- Email: [email protected]
Hypercalcemia, calcium in bile, and calcium in gallstones
1720
CORRESPONDENCE
genotypes: evidence in hemodiaiyzed patients and kidney recipients. Gastroenterology 1995; 1 0 8 : 5 8 1 - 5 8 3 . 2. Nousbaum J-B, Pol S, Naipas B, Landais P, Berthelot P, Br6chot C. Hepatitis C Virus type l b (11) infection in France and Italy. Ann Intern Med 1995; 1 2 2 : 1 6 1 - 1 6 8 . 3. F6ray C, Gigou M, Samuel D, Paradis V, Mishiro S, Maertens G, Reyn6s M, Okamoto H, Bismuth H, Br6chot C. Influence of the genotypes of hepatitis C virus on the severity of recurrent liver disease after liver transplantation. Gastroenterology 1995; 108:1088-1096. 4. Pol S, Debure A, Degott C, Camot F, Legendre C, Br6chot C, Kreis H. Chronic hepatitis in kidney allograft recipients. Lancet 1990;335:878-880.
Endoscopic Surveillance in Ulcerative Colitis Still Does Not Work Dear Sir: The report by Rozen et al.: again makes the case for endoscopic surveillance in ulcerative colitis while presenting persuasive data that leads to the opposite conclusion. In addition, the report includes a number of overly optimistic statements. They state "our protocol was adequate to identify all significant dysplasia and/or cancer at a curable stage." This is incorrect; of the four cancers they identified, one (25%) was responsible for the death of the patient (patient 8). They go on to say "survival from cancer was far better than expected because of its detection at earlier pathological stages, thus providing clinical justification for the effort involved and the endoscopic protocol used." According to their own figures, 800 endoscopic examinations were performed during a period of 15 years on 154 patients leading to the detection of three curable cancers, i.e., one cancer per 266 endoscopies. Furthermore, a 5-year survival rate of 75% in 4 patients can hardly be described as "far better than expected." O f the 3 patients that were found to have cancer, 1 (patient 12) had only left-sided colitis, a condition that many gastroenterologists exclude from regular colonoscopic surveillance on the grounds that an increased risk of cancer in this group has not been established. If gastroenterologists are expected to include these patients within their surveillance programs, a much greater work input would be necessary and, on the data currently available, would be difficult to justify. Another of the patients with cancer (patient 10) who was found to have a DALM was operated on 1 year later and in another institution. The authors do not indicate whether or not that operation was performed as a result of the surveillance protocol undertaken in their own hospital. If it was not, then this patient could not be rated as a success for their surveillance program. At most, 3 patients may have benefited from their program, but the 5-year survival rate of patients with cancer in ulcerative coiitis is between 34% and 6 2 % ) '2 It is therefore likely that only 1 or possibly 2 patients would have died in the absence of the surveillance program. This gives, at best, a success rate of one life per 400 endoscopic procedures. This small savings of life may be sufficient moral justification for the continuance of surveillance protocols. It is more difficult to justify then: on a cost-effective basis. ANTHONY AXON, M.D.
