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solved problems for what they are, and devised workable solutions or approaches to solutions for them. If such a genuine partnership between government and the people, including the health professions, were ever to come about, it might also then be possible to address the as yet unsolved problem of long-range planning within a democratic system, and the steady pursuit of a single course of action over a considerable length of time-an accomplishment which is actually essential for the survival of any democratic society in today's interdependent world. The second decade of federal medicine, begun in 1975, is pregnant with opportunities to make our system work. It also carries the potential, perhaps even the likelihood, of compounding the mess which has been created. The first decade has been pretty well botched. Let us hope there will be a chance for us all to get together and do a better job of it in this next decade. -MSMW

Pancreatic Cholera PANCREATIC CHOLERA is a relatively rare clinical syndrome characterized by a non-beta islet cell pancreatic neoplasm, profuse watery diarrhea, hypokalemia and metabolic acidosis.1-3 Although in most of the published case reports patients with this syndrome have had an intraabdominal neoplasm or pancreatic non-beta islet cell hyperplasia,4 recently we and others5 6 have seen patients who have all of the clinical manifestations of pancreatic cholera but in whom no intraabdominal pathology is found at laparotomy or postmortem examination or both. Patients in whom no pathology is found constitute a particularly frustrating problem for clinicians, since such a patient's unremitting, fulminant diarrhea serves as a constant stimulus for physicians to carry out more extensive (and usually more invasive), hazardous diagnostic procedures to "find the tumor." Evidence that pancreatic cholera may be associated with extraabdominal neoplasms is found in the report by Said and Faloona5 of five patients in each of whom there was pancreatic cholera syndrome and bronchogenic neoplasm. This observation has obvious important implications for the diagnostic evaluation of patients with pancreatic cholera and one hopes that adequate

documentation of this association will be forthcoming in future publications. From the clinical standpoint the pathogenesis of pancreatic cholera originates with a pronounced net secretion of isotonic fluid along the entire length of the small intestine. It has yet to be established whether this net secretion results from decreased absorption, increased secretion or a combination of the two processes. Whatever the mechanism, the result is that the colon is presented with excessive volumes (as high as 20 liters per 24 hours) of isotonic fluid having sodium, potassium and chloride concentrations similar to those in plasma. The mechanism through which the colon reabsorbs sodium and chloride can be conceptualized as involving two "exchange processes": sodium-for-potassium and chloride-for-bicarbonate.7 Thus, colonic absorption of sodium and chloride is accompanied by an increase in the intraluminal concentration of potassium and bicarbonate. In the pancreatic cholera syndrome colonic absorption of sodium and chloride is maximal and there is an associated maximal colonic "secretion" of potassium and bicarbonate. The fecal loss of the latter two

ions is primarily responsible for the hypokalemia and metabolic acidosis seen in this disorder. The hypokalemic acidosis can be significantly ameliorated in some patients by continuously aspirating ileal fluid using a tube with its tip positioned just above the ileocecal valve. This procedure, however, significantly increases the patient's total body loss of sodium chloride and parenteral administration of these ions must be increased correspondingly. The large fecal losses of water and electrolytes in this syndrome necessitate careful monitoring of the patient's state of salt and water balance and vigorous parenteral replacement therapy. When patients are first seen they are usually dehydrated and occasionally hypotensive. As they are given intravenous fluid their stool output increases and the greater the amount of fluid administered parenterally the greater the fecal losses. The difficult clinical decision to be made under these circumstances is what should be the patient's daily intake of salt and water. For example, in a patient with fecal losses of 12 to 16 liters daily the physician is continuously trying to determine to what extent the patient's fecal output is occurring solely in response to parenteral fluid administration and to what extent the fecal volumes represent the patient's "basal diarrheal state." Usually THE WESTERN JOURNAL OF MEDICINE

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one attempts to provide sufficient fluid and electrolytes to maintain intravascular volume and urine output without overloading the patient's cardiovascular system. Hypercalcemia is frequently present in patients with pancreatic cholera and on several occasions we have observed pronounced increases in serum calcium (to near lethal concentrations) following rapid intravenous administration of large volumes of saline. Serum calcium should be determined frequently in patients with pancreatic cholera particularly during the initial period of rehydration and any time the rate of parenteral fluid administration is increased. Although surgical operation has been the primary mode of therapy for pancreatic cholera,8'9 corticosteroids have reduced the diarrhea in certain patients.9 Recently two patients have been treated successfully with streptozotocin administered via a hepatic artery catheter'0 and we know of four additional patients who have had excellent clinical responses to streptozotocin administered intravenously. Although streptozotocin appears to offer great promise for patients with pancreatic cholera and metastatic tumor, surgical operation still remains the initial therapy for this disorder. At present, the leading etiologic candidate for the pancreatic cholera syndrome is vasoactive intestinal peptide (VIP )-an octacosapeptide originally isolated from hog small intestinal mucosa"l'2 and subsequently found to produce functional alterations in a number of tissues in vivo and in vitro.1'153 The biologic actions of VIP make it a reasonable candidate for the etiologic agent in the pancreatic cholera syndrome. Like cholera toxin and prostaglandins, each of which can produce clinical syndromes characterized by watery diarrhea, VIP stimulates adenylate *cyclase,`4"l increases cellular cyclic adenosine monophosphate (AMP) and produces net secretion of water and electrolytes'4 in small intestinal mucosa in vitro. Elevated concentrations of viP by radioimmunoassay have been reported in plasma and tumor tissue from patients with pancreatic cholera.-,'; Said and Faloonal also found increased plasma VIP in patients with pancreatic cholera but without a demonstrable neoplasm; however, BloomG found plasma VIP to be normal in each of eight such patients. There are several apparent discrepancies which have to be resolved before the precise role played by vIP in the pancreatic cholera syndrome can be 310

