HYPOGAMMAGLOBULINAEMIA AND GASTRIC CANCER

1100 The synthesis and identification of this important metabolite will facilitate investigation of the specificity of antisera used in immunoassays, and thus confirm or refute the accuracy of current assays. In addition, since morphine-6-glucuronide may have analgesic activity greater than that of morphine itself, 11 it may prove to be a useful therapeutic agent in its own right. ICRF Department of Medical Oncology, St Bartholomew’s and Hackney Hospitals, London ECI; and Salford Ultrafine Chemicals,* University of Salford 1.

S. P. JOEL R. J. OSBORNE N. S. NIXON* M. L. SLEVIN

Moore A. Be aware of renal function when prescribing morphine. Lancet 1984: ii: 284-85. 2. Hanks GW, Aherne GW. Morphine metabolism: Does the renal hypothesis hold water? Lancet 1985; i: 221-22. 3 Michie C, Chapman JR, Sear J, Moore RA. Opioid metabolism and the kidney. Lancet 1985; i: 586. 4. Schali C, Roch-Ramel F. Transport and metabolism of [3M] morphine in isolated, non-perfused proximal tubular segments of the rabbit kidney. J Pharmacol Exp Ther

McQuay H,

1982; 223: 811-15. RA, Sear J, Baldwin D,

et al. Morphine kinetics during and after renal transplantation. Clin Pharmacol Ther 1984; 35: 641-45. Shelly MP, Park GR. Morphine toxicity with dilated pupils. Br Med Journal 1984;

5. Moore 6.

289: 1071-72. RA, Baldwin D, Allen MC, Watson PJQ, Bullingham RES, M Quay HJ. Sensitive and specific morphine radioimmunoassay with iodine label: Pharmacokinetics of morphine in man after intravenous administration. Ann Clin Biochem 1984: 21: 318-26. Svensson JO, Rane A, Sawe J, Sjoqvist F. Determination of morphine, morphine-3glucuronide, and (tentatively) morphine-6-glucuronide in plasma and urine using ion-pair high performance liquid chromatography. J Chromatogr 1982; 230: 427-32. Yoshimura H, Oguri K, Tsukamoto H. Metabolism of drugs LX: The synthesis of codeine and morphine glucuronides. Chem Pharm Bull (Tokyo) 1968; 16: 2114-19. Shimomura K, Kamato O, Ueki S, Ida S, Oguri K, Yoshimura H, Tsukamoto H. Analgesic effects of morphine glucuronides. Tohoku J Exp Med 1971; 105: 45-52. Yoshimura H, Natsuki R, Ida S, Oguri K. Chemical reactivity of morphine and morphine-6-conjugates and their binding to rat brain. Chem Pharm Bull 1976; 24(S): 901-06.

7. Moore

8.

9.

10 11.

RENAL FAILURE AND USE OF MORPHINE IN INTENSIVE CARE

interested in Dr Ball and her colleagues’ comments (April 6, p 784) on the influence of renal failure on morphine clearance. We have described a patient with renal failure after orthotopic liver transplantation who was given a morphine infusion for postoperative analgesia and whose plasma morphine levels were very high.1 This prompted us to study in more detail the liver pharmacokinetics of morphine in patients transplantation (and we hope to report on this later). Patients are investigated immediately postoperatively as soon as cardiovascular stability has been attained, usually within 2 h of returning to the intensive care unit. At this time their renal function is not impaired. Various doses of morphine are administered and plasma levels2 are monitored for 24 h. One patient, a 49-year-old woman with primary biliary cirrhosis, was studied in the immediate postoperative period, after a 2 - 5 mg dose of morphine. Renal failure subsequently developed and she was studied again one month later with the same dose. During the first investigation renal function was normal (serum creatinine below 100 µmol/l, urea 6 - 8 mmol/l, urine output 2600 ml in the 24 h period). On the second occasion her renal failure was controlled by arteriovenous haemofiltration and dialysis (creatinine 390 µmol/l, urea 73.4 4 mmol/l, 24 h urine output 100 ml). Plasma morphine levels are shown in the figure. During the first study a peak 16.8 ng/ml was reached after 4 h and morphine levels returned to normal within 12 h. However, on the second occasion the peak was 32 - 2 ng/ml after 6 h, and morphine levels were above 20 ng/ml throughout the study. The first study was done when the patient had good renal function but impaired liver function after an ischaemic period of 297 min. During the second study she was in renal failure but her liver function, apart from a raised bilirubin, was essentially unchanged. Although the pattern of results was similar on both occasions, during the second study the peak plasma level was almost double that of the earlier one and the half-life was much longer. The