Gastroenterology Unit The General Infi*~ary Great George Street Leeds LS13EX, England 1. Rozen P, Baratz M, Fefer F, Gilat T. Low incidence of significant dysplasia in a successful endoscopic surveillance, program of pa-
GASTROENTEROLOGY Vol. 109, No. 5
tients with ulcerative colitis. Gastroenterology 1 9 9 5 ; 1 0 9 : 1 3 6 1 1370. 2. Sugita A, Greenstein AJ, Ribeiro MB, et al. Survival with colorectal cancer in ulcerative colitis: a study of 102 cases. Ann Surg 1993; 2 1 8 : 1 8 9 - 1 9 5 . 3. Gyde SN, Prior P, Thompson H, Waterhouse JAH, Allan RN. Survival of patients with colorectal cancer complicating ulcerative colitis. Gut 1 9 8 4 ; 2 5 : 2 2 8 - 2 3 1 . Reply. Dr. Axon addresses two issues: survival and cost benefit of surveillance in patients with ulcerative colitis. Ours was a prospective endoscopic follow-up study in which we had the benefit of access to the Israel Cancer Registry and Ministry of Interior Death Certificates.: Thus, our data on colorectai cancer occurrence and mortality rate are complete. Overall, 4.6% of the surveillance group (n = 154) developed high-grade dysplasia or colorectal cancer. To date, only 1 patient died from colorectal cancer, possibly due to surgery being delayed for 1 year after identifying high-grade dysplasia. Another patient, asymptomatic of cancer, in whom a DALM was detected on routine surveillance, chose to get another opinion and had surgery at another institution. Pathology records show that he had a Dukes' A cancer and is alive and cancer-free to date. Our report shows that significant dysplasia can be detected by consistent endoscopic-bioptic follow-up and that these are curable by prompt surgical intervention. Dr. Axon expresses skepticism whether this surveillance protocol is cost beneficial and, in part, we concur. The medical effort and costs are large; however, the clinical rewards to the individual are also great, namely, an improved chance to avoid death from colorectal cancer. For these reasons, we and others 2 have tried to draw conclusions from our experience to devise follow-up protocols that are most cost-beneficial for our own ulcerative colitis population: limit endoscopic surveillance to those who have ulcerative colitis affecting more than the rectosigmoid colon for 7 or more years and use alternating flexible sigmoidoscopy and colonoscopy with directed and systematically taken biopsy sampling at decreasing time intervals. In the meantime, other biological tests for dysplasia and chemopreventive-dietary measures may find their place in detecting and/or preventing dysplasia. PAUL ROZEN, M.D.
Department of Gastroenterology Tel Aviv Medical Center 6 Weizmann Street Tel Aviv 64239, Israel 1. Rozen P, Baratz M, Fefer F, Gilat T. Low incidence of significant dysplasia in a successful endoscopic surveillance program of patients with ulcerative colitis. Gastroenterology 1995; 1 0 8 : 1 3 6 1 1370. 2. Connell WR, Lennard-Jones JE, Williams CB, Talbot IC, Price AB, Wilkinson KH. Factors affecting the outcome of endoscopic surveillance for cancer in ulcerative colitis. Gastroenterology 1994; 107:934-944.
Hypercalcemia, Calcium in Bile, and Calcium in Gallstones Dear Sir: In the recent article by Gleeson et al.,: serum and biliary total and ionized calcium concentration were measured during an 8-hour period in 7 postcholecystectomy patients with T tubes before, during, and after a 4-hour intravenous infusion of 10% calcium gluconate. Serum [Ca 2+] showed significant correlation with both biliary [Ca~o~] and [Ca2+]. The authors suggest that "since serum calcium level is one
November 1995
determinant of biliary calcium concentration," "chronic hypercalcemia should cause equivalent changes in biliary lea2+], thereby increasing the relative risk of calcium precipitation with biliary anions to form calcium-rich gallstones." In addition, they suggest that their data "provide some support for the observation that hyperparathyroidism predisposes to radiopaque gallstone formation. ''~ Calcium in blood, calcium in bile, either total or ionized, and calcium in gallstones (GS) is one of the main topics in the pathogenesis o f GS. 2'3