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considered established. There are occasional asymptomatic normal subjects who have plasma VIP concentrations equal to or greater than those seen in pancreatic cholera.5 On the other hand, some patients with pancreatic cholera and a nonbeta islet cell pancreatic neoplasm have plasma viP concentrations which are not elevated.'0 The concentrations of vIP required to stimulate adenylate cyclase, cellular cyclic AMP and intestinal secretion in vitro are approximately 100 times greater than the highest plasma concentration of vIP in patients with pancreatic cholera.'4"15 In two patients with pancreatic cholera'0 intestinal adenylate cyclase activity was normal rather than elevated as one would expect from in vitro studies. Finally, in animals viP is a potent vasodilator and hypotensive agent"1"13; conversely, in patients with pancreatic cholera hypotension is not common and when present is usually attributable to dehydration and hypovolemia secondary to the diarrhea. JERRY D. GARDNER, MD Chief, Section on Gastroenterology Digestive Diseases Branch National Institute of Arthritis, Metabolism, and Digestive Diseases Bethesda, Maryland REFERENCES 1. Verner JV, Morrison AB: Islet cell tumor and a syndrome of refractory watery diarrhea and hypokalemia. Am J Med 25: 374, 1958 2. Matsumoto KK, Peter JB, Schultze RG, et al: Watery diarrhea and hypokalemia associated with pancreatic islet cell adenoma. Gastroenterology 50:231, 1966 3. Walsh JH, Sleisenger MH: Syndromes caused by functioning islet cell tumors, In Sleisenger MH, Fordtran JS (Eds): Gastrointestinal Disease. Philadelphia, W. B. Saunders, 1973, p 365 4. Verner JV, Morrison AB: Endocrine pancreatic islet disease with diarrhea-Report of a case due to diffuse hyperplasia of nonbeta islet tissue with a review of 54 additional cases. Arch Intern Med 133:492-499, 1974 5. Said SI, Faloona GR: Elevated plasma and tissue levels of vasoactive intestinal polypeptide in the watery-diarrhea syndrome due to pancreatic bronchogenic and other tumors. N Engl J Med 293:155-160, Jul 24, 1975 6. Bloom SR, Polak JM: The role of VIP in pancreatic cholera, In Thompson JC (Ed): Gastrointestinal Hormones. Austin, Univ. Texas Press, 1975, p 635 7. Fordtran JS: Diarrhea, In Sleisenger MH, Fordtran JS (Eds): Gastrointestinal Disease, Philadelphia, W. B. Saunders, 1973, p 291 8. Kraft AR, Tompkins RK, Zollinger RM: Recognition and management of the diarrheal syndrome caused by nonbeta islet cell tumors of the pancreas. Am J Surg 119:163-170, Feb 1970 9. Schein PS, DeLellis RA, Kahn CR, et al: Islet cell tumors: Current concepts and management. Ann Intern Med 79:239, 1973 10. Kahn CR, Levy AG, Gardner JD, et al: Pancreatic cholera: Beneficial effects of treatment with streptozotocin. N Engl J Med 292:941-945, May 1, 1975 11. Said SI, Mutt V: Polypeptide with broad biological activity: Isolation from small intestine. Science 169:1217-1218, Sep 18, 1970 12. Said SI, Mutt V: Isolation from porcine intestinal wall of a vasoactive octacosapeptide related to secretin and to glucagon. Eur J Biochem 28:199-204, 13 Jul 1972 13. Said SI: Vasoactive intestinal polypeptide (VIP): Current status, In Thompson JC (Ed): Gastrointestinal Hormones. Austin, Univ. Texas Press, 1975, p 591 14. Schwartz CJ, Kimberg DV, Sheerin HE, et al: Vasoactive intestinal peptide stimulation of adenylate cyclase and active electrolyte secretion in intestinal mucosa. J Clin Invest 54:536544, Sep 1974 15. Klaeveman HL, Conlon TP, Levy AG, et al: Effects of gastrointestinal hormones on adenylate cyclase activity in human jejunal mucosa. Gastroenterology 68:667, 1975

Pancreatic cholera.

EDITORIALS solved problems for what they are, and devised workable solutions or approaches to solutions for them. If such a genuine partnership betwe...
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