- Email: [email protected]
CIMETIDINE OR PARIETAL-CELL VAGOTOMY IN PATIENTS WITH JUXTAPYLORIC ULCERS
894
Discussion
antigenic constituents of circulating immune complexes detected so far include DNA in systemic lupus erythematosus; viral antigens in Burkitt’s lymphoma," The
hepatitis, 12
and
HTLV-positive lymphoma; 13
component of the skin and intestinal mucosa. The precise mechanism of toxicity is unknown but obviously involves immune factors.18-20 The possibility that glutens acts as a toxic lectin21 in susceptible individuals is of particular interest, since as a lectin, gluten shows oligomannosyl specificity2 and could therefore bind to the mannosylglycoprotein of jejunal mucosa. Such complexes could be both cytotoxic and immunogenic, resulting in antigluten23,24 and anti-90-kD-glycoprotein antibodies. Circulating 90 kD antigen-antibody complexes with targets in the gut and skin could thus be involved in both disorders. However, the possibility that 90 kD antigen-IgG complexes result from skin and/or gut lesions should be considered; multiple forms of circulating immune complexes are present in dermatitis herpetiformis and coeliac disease,3and some of them may be secondary. Since RF binds immune complexes ofIgG type only, it was not possible to study the nature of the antigen involved in the IgA2S or IgM type complexes3 or in the cutaneous IgA deposits in dermatitis herpetiformis. 21 We thank Dr T. Reunala and Dr M. Vuoristo for supplying serum and the Sigrid Juselius Foundation, Finland, for financial support.
samples,
Correspondence should be addressed to C. P. J. M., Fourth Department of Medicine, University of Helsinki, Uniomnkatu 38, 00170 Helsinki 17, Finland. REFERENCES
Mowbray JF, Hoffbrand AV, Holborow EJ, Seah PP, Fry L. Circulating immune complexes in dermatitis herpetiformis. Lancet 1973; i: 400. 2. Doe WF, Booth CC, Brown DL. Evidence for complement-binding immune complexes in adult coeliac disease, Crohn’s disease, and ulcerative colitis. Lancet 1.
1973; i: 402. 3. Mohammed I, Holborow EJ, Fry L, Thompson BR, Hoffbrand AV, Stewart JS. Multiple immune complexes and hypocomplementaemia in dermatitis herpetiformis and coeliac disease. Lancet 1976; ii: 487. 4. Maury CPJ, Teppo A-M. Massive cutaneous hyalinosis. Identification of the hyalin material as monoclonal kappa light chains, 90 kD glycoprotein and type I collagen. Am J Clin Pathol (in press). 5. Wager O, Teppo A-M. Binding affinity of human autoantibodies: Studies of cryoglobulin IgM rheumatoid factors and IgG autoantibodies to albumin. Scand J Immunol 1978; 7: 503. 6. Lambert P-H, Dixon FJ, Zubler RH, Agnello V, et al. A WHO collaborative study for the evaluation of eighteen methods for detecting immune complexes in serum. J Clin Lab Immunol 1978; 1: 1. 7. Burton DR, Boyd J, Brampton AD, Easterbrook-Smith SB, et al. The Clq receptor site on immunoglobulin G. Nature 1980; 288: 338. 8. Wager O, Lindström P, Räsänen JA, Kekomäki R, et al. Evaluation of six tests for circulating IgG complexes with special reference to IgM rheumatoid factors. Analysis of systemic lupus erythematosus and rheumatoid arthritis sera. Clin Exp
Immunol 1981; 46: 149. Wager O, Lindström P. Interference by rheumatoid factor and Clq with detection of IgG complexes. Studies of model systems by ELISA. Scand J Immunol 1982; 15:
319. 10. Sano H, Morimoto C. Isolation of DNA from DNA/anti-DNA antibody complexes in systemic lupus erythematosus. J Immunol 1981; 126: 538.
immune
11. Oldstone MBA, Theofilopoulos AN, Klein G, Gunven P. Immune complex associated with neoplasia: Presence of Epstein-Barr virus antigen-antibody complex in Burkitt’s lymphoma. Intervirology 1974; 4: 292. 12. Almeida J, Waterson AP. Immune complexes in hepatitis. Lancet 1969; n: 983. 13. Schüpbach J, Kalyanaraman VS, Sarngadharan MG, Bunn PA, Blayney DW, Gallo RC. Demonstration of viral antigen p24 in circulating immune complexes of two patients with human T-cell leukaemia/lymphoma virus (HTLV) positive lymphoma. Lancet 1984; i: 302. 14. Coonrod JD, Leach RP. Immunoelectrophoresis for detection of polysaccharides in immune complexes. J Clin Microbiol 1978; 8: 257. 15. Amoroso P, Vergani D, Wojcicka BM, McFarlane IG, Eddleston ALWF, Tee DEH, Williams R. Identification of biliary antigens in circulating immune complexes in primary biliary cirrhosis. Clin Exp Immunol 1980; 42: 95.
G. BODEMAR R. SJÖDAHL
M. STRÖM J. LINDHAGEN
bacterial
polysaccharides in5 infection; 14 biliary antigens in primary biliary cirrhosis;i5 carcinoembryonic antigen in colon cancer;16 and milk proteins in IgA deficiency.17 This study shows that an antigen in immune complexes in dermatitis herpetiformis and coeliac disease is 90 kD glycoprotein, a
9.
CIMETIDINE OR PARIETAL-CELL VAGOTOMY IN PATIENTS WITH JUXTAPYLORIC ULCERS
A. WALAN
Departments of Internal Medicine and Surgery, University of Linköping, and Department of Surgery, Central Hospital of Norrköping, Sweden
patients with
severe juxtapyloric ulcers randomly allocated to either long-term cimetidine treatment (400-800 mg/day) or to parietal-cell vagotomy (PCV). All were followed up for more than 3 years. The endoscopically proven relapse-rate with a dose of 400 mg
Summary
83
were
bed time was 54%; it fell to 32% when the dose was increased to 400 mg twice a day. In the PCV group the relapse-rate was 33%. Patients with prepyloric ulcers alone or in combination with duodenal ulcers relapsed at a higher rate (57% and 82%, respectively) than did patients with "pure" duodenal ulcer disease (17% and 14%, respectively). No patient, not even those with a history of bleeding or perforated ulcers, experienced any bleeding or perforation during relapses, either when on long-term cimetidine treatment or after operation. Previous haemorrhage or perforation per se is thus not an indication for surgery in favour of maintenance treatment with cimetidine. at
Introduction FOR patients with duodenal or gastric ulcers the recurrence is 15-20% during maintenance treatment with cimetidine for one year.I-3 There are very few published reports of longer durations of treatment. During the past decade parietal-cell vagotomy (PCV) has been established as the surgical treatment of choice for duodenal ulcers. PCV has a lower mortality rate and fewer, less severe side-effects than antral resections or other types ofvagotomies.4 The number of operations for peptic ulcer disease has fallen since the introduction of cimetidine. 5,6 This might indicate that cimetidine has been chosen as an alternative to surgery for rate
many patients. The aim of the present study was to investigate whether long-term cimetidine treatment could be an alternative to PCV in patients with duodenal or prepyloric ulcer disease. Because PCV might be less effective in preventing recurrence of prepyloric than duodenal ulcers,patients were grouped according to location of the ulcer at entry into the study.
