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Crohn's and stones.
Abstract
The American Journal of Gastroenterology is published by Nature Publishing Group (NPG) on behalf of the American College of Gastroenterology (ACG). Ranked the #1 clinical journal covering gastroenterology and hepatology*, The American Journal of Gastroenterology (AJG) provides practical and professional support for clinicians dealing with the gastroenterological disorders seen most often in patients. Published with practicing clinicians in mind, the journal aims to be easily accessible, organizing its content by topic, both online and in print. www.amjgastro.com, *2007 Journal Citation Report (Thomson Reuters, 2008)
... Gallstone disease is still one of the most common digestive diseases with an overall prevalence of 10% in the United States [22,23]. Since the pathogenesis of gallstones is not clearly understood, its analysis-using chemical and spectroscopic techniques have provided some clues [24,25]. ...
Cholelithiasis is the gallstone disease (GSD) where stones are formed in the gallbladder. The main function of the gallbladder is to concentrate bile by the absorption of water and sodium. GSD has high prevalence among elderly adults. There are three major types of gallstones found in patients, White, Black and Brown. The major chemical component of white stones is cholesterol. Black and brown stones contain different proportions of cholesterol and bilirubin. The pathogenesis of gallstones is not clearly understood. Analysis of the chemical composition of gallstones using various spectroscopic techniques offers clues to the pathogenesis of gallstones. Recent years has seen an increasing trend in the number of cases involving children. The focus of this study is on the analysis of the chemical composition of gallstones from child and adult patients using spectroscopic methods.
In this report, we present FTIR spectroscopic studies and fluorescence microscopic analysis of gallstones obtained from 67 adult and 21 child patients. The gallstones were removed during surgical operations at Soroka University Medical Center.
Our results show that black stones from adults and children are rich in bilirubin. Brown stones are composed of varying amounts of bilirubin and cholesterol. Green stones removed from an adult, which is rare, was found to be composed mainly of cholesterol. Our results also indicated that cholesterol and bilirubin could be the risk factors for gallstone formation in adults and children respectively. Fluorescence micrographs showed that the Ca-bilirubinate was present in all stones in different quantities and however, Cu-bilirubinate was present only in the mixed and black stones.
Analysis based on FTIR suggest that the composition of black and brown stones from both children and adults are similar. Various layers of the brown stone from adults differ by having varying quantities of cholesterol and calcium carbonate. Ring patterns observed mainly in the green stone using fluorescence microscopy have relevance to the mechanism of the stone formation. Our preliminary study suggests that bilirubin and cholesterol are the main risk factors of gallstone disease.
... Despite the existing knowledge of a causal relationship between IBD and gallstones, the true relative risk of this complication among IBD patients has not been well established; this could be mainly attributed to the lack of prospective well-controlled epidemiological and cohort studies as well as the inclusion, in many of the earlier studies, of selected patients not representative of the entire IBD population. 24 Indeed, for assessment of the genuine relative risk of GD in IBD, the inclusion of nonselected patients with mild to severe disease as well as the choice of a control population comprising subjects of similar age, sex, and geographical area is essential to minimize the influence of those demographic, environmental, and genetic factors that play an important role in GD formation. 25,26 The current prospective cohort study is the first to be designed to investigate the incidence of gallstones in patients with CD and UC with no gallbladder disease at enrollment as well as the clinical pattern of newly diagnosed GD in this subset of patients as compared with CD-and UC-free hospital controls; we found that the incidence of GD in CD patients was significantly higher than that observed in a control population recruited in the same geographical area; by contrast, the incidence of GD in UC patients was significantly lower and quite comparable to that observed in sex-, age-, and BMI-matched UC-free controls. ...
Unlabelled:
The risk for gallstones (GD) in inflammatory bowel diseases and the factors responsible for this complication have not been well established. We studied the incidence of GD in a cohort of Crohn's disease (CD) and ulcerative colitis (UC) patients and investigated the related risk factors. A case-controlled study was carried out. The study population included 634 inflammatory bowel disease (IBD) patients (429 CD, 205 UC) and 634 age-matched, sex-matched, and body mass index (BMI)-matched controls free of GD at enrollment, who were followed for a mean of 7.2 years (range, 5-11 years). The incidence of GD was calculated by dividing the number of events per person-years of follow-up. Multivariate analysis was used to discriminate among the impact of different variables on the risk of developing GD. The incidence rates of GD were 14.35/1,000 persons/year in CD as compared with 7.75 in matched controls (P=0.012) and 7.48/1000 persons/year in UC patients as compared with 6.06 in matched-controls (P=0.38). Ileo-colonic CD location (OR, 2.14), disease duration>15 years (OR, 4.26), >3 clinical recurrences (OR, 8.07), ileal resection>30 cm (OR, 7.03), >3 hospitalizations (OR, 20.7), multiple TPN treatments (OR, 8.07), and long hospital stay (OR, 24.8) were significantly related to GD in CD patients.
Conclusion:
Only CD patients have a significantly higher risk of developing GD than well-matched hospital controls. Site of disease at diagnosis, lifetime surgery, extent of ileal resections, number of clinical recurrences, TPN, and the frequency and duration of hospitalizations are independently associated with GD.
This study evaluates the relative value of clinical assessment and serum pancreatic enzymes in the discharge management of outpatients undergoing ERCP.
Two hundred thirty-one patients who underwent ERCP had a detailed clinical assessment performed 2 h after the procedure and blood drawn for amylase and lipase.
One-third of the patients who later developed pancreatitis had no pain 2 h after the end of the procedure, whereas an equal number who had no pancreatitis did complain of pain. Values below 276 U/L for amylase and 1000 U/L for lipase were useful in ruling out pancreatitis with negative predictive values of 0.97 and 0.98, respectively. Based on the data of this study a discharge algorithm for outpatients undergoing ERCP is proposed.
