Cholelithiasis in Inflammatory Bowel Disease A Case-Control Study DIONIGI LORUSSO,
M.D.,* SILVANA LEO, M.D.,*
ASCANIO MOSSA,t
M.D.,
GIOVANNI MISCIAGNA, M.D.,~: V I T O GUERRA, DIPL. STAT.~
From the Department of Surge*y,* Department of Radiology,'/" and Laboratory of Epidemiology,r Scientific Institute for Digestive Diseases, "S. De Bellis," Castellana G. (Bari), Italy
Lorusso D, Leo S, Mossa A, Misciagna G, Guerra V. Cholelithiasis in inflammatory bowel disease: a case-control study. Dis Colon Rectum 1990;33:791-794. Cholelithiasis is considered an extraintestinal manifestation of Crohn's ileitis but has not been associated with ulcerative colitis. To evaluate if an increased risk of cholelithiasis exists in patients with ulcerative colitis, biliary ultrasonography was performed on 159 patients with inflammatory bowel disease, 114 patients with ulcerative colitis, and 45 patients with Crohn's disease. A control population of 2453 residents of the town near the authors' institute was also studied. An echographic survey of gallstones was performed on the control subjects, who participated in the Multicentrica Italiana Colelitiasi (MICOL). Seventeen patients with inflammatory bowel disease had gallstones (10.7 percent), 11 patients with ulcerative colitis had gallstones (9.6 percent), and 6 patients with Crohn's disease had gallstones (13.3 percent). In the control population, diagnosis of cholelithiasis was made in 239 subjects (9.7 percent). An estimate of the relative risk (odds ratio) of gallstones in ulcerative colitis and Crohn's disease and also in 4 subgroups formed on the basis of the extent of disease (total ulcerative colitis, partial ulcerative colitis, Crohn's disease with ileitis, Crohn's disease without ileitis) with respect to the general population was calculated using logistic regression with gallstones, sex, age, and body mass index as i n d e p e n d e n t variables and inflammatory bowel disease as a dependent variable. The authors' findings show an increased risk of gallstones in both patients with C r o h n ' s disease (odds ratio = 3.6; 95 percent confidence limits = 1.2-10.4; P = 0.02) and patients with ulcerative colitis (odds ratio = 2.5; 95 percent confidence limits = 1.2-5.2; P = 0.01). The risk was highest in patients with Crohn's disease involving the distal ileum (odds ratio = 4.5; 95 percent confidence limits = 1.5-14.1; P = 0.009) and in patients with total ulcerative colitis extending to the cecum (odds ratio = 3.3; 95 percent confidence limits = 1.3-8.6; P = 0.01). These results
confirm that there is an increased risk of gallstones in Crohn's ileitis but they show that there also exists an increased risk in patients with total ulcerative colitis. [Key words: Ulcerative colitis; Crohn's disease; Cholelithiasis]
INFLAMMATORY BOWEL DISEASE has been associated with several extraintestinal manifestations. 1 Those involving the extrahepatic biliary tract are sclerosing cholangitis, bile duct carcinoma, and gallstones. 2 In reports of case studies, sclerosing cholangitis and bile duct carcinoma have been associated with ulcerative colitis, ~ while cholelithiasis has been associated with Crohn's ileitis or ileocolitis but not with Crohn's colitis or ulcerative colitis. 1,4 Two controlled studies on the association of cholelithiasis and inflammatory bowel disease have been published, 5'6 and the only published study regarding ulcerative colitis used symptomatic patients undergoing cholecystography as controls. 5 This study evaluated the frequency of gallstones in patients with ulcerative colitis and Crohn's Disease by ultrasonography in comparison with controls sampled from the general population.
Materials and Methods Address reprint requests to Dr. D. Lorusso: Istituto Scientifico "S. De Bellis," Divisione di Chirurgia, Via F. Valente, 4, 70013 Castellana Grotte (Bari), Italy.