SIR,—We

were

undergoing

morphine levels in patient after liver transplantation. Day 1 = immediate postoperative study. Day 30= patient in renal failure.

Plasma

difference in peaks may represent a different volume of distribution, though the sustained high plasma morphine levels on the second occasion cannot be explained in this way. These results support Ball and colleagues’ view that a renal mechanism for the clearance of morphine exists, despite the controversy over the assay method.3 Anaesthetics Department, Addenbrooke’s Hospital, Cambridge CB2 2QQ

MAIRE SHELLY G. R. PARK

Park GR. Morphine toxicity with dilated pupils. Br Med J 1984; 289: 1071-72. 2. Moore RA, Baldwin D, Allen MC, et al. Sensitive and specific morphine radioimmunoassay with iodine label: Pharmokinetics of morphine in man after intravenous administration. Ann Clin Biochem 1984; 21: 318-25 3. Faulding S, Hall GM. Plasma analgesic concentrations: Fact or fallacy? Br J Anaesth 1984; 56: 11-12. 1.

Shelly MP,

HYPOGAMMAGLOBULINAEMIA AND GASTRIC CANCER

SIR,—Dr Kinlen and colleagues (Feb 2, p 263) have suggested that the 50-fold increased incidence of stomach cancer in patients with common variable immunodeficiency (CVID) may be related to their high frequency of achlorhydria. However, they also point out that, since the excess of gastric cancer in patients with pernicious anaemia without immunodeficiency is less than 10-fold, other factors may contribute to the pathogenesis of gastric cancer in patients with CVID, such as an earlier onset of the atrophic gastritis or bacterial colonisation of the stomach in combination with the immune impairment. We think that achlorhydria may not be crucial in the pathogenesis of stomach cancer in patients with CVID. Like others we have found that only about half of the patients with CVID are achlorhydric and even fewer have pernicious anaemia. Therefore patients with CVID and pernicious anaemia would have at least a 10-fold greater risk of gastric cancer than would patients with pernicious anaemia without immune impairment. This difference suggests that achlorhydria is not essential in the development of stomach cancer in patients with CVID. The finding that only halfof the patients with CVID and stomach cancer are achlorhydric is also at variance with an important role - for achlorhydria in the pathogenesis of gastric cancer in such patients.2,3

1101 We speculate that patients with CVID

the increased incidence of gastric cancer in is related to their type of atrophic gastritis. Atrophic gastritis can be of type A or type B.4,5 In type A the atrophy is restricted to the mucosa of the gastric body and fundus, whereas in type B the antral mucosa is invariably affected with or without atrophy of the body and fundus. Type A is also