In contrast to clinical assessment, which is unreliable, it is possible to stratify patients according to their risk of developing pancreatitis according to their 2-h serum amylase and lipase values. This helps to rationalize the discharge management of outpatients undergoing ERCP at a time when careful utilization of resources, especially the avoidance of unnecessary hospital admissions, becomes increasingly more important.
Endoscopic sphincterotomy is commonly used to remove bile-duct stones and to treat other problems. We prospectively investigated risk factors for complications of this procedure and their outcomes.
We studied complications that occurred within 30 days of endoscopic biliary sphincterotomy in consecutive patients treated at 17 institutions in the United States and Canada from 1992 through 1994.
Of 2347 patients, 229 (9.8 percent) had a complication, including pancreatitis in 127 (5.4 percent) and hemorrhage in 48 (2.0 Percent). There were 55 deaths from all causes within 30 days; death was directly or indirectly related to the procedure in 10 cases. Of five significant risk factors for complications identified in a multivariate analysis, two were characteristics of the patients (suspected dysfunction of the sphincter of Oddi as an indication for the procedure and the presence of cirrhosis) and three were related to the endoscopic technique (difficulty in cannulating the bile duct achievement of access to the bile duct by "precut" sphincterotomy, and use of a combined percutaneous-endoscopic procedure). The overall risk of complications was not related to the patient's age, the number of coexisting illnesses, or the diameter of the bile duct. The rate of complications was highest when the indication for the procedure was suspected dysfunction of the sphincter of Oddi (21.7 percent) and lowest when the indication was removal of bile-duct stones within 30 days of laparoscopic cholecystectomy (4.9 percent). As compared with those who performed fewer procedures, endoscopists who performed more than one sphincterotomy per week had lower rates of all complications (8.4 percent vs. 11.1 percent, P=0.03) and severe complications (0.9 percent vs. 2.3 percent, P=0.01).
The rate of complications after endoscopic biliary sphincterotomy can vary widely in different circumstances and is primarily related to the indication for the procedure and to endoscopic technique, rather than to the age or general medical condition of the patients.
Recent anecdotal reports suggest that total parenteral nutrition may be associated with an increased incidence of both acalculous cholecystitis and cholelithiasis. The validity of this association, however, has not been tested in a large population of patients on long-term total parenteral nutrition. Therefore, we assessed the incidence of gallbladder disease among our patients 15 yr and older who had received a minimum of 3 mo of total parenteral nutrition. Of the patients meeting these criteria, 128 were on total parenteral nutrition a mean of 13.5 mo. Nineteen had gallbladder disease before receiving total parenteral nutrition, leaving 109 patients at risk. Of these patients, 25 (23%) developed gallbladder disease after the initiation of total parenteral nutrition. Because of their known propensity for cholelithiasis, 94 of our patients with ileal disorders (Crohn's disease or ileal resection, or both) were considered separately. The 40% incidence of gallbladder disease in these 94 patients was significantly higher than expected from a series of similarly defined patients with ileal disorders not receiving total parenteral nutrition (p < 0.05). We propose that the enhanced risk of gallbladder disease among patients on long-term total parenteral nutrition results from multiple factors working in concert to promote gallbladder stasis.
Objective : To determine whether prophylactic treatment with ursodeoxycholic acid can prevent gallstone formation in persons participating in a very-low-calorie weight reduction diet program. Design : Multicenter, double-blind, placebo-controlled, multidose clinical trial. Patients were treated with placebo or with 300 mg/d, 600 mg/d, or 1200 mg/d of ursodeoxycholic acid. Setting : 31 Health Management Resources weight management centers. Patients : 1004 patients were initially enrolled in a 16-week, 520-kcal/d, Health Management Resources liquid protein diet program. All patients had a body mass index of 38 kg/m 2 or more and a normal gallbladder ultrasonogram before study entry. Bile analysis was done in 32 patients. Measurements : Body weight and body mass index were measured before the diet was started and at 2-week intervals for 16 weeks. Gallbladder ultrasonography was done before enrollment and after 8 and 16 weeks of dieting. Bile was obtained by endoscopy and analyzed for cholesterol crystals and lipid levels. Results : Mean body weight for all patients at the start of dieting was 128.2 kg ± 23.2 kg ; mean initial body mass index was 44.2 kg/m 2 ± 6.0 kg/m 2 . Gallstones developed in 28% (95% Cl, 22% to 35%) of patients receiving placebo, in 8% (Cl, 5% to 13%) of patients treated with 300 mg/d of ursodeoxycholic acid, in 3% (Cl, 1% to 7%) of patients treated with 600 mg/d of ursodeoxycholic acid, and in 2% (Cl, 0.5% to 5%) of patients treated with 1200 mg/d of ursodeoxycholic acid. The differences between patients receiving placebo and patients receiving ursodeoxycholic acid were statistically significant. The percentage of ursodeoxycholic acid in bile increased stepwise with increasing doses of ursodeoxycholic acid. Conclusions : Ursodeoxycholic acid, 600 mg/d, is highly effective in preventing gallstone formation in patients having dietary-induced weight reduction.
A population of female civil servants in Rome, Italy, was investigated to determine the prevalence of symptomatic and asymptomatic gallstone disease and to define the associated factors. Field activities started in February 1981 and concluded in April 1982. Diagnosis was assessed by real time ultrasonography. Prevalence of gallstone disease increased with age from 2.5% in the 20- to 29-year-old age group to 25.0% in the 60- to 64-year-old age group, based on both presence of gallstones and history of cholecystectomy. Only one third of the women with gallstones had complained of at least one episode of biliary pain in the last five years. Frequency of "minor" dyspeptic symptoms was not different between women with and those without gallstones. In a multiple logistic function analysis, a positive association was found between age, body mass index, parity, and prevalence of gallstone disease. No association was demonstrated between the presence of gallstones or cholecystectomy and other major sex-specific factors, including age at menopause, use of oral contraceptives, and duration and frequency of menstrual cycle.
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 independent variables and inflammatory bowel disease as a dependent variable. The authors' findings show an increased risk of gallstones in both patients with Crohn'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.
