induces short-term local hemostasis. Aim of the study: To evaluate the safety and efficacy of rFVIIa on blood loss reduction in patients with normal blood coagulation undergoing transabdominal prostatectomy. Materials and Methods: Patients scheduled to undergo transabdominal prostatectomy were randomized to receive either

at a dose of 40 mg / kg completely prevented the need for red cell transfusion in all 12 patients. None of the patients developed venous thromboembolism or any other serious adverse event. Conclusion: A single bolus injection of rFVIIa appears to reduce peri-operative blood loss and requirement of blood transfusion in a safe and effective manner in patients without coagulation defects undergoing transabdominal prostatectomy. Definite conclusions, however, must await completion of subsequent larger studies. 107. Non-steroidal anti-inflammatory drugs do not cause first occurrence of heart failure, but are associated with relapsing heart failure; The Rotterdam Study. J. Feenstra, MD, PhD 1,2,5 , E.R. Heerdink, PharmD, PhD 3 , D.E. Grobbee, MD, PhD 4 , B.H.Ch. Stricker, MB, PhD 1, 2 . 1 Pharmacoepidemiology Unit, Departments of Epidemiology & Biostatistics and Internal Medicine, Erasmus Medical Center Rotterdam, The Netherlands. 2 Drug Safety Unit, Inspectorate for Health Care, The Hague, The Netherlands. 3 Department of Pharmacoepidemiology and Pharmacotherapy, University of Utrecht, Utrecht, The Netherlands. 4 Julius Center for Patient Oriented Research, Utrecht Medical Center, Utrecht, The Netherlands. 5 Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, The Netherlands. Address: Alberts Schweitzer Ziekenhuis Locatie Amstelwijck, Van der Steenhovenplein 1 Postbus 444 3300 AK Dordrecht, Tel.: 078 6541111 sein 459; Fax: 078 -6541999, e-mail: j.feenstra@ freeler.nl Introduction: Non-steroidal anti-inflammatory drugs (NSAIDs)

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have been associated with a first hospitalisation of congestive heart failure (CHF). Based on the pathophysiology of NSAIDinduced CHF, however, it seems more likely that NSAIDs may precipitate relapsing CHF in patients with prevalent heart failure, and that NSAIDs are less likely to induce a first occurrence of heart failure. Objective: to estimate the risk of NSAID-induced CHF in patients with incident CHF as well as in patients with prevalent CHF. Design: prospective population-based cohort study (Rotterdam Study). Methods: 7,277 participants of the Rotterdam Study were followed from the inclusion date until the first of one of the following events: a diagnosis of incident heart failure, death, removal from the study area or institutionalisation, or end of the follow-up period. Incident heart failure was encountered in 345 participants during follow-up. Excluded from the study population were all participants with prevalent CHF at baseline or an uncertain diagnosis during follow-up. Exposure to NSAIDs and other medication was calculated on the basis of automated data on filled drug prescriptions in the pharmacies within the study area. In a second analysis, we followed all participants with incident heart failure until the first relapse or the end of followup. Results: Current use of NSAIDs was associated with a relative risk of incident CHF of 1.11 (95% CI; 0.74–1.68), after adjustment for age, gender, and concomitant medication. In patients with prevalent heart failure who filled at least one NSAIDprescription since diagnosis of CHF, the univariate and multivariate risk estimates of NSAIDs-associated relapsing CHF were respectively 3.79 (95% CI: 1.13–12.73) and 9.89 (95% CI: 1.72– 57.01). Conclusion: NSAIDs are not associated with an increased risk of incident CHF. In patients with prevalent CHF, current use of NSAIDs is associated with a substantially increased risk of relapsing CHF, which is in accordance with the supposed pathophysiological mechanism. 108. Mortality over 2 centuries in a large pedigree with familial hypercholesterolaemia: gene-environment interaction. Eric J.G. Sijbrands 1 , Rudi G.J. Westendorp 2 , and John J.P. Kastelein 1 . 1 Dept. of Vascular Medicine and General Internal Medicine, Academic Medical Center, Amsterdam and dept. of 2 Clinical Epidemiology, Medical Faculty, Leiden University Medical Center. Tel.: 1 31.20.5669111, Fax: 1 31.20.6164629, email: e.j.sijbrands@ amc.uva.nl. Introduction: The mortality risk from heterozygous familial hypercholesterolaemia (FH) may have been overestimated in families that were investigated because several members had presented with premature vascular disease. The sequelae of the disorder have not been studied without such selection on cardiovascular disease. Aim of the study: To estimate all-cause mortality from untreated FH free from selection on coronary artery disease (natural history). Materials and Methods: In a large pedigree that went back to a single pair of ancestors in the nineteenth century, we traced all

persons over 20 years of age with 0.5 probability of carrying an FH causing mutation. All-cause mortality among the family members was compared to the Dutch population by standardised mortality ratios (SMR’s) and between groups with Poisson regression. Results: A total of 70 deaths took place among 250 persons in 6950 person-years. Mortality risk in mutation carriers was not increased during the nineteenth and early twentieth century; it rose after 1915, reached it’s maximum between 1935 and 1964 (SMR 1.78, 95% confidence interval 1.13 to 2.76, p 5 0.003) and declined thereafter. Strikingly, the mortality differed significantly between two branches of the pedigree (relative risk 3.26, 95% confidence interval 1.74 to 6.11, p 5 0.001). Conclusions: In contrast with previous studies, we found that mortality risk varies significantly among FH patients. This large variability of mortality risk over calendar time and between branches of the pedigree points to a strong interaction with environmental factors. Future research is required to identify those individuals with FH who are at extreme risk and need early and vigorous preventive measures. 109. Muscle tensing enhances cerebral artery blood velocity and oxygenation in patients with sympathetic failure. M.P.M. Harms 1 , W.N.J.M. Colier 3 , W. Wieling 1,2 , J.W.M. Lenders 4 , N.H. Secher 5 and J.J. van Lieshout 1,2 . 1 Cardiovascular Research Institute Amsterdam; 2 Dpt of Internal Medicine, Academic Medical Centre Amsterdam; 3 Departments of Physiology and 4 Internal Medicine, 5 University Hospital Nijmegen; The Copenhagen Muscle Research Centre, Department of Anaesthesia, Rigshospitalet, Copenhagen, Denmark. Introduction: In patients with sympathetic failure the standing position elicits orthostatic hypotension. In these patients when upright cerebral blood flow is close to the critical lower level of cerebral perfusion and an additional small reduction elicits symptoms of cerebral hypoperfusion. Orthostatic manoeuvres like tensing the legs may improve orthostatic tolerance and standing time although the effects on arterial pressure are limited. Aim of the study: To test the hypothesis that in patients with sympathetic failure muscle tensing improves orthostatic tolerance by enhancing cerebral perfusion and oxygenation. Materials and Methods: In eight patients (age 37–67 yrs, 3 females) with orthostatic hypotension related to PAF (n 5 7) or MSA (n 5 1) and eight healthy and age-matched controls the effects of leg muscle tensing by crossing the legs on cerebral perfusion (near-infrared spectroscopy determined cerebral oxygenation (oxy-hemoglobin, O2Hb) and transcranial Doppler ultrasound determined middle cerebral artery (MCA) mean blood velocity (Vmean) were assessed together with systemic circulatory variables (mean arterial pressure (Finapres) at brain level (MAPmca), cardiac output (CO) by modelling arterial flow from pressure, and total peripheral vascular resistance (TPR) as ratio of MAP and CO). Results: In the patients MAPmca dropped after 2 min of standing from 106 (85–134) to 36 (19–58) mmHg and CO to 66 (58–79) %. O2Hb decreased 2 8.2 (210.5 2 4.7) mol.l 21 and Vmean from 77 (64–123) to 55 (38–77) cm.s 21 . Leg tensing after 2 min standing raised MAPmca to 50 (28–73) mmHg, CO to 72

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Internistendagen 2001 (66–95) % and TPR from 84 (58–115) to 95 (68–118) %. O2Hb was 1 1.12 (0.52–3.27) mol.l 21 and MCA Vmean increased to 63 (45–80) cm.s 21 ( p , 0.05). In the controls the orthostatic decrease in O2Hb and Vmean was less with a smaller rise in MAPmca upon tensing (62 (56–73) to 71 (59–72) mmHg), an increase in CO (93 (75–109) to 103 (91–119) %) and TPR not significantly changed. O2Hb was 1 0.83 (20.11 2 2.04) mol.l 21 (n.s.) and MCA Vmean increased from 56 (46–77) to 64 (46–80) cm.s 21 . Conclusions: In patients with orthostatic hypotension related to sympathetic failure the higher MCA Vmean for a given level of arterial pressure supports a leftward shift of the lower limit of cerebrovascular autoregulation. Leg muscle tensing raises CO and TPR, probably by mechanical compression of the vascular beds in the legs and abdomen. Due to defective reflex vasodilatation mechanism in these patients the elevation in CO effectively raises MAPmca. This enhances cerebral oxygenation and artery blood velocity, and explains the improvement of orthostatic tolerance. 110. Plasma and urinary sex-hormones are differently related to lipids in healthy postmenopausal women. Marlies E. Ossewaarde 1 , Michiel L. Bots 1 , Yvonne T. van der Schouw 1 , Jos H.H. Thijssen 2 , H. Tineke Westerveld 3 , Frank H. de Jong 4 , Diederick E. Grobbee 1 , Julius Center for General Practice and Patient Oriented Research 1 , Dept. of Endocrinology 2 , Dept. of Internal Medicine 3 , University Medical Center Utrecht, Utrecht; Dept. of Internal Medicine, Erasmus University Medical School, Rotterdam 4 ; Heidelberglaan 100, 3584 CX Utrecht, Tel.: 030 2509354, Fax: 030 -2505485, e-mail: M.E.Ossewaarde@ jc.azu.nl Introduction: Studies on levels of endogenous sex-hormones and cardiovascular risk factors or clinically manifest disease in postmenopausal women show conflicting results. In most studies endogenous sex-hormones were measured in blood. However, measurement of urinary sex-hormones may provide an attractive alternative, as urine may reflect hormone levels over a longer period of time, and probably gives a more stable estimate of a woman’s estrogen status. Aim of the study: Endogenous sex-hormones may be measured in plasma and urine. We determined the extent to which these two methods provide different information on hormonal status by relating them to lipid profile in postmenopausal women. Materials and Methods: 30 healthy postmenopausal women collected one 24-hour urine-sample and a blood-sample was taken. Urinary estrone (UE), plasma estrone (PE), plasma androstenedione (PA) and serum lipids were measured. Sex-hormone levels were measured by means of specific radioimmunoassays. Linear regression analysis was used to determine associations between sex-hormones and lipids. Results are presented as bcoefficients in mmol / L per standard deviation of endogenous sex-hormone levels, adjusted for creatinin in 24-hour urine-samples, with corresponding 95% confidence intervals in parentheses. Results: Mean levels of endogenous sex-hormones were (with corresponding standard deviations in parentheses): PE 90.1 pmol / L (37.3), PA 4.5 nmol / L (2.3) and UE 7757 pmol / 24 hours (2659). PE and PA both showed significant associations with triglycerides (PE: 2 0.22 mmol / L (95%CI: 2 0.44; 2 0.01), PA: 2 0.23 mmol / L (95%CI: 2 0.45; 2 0.02)), very-low-density-

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lipoprotein (PE: 2 0.10 mmol / L (95%CI: 2 0.20; 2 0.004), PA: 2 0.11 mmol / L (95%CI: 2 0.20; 2 0.006)) and high-densitylipoprotein (PE: 0.18 mmol / L (95%CI: 0.06; 0.31), PA: 0.21 mmol / L (95%CI: 0.09; 0.33)). UE was inversely associated with total cholesterol (20.36 mmol / L (95%CI: 2 0.79; 0.07)) and low-density-lipoprotein (20.35 mmol / L (95%CI: 2 0.78; 0.08)). Adjustment for body mass index in a multivariate linear regression model did not change the results. Conclusion: Both plasma and urinary sex-hormones appear to be associated to serum lipids in healthy postmenopausal women. However, this relation appears to be different for sex-hormones in plasma and urine. Depending on future research questions, either blood-samples or urine-samples may be pre-ferred. 111. Inter-observer variability of clinical probability assessment in suspected pulmonary embolism. M.G.L. Leclercq, M. ¨ van Marwijk Kooy, H.R. Buller. Isala klinieken, locatie Sophia, Zwolle en Academisch Medisch Centrum, Amsterdam, postbus 10400, 8000 GK Zwolle, Tel.: 0384245750, e-mail: jl@ jagerleclercq.demon.nl The clinical probability of pulmonary embolism (PE), classified by either an overall judgement or a clinical model, gained new interest since the PIOPED investigators showed that clinicians are able to categorize patients into groups with a low, moderate and high probability, with a reasonable degree of accuracy to exclude PE. Recently clinical models have been designed to assess the clinical probability and have been used in management studies in suspected PE. The results of the accuracy and discriminatory power of the clinical probability however are in contrast with each other. Little is known about the inter-observer variability of the clinical probability. We performed a prospective study to investigate the interobserver variability of clinical probability assessment in in- and outpatients with suspected PE. The patients participated in a management study in which the outcome of the clinical probability was used in combination with a D-dimer test for further management. The clinical probability was tested by the clinical model described by Wells and colleagues and classified as low, moderate or high [1]. The model consists of risk factors for PE, signs and symptoms from history and physical examination and the results of chest X-ray, oxygen saturation tests and electrocardiography, as well as the likelihood for an alternative diagnosis. The clinical probability was assessed by the attending physician. A second physician with expertise in venous thrombosis then performed the same structured assessment independently on the same patient. Here we present the interim analysis of duplicate examinations of the first 40 patients. The clinical probability assessment varied in 12 (30%) patients. This was on account of a poor reproducibility of historical features including presence of (or worsening of chronic) dyspnoea, the likelihood of an alternative diagnosis and interpretation of chest X-ray or a combination of these factors. The presence of PE in the entire cohort was 35%. The observed accuracy and discriminatory power of the clinical probability was better while performed by the physician with expertise in venous thrombosis than performed by the attending physician. In conclusion even using a clinical model to categorize clinical

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probability, the inter-observer variability is high. A more objective and reliable clinical model must be developed to manage patients with suspected PE before it can be introduced into daily practice. Reference [1] Wells PS et al. Ann Intern Med 1998;129:997–1005 112. Possible association of post-streptococcal reactive arthritis and aortic arch arteritis. P.W. Kamphuisen 1 , C.M.A. de Gendt 2 , M.G.J. de Leede 2 , L. Verschoor 1 , M. Janssen 2 . Depts. of 1 2 Internal Medicine and Rheumatology, Rijnstate Hospital, Arnhem, The Netherlands. Dept. Internal Medicine, Rijnstate HospiTA, Arnhem, e-mail: tal, P.O. Box 9555, 6800 pkamphuisen@ rijnstate.nl Introduction: Post-streptococcal reactive arthritis (PSRA) is a syndrome following throat infection with b-haemolytic streptococci of Lancefield group A. Streptococcal infections are associated ¨ with several vascular syndromes like Henoch-Schonlein purpura, polyarteritis nodosa, and acute rheumatic fever. It is unclear whether PSRA can be also complicated by vasculitis. Case: A 42-year-old Moroccan woman was admitted with erythema nodosum and polyarthritis. Two weeks earlier, a sore throat was treated with feneticilline. Erythrocyte Sedimentation Rate (ESR) was 90 mm / hr, AST 1040 U / ml (n , 200), and anti-DNase B 214 U / ml (n , 200). PSRA was diagnosed and her complaints receded soon after starting diclofenac 150 mg / d. AST and anti-DNase B returned to normal in about six months. The patient received benzylpenicillin prophylaxis for two years. Five years later, she was re-admitted with high fever, abdominal pain, arthritis, erythema nodosum, and liver dysfunction preceded by a sore throat a few days earlier. She had normal arterial pulsation’s and a normal blood pressure. No signs of carditis were found, ESR, AST, and anti-DNase B increased to respectively 63 mm, 500 U / ml, and 1840 U / ml. Recurrence of PSRA was diagnosed, diclofenac and feneticilline were restarted and the patient recovered. Six months later she was re-admitted with complaints of headache, weakness, and paresthesia in the left arm after use. Blood pressure was not measurable, bilateral radial artery pulsations were completely absent, and a bruit was heard at the right carotid artery and between the scapulae. Angiographic examination showed subtotal stenosis of the aortic arch and right carotid artery and complete stenosis of the left subclavian and left carotid artery. MRI showed increased aortic wall thickness. ESR was 70 mm / hr, AST 290 U / ml, and anti-DNase B 400 U / ml. A throat swab was negative. Aortic arch arteritis was diagnosed and the patient was treated with 80 mg prednison. Her complaints and the interscapular bruit disappeared within a few days, but seven months after starting of the treatment radial artery pulsation’s are still absent. Discussion: This case report suggests that recurrent streptococcal infection was responsible for the development of aortitis and shows that PSRA can be complicated by vasculitis. 113. Haemolytic anaemia as a presentation of malignant hypertension. B.L.J. Kanen, A.B. Arntzenius, Spaarne Hospital Haarlem, Dept. of internal Medicine. Tugelaweg 105 B, 1091 VS

Amsterdam, Tel.: 020 -6938923 /06 -10800526, e-mail: boriskanen@ hotmail.com /boris wendy@ planet.nl ] A woman, 80 years of age, presented with fatigue, dizziness and a poor appetite. Haemoglobin-level was 6.6 mmol / l, the MVC 92 fl. Her medical history included a duodenal ulcer and hypertension treated with atenolol. One year previously macrocytic anaemia was found for which she was prescribed folic acid and vitamin B12 without further evaluation. She took no other medication. We saw a pale woman. Blood pressure was 150 / 80 mmHg with a regular heart rate of 85 beats per minute. Physical examination disclosed no pathological lymph nodes, petechiae, ecchymoses, or any other abnormalities. Laboratory investigation showed an anaemia of 6.1 mmol / l with a reticulocytosis of 126 3 10*9 g / l, a total bilirubin of 30 mmol / l, direct bilirubin 9 mmol / l, LDH 467 U / l and a haptoglobin of less than 0.06 g / l. The direct Coombs test was negative. In the blood-smear fragmentocytes were seen, D-dimer level was elevated to 2271 ng / l with a prolonged APTT and PT (45 and 15.5 seconds respectively). Thrombocyte count was 132 3 10*9 g / l. One day after admittance her blood pressure was 180 / 100 and rose to 210 / 110 mm Hg. By now she had a fierce headache, the haemoglobin-level was 5.1 mmol / l and LDH was 721 U / l. Electrocardiography suggested left ventricular hypertrophy, serum creatinin was 90 mmol / l (unchanged), serum sodium 139 mmol / l, potassium 3.0 mmol / L and urinary protein 1 1 1 . The sediment showed 15–20 red and 2–5 white blood cells per field and fundoscopic examination revealed grade 3 hypertensive retinopathy. After intravenous treatment with labetalol blood pressure was 130 / 75 mmHg and her headache disappeared. In retrospect the patient noticed ‘‘clouding of her mind’’ which was now improving. Haemoglobin-level rose to 6.9 mmol / l with normalisation of haemolytic parameters. No specific cause was found for accelerated hypertension or for Diffuse Intravascular Coagulation (DIC). Conclusion: Microangiopathic haemolytic anaemia and DIC can occur within the syndrome of malignant hypertension. What is remarkable in this case, is that the haemolytic anaemia was the primary reason for referral to hospital and that blood pressure was initially normal with symptoms of hypertensive encephalopathy (headache, clouding of consciousness) appearing later. This case shows that in a patient presenting with microangiopathic anaemia malignant hypertension should be considered in the differential diagnosis. 114. Evidence for safe exclusion of deep vein thrombosis (DVT) by a rapid ELISA D-dimer test in 434 consecutive outpatients with suspected DVT. J.J. Michiels, H.A.A. Kasbergen, P.H.Trienekens. Hemostasis and Thrombosis Research, Goodheart Institute Rotterdam, NL, Bloodcoagulation and Vascular Medicine University Hospital Antwerp, Belgium and STAR Medical Diagnostic Center Rijnmond Rotterdam, NL. A negative result of compression ultrasonography (CUS) safely excludes proximal DVT but usually overlooks distal calf vein thrombosis. The incidence of venous thromboembolic events after a negative CUS is 2 to 3% indicating the need to repeat CUS testing within one week (BMJ 1998;316:17, Ann Int Med

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Internistendagen 2001 1998;128:1). The rapid ELISA VIDAS D-dimer assay at a proper cut-of of 500 ng / ml did have a sensitivity of 100% for the exclusion of distal and proximal DVT as documented against venography in two clinical studies (Thrombosis and Haemostasis 1998;79:31, 2000;83:191). This may implicate that a negative rapid ELISA D-dimer test will always result in a negative CUS irrespective of clinical score. To test this hypothesis we performed a prospective study in 434 consecutive outpatients with suspected DVT. The prevalence of DVT was 23.5%. The CUS was positive in 102 with a rapid ELISA D-dimer test result of . 500 ng / ml in 101 and of , 500 ng / ml in one case. This patient with a negative ELISA D-dimer and positive CUS was clearly symptomatic with a 2 months history of DVT. The CUS was negative in 332 and the rapid ELISA D-dimer test was normal in 128 of which 127 had a negative CUS. Therefore, the performance of the rapid ELISA VIDAS D-dimer test for thrombosis exclusion has a sensitivity of 99% and a negative predictive value of 99.2% at a specificity of 38% irrespective of the clinical score of Wells. Therefore we conclude that it is safe to exclude DVT by a normal rapid ELISA D-dimer test in outpatients with suspected DVT. Attentive clinicians should be aware that after a negative rapid ELISA result, CUS is still indicated in patients with persistent complaints, signs and symptoms in search for an alternative diagnosis, or for DVT. The negative predictive value of the combination of a negative CUS and a rapid ELISA D-Dimer result of less than 1000 ng / ml is 99.6% at a specificity of 67%, thus obviating the need to repeat CUS in 2 / 3 of the patients with a negative CUS.