On the basis of the prospective survey of 1590 consecutive surgical patients with bile tract diseases45' who had systematic follow-up, stone analysis by I-R spectroscopy and/or x-ray diffractometry, bile analysis, and comparison of the content (stone and bile) with the container (gallbladder wall), we have accumulated data documenting that the precipitation of calcium salts in GS is mainly determined by parietal factors or biliary stasis, whereas the concentration of calcium in the main lumen of the gallbladder, either total or ionized, is of low importance for calcium precipitation on gallstones in humans. 4'5 In particular, the following findings have been observed: (1) different calcium salts electively precipitated in various sites of the bile tract; (2) in the same site (gallbladder [GB] or common bile duct [CBD]), one stone was sometimes calcified and another not calcified; (3) calcium carbonate and palmitate were mutually exclusive of each other, i.e., they were never present concurrently in large amounts in stones found in the same site; (4) in the same patient and in the same place (GB, CBD), there was a gradient of calcification according to stone site; calcium carbonate concentration in GB stones after cystic duct obstruction was null in GS impacted in the cystic duct and progressively greater in GS closer to the fundus; (6) similar findings have also been observed in other series] M In addition, we have recently observed that (1) calcium palmitate deposition was greater in the CBD than in the GB and, among CBD stones, calcium palmitate concentration was maximal in the brown stone impacted in the ampulla and increasingly less in stones located more cranially6; (2) in almost 30% of the entire series of 1590 patients, stones with a different structure or calcium concentration or also of different types (i.e., cholesterol and black stones; cholesterol, mixed, and combination stones) were found in the same patient in the same site6; (3) intralumihal and/or intraparietal black microlithiasis (i.e., within focal areas of adenomyomarosis) with a great calcium content were associated with cholesterol stones ( 9 8 % - 1 0 0 % cholesterol) in the main GB lumen in the absence of bile infection or severe inflammation of the GB wall) 2 W e hypothesize that this is mainly due to anatomic or pathological parietal conditions (presence of septa, pouches, etc.) either congenital or acquired as a consequence of chronic inflammation, which impair the free movement of the stones during their growth (points 1 and 2) 6 or to the concomitant presence in the same site of multiple microenvironments (main GB lumen, Rokitanky-Aschoff sinuses) with different physical-chemical conditions (point 3). 12 Concerning hyperparathyroidism (HPT), the fact that H P T predisposes to radiopaque GS is far from being proved. No other report confirmed the original article published in 1972 by Selle et al., 13 reporting a 25% incidence of GS (19 of 75) in patients with HPT. Eight of the 19 GS were radiopaque. 13 In the discussion, Block I3 reported a 15 % incidence of gallstones in patients with H P T in his personal series (17 of 122). He also raised the question as to whether the high incidence of peptic ulcer observed in these patients might reflect a group with other factors leading to cholelithiasis. H P T is a constant feature of MEN. W e know presently that somatostatinoma can be associated with H P T in patients with M E N 1 syndrome.
CORRESPONDENCE 1721
Somatostatinoma, determining bile stasis (not HPT!), is associated with GS in more than 75% of cases) 4 In our Italian series of patients with HPT, we have found a 12% incidence of GS (unpublished data). Our cumulative data suggest that (1) calcium deposition is related not only to bile p H but also to factors different from calcium concentration in blood or in buk luminal bile, such as the presence of infection arid/or the clearing capacity of the site or of the microenvironment in which stones actually form~2; (2) it is always associated with bile stasis, determining the precipitation of different calcium salts, according to stone site (GB, CBD, intraheparic ducts) 15 and to the presence or absence of infection; (3) anions are major determinants of insoluble calcium salts. 4 Anyway, gallstone calcification is poorly influenced by calcium concentration in the main bile stream and then by calcium concentration in blood. In conclusion, we suggest more caution before making inferences concerning GS calcification on the basis of calcium concentration in model bile or native bile because calcification is mostly a local phenomenon strictly related to the mutual relationships between the content and the container and to the effect of this relationship (mucus production, alterations in the local process of absorption and secretion, local changes in bile pH, etc.). W e also suggest caution before "stating" or "confirming" that patients with H P T have a greater than expected incidence of cholelithiasis and/or calcified GS. Finally, we suggest that for a better knowledge of the mechanisms of precipitation of calcium salts in GS, it is of paramount importance to consider the container (i.e., GB or CBD) not as a single entity but as the result of multiple microenvironments, each with its own pH, bile circulation, and concentration of solutes, potentially leading to the formation of different GS with different precipitation and/or concentration of calcium salts. FRANCESCO CETTA, M.D. FRANCESCO LOMBARDO, M.D.