To delineate relationships between biliary outputs of bile acids, phospholipids, and cholesterol, studies were carried out in 18 subjects with intact gallbladders and in six with cholecystectomy. Hepatic secretions of three biliary lipids were determined using an intestinal perfusion technique. In studies on subjects with normal gallbladders (study A), continuous infusion of liquid formula was given to stimulate gallbladder contraction, so that gallbladder storage was eliminated and duodenal outputs were equal to hepatic secretion rates. Bile acid pool size and bile lipid outputs were determined under steady-state conditions (intact EHC). Secretion rates of bile acids were then reduced by progressively withdrawing large amounts of bile from the EHC over a 12-hr period, during which biliary lipid secretions were measured continuously. In study B, six subjects without gallbladders ingested three meals of liquid formula during the day and had an overnight fast. Measurements of biliary lipid outputs were made hourly over the 24-hr period. A wide range of bile acid secretion rates occurred under these physiological conditions owing to the lowering of bile acid outputs during fasting. In both studies A and B, bile saturation with cholesterol increased as EHC became interrupted. However, the magnitude of this increase was variable from subject to subject and appeared to depend on two related factors. First, bile saturation was markedly increased in subjects who exhibited a severe reduction of bile acid output on interrupting the EHC. Second, the degree of uncoupling of cholesterol and phospholipid secretion in the lower range of bile acid outputs was also variable. When secretion of cholesterol was well-maintained in the face of decreasing bile acid and phospholipid outputs, bile became supersaturated. Subjects with high biliary cholesterol during intact EHC were especially prone to cholesterol-phospholipid dissociation. However, even at relatively low outputs of cholesterol, interruption of the EHC sometimes caused marked dissociation of secretions of cholesterol and phospholipids causing super-saturated bile at low rates of bile acid flux. Thus, the degree of coupling of cholesterol and phospholipids at low secretion of bile acids was variable from patient to patient and was a major determinant of the extent of increase in bile saturation.
Complications after endoscopic biliary sphincterotomy occur in 8% to 10% of patients when studied prospectively. It is not known whether the type of electrocautery current affects this rate. Theoretically, less edema of the ampulla after a pure cutting current sphincterotomy could decrease the risk of pancreatitis although the risk of postsphincterotomy hemorrhage might be greater.
One hundred seventy patients undergoing sphincterotomy were prospectively randomized to either a blended or pure cut current on the Valleylab electrosurgical unit. The settings were a blended three current at a power setting of 30 watts/sec for both the cut and coagulation currents or a pure cut current at a power setting of 30 watts/sec. The individual determining whether a complication occurred was blinded to the type of current used, and all patients were hospitalized for 24 hours post-procedure. Pancreatitis was defined as mild if fewer than 5 days, moderate if 5 to 14 days, and severe if more than 14 days of hospitalization were required.
Indications for sphincterotomy were choledocholithiasis in 111 patients, sphincter of Oddi dysfunction in 36 patients, stent placement in 15 patients, and miscellaneous in 8 patients. There were a total of 16 complications in 170 patients (9%); 4 (5%) were in the pure cut current group of 86 patients (one episode of bleeding that required transfusion of 4 U and three episodes of mild pancreatitis), and 12 (14%) were in the blended current group of 84 patients (7 mild, 2 moderate, and 1 severe pancreatitis; 1 case of cholangitis; and one episode of bleeding that required transfusion of 2 U). There were significantly fewer complications in the pure cut group (p < 0.05 by chi-square).
The use of pure cut current is associated with a lower incidence of pancreatitis, the most common ERCP complication, than with blended current sphincterotomy. An insufficient number of patients were studied to comment on the relative risk of hemorrhage. However, because the complication of hemorrhage is much less common than pancreatitis, pure cut current is safer overall.
Rome Group for the Epidemiology and Prevention of Cholelithiasis (GREPCO) (Dept. of Gastroenterology II and Institute of Systematic Medical Therapy, U. of Rome, 00185 Rome, Italy). Prevalence of gallstone disease in an Italian adult female population. Am J Epidemiol 1984; 119: 796–805.
A population of female civil servants in Rome, Italy, was investigated to determine the prevalence of symptomatic and asymptomatic gallstone disease and to define the associated factors. Field activities started in February 1981 and concluded in April 1982. Diagnosis was assessed by real time ultrasonog-raphy. Prevalence of gallstone disease increased with age from 2.5% in the 20-to 29-year-old age group to 25.0% in the 60- to 64-year-old age group, based on both presence of gallstones and history of cholecystectomy. Only one third of the women with gallstones had complained of at least one episode of biliary pain in the last five years. Frequency of “minor” dyspeptic symptoms was not different between women with and those without gallstones. In a multiple logistic function analysis, a positive association was found between age, body mass index, parity, and prevalence of gallstone disease. No association was demonstrated between the presence of gallstones or cholecystectomy and other major sex-specific factors, including age at menopause, use of oral contraceptives, and duration and frequency of menstrual cycle.
1. The incidence of gallstones in patients with Crohn's disease is increased compared with that in healthy control subjects. This is in part due to reduced terminal ileal bile salt absorption and consequent increased cholesterol saturation in bile. The aim of this study was to evaluate gallbladder contractility, a second important factor in the pathogenesis of gallstones, in Crohn's disease.
2. Thirty patients with Crohn's disease and no known biliary tract disease and nine healthy control subjects were studied. After an overnight fast, gallbladder volume was determined by real-time ultrasonography before and 10, 20, 30, 40, and 50 min after ingestion of a standard liquid fatty meal.