115. Accuracy of the Welch Allyn Vital Signs Monitor 52000 blood pressure measuring device. R.L. Braam, C.H.A. de Maat, Th. Thien. Department of Internal Medicine, University Medical Centre St. Radboud, Division of Hypertension and Vascular pathology, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands, Tel.: 024 -3618819 /3611111 /3233709, Fax: 024 -3541734. Introduction: The Welch Allyn Vital Signs Monitor (WA-VSM) is a small, light-weighted (2.5 kg.) device, measuring blood pressure (BP) oscillometrically. Objective: To determine the accuracy of the WA-VSM in normotensive and hypertensive persons using the protocols of the British Hypertension Society (BHS) 1993 and of the Association for the Advancement of Medical Instrumentation (AAMI). Methods: After calibration and a period of clinical use sequential measurements were carried out in 85 subjects with a variety of BPs. Two trained independent observers carried out simultaneous BP measurements using a mercury sphygmomanometer. These

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measurements were alternated with device measurements until a total of 7 measurements for each person was reached. The differences between the device- and the observer-measurements were calculated and subsequently the percentages of differences , 5, , 10 and , 15 mmHg. These percentages determine the achieved BHS-grade. Only devices with a grade A or B for diastolic and systolic blood BP (DBP,SBP) can be recommended for clinical use. Also the grades after first correcting for the systematic error can be calculated. Results: The percentages for , 5, , 10 and , 15 mmHg, were 43, 77 and 94 for DBP and 35, 68 and 90 for SBP. Therefore the grade is C for DBP and D for SBP. The mean difference (6SD) was 5.3 (66.7) for DBP and 7.5 (67.1) for SBP. After correction the grade for DBP and SBP both became B. Conclusion: The WA-VSM only achieved a grade C for DBP and a grade D for SBP, without correction and B for DBP and SBP with correction. Also the device did not meet the AAMIcriteria ( , 568). Although suitable for monitoring a patient based on our results the device can not be recommended for precise determination of the BP level. 116. Validation of the Welch Allyn Vital Signs Monitor against intra-arterial blood pressure measurements and measurements with the Dinamap 1846 SX. R.L. Braam, J.W.M. Lenders, Th. Thien. Department of Internal Medicine, University Medical Centre St. Radboud, Division of Hypertension and Vascular pathology, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands, Tel.: 024 -3618819 /3611111 /3233709, Fax: 024 -3541734 Objective: To validate the Welch Allyn Vital Signs Monitor (WA-VSM) to both intra-arterial (IA) measurements and BP measurements with the Dinamap 1846 SX (DIN). Methods: In 12 persons undergoing IA BP measurements, using a catheter placed in the brachial artery of the opposite arm, 10 supplementary BP measurements were done with the WA-VSM. Each device-measurement was compared to the mean systolic and diastolic IA BP registered during that device-measurement. In 26 other persons 10 simultaneous BP measurements were performed with the WA-VSM and the DIN in a random sequence, 5 at the left and 5 at the right arm. Subsequently the mean BP of all the 26 persons together were calculated separately for measurements 1 to 10. Results: The mean difference (6SD) between WA-VSM and IA-measurements was 2 4.8 (64.9) for diastolic BP (DBP) and 2 19.0 (67.3) for systolic BP (SBP). The mean difference (6SD) between WA-VSM and DIN-measurements was 2 1.5 (61.0) for DBP and 2 3.5 (61.4) for SBP (see figure).

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Conclusions: The mean difference for SBP and DBP between IA-measurements and BP measurements with the WA-VSM are comparable to those found for other oscillometrically measuring devices, however SD of differences are small [1]. Although the WA-VSM systematically measures BP lower, differences between WA-VSM and DIN are small. References [1] Van Egmond J, Lenders WM, Weernink E, Thien Th. Accuracy and Reproducibility of 30 devices for Self-Measurement of Arterial Blood Pressure. Am J Hypertens 1993;6:873–879. 117. D-Dimer testing in cancer patients with suspected deep venous thrombosis is clinically useful. M. ten Wolde, R.A. ¨ Kraaijenhagen, M.H. Prins, H.R. Buller. Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, Tel.: 020 -5667050, fax: 02 -6968833, e-mail: m.tenwolde@ amc.uva.nl Little is known about the value of a D-dimer test in cancer patients for the diagnosis of deep venous thrombosis (DVT). It is suggested that a D-dimer test might be of less value in cancer patients because of the lower negative predictive value (NPV) of the test in cancer patients than in non cancer patients. We evaluated the clinical usefulness of a whole blood rapid D-dimer  test (SimpliRED ) in cancer patients compared to non cancer patients. The sensitivity, specificity and predictive values of the test were assessed. In addition, we evaluated the safety and efficiency of withholding repeat ultrasonography in patients with a normal D-dimer test result. In consecutive patients with suspected DVT a D-dimer test and ultrasonogram were performed at the day of referral. The cancer status – defined as receiving (palliative) treatment for cancer or having received treatment for cancer in the past six months – was recorded at presentation. If the D-dimer test and ultrasonogram result at the day of referral were normal, DVT was considered absent and no further testing was performed. If the D-dimer test result was abnormal, ultrasonography was repeated one week later. Anticoagulant therapy was only instituted in those patients with an abnormal ultrasonography result. All patients were followed up for three months to record subsequent thromboembolic events. 1739 Patients were studied of whom 217 suffered from cancer (12%). The sensitivity of the D-dimer test in cancer patients (98%) was higher than in non-cancer patients (93%). The negative predictive value of the D-dimer test was 97% in both cancer and non cancer patients. In 63 of all 217 cancer patients (29%) the D-dimer and ultrasonography result were normal at the day of referral and anticoagulant treatment was withheld. In these 63 patients one thromboembolic event occurred during follow-up (1.6% [95% CI: 0.04%–8.53%]). In conclusion, the negative predictive value of a whole blood D-dimer test in cancer patients is as high as in non cancer patients. Secondly, the low complication rate after withholding anticoagulant treatment indicates that it is safe to reject the diagnosis DVT when both a normal ultrasonogram and a normal D-dimer test result are obtained. Lastly, the strategy of using a combination of a D-dimer test and ultrasonography is efficient. In a substantial proportion of cancer patients suspected of DVT repeat ultrasonography and

therefore an extra hospital visit could be avoided. Thus, D-dimer testing is clinically useful in cancer patients. 118. Diagnostic accuracy of the SimplifyE d-dimer test in patients suspected of deep venous thrombosis and pulmonary embolism. ten Wolde M., Koopman M.M.W., Oskam I.M., Meyers ¨ J.C.M., Buller H.R. Department of Vascular Medicine, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, Tel.: 020 5667050, Fax: 020 -6968833, e-mail: m.tenwolde@ amc.uva.nl The role of D-dimer tests in the diagnostic management of venous thromboembolism (VTE) is becoming increasingly important. It has been shown that conventional diagnostic procedures can be avoided in the diagnostic work-up of patients suspected of VTE when a normal D-dimer test result is obtained. Rapid D-dimer tests are the most suitable tests to fulfil this role regarding the acute nature of the disease. Of the rapid D-dimer tests the bedside D-dimer test has as an extra advantage that only a drop of blood is needed and that the result of the test is available within 10 minutes. However, most of all the available bedside tests are still limited by a rather laborious procedure. With the SimplifyE D-dimer test (AGEN Biomedical Ltd, Brisbane, Australia) this disadvantage is overcome. In this test a drop of whole blood or citrated plasma is applied at the test device and by way of immunochromatography a coloured line will appear when D-dimer levels are above the cut-off level (80 ml). In the present study we assessed the diagnostic accuracy of this new D-dimer assay. The sensitivity, specificity and negative predictive value were determined in consecutive patients with suspected deep venous thrombosis (DVT) and pulmonary embolism (PE). Patients were considered to have DVT in case of non-compressibility at ultrasonography. DVT was ruled out after a normal SimpliREDE D-dimer test result (AGEN Biomedical Ltd, Brisbane, Australia) in combination with normal ultrasonography or normal serial ultrasonography. The diagnosis PE was established after a high-probability ventilation perfusion (V/ Q) lung scintigram or by an abnormal angiogram. A normal V/ Q scintigram or a normal angiogram excluded PE. 67 Patients suspected of DVT were included. In 24 patients the diagnosis was confirmed (36%). The sensitivity, specificity and negative predictive value of the test was 92% (95% CI: 73%–99%), 61% (95% CI: 44%– 75%) and 93% (95% CI: 77%–99%), respectively. A total of 70 patients suspected of PE were screened. PE was present in 16 patients (23%). The sensitivity, specificity and negative predictive value of the test was 88% (95% CI: 62%–98%), 57% (95% CI: 43%–71%) and 94% (95% CI: 80%–99%), respectively. In conclusion, the SimplifyE D-dimer test shows a good accuracy, which is comparable with other available D-dimer assays. The easy practicability of this assay makes it an attractive exclusion test to rule out the diagnosis of VTE. 119. DNA typing for thrombophilia-related factor V Leiden and prothrombin G20210A mutations by multiplex PCR and reverse hybridisation LiPA in 473 thrombosis patients. W. Posthuma 1 , G.A.E. Ponjee 1 , J.J. Michiels 2 , E. Stef 3 , W.G. Quint 3 and L.J. van Doorn 3 . Reinier de Graaf Hospital Delft, Clinical Hemostasis and Thrombosis Goodheart Centre Rotterdam and

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Internistendagen 2001 University of Antwerp, Molecular Diagnostics Delft Diagnostic Laboratory. We performed DNA screening for multiple inherited mutations associated with thrombophilia by multiplex PCR followed by reverse hybridisation of PCR products on a line probe assay (liPA) with probes specific for wild type and mutant sequences (Leyte et al. Thromb Haemostas 2000; 354–5). DNA was isolated from 220 ul EDTA Blood with a Qiamp Blood Mini Kit (QIAGEN GmbH, Hilden Germany). DNA was eluted in 200 ul buffer (10 mM Tris-HCL, 0.5 M EDTA, PH 9.0). A multiplex PCR was performed by amplifying specific sequences of the wild and mutant Factor V Leiden (FVL) and prothrombin (FI)I. The labeled PCR products were simultaneously analysed by reverse hybridisation with specific probes for FV Arg506Gln and prothrombin G20210A on a LiPA in a semi-automated assay. Results: The clinical significance of the multiplex PCR-LiPA method for screening on inherited thrombophilia was tested in 473 patients with deep vein thrombosis. The most prevalent mutation in this population was FVL (Arg 506Glu) 27%, n 5 127 (n 5 123, 26% heterozygotes and n 5 4, 1% homozygotes. FII mutant G20219A was found in 29 (6%) patients (all heterozygotes). Conclusions: The simultaneous determination of FVL and FII mutant by multiplex PCR and LiPA is a reliable alternative for APC-resistance(APCR) testing and separate PCR tests for detection of mutants. With multiplex DNA and automatically LiPA method it becomes possible to type simultaneously and quickly thrombophilia related DNA mutations The semi-automatic method permits upscaling of the testing to type effectively in health care. In view of the high incidence of FVL and FII mutant in thrombosis patients, it is advised to first type on these two mutants instead of screening for APCR, protein C and S.

VIII. Gastroenterology 120. Ulcerative jejunitis: a good response to treatment with cladribine. G.C. Admiraal 1 , J.J.M. van Meyel 1 , C. Mulder 2 , W.L.E. Vasmel 1 and M. Vidakovic 1 , 1 Sint Lucas Andreas Ziekenhuis, address: J.Tooropstraat 164,1006 AE, Amsterdam. Tel.: 020 -5108770, fax: 020 -6838771, e-mail: j.vanmeyel@ slaz.nl. 2 Rijnstate Ziekenhuis, Arnhem. Introduction: Ulcerative jejunitis is a form of refractory celiac disease. Prognosis is poor. Patients are often non-responsive to treatment with steroids with or without azathioprine. Many patients appear to develop enteropathy associated T-cell lymphoma (EATL). This lymphoma has a very poor prognosis even with chemotherapy treatment. In literature we found that patients with celiac disease, who have ulcers, have monoclonal gene rearrangements on the T-cell receptor g in the intra-epithelial lymphocytes (IEL), suggesting a continuity from ulcerative jejunitis to lymphoma. Looking at the surface markers expressed by the IEL; patients who develop EATL express a high percentage surface CD3 (sCD3) negative but intracytoplasmatic CD3 (cCD3) positive cells [1]. This also suggests the development of lymphoma in patients with nonresponsive celiac disease, although this cannot yet be classified as EATL because of the lack of cytological abnormality [2].

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Case: We describe a 64-year-old man who was presented on our emergency ward with extreme pain in his left upper abdomen related to food-intake. His stools were normal and he was taking his diet persistently. He lost approximately 7 kilograms of weight in a short time. Two years ago he was diagnosed to have celiac disease, for which he was treated successfully with gluten-free diet. Physical examination of his abdomen showed signs of peritoneal inflammation in his left upper abdomen. 9 Laboratory results: ESR 16 mm / hr, leucocytes 11.10 / liter, CRP 97 mmol / l and albumen 29 gr / l. Liver and pancreas enzymes were normal. Upper gastrointestinal endoscopy showed many ulcers in his jejunum with stenosis of the lumen. On biopsy, ulceration was found combined with villous atrophy compatible with celiac disease. As a result of these findings the diagnosis ulcerative jejunitis was made. Our patient had 50% cCD3 positive / sCD3 negative IEL, which makes him at risk for developing EATL. He was treated according to a study protocol with cladribine 0.1 mg / kg / day intravenously during 5 days [3]. He underwent therapy without side effects. Six months later, he has gained over 20 kilograms in weight, endoscopic lesions disappeared and the percentage of cCD3 positive / sCD3 negative IEL decreased. Conclusion: Although cytological not malignant, ulcerative jejunitis may be considered as a developing lymphoma. Especially patients who express over 50% cCD3 positive / sCD3 negative IEL can be considered to have an early form of EATL. We describe a patient, with these characteristics, who was treated with cladribine, with good response. References [1] Cellier C, Patey N, Mauvieux L, Jabri B, Delabesse E, Cervoni JP, Burtin ML, Guy-Grand D, Bouhnik Y, Modigliani R, Barbier JP, Macintyre E, Brousse N and Cerf-Bensussan N. Abnormal intestinal intraepithelial lymphocytes in refractory sprue. Gastroenterology 1998;114(3):471–81. [2] Bagdi E, Diss TC, Munson P and Isaacson PG. Mucosal intra-epithelial lymphocytes in enteropathy associated T-cell lymphoma, ulcerative jejunitis and refractory celiac disease constitute a neoplastic population. Blood 1999;94(1):260–4. [3] Mulder C. Safety and activity of cladribine (leustatin  ) in refractory celiac disease. (study-protocol) 121. Hepatocellular carcinoma in a healthy liver. E.M.G. Jacobs, R.A. de Vries, Dep. of Internal Medicine, Rijnstate hospital, Arnhem, the Netherlands.Postbus 9555, 6800 TA Arnhem. Tel.: 026 -3788888. Fax: 026 -3787878, e-mail: ejacobs@ rijnstate.nl Devellopment of hepatocellular carcinoma (HCC) is one of the major risks of chronic liver disease, in particular cirrosis. With the exception of the fibrolammellar variant, HCC is almost invariable associated with the presence of cirrhosis or chronic viral hepatitis. A 53-year old woman was referred to our hospital with jaundice. She complained of attacks of progressive pain in the right upper quadrant of the abdomen. Her urine was dark colored, the feaces yellowish from time to time. Eating aggravated the

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complaints. Medical history revealed hypertension and hyperthyreoidea. For the latter she was treated with I 131 and external radiotherapy on the orbits. She had no history of alcohol abuse or hepatitis. Medication prescribed consisted of thiamazol, levothyroxin, atenolol, temazepam and pravastatine. Clinical examination revealed, except jaundice, no abnormalities as spider angiomata or hepatosplenomegalie were found. Laboratory results on admission: bilirubin total 88 (0.0–17.0) mmol / l, bilirubin conjugated 53(30.0–3.0) mmol / l, alkaline phosphatase 451 (1– 120) U / l, g-GT 637 (1–35) mmol / l, ASAT 148 (1–40) U / l,), ALAT 313 (1–45) U / l, LDH 559 (1–450) U / l. Hepatitis B and C serology were negative. No a 1 -antitrypsine deficiency, or elevated transferrin saturation. Ultrasound of the upper abdomen showed dilated intrahepatic bileducts. The diameter of the common bile duct (CBD) was 5 mm. There was a high-density signal with disturbing signals in the region of the gallbladder and the CBD, compatible with calcifications. The liver had an irregular aspect in the posterior part of the right lobe. Suspecting chole(docho)lithiasis our patient was proposed to undergo an ERCP. She refused, afraid of swallowing the endoscope even under sedation. Laparoscopic surgery was performed. A malignant tumour of the right liver lobe was found, with macroscopic growth into the liver hilus. Histological examination revealed a HCC in healthy liver tissue. There were no signs of chronic hepatitis, cirrhosis, a 1 antitrypsine deficiency or accumulation of copper or. Curative surgery of the HCC was performed in a specialised academic surgical liver centre. Unfortunately, due to septic complications, the patient died in the postoperative period. The occurrence of HCC without associated liver disease is extremely rare. Because these patients are not under surveillance the diagnosis will be made relatively late. As a consequence the prognosis will be unfavorable as illustrated by this case. 122. Post-ERCP pneumoperitoneum does not necessarily need surgical management. K. Rostami, J. Wolthuis, L. van Bergeijk. Department of Internal Medicine, Twenteborg Hospital, P.O. Box 7600, 7600 SZ Almelo, The Netherlands. Tel.: 0546 -833333; Fax: 056 -833418, e-mail: krostami@ hotmail.com Pneumoperitoneum is mostly attributed to a perforated viscus and generally requiring emergency surgery. We report a case of acute pancreatitis complicated by post-ERCP pneumoperitoneum.A 31-year-old woman was admitted because of prominent upper abdominal pain, nausea, and vomiting. The diagnosis of pancreatitis was made based on clinical presentation and high levels of serum amylase 2500 U / L (normal 5–160 U / L) and serum lipase 973 U / L (normal 0–190 U / L). Two days after ERCP, abdominal roentgenograms and MRI showed massive free air under the diaphragm. There were no signs of peritonitis. Treatment was initiated with gastric suction, antibiotics and parenteral alimentation followed by oral feeding, after which pneumoperitoneum disappeared. Conclusion: Peritoneal penetration is a poor indicator of severe organ injury. Post-ERCP pneumoperitoneum in this case displayed a benign outcome, and resolved with conservative measures. Lack of clinical awareness about these small but significant subset of patients who present with postendoscopic pneumoperitoneum is a source of needless laparotomies that at times can lead to serious postoperative complications.