From 1984 to 1988, 159 patients with inflammatory bowel disease, 114 patients with ulcerative colitis (72
791
792
Dis. Col. & Rect. September 1990
LORUSSO, E T AL.
percent), and 45 patients with Crohn's disease (28 percent) were admitted to the Scientific Institute for Digestive Diseases for the first time. The diagnosis of ulcerative colitis and Crohn's disease was made on the basis of specific clinical, radiologic, endoscopic, and histologic criteria. ~ The mean age of patients with ulcerative colitis was 41 years (S.D. +- 15). There were 71 (62 percent) men and 43 (38 percent) women. In 107 patients the extent of the disease was evaluated by total colonoscopy with biopsies taken from the cecum to the rectum, and in the other 7 patients the extent of disease was measured by double-contrast barium enema examination because colonoscopy was partial. Fifty-seven (50 percent) patients had total colitis (extending up to the cecum) and 57 (50 percent) patients had partial colitis (17 with proctitis, 18 with proctosigmoiditis, 17 with left-sided colitis, and 5 with extended colitis up to the hepatic flexure). The mean age of patients with Crohn's disease was 39 years (S.D. -+ 15). There were 24 (53 percent) men and 21 (47 percent) women. The extent of disease was evaluated in all patients by small-bowel x-ray, and either by colonoscopy (38 cases) or by double-contrast barium enema (7 cases). Data on previous surgical operations were obtained f r o m patient hospital records. The patients with Crohn's disease were subdivided into two groups on the basis of the ileal involvement: 1) 35 (78 percent) patients with regional enteritis or Crohn's ileocolitis, including patients operated on for ileal resection (16 of 35); 2) 10 (22 percent) patients with Crohn's colitis only. All patients with inflammatory bowel disease underwent biliary echography performed by the same operator (A.M.). Diagnosis of gallstones was made when one or more structures, distinct or coalescent, intensively echolucent, which move in the lumen with the patients changing position, with or without posterior shadow, were identified in the gallbladder. Patients who resulted cholecystectomized for gallstones at time of the survey entered the group of patients with gallstones (two patients in ulcerative colitis group and two patients in Crohn's disease group). During 1984 and 1985, the same echographist performed a separate ultrasonic survey of gallstones (participating in the Multicentrica Italiana Colelitiasi). The survey comprised 2453 subjects (systematic sam-
pling of the electoral registers, 75 percent response rate), residing in the town near our Institute, with a mean age 47 years (S.D. -+ 10). Data on the prevalence of cholelithiasis in this population control group are shown in Table 1. During the survey, all subjects were questioned about inflammatory bowel disease; one subject responded positive for ulcerative colitis and was included among the cases of the study. The association (odds ratio) between inflammatory bowel disease and gallstones in the case-control study was evaluated using logistic regression to control the effect of confounding and modifying factors. The statistical package used was Epilog version 3 (Epicenter Software, Pasadena, California). Results
The percentage of cholelithiasis in all patients with ulcerative colitis and Crohn's disease and in the four subgroups formed on the basis of the extent of disease is shown in Table 2. Table 3 shows the odds ratio of gallstones in inflammatory bowel disease by logistic regression; the control group is the population of Table 1 and the confounding variables are sex, age, and body mass index. There is an increased risk of gallstones in both the ulcerative colitis and Crohn's disease groups; the risk is higher in the Crohn's disease group than in ulcerative colitis group (odds ratio = 3.6 in Crohn's disease v s . 2.5 in ulcerative colitis), but also in this latter group it is significantly higher with respect to the control population (P = 0.01). To evaluate if the extent of ulcerative colitis increased the relative risk of cholelithiasis, the odds ratio was calculated separately for patients with total ulcerative colitis and for those with partial ulcerative colitis. The patients with disease extending up to the cecum have a relative risk of gallstones that is higher than the subjects with partial ulcerative colitis (Table 4). When subdividing the patients with Crohn's disease on the basis of involvement of the distal ileum, those patients with distal ileitis (regional enteritis and ileocolitis) have a relative risk of cholelithiasis that is higher than the patients with colitis only. However, these latter patients also have an increased relative risk of gallstones (Table 4).
TABLE 1. Prevalence of Cholelithiasis in a Sample (2453 Inhabitants, 75 Percent Response Rate) of the Population of the Town Near our Institute Cholelithiasis*
Males Females TOTAL
Number
N
Percent
1422 1031 2453
96 143 239
6.8 13.9 9.7
*Subjects with gallstones o r o p e r a t e d o n for gallstones.