3. Compared with healthy control subjects, patients with Crohn's disease had similar fasting gallbladder volumes (control, 18.7 ± 2.3 ml; Crohn's disease, 18.2 ± 2.3 ml). Percentage emptying was significantly impaired at 30, 40 and 50 min in patients with Crohn's disease compared with control subjects. Patients with Crohn's disease limited to the small bowel had gallbladder contractility that was comparable with that of control subjects, whereas in those with large-bowel disease, minimum residual gallbladder volume was significantly smaller than in control subjects. Patients with both large- and small-bowel Crohn's disease demonstrated the most marked abnormalities, with gallbladder volumes significantly larger than those of control subjects at 30, 40 and 50 min. Likewise, patients with Crohn's disease who had undergone previous bowel resection had impaired emptying at 30, 40 and 50 min.
4. In summary, gallbladder contractility is significantly impaired in patients with Crohn's disease, an abnormality which is most marked in those patients who have undergone bowel resection or have both large- and small-bowel disease. Impaired gallbladder contractility may thus be a second factor contributing to gallstone formation in certain patients with Crohn's disease.
Acute pancreatitis may occur after the performance of endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic sphincterotomy. During ERCP and endoscopic sphincterotomy, the pancreas is subjected to many types of potential injury--mechanical, chemical, hydrostatic, enzymatic, microbiological, allergic, and thermal. These factors may act independently or in concert to induce postprocedure pancreatitis. The potential role of each etiologic factor in the development of ERCP- and endoscopic sphincterotomy-induced pancreatitis is detailed. The management of this complication is reviewed. Patient factors that increase the risk for pancreatitis and techniques to prevent or limit this complication are described. A variety of agents have been shown to prevent or treat pancreatitis in animal models, but extrapolation to humans has been almost uniformly unsuccessful. Although postprocedure pancreatitis is unlikely to be completely eliminated, careful patient selection and attention to detail may reduce the incidence of this untoward event.
Long term total parenteral nutrition (TPN) induces biliary sludge and formation of gallstones. Cholecystectomy is hazardous in these patients because of the underlying medical problems. Therefore, a randomized, double-blind controlled study was designed to test the hypothesis that daily administration of cholecystokinin-octapeptide (CCK-OP) prevents the formation of biliary sludge in humans receiving long term TPN. Adult patients receiving TPN for more than 21 consecutive days were studied. After randomization of 15 patients, the study was concluded because statistical significance was achieved. Eight patients received saline solution (placebo) intravenously and seven received CCK-OP (50 nanograms per kilogram) intravenously over a ten minute period daily. The groups were similar with respect to age, sex, diagnosis, liver function tests, amylase levels, total TPN time and time of study. All of the patients underwent weekly ultrasound studies. Volume and emptying studies of the gallbladder in response to the study drug were performed after one week. None of the patients receiving CCK-OP had sludge whereas five of eight of the patients receiving placebo had sludge (p less than 0.02). The results of emptying studies showed significant contraction of the gallbladder in those in the CCK-OP group but not in the placebo group. These data suggest that CCK-OP given intravenously daily prevents TPN induced stasis and sludge of the gallbladder. We conclude that CCK-OP should be used as routine prophylaxis against biliary sludge and formation of gallstones in patients receiving long term TPN.
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 independent variables and inflammatory bowel disease as a dependent variable. The author's findings show an increased risk of gallstones in both patients with Crohn'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.
We retrospectively reviewed 137 cases of outpatient endoscopic sphincterotomy (ES) performed over a 4-year period in a single center and compared them with an equal number of inpatient ES. The indications for ES in outpatients as compared with inpatients were, respectively: choledocholithiasis, 60% and 70%; papillary stenosis, 35% and 15% (p less than 0.001); stent insertion, 3.6% and 14% (p less than 0.01); and ampullary tumor, 1.4% and 0.7%. Complications were noted within 2 to 4 hours of ES in 6.6% of outpatients, a rate similar to that of inpatients--7.3%. Outpatients with complications were immediately admitted and stayed in the hospital for a mean of 5 days. No delayed complications were noted and no deaths occurred. Thus, a policy whereby selected individuals undergo ES as outpatients, with hospitalization reserved only for those in whom a complication develops, is reasonable and safe.
• Extracorporeal shock wave lithotripsy has received increasing attention as a possible alternative to cholecystectomy. Good data, however, are not available on what percentage of the 500 000 Americans presently undergoing cholecystectomy annually might be eligible for extracorporeal shock wave lithotripsy. Therefore, we studied 100 consecutive adult patients undergoing cholecystectomy and applied present exclusion criteria to determine their suitability for extracorporeal shock wave lithotripsy. In each patient, preoperative history and operative findings were reviewed. Gallstone size and number were recorded, and cholesterol content and radiopacity were determined. Cholesterol stones were found in 74 patients, pigment stones in 21, and acalculous cholecystitis in 5. Of the 100 patients, only 19 (19%) had no exclusion criteria and, thus, would have been eligible for extracorporeal shock wave lithotripsy. These data suggest that approximately 95 000 Americans a year will be candidates for shock wave biliary lithotripsy.
(Arch Surg. 1989;124:1195-1200)
Lipid composition of fasting duodenal bile was studied in 56 patients with nonoperated Crohn's disease, 21 normals matched for age and sex, 13 patients with cholesterol cholelithiasis, and 9 patients with ileal resections. Crohn's patients had a significantly higher mean saturation index, calculated according to Thomas (0.84 +/- 0.51) when compared to normal (0.63 +/- 0.25). Patients with ileocolonic Crohn's disease and patients with severe bile acid malabsorption, particularly, showed an increased incidence of cholesterol saturated bile. Saturation in patients with nonoperated Crohn's disease was not increased to the levels found in patients with ileal resection or cholesterol gallstones. Bile acid composition of gallbladder bile was characterized by a significant decrease of the deoxycholate fractions in patients with Crohn's ileocolitis and colitis as well as in ileal resected patients. These qualitative changes of bile acid composition may influence cholesterol solubility. It is concluded that patients with nonoperated Crohn's disease may have an increased risk of developing cholesterol gallstones.