123. Clinical manifestations of hepatic sarcoidosis: a distinct entity? M.A. Hoefnagels, R. van Leusen, K.J. Parlevliet, R.A. de Vries. Department of Internal Medicine, Rijnstate Hospital, Arnhem. Introduction: The clinical features of sarcoidosis are variable depending on the affected organs. A diagnosis is usually made between the 20th and 40th year of life. There are often nonspecific systemic symptoms present. Although hepatic involvement is rather common, this occurs almost invariably without clinical symptoms and biochemical signs of liver disease. The presence of granulomas in the liver covers a wide range of differential diagnostic possibilities. The most common causes are infections (tuberculosis), autoimmune diseases (PBC) and drug reactions. Sarcoidosis with clinical manifestations of liver disease is rare, active systemic disease with localisation confined to the liver even more. In very few patients signs of liver dysfunction are present, leading to cholestasis, jaundice or even portal hypertension. Case history: We describe an eighty-year-old man with symptomatic hepatic sarcoidosis. This patient was admitted to hospital for analysis of 20-kg loss of weight in a few months despite a normal appetite. He didn’t have any other complaints. Because of hypertension, acetylsalicylic acid and amlodipine were prescribed earlier on. There was no alcohol abuse. Physical examination revealed hepatomegaly but no (other) signs of chronic liver disease and a normal body temperature. Laboratory tests showed bilirubin 11 mmol / l, ALP 693 U / l, gamma-GT 261U / l, ASAT 47 U / l, ALAT 23 U / l, calcium 2,87 mmol / l, albumin 26.4 g / l and gamma-globulin 21.7 g / l. Angiotensin-converting enzyme (ACE) 108 U / l (normal 18–55 U / l), serological markers for hepatitis B and C were negative as were autoimmune factors (ANA, AMF, ASMF). Chest X-ray was normal, not showing hilar lymphadenopathy or tuberculosis. Ultrasound and CT-scan of the abdomen showed steatosis hepatis, no dilated bile ducts. An ERCP was performed and showed a normal CBD and smaller bile ducts. In a liver biopsy non-caseating granulomas in the portal areas and in the parenchyma were found. A diagnosis of late-onset hepatic sarcoidosis was made with systemic symptoms but without extrahepatic localisation as far as we could establish. Treatment with prednison 20 mg daily was started, after two months there was a weight increase of 7 kg together with strong improvement of the cholestatic liver enzymes (ALP 209 U / l, gamma-GT 170 U / l). Conclusions: Isolated symptomatic hepatic sarcoidosis is quite rare. Treatment with corticosteroids is effective with rapid improvement of systemic symptoms and liver enzymes. The duration of treatment can take months to years. Whether corticosteroids prevent the occurrence of fibrosis and progression to cirrhosis is still subject of discussion in literature. 124. Enteral tube feeding: continuous or intermittent? I. Purmer, L. Flierman, L. Bos, D.J. Versluis. Department of Intensive Care and The Nutritional Support Team, Medical Centre Haaglanden, Post-box 432, 2501 CK The Hague, The Netherlands, Tel.: 070 -3302000, Fax: 070 -3809459, e-mail: d.versluis@ mchaaglanden.nl Introduction: Critical illness causes catabolism and anorexia

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Internistendagen 2001 affecting morbidity and mortality in due course. Adequate delivery of enteral tube feeding in patients who can not feed themselves is very important. Aim of the study: In a prospective study we evaluated the adequacy of continuous infusion of enteral tube feeding (ETF) and of intermittent infusion of ETF, and the factors that impact on the delivery of ETF. Materials and Methods: During three months we included all patients receiving ETF and nothing by mouth on an internal medicine ward with continuous infusion and on a neurological ward with intermittent infusion. The nutritional requirements were calculated using the Harris-Benedict equations for basal energy expenditure (BEE) and adding extra calories depending on the underlying disease. Minimally acceptable nutritional endpoints were defined as achieving the caloric delivery by not more than 250 calories less than the calculated caloric requirements (1.2 times BEE). Results: Patients were evaluated for 246 days of continuous ETF and for 141 days of intermittent ETF. In 62% of their days the patients on continuous ETF not met the estimated caloric goals compared to the patients on intermittent ETF, who not received the prescribed calories in only 20% of their days ( p , 0.05). The most commonly cited reasons for cessation of feeding on the wards were tube dislocation with a delay in tube replacement, gastro-intestinal intolerance (vomiting) and high gastric residual volume with an assumed aspiration risk. Diagnostic procedures, surgical procedures and routine nursing activities are less common noted reasons for cessation of ETF on the wards. Both continuous and intermittent ETF held for these factors, seemed at least avoidable in two thirds of the days of inadequate enteral caloric intake (42% and 13% of the days respectively). Conclusion: The significant difference of the success rate with which caloric requirements are met, is caused by the difference in manner in which enteral feeding is provided. Routine cycling of ETF allows for making up lost volume during the rest period compared to the continuous method of ETF. So, on a general ward intermittent ETF is preferred. Even more can be achieved by avoidance of prolonged discontinuation of feeding by developing strict infusion protocols and education of health care personnel. 125. Pneumoscrotum and pneumomediastinum following endoscopic retrograde cholangiopancreatography. C.P.C. de Jager, R.J. Bosma, E.H. Eddes, H.J.A. Hazenberg, Deventer Ziekenhuizen, HJP Fesevurstraat 7 7415 CM, Deventer, Tel.: 0570 -646666, fax: 0570 -628909, e-mail: jl@ jager-leclercq.demon.nl Endoscopic retrograde choloangiopancreatography (ERCP) is the standard therapy for common bile duct stone clearance. Perforation due to fausse route cannulation or (precut) papillotomy is a well-known complication although the incidence has decreased to less then 0.5 percent over the last decade [1]. We report an unusual case of perforation A 86-year old patient was admitted to the hospital with jaundice and fever. The clinical suspicion of cholangitis was confirmed by labaratory results (CRP 244 mg / l, white cell count 20.3 (per mm 3 ), conjugated bilirubin 60 mmol / l, ASAT 100, ALAT 80, AF 213, gGT 233 U / l) and common bile duct dilatation with stones

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on ultrasonography. ERCP was performed. A peripapillary diverticulum impacted with gallstones prevented successful cannulation of the ampulla of Vater. Promptly after removing the diverticulum stones by flushing and brushing, pneumoscrotum developed. Considering the absence of abdominal symptoms and lack of free air on the plain abdominal film a conservative approach followed. Approximately 12 hours later crepitus was noted in the abdominal and chest wall. Computed tomography (CT) showed intra- and retroperitoneal air, pneumomediastinum and subcutaneous emphysema. There were no signs of pancreatitis. Under the suspicion of a perforation, laparatomy was performed. Meticulous dissection including Kocher’s manouvre and perioperative cholangiography revealed no stones, obstruction or perforation. Cholecystectomy and biliary drainage by means of a common bile duct T-tube was performed. Despite extensive supportive care multiple organ failure developed and the patient died 11 days after admission. In retrospect an impacted stone in the papilla located in the wall of a duodenal diverticulum caused cholangitis. Despite negative findings on plain abdominal X-ray the suspicion for free abdominal perforation was never fully rejected. CT scan is a more sensitive means for detecting free air and could have been considered earlier. Surprisingly extensive postmortem analysis including cannulation of the common bile duct did not reveal a perforation. This absence of a distinct cause for free air makes us conclude that the origin of free air was probably related to microperforations of the bowel due to the ERCP procedure. Tracking along the superficial or transversal fascia resulted in the pneumoscrotum. So far only one case has been reported of pneumoscrotum following endoscopic sphincterotomy [2]. Our case demonstrates the occurrence of a pneumoscrotum and pneumomediastinum after ERCP without papillotomy or cannulation. References [1] Freeman, ML, Nelson, DB, Sherman, S, et al. Complications of endoscopic biliary sphincterotomy. N Engl J Med 1996;335: 909. [2] Hickman, pneumoscrotum following endoscopic spincterotomy, Surg. Endoc. 1990;4(4):230. 126. Crohn’s disease with respiratory tract involvement. E.M. de Gussem 1 , Dr A. Dees 1 , Dr D.J. Bac 1 . 1 Dep. of Internal Medicine, Ikazia Hospital, Rotterdam. Introduction: Pulmonary involvement of Crohn’s disease is rare, but not unknown. We describe a patient with pulmonary complaints and at the same time an exacerbation of Crohn’s disease, improving after treatment with steroids. Case: A 19-year old woman presented at the clinic with the following symptoms. Since one week dyspnoea associated with pain on the left thoracic chest, shoulders and chest worsening at inspiration and fever. She is known with Crohn’s disease for 4 months. Physical examination showed an tachypnoeic, pale, transpirating woman with a fever of 38.4 degrees Celsius. A chest X-ray on admission showed a sizeable cor in accordance with moderate inspiration and little pleural effusion. Labora-

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tory studies showed the following abnormalities: sedimentation rate 94 mm / hour, heamoglobine 7.2 mmol / l, heamatocrit 0.34 l / l, leukocytes 14.5 mmol / l, thrombocytes 671 3 10 9 / l, ALAT 57 U / l, alkaline phosphatase 129 U / l, GGT 44 U / l. To exclude a lungembolism a ventilation scan was done, this was negative and a sonography of the heart didn’t show any cardiac pathology. An abdominal sonography was done because of enzymatic liver abnormalities, which was also normal. Meanwhile the condition of the patient worsens, the fever remains and an arterial blood gas was done 6 days after admission: pH 7.52, pO 2 59.9 mmHg, pCO 2 37.6 mmHg, base excess 7.1 mmol / l, HCO 2 3 30 mmol / l. A colonoscopy done on the same day shows a severe segmental colitis with long and deep ulcerations. It was noted during examination that she had severe hypoxia, with saturations of around 80%. Hereafter, the patient was immediately started with a treatment on steroids intravenously. The following days the patients condition dramatically improved: she looked well, wasn’t dyspnoeic anymore, the fever was gone and she had good oxygen saturations. Conclusion: Respiratory abnormalities can be seen in Crohn’s disease, e.g. granulomatous bronchiolitis, upper airway obstruction with laryngeal involvement or subclinical lung abnormalities like decreased pulmonary function or pleural effusion. 127. Superior mesenteric artery syndrome. F. Mineur, A.A.M. Zandbergen, R.J.Th. Ouwendijk, Ikazia Hospital, Department of Internal Medicine, Montessoriweg 1, 3083 AN Rotterdam, Tel.: 010 -2975000, Fax: 010 -4859959, e-mail: ikazint@ knmg.nl Introduction: Superior mesenteric artery syndrome (SMAS) is a rare cause of gastro-intestinal obstruction in which the third part of the duodenum is compressed by the overlying superior mesenteric artery. Case: A 64-year old woman presented with progressive complaints of epigastric pain, abdominal distension, nausea and vomiting immediately or 15 minutes after eating. Her medical history revealed three transient ischaemic attacks, a rectal amputation for a Dukes C colon carcinoma in 1991 and a polypectomy of the ascending colon in 1994. Over the years she had lost 12 kg and had adapted her food from normal food to only nutritive fluids. More or solid food aggravated the symptoms. There were no pyrosis, swallowing or defecation problems. On physical examination we saw a woman tall 1.61 m. and weighting 46 kg. Besides the stoma, physical examination and routine laboratory tests showed no abnormalities. Chest X-ray, electrocardiogram, and CT abdomen were normal. Gastro-duodenoscopy showed a narrowed second part of the duodenal intestine with normal mucosa, suggesting an extraduodenal impression. Multiple biopsies revealed no abnormalities. Hypotonic duodenography showed reflux in the stomach and an impression of two thirds of the lumen, probably caused by the superior mesenteric artery. Angiographic CT revealed a distance of 5.4 mm (N 13.4–34.3) between the superior mesenteric artery and the aorta. The angle between the two vessels was 1.68 (N 28–658). The duodenum was situated between the two vessels. SMAS or Wilkie syndrome was diagnosed, and a side-to-side

duodenal jejunostomy was performed. The post-operative course was uncomplicated. At discharge from the hospital the diet was soft, without problems. Conclusion: Superior Mesenteric Artery Syndrome is a rare cause of nausea and vomiting and should be considered in the differential diagnosis of vomiting when upper endoscopy, routine X rays and laboratory investigation tests remain inconclusive. Angiographic CT can reveal the diagnosis.

IX. Infectious diseases 128. Plasma leptin, nutritional status and the acute phase response in patients with tuberculosis. R. van Crevel 1 , E. Karyadi 2 , M.G. Netea 1 , H. Verhoef 3 , R.H.H. Nelwan 4 , C.E. West 3 , J.W.M. van der Meer 1 . 1 Department of Internal Medicine, University Medical Center Nijmegen, Nijmegen, The Netherlands. Tel.: *3124 -3618819, Fax: *3124 -3541734, e-mail: r.vancrevel@ aig.azn.nl 2 SEAMEO-TROPMED, Regional Center for Community Nutrition, University of Indonesia, Jakarta, Indonesia 3 Division of Human Nutrition and Epidemiology, Wageningen University, Wageningen, The Netherlands 4 Working Group on Infectious Diseases, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia. Introduction: Tuberculosis patients often suffer from severe weight loss, which is considered to be immunosuppressive and to worsen disease outcome. Leptin, a product of adipocytes, is involved in energy balance and weight regulation, as well as in cellular immunity. Therefore, it may be involved in the crossregulation of the nutritional status and the immune response in tuberculosis. Aim of study: To investigate the relationship between plasma leptin concentrations and tuberculosis, and to evaluate the role of nutritional status and inflammation in this response. Methods: In a case-control study in an outpatient tuberculosis clinic in Jakarta, Indonesia, we investigated 60 patients with bacteriologically-proven active tuberculosis and 30 healthy control subjects. We determined plasma leptin concentrations, body mass index, body fat percentage, appetite, C-reactive protein concentrations (CRP), tuberculin reactivity and cytokine response. Results: In patients with untreated tuberculosis, plasma leptin concentrations were lower than in healthy controls (615 vs. 2550 ng / L; P , 0.001). Multivariate regression analysis showed that plasma leptin concentrations were positively associated with body fat mass (P , 0.0001), and inversely associated with plasma CRP (P 5 0.004). In tuberculosis patients, production of TNF-alpha was inversely correlated with plasma leptin concentrations. No significant correlation was found between plasma leptin and gamma-IFN or tuberculin skin-reactivity. Plasma leptin increased substantially following 2 months of antituberculous treatment. Multivariate analysis indicated that plasma leptin concentrations were associated with loss of appetite. However, the inhibitory effect of leptin on appetite was confounded by the acute phase response, which reduces appetite as well as leptin production. Conclusion: Our results do not support the concept that wasting in tuberculosis is caused by enhanced production of plasma leptin. Rather, loss of body fat mass (probably a direct result of

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Internistendagen 2001 proinflammatory cytokine production), leads to low plasma leptin concentrations, and prolonged inflammation may further suppress leptin production. As leptin is important for cell-mediated immunity, low leptin production during active tuberculosis may contribute to a worse disease outcome, especially in cachectic patients. The administration of leptin, or supplementation of micronutrients such as zinc, which is known to increase leptin production, may benefit tuberculosis patients 129. Adherence over 48 weeks in an antiretroviral clinical trial: variable within patients, affected by toxicities and independently predictive of virological response. E.H. Gisolf 1 , P.T. Nieuwkerk 2 , S.A. Danner 1,3 , M.A. Sprangers 2 , namens de Prometheus Studie Groep*. 1 Nationaal AIDS Therapie Evaluatie Centrum, Academisch Medisch Centrum, Amsterdam. 2 Afdeling Medische Psychologie, Academisch Medisch Centrum, Amsterdam 3 Afdeling voor Infectieziekten, Tropische Geneeskunde en AIDS, Academisch Medisch Centrum, Amsterdam. AMC F4 -222, Meibergdreef 9, 1105 AZ Amsterdam; Tel.: 020 -5669111, sein 58111, e-mail: E.H.Gisolf@ AMC.UVA.NL Introduction: Anti-HIV therapy usually consists of a combination of 3 or 4 different drugs. As protease inhibitors have short half-lives and HIV is prone to the development of resistance mutations, adherence is thought to be of major importance. However, prospective studies on adherence with a follow up of more than 6 months are not published so far. Objectives: To investigate adherence to antiretroviral therapy over 48 weeks, to investigate the association between adherence and treatment-related symptoms, and to investigate the impact of adherence on virological response over 48 weeks among established predictors of treatment success. Methods: Hundred-sixty protease inhibitor- and stavudine naive HIV-1 infected patients were treated according to a study protocol with ritonavir 400 mg bid and saquinavir 400 mg bid 1 / 2 stavudine 40 mg bid. Adherence and symptoms were assessed by a self-report questionnaire at weeks 12, 24, 36 and 48. Correlations between adherence and symptoms, predictors of HIV-1 RNA below 400 copies / ml at week 48 and of the area about the change from baseline over 48 weeks (ACFB) in serum HIV-1 RNA were assessed. Results: The percentages of patients reporting skipping medication, deviation from time schedule and dietary prescriptions at separate time-points ranged from 12% to 15%, 32% to 35% and 17% to 22%, respectively. The percentage that changed their level of adherence during 48 weeks ranged from 29% for skipping medication to 48% for deviation from time-schedule. Higher levels of experienced side-effects were associated with lower levels of adherence. Not skipping medication was an independent predictor of both having a serum HIV-1 RNA below 400 copies / ml at week 48 ( p 5 0.048) and the ACFB over 48 weeks in serum HIV-1 RNA ( p 5 0.014). Conclusions: Adherence was an independent predictor of virological response over 48 weeks. The level of adherence is variable within patients over time. This confirms the need for continued adherence monitoring in all patients as part of standard medical practice. The Prometheus Study Group: NATEC, Amsterdam: EH Gisolf, P

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Reiss, GJ Weverling, M Duurvoort, E Krijger, E Brouwer, GR Visser, A Klotz, C Benschop, F Wulfert. Academic Medical Center, Amsterdam: SA Danner, F de Wolf, S Jurriaans, P Portegies. Institute for Tropical Medicine, Antwerp: R Colebunders, J Pelgrom, H Wijnants, A de Roo, K Keersmaekers, M Vandenbruane, D van den Brande, T James. University Hospital Gent: F van Wanzeele, B van der Gucht. University Hospital Rotterdam: ME van der Ende, J Nouwen, R Deenenkamp, D van der Meyden. University Hospital Nijmegen: PP Koopmans, K Brinkman, H ter Hofstede, B Zomer. Ziekenhuis Walcheren, Vlissingen: WL Blok, C Ruissen. University Hospital Groningen: H Sprenger, G Law, P van der Meulen. OLVG locatie Prinsengracht, Amsterdam: C ten Veen. St Elisabeth Ziekenhuis, Tilburg: JR Juttmann, C van der Heul, R Santegoets, B van der Ven. Kennemer Gasthuis, Haarlem. RW ten Kate, M Schoemaker. Ziekenhuis Leyenburg, Den Haag: RH Kauffmann, JM Henrichs, A Maat, E Prins. Medisch Spectrum Twente, Enschede: CH ten Napel, K Pogany, T Duyts, T Lansink. Vrije Universiteit Brussel: P Simons, P Lacor, A de Waele. University Hospital Leuven: E van Wijngaarden, M Lejeune. Virtual Central Laboratory, Zeist: R Scholte, J Dijkman. 130. Recurrent infections and immunodeficiency: beware of secondary causes. J.A.H.R. Claassen, R.A. de Vries, C. Richter, Dept. of Internal Medicine, Rijnstate Hospital, P.O. Box 9555, 6800 TA Arnhem, Tel.: 026 -378888, Fax: 026 -3786737, e-mail: jurgen@ ephysician.md Introduction: Recurrent or opportunistic infections are the hallmark symptoms of a defective immune system. In the adult, secondary or acquired immunodeficiency is the most likely cause. A clear indicator of the underlying disorder is not always present. We describe three cases that highlight the importance of a thorough search for underlying disease in immunodeficiency. Patients: Patient 1, a 56-year old Caucasian male, presented with recurrent infections, general malaise, weight loss, subfebrile fever and arthritis of the left ankle. For three years, he had had recurrent episodes of bone pain, often in combination with fever, malaise and night sweats. No lymphadenopathy was noted. Laboratory examination showed elevated erythrocyte sedimentation rate (ESR), normocytic anemia, a relative lymphopenia and a marked hypogammaglobulinemia, with decreased levels of IgA, IgM and IgG. Bone marrow analysis was normal. All microbial cultures were negative, as was serology for HIV, EBV, borrelia etc. CT of thorax, abdomen, and skeletal X-rays were all normal. Crista bone biopsy showed a B-cell non-Hodgkin lymphoma, stage IVB. He received chemotherapy, radiotherapy and i.v. immunoglobulin, with good clinical response. Patient 2, a 40-year old Asian male, presented with pneumococcal pneumonia. He had a 2-year history of recurrent upper airway infections, fever, malaise and weight loss. There was a hypogammaglobulinemia with undetectable levels of IgA and IgM and low IgG. The number of T-helper cells was reduced. HIVinfection was excluded. On radiological examination of the chest a mass in the anterior mediastinum was present. At the same time, myasthenia gravis (MG) was diagnosed. Thymoma was suspected and was confirmed by surgical resection and histological examination. The MG subsided completely; administration of i.v. immunoglobulin is continued in the outpatient setting.

