PATHOGENESIS OF JUVENILE TROPICAL PANCREATITIS SYNDROME

456

that most of these patients react with (pre)psychotic symptoms on glycine or serine loading, whereas patients with other forms of psychosis do not. Some disturbance of serine-glycine metabolism therefore seems to be in- . volved in the schizophreniform psychotic syndrome described here. for reprints should be addressed to L.P., Erasmus University Rotterdam, P.O. Box Rotterdam, The Netherlands.

Requests psychiatry,

department of 1738, 3000DR

REFERENCES

Sternlieb I, Richman J. Psychiatric manifestations in patients with Wilson’s disease. Birth Defects. Orig Article Vol. IV 1968; 2: 85-87. 2. Lehmann J. Mental and neuromuscular symptoms in tryptophan deficiency. Acta Psychiat Scand 1972; suppl. 237: 16-17. 3. Dean G. The Porphyrias. 2nd ed. Bristol: Western Printing Services, 1971. 4. Osmond H, Smythies JR. Schizophrenia: a new approach. J Ment Sci 1952; 1.

Scheinberg IH,

5. Kowalson B. Metabolic dysperception: The role of the family physician in its diagnosis and management. In: Hawkins D, Pauling L, eds. Orthomolecular psychiatry. San Francisco: W. H. Freeman, 1973: 404-10. 6. Labbé RF. Porphyrins and related compounds. In: Tietz DW, ed. Fundamentals of clinical chemistry. 2nd ed. Philadelphia: WB Saunders, 1976 455-73. 7. Spackman DH, Stein WH, Moore S. Automatic recording apparatus for use in the chromatography of amino acids. Anal Chem 1958; 30: 1190-205 8. Stein JA, Tschudy P. Acute intermittent porphyria, a clinical and biochemical study of 46 patients. Medicine, Baltimore 1970; 49: 1-16. 9. Meyer UA, Schmid R. The porphyrias. In: Stanbury JB, Wyngaarden JB, Frederickson DS, eds. The metabolic basis of inherited disease. New York. McGraw-Hill, 1978: 1166-220. 10. Lehninger AL. Biochemistry. 2nd ed. Worth Publishers, New York. 1975. 693-727. 11. Bruinvels J. Dysmethylation, a possible cause of schizophrenia? In. van Praag HM, ed. On the origin of schizophrenic psychoses. Amsterdam

Erven Bohn, 1975: 30-39. Rosegay A, Walker RW,

12. Mandel LR,

van den Heuvel WJ, Rokach J. 5methyltetrahydrofolic acid as a mediator in the formation of pyridoindoles. Science 1974; 186: 741-42. 13. Meller E, Rosengarten H, Friedhoff AJ, Stebbius RD, Silber R. 5-methyltetrahydrofolic acid is not a methyl-donor for biogenic amines. Enzymatic formation of formaldehyde. Science 1975; 187: 171-73. 14. Brimblecombe RW, Pinder RM. Hallucinogenic agents. Bristol: Wright-

98: 309-15.

Scientechnica, 1975.

Hypothesis PATHOGENESIS OF JUVENILE TROPICAL PANCREATITIS SYNDROME CHUKWUEDU NWOKOLO

JOHN OLI

University of Nigeria Teaching Hospital, Enugu, Nigeria The

name juvenile tropical pancreatitis syndrome (JTPS) is proposed for a disease which affects young people of both sexes in certain parts of the tropics and which is characterised by abdominal pain, diabetes, steatorrhœa, and pancreatic calcification. The condition seems to start with blockage of the pancreatic ducts by laminated secretions or inspissated mucus plugs which later calcify. Chronic pancreatitis follows. The hypothesis is that plugs are the result of pancreatic stasis due to prolonged lack of food in the stomach and/or gastroenteritis and dehydration. Most plugs are probably dislodged during convalescence when protein-containing foods are eaten and stimulate vigorous flow of pancreatic juice. The sluggish pancreatic flow produced by very-low-protein diets may not dislodge plugs. Repeated infection and anorexia can enlarge the plugs which ultimately calcify. JTPS therefore occurs in third-world areas with a high rate of childhood infections, and where low-protein staples are taken. Cereal staples seem to reduce the incidence of

Summary

JTPS

in endemic

areas

because of their

protein content.

view is contested.8 A satisfactory hypothesis on the pathogenesis of the condition should explain not only the geographical distribution and the age of onset, but also the peculiar pathological picture and the clinical features of the disease. MAIN FEATURES OF