ME, Pinn V, Schwartz RS, Nathanson L. Carcinoembryonic antigenantibody complexes in a patient with colonic carcinoma and nephrotic syndrome. N Engl J Med 1973; 289: 520. Cunningham-Rundles C. The identification of specific antigens in circulating immune complexes by an enzyme-linked immunosorbent assay: Detection of bovine kappacasein IgG complexes in human sera. Eur J Immunol 1981; 11: 504. Falchuk ZM. Update on gluten-sensitive enteropathy. Am J Med 1979; 67: 1085. Katz SI, Strober W. The pathogenesis of dermatitis herpetiformis. J Invest Dermatol
16. Constanza
17.
18. 19.
1978; 70: 63 20. 21.
Kagnoff MF, Weiss JB, Brown RJ, Lee T, Schanfield MS. Immunoglobulin allotype markers in gluten-sensitive enteropathy. Lancet 1983; i: 952. Weiser MM, Douglas AP. An alternative mechanism for gluten toxicity in coeliac disease. Lancet 1976; i: 567.
22.
Köttgen E, Volk B, Kluge F, Gerok W. Gluten, a lectin with oligomannosyl specificity and the causative agent of gluten-sensitive enteropathy. Biochem Biophys Res
Commun 1982; 109: 168. 23. Eterman KP, Feltkamp TEW. Antibodies to gluten and reticulin in gastrointestinal diseases. Clin Exp Immunol 1978; 31: 92. 24. Lane AT, Huff JC, Zone JJ, Westen WL. Class-specific antibodies to gluten in dermatitis herpetiformis J Invest Dermatol 1980; 80: 402. 25. Zone JJ, Lasalle BA, Provost TT. Circulating immune complexes of IgA type in dermatitis herpetiformis. J Invest Dermatol 1980; 75: 152. 26. Unsworth DJ, Payne AW, Leonard JN, Fry L, Holborow EJ. IgA in dermatitisherpetiformis skin is dimeric Lancet 1982; i: 478.
895
Patients and Methods Patients
patients with active juxtapyloric ulcers fulfilled the criteria for peptic ulcers-ie, endoscopically or radiologically verified ulcers with a history of illness for at least 3 years, together with either (1) one or more complications (haemorrhage or perforation) and recurrence of peptic ulcer symptoms at least once a year during the past 3 years, or (2) no complication but at least three periods with peptic ulcer symptoms during each of the past 3 years. Patients with ulcers proximal to the prepyloric region were not included. Both the physicians and the surgeons judged all patients to be suitable 85
insulin test (0-22 IU/kg intravenously) was done to estimate the completeness of vagotomy. The insulin test was interpreted as positive or negative according to the criteria of Bank et al. 10 The pentagastrin test was also repeated 2 months after PCV.
severe
candidates for surgery. Patients with pyloric stenosis and retention were excluded, as were patients regularly taking more alcohol than an amount corresponding to 30 ml pure alcohol. All patients claimed they were not taking acetylsalicylate-containing tablets or other anti-
inflammatory drugs regularly.
-
prepyloric ulcer group if they had active ulcers in the pylorus or within 2 cm proximal to the pylorus on endoscopic examination, or the duodenal ulcer group if they had active ulcers only in the duodenal bulb on endoscopic examination. The duodenal ulcer group was further divided into those with a previous ulcer in the prepyloric region verified by endoscopy or X-ray (DU/PU), or those without a previously verified ulcer in the prepyloric region (DU). A gastric ulcer proximal to the prepyloric region had never been demonstrated in any of the patients. Patients
were
put into the
Baseline Treatment At entry the patients were treated with cimetidine for 6-18 weeks until their active ulcers healed. Patients were then asked for their informed consent for random allocation to PCV or to long-term cimetidine treatment. 2 patients changed their minds after randomisation and did not want to be operated on, which left 40 patients in the PCV group and 43 patients in the cimetidine group.
Results
The
-Medical Treatment Withdrawals.-l patient defaulted from follow-up after at 1 year. 2 patients did not want to continue maintenance treatment after their first relapse. 2 patients (aged 67 and 72 years) died from myocardial infarction after 21 (one relapse) and 27 (no relapse) months, respectively. Both of them had hypertension and 1 smoked more than 30 cigarettes per day. 38 patients were thus suitable for analysis for the whole period. Relapse-rate (table II).- The patients who stopped treatment or died before a relapse were excluded from the calculation of relapse-rate. 22 patients (22/41, 54%) relapsed on 400 mg at bed time after a median of 8 - 5 months (range 3-36). 20 of these have continued with 400 mg twice daily. 12 (12/19, 63%) of these had a second relapse after a median of 6 months (range 0-27). The relapse-rate was thus at least 32% (12/38) in those patients who remained in the study. 9 (29%) of the 31 patients who had a duodenal ulcer on endoscopy at entry relapsed after the dose of cimetidine was increased to 400 mg twice a day. 9 (36%) of the 25 belonging to the "pure" duodenal ulcer group (DU) relapsed on 400 mg at night. In the 3 years after the dose was increased to 400 mg twice daily the relapse-rate in patients with "pure" duodenal ulcer disease dropped to 17% (4/24). 3 of the 7 patients who had a
endoscopy
Maintenance Treatment
TABLE I- COMPARISON OF TREATMENT GROUPS
started with cimetidine 400 mg at bed time. They were seen in the outpatient clinic every third month by one of us (M. S.) and a new supply of medicine was delivered and the number of unused tablets was counted. A routine blood laboratory screen was done at least once a year. Endoscopy was performed by the same experienced endoscopist every six months or when symptoms indicated a new ulcer. When a relapse occurred the dose of cimetidine was increased to 1-0-1-66ga day until the ulcer healed, then reduced to a maintenance dose of 400 mg twice a day instead of 400 mg at bed time. The patients who remained free from recurrent ulcers were followed up for at least 3 years before maintenance treatment was were followed up for at least 3 stopped. Those with a recurrence years on 400 mg twice a day or until a second relapse, after which they were offered surgical treatment. In the calculation of relapse-rate during treatment with 400 mg cimetidine twice a day, patients without any relapse on 400 mg at bed time were incorporated into the relapse-free group. All
comparability of the two groups is shown in table I.
patients
previously verified prepyloric
ulcer.
TABLE II-RELAPSE-RATE IN PATIENTS OPERATED WITH PCV
(40) OR DURING MAINTENANCE CIMETIDINE TREATMENT (43)
Treatment
Surgical PCV
*Patients with duodenal ulcer and
done by experienced surgeons, mainly as described by and Johnston,8,9 except that (i) the most proximal antral branch of both nerves of Latarget were divided, and (ii) the gastrocolic omentum was divided only when it was considered necessary. The patients were followed up for 3 years after operation in the same way as those given maintenance cimetidine. When a relapse occurred cimetidine 1 g a day was given until the ulcer healed. After a second relapse the patients were offered re-operation or maintenance treatment with cimetidine 400 mg at bed time. was
Amdrup
Secretory A
Tests
gastric secretory
measure
test was
done before
randomisation,
to
basal acid output (BAO) and peak acid output (PAO) after 6 feg/kg subcutaneously. 6-8 weeks after PCV an
pentagastrin
I
I
I
R = relapse; NR = no relapse. *I patient died post-op. 1 patient died, I patient withdrawn. Patients with relapse on cimetidine
400 mg
nightly.
1
patient died,
2
withdrawn.