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Patient 3, a 52-year old Caucasian male, was admitted to the ICU with pneumococcal sepsis and respiratory failure. It was his second episode with severe pneumococcal pneumonia. During further analysis, low IgA, IgM and IgG levels were found. Diagnostic evaluation revealed a plasmocytoma. After successful treatment including i.v. immunoglobulin, he recovered well. Recently, after several courses of chemotherapy, he underwent bone marrow transplantation. Conclusion: When a deficiency of the immune system is diagnosed, and underlying causes like HIV-infection, use of immunosuppressive drugs, overt malnutrition or malignancy have been excluded, the diagnostic pathway leads to primary immunodeficiency such as common variable immunodeficiency. A thorough search for occult disease however has to be performed, with important potential therapeutic consequences. 131. Fibrosing mediastinitis: a rare cause of fever. J.A.M. Wilmer, R.A. de Vries, C. Richter, Dept. of Internal Medicine, Rijnstate Hospital, Arnhem. Introduction: Fever of unknown origin (F.U.O.) is always a diagnostic challenge for clinicians. We describe a patient with a rare cause of F.U.O.: fibrosing mediastinitis, responding surprisingly well to corticosteroids. Case: A 47-yr-old female patient was admitted for analysis of periods of fever up to 408C for five months with night sweats and general deterioration. She used to be in perfect health. Between four and eight years before admission the patient had spent holidays in South-East Asia. On physical examination the only abnormal finding was a temperature of 38.58C. Laboratory investigations showed: ESR 90 mm / hr, CRP 157 mg / L, a slight normochromic anemia and leukocytosis. Serology for HBV, HIV, Borrelia, CMV, Toxoplasmosis, Lues, EBV, Brucellosis, Bartonellosis, Histoplasmosis and auto-immune factors was negative. Cultures of blood and urine were also negative. CT-scans of the chest and the abdomen were normal. The consulting dentist found a peri-apical abscess in the left mandibula. Gallium-67-scintigraphy revealed an increased uptake in the left mediastinum and the left side of the neck. In addition an ultrasound and MRI of the neck were performed showing thrombosis of the left jugular vein and abnormal enlarged infraclavicular lymph nodes. On histological examination of the surgical excision biopsy in our clinic and a university clinic a chronic fibrosing non-specific inflammation was seen. The culture of this biopsy was negative for tuberculosis. We concluded that the patient was suffering from fibrosing mediastinitis complicated by thrombosis. Because of the peri-apical abscess the patient was treated with clindamycin and ciprofloxacin for 14 days, but the patient’s temperature remained elevated. Almost immediately after starting treatment with corticosteroids the fever disappeared and the condition of the patient as well as the laboratory results improved remarkably. The thrombosis of the jugular vein was treated with anticoagulant therapy (acenocoumarol). A few months after admission the patient had completely recovered. Discussion: Fibrosing mediastinitis is considered to be a nonspecific inflammatory reaction to various infections such as histoplasmosis and tuberculosis. Idiopathic forms are also described. In our case we can not rule out a relationship with the

peri-apical abscess. The literature is not conclusive about the effect of treatment with corticosteroids, however in our patient the response was excellent. 132. Streptococcus bovis bacteremia with multiple liver abcesses. K.-W. Mui, L. van Bergeijk, Th.F. Veneman. Department of Internal Medicine, Twenteborg Hospital, P.O. Box 7600, 7600 CG Almelo, The Netherlands. Tel.: 0546 -833333; Fax: 0546 -833418, e-mail: bergeijk@ knmg.nl Streptococcus bovis (S.bovis) bacteremia is associated with gastrointestinal neoplasms and endocarditis. Therefore, an extensive search for these abnormalities is advocated after the diagnosis is made. We describe a case of S. bovis bacteremia with multiple liver abscesses and air in the biliary system with no gastrointestinal carcinoma and no endocarditis. A 74-year old man was admitted to our hospital because of fever and diabetes mellitus de novo. Laboratory evaluation revealed an elevated ESR (58 mm / hr) and CRP (313 mg / l), hyperglycemia (37.3 mmol / l) and leucocytosis (21.7 3 E9 / l). Also the liver-enzymes were elevated. Blood cultures appeared positive for S. bovis, which was treated with amoxicillin and ciprofloxacin. Abdominal ultrasound showed air in the gallbladder and bile ducts. ERCP revealed spiky bile ducts with possible intrahepatic abcesses. CT-scan showed 3 hepatic abcesses in the right liver lobe. Percutaneous drainage was performed and cultures of the aspiration fluid were all positive for S. bovis. Barium enema of the colon, small-bowel x-rays as well as gastro- and sigmoidoscopy were all normal. Transthoracic echocardiography revealed no valve vegetations. Control CT-abdomen showed the same hypodense multiple inhomogeneous areas in the liver as well as in the pancreas, with lymph nodes in the liver hilus. Fine needle biopsies from the pancreatic region were taken, showing necrotic material. Since our patient clinically deteriorated, laparotomy was performed, revealing a necrotic pancreas. Conclusion: This is the first report of a patient with S. bovis bacteremia with multiple liver abscesses and air in the biliary system with no gastrointestinal carcinoma and no endocarditis. The port of entry for S. bovis may have been a necrotic pancreatitis e causa ignota. The association between S. bovis bacteremia, pancreatitis and diabetes mellitus has not yet been described. A possible explanation for this phenomenon is that patients with diabetes mellitus are immune-compromised, and therefore more vulnerable to infections of any kind. 133. EM confirmed cryptosporidiosis leading to an unsuspected AIDS diagnosis. M.W.C.J. Schoofs 1 , E. Maartense 1 , F. Eulderink 2 . Departments of Internal Medicine 1 and Pathology 2 . Reinier de Graaf Gasthuis, R. De Graafweg 3, 2625 AD Delft, The Netherlands, Tel.: 0031 -152603060. A 68-year-old woman was admitted because of persisting diarrhoea and weight loss of 17 kg during the past three months. Granulomas in a colon biopsy had led 2 years previously to presumptive diagnosis of Crohn’s disease. Despite appropriate treatment her symptoms persisted. Later on celiac sprue was suspected when partial villous atrophy was seen in jejunum biopsies. However, endomysium and gliadin antibodies could not

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Internistendagen 2001 be detected. A gluten-free diet did not control her symptoms. Four weeks prior to admission candida oesophagitis was observed and confirmed by oesophagus biopsy, and Nystatin treatment was started. On examination the patient weighed 48 kilograms. There was a white coating in the mouth, suspect for candida stomatitis, but no other abnormalities were found. Laboratory investigation showed: ESR 7 mm / hour, leucocytes 3.8 3 10 9 / L, sodium 135 mmol / L, potassium 2,4 mmol / L and albumin 20 g / L. Stool cultures showed no micro-organisms and the examination for parasitic infections was negative. However, on microscopic examination of duodenal biopsies the presence of cryptosporidia on the mucosal epithelia was suspected and confirmed by electron microscopy (EM), which excluded the possibility of the yeast form of candida. ¨ Afterwards cryptosporidium oocysts were demonstrated in the stools. A strongly decreased number of CD4 1 lymphocytes: 0.01 3 10 6 / mL indicated immunodeficiency. The test on antibodies against HIV, after informed consent, was positive and HIV-1 infection was confirmed by Western blot. The viral load was 1.75 3 10 5 eq / mL. A highly active antiretroviral treatment (HAART) regimen was prescribed, besides pneumocystis carinii prophylaxis with cotrimoxazole and symptomatic loperamide. The diarrhoea disappeared in three weeks and loperamide was gradually discontinued. The patient left hospital in reasonably well condition. This patient had never used drugs or had any other risk factors related to HIV infection. Her husband, who died in 1986 and who had received several blood transfusions in the beginning of the eighties, possibly infected her. Cryptosporidiosis is an uncommon finding. The parasite is small and easily overlooked in bowel biopsies. In this case EM investigation on suspected gastrointestinal biopsies confirmed the diagnosis, which led to the detection of unsuspected aids. The previous diagnoses of Crohn’s disease and celiac sprue were refuted. Hopefully, restoring immunity with the prescribed HAART-regimen will control the cryptosporidium infection. 134. Case-report, category (H): infectious diseases. I. Leeuwenburgh, J.T.N. Driessen, P.J. Stijnen, P.H.J. van Keulen, G.P. Verburg. Department of Internal Medicine, Amphia ziekenhuis locatie Langendijk, Langendijk 75, 4819 EV Breda Tel.: 076 5277911 fax: 076 -5277199, e-mail: i leeuwenburgh@ hotmail.com ] A thirty-four-year-old woman was admitted to our hospital with high fever 14 days after a holiday to Birma. Physical examination revealed an ill woman with a temperature of 408C without auscultatory abnormalities over both lungs but with an extremely painful subcutaneous nodule on her left lower leg. The white cell count was 17.7 3 10 9 / l with 83 percent neutrophils and 10 percent band forms. The ESR was 114 mm / hour and C-reactive protein was 191 mg / l. The chest x-ray showed signs of infiltration in the right upper lobe. Bloodcultures, sputumculture and a culture of aspirate from the nodule on her leg all contained Burkholderia pseudomallei. She was treated with ceftazidime intravenously for five weeks after which the parameters of infection had completely normalized. This was followed by an oral treatment with amoxicillinclavulanate for another six months.

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Melioidosis is a disease caused by the gram-negative microorganism Burkholderia (Pseudomonas) pseudomallei and is endemic in southeast Asia and northern Australia. In non-endemic areas this disease is rarely seen, only in people with a history of traveling to an endemic area. The clinical spectrum of the disease is wide and varies from an acute fulminant septicemia to a sub-clinical disease and can affect any organ system, but most frequently the lungs. The mortality of the septicemic form after adequate treatment is 40% and there is a high relapse rate (4–20%). Melioidosis can become chronic with formation of abscesses or can even remain sub-clinical for many years, probably by survival of the micro-organism within phagocytic cells. There is always a risk of reactivation especially at moments of immunosuppression. Because Pseudomonas pseudomallei is difficult to eradicate, treatment has to be prolonged. The optimal regimen consists of ceftazidim intra-venously up to six weeks followed by oral treatment with amoxicillin-clavulanate of which the optimal duration remains to be determined; in literature it varies between 2 and 12 months. When a patient returns from an endemic area with fever or pneumonia, one has to be aware of the possibility of melioidosis. 135. Plumber’s arthritis? F.P. Vleggaar 1 , P.H.L.M. GeelhoedDuijvestijn 1 , C.L. Jansen 2 , J.A.E.M. Mutsaers 2 . Department of Internal Medicin and Gastroenterology 1 and Department of Medical Microbiology 2 , Medical Center Haaglanden, location Westeinde Hospital, Lijnbaan 32, Tel.: 070 -3302000, The Hague, e-mail: frank vleggaar@ hotmail.com ] A 50-year old plumber presented with severe bilateral shoulder pain and malaise since 5 days. He noticed relief of pain while holding his hands behind his head. Besides splenectomy for traumatic rupture of the spleen at the age of 17 where he appeared to have one kidney, his medical history had been unremarkable. Physical examination revealed a sick man with faint erythema of the head, neck and thorax. His temperature, blood pressure and heart rate were 398C, 125 / 65 mm Hg and 150 irregular beats per minute, respectively. A mass was present near the left sternoclavicular joint. Local pressure was somewhat painful. Laboratory investigations showed a raised ESR (64 mm / h), with normal hemoglobin level and leucocytosis (23.4*10 9 ) with a marked shift to the left (46% band cells). CRP was strongly elevated (423) as were serum kreatinin (165), ureum (14.6), alkaline phosphatase, – GT and LD. ECG demonstrated atrial fibrillation with a rapid ventricular response. X-ray examination of the thorax and abdominal ultrasonography did not show abnormalities. Ultrasonography of the sternoclavicular joint showed inflammation around the sternocleidomastoid muscle insertion and arthritis. Puncture of the joint showed Gram-positive cocci, which appeared to be Streptococcus pneumoniae. Culture of blood and pharynx also showed Streptococcus pneumoniae. Instant intravenous therapy with highdose penicillin, initially combined with gentamycin, resulted in slow but continuous clinical and biochemical improvement. All strains were susceptible to penicillin (MIC: 0.003 mg / ml). A few weeks later MRI demonstrated spondylodiscitis of L2–3. Asplenia is a well-known risk factor for the development of fulminant infection with encapsulated bacteria, such as Strep-

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tococcus pneumoniae and Haemophilus influenzae. Inability to remove bacteria from the circulation and defective production of antibodies against T-cell independent antigen such as the polysaccharide capsule probably both account for a patients increased susceptibility for severe infection. Furthermore, immunoglobulin subtype studies showed complete absence of IgG2 and 4. Arthritis due to Streptococcus pneumoniae is rare, and the more when the sternoclavicular joint is infected. Septic arthritis is usually found in patients with diabetes, cirrhosis, renal insufficiency, rheumatoid arthritis (RA) and malignancy. In general, the infected joint has already been affected by another condition, such as RA, gout, SLE or hemophilic arthropathy. Bacterial arthritis of the sternoclavicular joint is mostly found in i.v. drug users. None of these disorders were present in our patient.

136. Development of resistance of Staphylococcus epidermidis to teicoplanin during teicoplanin therapy. V. Zwart 1 , M.G.R. Hendrix 2 , W.M. Smit 1 . 1 Medisch Spectrum Twente, P.O. Box 50000, 7500 KA Enschede. Tel 053 -4872440, Fax 053 -4873085, e-mail: leo.vd.ende@ hetnet.nl. 2 Regional laboratory of public health, Enschede. A 63-year-old woman was diagnosed with acute myeloid leukaemia in April 1999. Remission induction chemotherapy with cytarabine and daunorubicin resulted in a complete remission. After consolidation therapy with cytarabine and amsacrin, autologous peripheral blood stem cells (PBSC) were mobilised, processed and cryopreserved. In September 1999 a PBSC transplantation was performed. The conditioning regimen consisted of cyclophosphamide 60 mg / kg days 2 5 and 2 4 and total body irradiation. At day 2 1, blood cultures taken as part of a surveillance protocol from the central venous catheter showed growth of Staphylococcus epidermidis and flucloxacilline was started. The next day, she had chills and fever up to 39.58C. Antimicrobial susceptibility tests using the Elipsometer test (Etest) revealed sensitivity to teicoplanin (MIC 4 mg / L) and vancomycin (MIC 2 mg / L). Flucloxacilline was changed into teicoplanin 400 mg once daily, which resulted in disappearance of fever within two days. Routine blood cultures taken at day 3 and 7 continued to show Staphylococcus epidermidis. However, subpopulations were isolated with decreasing susceptibility of teicoplanin (MIC 6 mg / L). After two weeks without fever and granulocytes being risen above 0.3 3 10 9 / l, teicoplanin was stopped but started again three days later because of recurrence of fever. This time however, the patient continued to be subfebrile although her clinical condition remained stable. The central venous catheter could not be removed because of persisting thrombocytopenia in the presence of anti-HLA antibodies, necessitating frequent HLAidentical platelet transfusions. After a total period of twenty-eight days of teicoplanin administration, blood culture isolates showed subpopulations of Staphylococcus epidermidis with complete resistance to teicoplanin (MIC 64 mg / l). Only a slight decrease in sensitivity to vancomycine was found (MIC 8 mg / l). Teicoplanin was changed into clindamycine resulting in normo-temperature. All the collected isolates were subsequently analysed further. Population Analysis Profiles and E-test results demonstrated that the resistance pattern was of a heterogeneous phenotype and that

only a minority of the total bacterial population had become resistant. Moreover, during teicoplanin therapy a sharp rise in the percentage of resistant bacteria was observed. All isolated strains were genetically closely related as was demonstrated by identical banding patterns obtained by arbitrarily primed PCR. Coagulase –negative staphylococci were the first organisms in which acquired glycopeptide resistance was recognised. However, the development of overt teicoplanin resistance of Staphylococcus epidermidis during teicoplanin therapy, as demonstrated by this case report, has rarely been described before and necessitates increasing awareness of physicians.

137. Clostridium difficile induced colitis after amoxicillin containing Helicobacter pylori eradication therapy. C. Colder, S.Y. de Boer, Department of Internal Medicine. Slingeland Hospital, P.O. box 169, 7000 AD Doetinchem, The Netherlands, e-mail: syde.boer@12 move.nl Although the incidence of symptomatic Clostridium difficile colitis after Helicobacter pylori eradication seems to be very low, diarrhoea during and after triple eradication therapy is a well known adverse effect, which may not always be recognized as being caused by C.difficile. In 1993, 1994, 1996 and 1999 three women (57, 81 and 72 yr) and one man (58 yr) were referred for ongoing diarrhoea without blood loss. Before referral, their family doctors prescribed H.pylori eradication therapy because of symptomatic duodenitis and H. pylori associated antrum gastritis. The treatment consisted of bismuthsubcitrate, amoxicillin, and metronidazole during 10 days in three patients and in the last patient omeprazole, clarythromycine and amoxicillin for 7 days. After a period of at least 4 weeks of watery diarrhoea (stool frequency . 6 3 daily) without blood loss, the first three patients were admitted to hospital for 10, 14 and 4 days respectively. In the first patient the C.difficile endotoxin stool test was positive, but culture was negative. However, in this patient pseudomembranous colitis was histologically proven. In the other patients positive C.difficile antigen test, positive culture of stool or rectal biopsy (vancomycin and metronidazole (!) sensitive) and mild (non-pseudomembranous) infectious colitis was found. Rapid clinical improvement was observed during ten day treatment of the first two patients with oral vancomycine and of the last two patients (paradoxically) with oral metronidazole. Amoxicillin is an antibiotic known to have a relative high risk to induce C.difficile colitis, although almost all antibiotics (including clarythromycin and even metronidazole) may cause it. However, metronidazole can be used to treat C.difficile colitis. Conclusion: in four patients with chronic diarrhoea after amoxicillin containing H.pylori eradication therapy, C.difficile induced colitis was recognised. Since amoxicillin is still a major component of H.pylori eradication therapy, C.difficile colitis must be considered in patients with ongoing diarrhoea after anti H.pylori treatment. The absence of pseudomembranes does not rule out C.difficile infection. Diagnosis is sometimes ‘‘difficile’’ and can be made with a clostridium antigen test, clostridium endotoxin test, stool culture and / or biopsy culture. Metronidazole must be considered as the first choice of treatment.