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TABLE 2. Prevalence of Cholelithiasis in 114 Patients with Ulcerative Colitis and 45 with Crohn's Disease Cholelithiasis
Ulcerative Colitis Total colitis Partial colitis C r o h n ' s Disease Regional enteritis a n d ileocolitis C r o h n ' s colitis
Patients N
N
Percent
114 57 57 45 35 10
11 6 5 6 5 1
9.6 10.5 8.8 13.3 14.3 10.0
TABLE 3. Odds Ratio of Cholelithiasis in Ulcerative Colitis (UC) and Crohn's Disease (CD) as Derived by Unconditional Logistic Regression
Ulcerative colitis C r o h n ' s disease
O d d s Ratio
95 P e r c e n t C o n f i d e n c e Limits O d d s Ratio
P
2.5 3.6
1.2-5.2 1.2-10.4
0.01 0.02
U n c o n d i t i o n a l logistic r e g r e s s i o n for UC: Y = 0.91 (gallstones) - 0.12 (sex) - 0.04 (age) - 0.22 (body m a s s index) + 4.35, a n d for CD: Y = 1.28 (gallstones) + 0.05 (sex) - 0.06 (age) - 0.35 (body mass index) + 6.54. TABLE 4. Odds Ratio (OR) of Cholelithiasis in Subgroups of Patients with Ulcerative Colitis and Crohn's Disease I n f l a m m a t o r y Bowel Disease Ulcerative colitis C r o h n ' s Disease
Subgroups
O R
95 P e r c e n t C o n f i d e n c e Limits
P
Total colitis Partial colitis Regional enteritis a n d ileocolitis C r o h n ' s colitis
3.3 1.9 4.5 2.5
1.3-8.6 0.7-5.4 1.5-14.1 0.2-26.9
0.01 0.17 0.009 0.44
Discussion Our findings show an increased risk of gallstones in both patients with ulcerative colitis and Crohn's disease. The risk is highest for patients with Crohn's disease involving the distal ileum (odds ratio = 4.5; 95 percent confidence limits = 1.5-14.1; P = 0.009) and then for those with total ulcerative colitis (odds ratio = 3.3; 95 percent confidence limits = 1.3-8.6; P = 0.01), but there also exists a lesser degree of risk for patients with Crohn's colitis and partial ulcerative colitis. Current opinion is that the same prevalence of cholelithiasis exists for patients with ulcerative colitis or Crohn's colitis as in the general population; it is considered to be significantly higher only in patients with Crohn s ileitis. 2 A higher incidence of gallstones in the distal ileitis has been confirmed by both case-control 6 and cohort s studies. The frequency of cholelithiasis reported in patients with Crohn's disease involving ileum ranges from 17 to 34 percent 6's-1~ and it is positively correlated with the duration and extent of disease, s There are no sound analytical epidemiologic studies to test the association between ulcerative colitis, Crohn's colitis, and gallstones. In a case series study without systematic search of gallstones, 1 the prevalence of cholelithiasis in patients with ulcerative colitis was 5 percent and it was 5 percent also in Crohn's colitis. In another case review with an ultrasound sur-
veT of gallstones in patients with ulcerative colitis, 4 the prevalence of cholelithiasis was 7.6 percent. The only case-control study on cholelithiasis and ulcerative colitis or Crohn's colitis is that of Baker et al. 5 The findings of this study correlated cholelithiasis only with Crohn's disease involving the distal ileum, and reported the following prevalence of gallstones: granulomatous ileocolitis, 31.2 percent; regional enteritis, 26.8 percent; granulomatous colitis, 10.5 percent; ulcerative colitis, 7.5 percent; control group, 11.7 percent. Our findings show, however, an increased risk of cholelithiasis also in patients with Crohn's colitis or ulcerative colitis, without involvement of the ileum. Various explanations can be proposed for these differences. In the study of Baker et al., the control group was drawn from subjects who had oral cholecystograms in the same hospital because of symptoms suggesting gallbladder dysfunction; all patients were matched to controls only for age and sex. Selecting controls from symptomatic subjects may have overestimated the frequency of gallstones in this group, so diluting the association between gallstones and diseases. In our study, we used controls from the general population and furthermore we considered as confounding factors in multivariate analysis age, sex, and body mass index. Our findings confirm that there is an increased risk of gallstones in Crohn's ileitis. These patients have
794
LORUSSO, ET AL.