Recent anecdotal reports suggest that total parenteral nutrition may be associated with an increased incidence of both acalculous cholecystitis and cholelithiasis. The validity of this association, however, has not been tested in a large population of patients on long-term total parenteral nutrition. Therefore, we assessed the incidence of gallbladder disease among our patients 15 yr and older who had received a minimum of 3 mo of total parenteral nutrition. Of the patients meeting these criteria, 128 were on total parenteral nutrition a mean of 13.5 mo. Nineteen had gallbladder disease before receiving total parenteral nutrition, leaving 109 patients at risk. Of these patients, 25 (23%) developed gallbladder disease after the initiation of total parenteral nutrition. Because of their known propensity for cholelithiasis, 94 of our patients with ileal disorders (Crohn's disease or ileal resection, or both) were considered separately. The 40% incidence of gallbladder disease in these 94 patients was significantly higher than expected from a series of similarly defined patients with ileal disorders not receiving total parenteral nutrition (p less than 0.05). We propose that the enhanced risk of gallbladder disease among patients on long-term total parenteral nutrition results from multiple factors working in concert to promote gallbladder stasis.
To determine whether prophylactic treatment with ursodeoxycholic acid can prevent gallstone formation in persons participating in a very-low-calorie weight reduction diet program.
Multicenter, double-blind, placebo-controlled, multidose clinical trial. Patients were treated with placebo or with 300 mg/d, 600 mg/d, or 1200 mg/d of ursodeoxycholic acid.
31 Health Management Resources weight management centers.
1004 patients were initially enrolled in a 16-week, 520-kcal/d, Health Management Resources liquid protein diet program. All patients had a body mass index of 38 kg/m2 or more and a normal gallbladder ultrasonogram before study entry. Bile analysis was done in 32 patients.
Body weight and body mass index were measured before the diet was started and at 2-week intervals for 16 weeks. Gallbladder ultrasonography was done before enrollment and after 8 and 16 weeks of dieting. Bile was obtained by endoscopy and analyzed for cholesterol crystals and lipid levels.
Mean body weight for all patients at the start of dieting was 128.2 kg +/- 23.2 kg; mean initial body mass index was 44.2 kg/m2 +/- 6.0 kg/m2. Gallstones developed in 28% (95% CI, 22% to 35%) of patients receiving placebo, in 8% (CI, 5% to 13%) of patients treated with 300 mg/d of ursodeoxycholic acid, in 3% (CI, 1% to 7%) of patients treated with 600 mg/d of ursodeoxycholic acid, and in 2% (CI, 0.5% to 5%) of patients treated with 1200 mg/d of ursodeoxycholic acid. The differences between patients receiving placebo and patients receiving ursodeoxycholic acid were statistically significant. The percentage of ursodeoxycholic acid in bile increased stepwise with increasing doses of ursodeoxycholic acid.
Ursodeoxycholic acid, 600 mg/d, is highly effective in preventing gallstone formation in patients having dietary-induced weight reduction.
In humans, the patterns of cholesterol and bile acid biodynamics in the absence of the small intestine are not yet known. They are described in two parenterally fed patients several months after total enterectomy and bile diversion.
After an intravenous pulse of [3H]cholesterol, a long-term study involved the analysis of both the decay in the specific activity of plasma cholesterol and the biliary outputs of sterols and bile acids.
Plasma cholesterol input reached 2-3 g/day (vs. 1 g/day in healthy patients), mostly from synthesis. As assessed by sterol balance, whole body cholesterol synthesis approximated 6 g/day (vs. 0.6-0.8 g/day). Unusually, about 60% of the newly synthesized cholesterol was eliminated, without prior transit into the bloodstream, from the liver into the bile. Bile acid conversion concerned over 90% (vs. 40%-50%) of the cholesterol meant to be excreted, issued from plasma or hepatic synthesis. In addition to cholic and chenodeoxycholic acids, one patient secreted up to 1 g/day of 7-epicholic acid.
The stimulation (up to 10-fold) of the cholesterol and bile acid synthesis, stronger than that observed following ileal bypass or resection or complete bile diversion, could well be partially linked to the absence of small bowel tissue per se.
It has been claimed that the prevalence of gallstone disease (GD) is unusually high in Sweden. The prevalence is not known in either men or women.
An ultrasound technique was used in a population-based screening study to identify all subjects with GD and subjects with a history of cholecystectomy. Eight hundred 40- and 60-year-old men and women were asked to participate.
Five hundred and fifty-six subjects were included, giving a response rate of 70%. The overall prevalence of GD was 15%. Women had a higher prevalence both at 40 and 60 years of age--11% and 25%, respectively--as compared with men, at 4% and 15%. Fifty per cent of subjects with GD had been cholecystectomized.
Gallstone disease is common in Stockholm, and the prevalence is equal to that of other European cities where similar studies have been performed. Subjects with GD were more often cholecystectomized than in other parts of Europe.
Many centers routinely admit patients for observation after endoscopic therapy of choledocholithiasis although this is contrary to the current mandate for cost containment. The purpose of this study was to determine the safety, success, and complication rates of outpatient therapeutic ERCP in the management of choledocholithiasis.
Over a 4-month period, 97 consecutive outpatients undergoing endoscopic treatment for choledocholithiasis were enrolled in a prospective manner. Each subject was observed 1-3 h postprocedure before discharge with follow-up at 10 days.
Successful endoscopic management of choledocholithiasis was achieved in 100% of patients. Complication rates were as follows: pancreatitis (2.1%), postsphincterotomy bleeding (3.2%), perforation (0%), and sepsis (0%). One patient required admission during the observation period, and two others with pancreatitis were readmitted within 24 h of discharge. There was no apparent adverse clinical outcome related to this policy.
Endoscopic therapy of choledocholithiasis may be performed safely on an outpatient basis, realizing significant cost savings.
An increased risk of gallstone development has been found in patients with Crohn's disease. This has been suggested to be due to abnormal bile acid metabolism. We investigated the possibility that Crohn's disease might alter gallbladder mechanical function and predispose to gallstone formation by incomplete emptying or prolonged contraction time of the gallbladder.
