Gut, 1977, 18, 1032-1035

Chronic laxative abuse associated with pancreaticislet cell hyperplasiaM. LESNA, A. N. HAMLYN, C. W. VENABLES, AND C. 0. RECORD

From the Departments of Pathology and Gastroenterology, Royal Victoria Infirmary, Newcastle upon Tyne

SUMMARY Marked pancreatic islet cell hyperplasia was found in a patient with laxative-induceddiarrhoea. It is suggested that laxative abuse might be an important aetiological factor in patientswith pancreatic islet cell hyperplasia and the watery diarrhoea syndrome but in whom no hormonalexcess can be demonstrated.

The abuse of laxatives is a well-recognised cause ofwatery diarrhoea and is most frequently seen inmiddle-aged women (Cummings et al., 1974). Thediagnosis of this condition can frequently be difficultbecause such patients ingest laxatives only inter-mittently and vegetable laxatives cannot easily bedetected in stool and urine. The watery diarrhoeasyndrome is an important differential diagnosis and,in the absence of a tumour mass, this is frequentlyassociated with pancreatic islet cell hyperplasia(Verner and Morrison, 1974). In this paper wedescribe a patient with watery diarrhoea caused bychronic laxative abuse in whom marked pancreaticislet cell hyperplasia was also found.

Case history

A thirty-nine year old Caucasian male first presentedin 1971 when he required five admissions to hospitalfor pilonidal sinus surgery. In 1972 he developed adischarging sinus in the right groin and after excisionfirst developed diarrhoea with the passage of blood-stained mucus. Investigations, including bariummeal, barium enema, and sigmoidoscopy, werenormal. The diarrhoea continued and after losing19 kg (3 stones) in weight he was admitted forinvestigation but no abnormality was found apartfrom a low serum folate. About this time he firstcomplained of cramping lower abdominal pain. In1973 he was admitted on three occasions forvasectomy, re-excision of a pilonidal sinus, andappendicectomy (appendix histology normal) butduring this time the diarrhoea had subsided. In early1974 he was admitted with chest pain and later thatyear he developed heartburn, vomiting, and weightloss of 16 kg (2j stones). Investigations were normal

Received for publication 30 May 1977

but a laparotomy and cholecystectomy were per-formed. Neurological and psychiatric assessments atthis time were normal.

In August 1974 he had a lymph node biopsy andsoon after this presented to Medical Outpatientswith intractable diarrhoea with a stool volume of3 1 per day, some lower abdominal pain, and weightloss. At this time laxative abuse was considered butthis he denied and tests for phenolphthalein andmagnesium in the stool were negative. The waterydiarrhoea syndrome was also considered but serumgastrin, enteroglucagon, secretin, vasoactive in-testinal polypeptide, and urinary 5 hydroxyindolacticacid concentrations were normal. He never becamehypokalaemic. In May 1975 he was admitted for afurther laparotomy because of continuing disablingsymptoms but the intra-abdominal organs werecompletely normal. A distal pancreatectomy wasperformed and a 10 cm segment of the ileum wasreversed in an attempt to slow down intestinaltransit. Postoperatively there was an immediatecessation of symptoms and his weight returned tonormal. However, six months later the diarrhoeareturned, the bowels being opened 15-20 times perday and he again lost 12-7 kg (2 stones) in weight.Further endocrine assessment revealed normalserum gastrin and secretin, normal plasma and stoolprostoglandins, but pancreatic and total glucagonconcentrations were slightly raised at 205 (0-150)and 385 (0-250) pg/ml respectively. The smallincreases in glucagon were not thought to be of anyclinical significance. Phenolphthalein was sub-sequently recovered from both stool and urine onseveral occasions. The day after it was suggested tohim that a food contaminant might be causing hissymptoms the diarrhoea ceased and he becamerather constipated. No other self-induced illnesshas appeared as yet.

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Chronic laxative abuse associated with pancreatic islet cell hyperplasia

PATHOLOGICAL FINDINGSPart of the tail of the pancreas was stained byroutine methods after formol saline fixation whilethe remainder was deep frozen for immunohisto-chemical studies. Light microscopy revealed verynumerous pancreatic islets of variable size, somehaving formed newly by budding from the ducts.The smallest islets were composed only of a fewcells but areas of 'confluent' large islets showinghyperplasia of all endocrine cell types were alsopresent (Fig. 1). A point-counting technique usedon multiple sections of pancreatic tissue showed thatthe area of pancreatic islets in this patient was morethan twice that found in two control subjects.

Moderately increased numbers of argyrophilic Acells of the islets were demonstrated by Grimeliussilver impregnation technique and prominent hyper-plasia of the D cells in the Hellestrom-Hellmanstaining method was also seen (Fig. 2).One of the most striking findings in all sections

was the presence of clusters of large poorly-definedareas of eosinophilic cells in the acinar exocrinetissue, rather suggestive of newly forming pancreaticislets (Fig. 3). In the majority of staining methodsthese cells were still reminiscent ofexocrine pancreatictissue rather than islet cells.

Immunohistochemical studies showed that pan-creatic islet cells stained brightly with glucagon,somatostatin, and insulin antibodies but wereunreactive to gastrin antibodies.