l i t h o g e n i c bile d u e to i n c r e a s e d biliary c h o l e s t e r o l s a t u r a t i o n , 11 w h i c h in t u r n is d u e to i n c r e a s e d fecal loss a n d s u b s e q u e n t d e c r e a s e d bile salt pool. 12 I n addition, o u r results s u g g e s t a n i n c r e a s e d risk o f gallstones also f o r patients with ulcerative colitis a n d p a r ticularly f o r patients with total ulcerative colitis. T h e capacity o f the n o r m a l c o l o n to a b s o r b bile acids 13'14 a n d also a n increase in fecal bile acid e x c r e t i o n in patients with ulcerative colitis has b e e n d e m o n s t r a t ed, 15 w h i c h c o u l d j u s t i f y these results. H o w e v e r , these f i n d i n g s a r e in c o n t r a s t with the s t u d y by Kruis et al., 16 w h o did n o t f i n d i n c r e a s e d e x c r e t i o n o f fecal bile acids in ulcerative colitis. M o r e o v e r , the biliary cholesterol s a t u r a t i o n i n d e x in patients with ulcerative colitis d o e s n o t d i f f e r f r o m t h a t o f n o r m a l subj e c t s in c o n t r a s t with t h a t f o u n d in ileal C r o h n ' s disease. 11 H o w e v e r , these last two studies did n o t rep o r t d a t a o n t h e e x t e n t o f the disease in the e x a m i n e d cases. H o l m q u i s t et al. 17 f o u n d a n i n c r e a s e d fecal bile acid e x c r e t i o n t h a t was significantly c o r r e l a t e d to the i n v o l v e m e n t o f t h e a s c e n d i n g c o l o n at e n d o s c o p y in p a t i e n t s with c o l o n i c i n f l a m m a t o r y b o w e l disease w i t h o u t ileitis. T h e r e f o r e , patients with total colitis m a y h a v e t h e s a m e d e c r e a s e d a b s o r p t i o n o f bile acids existing in distal ileitis a n d this m i g h t e x p l a i n the h i g h e s t risk o f cholelithiasis d e m o n s t r a t e d in o u r s t u d y in b o t h patients with C r o h n ' s ileitis a n d total ulcerative colitis.
References 1. Greenstein AJ, Janowitz HD, Sachar DB. The extra-intestinal complications of Crohn's disease and Ulcerative colitis: a study of 700 patients. Medicine 1976;55:401-12. 2. Christophi C, Hughes ER. Hepatobiliary disorders in inflammatory bowel disease. Surg Gynecol Obstet 1985;160:18793.