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Internistendagen 2001 138. HIV-associated nephropathy. M.J.H. Pronk, C.M. Bruijnvan Duinen, R.H. Kauffmann, Ziekenhuis Leyenburg, Leyweg 275, 2545 CH, Den Haag, Tel.: 070 -3592000, e-mail: b.schwarz@ wanadoo.nl Introduction: HIV-associated nephropathy (HIVAN) is a chronic glomerulonephritis which predominantly occurs in blacks. It is clinically characterized by rapidly progressive renal insufficiency and absence of hypertension and edema in spite of substantial proteinuria. Urine sediment is usually normal. Ultrasonography shows enlarged echogenic kidneys. The pathological features are those of focal global glomerulosclerosis and other light and electron microscopic changes, characteristic of HIVAN. Corticosteroid treatment results in a temporal improvement of renal function, while ACE-inhibitors provide renal function stabilization. Although some positive results have been reported, the effects of HAART leave room for interpretation. Materials and Methods: 8 patients with HIVAN were treated in Leyenburg Hospital since 1993. Histological data of 2 black females, both with endstage renal failure, are not available. The other 6 patients are presented here: 4 black males with an average age of 38 (31 to 48), 1 black female, aged 38, and 1 white male, 46 years of age. Only one of our patients presented with hypertension, none of them had edema. Mean serum creatinine was 267 mmol / l (160 to 516), mean serum albumin was 26.6 g / l (21.1 to 40.9) and proteinuria varied from 0.5 to 10.3 gram per 24 hours (mean 3.5). Urine sediments were all normal. Mean CD4 lymphocyte count was 137 / ml ( , 50 to 270). Ultrasonography showed echogenic kidneys in 5 patients, 4 of them also had enlarged kidneys. In 4 patients we found histological features consistent with HIVAN, in the biopsy of the white male we particularly saw mesangial changes (possibly early stage HIVAN) and 1 patient showed more extracapillary changes than usually seen in HIVAN. Results: All patients were prescribed prednisone. Two of them received no antiretroviral therapy. One patient continued nevirapin, which had been started earlier. One patient started HAART shortly after starting prednisone, 2 started HAART and prednisone at the same time. Two patients were given enalapril, one of them stopped using it because of hyperkalemia. In all 6 patients serum albumin normalised. Prednisone used as monotherapy, in a dose of at least 30 mg, resulted in renal function improvement. Combination with HAART however, not only improved but stabilized renal function, while prednisone could be tapered and in one case even stopped. Conclusion: Although the results as described above suggest a positive effect of HAART on renal function in patients with HIVAN, a longer period of folluw-up is necessary to obtain conclusive results on its effects on HIVAN. 139. Vertebral osteomyelitis by Streptococcus Pneumoniae. M. van der Vegt, A. Hollander, R.B. Noordveld Introduction: Vertebral osteomyelitis was first described by Hippocrates. Mortality is now rare, but complications can still be serious. The illness can be caused by several micro-organisms, but is rarely caused by Streptococcus Pneumoniae. Case: A 59-year old male was admitted with back pain and fever. His symptoms were progressive. His body temperature was 38.78C.

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Laboratory results showed an ESR of 84 mm / h, leucocytes 18.0 3 10E9 / l, CRP 235 mg / l. Two blood cultures were positive for Streptococcus Pneumoniae. MRI of the lumbar spine showed high signal intensity at the level L2–L3, probably caused by liquid inflammation material. The disk space was dramatically narrowed. There was light compression on the dural space. Treatment consisted of intravenous penicillin for 6 weeks. During the first 2 weeks the patient was treated in the hospital. CRP dropped to 97, and his symptoms improved. During the last 4 weeks he was treated at home with a penicillin pump and physiotherapy was given to promote mobility. After 6 weeks of intravenous antibiotics there were no signs left of active infection and the patient was further rehabilitated. Discussion: Vertebral osteomyelitis has an incidence of 1: 250.000 persons. It seems to be rising due to increased use of intravascular lines and increasing age. Patients have symptoms of back pain and fever. As in our patient, pain usually begins insidiously and progressively worsens. Hematogenous spread is by far the most common route of infection. Vertebral osteomyelitis characteristically causes destruction of two adjacent vertebral bodies with collapse of intervertebral disk space. Staphylococcus Aureus can be isolated in 50% of the patients. Streptococcus Pneumoniae was seen in only 28 cases in English literature from 1900 onwards. 46% of patients with osteomyelitis caused by Streptococcus Pneumoniae experienced recent infection of upper or lower airways. MRI is usually the best procedure for correct diagnosis. When MRI and clinical findings are typical and blood cultures are positive, CT-guided needle biopsy is obsolete. Most patients respond well to prolonged antimicrobacterial therapy. Longer therapy may be necessary in advanced disease, for example bone destruction or spinal instability. Surgery can be necessary when acute spinal cord symptoms are present or when illness progresses despite adequate therapy. Conclusion: Vertebral osteomyelitis is a rare disease, especially when caused by Streptococcus Pneumoniae. Despite the fact that mortality rate has fallen from 25% to 5% in recent years, vertebral osteomyelitis is still a serious disease with disabling complications. Reducing the time gap between diagnosis and treatment can reduce these complications. 140. Relation of endotoxin and cytokine-levels to antibioticinduced morphological changes of E. coli in neutropenic mice, comparing four different beta-lactam antibiotics. J. Buijs 1 , A. Dofferhoff 1 , J. Mouton 1 , J. van der Meer 2 , Canisius-Wilhelmina Hospital 1 , UMC St. Radboud 2 , Weg door Jonkerbos 100, Nijmegen, Tel.: 024 -3658740, Fax: 024 -3658738, e-mail: jacqbuijs@ hotmail.com. Introduction: Aztreonam and ceftazidime bind to penicillinbinding protein (PBP)-3 on E.coli cell walls, leading to proliferation without septation and formation of long bacterial strands, i.e. filaments. Imipenem and meropenem bind to PBP-2, causing formation of large rounded cells, i.e. spheroplasts. In vitro, lysis of filaments is associated with excessive endotoxin-liberation from

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the cell-wall in comparison to normal bacteria and spheroplasts. We hypothesized that b-lactam-induced morphological changes of E.coli in vivo may lead to stimulation of the cytokine-cascade with a worse clinical outcome of gram-negative infections. Aim of the study: To investigate the in vivo occurrence and clinical sequelae of morphological changes of bacteria induced by Beta-lactam-antibiotics with different PBP-specifities. Animals and Methods: Fifteen neutropenic Swiss mice were challenged with 0.94 3 10 7 CFU of E.coli ATCC 25922 in the left thigh muscle. Two hours after inoculation they were treated with aztreonam, ceftazidime, imipenem, meropenem or saline 0.9% intravenously in groups of three. Antibiotic dosages were adjusted to 200 3 MIC peak-level (0.05 mg, 0.05 mg, 0.005 mg and 0.05 mg, respectively). Four hours after treatment, all mice were sacrificed for bacterial cell counts (CFU’s) in muscle, spleen and liver, morphological studies of the bacteria (HE- and fluorescencestudies), collection of plasma for TNF-alpha, IL-6 and endotoxinlevels. Results: In the 4 treatment groups, reduction of CFU’s in muscle, liver and spleen was comparable to controls. Mice treated with aztreonam or ceftazidime showed massive filament-formation in histological sections. Thigh muscles of imipenem and meropenem treated mice showed spheroplast-formation, whereas in controls gram-negative rods were seen. In the treated groups, significant higher TNF-levels were found ( p 5 0.007), particularly in the filament-group. Circulating IL-6-levels demonstrated a high correlation ( p 5 0.01 level) with TNF-concentrations. Plasma endotoxin-levels tended to be lower in the antibiotic treated mice. Conclusion: Use of b-lactam antibiotics in E.coli-sepsis in mice causes filament- and spheroplast-formation and higher circulating TNF-levels, particularly in the filament-group. Antibiotic-induced morphological changes of bacteria may be related to an adverse clinical outcome of sepsis, and should be prevented by an adequate choice of antimicrobial agent and dosing-regimen, paying special attention to the antibiotics PBP-specifity. 141. Epidural abscess: treatment without surgery. S. Schiltmans 1 , R.H. Boerman 2 , R.A. de Vries 1 , C. Richter 1 , 1 Department of Internal Medicine, 2 Department of Neurology, Rijnstate Hospital, Arnhem. Introduction: A epidural abscess is usually treated by laminectomy and i.v. antibiotics. However, neurosurgery can be avoided in selected cases. We describe a patient with an epidural abscess, who could be managed conservatively with antibiotics under close observation. Case history: A 23 year old male immigrant from Azerbaijan was admitted to the surgeon with severe pain, mainly located in the back with slight radiation to the legs, and with high fever (40.08C). The symptoms had started one week earlier. No surgical or urological diagnosis could be established; ultrasound of the abdomen was normal. The internist was consulted. The patient was ill with normal blood pressure and tachycardia (110 / min). Body temperature was 38.78C. The only abnormal finding on physical examination was a slight tenderness over the lower spine and the left flank. Laboratory results showed elevated ESR of 84 mm / h, CRP of 302 mg / l, leucocytes of 11.4 with no left shift in the differential count. Blood cultures were taken and an urgent MRI was ordered because of suspicion of a spondylitis.

A large epidural abscess was found extending from Th 12 to L5. Staphylococcus aureus was cultured from blood and the patient was treated with flucloxacilline i.v. 12 g., later 6 g i.v. for 6 weeks. No signs of spinal cord compression were detected during daily examination. Because the infectious agent was known and no neurological deterioration occurred the patient was managed conservatively. He recovered gradually in a few weeks and was discharged free of pain and in a good clinical condition. Conclusion: Epidural abscess is a rare complication of bacteraemia (in most cases staphylococcus aureus). Predisposing factors can be back- or abdominal surgery, injuries to the skin, i.v. drug abuse, alcoholism, or diabetes mellitus. In our patient none of these factors were present. In this case it has been demonstrated that antibiotic treatment alone is sufficient and successful provided it is accompanied by serial neurological examination. However, signs of spinal cord or cauda compression should always be an indication for urgent neurosurgical treatment.

X. Nephrology 142. Highly purified dialysate enables safe use of super-flux 1 dialyzers: no need for a bacterial filter. A. van Tellingen , 2 1 1 3 M.P.C. Grooteman , M.J. Nube´ , R. Pronk , J. van Loon , M.G. 2 1 2 Vervloet , Medical Centre Alkmaar, Academic Hospital VU, 3 Leiden University Medical Centre, Wilhelmina-laan 12, 1815 JD Alkmaar, Tel.: 072 -5484444, Fax: 072 -5482159, e-mail: avantellingen@ worldmail.nl Introduction: In hemodialysis (HD) patients, back-transport of bacterially derived products from the dialysate to the circulation has been correlated with both acute and long-term complications, ¨ such as dialysis related amyloıdosis, atherosclerosis and malnutrition. Aim of the study: In the present study both the design and the effectiveness of our water treatment system to produce highly purified dialysate without the need for a bacterial filter is described. Materials and Methods: Bacterial counts and lipopolysaccharides (LPS) in dialysate as well as LPS concentrations in plasma were measured in 37 patients undergoing HD for 12 weeks with two of the following dialyzers: high-flux polysulfon (PS: F 60), super-flux PS (F 500S), super-flux cellulosic tri-acetate (CTA: Tricea 150G) or super-flux CTA with filtered dialysate (Tricea 150G f ), resulting in 72 periods in which measurements were obtained. Blood samples were drawn from the afferent line at the start of the dialysis session (t 0 ) and from the efferent line 180 min (t 180 ) afterwards. Dialysate samples were taken at t 180 from the outlet port of the dialysis machine. Results: Filtered dialysate showed significantly lower bacterial counts, if compared to standard dialysate (filtered: 0 [0–3] CFU / ml, standard: 26 [0–310] CFU / ml, p , 0.001). As for LPS, marked differences were not observed between filtered and standard dialysate, whereas mean plasma LPS concentrations were below the value of the dialysate (plasma: t 0 0.03260.005 resp. t 180 0.02860.006 EU / ml, dialysate: 0.05160.005 EU / ml, p , 0.001). Interestingly, LPS concentrations decreased significantly in both CTA modalities during HD (Tricea 150G; t 0 mean: 0.03260.004,

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Internistendagen 2001 t 180 mean: 0.02760.005 EU / ml, p 5 0.003 resp. Tricea 150G f ; t 0 mean: 0.03460.007, t 180 mean: 0.02760.007 EU / ml, p , 0.001). Marked differences were not observed between the various modalities. Furthermore, significant correlations were not found between neither dialysate cultures and the LPS concentrations in the dialysate nor between dialysate cultures and the LPS concentrations in plasma. Conclusion: Concomitant use of highly purified dialysate, at least at levels found in our centre, and super-flux dialyzers did not result in back-transport of bacterial fragments. Remarkably, plasma LPS concentrations even decreased with super-flux CTA devices. 143. A man with uveitis and renal failure. J.T.N. Driessen, G.A.M. Veltman, P.J. Stijnen, Amphia ziekenhuis locatie Langendijk, Langendijk 75, 4819 EV Breda, Tel.: 076 -5277911, Fax: 076 -5277410. Case: A 63-year old male was admitted to our hospital with renal insufficiency. A month before an ophtalmologist diagnosed unilateral uveitis. A year before admission his serum creatinine was 112 mmol / l. He had ocular symptoms and complained of fatigue. Physical investigation was normal with a blood pressure of 120 / 80 mmHg. Laboratory data: ESR 70 mm / h, Hb 7.3 mmol / l, serum creatinine rising from 191 mmol / l to 468 mmol / l in 3 weeks (creatinine clearance 16 ml / min), urine analysis: protein 0.72 g / 24 hrs, sediment: sporadic erytrocytes, some hyaline and granular casts, no eosinophils. A renal biopsy in normal (-sized) kidneys showed normal glomeruli and diffuse cellular infiltrate of the interstitium with mostly lymphocytes and some plasma cells, eosinophils and tubular necrosis, compatible with a interstitial nephritis (TIN). IF was negative. He developed uveitis of his other eye. Other investigations could not reveal a specific cause of his TIN or uveitis. Prednisone, initially 60 mg daily, was given and his serum creatinine dropped to 130 mmol / l with normalisation of ESR, Hb and sediment. Discussion: Our patient had an idiopathic TIN and uveitis syndrome (TINU-syndrome). It is an entity unknown to many ophtalmologists and internists. Since 1975 about 50 patients are described in the literature until now. Most patients are young and female, but occasionally it is seen in middle-aged man or elderly patients. The cause is unknown. It is an inflammatory disease with auto-immune characteristics. Uveitis can precede, follow or occur simultaneously with TIN. Renal insufficiency can disappear spontaneously, but progression to end-stage renal failure is described. Despite the small number of patients reported, data suggest a beneficial effect of steroids with complete recovery of renal function in most patients. Conclusion: In patients with uveitis or TIN the possibiity of TINU-syndrome should be considered, because in some patients end-stage renal failure develops. Data suggest that steroids can prevent this. 144. Colchicine in fertile female with familial Mediterranean ¨ Balak 1 , M. Koot 1 , G. fever (FMF); is contraception needed? O. Thyssen 2 , J. van der Meulen 1 . 1 Department of Internal Medicine, 2 Pharmacy, Albert Schweitzer Hospital, locatie Dordwijk, Postbus

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306, 3300 AH Dordrecht, Tel.: 078 -6523333, Fax: 078 -6523377, e-mail: o.balak@ hccnet.nl Case: In 1997, a 23-year-old female Armenian refugee was referred because of recurrent attacks of fever with abdominal pain. The attacks began without any identifiable provocation and lasted 1–3 days. The family history was inconclusive. Physical examination revealed no abnormalities. Laboratory investigations showed: ESR 82 mm / hr, creatinine 62 mmol / l, serum albumin 40 g / l, proteinuria 0.98 g / 24-h and creatinine clearance 110 ml / min. Her history and the proteinuria were suggestive of familial Mediterranean fever (FMF) complicated by renal amyloidosis. Therapy with colchicine in combination with contraception was advised. She refused because she wanted to become pregnant. Eighteen months later the patient presented with lower limb oedema. Laboratory investigations showed this time: ESR 112 mm / hr, creatinine 73 mmol / l, serum albumin 12 g / l; proteinuria 13.3 g / 24-h and creatinine clearance 126 ml / min. A renal biopsy was performed and showed amyloidosis. By genetic testing the patient was proven to have FMF because she was homozygous for the missense mutation M694V. Treatment was started with colchicine to prevent further deposition of amyloidosis. With this regimen the proteinuria decreased to 3,1 g / 24-h, but creatinine clearance decreased to 65 ml / min as well. Discussion: FMF, a recessively inherited disorder, occurs in patients from the Mediterranean area such as Arabs, Armenians, Jews and Turks. From the prevalence of FMF in Turkey, one may estimate that there are around 100 Turkish FMF patients in the Netherlands. Characteristic features of FMF are self-limiting attacks of fever with pleuritis, peritonitis or arthritis. The first attack starts around the age of sixteen. The most serious complication of untreated FMF is renal amyloidosis. Colchicine is the therapy for FMF; it prevents the attacks and the development of amyloidosis. In the Netherlands, colchicine is registered with the restriction that it may only be prescribed to fertile female when appropriate contraceptive measures have been taken. Adherence to this restriction would not only be very difficult for the estimated 50 Turkish female FMF patients in the Netherlands but also not in accordance with the literature. There, it is advised to continue colchicine and when pregnancy occurs, to perform amniocentesis for karyotyping and reassurance. Conclusion: Withholding colchicine in female FMF patients, who don’t want to take contraception, exposes them to the development or progression of renal amyloidosis. Colchicine may be started or continued in these patients and during the pregnancy amniocentesis for karyotyping should be performed. 145. Acute renal failure associated with salmonella enteritidis infection. H. Akol, M.P. Hendriks, M.I. Koolen, J.L.J. Jansen, A.A.M.J. Hollander. Department of Internal Medicine, Bosch Medicentrum, ‘ s-Hertogenbosch, The Netherlands. Introduction: Salmonella infections cause mostly acute, selflimiting diarrhoea. Extra intestinal illness is rare. We describe two patients, who where admitted in our hospital because of acute renal failure caused by salmonella enteritidis infection. Case I: A 65 year-old man was admitted with a 5-day history of severe watery stool and generalised abdominal pain. Physical examination revealed a dehydrated, severely ill man. Blood

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pressure was 110 / 50 mmHg, the pulse was 100 bpm, temperature was 35.98C. The abdominal examination showed no abnormal findings. Laboratory results showed a blood urea nitrogen (BUN) of 45.2 mmol / l and a creatinine of 1041 mmol / l. The urine sediment was normal. Blood and stool cultures showed salmonella enteritidis. The patient was rehydrated and the salmonella bacteriemia was treated with ofloxacilin and subsequently with cotrimoxazol. The patient was discharged in good health with a serum creatinine of 134 mmol / l. Case II: An 80 year-old man with history of COPD had a three days history of severe diarrhoea, vomiting and fever after eating an egg. Physical examination revealed a severely ill and dehydrated patient. Blood pressure was normal with a pulse of 100 bpm; temperature was 37.58C. The abdomen was slightly distended and auscultation revealed subileus murmurs. Serum creatinine was 884 mmol / l; BUN was 70 mmol / l. Urine sediment and myoglobine were normal. The x-ray of the abdomen showed small bowel ileus. Blood and stool cultures showed salmonella enteritidis. Rehydration and amoxicllin were immediately started. The condition of the patient deteriorated with persisting ileus and later suspicion of perforation. He was not operated because of his severe emphysema and his poor clinical condition. Despite maximal conservative treatment the patient died. The autopsy showed vulnerable but not perforated small intestines with adhesions distal in the ileum. The right kidney showed small infarction. Discussion: Both patients developed serious acute renal failure caused by Salmonella enteritidis infection. In the literature only eight other patients with S. enteritidis and acute renal failure are described. The causes of the renal insufficiency are dehydration with acute tubule necrosis, rhabdomyolysis, glomerulonefritis and interstitial nephritis. In our patients no signs of rhabdomyolysis or glomerulonephritis were found. The renal insufficiency was probably caused by dehydration. Both cases emphasise that Salmonella enteriditis infection can have a severe course with extra- intestinal disease leading to severe morbidity and even mortality. In elderly patients the disease legitimate extra attention to minimise complications. 146. An index for renal outcome in ANCA-associated glomerulonephritis. E.A.F.J. van Gurp 1 , C.E. Vergunst 2 , E.C. Hagen 1 , J.C. 3 ¨ 4 . R. Waldherr 5 , F. Ferrario 6 , F. J. van Houwelingen , L.H. Noel van der Woude 7 , J. A. Bruijn 2 , I. M. Bajema 8 for the EC / BCR Project for ANCA-Assay Standardisation. 1 Department of Internal Medicine, Eemland Hospital, Amersfoort, The Netherlands; 2 Department of Pathology, and 3 Medical Statistics, Leiden University Medical Center, The Netherlands; 4 Department of Nephroˆ Necker, Paris, France; 5 Department of Pathology, logy, Hopital University of Heidelberg, Germany; 6 Department of Nephrology, Ospedale San Carlo Borromeo, Milan, Italy; 7 Medical Faculty Mannheim, University of Heidelberg, Germany; 8 Department of Pathology, Erasmus Medical Center Rotterdam, The Netherlands. We performed a multiple regression analysis in which histological, clinical and serological parameters of 161 patients with ANCA-associated glomerulonephritis were taken into account, at the time of renal biopsy (t 5 0). Renal functions at t 5 0 and t 5 1

(one year after renal biopsy) were calculated, using the Cockroft formula. Our aim was to analyze to what extent the variation in renal function, measured by the GFR, could be predicted by these parameters. The histological data included: normal glomeruli, fibrinoid necrosis, extracapillary proliferation, granulomas, interstitial edema, focal and diffuse infiltrates, fibrosis, tubular cylinders / casts, tubular atrophy, tubular necrosis, sclerosis, mesangial proliferation, mesangial matrix expansion, arteriosclerosis and infiltrates in arterioles. ANCA-ELISA test results were scored as: anti-MPO 1 , anti-PR3 1 , double 1 or double 2 . Diagnoses incorporated: Wegener’s granulomatosis, microscopic polyangiitis and idiopathic rapidly progressive glomerulonephritis (renal limited vasculitis). Also age and sex were included. Additionally, we used an even larger amount of histological parameters to analyze whether there were histological differences between patients with anti-PR3 and anti-MPO ANCA-test results. Results:

GFR (t 5 0)

GFR (t 5 1)

a b

Independent predictors a

R2 b

Tubular atrophy Normal glomeruli Fibrinoid necrosis Extracapillary proliferation Age GFR (t 5 0) Normal glomeruli Fibrinoid necrosis Age

0.164 0.205 0.243 0.258 0.401 0.536 0.558 0.574 0.608

In order of significance. Cumulative and adjusted for the amount of parameters used.