characterised by achlorhydria, raised serum gastrin concentrations, and a high frequency of ’antibodies to parietal cells and intrinsic factor, while in type B gastric acid secretion varies between absent and normal, parietal cell and intrinsic factor antibodies are absent and serum gastrin concentrations are not increased.4-6 Pernicious anaemia is common in type A but associated with type B only when the atrophy has extended to the gastric body and fundus. Unlike achlorhydric patients without immunodeficiency, patients with CVID and achlorhydria have normal serum gastrin concentrations.7,8 Also, patients with CVID have decreased gastrin concentrations in the antral mucosa (2.5±1.11 µg/g, n=9 vs 24- 3±2’ 7 µg/g in 30 normal subjects; p<0 . 001), independent of the acid secretory capacity of their stomachs. We therefore speculate that atrophy of the antral mucosa (type B atrophic gastritis) and not of the fundic mucosa is important in the pathogenesis of gastric cancer in patients with CVID. In patients with stomach cancer and pernicious anaemia without immune impairment, the carcinoma is usually located in the body or the fundus of the stomach,9 which supports a relation between mucosal atrophy of gastric body and fundus and the malignant lesion. If atrophy of the antral mucosa is important in the development of gastric cancer in patients with CVID, their tumours would occur in the distal part of the stomach. To our knowledge, no systematic studies on the site of gastric cancer in patients with CVID have been reported. Department of Gastroenterology, Hospital, University of Nijmegen, Nijmegen, The Netherlands St Radboud

C. B. H. W. LAMERS

J. B. M. J. JANSEN

Twomey JJ, Jordan PH, Laughter AH, Meuwissen HG, Good RA. The gastric disorder in immunoglobulin-deficient patients. Ann Intern Med 1970; 72: 499-504. 2. Hermans PE, Huizenga KA. Association of gastric carcinoma with idiopathic lateonset immunoglobulin deficiency. Ann Intern Med 1972; 76: 605-09. 3. Hermans PE, Diaz-Buxo JA, Stobo JD. Idiopathic late-onset immunoglobulin deficiency. Am J Med 1976; 61: 221-36. 4. Strickland RG, McKay IR. A reappraisal of the nature and significance of chronic atrophic gastritis. Am J Dig Dis 1973; 18: 426-40. 5 Lamers CBHW, Jansen JBMJ. Antral mucosal atrophy: endoscopy, histopathology and gastrin; relation to gastric cancer. In: Yap SH, vd Sluis RF, Lamers CBHW, eds. Recent advances in diagnostic and therapeutic endoscopy. Aalsmeer: MurKostverloren, 1983: 14-18. 6 Strickland RG, Bhatal PS, Korman MG, Hansky J. Serum gastrin and the antral mucosa in atrophic gastritis. Br Med J 1971; iv: 451-53. 7. Hughes WS, Brooks FR, Conn HO. Serum gastrin levels in primary hypogammaglobulinemia and pernicious anaemia Ann Intern Med 1972; 77: 1

746-50.

Jansen JBMJ, Lamers CBHW. Value of bombesin provocation in patients with gastric diseases. Neth J Med (in press) 9. Morson BC, Sobin LH, et al. Precancerous conditions and epithelial dysplasia in the stomach. J Clin Pathol 1980, 33: 711-21. 8

WHEN DOES ATRIAL NATRIURETIC PEPTIDE BLOCK ALDOSTERONE SECRETION?

SIR,—Dr Richards and colleagues (March 9, p 545) demonstrated marked increase in natriuresis after intravenous injections of 100 pg human alpha atrial natriuretic peptide (a-ANP) in healthy subjects without any changes in aldosterone levels. This observation contrasts with the finding that human ANP inhibits aldosterone secretion in primary cultures of bovine adrenal cells. In a preliminary study, we examined the effect of human a-ANP on aldosterone excretion and natriuresis in nude thymus-aplastic mice harbouring heterotransplanted human Conn’s adenoma tissue. Nude mice bearing hormonally inactive thyroid carcinoma tissue transplants served as controls. Conn’s adenoma tissue was obtained during surgery on a 58-yearold woman. Minced adenoma tissue was heterotransplanted subcutaneously into nude mice.2 The mice received subcutaneous injections of 2 µg human a-ANP three times daily (Bissendorf Peptide, West Germany) or laevulose 5% as placebo. Pooled urine a

samples were collected during 24 h with the mice in metabolic cages, for measurement of aldosterone-18-glucuronide (Sorin), sodium, and potassium excretion. In controls human ANP raised the urinary sodium-potassium -

