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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{at}t-online.de
References
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 1 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.
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Olov Ekwall, M.D.
Fredrik Rorsman, M.D.
Olle Kämpe, M.D.
University Hospital
SE-751 85 Uppsala, Sweden
olov.ekwall{at}medsci.uu.se
References
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{at}baylordallas.edu
References
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