In a fresh examination of the problem, we studied the literature on the subject as well as 30 patients seen by us at the University of Nigeria Teaching Hospital, Enugu, Eastern Nigeria, from 1973 to 1979. The major clinical features of the disease are summarised in tables I and II. The disease usually presents in childhood with severe abdominal pain; but diabetes, malabsorption, and pancreatic calcification usually follow within 10 years. Diabetes and exocrine pancreatic disease may antedate calcification by several years. During episodes of abdominal pain, the serum amylase is often raised to 400-1000 Somogyi units/dl (7501875IU/1). 28 out of 30 patients were children of farmers or manual workers, and JTPS cases constitute between 2 and 8% of adult hospital diabetics. The histological characteristics of the disease as described by Banwell et aI.,3 and by Kajubi et al."are seen in both of our two cases from whom histological material was available. There is usually dilatation and obstruction of the main duct and ductules of the pancreas. Many of these ducts contain inspissated mucus or laminated secretions undergoing calcification, and others contain calculi. Sometimes there is metaplasia of duct cells towards mucusTABLE

INTRODUCTION

,

A SYNDROME of pancreatic insufficiency occurring in young people in the tropics and characterised by abdominal pain, diabetes, malabsorption, and pancreatic calcification was first noticed in Indonesia in 1959.’ Since then, the condition has been reported from the following countries, all of which are within 150of the equator-Uganda,2Nigeria,4,5 Zaire,6 Malawi,’ Kerala in S. India,8.9 Ceylon,8 and Singapore.8 We propose the name juvenile tropical pancreatitis syndrome (JTPS) for the condition. Its aetiology is unknown, although the view of Zuidema,’ who attributed the condition to malnutrition, is widely cited;1,6,10 this

JTPS

‘

I-MAJOR CLINICAL FEATURES IN 30 PATIENTS JUVENILE TROPICAL PANCREATITIS SYNDROME

WITH

457 TABLE II-AGE AT ONSET OF ABDOMINAL PAIN AND DIABETES IN 30 PATIENTS

the lower social strata and have a daily protein intake of 35-45 g per day, there can be no question in them of whether a high-protein diet stimulates the pancreas to produce an excessive quantity of pancreatic juice. OUR HYPOTHESIS

The pancreas may be only partly affected. Some infiltration by lymphocytes and plasma cells occurs, and narrowing of part of the main duct described in some Asian casesl2 is not obvious in African

producing forms.

Our hypothesis is that the laminated secretions or inspissated mucus plugs in JTPS which cause obstruction of ducts, and ultimately pancreatitis, are a result of pancreatic stasis rather than hypersecretion; and that the stasis is caused by the effects of recurrent infection and low-protein diets on pancreatic secretory mechanisms in poor tropical countries. This is further elaborated below. NORMAL REGULATION OF PANCREATIC SECRETION

cases.

pancreatic secretion is regulated partly through nervous, but mostly through humoral, mechanisms-i.e., secretin and pancreozymin. Without pancreatic stimulation, as for example in fasting, very little pancreatic juice is secreted. Pancreatic juice secretion is normally induced by:14,lS (a) distenNormal

COMPARISON OF

JTPS

WITH CHRONIC CALCIFYING

PANCREATITIS

JTPS must be distinguished from chronic calcifying pancreatitis (CCP),10," a disease primarily of middleaged alcoholic men and seen chiefly in Europe and America. Alcoholism does not feature in the history of JTPS, which typically afflicts people of both sexes under 20 years of age and especially those in the lower social classes. Table diseases. One

III

compares the main features of the two

on the pathogenesis of CCP attributes the lesions in the pancreatic ducts in chronic alcoholics on a high-protein diet to precipitation of mucoprotein plugs in the ducts. These plugs ultimately become calcified. The precipitation is thought to arise from excessive production of pancreatic juice of high protein content which also contains an abnormal protein, lactoferrin. Chronic pancreatitis develops proximal I to the mucoprotein plugs and the calculi. 13 In JTPS the essential pathological abnormality is dilatation and/or obstruction of the ducts by plugs described as laminated secretions or inspissated mucus. There is also severe fibrosis with replacement of parenchyma by fibrous tissue.3,11 Since the patients belong to

theory

TABLE III-COMPARISON BETWEEN CHRONIC CALCIFYING PANCREATITIS AND JUVENILE TROPICAL PANCREATITIS SYNDROME

sion of the stomach which induces a nervous reflex which causes secretion of pancreozymin by the duodenum or jejunum; (b) entry of hydrochloric acid into the duodenum which stimulates secretin production; and (c) liberation of protein and lipid digestion products (peptones, soaps, protein hydrolysates) which leads to the production of large quantities of secretin and pancreozymin (this mechanism is by far the most important in nature). Carbohydrate has no effect on the production of secretin or pancreozymin, except for that produced by gastric distension. RELATION OF,INFECTION AND HOT CLIMATE TO PANCREATIC STASIS