Seventeen patients with Crohn's disease (CD) and 20 healthy controls (CO) of similar age and sex (CD: 7 males, 31 +/- 13 years; 10 females, 30 +/- 9; CO: 10 males, 26 +/- 12; 10 females, 26 +/- 9) were compared. None of the patients or controls had gallstones. Using ultrasonography with computed volume calculation, the gallbladder was assessed in fasting state and every 10 min for 70 minutes after ingestion of a standard fatty meal.
Neither maximum volume (CD: 22 +/- 9 ml, CO: 25 +/- 15), residual volume after stimulation (CD: 3 +/- 2 ml, CO: 6 +/- 6 ml), volume decrease in % (CD: 83 +/- 5%, CO: 78 +/- 9%), nor rate constants of emptying (CD: = 0.034/min, CO: = 0.033/min) were different between patients and controls.
Abnormal gallbladder contractility does not seem to be a major cause of an increased risk of gallstone formation in Crohn's disease.
Because of possible complications, it has been common practice to admit most if not all patients undergoing therapeutic ERCP. Therefore, little descriptive data exist on the safety of outpatient therapeutic ERCP.
We assessed 262 consecutive ERCPs in 209 patients undergoing outpatient therapeutic ERCP over a 5-year period, with particular attention to the development of complications. All outpatient endoscopic sphincterotomies and stent placements performed over a 5-year period were prospectively entered into an ongoing data base that was used for the analysis. In addition, hospital and office records for all patients were retrospectively reviewed, including a 30 to 45 day follow-up in a private office setting.
Suspected or documented choledocholithiasis was the most common indication for ERCP and was present in 132 (50%), followed by malignant obstruction in 77 (29%), type I sphincter of Oddi dysfunction (on the basis of symptoms, liver test abnormalities, and bile duct dilatation) in 36 (14%), chronic pancreatitis in 10 (3.8%), HIV cholangiopathy in 4 (1.5%), and other conditions in 3 (1.1%). Overall, 181 patients (69%) underwent a sphincterotomy. The 30-day post-ERCP complication rate was 5.7% (95% CI: 3.2% to 9.3%), occurring in 15 of 262 cases. Complications necessitating hospitalization developed in 9 of the 262 ERCPs for a rate of 3.4% (95% CI: 1.6% to 6.4%). The mean duration of hospital stay among patients admitted for a complication was 2.7 +/- 1.8 days (range, 1 to 7 days). All patients were discharged without permanent sequelae. No 30-day procedure-related fatalities were reported.
In this selected series of 262 consecutive cases, endoscopic sphincterotomy and stent placement were safely performed in an ambulatory setting. Prior to recommending a generalized change in existing practice, however, this finding requires validation with larger series of cases, including the performance of other outpatient therapeutic ERCP techniques.
Patients with ileal disease, resection, or bypass are at increased risk of developing pigment gallstones, but the pathophysiological mechanisms are unknown. The aim of this study was to test the hypothesis that ileectomy induces enterohepatic cycling of bilirubin.
Ileectomy or sham operation was performed in adult male Sprague-Dawley rats with the following control procedures: no operation, ileal transection, proximal or distal jejunectomy, ileocolonic transposition, and ileocecectomy. Bilirubin and bile salt secretion rates were measured after bile duct cannulation performed 3-11 days after intestinal surgery. Also measured were bilirubin and bile salt concentrations in the colon as well as indices of hemolysis in blood.
Compared with controls, bilirubin secretion rates were increased significantly 3-5 days after ileectomy, distal jejunectomy, ileocolonic transposition, and ileocecectomy, with no hemolysis occurring. Bile salt secretion rates also increased significantly after ileectomy but decreased markedly with prevention of coprophagy, whereas bilirubin secretion rates remained elevated. By 8-11 days after surgery, intestinal adaptation normalized bile salt reabsorption, and hypersecretion of bilirubin was abolished. Colonic levels of unconjugated bilirubin and bile salts were increased fivefold and eightfold respectively in ileectomized animals, but unconjugated bilirubin levels remained normal in bile.
These results are consistent with the hypothesis that enterohepatic cycling of bilirubin occurs with bile salt malabsorption.
We evaluated the safety of outpatient therapeutic ERCP since most complications are apparent within a few hours.
We reviewed 190 patients undergoing planned outpatient therapeutic ERCP from a cohort of 409 consecutive therapeutic ERCP procedures. Patients were selected for outpatient therapeutic ERCP based on relative good health and overnight accommodation near our institution.
Outpatient therapeutic ERCPs included plastic biliary stent insertion (n = 71), biliary sphincterotomy (45), pancreatic stent insertion (28), Wallstent insertion (19), biliary balloon or catheter dilation (10), pancreatic balloon or catheter dilation (8), biliary stone extraction with prior sphincterotomy (7), pancreatic sphincterotomy (5), and duodenal ampullectomy (1). Admission was necessary in 31 (16%) because of complications in 22 (11.6%) and observation of post-ERCP symptoms in 9. Twenty-six (13%) of these patients were admitted directly from the endoscopy unit recovery room and 5 (3%) from home after a median interval of 24 hours following discharge (range 5 to 48 hours). Reasons for admission were pancreatitis in 17, hemorrhage in 3, cholangitis in 3, endoscopic but not clinical hemorrhage in 4, pain in 4, and vomiting in 1. Of the patients who were admitted from home, 3 had pancreatitis (following sphincterotomy in 1, pancreatic stenting in 1, pancreatic balloon dilation in 1) and 2 had hemorrhage (postsphincterotomy in 1 and ampullectomy in 1). In comparison, of the 219 consecutive inpatients undergoing therapeutic ERCP, 28 (13%) developed complications with 1 (0.4%) death.
A policy of selective outpatient therapeutic ERCP, with admission reserved for those with established or suspected complication, appears to be safe and reduces health care costs.
We have evaluated a new urinary trypsinogen-2 test strip, based on the principle of immunochromatography, in the diagnosis of acute pancreatitis induced by endoscopic retrograde cholangiopancreatography (ERCP).