§3 patients still on 400 (13-29).
months
mg twice
a
day without symptoms
for
a
median of 24
896
prepyloric ulcer at entry had a relapse during the 3 years they were on up to 400 mg cimetidine twice a day. The relapse-rate among patients with prepyloric ulcer disease either active at entry (3/7) or verified earlier (5/7) was thus 57% (8/14). Patients with previous haemorrhage or perforation had a lower rate of relapse (9/25) than those without such a complication (13/16). (p<905) 7 of the 12 patients who were offered surgery at second relapse agreed to the operation. 2 of these 7 patients have relapsed after PCV. 1, a DU/PU patient, was re-operated on (an antrectomy) and the other, a DU patient, remains well on continuous treatment with cimetidine 400 mg at night. Only 4 of the patients with recurrences visited the outpatient clinic between appointments because of severe peptic ulcer symptoms. No patient had haemorrhage, perforation, or signs of pyloric stenosis during medical treatment. There was no indication of poorer compliance with treatment (measured as number of tablets returned) among patients with relapses, compared with those without relapse. Side-effects.-l patient with relapse had slightly raised transaminases during cimetidine treatment which were restored to normal postoperatively. 1 patient reported slight impotence during treatment with 1 g cimetidine a day but had no complaints on a maintenance dose of 400 mg twice a day. Surgical Treatment Completeness of vagotomy. -2 months after PCV the insulin test was positive in 4 patients (4/39, 11%). The mean value of BAO was reduced by 79% and of PAO by 49%. Relapse-rate (table II).—The patients were followed up for 3 years after the PCV. 2 patients refused to return for follow-up visits and endoscopic examinations. They were contacted by phone regularly and reported no complaints. They are regarded as being free of relapses. 13 patients (13/39, 33%) have hitherto relapsed after a median of 16 months (range 4-35), mostly with only mild symptoms and without any serious complication such as perforation or haemorrhage. 7 (22%) of the 32 patients who had a duodenal ulcer preoperatively relapsed. 4 of these relapses (4/28, 14%) occurred in the patients in whom only duodenal ulcers had been found at earlier examinations. The other 3 relapses occurred among the 4 patients in whom earlier investigations had shown both duodenal and prepyloric ulcers (DU/PU). Of the 7 patients who had a prepyloric ulcer preoperatively 6 relapsed. Thus the relapse-rate among patients with prepyloric ulcers either active at entry (6/7) or verified by earlier examinations (3/4) was 82% (9/11). Patients with previous haemorrhage or perforation did not have a higher rate of relapse (6/21) than those without such a complication (7/18). 7 (18%) of the PCV group needed continuous medical treatment because of repeated relapses or chronic symptoms. 4 of these had a duodenal ulcer at entry but only 1 (1/28, 4%) had had pure duodenal ulcer disease. 8 patients visited the outpatient clinic between the scheduled appointments because of peptic ulcers. Complications and side-effects.—1 severe complication occurred. A 64-year-old patient died of pulmonary embolism 3 days after operation. Almost all patients complained of dysphagia and postprandial epigastric fullness during the first postoperative month. These complaints disappeared within 8 weeks, except in 2 patients who continue to have slight postprandial epigastric fullness not severe enough to interfere with daily living. 2 other patients had mild but persistent symptoms of oesophageal reflux postoperatively.
when
Apart from the 13 patients described above who had ordinary ulcer relapses, 4 patients (4/39, 11%) had endoscopically verified deep ulcerations proximal to the angulus on the lesser curvature soon after the operation. They were all insulin negative. Healing occurred in 3 patients after treatment with cimetidine and antacids for 12-24 weeks. In the 4th patient the ulcer did not heal despite treatment for 2 years. He therefore underwent local resection of the ulcerated area.
Discussion In the present study all patients randomised to cimetidine started with 400 mg every night, the dose shown in many trials to be effective for at least 1 year.2 The recurrence-rate was 54% with cimetidine 400 mg every night and 32% when the dose was increased to 400 mg twice daily for maintenance treatment for 3 years. The recurrence-rates reported in general ulcer populations2 for 1 year of cimetidine treatment are around 20%. There are as yet no reports of comparable trials on maintenance treatment for 3 years. Our recurrence-rate after PCV was considerably higher than in most other PCV trials. 11-13However, the low number of positive insulin tests and the pronounced decrease in BAO and PAO postoperatively indicated that the surgical technique was satisfactory and that the relatively high recurrence-rate after PCV was not due to a smaller degree of inhibition of acid secretion in this than in other published
studies. 14,15 The ulcers in our patients were severe. Over 55% of the patients had had either perforation or bleeding; the others had had at least three periods of peptic ulcer symptoms during each of the 3 years before they entered the trial. Median duration of the ulcer disease was high (17.5 years). The high recurrence-rate in this study was due mainly to the very high recurrence-rate, either with cimetidine treatment or after PCV, among patients with prepyloric ulcers alone or in combination with duodenal ulcers. Little interest has been focused on prepyloric ulcers and maintenance cimetidine treatment. Our finding after PCV is similar to that of Andersen-et al,16 who have shown a higher recurrence-rate of symptoms postoperatively in patients with prepyloric ulcers (33%) than in patients with duodenal ulcers (15%). There are probably aetiological factors apart from acid and pepsin in prepyloric ulcer disease which are not influenced by a reduction in gastric acidity and secretion. Both patients with active prepyloric ulcers and patients with an active duodenal ulcer and previous pyloric or prepyloric ulcers had a high recurrence-rate, either with cimetidine treatment or after PCV. This finding emphasises the importance of verifying the location of earlier ulcers, especially if an operation with PCV is being considered. Patients with prepyloric ulcer disease alone or in combination with duodenal ulcer disease need a higher maintenance dose of cimetidine in order to remain free from recurrences. We also believe that more frequent endoscopic examinations are needed for these patients even if they are almost symptomfree. Since the value of PCV diminishes in patients with active or previous prepyloric ulcer disease, for whom the most suitable operation still seems to be resection, which carries a greater risk of side-effects than does PCV, it would seem logical to make cimetidine the first line of treatment for these patients. Gray et al17 and Gear18 have found lower recurrence-rates with PCV than with long-term cimetidine treatment 400 mg
897 in patients with duodenal ulcers; however, Gear included relapses not only during but also after the end of cimetidine treatment. In two extensive studies Andersen et al compared PCV both with intermittent cimetidine treatment 1 g a day19 and with continuous prophylactic treatment with 400 mg at bed time20 in patients with duodenal ulcers. In their hands most patients (63% and 67%, respectively) randomised to cimetidine treatment were operated on within 3 years. We found no difference in the relapse-rate between medically (32%) or surgically (33%) treated patients after increasing the maintenance dose to 400 mg twice a day. However, in the subgroup of patients with only duodenal ulcers PCV seemed superior to long-term cimetidine 400 mg nightly (relapse-rate 14% compared with 36%, p=ns). Increasing the dose to 400 mg twice daily kept a greater proportion of patients (relapse-rate 17%) free from
nightly
recurrences.
