Cryptosporidiosis—Revisited

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and 14C was in molecules more polar than 25-OHD. Thus little 25-OHD could have been available in bile for subsequent reabsorption. The authors conclude that although significant proportions of either oral or intravenously administered vitamin D are excreted in bile, these are largely highly polar vitamin D metabolites that are biologically inactive. Therefore, the concept of a large conservative enterohepatic circulation of 25-OHD is erroneous and cannot be used to explain vitamin D deficiency commonly associated with small bowel disease, resection, or bypass.

et al. summarized above, indicate that several vitamin D homologues are excreted in bile and may undergo enterohepatic cycling. In most studies the radioactive homologues in bile were shown to be more polar metabolites than the intravenously administered parent compound. An exception is a study with 25OHD that suggested little enteric recirculation of metabolites. However, in that study there also was enteral reabsorption of the tracer, implying significant recirculation of 25-OHD (Proc Sot Exp Biol Med 1975;149:570-2). Overall, the enterohepatic recirculation of vitamin D homologues is an interesting phenomenon that has been worthy of study. However, physiologic utility of this recirculation has now

Comment.

become increasingly questionable because it appears that mostly the highly polar and therefore inactive metabolites of vitamin D undergo recirculation. Thus, disruption of an enterohepatic cycling of vitamin D metabolites cannot be used to account for the frequency of osteomalacia occurring with a variety of gastrointestinal diseases. Oh well, there goes another great theory spoiled by ugly facts!

It is more than 60 yr since an antirachitic factor was isolated from cod liver oil and named vitamin D (Br Med J 1973;1:629-30, Endocr Rev 1982;3:331-66). It was soon discovered that precursors (or provitamins) existed in both animals and plants. Animal provitamin D (7-dehydrocholesterol] present in skin is converted to vitamin D3 (cholecalciferol) by UV radiation. Plant provitamin D (ergosterol) also acquires vitamin D activity upon exposure to UV light, which transforms it to calciferol. Dietary sources supplement and may replace skin production. After the advent of radioactive preparations of vitamin D in the 1960s there was a massive explosion of information concerning the metabolism of vitamin D. It has now been accepted that the mode of action of vitamin D is analogous to that of classic steroid hormones: the vitamin in reality is a steroid hormone and vitamin D can be regarded as a prohormone (Am J Med 1979;67:989-98). Activation requires a two-step metabolic conversion. The first step is conversion to 25-OHD by a liver mitochondrial enzyme (Biochem Biophys Res Commun 197Y:YO:615-22, Biochem J 1979; 184:491-Y, Arch Biochem Biophys 1980;203:529-41). The 25OHD is bound to a specific carrier protein and is the circulating form of vitamin D (Biochem J 1969;115:269-77, J Clin Invest 1971;50:2159-67). It serves as substrate for further hydroxylation to 1,25-dihydroxyvitamin D (1,25-[OH],D) and 24.25-dihydroxyvitamin D (24,25-[OH],D]. This is accomplished by two hydroxylases located in the mitochondrial fraction of the kidney cortex (J Clin Endocrinol Metab 1973;36:1153-61, J Biol Chem 1974; 249:7584-92). There is considerable evidence that production of 1,25-[OH],D is stringently regulated by a variety of endocrine signals including PTH and “calcium demand” of the organism. 1.25.Dihydroxyvitamin D is recognized as the most active form of the vitamin. The level of 1,25-[OHllD is thought to regulate production of 24.25.[OHIZD (J Biol Chem 1979;254:2722-Y, Am J Med 1979:67:989-98). There is controversy whether this latter metabolite plays a direct role in bone metabolism (N Engl J Med 1984:311:47-9) or is simply a less active catabolite. In addition to these metabolites an incredible array of cousins of the vitamin D c.lan ha\re been identified. By 1982 a total of 20 metabolites of vitamin 1) had been chemically characterized and 19 of these are produced under in vivo conditions (Endocr Rev 1982:3:331-663. Their various roles in the expression or catabolism of vitamin D bioactivity awaits clarification. None of the metabolites with the exception of 1,24,25-[OH] ,D have activity comparable to the three hydroxymetabolites mentioned earlier (Endocr Rev 1982;3:33166. N Engl J Med 1984:311.47-Y). Bile acids are necessary for the normal intestinal absorption of vitamin D. Absorption apparently occurs only by diffusion and is most efficient in the proximal small bowel (Ann Intern Med 1977:87:629-30. Gut 1978;19:267-72). When 25-OHD is administered orally, plasma levels of 25.OHD increase (Lancet lY74;ii: 121-3) and absorption of this metabolite is also by passive diffusion (Am J Physiol 1979;236:E441-5). Other studies have shown that intravenous adminstration of radiolabeled 25OHD, 1.25-]OH12D. and 24,25-[OH],D is followed by the secretion of radioactive material in bile (Proc Sot Exp Biol Med 1975; 149:57(1-2. J Clin Invest 1980;65:277-84. J Lab Clin Med 1980;96:278-84). These studies. as well as the study by Clements