One hundred six consecutive patients undergoing ERCP (with opacification of the pancreatic duct) at the Helsinki University Central Hospital were included in the study. Patients were tested with a urinary trypsinogen-2 test strip six hours after ERCP. Quantitative trypsinogen-2 as well as serum and urine amylase values were measured before the procedure and six hours after it.
In patients developing pancreatitis after ERCP, the median urinary trypsinogen-2 concentration six hours after the endoscopic procedure was 1780 micrograms/l (range 29-10,700 micrograms/l), and in patients without pancreatitis the median concentration was 3.6 micrograms/l (range 0.1-3390 micrograms/l; P < 0.0001). The sensitivity and specificity figures for the urinary trypsinogen-2 test strip results in diagnosing post-ERCP pancreatitis were comparable (81% and 97%, respectively) to those for serum amylase (91% and 96%) and urine amylase measurements (81% and 95%). The test strip showed a good correlation (kappa = 0.75) with the quantitative trypsinogen-2 assay.
The increase in urinary trypsinogen-2 concentration after ERCP reflects pancreatic injury, and can be detected by the test strip. Patients should be tested before the ERCP procedure as well, since elevated baseline values occur. The test is reliable and easy to perform even on an outpatient basis. However, its clinical usefulness requires evaluation in further trials.
There is a lack of multicenter prospective studies on complications of diagnostic and therapeutic endoscopic retrograde cholangiopancreatography (ERCP).
We studied 2769 consecutive patients undergoing ERCP at nine centers in the Triveneto region of Italy over a 2-year period. Six centers performed ERCP on less than 200 patients per year (small centers). General and ERCP-specific major complications were predefined. Data were collected at the time of ERCP, before discharge, and in cases of readmission within 30 days. ERCP was defined as therapeutic when endoscopic sphincterotomy (n = 1583), precut (n = 419), or drainage (n = 701) had been carried out, singularly or in combination.
One hundred eleven major complications (4.0%) were recorded: moderate-severe pancreatitis 36 (1.3%), cholangitis 24 (0.87%), hemorrhage 21 (0.76%), duodenal perforation 16 (0.58%), others 14 (0.51%). Among 942 diagnostic ERCPs there were 13 major complications (1.38%) and 2 deaths (0.21%), whereas among 1827 therapeutic ERCPs there were 98 major complications (5.4%) and 9 deaths (0.49%). The difference in the incidence of complications between diagnostic and therapeutic ERCPs was statistically significant (p < 0.0001). Small center and precut were recognized as independent risk factors for overall major complications of therapeutic ERCP, whereas the following risk factors were identified in relation to specific complications: (1) pancreatitis: age less than 70 years, pancreatic duct opacification, and nondilated common bile duct; (2) cholangitis: small center, jaundice; (3) hemorrhage: small center; and (4) retroperitoneal duodenal perforation: precut, intramural injection of contrast medium, and Billroth II gastrectomy.
Major complications are mostly associated with therapeutic procedures and low case volume. Present data support a policy of centralization of ERCP in referral centers. A more selected and safer use of precut may be expected to further limit the adverse events of ERCP.
Same-day discharge after endoscopic biliary sphincterotomy (ES) is a common clinical practice, but there have been few data to guide appropriate selection of patients. Using a prospective, multicenter database of complications, we examined outcomes after same-day discharge as it was practiced by a variety of endoscopists and evaluated the ability of a multivariate risk factor analysis to predict which patients would require readmission for complications.
A 150-variable database was prospectively collected at time of ES, before discharge and again at 30 days in consecutive patients undergoing ES at 17 centers. Complications were defined by consensus criteria and included all specific adverse events directly or indirectly related to ES requiring more than 1 night of hospitalization.
Six hundred fourteen (26%) of 2347 patients undergoing ES were discharged on the same day as the procedure, ranging from none at 6 centers to about 50% at 2 centers. After initial observation and release, readmission to the hospital for complications occurred in 35 (5.7%) of 614 same-day discharge patients (20 pancreatitis and 15 other complications, 3 severe). Of the same-day discharge patients, readmission was required for 14 (12.2%) of 115 who had at least one independently significant multivariate risk factor for overall complications (suspected sphincter of Oddi dysfunction, cirrhosis, difficult bile duct cannulation, precut sphincterotomy, or combined percutaneous-endoscopic procedure) versus 21 (4.2%) of 499 without a risk factor (odds ratio 3.1: 95% confidence interval [1.6, 6.3], p < 0.001). Of complications presenting within 24 hours after ES, only 44% presented within the first 2 hours, but 79% presented within 6 hours.
Same-day discharge is widely utilized and relatively safe but results in a significant number of readmissions for complications. For patients at higher risk of complications, as indicated by the presence of at least one of five independent predictors, observation for 6 hours or overnight may reduce the need for readmission.
Crohn's disease (CD) is associated with a high prevalence of gallstone disease but the relative risk has not been completely established. Ileal disease or resection have been considered as contributing factors to the increased risk. The aim of this study was to evaluate the prevalence of gallstone disease in a defined cohort of CD patients, to evaluate possible risk factors, and to evaluate the relative risk compared with the general population.
All inhabitants in Stockholm County born in 1933-1935 or 1953-1955, with CD diagnosed between 1955-1989 and not having had a previous cholecystectomy, were invited for an ultrasonography of the gallbladder. The prevalence of gallstone disease was related to disease extent, previous intestinal resections, age, and gender. The relative risk of developing gallstones was calculated using a recent study of gallstone disease in general, with similar age groups as controls.
We found that 26.4% had gallstone disease (relative risk [RR] = 1.8; 95% confidence interval [CI], 1.2-2.7). The number of previous intestinal resections was the only significant risk factor. There was no significant difference in gallstone disease between gender (28.2% vs 24.1%) or age (34% vs 21.8%).