Because of the dependence of the pancreas on excitatory mechanisms, those conditions which keep the stomach empty for long periods may predispose to pancreatic stasis. Severe and recurrent childhood infections of the kind especially prevalent in developing tropical countries are therefore potential causes of pancreatic stasis because they result in repeated episodes of severe anorexia, vomiting, and diarrhoea. A hot humid climate, especially in the presence of other causes of dehydration, further reduces the fluid available for pancreatic secretion and could also predispose to stasis. The seriousness of the problem of infections in the tropics is shown by the fact that together with malnutrition they are responsible for the 30-fold to 50-fold difference in mortality in the 1-4 year old age-group between tropical developing countries and the advanced countries of Europe and America. 16, 17 ’

FACILITATION OF VIGOROUS FLOW OF PANCREATIC

JUICE

BY PROTEIN-RICH DIET DURING CONVALESCENCE

The diet during convalescence from pancreatic stasis is important in determining the fate of any mucus plugs formed. A vigorous flow of pancreatic juice such as would follow a protein-rich diet could dislodge or dissolve a plug. A sluggish flow after a nearly pure carbohydrate diet is less effective. Another infection occurring soon afterwards may extend a plug and permit it to soli-

458

dify and ultimately calcify. Chronic pancreatitis velops behind organised plugs and calculi. 13

de-

Our view is that the absence, or lower incidence, of JTPS in countries with a high-protein intake may be related to the vigour of pancreatic secretion during convalescence and its ability to dislodge mucus plugs formed during periods of infection and pancreatic stasis. We summarise our view thus-the higher the incidence of anorexiogenic infections in a community, the greater the number of mucus plugs formed in the pancreatic ducts during infection and the resulting pancreatic stasis; the higher the incidence of protein malnutrition, the greater the tendency to consolidation and persistence of these plugs during convalescence. .

APPARENT INTRAZONAL VARIATIONS IN AREAS WHERE

JTPS

IS ENDEMIC

Table IV is derived from the medical literature as well from discussions with some physicians who have worked in the tropical areas indicated. It suggests that there may be intrazonal variations within the regions where JTPS is endemic. These impressions if confirmed would suggest a link between these variations and the protein content of the staple foods. Cereal staples such as sorghum, maize, and rice contain 6-12% protein whereas tubers such as cassava (manioc) and yam contain less than 2% protein.I8 Given the very low-protein diet among the poor, cereal staples are of greater value for pancreatic stimulation than tuber staples, and the incidence of JTPS in places where low-protein staples are consumed would be expected to be higher than elsewhere, as suggested in table iv. as

MALNUTRITION AND

JTPS

The higher incidence of JTPS among the poor classes in Indonesia led Zuidema to postulate that the disease TABLE IV-RELATION OF MAIN STAPLES AND THEIR PROTEIN

CONTENT TO CLINICAL IMPRESSIONS ON INCIDENCE OF TROPICAL PANCREATITIS SYNDROME

JUVENILE

is due

to

damage of the

pancreas

by malnutrition. Pitout that only a

chumoni8 argued against this, pointing

minority of cases of kwashiorkor have irreversible pancreatic fibrosis and atrophy. Similar views are held by Banwell et awl. It should also be mentioned that the signs of malnutrition emphasised by Zuidema could well have

°

been due to uncontrolled diabetes and exocrine pancreatic failure, with the malnutrition being a result rather than a cause of the pancreatic disease. The occurrence of pancreatic duct plugs in fatal cases of kwashiorkor are mentioned by Trowell et al., though not emphasised.19 Our hypothesis explains the higher incidence of JTPS in the lower social classes, its geographical distribution in infection-ridden tropical lands, why the disease starts in childhood, and the pathogenesis of the abnormalities of the pancreas. It can be tested in animals by experiments designed to examine the effects of recurrent infections, prolonged anorexia, and graded protein content of food on the formation and evolution of mucus plugs in pancreatic ductules. OTHER