Only mesangial matrix expansion and mesangial proliferation showed a slight tendency (but not significant) to differ between the different ANCA-test results. Conclusion: Renal function, expressed by GFR, at time of biopsy, is the best predictor for renal function one year after biopsy in patients with ANCA-associated glomerulonephritis. Together with normal glomeruli, fibrinoid necrosis and age, it explains for over 60% of the variation in GFR one year after biopsy. It is remarkable, that ANCA-test results have no independent contribution in predicting patient prognosis. This result is in line with our finding that none of the involved histological parameters show a significant difference between the patients with different ANCA-test results. 147. Use of urea containing dialysate to avoid disequilibrium syndrome enabling intensive dialysis treatment of a diabetic patient with renal failure and severe metformin induced lactic acidosis. R.J. Bosma, C.J. Doorenbos, P.J.N. Lamberts, Deventer Ziekenhuizen, H. J.P. Fesevurstraat 7, 7415 CM, Deventer, Tel.: 0570 -646666, Fax: 0570 -628909, e-mail: r.jbosma@ freeler.nl Introduction: Metformin decreases insulin resistance in type II diabetes mellitus. It suppresses gluconeogenesis in the liver and it enhances peripheral glucose uptake. Metformin is eliminated by

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Internistendagen 2001 the kidneys and it is contraindicated in renal impairment. Metformin causes a slight increase in blood lactate levels. Severe lactic acidosis (reported mortality 50%) develops rarely, predominantly when contraindications like renal failure are overlooked. Bicarbonate hemodialysis successfully corrects the metabolic acidosis and removes lactate and metformin. Dialysis disequilibrium syndrome may develop in uremic patients, when treatment is started with rapid intensive hemodialysis and when there is a concomitant severe metabolic acidosis. The symptoms of headache, disorientation, restlessness, confusion, seizures, coma and death are attributed to cerebral edema, due to a brain to plasma urea gradient, caused by rapid removal of urea from the blood and delayed urea diffusion from the brain to the blood. Furthermore, a decrease in cerebral intracellular pH may contribute to the syndrome. Case: A 66-year-old female patient developed severe metformin intoxication (level 19.4 mg / l, therapeutic level 1 mg / l) with lactic acidosis (13.5 mmol / l) due to pre-existent renal failure, further aggravated by vomiting and the continued use of an ACE inhibitor. On admission the patient was anuric and this prevented renal excretion of the drug. Other relevant lab results were: urea 28.8 mmol / l, creatinin 640 mmol / l with severe hyperkalemia (7.8 mmol / l). Prolonged dialysis treatment resulted in significant removal of metformin (the level decreased to 8.4 mg / l), but she developed symptoms consistent with the disequilibrium syndrome (the urea level had fallen to 10.4 mmol / l). A relapse of lactic acidosis called for a second dialysis treatment to further remove metformin and to correct the acidosis. Urea was added to the dialysate in a concentration similar to that in her blood to prevent a deterioration of the disequilibrium. This allowed repeated dialysis treatment with successful removal of metformin and correction of lactic acidosis without further neurological problems. Conclusion: In patients with renal failure with elevated blood urea levels and severe lactic acidosis due to metformin intoxication, repeated prolonged bicarbonate dialysis is needed to remove the accumulated metformin. Addition of urea to the dialysate permits this intensive treatment while avoiding the provocation of the disequilibrium syndrome. 148. The relation between fluid status and structural cardiac abnormalities in patients (pts) on peritoneal dialysis (PD). Constantijn J.A.M. Konings, Jeroen P. Kooman, Frank M. van der Sande, Karel M.L. Leunissen. Dept. of Internal Medicine, University of Maastricht, The Netherlands. JKOO@ SINT. AZM.NL Left ventricular (LV) hypertrophy (LVH) and a reduced LV systolic function are risk factors for cardiovascular mortality in PD pts. Overhydration likely contributes to structural cardiac abnormalities in PD pts. However, as the assessment of fluid status is notoriously difficult to assess in PD pts, few studies have focused on the relation of fluid status and cardiac structure. The aims of the present study were to assess the relation between fluid status, blood pressure (BP) and cardiac abnormalities in PD pts and to investigate which body fluid compartment is best related to hemodynamic variables. In 26 PD pts (20 male; 6 female, mean age 52, 9 years, SD611.8), the relation between plasma volume (PV; dextran 70), extracellular water (ECW; bromide), total body water (TBW; deuterium), BP (24-hour ambulatory measurements)

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Results: PV ECW TBW Systolic BP Diastolic BP

LVM 0.65* ns 0.49* 0.50* 0.41*

2 0.54* ns 2 0.41* ns ns

LVEF

ns 0.60*

PV

ECW

0.66* 0.83*

0.77*

ns ns

ns 0.46*

TBW

and LV mass (LVM) and LV ejection fraction (LVEF) (echocardiography) was studied. All but 2 pts used antihypertensive drugs. Despite the relation between LVM and fluid status, no difference in fluid status was observed between pts with and without LVH (LV mass index . 130 g / m and . 110 g / m in females (PV:body weight 3.6 vs. 4.1%). Conclusion: 1. Also in PD pts on antihypertensive treatment, fluid status is (weakly) related to BP. 2. Fluid status is also related to structural cardiac abnormalities, although a large overlap in hydration status is present between patients with and without LVH. 3. PV is better related to BP and cardiac structure than ECW or TBW.

XI. Intensive care 149. Severe bullous emphysema due to cocaine smoking. J.M. van der Klooster 1 , A.F. Grootendorst 1 , Afdeling Intensive Care Geneeskunde, Medisch Centrum Rijnmond-Zuid 1 ,Olympiaweg 350, 3078 HT Rotterdam, Tel.: 010 -2911911, Fax: 010 -2911083, e-mail: jmvanderklooster@ planet.nl Pulmonary emphysema is characterised by permanent enlargement of airspaces distal to the terminal bronchiole, accompanied by destruction of alveolar walls. The loss of elastic tissue contained in the interalveolar septa is due to an imbalance between proteinase and antiproteinase activity, most commonly caused by cigarette smoking. Congenital deficiency of a 1 -antitrypsin, the most well known antiproteinase, is an important risk factor for the development of premature emphysema. However, toxic damage due to the inhalation of cocaine is another rare cause of severe bullous emphysema. A 40-year-old man was admitted because of progressive dyspnea, cough and fever. He had been smoking cocaine, so called free-basing, for the past 17 years. His medical history consisted of recurrent respiratory tract infections. Chest radiography and computed tomography showed impressive bilateral bullous emphysema with a large air-fluid collection in the right lung, suggesting pulmonary abscess formation. Because of progressive respiratory failure he was intubated and mechanically ventilated. Further treatment consisted of intravenous broad-spectrum antibiotics and chest tube drainage because of ventilator-associated pneumothorax. The patient died of therapy resistant respiratory failure as a consequence of pneumonia in the scarce residual pulmonary tissue. The definitive diagnosis of cocaine-induced pulmonary emphysema was established after ~ 1 -antitrypsin concentration was found to be within the normal range.

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Besides congenital a 1 -antitrypsin deficiency, cocaine smoking should be considered as a possible cause of severe premature bullous emphysema. Abscess formation and rapidly progressive respiratory failure may complicate this condition. 150. Tetraplegia and respiratory failure due to severe polyneuropathy associated with the use of antituberculous drugs in a patient undergoing chronic hemodialysis. J.M. van der Klooster 1 , A.F. Grootendorst 1 , Afdeling Intensive Care Geneeskunde, Medisch Centrum Rijnmond-Zuid 1 , Olympiaweg 350, 3078 HT Rotterdam, Tel.: 010 -2911911, Fax: 010 -2911083, e-mail: jmvanderklooster@ planet.nl Tetraplegia is a well-known but uncommon neurological complication of infection with Mycobacterium tuberculosis. If progressive neuromuscular symptoms develop in a hemodialysis patient with tuberculosis, one should consider tuberculous meningitis or spondylitis (Pott’s disease). However, antituberculous drugs may also be associated with severe neurological sequelae. A 58-year-old man from Somalia, with a history of diabetes mellitus, diabetic retinopathy, diabetic polyneuropathy and chronic renal failure due to diabetic nephropathy, was admitted to the intensive care unit because of respiratory failure due to Haemophilus parainfluenzae pneumonia. Furthermore, progressive visual disturbances and paraplegia of the legs had developed within two months after commencing treatment with antituberculous drugs for tuberculous mediastinal lymphadenitis. Initial treatment consisted of ethambutol, isoniazide, pyrazinamide, rifampicin and pyridoxine, in doses regarded safe for hemodialysis patients. After several days of mechanical ventilation and broad-spectrum antibiotics, progressive tetraplegia and respiratory failure were noted. Tuberculosis of the central nervous system and vertebral column were excluded after CT-scan of the brain and spinal cord and examination of the cerebrospinal fluid. Since drug neurotoxicity was suspected, isoniazide and pyrazinamide were withdrawn first. However, repeated electromyography showed severe and progressive peripheral polyneuropathy during continued use of ethambutol. Visual evoked potentials showed cortical blindness. Despite their ‘non-toxic’ concentrations, all other drugs were discontinued. Further treatment consisted of prolonged mechanical ventilation, hemodialysis and administration of thiamine, pyridoxine and zinc sulphate. During the following 6 months, no neurological improvement occurred. The patient died from therapy resistant peripheral polyneuropathy and ventilator associated pneumonia. Development of peripheral polyneuropathy in a patient using antituberculous drugs is most commonly associated with isoniazide therapy and concomitant pyridoxine deficiency. Symptoms are generally mild and reversible and usually not life-threatening. Ethambutol is well known for its ocular toxicity, but has rarely been reported as the sole cause op peripheral neuropathy. Ethambutol ocular toxicity is manifested by bilateral optic neuritis that may progress to optic atrophy with permanent visual impairment, also in patients treated with presumably safe dosages. Reported predisposing factors are older age, low serum zinc levels, renal failure and hemodialysis, and the combined use of ethambutol and isoniazide.

In our patient, deterioration of the ocular and peripheral neuropathy despite withdrawal of isoniazide suggests a prominent role for ethambutol in the persistence and possible exacerbation of these complications. It should be noted that all risk factors for ethambutol-induced neuropathy were present in our patient, superimposed on diabetic polyneuropathy and diabetic retinopathy. Impaired communication probably was a very important factor in the late recognition of his symptoms. 151. Severe complicated Posthysteroscopic hyponatremia: case-report. Trof R.J., Hylkema B.S. Medisch Spectrum Twente, ziekenhuis Enschede, Postbus 50000, 7500 KA Enschede. A 34-year-old woman was admitted for hysteroscopic myomectomy. A 1.5% glycine solution was used for irrigation. During operation a large quantity of this fluid was supposed to be absorbed in the circulation, leading to massive pulmonary edema and a hypo-osmolar dilution hyponatremia (92 mmol / l), resulting in a cardiac arrest. After 45 minutes of resuscitation by cardiac massage and high PEEP ventilation the patient was admitted at the ICU. Hyponatremia was corrected with hypertonic NaCl. Patient had to be ventilated for almost three weeks because weaning was complicated by two episodes of presumed neurogenic pulmonary edema after epileptic seizures caused by post-anoxic encephalopathy. Two months after admission the patient left the hospital with almost complete neurological recovery. Hysteroscopic ablation is nowadays the treatment of choice in menorrhagia, leiomyoma uteri or dysfunctional uterine bleeding. Hypotonic solutions as glycine 1.5% or sorbitol 3% are used for irrigation, for better visualization, and for washing away the debris. In literature the risk of glycine induced hypo-osmolar hyponatremia is well described, especially in transurethral resection of the prostate, known as the post-TURP-syndrome. However, leading to situations as described in this case is rare. Because of the hypotonic character of the glycine solution, absorption by uterine vasodilatation leads to hypo-osmolality, and therefore dilution hyponatremia. The working of the anti-diuretic hormone (ADH) enhances this mechanism, either endogenous produced because of decrease in ECV or exogenous given to control bleeding. The rapidly decrease in plasma sodium causes a fluid shift resulting in cerebral edema leading to respiratory failure. During operation, hypo-osmolality should be suspected in case of disturbance in the irrigation fluid balance. If there’s a discrepancy of more than 1.5 L, one should be alerted to the possibility of hyponatremia. Treatment is aimed on rapid correction of the serum sodium with hypertonic NaCl to prevent development of cerebral edema, and therefore mortality. In order to prevent hypo-osmolar hyponatremia, the use of isotonic irrigation fluids as sorbitol-mannitol or mannitol has recently been recommended. Isotonic fluids are not metabolized and do not lead to hypo-osmolality. In conclusion, the use of hypotonic irrigation solutions in hysteroscopic procedures can lead to acute life threatening hypoosmolar dilution hyponatremia as described in this case report. The intake and output of the irrigation fluid should be closely

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Internistendagen 2001 monitored in order to suspect hypo-osmolality. Therapy should be instituted before respiratory failure occurs. The use of isotonic solutions should be considered. 152. A rare case of gas in the wall of the stomach due to 1,2 emphysematous gastritis. W.N.K.A. van Mook , S. van der Geest 1,2 , M.L.M.J. Goessens 2,3 , E. Schoon 1,4 , G. Ramsay 2,3 . 1 2 3 Departments of Internal Medicine, Intensive Care, Surgery and 4 Gastroenterology. Introduction: Emphysematous gastritis is a rare variant of phlegmonous gastritis due to invasion of the stomach wall by gas-forming bacteria. Case report: A 66 year old female patient was transferred to the Intensive Care Unit (ICU) because of septic shock. Her medical history revealed tuberculosis, rheumatoid arthritis for which she was treated with prednisone and methotrexate. She was admitted for corneal transplantation after a complicated herpes zoster infection. In the ICU she complained of pain in all joints. Physical examination revealed hypotension, hypothermia, no signs of active eye infection, and joints were swollen and tender without redness. The abdomen was tender without guarding or rebound tenderness. Abdominal echography was normal. She was treated with amoxicilline / clavulanic acid and gentamicine intravenously. Considering the use immunosuppression a laparoscopy was performed, but no abnormalities were found. Blood cultures grew St. aureus and flucloxacilline, gentamicine and rifampicine were started. Gram staining and cultures of synovial fluid from the right knee were negative. Transesophageal echocardiography showed no vegetations. An otitis externa grew St. aureus. An abdominal x-ray because of increasing abdominal pain with guarding showed gas in the wall of the stomach. Gastroscopy showed absent mucosal folds, edema, necrosis and echymoses on a pussy surface in corpus, cardia and fundus. Cultures of stomach fluid yielded Klebsiella pneumoniae. Ciprofloxacin and metronidazol were added. The relatives wishes not to operate were respected, and the patient died. Postmortem examination showed transmural imbibition in the area of the greater curve, as well as several gasfilled bullae with a diameter of 1 cm. Cultures of stomach yielded Candida albicans. Discussion: Since the first description of the disease in 1889 only 39 cases have been described in the literature including this case. In most cases prior damage to the mucosa was present, most often due to ingestion of corrosives or alcohol. Organisms isolated include Clostridium perfringens, Proteus mirabilis and vulgaris, E. aerogenes, E. coli, St. aureus, P. aeruginosa, non-hemolytica and alfa-hemolytic streptococci, Str. viridans, Klebsiella pneumoniae, Str. faecalis, bacteroides species, E.cloacae and Candida albicans. Several risk factors for this condition have been described. Conclusion: A rare case of emphysematous gastritis is presented in which St. aureus, Klebsiella pneumoniae and Candida albicans were identified as potential causative microorganisms.

XII. Rheumatology 153. Preliminary results of three infliximab infusions in active rheumatoid arthritis. M.W.M. van de Brand, E.J. ter Borg, H.

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van Mourik, and H.C.M. Haanen. Department of Rheumatology, St Antonius Hospital Nieuwegein; Tel.: 030 -6099111, fax: 030 6056357, e-mail: internsecr@ antonius.net Introduction: Active rheumatoid arthritis (RA) has a large impact on the patients’ daily life. Moreover, on the long term more joint destruction will be seen while life expectancy is reduced. Recently anti-TNFa therapy has become available and results on the short term are very promising. Aim of the study: To investigate the feasibility of infliximab infusions in patients with active RA in a large non-university hospital. Materials and Methods: We evaluated the effects of the first three infliximab infusions (3 mg / kg at week 1, 2 and 6) in 10 patients with RA (1988 ACR criteria) and active disease: . 6 tender and swollen joints and 2 of the following: morning stiffness . 45 minutes, CRP . 20 mg / l, ESR . 28 mm / h. All the patients (had) used MTX. Prior to inclusion dosage of DMARD’s had to stable during 2 months and dosage of prednisone and NSAID during 1 month. From one month before the start of the infusions intra-articular corticosteroid injections were forbidden. The major endpoint was the DAS28, a composed-disease-activity-index containing: ESR, VAS-disease-activity of the patient and number of tender and swollen joints. Results: Ten patients (7 females and 3 males) with active RA (DAS28 . 5.4) were included. Mean age was 51.6 years, mean disease duration was 12.6 (3-30) years and all but one were rheumatoid factor positive. Mean number of DMARDs was 5.3 (1-8) and all but two used prednisone (2.5-15 mg / day). At the time of the study all used DMARDs: 6 MTX, 1 aurothioglucose, 2 azathioprine and 1 SAPS and hydroxychloroquine. Only one patient experienced side effects (rash and hypotension during all three infusions) and had to stop treatment. In all patients the DAS28 ( p , 0.001) fell as did ESR ( p , 0.01) and CRP ( p , 0.005). VAS score ( p , 0.02) and platelets ( p , 0.01) decreased and serum albumen ( p , 0.005) rose. Most patients reported they were less tired though level of haemoglobin did not change. During the study prednisone dosage could be reduced in 4 patients. Conclusions: Infliximab infusions are very useful in the treatment of patients with active rheumatoid arthritis. The implementation of this treatment in the setting of a large non-university hospital is feasible. Side effects are rare but costs very high. Long-term results have to be awaited in order to decide which patients have to be treated with infliximab in the next future. 154. The bar code image by radionuclear scanning. F. Douma 1 , H.C.M. Haanen 1 , P.H.Th.J. Slee 1 , A.B.M. Geers 1 , J.F. Verzijlbergen 2 . St. Antonius Hospital, Nieuwegein, Department of Internal Medicine 1 and Nuclear Medicine 2 , Koekoekslaan 1, 3435 CM Nieuwegein, Tel.: 030 -6092088, Fax: 030 -6056357, e-mail: H.Haanen@ Antonius.net. A 47-year-old man visited our clinic in June 2000 with malaise and weight loss of 7 kg in 7 weeks. Medical history: hypercholesterolaemia, for which he uses simvastatin. Since 1999 he noticed small nodules underneath the skin. Family history: his mother may have suffered from sarcoidosis.