Patients with Crohn's disease, regardless of gender and age, have almost a doubled risk of developing gallstone disease compared with the general population. Circumstances related to laparotomy may contribute to the increased risk. The lack of association between the disease extent and the site of previous intestinal resection, together with a previous finding of normal cholesterol saturation of the bile in patients with CD, indicate that these patients may develop pigment stones rather than cholesterol stones.
Acute pancreatitis is a common complication after endoscopic sphincterotomy (ES) and endoscopic retrograde cholangiopancreatography (ERCP). The aim of this study was to detect the time when the peak of serum amylase was predictive for pancreatitis or severe hyperamylasemia, to plan a prolonged follow-up in the hospital and for outpatients.
In a prospective series of 409 consecutive patients undergoing ES, serum amylase activity was measured immediately before the procedure and 2, 4, 8, and 24 h thereafter; the data obtained at 2, 4, and 8 h were compared with those at 24 h and with the outcome. Sensitivity for long-lasting severe hyperamylasemia (more than five times the upper normal limit) and pancreatitis were also defined for all sampling times.
At 24 h after ES, amylase was still more than five times the upper normal limit in 26 patients, 19 of whom had mild/moderate acute pancreatitis. There was a significant difference (p < 0.01 at all sampling times) between the 26 patients with 24-h severe hyperamylasemia and those with lower levels. The sensitivity of amylase measurement in detecting pancreatitis or long-lasting severe hyperamylasemia was highest at 8 h. However, the 4-h assessment appears to be a reliable predictor in practice, as more than two-thirds of cases of pancreatitis (all but one with computed tomography-confirmed pancreatitis) occurred among patients whose 4-h amylasemia was higher than five times the upper normal limit.
Serum amylase assessment 4 h after ES minimizes the likelihood of underestimating the risk of postprocedure pancreatitis. It is therefore a reliable, cost-effective follow-up, particularly in outpatients.
Patients with ileal disease, bypass, or resection are at increased risk for developing gallstones. In ileectomized rats, bilirubin secretion rates into bile are elevated, most likely caused by increased colonic bile salt levels, which solubilize unconjugated bilirubin, prevent calcium complexing, and promote its absorption and enterohepatic cycling. The hypothesis that ileal disease or resection engenders the same pathophysiology in humans was tested.
Sterile gallbladder bile samples were obtained intraoperatively from 29 patients with Crohn's disease and 19 patients with ulcerative colitis. Bilirubin, total calcium, biliary lipids, beta-glucuronidase activities, and cholesterol saturation indices in bile were measured, and markers of hemolysis and ineffective erythropoiesis in blood were assessed.
Bilirubin conjugates, unconjugated bilirubin, and total calcium levels were increased 3-10-fold in bile of patients with ileal disease and/or resection compared with patients with Crohn's colitis or ulcerative colitis. Biliary bilirubin concentrations correlated positively with the anatomic length and duration of ileal disease. Endogenous biliary beta-glucuronidase activities were comparable in all groups, and both the hemogram and serum vitamin B12 levels were normal.
This study establishes that increased bilirubin levels in bile of patients with Crohn's disease are caused by lack of functional ileum, supporting the hypothesis that enterohepatic cycling of bilirubin occurs.
Outpatient endoscopic sphincterotomy (OES) is low risk
- S Villagomez
- G Triadafilopoulos
- S A Cummings
Villagomez S, Triadafilopoulos G, Cummings SA. Outpatient
endoscopic sphincterotomy (OES) is low risk. Am J Gastroenterol 1995;90:1617A.
Gallbladder bile com-position in Crohn's disease
- Dawes Lg S Stryker
Dawes LG, Stryker S, Rege RV, et al. Gallbladder bile com-position in Crohn's disease. Surg Forum 1991;42:188 –9.
Enterohepatic cycling of bilirubin in patients with ileal Crohn's disease: A patho-physiological mechanism for pigment gallstone disease
- Ma Brink
- Slors
- Carey Jrm
- Mc
Brink MA, Slors JRM, Carey MC, et al. Enterohepatic cycling of bilirubin in patients with ileal Crohn's disease: A patho-physiological mechanism for pigment gallstone disease. Gas-troenterology 1996;110:A1159 (abstract).
Same-day dis-charge after endoscopic biliary sphincterotomy (ES): A pro-spective multicenter study
- Freeman Ml Nelson
- Db
- S Sherman
Freeman ML, Nelson DB, Sherman S, et al. Same-day dis-charge after endoscopic biliary sphincterotomy (ES): A pro-spective multicenter study. Am J Gastroenterol 1996;91: 1933A.
TNF-in Chronic Hepatitis C: The Smoking Gun? Infection with the hepatitis C virus (HCV) is a major cause of chronic liver disease in the United States and throughout the world. The major modes of transmission are parenteral, via transfusion (before 1992) and intravenous drug abuse
- M D Afdhal
Reprint requests and correspondence: Nezam H. Afdhal, M.D.,
F.R.C.P.I., Evans 201, Boston Medical Center, 88 East Newton
Street, Boston, MA 02118.
Received Jan. 12, 1999; accepted Jan. 19, 1999.
TNF-in Chronic Hepatitis C:
The Smoking Gun?
Infection with the hepatitis C virus (HCV) is a major cause
of chronic liver disease in the United States and throughout
the world. The major modes of transmission are parenteral,
via transfusion (before 1992) and intravenous drug abuse. In
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Editorials
AJG – Vol. 94, No. 5, 1999
Rome Group for Epidemiology and Prevention of Cholelithiasis (GREPCO)
Rome Group for Epidemiology and Prevention of Cholelithiasis (GREPCO). Prevalence of gallstone disease in an Italian
adult female population. Am J Epidemiol 1984;119:796 -805.
Gallbladder bile composition in Crohn's disease
- L G Dawes
- S Stryker
- R V Rege
Dawes LG, Stryker S, Rege RV, et al. Gallbladder bile composition in Crohn's disease. Surg Forum 1991;42:188 -9.
- Murray FE