E. URBAN, M.B.8.S

CRYPTOSPORIDIOSIS-REVISITED Portnoy D, Whiteside ME, Buckley E III, MocLeod CL (Departments of Microbiology and Infectious Disease, Montreal General Hospital, McGill University; Division of Tropical Medicine, University of Miami School of Medicine; and the Department of Medicine, Duke University Medical Center) Treatment of intestinal Lryptosporidiosis with spiramycin. Ann Intern Med 1984;101:202-4. Nine male patients with acquired immunodeficiency syndrome (seven homosexuals and two Haitians) and one female patient who had an allogeneic bone marrow transplant for acute myeloblastic leukemia in relapse developed severe debilitating diarrhea. Cryptosporidial organisms were found in the stools of each. Small bowel biopsy specimens, obtained from 4 patients, were all positive for this parasite. Each patient was treated with spiramycin (l3 g/day) for 21 wk. Nine adults orally received 3 g/day of spiramycin in divided doses. Six had complete resolution of diarrhea, 5 patients within the first week of treatment. The sixth patient had gradual symptomatic improvement during the first month of treatment but had a relapse within 2 wk of stopping therapy. Retreatment was unsuccessful, and stool examinations that had been negative became positive when he died. Only 3 of the 6 patients whose diarrhea resolved with spiramycin treatment had negative stool examinations. In the other 4 patients, diarrhea persisted but was decreased after the institution of spiramycin. Stool specimens became negative in 2 of these 4 patients. Since the time that I have reviewed this topic previously (Castroenterology 1983;84:657), the number of articles published on this disease has come close to equaling the number of patients harboring this protozoan. I would, therefore, just like to make a few brief comments on the aspects of this infection that concern me. I am not sure that everyone appreciates the difficulties that may be involved in the detection of this parasite. Although the diagnosis can be made by obtaining small bowel or rectal biopsy specimens, these minute organisms (3-5 Frn] can easily be missed. Moreover, multiple biopsy specimens should be taken as this parasite may not be uniformly distributed throughout the Comment.

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bowel. To confirm this diagnosis, whenever possible, specimens should also be sent for electron microscopic examination. Many physicians are not bothering to perform intestinal biopsies, but instead are relying on stool examinations to detect this parasite. Performed correctly, special stool concentration techniques (J Infect Dis 1983;147:824) are an excellent way to detect the oocysts of this organism and are less invasive and less costly. They may even be more sensitive than small bowel biopsies, although this remains to be seen. Performed incorrectly, however, they often yield erroneous results, as yeast may easily be confused with oocysts. Because the oocysts are passed intermittently, several stools should be examined. Therefore, although both stool examinations and intestinal biopsy specimens may be useful in the detection of cryptosporidiosis, each has its own potential problems. This should be kept in mind when attempting to diagnose this disease, as well as when assessing the efficacy of newer agents to treat it. Portnoy et al. have now shown that treatment with spiramycin with resulted in significant clinical improvement in 10 patients this infection. Several of these patients improved despite failure to eradicate this parasite from their GI tracts. Given the difficulties in detecting this organism, one may ask whether any of the patients were really free of this parasite? In order to explain the continued diarrhea in patients without detectable organisms, the authors have suggested that prolonged or severe infection can result in mucosal damage that can persist after successful treatment. This suggestion, although reasonable, will require further studies. Regardless of whether or not spiramycin can totally eradicate this parasite from the GI tract, in the small number of patients studied by Portnoy et al., it has been proven that spiramycin can be therapeutically useful. Further experience with this agent will be necessary, however, before we can truly assess its efficacy. Spiramycin has not yet been approved for routine use by the Food

and Drug Administration (FDA). Physicians wishing to use spiramycin in the United States can obtain this agent in Canada, with special permission from the Anti-Infective Drug Division of the FDA. Future studies along these lines should prove interesting and hopefully rewarding. T. A. BRASITUS. M.D.