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Physical examination: multiple small painless nodules underneath the skin, with an average diameter of a few centimeters spread over the entire body. BP 160 / 100 mmHg. Further physical examination was unremarkable. Laboratory investigation: serum creatinin 315 `ımol / l, albumin 44 g / l, calcium 3,45 mmol / l, phosphate 1,18 mmol / l. PTH was not detectable, 25-hydroxyvit. D3 en 1,25-hydroxyvit D were normal. ACE 48 U / l, later 84 U / l, CK 61 U / l. Calcium in 24-hour urine: 3,0 mmol. Additional imaging investigation: Chest X-ray: a small density in the right upper lobe. CT-chest: diffuse multiple small foci in the lung and enlarged lymph nodes in the mediastinum. Ultrasound of the upper leg showed nodules measuring a few millimeters to several centimeters with intramuscular localization. MRI of the upper arm: multiple dense areas in the muscles. After administering gadolinium there was enhancement around these areas. A Gallium-scan showed scattered linear uptake in all skeletal muscles resembling the pattern of bar codes and dense uptake supraclavicular left as well as a dozen hotspots diffusely in the parenchyma of the lung. Histology of a skin and muscle biopsy taken from the upper leg: extensive non-caseating granulomata between the muscle fibers with giant cells and epitheloid cells. The skin and subcutis were normal. Diagnosis: extensive sarcoidosis localized in the lungs, lymph nodes and muscles with hypercalcaemia. The patient was treated with 60 mg prednison daily with complete correction of the serum calcium and kidney function. The gallium scan did normalize. This case is presented because of the exceptional images seen on the Gallium scan, where the Gallium uptake in the muscles did look like bar codes. The bar code pattern disappeared during treatment with prednison.

XIII. Other 155. Topical steroids reduce symptoms in non-smoking nonallergic noninfectious perennial rhinitis (NANIPER) patients. J.P.M. Braat 1,2 , P.G. Mulder 1 , V. Van der Velden 1 , S. Veen van 1 , W.J. Fokkens 1 , A.C.M. Van Vliet 2 . 1 Department of Ear-, Nose and Throat Surgery Erasmus Medical Center Rotterdam. 2 Department of Medicine Albert Schweitzer Hospital Dordrecht. Previous studies have pointed to the clinical relevance of neuropeptides and their peptidases in non-smoking NANIPER patients. Because on the one hand exogenous neuropeptide Y (NPY) reduces nasal airways resistance and mucus secretion in atopic rhinitis via neural sensory mechanisms and on the other hand topical steroids increase peptidase activity in atopic asthma their therapeutic applications are suggested in these patients. To investigate this 49 NANIPER patients were divided in 3 groups and treated double blind for 8 weeks with (a) NPY (2,3 nmol) plus thiorphan (a neutral endopeptidase inhibitor) and enalapril (an angiotensinogen converting enzyme inhibitor) (b) fluticason propionate (FP) or (c) placebo nosesprays. Complaints and quality of life (QoL) were scored, nasal lavages were performed and nasal reactivity measured (1 histamine and 3 cold dry air (CDA)

provocations), all pre- and post treatment. Lavage contents of markers for mucus cells (total protein per albumin), vasopermeability (IgG and albumin), serous cells (lysozyme) and mucosal immunity (IgG) as well as the activity of neutral endopeptidase (NEP) were measured. Nasal complaint scores (median; range) after FP improved significantly (pre 1.57; 1.27–2.05 vs. post 1.08; 0.69–1.54; P 5 0.025), but not after NPY or placebo (1.14; 0.61–1.78 vs. 0.87; 0.34–1.45; P 5 0.23 resp. 1.55; 0.86 1.09 vs. 1.39; 0.93–1.82; P 5 0.43). QoL scores (median; range) for placebo deminished significantly (1.90; 0–4.81 vs. 1.11; 0–3.79; P 5 0.03), while QoL scores for FP and NPY were not affected (1.70; 0.21–2.64 vs. 1.71; 0–5.48; P 5 0.44 resp. 1.81; 0–3.27 vs. 1.24; 0–4.34; P 5 0.39). CDA reactivity after FP tended to be low. In nasal lavages NEP activity seemed to increase after FP, while total protein per albumin seemed to decrease. NPY and placebo treatment had no effect on these parameters. No significant differences in other markers were observed. In conclusion: topically applied FP resulted in a significant reduction in clinical symptoms in non-smoking NANIPER patients. Our study supports the neural mechanism that FP treatment increases NEP activity thereby reducing liberated neuropeptides by non-specific stimuli and decreasing mucus cell activity. 156. Non-bacterial thrombotic (marantic) endocarditis associated with giant-cell arteritis. D.A. Hesselink 1 , J.M. van der Klooster 1 , L.J.D.M. Schelfhout 1 , M.G. Scheffer 2 , Departments of Internal Medicine 1 and Cardiology 2 , Medisch Centrum RijnmondZuid, Olympiaweg 350, 3078 HT Rotterdam, Tel.: 010 -2911911, Fax: 010 -2911083, e-mail: jmvanderklooster@ planet.nl Infective endocarditis is a disease caused by microbial infection of the endothelial lining of the heart. Its characteristic lesion is vegetation, which usually develops on a heart valve. However, sterile vegetations may also develop within the heart. Since these vegetations are primarily thrombotic rather than inflammatory, the term non-bacterial thrombotic endocarditis (NBTE) is used. The aetiology, pathogenesis and characteristics of NBTE are discussed in more detail. A 64-year old woman was hospitalised because of high fever and headache. Diagnostic work-up included transthoracic echocardiography, which revealed vegetation on the mitral valve. A presumptive diagnosis of infective endocarditis was made and the patient was treated with broad-spectrum antibiotics. Extensive serologic and microbiologic investigations did not reveal any pathogen and despite antibiotic treatment, fever persisted for six weeks. Echocardiography showed a constant size of the valvular vegetation. It was therefore concluded that the vegetation consisted of a non-bacterial thrombotic lesion. A search for the cause of her fever was restarted. Histopathologic examination of the temporal artery revealed giant-cell arteritis for which treatment with prednison was initiated. Fever subsided within 24 hours and the patient has remained in an excellent clinical condition up until now, six months after discharge. Since NBTE has been observed systemic lupus erythematosus and polyarteritis nodosa, it seems plausible that a related disease such as giant-cell arteritis may have induced the cardiac lesion observed in our patient. To our knowledge this is the first case of

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Internistendagen 2001 NBTE associated with giant-cell arteritis. The importance of revising the diagnosis of infective endocarditis into NBTE is emphasised, if no pathogen can be demonstrated after extensive investigations. 157. Cardiac tamponade secondary to chest tube placement. D.A. Hesselink 1 , J.M. van der Klooster 1 , E.H. Bac 1 , M.G. Scheffer 2 , J.W. Brouwers 3 , Departments of Internal Medicine 1 , Cardiology 2 and Pulmonology 3 , Medisch Centrum RijnmondZuid, Olympiaweg 350, 3078 HT Rotterdam, Tel.: 010 -2911911, Fax: 010 -2911083, e-mail: jmvanderklooster@ planet.nl Cardiac tamponade is characterised by an increase in intrapericardial pressure secondary to fluid accumulation within the pericardial space. This leads to an elevated intracardiac pressure, progressive limitation of diastolic filling and a reduction in stroke volume. If cardiac tamponade is not recognised and treated promptly, it may be rapidly fatal. The most common causes of cardiac tamponade are metastatic malignancy, idiopathic pericarditis and uraemia. Iatrogenic trauma complicating diagnostic or intervention procedures may result in cardiac tamponade as well. Since catheter-based procedures are frequently performed, an increased number of procedure-related complications is encountered nowadays. A 69-year old woman was hospitalised because of a left-sided pneumothorax due to chronic obstructive pulmonary disease. During chest tube placement she developed hypotension and a decrease in peripheral oxygen saturation. A diagnosis of heart tamponade was established after transthoracic Doppler ultrasonography. The patient was successfully treated with ultrasonographyguided pericardiocentesis and a pericardial drain. Cardiac tamponade following chest tube placement is a rare and serious complication. If the clinical condition deteriorates following chest tube placement, cardiac tamponade should be included in the differential diagnosis. 158. A case of systemic lupus erythematosus with rare cutaneous manifestations: lupus panniculitis, Lupus Pernio and massive dystrophic calcinosis cutis. K.T.M. Oud 1 , T.R. Hendriksz 2 , E.F.H. van Bommel 1 . Dept. Of Internal medicine 1 and Radiology 2 , Albert Schweitzer Hospital, Dordrecht. We present a 36-year-old female with a two-year history of systemic lupus erythematosus (SLE) who developed three types of rare skin lesions. While receiving high-dose steroids and having no systemic signs or symptoms, distinct skin lesions developed. Physical examination showed large subcutaneous nodules and plaques on her buttock, both upper legs and hollow of the knees leaving some depressed atrophic scars, clinical suspected for lupus panniculitis. Radiologic investigation (plain radiograph, ultrasound, MRI) showed almost symmetric massive deposits of calcium in the fascia and muscles, mainly around the proximal part of the upper legs. All this has led to progressive immobility because of stiffness and pain of both upper legs and knees. Serum calcium and phosphorus levels were normal. Calcinosis cutus developed primarily in areas of panniculitits. At the same time she developed violaceous and pustules skin lesions, with some deep ulcera on both hands, suspected for lupus pernio. Histologic

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examination of the skin and muscle / fascia biopsy showed findings compatible with the clinical diagnosis. Lupus panniculitis, lupus pernio and particularly dystrophic calcinosis cutis are rare in SLE. To our knowledge, there are no prior reports of these findings concurrently affecting one patient with SLE. Therapeutic options, particularly with regard to calcinosis cutis are discussed but no evident efficacy of a specific treatment seems evident. 159. Campylobacter jejuni peritonitis in a CAPD patient: case description and a review of the literature. O.M. Smit, S. Lobatto, A. van Es, Department of Internal Medicine, Ziekenhuis Hilversum, Van Riebeeckweg 212, 1213 XZ Hilversum, Tel.: 035 6887671, Fax: 035 -6887670, e-mail: slobatto@ zhh.nl A 58-year old male patient, on chronic ambulatory peritoneal dialysis (CAPD) for three years, presented with abdominal pains and diarrhoea over the previous 24 hours. He reported that the dialysate had remained clear. The patient was not acutely ill, and on physical examination there was no abdominal tenderness. Laboratory examination showed mild leukocytosis, and the dialysate contained 5–15 WBC’s / hpf. A Gram stain of the dialysate did not reveal any bacteria. The initial diagnosis was CAPD peritonitis, possibly secondary to an intestinal infection. Antibiotic therapy was instituted with intraperitoneal cephradine, and metronidazole i.v. In spite of this treatment, the dialysate became more cloudy, although the patient did not become more severely ill. On the sixth hospital day the initial culture of the dialysate grew campylobacter jejuni. Antibiotic treatment was switched to oral azithromycin, after which the patient made a rapid and uneventful recovery. Although the majority of cases of CAPD peritonitis is caused by micro organisms that populate the skin, intestinal flora must also be taken into consideration when antibiotic therapy is chosen to treat a patient presenting with this illness. Just over twenty cases of CAPD peritonitis caused by campylobacter jejuni have been described in the literature to date. Although apparently a rare cause of CAPD peritonitis, it should be considered as a causative agent in patients presenting with CAPD peritonitis and diarrhoea, in whom peritonitis does not respond to initial treatment. 160. Interstitial pneumonia, hepatitis and minocycline. N.E.T. Rikken 1 , G.J.M. Gerritsen 2 , H.R. Haak 1 . 1 Department of Internal Medicine, Diaconessenhuis, Eindhoven, Netherlands. 2 Netherlands Pharmacovigilance Foundation Lareb, ’ s Hertogenbosch, Netherlands. A 28 year old Caucasian man was admitted to the hospital because of dyspnoe and jaundice, after a flu-like episode 6 weeks earlier. The last year he used minocycline 100 mg daily because of acne vulgaris. On examination we saw an ill-appearing, deeply jaundiced, tachypnoeic patient. Chest examination revealed crackles in the lower lungzones. No abdominal masses were palpable. Chest radiograph revealed diffuse smallsized consolidations in both lungs. Abdominal ultrasonography was normal. Laboratorium tests showed abnormal liver function tests (ASAT 311 U / l, ALAT 523 U / l, gGT 109 U / l, AF 156 U / l), a Creactive protein of 12 mg / l and 0.2 3 10 9 / l eosinophils. The ANA

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was negative with an ANCA with atypical response. Virus serology was negative. The arterial bloodgas analysis showed hypoxemia. An open lung biopsy was performed. Ventilatory support was necessary for one week. Cultures from the lungbiopsy were negative for bacteria, virusses, Legionella, Mycoplasma, CMV, Pneumocystis carinii and tuberculosis. The biopsy revealed dense infiltration with leucocytes; no granulomas or eosinophils were seen. Signs of usual interstitial pneumonia and organizing pneumonia were present. Having excluded infectious causes, the most likely diagnosis was interstitial pneumonia and hepatitis due to an auto-immune reaction associated with minocycline therapy. Prednison treatment (60 mg daily) was started with immediate clinical improvement. Within one month the liverfunction tests returned to normal; the chest radiograph normalized within 8 months. Minocycline is a semisynthetic tetracycline used to treat acne vulgaris. Serious adverse reactions have been reported. Hypersensitivity reactions, including serum sickness-like syndrome, pulmonary eosinophilia, and other organ involvements like hepatitis, occur early in the course of therapy with signs of eosinophilia, attributed to a reactive metabolite of minocycline. Auto-immune reactions, like drug-induced lupus, auto-immune hepatitis and vasculitis, occur after a prolonged use of minocycline, usually combined with a positive ANA. The combination of interstitial pneumonia and hepatitis in this patient can be related to both mentioned mechanisms. The auto-immune reaction is more likely because of the prolonged use of the minocycline, even though the ANA is negative; unfortunately liverbiopsy was not performed. Discontinuation of the drug, supportive therapy and if necessary corticosteroids, is the recommended treatment for either type of reaction. It is essential to keep in mind these possible life-threatening adverse effects of minocycline and to provide for adequate management. 161. Itraconazol and grapefruit juice: a dangerous cocktail? N. Talstra, E.W. Muller, Slingeland Ziekenhuis Doetinchem, Postbus 169, 7000 AD Doetinchem, Tel.: 0314 -329911, fax: 0314 -329068, e-mail: nctalstra@ yahoo.com Case report: A 53 year old male was admitted to our hospital because of progressive jaundice.His medical history included Allergic Broncho-Pulmonary Aspergillosis, known since 1995. He was intermittently treated with itraconazol since 1996. On admission he had a fever (38.78C), he was jaundiced and hepatosplenomegaly was found. Laboratory investigation showed cholestatic hepatitis (bilirubin 186 (mol / l, alkaline phosphatase 177 U / L, (GT 161 U / l, ASAT 1760 U / l, ALAT 1530 U / l and LDH 869 U / l), with impaired synthetic function (albumin 32 g / l, PTT 17 sec (N , 15) and cholinesterase 3310 U / l (N . 5000)). Ultrasonography confirmed the presence of hepatosplenomegaly. There was no extrahepatic biliary obstruction. The patient refused to undergo a liver biopsy. Itraconazol was withheld. The fever disappeared in two days without antibiotic therapy. Viral, toxic and autoimmune causes of hepatitis were excluded and serum ceruloplasmin was normal. Serum ferritin level was elevated:

3175 mg / l (N30-280) and the patient was found to be heterozygotic for the HFE mutation. All liver function parameters, including serum ferritin, gradually normalised and hepatosplenomegaly slowly subsided in the course of four months. Further history taking revealed that the patient had started on a ‘health diet’ recently, that included liberal amounts of grapefruit juice. Discussion: Several side effects of itraconazol are known, including mild elevations of liver enzymes. Fewer than 10 cases of itraconazol-induced serious hepatitis, similar to our patient, have been reported. Itraconazol is metabolized through the cytochrome P450 isoenzyme 3A4 (CYP3A4). It is noteworthy, in our case, that grapefruit juice is a well known inhibitor of CYP3A4, thereby potentially creating toxic drug levels. Unfortunately, no serum sample for determining the itraconazol level was obtained on admission. Nevertheless, the normalisation of liver function after withholding itraconazol and th exclusion of other possible causes of hepatitis indicate that this patient’s hepatitis was caused by itraconazol. This was possibly brought about by the use of grapefruit juice. Conclusion: We present a patient who suffered serious hepatitis due to itraconazol. The occurrence of his liver disease coincided with the start of a ’health diet’ containing liberal amounts of grapefruit juice. Patients who use drugs that are metabolized through CYP3A4 should be warned against consumption of grapefruit juice. 162. Intrahepatic cholestasis in early pregnancy. E.M.G. Jacobs 1 , A. Huisman 2 , R. A. de Vries 1 . Department of Internal Medicine 1 , Gynaecology 2 , Rijnstate Hospital, Arnhem. Postbus 9555, 6800 TA Arnhem. Tel.: 026 -3788888. Fax: 026 -3787878, e-mail: ejacobs@ rijnstate.nl A 26-year old woman G1P0, 17 weeks pregnant, was referred to our hospital because of jaundice and pruritus, occurring after a flu three weeks earlier. Nausea and vomiting resulted in a weight loss of three kilogram. Prior to pregnancy oral contraceptives were used without any problem. The medical history revealed no signs of liver disease and also the family history was negative for (cholestatic) disease. Except jaundice, physical examination showed no abnormalities. The size of the uterus was conform amenorrhea. Laboratory results at presentation: total bilirubin 84 mmol / l (0.0–17.0), conjugated bilirubin 64 mmol / l (0.0–3.0), alkaline phosphatase(ALP) 62 U / l (1–120), g-glutamyl transpeptidase (g-GT) 12 U / l (1–35), aspartate aminotransferase (AST) 61 U / l (1–41), alanine aminotransferase (ALT) 252 U / l (1–45). There were no serological markers present of hepatitis A, B, C, or EBV, CMV and toxoplasmose. Auto-immune serology (ANA, AMF and ASMF) also was negative. During pregnancy light jaundice persisted and liverenzymes fluctuated with peak values for bilirubin 84 mmol / l, ALP 488 U / l, g-GT 146, AST 130 U / l and ALT 250 U / l. A liverbiopsy revealed intrahepatic cholestasis with formation of new bile ducts and mild fibrosis. The diagnosis of cholestasis of pregnancy was made. In the differential diagnosis hyperemesis gravidarum, viral hepatitis and BRIC were considered. For severe complaints of pruritus cholestyramine was prescribed without sufficient result. Therefore ursodeoxycholic acid was added with satisfying effect.