QUESTIONS

The recurring question about why only a few of those exposed to similar environmental stresses get a particular disease must also be raised in connection with JTPS. In connection with a similar disease, chronic calcifying pancreatitis, Sarles13 mentioned the possibility of genetic selection. We have no evidence of this in JTPS in our cases, and we have seen only one published reference to the

occurrence

of the disease in

two

brothers.’1 A histo-

compatibility system study on all forms of diabetes in our hospital may throw fresh light on the subject. There is also the possibility that toxic factors from staple foods, or viruses, or other microbes may damage the pancreatic ducts and so cause a predisposition to the ready formation of mucus plugs. Measles, infectious hepatitis viruses, enteroviruses, arboviruses, and herpes viruses are very common in developing communities in the tropics, but there are no reports as yet of their specific effects on pancreatic ducts. An editorial in The Lancet2’ drew attention to evidence suggesting that cyanides derived from cassava may damage the beta cells of the pancreas and so produce a predisposition to diabetes. The place of such chemical toxins, as well as factors inhibiting pancreatic secretions,21 and their possible roles in the production of beta-cell damage and pancreatic stasis, respectively, in the tropics deserve further investigation. Requests for reprints should be addressed to C.N., department N medicine, University of Nigeria, Enugu Campus, Enugu, Nigeria. REFERENCES 1. Zuidema PJ. Cirrhosis and disseminated calcification of the pancreas in patients with malnutrition. Trop Geog Med 1959; 11: 70-74. 2. Shaper AG. Chronic pancreatic disease and protein malnutrition. Lancet 1960; i: 1223-24. 3. Banwell JG, Hutt MSR, Leonard PJ, et al. Exocrine pancreatic disease and malabsorption syndrome in tropical Africa. Gut 1967; 8: 388-401. 4. Kinnear TWG. The pattern of diabetes mellitus in a Nigerian teaching hospital. E Afr Med J 1963; 40: 288-94. 5. Olurin EO, Olurin O. Pancreatic calcification: a report of 45 cases. Br MedJ 1969; ii: 534-39. 6. Sonnet J, Brisbois P, Bastin JP. Chronic pancreatitis with calcifications. Congolese Bantus. Trop Geog Med 1965; 18: 97-113.

459

Reviews of Books Neuropsychiatric Side Effects of Drugs in the Elderly vol. IX. Edited by ALVIN J. LEVENSON, University of Texas Medical School at Houston, Texas. New York: Raven Press. 1979. Pp. 252.$26.

Ageing,

factual, dull and arid, with clear presentation of knowledge, without any literary flair. Not often does one find a Richard Asher type article, let alone a book. Some of the most dry chronicles are about drugs and their side-effects, although Laurence’s Clinical Pharmacology is an exception. To have a new book about side-effects of drugs which is not only informative, but crisp without being barren, is therefore pleasant. Although there are twenty-three authors, the uniform style maintained is one that will persuade a reader that it is worth knowing more about the unwanted side-effects of the drugs he prescribes. Multiauthortitles and books are now the order of the day, but the need for six authors for one ten-page chapter about cardiac glycosides is difficult to accept. Six of the thirteen references in this chapter are by one of the authors, and most of the account concentrates on the pharmacokinetics of digoxin, the neurological and psychiatric effects of digitalis intoxication being dealt with in little more than a list. The three-page chapter which gives an overall view of the risk of drug use and abuse in the elderly is followed by an easily understood chapter on sites and mechanism of drug actions and interactions. A firmer line could have been taken in several of the subsequent chapters to avoid repetition of some of the information on pharmacokinetics and pharmacodynamics of drugs in the elderly patients. These later chapters cover antibiotics, antihypertensive agents, autonomic agents, psychotherapeutic drugs, antiparkinsonian drugs, cerebral cogni-active agents, analgesics and antipyretics, steroidal drugs, anti-diabetic agents, laxatives and cathartics, cancer chemotherapeutic agents, and ethyl alcohol. The reference lists vary widely (one has 181 references) and several chapters include English-language references from European journals. One who is not aware of the title would not readily realise that the text is concerned with the elderly (in two chapters case-histories are given of patients in their twenties). Nevertheless, overall the book does highlight how vulnerable elderly patients are to almost every drug. This informative and easy-to-read volume will be of interest to undergraduates and postgraduates alike, and will be constantly referred to by anyone who is concerned whether the drugs he prescribes may be doing more harm than MEDICAL literature is often

emphasis

on

good. Antibiotics and Chemotherapy: Current Topics Current Status of Modern Therapy, vol. IV. Edited by R. N. GRUNEBERG, University College Hospital, London. Lancaster: M.T.P. Press. 1980. Pp. 219. 12.95.