lnteruniversity Centerfor Research in Hepatobiliary Diseases Institute of Surgical Clinics University of Siena 53100 Siena, Italy 1. Gleeson D, Murphy GM, Dowling RH. Changes in serum calcium levels influence biliary calcium levels in humans. Gastroenterology 1994; 1 0 7 : 1 8 1 2 - 1 8 1 8 . 2. Moore EW. Biliary calcium and gallstone formation. Hepatology 1990; 12:206S-218S. 3. Heuman DM, Moore EW, Vlahcevic Z. Pathogenesis and dissolution of gallstones. In: Zakim D, Boyer TD, eds. Hepatology, A textbook of liver disease. Philadelphia: Saunders, 1990:1480-1516. 4. Cetta F, Lombardo F, Gargano V, Lore F. Calcium in bile and calcium in gallstones. Data from stone and bile analysis in 1000 consecutive surgical cases (abstr). Gastroenterology 1992; 102:A307. 5. Cetta F. The role of bacteria in pigment gallstone disease. Ann Surg 1 9 9 1 ; 2 1 3 : 3 1 5 - 3 2 6 . 6. Cetta F, Lombardo F, Rossi S. Large foreign body as a nidus for a common duct stone in a patient without spontaneous biliary enteric fistula or previous abdominal surgery. HPB Surg 1993; 6 : 2 3 5 - 2 4 3 . 7. Phemister DB, Rewbridge AG, Rudisill HJ. Calcium carbonate gallstones and calcification of the gallbladder following cystic duct obstruction. Ann Surg 1 9 3 1 ; 9 4 : 4 9 3 - 5 1 6 . 8. Trotman BW, Soloway RD. Pigment gallstone disease: summary of the National Institutes of Health international workshop. Hepatotogy 1982; 2 : 8 7 9 - 8 8 4 . 9. Malet PF, Takabayashi A, Trotman BW, et al. Black and brown pigment gallstones differ in microstructure and microcomposition. Hepatology 1 9 8 4 ; 4 : 2 2 7 - 2 3 4 . 10. Kaufman HS, Magnuson TH, Lillemoe KD, Frasca P, Pitt HA. The
1722
CORRESPONDENCE
GASTROENTEROLOGY Vol. 109, No. 5
role of bacteria in gallbladder and common duct stone formation. Ann Surg 1 9 8 9 ; 2 0 9 : 5 8 4 - 5 9 2 . 11. Crowther RS, Soloway RD. Pigment gallstone pathogenesis: from man to molecules. Semin Liver Dis 1 9 9 0 ; 1 0 : 1 7 1 - 1 8 0 . 12. Cetta F, Lombardo F, Malet PF. Black pigment gallstones with cholesterol gallstones in the same gallbladder. Dig Dis Sci 1995;40:534-538. 13. Selle JG, Altemeir WA, Fullen WD, Goldsmith RE. Cholelithiasis in hyperparathyroidism. A neglected manifestation. Arch Surg 1972; 1 0 5 : 3 6 9 - 3 7 4 .
14. Diliberto JP, Marks JW, Shoenfield U. Classification and pathogenesis of gallstones. In: Braasch JW, Tompkins RK, eds. Surgical disease of the biliary tract and pancreas. St. Louis: Mosby, 1994:50-67. 15. Cetta F, Lombardo F, Cariati A. The role of the content (decreased level of apolipoprotein AI) and the container (bile duct stricture, sectorial dilatation of the ducts determining bile stasis) in the pathogenesis of hepatolithiasis, either pigment or cholesterol. Hepatology 1994; 1 9 : 1 5 3 9 - 1 5 4 1 .
Correction Gu6ant J-L, Saunier M, Gastin I, Safi A, Lamireau T, Duclos B, Bigard MA, Gr~sbeck R. Decreased activity of intestinal and urinary intrinsic factor in GrSsbeck-lmerslund disease. Gastroenterology 1 9 9 5 ; 1 0 8 : 1 6 2 2 - 1 6 2 8 .
The title of this article should have appeared as "Decreased Activity of Intestinal and Urinary Intrinsic Factor Receptor in Gr~isbeck-Imerslund Disease."