Dis.CoL&Rect. September1990
3. Mir-Madjlessi SH, Farmer RG, Sivak MV Jr. Bile duct carcinoma in patients with ulcerative colitis. Relationship to sclerosing cholangitis: report of six cases and review of the literature. Dig Dis Sci 1987;32:145-54. 4. Scholmerich J, Braun G, Volk BA, Spamer C, Hoppe-Seyler P, Gerok W. Detection of extraintestinal and intestinal abnormalities in inflammatory bowel disease by ultrasound. Dig Surg 1987;4:82-7. 5. Baker AL, Kaplan MM, Norton RA, PattersonJF. Gallstones in inflammatory bowel disease. Am J Dig Dis 1974; 19:109-12. 6. Whorwell PJ, Hawkins R, Dewbury K, Wright R. Ultrasound survey of gallstones and other hepatobiliary disorders in patients with Crohn's disease. Dig Dis Sci 1985;29:930-3. 7. Schachter H, Kirsner JB. Definitions of inflammatory bowel disease of unknown etiology. Gastroenterology 1975;68: 591-600. 8. Andersson H, Bosaeus I, Fasth S, Hellberg R, Hulten L. Cholelithiasis and urolithiasis in Crohn's disease. Scand J Gastroenterol 1987;22:253-6. 9. Cohen S, Kaplan M, Gottlieb L, PattersonJF. Liver disease and gallstones in regional enteritis. Gastroenterology 1971;60: 237--45. 10. Hill GL, Mair WSJ, Goligher JC. Gallstones after ileostomy and ileal resection. Gut 1975; 16:932-6. 11. Marks JW, Conley DR, Capretta TL, et al. Gallstone prevalence and biliary lipid composition in inflammatory bowel disease. Am J Dig Dis 1977;22:1097-1100. 12. Heaton KW, Austad WI, Lack I, Tyor MP, Enterohepatic circulation of C14-1abelled bile salts in disorders of the distal small bowel. Gastroenterology 1968;55:5-16. 13. Morris JS, Heaton KW. The fate of labelled bile salts introduced into the colon. Scand J Gastroenterol 1974;9:33-9. 14. Mekhjian HS, Sidney FP, Alan FH. Colonic absorption of unconjugated bile acids: perfusion studies in man. Dig Dis Sci 1979;24:545-50. 15. Fromm H, Thomas PJ, Hofmann AF. Sensitivity and specificity in tests of distal ileal function: prospective comparison of bile acid and vitamin B12 absorption in ileal resection patients. Gastroenterology 1973;64:1077-90. 16. Kruis W, Kalek D, Stellaard F, Paumgartner G. Altered fecal bile acid pattern in patients with inflammatory bowel disease. Digestion 1986;35:189-98. 17. Holmquist L, Anderson H, Rudic N, Ahr6en C, Fallstrom SP. Bile acid malabsorption in children and adolescents with chronic colitis. Scand J Gastroenterol 1986;21:87-92.
M.D.,* SILVANA LEO, M.D.,*
ASCANIO MOSSA,t
M.D.,
GIOVANNI MISCIAGNA, M.D.,~: V I T O GUERRA, DIPL. STAT.~
From the Department of Surge*y,* Department of Radiology,'/" and Laboratory of Epidemiology,r Scientific Institute for Digestive Diseases, "S. De Bellis," Castellana G. (Bari), Italy
Lorusso D, Leo S, Mossa A, Misciagna G, Guerra V. Cholelithiasis in inflammatory bowel disease: a case-control study. Dis Colon Rectum 1990;33:791-794. Cholelithiasis is considered an extraintestinal manifestation of Crohn's ileitis but has not been associated with ulcerative colitis. To evaluate if an increased risk of cholelithiasis exists in patients with ulcerative colitis, biliary ultrasonography was performed on 159 patients with inflammatory bowel disease, 114 patients with ulcerative colitis, and 45 patients with Crohn's disease. A control population of 2453 residents of the town near the authors' institute was also studied. An echographic survey of gallstones was performed on the control subjects, who participated in the Multicentrica Italiana Colelitiasi (MICOL). Seventeen patients with inflammatory bowel disease had gallstones (10.7 percent), 11 patients with ulcerative colitis had gallstones (9.6 percent), and 6 patients with Crohn's disease had gallstones (13.3 percent). In the control population, diagnosis of cholelithiasis was made in 239 subjects (9.7 percent). An estimate of the relative risk (odds ratio) of gallstones in ulcerative colitis and Crohn's disease and also in 4 subgroups formed on the basis of the extent of disease (total ulcerative colitis, partial ulcerative colitis, Crohn's disease with ileitis, Crohn's disease without ileitis) with respect to the general population was calculated using logistic regression with gallstones, sex, age, and body mass index as i n d e p e n d e n t variables and inflammatory bowel disease as a dependent variable. The authors' findings show an increased risk of gallstones in both patients with C r o h n ' s disease (odds ratio = 3.6; 95 percent confidence limits = 1.2-10.4; P = 0.02) and patients with ulcerative colitis (odds ratio = 2.5; 95 percent confidence limits = 1.2-5.2; P = 0.01). The risk was highest in patients with Crohn's disease involving the distal ileum (odds ratio = 4.5; 95 percent confidence limits = 1.5-14.1; P = 0.009) and in patients with total ulcerative colitis extending to the cecum (odds ratio = 3.3; 95 percent confidence limits = 1.3-8.6; P = 0.01). These results
confirm that there is an increased risk of gallstones in Crohn's ileitis but they show that there also exists an increased risk in patients with total ulcerative colitis. [Key words: Ulcerative colitis; Crohn's disease; Cholelithiasis]
INFLAMMATORY BOWEL DISEASE has been associated with several extraintestinal manifestations. 1 Those involving the extrahepatic biliary tract are sclerosing cholangitis, bile duct carcinoma, and gallstones. 2 In reports of case studies, sclerosing cholangitis and bile duct carcinoma have been associated with ulcerative colitis, ~ while cholelithiasis has been associated with Crohn's ileitis or ileocolitis but not with Crohn's colitis or ulcerative colitis. 1,4 Two controlled studies on the association of cholelithiasis and inflammatory bowel disease have been published, 5'6 and the only published study regarding ulcerative colitis used symptomatic patients undergoing cholecystography as controls. 5 This study evaluated the frequency of gallstones in patients with ulcerative colitis and Crohn's Disease by ultrasonography in comparison with controls sampled from the general population.