The main explanation for the high recurrence-rate within 3 years after PCV among patients with pure duodenal ulcer disease (4/28, 14%) is probably related to the intensive nature of follow-up. These patients underwent endoscopic examination every 6 months whether they had symptoms or not and visited the outpatient clinic every 3rd month. If the follow-up had been similar to that in most other PCV trials, namely, endoscopy only when symptoms clearly appeared, 6 of the total ulcer recurrences in the PCV group may not have been detected. Results similar to ours have recently been reported by Maddern et al. 21They found that among 119 duodenal ulcer patients who had had no clinic recurrence after PCV, and who were asked to undergo endoscopy, 11I (9%) had an ulcer at the time of the examination. Patients with previous episodes of bleeding or perforation relapsed to the same extent during long-term cimetidine treatment as after PCV but without recurrence of either bleeding or perforation. There thus seems to be no reason for recommending PCV just because the patients have had
previous complications. The high number of lesser curvature ulcerations (4/39, 11 %) in the early postoperative period after PCV are the same as that (7%) found by Cuilleret et al,22 who did routine endoscopies shortly after PCV. 6 weeks after operation and 2 days after an insulin test 1 of these 4 patients had a haematemesis. The other patients had no symptoms or only moderate epigastric pain. The patient whose ulcer did not heal within 2 years was re-operated on, with local resection of the ulcer. There was no sign of a foreign body reaction or malignancy in the specimen to explain the inability of the ulcer to heal. Ahn et al23 have shown that gastric blood flow, measured peroperatively by means of laser Doppler flowmetry, decreased by 60% (range 45-80) over the lesser curvature, whereas that to the greater curvature did not change immediately after PCV. Perhaps these lesser curvature ulcerations were ischaemic and represent a mild form of the serious condition, lesser curvature necrosis. Out of 43 patients originally considered for surgery but instead given maintenance cimetidine only 7 (16%) have been operated on during at least 36 months’ observation. Among the 40 patients in the PCV group, 7 patients (18%) are on maintenance treatment with cimetidine because they have had more than one relapse. Maintenance therapy with cimetidine in an adequate dose would thus seem to be practically as effective as PCV and the two treatments may sometimes be complementary. The optimum duration of cimetidine treatment still has to be determined.
SIGNIFICANCE OF LYMPHOCYTOSIS IN ADULTS E. TIDMARSH P. O. SKACEL
I. CHANARIN D. HARRISINGH
Haematology Department, Northwick Park Hospital and MRC Clinical Research
Summary
Centre, Harrow,
Middlesex
11/19 adults with a persistent increase in the total lymphocyte count, but with neither
lymphodenopathy, hepatomegaly, nor splenomegaly, proved have a monoclonal increase in B lymphocytes indicative of chronic lymphatic leukaemia (CLL). All remaining 8 patients had increased numbers of T-lymphocytes, more often of the helper than of the suppressor subsets. All the patients with a lymphocyte count in excess of 10 000/µl, but only 5/13 patients with a lymphocyte count below 10 000/µl had CLL. In adults a sustained lymphocytosis is thus not an adequate basis for the diagnosis of early CLL, which requires the of a demonstration monoclonal population. The T-lymphocytosis is likely to be reactive rather than neoplastic to
in
nature.
Introduction THERE is wide agreement that the number of lymphocytes in peripheral blood in healthy adults does not
circulating
G, Walan A. Maintenance treatment of recurrent peptic ulcer by cimetidine. 1978; n: 403-07. Burland WL, Hawkins BW, Horton RJ, et al. The longer term treatment of duodenal ulcer with cimetidine. In: Wastell C, Lance P, eds. Cimetidine. The Westminster
1 Bodemar
Lancet
2.
Hospital Symposium. Edinburgh: Churchill Livingstone, 1978: 66-78. RJ, Ciclitira PJ, Farthing MJG, et al. Cimetidine in the prevention of gastric 55: 393-95. ulcer relapse Postgraduate Med 1979; J 4. Becker HD, Caspary WF. Postgastrectomy and postvagotomy syndromes. Berlin: Springer Verlag, 1980 5. Fineberg HK, Perlman ZA. Surgical treatment of peptic ulcer in the United 3. Machell
6. 7. 8. 9. 10.
11.
12. 13. 14.
15.
16.
17.
18.
19.
States-Trends before and after the introduction of cimetidine. Lancet 1981, i. 1307-08. Rohner HG, Blomer A, Echterhoff HM, et al. Surgical treatment of peptic ulcer disease five years before and after introduction of cimetidine. Z Gastroent 1983; 21: 585-92. Andersen D, Höstrup H, Amdrup E. The Aarhus County Vagotomy Trial II An interim report. World J Surg 1978, 2: 91-100. Amdrup E, Jensen H-E. Selective vagotomy of the parietal cell mass preserving innervation of the undrained antrum. Gastroenterology 1970, 59: 522-27 Johnston D, Wilkinson AR. Highly selective vagotomy without a drainage procedure in the treatment of duodenal ulcer. Br J Surg 1970, 57: 289-96 Bank S, Marks IN, Louw JH. Histamine- and insulin-stimulated gastric acid secretion after selective and truncal vagotomy. Gut 1967; 8: 36-41. Amdrup E, Jensen H-E, Johnston D, et al. Clinic results of parietal cell vagotomy (highly selective vagotomy) two to four years after operation. Ann Surg 1974; 108: 279-84. Goligher JC, Hill GL, Kenny TE, et al Proximal gastric vagotomy without drainage for duodenal ulcer: results after 5-8 years. Br J Surg 1978; 65: 145-51. Liavâg I, Roland M A seven year follow-up of proximal gastric vagotomy. Clinical results. Scand J Gastroenterol 1979; 14: 49-56. Johnston D, Wilkinson AR, Humphrey CS, et al. Serial studies of gastric secretion in patients after highly selective (parietal cell) vagotomy without a drainage procedure for duodenal ulcer. Gastroenterology 1973; 64: 1-11 Liavâg I, Roland M. A seven year follow-up of proximal gastric vagotomy. Scand J Gastroenterol 1979; 14: 409-16. Andersen D, Amdrup E, Höstrup H, Hanberg Sörensen F. The Aarhus County Vagotomy Trial. Trends in the problem of recurrent ulcer after parietal cell vagotomy and selective gastric vagotomy with drainage. World J Surg 1982; 6: 86-92 Gray GR, Smith IS, McWhinnie D, Gillespie G Five year study of cimetidine or surgery for severe duodenal ulcer dyspepsia Lancet 1982; i: 787-88. Gear MWL Proximal gastric vagotomy versus long term maintenance treatment with cimetidine for chronic duodenal ulcer: a prospective randomised trial. Br Med J 1983; 286: 98-99. Andersen D, Amdrup E, Hanberg Sorensen F, Jensen KB. Surgery or cimetidine? I. Comparison of two plans of treatment Operation or repeated cimetidine World J
Surg 1983; 7: 372-77. D, Amdrup E, Hanberg Sörensen F, Jensen KB. Surgery or cimetidine? II. Comparison of two plans of treatment: Operation or cimetidine given as a low maintenance dose. WorldJ Surg 1983, 7: 378-84. Maddern GJ, Jamieson GG, Britten-Jones R, et al. Ulcer recurrence following highly selective vagotomy. Gastroenterology 1984; 86: 1170. Cuilleret J, Etaix JP, Picq P, et al. Ulcérations gastriques précocés aprés vagotomie hypersélective pour ulcére duodénal. La Nouv Presse Méd 1977; 6: 1843-45 Ahn H, Johansson K, Lindhagen J, et al. Laser-Doppler flowmetry in the assessment of gastric blood flow in man. Scand J Gastroenterol 1984, 19 (suppl 98): 33.
