Correspondence

Malabsorption Due to Cholecystokinin Deficiency in a Patient with Autoimmune Polyglandular Syndrome Type I

N Engl J Med 2001; 345:64-66July 5, 2001

Article

To the Editor:

Högenauer and colleagues (Jan. 25 issue)1 report on a patient with intermittent severe diarrhea and malabsorption, which lasted several months and “improved spontaneously.” There was no increase in serum cholecystokinin levels, and no endocrine cells could be demonstrated on one occasion by immunohistochemical studies in biopsy specimens of the duodenal mucosa. The authors concluded that the diarrhea and severe malabsorption were caused by a deficiency of cholecystokinin-producing enteroendocrine cells in the mucosa of the patient's proximal small intestine.

A deficiency of gut hormones can be experimentally induced by several means: the suppression of hormone secretion by somatostatin, the development of specific receptor antagonists, and the generation of receptor-deficient mouse strains by targeted gene disruption. All three approaches have been used to study the consequences of cholecystokinin deficiency in humans and animals. Subjects who received injections of the somatostatin analogue octreotide2 or oral treatment with the cholecystokinin antagonist loxiglumide3 had cholecystoparesis but only slightly reduced secretion of pancreatic enzymes and mild steatorrhea (10 to 20 g of fat excreted). Mice with a deficiency of the cholecystokinin-A receptor have normal food intake and weight gain.4 They are susceptible to gallstone formation but do not have diarrhea or malabsorption.5

Thus, the available data on cholecystokinin deficiency do not support the contention that the patient's symptoms were due only to cholecystokinin deficiency. The immunohistologic finding reported by Högenauer et al. (an absence of chromogranin-positive cells) would mean a complete loss of all gut endocrine cells, or it might be a consequence of the methods used.

Werner Creutzfeldt, M.D.
University of Göttingen, D-37070 Göttingen, Germany
wcreutzfeldt@t-online.de

5 References

1. 1

   Hogenauer C, Meyer RL, Netto GJ, et al. Malabsorption due to cholecystokinin deficiency in a patient with autoimmune polyglandular syndrome type 1. N Engl J Med 2001;344:270-274
   Full Text | Web of Science | Medline

2. 2

   Lembcke B, Creutzfeldt W, Schleser S, Ebert R, Shaw C, Koop I. Effect of somatostatin analogue sandostatin (SMS 201-995) on gastrointestinal, pancreatic and biliary function and hormone release in normal men. Digestion 1987;36:108-124
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   Schmidt WE, Creutzfeldt W, Schleser A, et al. Role of CCK in regulation of pancreaticobiliary functions and GI motility in humans: effects of loxiglumide. Am J Physiol 1991;260:G197-G206
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4. 4

   Kopin AS, Mathes WF, McBride EW, et al. The cholecystokinin-A receptor mediates inhibition of food intake yet is not essential for the maintenance of body weight. J Clin Invest 1999;103:383-391
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   Schmitz F, Wang DQ-H, Blaeker M, et al. CCK-A receptor deficient mice have increased susceptibility to cholesterol gallstones. Hepatology 1996;24:Suppl:246A-246A abstract.
   

To the Editor:

We have previously reported the identification of tryptophan hydroxylase as an endogenous autoantigen in patients with the autoimmune polyendocrine (or polyglandular) syndrome type I.1 Tryptophan hydroxylase is a rate-limiting enzyme in the synthesis of serotonin and is expressed in serotonin-producing enterochromaffin cells. The presence of tryptophan hydroxylase autoantibodies is correlated with malabsorption and loss of serotonin-producing enterochromaffin cells in patients with autoimmune polyendocrine syndrome type I.1,2

To determine whether there is a link between our earlier findings and the report by Högenauer et al., we performed immunohistochemical staining of serial sections from normal duodenal mucosa with the use of specific antibodies against serotonin (Medicorp, Montreal) and cholecystokinin (Sigma, St. Louis), as previously described.1 Figure 1Figure 1Enterochromaffin Cells Containing Both Serotonin and Cholecystokinin in Consecutive Sections of Normal Human Duodenum (×200). shows mucosal enterochromaffin cells containing both serotonin and cholecystokinin. This finding suggests that serotonin and cholecystokinin can be synthesized by the same subpopulation of enterochromaffin cells. Both serotonin and cholecystokinin stimulate postprandial secretion of pancreatic enzymes,3 and serotonin also affects the motility of the gut.4 We postulate that malabsorption in autoimmune polyendocrine syndrome type I is caused by a depletion of enterochromaffin cells that produce both serotonin and cholecystokinin, due to an autoimmune attack directed against tryptophan hydroxylase. Other, unknown functions of these enterochromaffin cells that are not mediated by serotonin or cholecystokinin cannot be ruled out.