THE UTILITY OF MANOMETRY IN DIAGNOSIS OF PANCREATICO-BILIARY DISORDERS Gregg JA, Carr-Locke DL [New England Baptist Hospital, Boston Massachusetts and Leicester Royal Infirmary, Leicester, England) Endoscopic pancreatic and biliary manometry in pancreatic, biliary and papillary disease, and after endoscopic sphincterotomy and surgical exploration. Gut 1985;25:1247-54. The authors report on the results of endoscopic manometry of the sphincter of Oddi in 162 patients with a variety of disorders affecting the sphincter, biliary, and pancreatic ducts. Normal controls consisted of 43 volunteers who had been studied previously using the same techniques and who have been reported in previous articles by these authors. Endoscopy was performed under sedation with intravenous diazepam only. The manometry catheter, with a 1.2-mm-diameter side hole located 4 mm from its sealed tip, was perfused at 0.62 mlimin with 0.9% saline using a Harvard pump. The catheter position was verified by aspiration of bile or pancreatic fluid together with fluoroscopic verification. Pressures were recorded from the duct

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and high-pressure zones and duodenal pressure was recorded by a station pull-through method. The pressures were recorded as the pressure in millimeters of mercury above duodenal pressure. Mean normal values derived from the 43 volunteers were as follows: pancreatic duct pressure, 10.7 mmHg; pancreatic duct sphincter peak pressure, 47.2; pancreatic duct sphincter trough pressure, 15.9; common bile duct pressure, 2.0; bile duct sphincter peak pressure, 51.2; and bile duct sphincter trough pressure, 13.2 mmHg. The authors describe separate pancreatic duct and bile duct sphincters-a finding that will be discussed in the comments section. Eight patient groups were studied. The composition of each group and the abnormal manometric findings will be summarized together. (1) Group PC consisted of 4 asymptomatic postcholecystectomy patients. Only an increased common bile duct pressure was seen (6.0 -+ 1.8 mmHg). (2) Group CDS consisted of 13 patients with common duct stones, 10 of the patients were postcholecystectomy. In this group higher common bile duct pressures (14.2 + 5.8 mmHg) than normals or patients with postcholecystectomy alone were noted. In addition, elevated pancreatic duct sphincter peak (67.3 +- 22.7) and trough (30.3 * 15.7) pressures were noted. (3) Group P contained 12 patients with acute or chronic relapsing pancreatitis. Elevated pancreatic duct sphincter peak pressures (60.4 * 25.2) and bile duct sphincter peak pressures (66.1 * 17.2) only were noted in this group. (4) Group S included 44 patients who carried the diagnosis of papillary stenosis. The authors defined this entity as a history of recurrence or constant biliarylike pain. The papilla is calibrated at the time of sphincter examination by the diameter of the cannula. A common bile duct diameter of >lO mm after cholecystectomy and a pancreatic duct diameter of >5 mm are seen on endoscopic retrograde cholangiopancreatography (ERCP). In addition, there is evidence of delayed drainage of contrast from the ductal system after 30 min. Of these 44 patients, 38 had had a previous cholecystectomy. This group demonstrated elevated pressures in all the areas studied, with pancreatic duct pressure of 18.9 t 6.8, pancreatic duct sphincter peak pressure of 72.5 * 21.1, pancreatic duct sphincter trough pressures of 23.5 2 11.1, common bile duct pressure of 9.9 t 4.0, bile duct sphincter pressures of 67.1 ? 11.9, and bile duct sphincter trough pressures of 26.4 * 12.4 mmHg. (5) Group SPD consisted of 5 patients with stenosis of the pancreatic duct orifice noted at ERCP. Four patients had a previous surgical choledochal sphincterplasty and 1 had had an endoscopic sphincterotomy. Pancreatic duct (22.4 ? 10.9) and pancreatic duct sphincter peak (98.3 _t 15.7) and trough (25.9 * 9.2) pressures were elevated compared with normals. (6) Group PSS consisted of 20 patients with recurrent pain suggestive of biliary or pancreatic disease who had already had a surgical transduodenal sphincteroplasty after cholecystectomy. An elevated pancreatic duct pressure (17.0 2 7.5), but normal pancreatic duct sphincter pressure, was seen. Normal common bile pressures but decreased bile duct sphincter peak and trough pressures were reported. (7) Group PES included 56 patients who were studied after endoscopic sphincterotomy of the choledochal sphincter for choledocholithiasis of papillary stenosis. The postprocedure data indicate normal pressures apart from a de-