20. Andersen
21. 22. 23.
Discussion
antigenic constituents of circulating immune complexes detected so far include DNA in systemic lupus erythematosus; viral antigens in Burkitt’s lymphoma," The
hepatitis, 12
and
HTLV-positive lymphoma; 13
component of the skin and intestinal mucosa. The precise mechanism of toxicity is unknown but obviously involves immune factors.18-20 The possibility that glutens acts as a toxic lectin21 in susceptible individuals is of particular interest, since as a lectin, gluten shows oligomannosyl specificity2 and could therefore bind to the mannosylglycoprotein of jejunal mucosa. Such complexes could be both cytotoxic and immunogenic, resulting in antigluten23,24 and anti-90-kD-glycoprotein antibodies. Circulating 90 kD antigen-antibody complexes with targets in the gut and skin could thus be involved in both disorders. However, the possibility that 90 kD antigen-IgG complexes result from skin and/or gut lesions should be considered; multiple forms of circulating immune complexes are present in dermatitis herpetiformis and coeliac disease,3and some of them may be secondary. Since RF binds immune complexes ofIgG type only, it was not possible to study the nature of the antigen involved in the IgA2S or IgM type complexes3 or in the cutaneous IgA deposits in dermatitis herpetiformis. 21 We thank Dr T. Reunala and Dr M. Vuoristo for supplying serum and the Sigrid Juselius Foundation, Finland, for financial support.
samples,
Correspondence should be addressed to C. P. J. M., Fourth Department of Medicine, University of Helsinki, Uniomnkatu 38, 00170 Helsinki 17, Finland. REFERENCES
Mowbray JF, Hoffbrand AV, Holborow EJ, Seah PP, Fry L. Circulating immune complexes in dermatitis herpetiformis. Lancet 1973; i: 400. 2. Doe WF, Booth CC, Brown DL. Evidence for complement-binding immune complexes in adult coeliac disease, Crohn’s disease, and ulcerative colitis. Lancet 1.
1973; i: 402. 3. Mohammed I, Holborow EJ, Fry L, Thompson BR, Hoffbrand AV, Stewart JS. Multiple immune complexes and hypocomplementaemia in dermatitis herpetiformis and coeliac disease. Lancet 1976; ii: 487. 4. Maury CPJ, Teppo A-M. Massive cutaneous hyalinosis. Identification of the hyalin material as monoclonal kappa light chains, 90 kD glycoprotein and type I collagen. Am J Clin Pathol (in press). 5. Wager O, Teppo A-M. Binding affinity of human autoantibodies: Studies of cryoglobulin IgM rheumatoid factors and IgG autoantibodies to albumin. Scand J Immunol 1978; 7: 503. 6. Lambert P-H, Dixon FJ, Zubler RH, Agnello V, et al. A WHO collaborative study for the evaluation of eighteen methods for detecting immune complexes in serum. J Clin Lab Immunol 1978; 1: 1. 7. Burton DR, Boyd J, Brampton AD, Easterbrook-Smith SB, et al. The Clq receptor site on immunoglobulin G. Nature 1980; 288: 338. 8. Wager O, Lindström P, Räsänen JA, Kekomäki R, et al. Evaluation of six tests for circulating IgG complexes with special reference to IgM rheumatoid factors. Analysis of systemic lupus erythematosus and rheumatoid arthritis sera. Clin Exp
Immunol 1981; 46: 149. Wager O, Lindström P. Interference by rheumatoid factor and Clq with detection of IgG complexes. Studies of model systems by ELISA. Scand J Immunol 1982; 15:
319. 10. Sano H, Morimoto C. Isolation of DNA from DNA/anti-DNA antibody complexes in systemic lupus erythematosus. J Immunol 1981; 126: 538.
immune
11. Oldstone MBA, Theofilopoulos AN, Klein G, Gunven P. Immune complex associated with neoplasia: Presence of Epstein-Barr virus antigen-antibody complex in Burkitt’s lymphoma. Intervirology 1974; 4: 292. 12. Almeida J, Waterson AP. Immune complexes in hepatitis. Lancet 1969; n: 983. 13. Schüpbach J, Kalyanaraman VS, Sarngadharan MG, Bunn PA, Blayney DW, Gallo RC. Demonstration of viral antigen p24 in circulating immune complexes of two patients with human T-cell leukaemia/lymphoma virus (HTLV) positive lymphoma. Lancet 1984; i: 302. 14. Coonrod JD, Leach RP. Immunoelectrophoresis for detection of polysaccharides in immune complexes. J Clin Microbiol 1978; 8: 257. 15. Amoroso P, Vergani D, Wojcicka BM, McFarlane IG, Eddleston ALWF, Tee DEH, Williams R. Identification of biliary antigens in circulating immune complexes in primary biliary cirrhosis. Clin Exp Immunol 1980; 42: 95.
G. BODEMAR R. SJÖDAHL
M. STRÖM J. LINDHAGEN
bacterial
polysaccharides in5 infection; 14 biliary antigens in primary biliary cirrhosis;i5 carcinoembryonic antigen in colon cancer;16 and milk proteins in IgA deficiency.17 This study shows that an antigen in immune complexes in dermatitis herpetiformis and coeliac disease is 90 kD glycoprotein, a
9.
CIMETIDINE OR PARIETAL-CELL VAGOTOMY IN PATIENTS WITH JUXTAPYLORIC ULCERS
A. WALAN
Departments of Internal Medicine and Surgery, University of Linköping, and Department of Surgery, Central Hospital of Norrköping, Sweden
patients with
severe juxtapyloric ulcers randomly allocated to either long-term cimetidine treatment (400-800 mg/day) or to parietal-cell vagotomy (PCV). All were followed up for more than 3 years. The endoscopically proven relapse-rate with a dose of 400 mg
Summary
83
were
bed time was 54%; it fell to 32% when the dose was increased to 400 mg twice a day. In the PCV group the relapse-rate was 33%. Patients with prepyloric ulcers alone or in combination with duodenal ulcers relapsed at a higher rate (57% and 82%, respectively) than did patients with "pure" duodenal ulcer disease (17% and 14%, respectively). No patient, not even those with a history of bleeding or perforated ulcers, experienced any bleeding or perforation during relapses, either when on long-term cimetidine treatment or after operation. Previous haemorrhage or perforation per se is thus not an indication for surgery in favour of maintenance treatment with cimetidine. at
Introduction FOR patients with duodenal or gastric ulcers the recurrence is 15-20% during maintenance treatment with cimetidine for one year.I-3 There are very few published reports of longer durations of treatment. During the past decade parietal-cell vagotomy (PCV) has been established as the surgical treatment of choice for duodenal ulcers. PCV has a lower mortality rate and fewer, less severe side-effects than antral resections or other types ofvagotomies.4 The number of operations for peptic ulcer disease has fallen since the introduction of cimetidine. 5,6 This might indicate that cimetidine has been chosen as an alternative to surgery for rate
many patients. The aim of the present study was to investigate whether long-term cimetidine treatment could be an alternative to PCV in patients with duodenal or prepyloric ulcer disease. Because PCV might be less effective in preventing recurrence of prepyloric than duodenal ulcers,patients were grouped according to location of the ulcer at entry into the study.