Olov Ekwall, M.D.
Fredrik Rorsman, M.D.
Olle Kämpe, M.D.
University Hospital, SE-751 85 Uppsala, Sweden
olov.ekwall@medsci.uu.se

4 References

1. 1

   Ekwall O, Hedstrand H, Grimelius L, et al. Identification of tryptophan hydroxylase as an intestinal autoantigen. Lancet 1998;352:279-283
   CrossRef | Web of Science | Medline

2. 2

   Ward L, Paquette J, Seidman E, et al. Severe autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy in an adolescent girl with a novel AIRE mutation: response to immunosuppressive therapy. J Clin Endocrinol Metab 1999;84:844-852
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3. 3

   Li Y, Hao Y, Zhu J, Owyang C. Serotonin released from intestinal enterochromaffin cells mediates luminal non-cholecystokinin-stimulated pancreatic secretion in rats. Gastroenterology 2000;118:1197-1207
   CrossRef | Web of Science | Medline

4. 4

   Grider JR, Foxx-Orenstein AE, Jin JG. 5-Hydroxytryptamine4 receptor agonists initiate the peristaltic reflex in human, rat, and guinea pig intestine. Gastroenterology 1998;115:370-380
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Author/Editor Response

The authors reply:

To the Editor: Dr. Creutzfeldt suggests that cholecystokinin deficiency, no matter how severe, cannot cause severe steatorrhea. Although he may be correct, it also seems possible that in the studies in humans that he cites, cholecystokinin was not inhibited to the same extent and for the same period of time as may have been the case in our patient. In this regard, it is noteworthy that although octreotide causes only modest steatorrhea, patients with somatostatinoma have severe steatorrhea (up to 76 g of fat per day).1 The cited findings in animals may not be completely relevant to people because of several species differences in the biologic characteristics of cholecystokinin.2,3 Our patient had severe cholecystokinin deficiency, and in our opinion, this was the main cause of his steatorrhea. He also had deficiencies of peptide YY and gastric inhibitory polypeptide. The results of staining with antibodies against chromogranin A and Leu 7 suggest a deficiency of all enteroendocrine-cell subtypes and their products.4 In addition to cholecystokinin deficiency, these other deficiencies probably accentuated the patient's steatorrhea and diarrhea.

Ekwall et al. demonstrate that cholecystokinin-producing enteroendocrine cells also synthesize serotonin and therefore contain the enzyme tryptophan hydroxylase. This important observation is supported by previous studies, which demonstrated the presence of serotonin in motilin- and secretin-producing enteroendocrine cells.4,5 Ekwall et al. propose that the autoimmune attack in patients who have autoimmune polyendocrine syndrome type I with malabsorption could be targeting tryptophan hydroxylase in cholecystokinin-producing cells. This is an attractive explanation for the disappearance of cholecystokinin-producing cells in our patient. Since our immunohistochemical studies indicate an absence of all enteroendocrine cells in the small intestine, further studies would need to determine whether all such cells contained tryptophan hydroxylase. It would be interesting to test serum samples from our patient (obtained when he had severe steatorrhea and when he did not) for the presence of tryptophan hydroxylase or cholecystokinin-directed autoantibodies, or both, with the complementary DNA-library–based methods used by Ekwall et al.

Christoph Högenauer, M.D.
George J. Netto, M.D.
John S. Fordtran, M.D.
Baylor University Medical Center, Dallas, TX 75246
carolby@baylordallas.edu

5 References

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   Boden G, Shimoyama R. Somatostatinoma. In: Cohen S, Soloway RD, eds. Hormone-producing tumors of the gastrointestinal tract. Vol. 5 of Contemporary issues in gastroenterology. New York: Churchill Livingstone, 1985:85-99.
   

2. 2

   Rehfeld JF. Cholecystokinin. In: Schultz SG, Makhlouf GM, Rauner BB, eds. The gastrointestinal system. Vol. 2. Neural and endocrine biology. Section 6 of Handbook of physiology. Bethesda, Md.: American Physiological Society, 1989:337-58.
   

3. 3

   Miller LJ. Does the human pancreas have a type A or B personality? Gastroenterology 1996;111:1767-1770
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4. 4

   Facer P, Bishop AE, Cole GA, et al. Developmental profile of chromogranin, hormonal peptides, and 5-hydroxytryptamine in gastrointestinal endocrine cells. Gastroenterology 1989;97:48-57
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5. 5

   Cetin Y. Secretin-cells of the mammalian intestine contain serotonin. Histochemistry 1990;93:601-606
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Citing Articles (1)

Citing Articles

1. 1

   Robert T. Jensen. (2002) Involvement of Cholecystokinin/Gastrin-Related Peptides and their Receptors in Clinical Gastrointestinal Disorders. Pharmacology and Toxicology 91:6, 333-350
   CrossRef