Materials and Methods Address reprint requests to Dr. D. Lorusso: Istituto Scientifico "S. De Bellis," Divisione di Chirurgia, Via F. Valente, 4, 70013 Castellana Grotte (Bari), Italy.
From 1984 to 1988, 159 patients with inflammatory bowel disease, 114 patients with ulcerative colitis (72
791
792
Dis. Col. & Rect. September 1990
LORUSSO, E T AL.
percent), and 45 patients with Crohn's disease (28 percent) were admitted to the Scientific Institute for Digestive Diseases for the first time. The diagnosis of ulcerative colitis and Crohn's disease was made on the basis of specific clinical, radiologic, endoscopic, and histologic criteria. ~ The mean age of patients with ulcerative colitis was 41 years (S.D. +- 15). There were 71 (62 percent) men and 43 (38 percent) women. In 107 patients the extent of the disease was evaluated by total colonoscopy with biopsies taken from the cecum to the rectum, and in the other 7 patients the extent of disease was measured by double-contrast barium enema examination because colonoscopy was partial. Fifty-seven (50 percent) patients had total colitis (extending up to the cecum) and 57 (50 percent) patients had partial colitis (17 with proctitis, 18 with proctosigmoiditis, 17 with left-sided colitis, and 5 with extended colitis up to the hepatic flexure). The mean age of patients with Crohn's disease was 39 years (S.D. -+ 15). There were 24 (53 percent) men and 21 (47 percent) women. The extent of disease was evaluated in all patients by small-bowel x-ray, and either by colonoscopy (38 cases) or by double-contrast barium enema (7 cases). Data on previous surgical operations were obtained f r o m patient hospital records. The patients with Crohn's disease were subdivided into two groups on the basis of the ileal involvement: 1) 35 (78 percent) patients with regional enteritis or Crohn's ileocolitis, including patients operated on for ileal resection (16 of 35); 2) 10 (22 percent) patients with Crohn's colitis only. All patients with inflammatory bowel disease underwent biliary echography performed by the same operator (A.M.). Diagnosis of gallstones was made when one or more structures, distinct or coalescent, intensively echolucent, which move in the lumen with the patients changing position, with or without posterior shadow, were identified in the gallbladder. Patients who resulted cholecystectomized for gallstones at time of the survey entered the group of patients with gallstones (two patients in ulcerative colitis group and two patients in Crohn's disease group). During 1984 and 1985, the same echographist performed a separate ultrasonic survey of gallstones (participating in the Multicentrica Italiana Colelitiasi). The survey comprised 2453 subjects (systematic sam-
pling of the electoral registers, 75 percent response rate), residing in the town near our Institute, with a mean age 47 years (S.D. -+ 10). Data on the prevalence of cholelithiasis in this population control group are shown in Table 1. During the survey, all subjects were questioned about inflammatory bowel disease; one subject responded positive for ulcerative colitis and was included among the cases of the study. The association (odds ratio) between inflammatory bowel disease and gallstones in the case-control study was evaluated using logistic regression to control the effect of confounding and modifying factors. The statistical package used was Epilog version 3 (Epicenter Software, Pasadena, California). Results