ME, Pinn V, Schwartz RS, Nathanson L. Carcinoembryonic antigenantibody complexes in a patient with colonic carcinoma and nephrotic syndrome. N Engl J Med 1973; 289: 520. Cunningham-Rundles C. The identification of specific antigens in circulating immune complexes by an enzyme-linked immunosorbent assay: Detection of bovine kappacasein IgG complexes in human sera. Eur J Immunol 1981; 11: 504. Falchuk ZM. Update on gluten-sensitive enteropathy. Am J Med 1979; 67: 1085. Katz SI, Strober W. The pathogenesis of dermatitis herpetiformis. J Invest Dermatol
16. Constanza
17.
18. 19.
1978; 70: 63 20. 21.
Kagnoff MF, Weiss JB, Brown RJ, Lee T, Schanfield MS. Immunoglobulin allotype markers in gluten-sensitive enteropathy. Lancet 1983; i: 952. Weiser MM, Douglas AP. An alternative mechanism for gluten toxicity in coeliac disease. Lancet 1976; i: 567.
22.
Köttgen E, Volk B, Kluge F, Gerok W. Gluten, a lectin with oligomannosyl specificity and the causative agent of gluten-sensitive enteropathy. Biochem Biophys Res
Commun 1982; 109: 168. 23. Eterman KP, Feltkamp TEW. Antibodies to gluten and reticulin in gastrointestinal diseases. Clin Exp Immunol 1978; 31: 92. 24. Lane AT, Huff JC, Zone JJ, Westen WL. Class-specific antibodies to gluten in dermatitis herpetiformis J Invest Dermatol 1980; 80: 402. 25. Zone JJ, Lasalle BA, Provost TT. Circulating immune complexes of IgA type in dermatitis herpetiformis. J Invest Dermatol 1980; 75: 152. 26. Unsworth DJ, Payne AW, Leonard JN, Fry L, Holborow EJ. IgA in dermatitisherpetiformis skin is dimeric Lancet 1982; i: 478.
895
Patients and Methods Patients
patients with active juxtapyloric ulcers fulfilled the criteria for peptic ulcers-ie, endoscopically or radiologically verified ulcers with a history of illness for at least 3 years, together with either (1) one or more complications (haemorrhage or perforation) and recurrence of peptic ulcer symptoms at least once a year during the past 3 years, or (2) no complication but at least three periods with peptic ulcer symptoms during each of the past 3 years. Patients with ulcers proximal to the prepyloric region were not included. Both the physicians and the surgeons judged all patients to be suitable 85
insulin test (0-22 IU/kg intravenously) was done to estimate the completeness of vagotomy. The insulin test was interpreted as positive or negative according to the criteria of Bank et al. 10 The pentagastrin test was also repeated 2 months after PCV.
severe
candidates for surgery. Patients with pyloric stenosis and retention were excluded, as were patients regularly taking more alcohol than an amount corresponding to 30 ml pure alcohol. All patients claimed they were not taking acetylsalicylate-containing tablets or other anti-
inflammatory drugs regularly.
-
prepyloric ulcer group if they had active ulcers in the pylorus or within 2 cm proximal to the pylorus on endoscopic examination, or the duodenal ulcer group if they had active ulcers only in the duodenal bulb on endoscopic examination. The duodenal ulcer group was further divided into those with a previous ulcer in the prepyloric region verified by endoscopy or X-ray (DU/PU), or those without a previously verified ulcer in the prepyloric region (DU). A gastric ulcer proximal to the prepyloric region had never been demonstrated in any of the patients. Patients
were
put into the
Baseline Treatment At entry the patients were treated with cimetidine for 6-18 weeks until their active ulcers healed. Patients were then asked for their informed consent for random allocation to PCV or to long-term cimetidine treatment. 2 patients changed their minds after randomisation and did not want to be operated on, which left 40 patients in the PCV group and 43 patients in the cimetidine group.
Results
The
-Medical Treatment Withdrawals.-l patient defaulted from follow-up after at 1 year. 2 patients did not want to continue maintenance treatment after their first relapse. 2 patients (aged 67 and 72 years) died from myocardial infarction after 21 (one relapse) and 27 (no relapse) months, respectively. Both of them had hypertension and 1 smoked more than 30 cigarettes per day. 38 patients were thus suitable for analysis for the whole period. Relapse-rate (table II).- The patients who stopped treatment or died before a relapse were excluded from the calculation of relapse-rate. 22 patients (22/41, 54%) relapsed on 400 mg at bed time after a median of 8 - 5 months (range 3-36). 20 of these have continued with 400 mg twice daily. 12 (12/19, 63%) of these had a second relapse after a median of 6 months (range 0-27). The relapse-rate was thus at least 32% (12/38) in those patients who remained in the study. 9 (29%) of the 31 patients who had a duodenal ulcer on endoscopy at entry relapsed after the dose of cimetidine was increased to 400 mg twice a day. 9 (36%) of the 25 belonging to the "pure" duodenal ulcer group (DU) relapsed on 400 mg at night. In the 3 years after the dose was increased to 400 mg twice daily the relapse-rate in patients with "pure" duodenal ulcer disease dropped to 17% (4/24). 3 of the 7 patients who had a
endoscopy
Maintenance Treatment
TABLE I- COMPARISON OF TREATMENT GROUPS
started with cimetidine 400 mg at bed time. They were seen in the outpatient clinic every third month by one of us (M. S.) and a new supply of medicine was delivered and the number of unused tablets was counted. A routine blood laboratory screen was done at least once a year. Endoscopy was performed by the same experienced endoscopist every six months or when symptoms indicated a new ulcer. When a relapse occurred the dose of cimetidine was increased to 1-0-1-66ga day until the ulcer healed, then reduced to a maintenance dose of 400 mg twice a day instead of 400 mg at bed time. The patients who remained free from recurrent ulcers were followed up for at least 3 years before maintenance treatment was were followed up for at least 3 stopped. Those with a recurrence years on 400 mg twice a day or until a second relapse, after which they were offered surgical treatment. In the calculation of relapse-rate during treatment with 400 mg cimetidine twice a day, patients without any relapse on 400 mg at bed time were incorporated into the relapse-free group. All
comparability of the two groups is shown in table I.
patients
previously verified prepyloric
ulcer.
TABLE II-RELAPSE-RATE IN PATIENTS OPERATED WITH PCV
(40) OR DURING MAINTENANCE CIMETIDINE TREATMENT (43)
Treatment
Surgical PCV
*Patients with duodenal ulcer and
done by experienced surgeons, mainly as described by and Johnston,8,9 except that (i) the most proximal antral branch of both nerves of Latarget were divided, and (ii) the gastrocolic omentum was divided only when it was considered necessary. The patients were followed up for 3 years after operation in the same way as those given maintenance cimetidine. When a relapse occurred cimetidine 1 g a day was given until the ulcer healed. After a second relapse the patients were offered re-operation or maintenance treatment with cimetidine 400 mg at bed time. was
Amdrup
Secretory A
Tests
gastric secretory
measure
test was
done before
randomisation,
to
basal acid output (BAO) and peak acid output (PAO) after 6 feg/kg subcutaneously. 6-8 weeks after PCV an
pentagastrin
I
I
I
R = relapse; NR = no relapse. *I patient died post-op. 1 patient died, I patient withdrawn. Patients with relapse on cimetidine
400 mg
nightly.
1
patient died,
2
withdrawn.