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Internistendagen 2001 After premature contractions at 32 1 2 weeks a healthy son was born. Prescription of the medication was interrupted after delivery and complaints of pruritus disappeared within 48 hours. Three months later ALP and g-GT were still unexpected elevated, 175 and 100 U / l respectively. The occurrence of cholestasis of pregnancy is unusual in the first trimester. Pruritus can be disabling, mostly well responding to cholestyramine and / or ursodeoxycholic acid. Generally the cholestasis progresses in the course of pregnancy, although pruritus, icterus and liverenzymes can fluctuate. The prognosis for the pregnant woman is usually good. However there is a high rate of premature labour and neonatal death. After delivery pruritus normally disappears within 48 hours, liverenzymes do normalise in weeks. In our patient cholestasis rised remarkable early in pregnancy, with a slow decrease of liverenzymes post parturation. Cholestasis of pregnancy superposed on pre-existing liverdisease therefore certainly cannot be ruled out. 163. Impact of comorbidity on quality of life in house dust mite allergic patients. I. Terreehorst,1,7 H.J. Duivenvoorden,2 Z. Tempels-Pavlica,3 A.J. Oosting,4 J. G.R. de Monchy,3 C.A.F.M. Bruijnzeel-Koomen,4 R.C. Aalberse,5 M.W.M. Post,6 R. Gerth van Wijk 1 . 1 Dept. of Allergology, University Hospital Rotterdam, 2 Institute of Medical Psychology and Psychotherapy NIHES, Erasmus University Rotterdam, 3 dept. of Allergology, University Hospital Groningen, 4 dept. of Dermatology, University Medical Centre Utrecht, 5 Central Laboratory of the Blood Transfusion Service Amsterdam, 6 Julius Centre, University Medical Centre Utrecht, 7 Albert Schweitzer Hospital-Amstelwijck, Dordrecht. Introduction: Compared with healthy subjects, patients with rhinitis, asthma or atopic dermatitis may be hampered in day to day functioning because of their disease. In many patients, however, more than one atopic disorder may be present. Objectives of the study: 1. Do diagnoses made by physicians have differential power on quality of life? 2. Does symptom severity assessed by means of visual analogue scales (VAS) have differential power on quality of life? Material and Methods: 220 house dust mite allergic adult patients with asthma, rhinitis and / or atopic dermatitis took part in this study. Diagnosis was assessed by both history (taken by physician) and previously defined criteria such as criteria of Hanifin and Rajka for dermatitis and lung function tests for asthma. All patients filled in SF-36 and VAS for nasal complaints, lung complaints, sleeplessness and itching. Statistical analysis was done by means of multiple linear regression Results: The diagnosis asthma had a significant negative effect on the scales physical functioning, role physical functioning and general health of SF-36. Asthma severity assessed by VAS had a significant negative effect on the subscales physical functioning, role physical functioning, bodily pain, general health, emotional functioning and vitality. Sleeplessness had a significant negative effect on role physical functioning, bodily pain, general health, mental health, social functioning and vitality. The diagnosis of rhinitis, or atopic dermatitis did not have a differential power on quality of life. The presence of asthma symptoms or the presence

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of sleep disorders as represented by visual analogue scores had an unfavourable effect on quality of life. Conclusion: Patients with rhinitis, asthma or atopic dermatitis are impaired in quality of life. The mere diagnosis of rhinitis, or atopic dermatitis has no differential power on quality of life, however the presence of asthma expressed in terms of diagnostic criteria or symptom severity or the presence of sleep disorders may have an unfavourable effect on quality of life. 164. Comparison of a generic and a rhinitis-specific quality of life instrument in patients with house dust mite allergy: Relationship between the SF-36 and Rhinitis Quality of Life Questionnaire (RQLQ). I. Terreehorst,1,7 H.J. Duivenvoorden,2 Z. Tempels-Pavlica,3 A.J. Oosting,4 J. G.R. de Monchy,3 C.A.F.M. Bruijnzeel-Koomen,4 R.C. Aalberse,5 M.W.M. Post,6 R. Gerth van Wijk 1 1 Dept. of Allergology, University Hospital Rotterdam, 2 Institute of Medical Psychology and Psychotherapy NIHES, Erasmus University Rotterdam, 3 Dept. of Allergology, University Hospital Groningen, 4 Dept. of Dermatology, University Medical Centre Utrecht, 5 Central Laboratory of the Blood Transfusion Service Amsterdam, 6 Julius Centre, University Medical Centre Utrecht, Dept. Of Internal Medicine, 7 A. Schweitzer HospitalAmstelwijck, Dordrecht. Introduction: Generic and disease-specific quality of life questionnaires attempt to estimate the burden of disease. In allergic rhinitis both the generic SF-36 and the disease-specific RQLQ are often used. In the current study sample rhinitis in contrast to asthma had no effect on the SF-36. Therefore, an exploration of the interrelation between SF-36 and a questionnaire designed for rhinitis patients was warranted. Objectives of the study: To unravel the interrelationships between SF-36 and RQLQ in terms of dimensions required to adequately represent the structure of these quality of life aspects, to determine the subscales dominating this structure and to estimate the overlap between the two instruments. Material and Methods: All 220 patients took part in a national study to the effect of mattress encasings on allergic complaints. The study group consisted of adult house dust mite allergic patients with allergic rhinitis, asthma and / or atopic dermatitis. Patients filled in both SF-36 and rhinitis quality of life questionnaire. Analysis was done by method of canonical correlations for continuous data. Results: Canonical correlation analysis revealed that only the first canonical variate accounted for significant relationships between SF-36 and RQLQ. Of the RQLQ subscales general complaints, emotional problems and, to a lesser degree, sleeping problems and eye symptoms correlated best whereas all SF-36 subscales loaded highly, though negatively on the first canonical variate. Conclusion: Canonical correlation analysis of the generic SF-36 and the disease-specific RQLQ revealed a moderate association between both instruments. This may explain the lack of impact of rhinitis diagnosis and nasal symptoms on generic quality of life in patients with multiple atopic disorders. ¨ 165. Left flank pain as a first manifestation of sarcoıdosis. J.W.G. Tielen, J.L. van Opstal, S.E. Louwerse, R.B. Noordveld,

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M.I. Koolen. Bosch Medicentrum, Nieuwstraat 34, 5211 NL, ’ s-Hertogenbosch, Fax: 0736162257, e-mail: kleurmerk@ wxs.nl ¨ is a chronic multisystem disease of Introduction: Sarcoıdosis unknown cause, usually presenting with one or more of the following abnormalities: bilateral hilar adenopathy, pulmonary ¨ infiltrates, skin and eye lesions. Extrapulmonary sarcoıdosis occurs rarely. Here we demonstrate a patient with skeletal and neurological localizations as first manifestations of the disease. Case Report: A 37-year old male was referred to our emergency-room under suspicion of left-sided renal colics. This could not be confirmed. However, because of elevated liver enzymes the patient was referred to our department. Physical examination revealed an enlarged spleen 3 cm under the left costal margin. There were no palpable lymph-nodes. Laboratory tests revealed an elevated ESR [47 mm / hr], a slightly elevated calcium [2,61 mmol / l] with normal albumin, raised liver-enzymes (alkaline fosfatase [196 iu], -GT [135 iu], alat [61 iu]), and a slightly elevated 1,25 vit D3 [125.5 pmol / l]. Serum creatinin [94 mmol / l] and ACE [46 u / l] were normal. Ultrasonography revealed a slightly enlarged spleen, no lymphadenopathy. Chest radiograph and CT-scan revealed pleural and diffuse interstitial abnormalities, together with slightly increased mediastinal lymph-nodes. ¨ Under the suspicion of sarcoıdosis a bronchoscopy was performed. Broncho-alveolar-lavage showed 2,8.10 6 cells / l [71% macrophages, 27% lymphocytes] and a raised CD 4 :CD 8 ratio ¨ (9:1) compatible with sarcoıdosis. All cultures were negative. Treatment with 40 mg prednison daily, was started. However, two weeks later, because of a renewed painful attack at his left flank an MR was made, showing an expansive mass at Thoracic 9 with slight compression of the myelum. The biopsymaterial of this vertebra showed proliferation of connective tissue with chronic inflammation, no granuloma could be demonstrated. During treatment, the patient developed complaints of progressive headache and diplopia. A contrast-enhanced T 1 –weighted MR scan showed thickened, enhancing leptomeninges. Liquor analyses showed pleocytosis [105.10 6 / cells / l, 82% monocytes and increased protein [0.97 g / l]. These data support the diagnoses of ¨ neurosarcoıdosis and therefore the prednison dose was raised to 60 mg / daily. Since then his condition improved considerably. ¨ Conclusion: Extrapulmonary manifestations of sarcoıdosis are ¨ ¨ relatively rare (neurosarcoıdosis 5%, muskuloskeletal sarcoıdosis 10–15%). In this patient the primary manifestations were extrapulmonary. The ACE test was not helpful in making the diagnosis. According to the literature high doses of prednison should be ¨ prescribed for the treatment of neurosarcoıdosis, eventually combined with other immune suppressive therapy. 166. Protocol and guideline in lithium-induced polyuria. J.J.D. Tilanus, L. Timmerman 1 , H.A.P.C. Oomen 2 . W. Boer 3 . 1 Psychiatric Center Adhesie GGZ Midden-Overijssel, Almelo, 2 Endegeest Convent, Psychiatric Center RijnGeestGroep, Leiden, 3 Department of Nephrology, University Medical Centre, Utrecht, the Netherlands. Lithium, first drug of choice for manic-depressive illness,

reduces vasopressin function in the renal tubules and this can result in a decrease of water reabsorption. Polyuria occurs in 25% or more of treated patients. Lithium has been associated with the induction of this specific type of acquired, reversible, renal diabetes insipidus since the seventies. The phenomenon is of clinical interest because of (a) the large population that lithium is prescribed to, (b) the frequency of lasting volumes over 3000 ml / 24 h and (c) the adverse efect on compliance to a medication that is of vital importance to bipolar psychiatric patients. Internists are regularly consulted to advise on prevention, diagnosis and treatment of lithium-induced-nephrogenic-diabetes-insipidus (LINDI). A protocol for that purpose has been put forward by the Endegeest Convent workgroup of consulting internists in the Dutch Mental Health Care System, in cooperation with the Department of Nephrology, University Medical Centre, Utrecht. A questionnaire was developed by psychiatric investigators to evaluate the actual procedure by internists consulted on LINDI. It comprises questions on the subject of the indication for referral, the observed prevalence, the diagnostics, and counteracting treatment such as amiloride or other options. The results of this questionnaire show that an effective guideline should encompass consensus in LINDI on: (1) the parameters of observation in screening and follow-up of lithiumtreatment,(2) the parameters to distinguish benign polyuria from both (a) coexistent renal disorder and (b) progressive, irreversible tubular disorders during lithiumtreatment, (3) a reference point of renal function at which lithium should be discontinued. 167. ‘Routine’ thrombophilia investigation in a district hospital. A.D. van Zuilen and E.W. Muller, Slingeland Hospital Doetinchem, PO box 169, 7000 AD Doetinchem.Tel. 0314 329911, fax 0314 -329068, e-mail: avzuilen@ hotmail.com Introduction: Abnormalities that predispose to thrombosis (thrombophilic factors) play a role in venous thromboembolism (VTE), recurrent spontaneous abortion and possibly in some patients with arterial disease. With the exception of the Dutch Gynaecological Society guidelines in patients with spontaneous abortion, there are no comprehensive guidelines for thrombophilia investigation. This gives the opportunity to study current ‘routine’ practice. The first step in thrombophilia investigation in our laboratory is a PCP-test, a screening test for activated protein C resistance or deficiency. Measurement of antithrombin III (ATIII) and homocysteine after methionine loading (Hcy) is also possible in our laboratory. Aim of the study: To evaluate the appropriateness and patient management consequences of ’routine’ thrombophilia investigations in our hospital. Materials and Methods: 100 consecutive patients in whom a PCP-test had been ordered were collected from August– November 1999. Physicians who had ordered the tests were asked to fill out a questionaire regarding, among others, the reason for thrombophilia testing, other thrombophilic factors studied and the consequences of the results for patient management. When the questionaire was not returned the hospital records were studied by the authors. Results: Reasons for PCP-test were: VTE in 46 persons,

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Internistendagen 2001 recurrent abortion in 8, family investigation after finding Factor V Leiden (FVL) in a relative in 13, arterial disease (mainly cerebrovascular) in 19 and other or no identifiable reason in 14. Other investigations were: ATIII in 40, Hcy in 26, protein C in 14, protein S in 11, lupus anticoagulans and other factors in 9, prothrombin mutation and FVIII in none. Total yield in patients with VTE was 7 patients heterozygote for FVL. Of these patients two were advised lifelong anticoagulation, two for 12 months, one for 3 months, one was given special perioperative profylaxis, and one got no particular advise. Conclusions: 1. The reasons for ordering thrombophilia tests were questionable in more than half the cases. 2. When thrombophilia investigation was initiated it was performed inconsistently and incompletely. 3. The availability of tests in the laboratory seems to influence the choice of tests more than knowledge of thrombophilia itself. 4. The consequences for patient management were minimal and questionable. 5. Critical guidelines for thrombophilia investigation in routine practice, including consequences for patient management are needed. 168. Acute iron overdose: not to be un(der)treated. A.P.B.F. Mensink, B. M. Kos, B / C. B.S. Hylkema, and B.W.M. Smit. Department of Internal Medicine, Medisch Spectrum Twente, P.O Box 7500 KA, Enschede. Tel.: 053 -4872000, Fax: 053 -4873471, e-mail: p.mensink@ a1.nl Iron preparations are among the most prescribed drugs. Accidental poisoning of iron is not uncommon in children. Intentional overdose of iron by adults is far less common. Overdose of iron can lead to severe tissue damage and organfailure. In this case report we describe a 31-year old woman, which was admitted 2 hours after ingestion of 20-gram ferrofumarate (6.5-gram elemental iron). She complained about abdominal discomfort. Physical examination showed no abnormalities. Blood analyses at admission were leukocytes 8.8 3 10e9 / l and glucose 7.1 mmol / l. At a plain abdominal X-ray, multiple iron tablets were seen in the stomach and first part of the duodenum. Therefore gastric lavage and bowel irrigation was performed, together with charcoal therapy. However, within 6 hours after presentation she developed hypotension and progressive abdominal complaints, for which the infusion of crystalloid and deferoxamine therapy (2-gram intramuscular injection) was started. Serum iron levels appeared to be 31 and 35 mmol / l, respectively 3 and 12 hours after ingestion (normal range 10–25 mmol / l), returning to normal range next day. The patient recovered without complications. Ferrous iron is absorbed in the duodenum and jejunum. A slow release into plasma results in peak levels 4 to 6 hours after ingestion. Generally accepted lethal dose are 200–250 mg / kg, serum iron concentrations above 90 mmol / l have been recommended as an indication for active treatment with chelating agents. Free iron may result in the release of serotonin and histamine, resulting in a capillary leak syndrome and metabolic acidosis. Free iron intoxication may also cause injury to mitochondria and lipid peroxidation and thereby life threatening liver, renal, myocardial and respiratory failure. Recognition of clinical symptoms of iron overdose i.e. hypotension and metabolic acidosis or laboratory abnormalities as hypoglycaemia and leukocytosis is essential to prevent fatal complications. Treatment consists of aggressive

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gastric lavage and (total) bowel irrigation to prevent the mucosal damage of active iron and secondary complications. The initiation of treatment with bowel irrigation and (chelating) deferoxamine has to be taken on clinical grounds and not on serum iron concentrations at admission. Conclusion: acute intentional iron poisoning by adults is very uncommon but can be fatal. Patients have to be observed accurately and treated aggressively on the basis of clinical signs and basic laboratory findings. Next to this, plain abdominal X-ray gives useful information about severity of iron ingestion. Free serum iron levels, measured at presentation, are not useful in this matter. 169. European criteria for the diagnosis of the chronic myeloproliferative disorders essential thrombocythemia, polycythemia vera and idiopathic myelofibrosis or agnogenic ¨ myeloid metaplasia. Jan Jacques Michiels and Jurgen Thiele. Department of Hematology University Hospital Antwerp, Goodheart Institute Rotterdam, MPD Center Europe and Institute of Pathology, University of Cologne. According to strict clinical, hematological and morphological criteria the Philadelphia (Ph) chromosome negative chronic myeloproliferative disorders essential thrombocythemia (ET), polycythemia vera (PV), and agnogenic myeloid metaplasia (AMM) or idiopathic myelofibrosis (IMF) are three distinct myeloproliferative disease (MPD) entities in terms of clinical manifestations, natural history and life expectancy. The diagnostic criteria as defined by the PVSG overlook the early stages of ET, PV and AMM / IMF. A new set of clinical and pathological criteria for the diagnosis and staging of ET, PV and AMM / IMF is presented by including bone marrow histopathology as a specific clue to detect the early, overt and advanced stages of ET, PV and AMM / IMF. The combined use of clinical data and morphological characteristics from bone marrow biopsies, in particular megakaryocytopoiesis and bone marrow cellularity indeed reveals diagnostic features, which enables a clear-cut distinction between ET, PV and AMM / IMF. The characteristic increase and clustering of enlarged megakaryocytes with mature cytoplasm and multilobulated nuclei and their tendency to cluster in a normal or only slightly increased cellular bone marrow represent the hallmark of ET. The characteristic increase and clustering of enlarged mature and pleiomorphic megakaryocytes with multilobulated nuclei and proliferation of erythropoiesis in a moderate to marked hypercellular bone marrow with hyperplasia of dilated sinuses are the specific diagnostic features of untreated PV. The early prefibrotic stages as well as the various myelofibrotic stages of classical AMM / IMF appear to be a distinct neoplastic dual proliferation of abnormal megakaryopoiesis and granulopoiesis. The histopathology of the bone marrow in prefibrotic AMM or classical IMF is dominated by atypical, enlarged and immature megakaryocytes with cloud-like immature nuclei, which are not seen in ET, PV, MDS and CML at diagnosis and during follow-up. The proposed European Clinicopathogical diagnostic criteria of ET, PV and AMM / IMF makes possible to differentiate ET from reactive thrombocytosis and from thrombocythemia as the presenting symptom of the various MPDs, MDS and Ph-chromosome positive CML. In addition it is demonstrated that myelofibrosis is

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not a feature of ET and usually not present in PV at time of diagnosis. Myelofibrosis becomes apparent during long-term follow-up of PV and constitutes a prominent feature of AMM / IMF during the natural history of the disease. Life expectancy is normal in ET, normal during the 1 st ten years and compromised during the 2 nd ten years of follow-up in PV, but appears to be significantly shortened even for the early prefibrotic stage of AMM / IMF. 170. Paroxysmal nocturnal hemoglobinuria presenting with hemolysis and acute renal failure. M.R. Korte 1 , Dr. J.L.C.M. 1 2 1 van Saasse , Dr. J.H. van den Ingh , Department of Internal medicine and 2 Pathology, Medisch Centrum Rijnmond-Zuid, Olympiaweg 350, 3078 HT Rotterdam, tel: 0102911911, fax: 0102911083, e-mail: m.r.korte@ planet.nl Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic disease, which is characterised by chronic hemolysis and intermittent episodes of hemoglobinuria. PNH is caused by a somatic mutation of the X-linked PIGA gene. This gene encodes for a protein involved in the synthesis of the glycosylphosphatidylinositol (GPI) anchor by which many proteins are attached to the membranes of cells. As a result erythrocytes are unusual

susceptible for complement-activated lysis. PNH is associated with recurrent episodes of thrombosis and hemolytic anemia. Renal insufficiency is an uncommon complication of PNH. We report a patient presenting with acute renal failure (ARF) and elevated lactate dehydrogenase. Treatment consisted of a short period of hemodialysis and immunosuppressive medication. The final diagnosis of PNH was made after full recovery from the ARF. Flowcytometry using monoclonal antibodies of CD 59 on erythrocytes demonstrated a deficient expression of anchored proteins CD 24, CD 59, CD 66b and CD 13 in 70% of the granulocytes. Low-grade hemolysis persisted over a period of 4 years with recurrent episodes of hemoglobinuria. Renal failure did not reoccur. Only 5 patients with reversible ARF caused by PNH were reported since 1971. It is known that the iron deposition in the renal tubules, which occurs in hemolysis, is related to slowly progressive renal failure. This explanation seems unlikely for ARF. We suggest that hemoglobin may act as a toxic pigment inducing damage to the tubules and a subsequent ARF by enabling the formation of met-hemoglobin. PNH with a hemolytic crisis should be considered in a patient presenting with otherwise unexplained ARF.

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