CORRESPONDENCE
genotypes: evidence in hemodiaiyzed patients and kidney recipients. Gastroenterology 1995; 1 0 8 : 5 8 1 - 5 8 3 . 2. Nousbaum J-B, Pol S, Naipas B, Landais P, Berthelot P, Br6chot C. Hepatitis C Virus type l b (11) infection in France and Italy. Ann Intern Med 1995; 1 2 2 : 1 6 1 - 1 6 8 . 3. F6ray C, Gigou M, Samuel D, Paradis V, Mishiro S, Maertens G, Reyn6s M, Okamoto H, Bismuth H, Br6chot C. Influence of the genotypes of hepatitis C virus on the severity of recurrent liver disease after liver transplantation. Gastroenterology 1995; 108:1088-1096. 4. Pol S, Debure A, Degott C, Camot F, Legendre C, Br6chot C, Kreis H. Chronic hepatitis in kidney allograft recipients. Lancet 1990;335:878-880.
Endoscopic Surveillance in Ulcerative Colitis Still Does Not Work Dear Sir: The report by Rozen et al.: again makes the case for endoscopic surveillance in ulcerative colitis while presenting persuasive data that leads to the opposite conclusion. In addition, the report includes a number of overly optimistic statements. They state "our protocol was adequate to identify all significant dysplasia and/or cancer at a curable stage." This is incorrect; of the four cancers they identified, one (25%) was responsible for the death of the patient (patient 8). They go on to say "survival from cancer was far better than expected because of its detection at earlier pathological stages, thus providing clinical justification for the effort involved and the endoscopic protocol used." According to their own figures, 800 endoscopic examinations were performed during a period of 15 years on 154 patients leading to the detection of three curable cancers, i.e., one cancer per 266 endoscopies. Furthermore, a 5-year survival rate of 75% in 4 patients can hardly be described as "far better than expected." O f the 3 patients that were found to have cancer, 1 (patient 12) had only left-sided colitis, a condition that many gastroenterologists exclude from regular colonoscopic surveillance on the grounds that an increased risk of cancer in this group has not been established. If gastroenterologists are expected to include these patients within their surveillance programs, a much greater work input would be necessary and, on the data currently available, would be difficult to justify. Another of the patients with cancer (patient 10) who was found to have a DALM was operated on 1 year later and in another institution. The authors do not indicate whether or not that operation was performed as a result of the surveillance protocol undertaken in their own hospital. If it was not, then this patient could not be rated as a success for their surveillance program. At most, 3 patients may have benefited from their program, but the 5-year survival rate of patients with cancer in ulcerative coiitis is between 34% and 6 2 % ) '2 It is therefore likely that only 1 or possibly 2 patients would have died in the absence of the surveillance program. This gives, at best, a success rate of one life per 400 endoscopic procedures. This small savings of life may be sufficient moral justification for the continuance of surveillance protocols. It is more difficult to justify then: on a cost-effective basis. ANTHONY AXON, M.D.