§3 patients still on 400 (13-29).
months
mg twice
a
day without symptoms
for
a
median of 24
896
prepyloric ulcer at entry had a relapse during the 3 years they were on up to 400 mg cimetidine twice a day. The relapse-rate among patients with prepyloric ulcer disease either active at entry (3/7) or verified earlier (5/7) was thus 57% (8/14). Patients with previous haemorrhage or perforation had a lower rate of relapse (9/25) than those without such a complication (13/16). (p<905) 7 of the 12 patients who were offered surgery at second relapse agreed to the operation. 2 of these 7 patients have relapsed after PCV. 1, a DU/PU patient, was re-operated on (an antrectomy) and the other, a DU patient, remains well on continuous treatment with cimetidine 400 mg at night. Only 4 of the patients with recurrences visited the outpatient clinic between appointments because of severe peptic ulcer symptoms. No patient had haemorrhage, perforation, or signs of pyloric stenosis during medical treatment. There was no indication of poorer compliance with treatment (measured as number of tablets returned) among patients with relapses, compared with those without relapse. Side-effects.-l patient with relapse had slightly raised transaminases during cimetidine treatment which were restored to normal postoperatively. 1 patient reported slight impotence during treatment with 1 g cimetidine a day but had no complaints on a maintenance dose of 400 mg twice a day. Surgical Treatment Completeness of vagotomy. -2 months after PCV the insulin test was positive in 4 patients (4/39, 11%). The mean value of BAO was reduced by 79% and of PAO by 49%. Relapse-rate (table II).—The patients were followed up for 3 years after the PCV. 2 patients refused to return for follow-up visits and endoscopic examinations. They were contacted by phone regularly and reported no complaints. They are regarded as being free of relapses. 13 patients (13/39, 33%) have hitherto relapsed after a median of 16 months (range 4-35), mostly with only mild symptoms and without any serious complication such as perforation or haemorrhage. 7 (22%) of the 32 patients who had a duodenal ulcer preoperatively relapsed. 4 of these relapses (4/28, 14%) occurred in the patients in whom only duodenal ulcers had been found at earlier examinations. The other 3 relapses occurred among the 4 patients in whom earlier investigations had shown both duodenal and prepyloric ulcers (DU/PU). Of the 7 patients who had a prepyloric ulcer preoperatively 6 relapsed. Thus the relapse-rate among patients with prepyloric ulcers either active at entry (6/7) or verified by earlier examinations (3/4) was 82% (9/11). Patients with previous haemorrhage or perforation did not have a higher rate of relapse (6/21) than those without such a complication (7/18). 7 (18%) of the PCV group needed continuous medical treatment because of repeated relapses or chronic symptoms. 4 of these had a duodenal ulcer at entry but only 1 (1/28, 4%) had had pure duodenal ulcer disease. 8 patients visited the outpatient clinic between the scheduled appointments because of peptic ulcers. Complications and side-effects.—1 severe complication occurred. A 64-year-old patient died of pulmonary embolism 3 days after operation. Almost all patients complained of dysphagia and postprandial epigastric fullness during the first postoperative month. These complaints disappeared within 8 weeks, except in 2 patients who continue to have slight postprandial epigastric fullness not severe enough to interfere with daily living. 2 other patients had mild but persistent symptoms of oesophageal reflux postoperatively.
when
Apart from the 13 patients described above who had ordinary ulcer relapses, 4 patients (4/39, 11%) had endoscopically verified deep ulcerations proximal to the angulus on the lesser curvature soon after the operation. They were all insulin negative. Healing occurred in 3 patients after treatment with cimetidine and antacids for 12-24 weeks. In the 4th patient the ulcer did not heal despite treatment for 2 years. He therefore underwent local resection of the ulcerated area.
Discussion In the present study all patients randomised to cimetidine started with 400 mg every night, the dose shown in many trials to be effective for at least 1 year.2 The recurrence-rate was 54% with cimetidine 400 mg every night and 32% when the dose was increased to 400 mg twice daily for maintenance treatment for 3 years. The recurrence-rates reported in general ulcer populations2 for 1 year of cimetidine treatment are around 20%. There are as yet no reports of comparable trials on maintenance treatment for 3 years. Our recurrence-rate after PCV was considerably higher than in most other PCV trials. 11-13However, the low number of positive insulin tests and the pronounced decrease in BAO and PAO postoperatively indicated that the surgical technique was satisfactory and that the relatively high recurrence-rate after PCV was not due to a smaller degree of inhibition of acid secretion in this than in other published
studies. 14,15 The ulcers in our patients were severe. Over 55% of the patients had had either perforation or bleeding; the others had had at least three periods of peptic ulcer symptoms during each of the 3 years before they entered the trial. Median duration of the ulcer disease was high (17.5 years). The high recurrence-rate in this study was due mainly to the very high recurrence-rate, either with cimetidine treatment or after PCV, among patients with prepyloric ulcers alone or in combination with duodenal ulcers. Little interest has been focused on prepyloric ulcers and maintenance cimetidine treatment. Our finding after PCV is similar to that of Andersen-et al,16 who have shown a higher recurrence-rate of symptoms postoperatively in patients with prepyloric ulcers (33%) than in patients with duodenal ulcers (15%). There are probably aetiological factors apart from acid and pepsin in prepyloric ulcer disease which are not influenced by a reduction in gastric acidity and secretion. Both patients with active prepyloric ulcers and patients with an active duodenal ulcer and previous pyloric or prepyloric ulcers had a high recurrence-rate, either with cimetidine treatment or after PCV. This finding emphasises the importance of verifying the location of earlier ulcers, especially if an operation with PCV is being considered. Patients with prepyloric ulcer disease alone or in combination with duodenal ulcer disease need a higher maintenance dose of cimetidine in order to remain free from recurrences. We also believe that more frequent endoscopic examinations are needed for these patients even if they are almost symptomfree. Since the value of PCV diminishes in patients with active or previous prepyloric ulcer disease, for whom the most suitable operation still seems to be resection, which carries a greater risk of side-effects than does PCV, it would seem logical to make cimetidine the first line of treatment for these patients. Gray et al17 and Gear18 have found lower recurrence-rates with PCV than with long-term cimetidine treatment 400 mg
897 in patients with duodenal ulcers; however, Gear included relapses not only during but also after the end of cimetidine treatment. In two extensive studies Andersen et al compared PCV both with intermittent cimetidine treatment 1 g a day19 and with continuous prophylactic treatment with 400 mg at bed time20 in patients with duodenal ulcers. In their hands most patients (63% and 67%, respectively) randomised to cimetidine treatment were operated on within 3 years. We found no difference in the relapse-rate between medically (32%) or surgically (33%) treated patients after increasing the maintenance dose to 400 mg twice a day. However, in the subgroup of patients with only duodenal ulcers PCV seemed superior to long-term cimetidine 400 mg nightly (relapse-rate 14% compared with 36%, p=ns). Increasing the dose to 400 mg twice daily kept a greater proportion of patients (relapse-rate 17%) free from
nightly
recurrences.