The percentage of cholelithiasis in all patients with ulcerative colitis and Crohn's disease and in the four subgroups formed on the basis of the extent of disease is shown in Table 2. Table 3 shows the odds ratio of gallstones in inflammatory bowel disease by logistic regression; the control group is the population of Table 1 and the confounding variables are sex, age, and body mass index. There is an increased risk of gallstones in both the ulcerative colitis and Crohn's disease groups; the risk is higher in the Crohn's disease group than in ulcerative colitis group (odds ratio = 3.6 in Crohn's disease v s . 2.5 in ulcerative colitis), but also in this latter group it is significantly higher with respect to the control population (P = 0.01). To evaluate if the extent of ulcerative colitis increased the relative risk of cholelithiasis, the odds ratio was calculated separately for patients with total ulcerative colitis and for those with partial ulcerative colitis. The patients with disease extending up to the cecum have a relative risk of gallstones that is higher than the subjects with partial ulcerative colitis (Table 4). When subdividing the patients with Crohn's disease on the basis of involvement of the distal ileum, those patients with distal ileitis (regional enteritis and ileocolitis) have a relative risk of cholelithiasis that is higher than the patients with colitis only. However, these latter patients also have an increased relative risk of gallstones (Table 4).
TABLE 1. Prevalence of Cholelithiasis in a Sample (2453 Inhabitants, 75 Percent Response Rate) of the Population of the Town Near our Institute Cholelithiasis*
Males Females TOTAL
Number
N
Percent
1422 1031 2453
96 143 239
6.8 13.9 9.7
*Subjects with gallstones o r o p e r a t e d o n for gallstones.
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TABLE 2. Prevalence of Cholelithiasis in 114 Patients with Ulcerative Colitis and 45 with Crohn's Disease Cholelithiasis
Ulcerative Colitis Total colitis Partial colitis C r o h n ' s Disease Regional enteritis a n d ileocolitis C r o h n ' s colitis
Patients N
N
Percent
114 57 57 45 35 10
11 6 5 6 5 1
9.6 10.5 8.8 13.3 14.3 10.0
TABLE 3. Odds Ratio of Cholelithiasis in Ulcerative Colitis (UC) and Crohn's Disease (CD) as Derived by Unconditional Logistic Regression
Ulcerative colitis C r o h n ' s disease
O d d s Ratio
95 P e r c e n t C o n f i d e n c e Limits O d d s Ratio
P
2.5 3.6
1.2-5.2 1.2-10.4
0.01 0.02
U n c o n d i t i o n a l logistic r e g r e s s i o n for UC: Y = 0.91 (gallstones) - 0.12 (sex) - 0.04 (age) - 0.22 (body m a s s index) + 4.35, a n d for CD: Y = 1.28 (gallstones) + 0.05 (sex) - 0.06 (age) - 0.35 (body mass index) + 6.54. TABLE 4. Odds Ratio (OR) of Cholelithiasis in Subgroups of Patients with Ulcerative Colitis and Crohn's Disease I n f l a m m a t o r y Bowel Disease Ulcerative colitis C r o h n ' s Disease
Subgroups
O R
95 P e r c e n t C o n f i d e n c e Limits
P
Total colitis Partial colitis Regional enteritis a n d ileocolitis C r o h n ' s colitis
3.3 1.9 4.5 2.5
1.3-8.6 0.7-5.4 1.5-14.1 0.2-26.9
0.01 0.17 0.009 0.44
Discussion Our findings show an increased risk of gallstones in both patients with ulcerative colitis and Crohn's disease. The risk is highest for patients with Crohn's disease involving the distal ileum (odds ratio = 4.5; 95 percent confidence limits = 1.5-14.1; P = 0.009) and then for those with total ulcerative colitis (odds ratio = 3.3; 95 percent confidence limits = 1.3-8.6; P = 0.01), but there also exists a lesser degree of risk for patients with Crohn's colitis and partial ulcerative colitis. Current opinion is that the same prevalence of cholelithiasis exists for patients with ulcerative colitis or Crohn's colitis as in the general population; it is considered to be significantly higher only in patients with Crohn s ileitis. 2 A higher incidence of gallstones in the distal ileitis has been confirmed by both case-control 6 and cohort s studies. The frequency of cholelithiasis reported in patients with Crohn's disease involving ileum ranges from 17 to 34 percent 6's-1~ and it is positively correlated with the duration and extent of disease, s There are no sound analytical epidemiologic studies to test the association between ulcerative colitis, Crohn's colitis, and gallstones. In a case series study without systematic search of gallstones, 1 the prevalence of cholelithiasis in patients with ulcerative colitis was 5 percent and it was 5 percent also in Crohn's colitis. In another case review with an ultrasound sur-