Gastroenterology Unit The General Infi*~ary Great George Street Leeds LS13EX, England 1. Rozen P, Baratz M, Fefer F, Gilat T. Low incidence of significant dysplasia in a successful endoscopic surveillance, program of pa-
GASTROENTEROLOGY Vol. 109, No. 5
tients with ulcerative colitis. Gastroenterology 1 9 9 5 ; 1 0 9 : 1 3 6 1 1370. 2. Sugita A, Greenstein AJ, Ribeiro MB, et al. Survival with colorectal cancer in ulcerative colitis: a study of 102 cases. Ann Surg 1993; 2 1 8 : 1 8 9 - 1 9 5 . 3. Gyde SN, Prior P, Thompson H, Waterhouse JAH, Allan RN. Survival of patients with colorectal cancer complicating ulcerative colitis. Gut 1 9 8 4 ; 2 5 : 2 2 8 - 2 3 1 . Reply. Dr. Axon addresses two issues: survival and cost benefit of surveillance in patients with ulcerative colitis. Ours was a prospective endoscopic follow-up study in which we had the benefit of access to the Israel Cancer Registry and Ministry of Interior Death Certificates.: Thus, our data on colorectai cancer occurrence and mortality rate are complete. Overall, 4.6% of the surveillance group (n = 154) developed high-grade dysplasia or colorectal cancer. To date, only 1 patient died from colorectal cancer, possibly due to surgery being delayed for 1 year after identifying high-grade dysplasia. Another patient, asymptomatic of cancer, in whom a DALM was detected on routine surveillance, chose to get another opinion and had surgery at another institution. Pathology records show that he had a Dukes' A cancer and is alive and cancer-free to date. Our report shows that significant dysplasia can be detected by consistent endoscopic-bioptic follow-up and that these are curable by prompt surgical intervention. Dr. Axon expresses skepticism whether this surveillance protocol is cost beneficial and, in part, we concur. The medical effort and costs are large; however, the clinical rewards to the individual are also great, namely, an improved chance to avoid death from colorectal cancer. For these reasons, we and others 2 have tried to draw conclusions from our experience to devise follow-up protocols that are most cost-beneficial for our own ulcerative colitis population: limit endoscopic surveillance to those who have ulcerative colitis affecting more than the rectosigmoid colon for 7 or more years and use alternating flexible sigmoidoscopy and colonoscopy with directed and systematically taken biopsy sampling at decreasing time intervals. In the meantime, other biological tests for dysplasia and chemopreventive-dietary measures may find their place in detecting and/or preventing dysplasia. PAUL ROZEN, M.D.
Department of Gastroenterology Tel Aviv Medical Center 6 Weizmann Street Tel Aviv 64239, Israel 1. Rozen P, Baratz M, Fefer F, Gilat T. Low incidence of significant dysplasia in a successful endoscopic surveillance program of patients with ulcerative colitis. Gastroenterology 1995; 1 0 8 : 1 3 6 1 1370. 2. Connell WR, Lennard-Jones JE, Williams CB, Talbot IC, Price AB, Wilkinson KH. Factors affecting the outcome of endoscopic surveillance for cancer in ulcerative colitis. Gastroenterology 1994; 107:934-944.
Hypercalcemia, Calcium in Bile, and Calcium in Gallstones Dear Sir: In the recent article by Gleeson et al.,: serum and biliary total and ionized calcium concentration were measured during an 8-hour period in 7 postcholecystectomy patients with T tubes before, during, and after a 4-hour intravenous infusion of 10% calcium gluconate. Serum [Ca 2+] showed significant correlation with both biliary [Ca~o~] and [Ca2+]. The authors suggest that "since serum calcium level is one
November 1995
determinant of biliary calcium concentration," "chronic hypercalcemia should cause equivalent changes in biliary lea2+], thereby increasing the relative risk of calcium precipitation with biliary anions to form calcium-rich gallstones." In addition, they suggest that their data "provide some support for the observation that hyperparathyroidism predisposes to radiopaque gallstone formation. ''~ Calcium in blood, calcium in bile, either total or ionized, and calcium in gallstones (GS) is one of the main topics in the pathogenesis o f GS. 2'3