The main explanation for the high recurrence-rate within 3 years after PCV among patients with pure duodenal ulcer disease (4/28, 14%) is probably related to the intensive nature of follow-up. These patients underwent endoscopic examination every 6 months whether they had symptoms or not and visited the outpatient clinic every 3rd month. If the follow-up had been similar to that in most other PCV trials, namely, endoscopy only when symptoms clearly appeared, 6 of the total ulcer recurrences in the PCV group may not have been detected. Results similar to ours have recently been reported by Maddern et al. 21They found that among 119 duodenal ulcer patients who had had no clinic recurrence after PCV, and who were asked to undergo endoscopy, 11I (9%) had an ulcer at the time of the examination. Patients with previous episodes of bleeding or perforation relapsed to the same extent during long-term cimetidine treatment as after PCV but without recurrence of either bleeding or perforation. There thus seems to be no reason for recommending PCV just because the patients have had
previous complications. The high number of lesser curvature ulcerations (4/39, 11 %) in the early postoperative period after PCV are the same as that (7%) found by Cuilleret et al,22 who did routine endoscopies shortly after PCV. 6 weeks after operation and 2 days after an insulin test 1 of these 4 patients had a haematemesis. The other patients had no symptoms or only moderate epigastric pain. The patient whose ulcer did not heal within 2 years was re-operated on, with local resection of the ulcer. There was no sign of a foreign body reaction or malignancy in the specimen to explain the inability of the ulcer to heal. Ahn et al23 have shown that gastric blood flow, measured peroperatively by means of laser Doppler flowmetry, decreased by 60% (range 45-80) over the lesser curvature, whereas that to the greater curvature did not change immediately after PCV. Perhaps these lesser curvature ulcerations were ischaemic and represent a mild form of the serious condition, lesser curvature necrosis. Out of 43 patients originally considered for surgery but instead given maintenance cimetidine only 7 (16%) have been operated on during at least 36 months’ observation. Among the 40 patients in the PCV group, 7 patients (18%) are on maintenance treatment with cimetidine because they have had more than one relapse. Maintenance therapy with cimetidine in an adequate dose would thus seem to be practically as effective as PCV and the two treatments may sometimes be complementary. The optimum duration of cimetidine treatment still has to be determined.
SIGNIFICANCE OF LYMPHOCYTOSIS IN ADULTS E. TIDMARSH P. O. SKACEL
I. CHANARIN D. HARRISINGH
Haematology Department, Northwick Park Hospital and MRC Clinical Research
Summary
Centre, Harrow,
Middlesex
11/19 adults with a persistent increase in the total lymphocyte count, but with neither
lymphodenopathy, hepatomegaly, nor splenomegaly, proved have a monoclonal increase in B lymphocytes indicative of chronic lymphatic leukaemia (CLL). All remaining 8 patients had increased numbers of T-lymphocytes, more often of the helper than of the suppressor subsets. All the patients with a lymphocyte count in excess of 10 000/µl, but only 5/13 patients with a lymphocyte count below 10 000/µl had CLL. In adults a sustained lymphocytosis is thus not an adequate basis for the diagnosis of early CLL, which requires the of a demonstration monoclonal population. The T-lymphocytosis is likely to be reactive rather than neoplastic to
in
nature.
Introduction THERE is wide agreement that the number of lymphocytes in peripheral blood in healthy adults does not
circulating
G, Walan A. Maintenance treatment of recurrent peptic ulcer by cimetidine. 1978; n: 403-07. Burland WL, Hawkins BW, Horton RJ, et al. The longer term treatment of duodenal ulcer with cimetidine. In: Wastell C, Lance P, eds. Cimetidine. The Westminster
1 Bodemar
Lancet
2.
Hospital Symposium. Edinburgh: Churchill Livingstone, 1978: 66-78. RJ, Ciclitira PJ, Farthing MJG, et al. Cimetidine in the prevention of gastric 55: 393-95. ulcer relapse Postgraduate Med 1979; J 4. Becker HD, Caspary WF. Postgastrectomy and postvagotomy syndromes. Berlin: Springer Verlag, 1980 5. Fineberg HK, Perlman ZA. Surgical treatment of peptic ulcer in the United 3. Machell
6. 7. 8. 9. 10.
11.
12. 13. 14.
15.
16.
17.
18.
19.
States-Trends before and after the introduction of cimetidine. Lancet 1981, i. 1307-08. Rohner HG, Blomer A, Echterhoff HM, et al. Surgical treatment of peptic ulcer disease five years before and after introduction of cimetidine. Z Gastroent 1983; 21: 585-92. Andersen D, Höstrup H, Amdrup E. The Aarhus County Vagotomy Trial II An interim report. World J Surg 1978, 2: 91-100. Amdrup E, Jensen H-E. Selective vagotomy of the parietal cell mass preserving innervation of the undrained antrum. Gastroenterology 1970, 59: 522-27 Johnston D, Wilkinson AR. Highly selective vagotomy without a drainage procedure in the treatment of duodenal ulcer. Br J Surg 1970, 57: 289-96 Bank S, Marks IN, Louw JH. Histamine- and insulin-stimulated gastric acid secretion after selective and truncal vagotomy. Gut 1967; 8: 36-41. Amdrup E, Jensen H-E, Johnston D, et al. Clinic results of parietal cell vagotomy (highly selective vagotomy) two to four years after operation. Ann Surg 1974; 108: 279-84. Goligher JC, Hill GL, Kenny TE, et al Proximal gastric vagotomy without drainage for duodenal ulcer: results after 5-8 years. Br J Surg 1978; 65: 145-51. Liavâg I, Roland M A seven year follow-up of proximal gastric vagotomy. Clinical results. Scand J Gastroenterol 1979; 14: 49-56. Johnston D, Wilkinson AR, Humphrey CS, et al. Serial studies of gastric secretion in patients after highly selective (parietal cell) vagotomy without a drainage procedure for duodenal ulcer. Gastroenterology 1973; 64: 1-11 Liavâg I, Roland M. A seven year follow-up of proximal gastric vagotomy. Scand J Gastroenterol 1979; 14: 409-16. Andersen D, Amdrup E, Höstrup H, Hanberg Sörensen F. The Aarhus County Vagotomy Trial. Trends in the problem of recurrent ulcer after parietal cell vagotomy and selective gastric vagotomy with drainage. World J Surg 1982; 6: 86-92 Gray GR, Smith IS, McWhinnie D, Gillespie G Five year study of cimetidine or surgery for severe duodenal ulcer dyspepsia Lancet 1982; i: 787-88. Gear MWL Proximal gastric vagotomy versus long term maintenance treatment with cimetidine for chronic duodenal ulcer: a prospective randomised trial. Br Med J 1983; 286: 98-99. Andersen D, Amdrup E, Hanberg Sorensen F, Jensen KB. Surgery or cimetidine? I. Comparison of two plans of treatment Operation or repeated cimetidine World J
Surg 1983; 7: 372-77. D, Amdrup E, Hanberg Sörensen F, Jensen KB. Surgery or cimetidine? II. Comparison of two plans of treatment: Operation or cimetidine given as a low maintenance dose. WorldJ Surg 1983, 7: 378-84. Maddern GJ, Jamieson GG, Britten-Jones R, et al. Ulcer recurrence following highly selective vagotomy. Gastroenterology 1984; 86: 1170. Cuilleret J, Etaix JP, Picq P, et al. Ulcérations gastriques précocés aprés vagotomie hypersélective pour ulcére duodénal. La Nouv Presse Méd 1977; 6: 1843-45 Ahn H, Johansson K, Lindhagen J, et al. Laser-Doppler flowmetry in the assessment of gastric blood flow in man. Scand J Gastroenterol 1984, 19 (suppl 98): 33.
20. Andersen
21. 22. 23.