veT of gallstones in patients with ulcerative colitis, 4 the prevalence of cholelithiasis was 7.6 percent. The only case-control study on cholelithiasis and ulcerative colitis or Crohn's colitis is that of Baker et al. 5 The findings of this study correlated cholelithiasis only with Crohn's disease involving the distal ileum, and reported the following prevalence of gallstones: granulomatous ileocolitis, 31.2 percent; regional enteritis, 26.8 percent; granulomatous colitis, 10.5 percent; ulcerative colitis, 7.5 percent; control group, 11.7 percent. Our findings show, however, an increased risk of cholelithiasis also in patients with Crohn's colitis or ulcerative colitis, without involvement of the ileum. Various explanations can be proposed for these differences. In the study of Baker et al., the control group was drawn from subjects who had oral cholecystograms in the same hospital because of symptoms suggesting gallbladder dysfunction; all patients were matched to controls only for age and sex. Selecting controls from symptomatic subjects may have overestimated the frequency of gallstones in this group, so diluting the association between gallstones and diseases. In our study, we used controls from the general population and furthermore we considered as confounding factors in multivariate analysis age, sex, and body mass index. Our findings confirm that there is an increased risk of gallstones in Crohn's ileitis. These patients have
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l i t h o g e n i c bile d u e to i n c r e a s e d biliary c h o l e s t e r o l s a t u r a t i o n , 11 w h i c h in t u r n is d u e to i n c r e a s e d fecal loss a n d s u b s e q u e n t d e c r e a s e d bile salt pool. 12 I n addition, o u r results s u g g e s t a n i n c r e a s e d risk o f gallstones also f o r patients with ulcerative colitis a n d p a r ticularly f o r patients with total ulcerative colitis. T h e capacity o f the n o r m a l c o l o n to a b s o r b bile acids 13'14 a n d also a n increase in fecal bile acid e x c r e t i o n in patients with ulcerative colitis has b e e n d e m o n s t r a t ed, 15 w h i c h c o u l d j u s t i f y these results. H o w e v e r , these f i n d i n g s a r e in c o n t r a s t with the s t u d y by Kruis et al., 16 w h o did n o t f i n d i n c r e a s e d e x c r e t i o n o f fecal bile acids in ulcerative colitis. M o r e o v e r , the biliary cholesterol s a t u r a t i o n i n d e x in patients with ulcerative colitis d o e s n o t d i f f e r f r o m t h a t o f n o r m a l subj e c t s in c o n t r a s t with t h a t f o u n d in ileal C r o h n ' s disease. 11 H o w e v e r , these last two studies did n o t rep o r t d a t a o n t h e e x t e n t o f the disease in the e x a m i n e d cases. H o l m q u i s t et al. 17 f o u n d a n i n c r e a s e d fecal bile acid e x c r e t i o n t h a t was significantly c o r r e l a t e d to the i n v o l v e m e n t o f t h e a s c e n d i n g c o l o n at e n d o s c o p y in p a t i e n t s with c o l o n i c i n f l a m m a t o r y b o w e l disease w i t h o u t ileitis. T h e r e f o r e , patients with total colitis m a y h a v e t h e s a m e d e c r e a s e d a b s o r p t i o n o f bile acids existing in distal ileitis a n d this m i g h t e x p l a i n the h i g h e s t risk o f cholelithiasis d e m o n s t r a t e d in o u r s t u d y in b o t h patients with C r o h n ' s ileitis a n d total ulcerative colitis.
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