ratio from 0.58 to 0.79. 24 h aldosterone excretion increased from 2.88 to 7.0 ng. In the mice bearing Conn’s adenoma tissue the sodium-potassium ratio rose from 0.42 to 0 -72 and 24 h aldosterone excretion fell from 11 -7to 5 -3ng. Since we know nothing about the time course of the presumably counterregulatory increase in aldosterone secretion in control mice, this finding seems compatible with the results of Richards et al. However, aldosterone suppression by ANP in the functionally isolated heterotransplanted Conn’s adenoma tissue is comparable with the previous in vitro results.1 Little is known about the mode of action of ANP receptors, but the discrepancies in the effects ofANP when studied in vivo or in vitro could be explained if ANP were to act on pathways which in vivo were under endogenous inhibitory control, this inhibition being lost after transplantation or on isolation of the adrenal tissue. Thus, these procedures would sensitise aldosterone-secreting cells to the suppressive effect of ANP. Dopaminergic structures might be involved because endogenous dopaminergic aldosterone inhibition is also absent in vitro and after transplantation of adrenal tissue. -4 Departments of Endocrinology and Abdominal

Surgery,

Johann Wolfgang Goethe University, D-6000 Frankfurt am Main 70, West Germany; and German Diagnostic Clinic, Wiesbaden

E. JUNGMANN H. J. C. WENISCH S. ABDELHAMID C. TIMM K. SCHÖFFLING

1. Cantin M, Gutkowska J, Thibault G, et al. The heart is an endocrine gland. In: Labrie J, Proulx L, eds. Endocrinology. Amsterdam: Elsevier. 1984; 684-89. 2. Jungmann E, Schwedes U, Usadel KH, Obert I, Schöffling K. Missing endogenous dopaminergic inhibition of aldosterone secretion in human Conn’s adenoma tissue after heterotransplantation to thymus aplastic mice. Horm Metabol Res 1983; 15: 413. 3. Lauer CG, Braley LM, Menachery AI, Williams GH. Metoclopramide inhibits aldosterone biosynthesis in vitro. Endocrinology 1982; 111: 283-43 4. Jungmann E, Germann G, Austin I, et al. Aldosterone responsiveness to haloperidol in rats: Effects of adrenal autotransplantation or demedullation. Acta Endocrinol 1985; suppl 267: 31.

ENGRAVING AND RISK OF LEGIONELLOSIS

SIR,—A virulent strain of Legionella pneumophila serogroup 1 has been found to survive and colonise components of a model water system supplied only with warm tap water. Brown slime-like material was visible to the naked eye, and encapsulated in this debris 1 were large numbers of L One of us (N. J. M.) has an interest in glass engraving and uses a siphon to maintain a flow of water to cool the diamond engraving wheels and to keep down dust. In the silicone tubes that carry tap water from the reservoir to the wheel an orange-brown slime built up, similar to that observed in the laboratory model. 1,2 Examination of this slime with fluorescein-labelled monoclonal antibodies2 demonstrated microcolonies of L pneumophila serogroup 1. The strain was also recovered by standard cultural techniques. Diamond wheels are very efficient at producing aerosols, the known route of transmission of L pneumophila, and people using such equipment in their work or hobbies, represent a hitherto unrecognised risk group for legionellosis. Clinicians should be aware that legionellosis can be contracted from other sources than humidifiers, air-conditioning, and hot water systems.

pneumophila.

PHLS Centre for Applied Microbiology and Porton Down, Salisbury, Wiltshire SP4 0JG

Research,

G. M. SCHOFIELD

Division

of Biological Sciences, College of Agriculture, Auchincruive, Ayr West of Scotland

N. J. MARTIN

GM, Wright AE. Growth of Legionella pneumophila in a model hot water distribution system. J Gen Microbiol 1984; 130: 1751-56. 2 Schofield GM, Locci R. Colonisation of components of a model hot water system by Legionella pneumophila. J Appl Bact 1985; 58: 151-62 1 Schofield