THE

eight chapters

of this book contain reviews of

some

JW, Pilbeam SJ. Diabetes in Nyasaland (Malawi). Trans Roy Sec. Trop Med Hyg 1964; 58: 575-78. 8. Pitchumoni CS. Pancreas in primary malnutrition disorders. Am J Clin Nutr 1973; 26: 374-79. 9. Geevarghese PJ, Pillai VK, Joseph MP, Pitchumoni CS. The diagnosis of pancreatogenous diabetes mellitus. J Assoc Phys India 1962; 10: 173-75. 7. Goodal

10. White TT. Pancreatitis. London: Edward Arnold, 1966; 4. 11. Kajubi SK, Shaper AG, Owor R. Chronic pancreatic disease. In: Shaper AG, Kibukamusoke JW, and Hutt MSR eds. Medicine in a tropical environment. London- British Medical Association, 1972: 380-94. 12. Waller LS. The ætiology of pancreatitis. In: Topics in gastroenterology vol 3. Truelove SC and Goodman MJ eds. Blackwell Scientific publications,

1975; 108.

calcifying pancreatitis - chronic alcoholic pancreatitis. Gastroenterology 1974; 66: 604-16.

13. Sarles H. Chronic

aspects of antibacterial treatment in which there has been or development in recent years. There are excellent articles on prophylactic antimicrobial drug therapy and on the cephalosporin group of antibiotics. So-called antibacterial prophylaxis accounts for much of the misuse of antibacterial agents in hospital. Dr M. W. Casewell enumerates the few situations in which prophylaxis is indicated and justifiable; he points out that misuse, particularly in association with surgery, is often based on small uncontrolled trials. It would be unfortunate if readership of this book does not include those who might benefit from Casewell’s critical appraisal. Dr R. J. Williams and Prof. J. D. Williams have provided a lucid guide through the maze of the cephalosporins, their structure, the complexity of resistance mechanisms, and the limitations of their clinical use, a point also emphasised by several other contributors to the book. Dr J. B. Selkon’s thoughtful article on antibiotic policies will find support both from microbiologists and clinicians. He reaffirms that the paramount consideration must always be the most effective treatment of the individual patient; however, without losing sight of this, he has been able to limit the misuse of antibiotics in hospital and provides impressive figures to prove it. Dr Gruneberg’s approach to prescribing policies clearly requires not only knowledge but also considerable tact; he, too, claims a degree of success, whilst admitting that some units remain unresponsive to his advice. Chapters on the treatment of endocarditis, gonorrhoea, and anaerobic infections, and on the use of combinations of antibacterial drugs provide a useful review of the literature in each area. The informed reader may find himself disagreeing with some of the conclusions drawn, but, in general, they convey useful guidance. It is a pity, therefore, that enjoyment of this book is marred by a poor standard of presentation and writing. With two or three exceptions, the style is cumbersome and indigestible; for example, there are phrases such as "only relatively recently assumed importance clinically" (p. 117) and "haphazardly personal selected topical antibiotics" (p. 52), an unpunctuated 65 word sentence (p. 171), and spelling mistakes

change

galore.

Advances in Cancer Research Vol. XXy. Edited by GEORGE KLEIN, Karolinska Institute, Stockholm, and SIDNEY WEINHOUSE, Temple University Medical School, Philadelphia. New York and London: Academic Press.

1979.Pp.359.$34. THIS volume of the series again provides the reader with expert reviews. The regrowth of interest in cancer induction (some would argue that it has never diminished) is served by reviews of topics concerning chemical carcinogenesis and viral oncogenesis. The carcinogenic potential of hydrazines is described by Dr J. Balo (Budapest), particularly with reference to,bis early work on the antituberculous compound, isoniazid. This is further developed in an extensive account by Dr K. M. Pozharisski and colleagues (Leningrad) of experimentallyinduced intestinal cancers. Together, these reviews point to an

14. White TT. Pancreatitis. London: Edward Arnold, 1966: 34-56. 15. Davenport HW. Physiology of the digestive tract. Chicago: Year Book Medical Publishers, 1966; 130-40. 16. Wharton BA. Kwashiorkor. In: Medicine in a tropical environment. London: British Medical Association, 1972; 262. 17. Jelliffe DB. General background. In: Jelliffe DB and Stanfield JP eds. Diseases of children in the subtropics and tropics, 3rd edition. London: Edward Arnold, 1978; 15. 18. Platt BS. Tables of representative values of foods commonly used in tropical countries. London: HM Stationery Office, 1962; 6-9. 19. Trowell HC, Davies JNP, Dean RFA. Kwashiorkor. London: Edward Arnold, 1954; 147. 20. Editorial. Diabetes, cyanide and rat poison. Lancet 1979; ii: 341-42. 21. Harper AA. The regulation of pancreatic secretion. In: Truelove SC and Goodman MJ eds. Topics in gastroenterology, vol 3. Oxford, Blackwell Scientific Publications, 1975: 69-95.