Discussion

The term 'nesidioblastosis' was introduced byLaidlaw (1938) to designate diffuse proliferation ofislet cells. It has been derived from Greek for 'thecells that differentiate out of the duct epithelium tobuild islets . . .'. Nesidioblastosis has been associatedwith the watery diarrhoea syndrome and in 11 out of54 cases reviewed by Verner and Morrison (1974)the only abnormality demonstrated was diffusehyperplasia of non-beta pancreatic islet tissue. Eightof these cases were cured by hemipancreatectomyor by complete removal of pancreatic tissue. Thepancreatic histology of the patient described indetail by these authors was very similar to that foundin the present report, and included increased numberof islets, neoformation of islets by budding fromthe ducts, newly formed small islets, and prominentgroups of centroacinar cells. Polak et al. (1975)demonstrated extremely numerous D cells in thepancreatic islets in cases of severe watery diarrhoea

Fig. 1 Hyperplasia ofpancreatic islets. Holmesstaining.

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M. Lesna, A. N. Hamlyn, C. W. Venables, and C. 0. Record

Fig. 2 Hellestrom-Hellman staining ofarepresentative pan-creatic islet demonstra-ting hyperplasia ofDcells.

Fig. 3 Acinoinsulartransformation in thevicinity andaroundsmallpancreatic islets.Haematoxylin andeosin.

unassociated with pancreatic tumour and withoutincreased circulating vasoactive intestinal poly-peptide and described secretion of somatostatin bythese cells. The term 'pseudo-Verner-Morrisonsyndrome' was first used by these authors to describe

such a condition (Bloom and Polak, 1976). Twocases of 'pancreatic cholera', one of which wasattributed to islet cell hyperplasia, were describedby Sircus et al. (1970). In other instances pancreaticislet cell hyperplasia has been associated with

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Chronic laxative abuse associated with pancreatic islet cell hyperplasia 1035

antropyloric gastrinoma (Larsson et al., 1973) andwith familial endocrine adenomatosis (Vance et al.,1969). The problem of acinoinsular differentiationis still the subject of discussion and controversy buthas been extensively studied by SetAlo (1970) whenlight and electron microscopy has shown so-called'mixed cells' on the border of the pancreatic islets.A mixed cell or cell undergoing transformationshould contain simultaneously both the exocrine andendocrine granules, appearances which we havedemonstrated in pancreatic tissue of our patient.

It is possible that laxative abuse may have inducedhyperplasia and neoformation of islet cells in thepatient described, although other alternatives suchas laxative abuse and the pseudo-Verner-Morrisonsyndrome, occurring simultaneously cannot beentirely excluded. It is known that the laxative abusesyndrome is often associated with a variety ofabnormal, but misleading, results of various in-vestigations and these often include abnormalpancreatic function, achlorhydria, and spurioushormonal change (Cummings et al., 1974). Manysuch patients may undergo laparotomy or evenresection of the pancreas in pursuit of a mysterioushormonally active gastrointestinal neoplasm beforethe precise nature of their illness is established.

Laxative abuse is notoriously difficult to diagnose,may cause watery diarrhoea, and should be con-sidered in patients in whom no hormonal excesscan be demonstrated.

We thank Dr J. Polak for the immunocytochemicalstudies and Dr S. Bloom and Dr K. Buchanan forhormonal determinations.

References

Bloom, S. R., and Polak, J. M. (1976). VIP measurement in

distinguishing Verner-Morrison syndrome and pseudo-Verner-Morrison syndrome. Clinical Endocrinology, 5,223s-228s.

Cummings, J. H., Sladen, G. E., James, 0. F. W., Sarner,M., and Misiewicz, J. J. (1974). Laxative-induced diarr-hoea: a continuing clinical problem. British MedicalJournal, 1, 537-541.

Jacobs, W. H., Halperin, P., and Mantz, F. A. (1972).Watery diarrhea and hypokalemia due to nonbeta-isletcell hyperplasia of the pancreas. American Journal ofGastroenterology, 57, 333-340.

Kraft, A. R., Tompkins, R. K., and Zollinger. R. M. (1970).Recognition and management of the diarrheal syndromecaused by nonbeta islet cell tumors of the pancreas.American Journal of Surgery, 119, 163-170.

Laidlaw, G. F. (1938). Nesidioblastoma: the islet tumourof the pancreas. American Journal of Pathology, 14,125-134.

Larsson, L. I., Ljungberg, O., Sundler, F., HAkanson, R.,Svensson, S. O., Rehfeld, J., Stadil, F., and Holst, J. (1973).Antro-pyloric gastrinoma associated with pancreaticnesidioblastosis and proliferation of islets. VirchowsArchives Abteilung A. Pathologische Anatomie, 360,305-3 14.

Polak, J. M., Bloom, S. R., Arimura, A., and Pearse, A. G. E.(1975). Pancreatic D cells in normal and pathologicalhuman pancreas. Gut, 16, 837 (Abstract.)

Setal6, G. (1970). Light microscopic demonstration ofacino-insular transformation. Acta Morphologica AcademiaScientiarum Hungaricae, 18, 359-367.

Sircus, W., Brunt, P. W., Walker, R. J., Small, W. P.,Falconer, C. W. A., and Thomson, C. G. (1970). Two casesof 'pancreatic cholera' with features of peptide-secretingadenomatosis of the pancreas. Gut, 11, 197-205.

Vance, J. E., Stoll, R. W., Kitabchi, A. E., Williams. R. H.,and Wood, F. C., Jr. (1969). Nesidioblastosis in familialendocrine adenomatosis. Journal of the American Medic4lAssociation, 207, 1679-1682.

Verner, J. V., and Morrison, A. B. (1974). Endocrine pan-creatic islet disease with diarrhea: report of a case due todiffuse hyperplasia of nonbeta islet tissue with a review of54 additional cases. Archives of Internal Medicine, 133,492-500.

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