On the basis of the prospective survey of 1590 consecutive surgical patients with bile tract diseases45' who had systematic follow-up, stone analysis by I-R spectroscopy and/or x-ray diffractometry, bile analysis, and comparison of the content (stone and bile) with the container (gallbladder wall), we have accumulated data documenting that the precipitation of calcium salts in GS is mainly determined by parietal factors or biliary stasis, whereas the concentration of calcium in the main lumen of the gallbladder, either total or ionized, is of low importance for calcium precipitation on gallstones in humans. 4'5 In particular, the following findings have been observed: (1) different calcium salts electively precipitated in various sites of the bile tract; (2) in the same site (gallbladder [GB] or common bile duct [CBD]), one stone was sometimes calcified and another not calcified; (3) calcium carbonate and palmitate were mutually exclusive of each other, i.e., they were never present concurrently in large amounts in stones found in the same site; (4) in the same patient and in the same place (GB, CBD), there was a gradient of calcification according to stone site; calcium carbonate concentration in GB stones after cystic duct obstruction was null in GS impacted in the cystic duct and progressively greater in GS closer to the fundus; (6) similar findings have also been observed in other series] M In addition, we have recently observed that (1) calcium palmitate deposition was greater in the CBD than in the GB and, among CBD stones, calcium palmitate concentration was maximal in the brown stone impacted in the ampulla and increasingly less in stones located more cranially6; (2) in almost 30% of the entire series of 1590 patients, stones with a different structure or calcium concentration or also of different types (i.e., cholesterol and black stones; cholesterol, mixed, and combination stones) were found in the same patient in the same site6; (3) intralumihal and/or intraparietal black microlithiasis (i.e., within focal areas of adenomyomarosis) with a great calcium content were associated with cholesterol stones ( 9 8 % - 1 0 0 % cholesterol) in the main GB lumen in the absence of bile infection or severe inflammation of the GB wall) 2 W e hypothesize that this is mainly due to anatomic or pathological parietal conditions (presence of septa, pouches, etc.) either congenital or acquired as a consequence of chronic inflammation, which impair the free movement of the stones during their growth (points 1 and 2) 6 or to the concomitant presence in the same site of multiple microenvironments (main GB lumen, Rokitanky-Aschoff sinuses) with different physical-chemical conditions (point 3). 12 Concerning hyperparathyroidism (HPT), the fact that H P T predisposes to radiopaque GS is far from being proved. No other report confirmed the original article published in 1972 by Selle et al., 13 reporting a 25% incidence of GS (19 of 75) in patients with HPT. Eight of the 19 GS were radiopaque. 13 In the discussion, Block I3 reported a 15 % incidence of gallstones in patients with H P T in his personal series (17 of 122). He also raised the question as to whether the high incidence of peptic ulcer observed in these patients might reflect a group with other factors leading to cholelithiasis. H P T is a constant feature of MEN. W e know presently that somatostatinoma can be associated with H P T in patients with M E N 1 syndrome.
CORRESPONDENCE 1721
Somatostatinoma, determining bile stasis (not HPT!), is associated with GS in more than 75% of cases) 4 In our Italian series of patients with HPT, we have found a 12% incidence of GS (unpublished data). Our cumulative data suggest that (1) calcium deposition is related not only to bile p H but also to factors different from calcium concentration in blood or in buk luminal bile, such as the presence of infection arid/or the clearing capacity of the site or of the microenvironment in which stones actually form~2; (2) it is always associated with bile stasis, determining the precipitation of different calcium salts, according to stone site (GB, CBD, intraheparic ducts) 15 and to the presence or absence of infection; (3) anions are major determinants of insoluble calcium salts. 4 Anyway, gallstone calcification is poorly influenced by calcium concentration in the main bile stream and then by calcium concentration in blood. In conclusion, we suggest more caution before making inferences concerning GS calcification on the basis of calcium concentration in model bile or native bile because calcification is mostly a local phenomenon strictly related to the mutual relationships between the content and the container and to the effect of this relationship (mucus production, alterations in the local process of absorption and secretion, local changes in bile pH, etc.). W e also suggest caution before "stating" or "confirming" that patients with H P T have a greater than expected incidence of cholelithiasis and/or calcified GS. Finally, we suggest that for a better knowledge of the mechanisms of precipitation of calcium salts in GS, it is of paramount importance to consider the container (i.e., GB or CBD) not as a single entity but as the result of multiple microenvironments, each with its own pH, bile circulation, and concentration of solutes, potentially leading to the formation of different GS with different precipitation and/or concentration of calcium salts. FRANCESCO CETTA, M.D. FRANCESCO LOMBARDO, M.D.
lnteruniversity Centerfor Research in Hepatobiliary Diseases Institute of Surgical Clinics University of Siena 53100 Siena, Italy 1. Gleeson D, Murphy GM, Dowling RH. Changes in serum calcium levels influence biliary calcium levels in humans. Gastroenterology 1994; 1 0 7 : 1 8 1 2 - 1 8 1 8 . 2. Moore EW. Biliary calcium and gallstone formation. Hepatology 1990; 12:206S-218S. 3. Heuman DM, Moore EW, Vlahcevic Z. Pathogenesis and dissolution of gallstones. In: Zakim D, Boyer TD, eds. Hepatology, A textbook of liver disease. Philadelphia: Saunders, 1990:1480-1516. 4. Cetta F, Lombardo F, Gargano V, Lore F. Calcium in bile and calcium in gallstones. Data from stone and bile analysis in 1000 consecutive surgical cases (abstr). Gastroenterology 1992; 102:A307. 5. Cetta F. The role of bacteria in pigment gallstone disease. Ann Surg 1 9 9 1 ; 2 1 3 : 3 1 5 - 3 2 6 . 6. Cetta F, Lombardo F, Rossi S. Large foreign body as a nidus for a common duct stone in a patient without spontaneous biliary enteric fistula or previous abdominal surgery. HPB Surg 1993; 6 : 2 3 5 - 2 4 3 . 7. Phemister DB, Rewbridge AG, Rudisill HJ. Calcium carbonate gallstones and calcification of the gallbladder following cystic duct obstruction. Ann Surg 1 9 3 1 ; 9 4 : 4 9 3 - 5 1 6 . 8. Trotman BW, Soloway RD. Pigment gallstone disease: summary of the National Institutes of Health international workshop. Hepatotogy 1982; 2 : 8 7 9 - 8 8 4 . 9. Malet PF, Takabayashi A, Trotman BW, et al. Black and brown pigment gallstones differ in microstructure and microcomposition. Hepatology 1 9 8 4 ; 4 : 2 2 7 - 2 3 4 . 10. Kaufman HS, Magnuson TH, Lillemoe KD, Frasca P, Pitt HA. The
1722
CORRESPONDENCE
GASTROENTEROLOGY Vol. 109, No. 5
role of bacteria in gallbladder and common duct stone formation. Ann Surg 1 9 8 9 ; 2 0 9 : 5 8 4 - 5 9 2 . 11. Crowther RS, Soloway RD. Pigment gallstone pathogenesis: from man to molecules. Semin Liver Dis 1 9 9 0 ; 1 0 : 1 7 1 - 1 8 0 . 12. Cetta F, Lombardo F, Malet PF. Black pigment gallstones with cholesterol gallstones in the same gallbladder. Dig Dis Sci 1995;40:534-538. 13. Selle JG, Altemeir WA, Fullen WD, Goldsmith RE. Cholelithiasis in hyperparathyroidism. A neglected manifestation. Arch Surg 1972; 1 0 5 : 3 6 9 - 3 7 4 .
14. Diliberto JP, Marks JW, Shoenfield U. Classification and pathogenesis of gallstones. In: Braasch JW, Tompkins RK, eds. Surgical disease of the biliary tract and pancreas. St. Louis: Mosby, 1994:50-67. 15. Cetta F, Lombardo F, Cariati A. The role of the content (decreased level of apolipoprotein AI) and the container (bile duct stricture, sectorial dilatation of the ducts determining bile stasis) in the pathogenesis of hepatolithiasis, either pigment or cholesterol. Hepatology 1994; 1 9 : 1 5 3 9 - 1 5 4 1 .
Correction Gu6ant J-L, Saunier M, Gastin I, Safi A, Lamireau T, Duclos B, Bigard MA, Gr~sbeck R. Decreased activity of intestinal and urinary intrinsic factor in GrSsbeck-lmerslund disease. Gastroenterology 1 9 9 5 ; 1 0 8 : 1 6 2 2 - 1 6 2 8 .
The title of this article should have appeared as "Decreased Activity of Intestinal and Urinary Intrinsic Factor Receptor in Gr~isbeck-Imerslund Disease."