Gerda Rudolph

Development of dominant bile duct stenoses in patients with primary sclerosing cholangitis treated with ursodeoxycholic acid: outcome after endoscopic treatment

BACKGROUND/AIMS Primary sclerosing cholangitis is characterized by progressive fibrotic inflammation and obliteration of intra- and/or extrahepatic bile ducts. METHODS In a prospective study of 106 patients treated for up to 13 years with ursodeoxycholic acid, the development of major bile duct stenoses and the efficacy of endoscopic measures have been evaluated. RESULTS Of 106 patients ten had major duct stenoses at entry, and during a median follow-up period of 5.0 years another 43 developed a dominant stenosis. Fifty-two patients with dominant stenoses were treated endoscopically by repeated balloon dilatations and five patients were temporarily stented. Complications of endoscopic procedures were pancreatitis (5.2%), bacterial cholangitis (3.3%) and bile duct perforation (0.5%). Five years after the first dilatation of a dominant stenosis the Kaplan-Meier survival rates free of liver transplantation were 100% in stage 2, 72% in stage 3 and 50% in stage 4 disease. The actuarial survival free of liver transplantation of the whole group at 3, 5 and 7 years were 0.987, 0.935 and 0.891 and the corresponding survival rates predicted with the Mayo multicenter survival model were 0.860, 0.775 and 0.737 (P<0.001). CONCLUSIONS In advanced disease, occlusion of major bile ducts with time occurs in the majority of patients. Endoscopic opening of dominant stenoses is effective and appears to be a valuable addition to the medical treatment of such patients.

Efficacy of ursodeoxycholic acid treatment and endoscopic dilation of major duct stenoses in primary sclerosing cholangitis: An 8-year prospective study

BACKGROUND/AIMS Primary sclerosing cholangitis is characterized by progressive fibrotic inflammation and obliteration of intra- and extrahepatic bile ducts. Ursodeoxycholic acid treatment leads to improvement of biochemical parameters of cholestasis and in part also of liver histology. During treatment, obstruction of major ducts may lead to deterioration of liver function, which may be prevented by endoscopic dilation of the stenoses. Controlled trials for evaluation of the beneficial effects of ursodeoxycholic acid treatment and of endoscopic measures in patients with major duct stenoses have become clinically difficult. Estimation of survival probabilities without treatment allows comparison of actuarial survival with the estimated survival probabilities. METHODS/RESULTS We studied survival in 65 patients with PSC treated with ursodeoxycholic acid (750 mg/day) and by endoscopic measures whenever necessary. Patients with decompensated cirrhosis in whom transplantation was foreseen were excluded. The study was started in May 1987 and the mean follow-up period was 45.0+/-3.5 (mean+/-SEM) months. Liver histology was performed in each of the patients before entry into the study and revealed that 21% were in stage 1, 37% in stage 2, 21% in stage 3 and 20% in stage 4. Of 65 patients, 12 had major duct stenosis at entry and another 11 developed major duct stenosis during ursodeoxycholic acid treatment, which was successfully treated by repeated endoscopic balloon dilations. The actuarial Kaplan-Meier survival probabilities without liver transplantation after treatment with ursodeoxycholic acid and dilation of major duct stenoses were significantly improved compared to the predicted survival rates with p=0.001. CONCLUSIONS Ursodeoxycholic acid does not prevent major bile duct occlusion. When ursodeoxycholic acid treatment and endoscopic opening of duct stenoses are combined, survival may be significantly improved.

Acute Effects of Ursodeoxycholic and Chenodeoxycholic Acid on the Small Intestinal Absorption of Bile Acids

The effects of ursodeoxycholic acid and chenodeoxycholic acid on the small-intestinal absorption of endogenous bile acids were studied in patients with ileostomies who served as a model to investigate small-intestinal absorption in humans. In the control period, the eight patients excreted 327 +/- 91 (mean +/- standard error of the mean) mumol/8 h cholic acid and 214 +/- 38 mumol/8 h chenodeoxycholic acid by their ileal fluid. Following ursodeoxycholic acid administration (500 mg), ileal excretion of cholic acid increased to 517 +/- 96 mumol/8 h, and that of chenodeoxycholic acid increased to 337 +/- 42 mumol/8 h, indicating decreased absorption of these bile acids. Following chenodeoxycholic acid administration (500 mg), no significant increase of cholic acid excretion was observed, whereas chenodeoxycholic acid excretion increased as expected. It is concluded that following ursodeoxycholic acid administration the absorption of common bile acids from the small intestine decreases markedly. This effect of ursodeoxycholic acid on intestinal absorption of common bile acids probably is responsible for the decrease of their plasma concentrations, the reduction of their pool sizes, the increase of their fractional turnover rates, and most likely also contributes to the increased hepatic synthesis of cholic acid.

Influence of dominant bile duct stenoses and biliary infections on outcome in primary sclerosing cholangitis

BACKGROUND/AIMS In primary sclerosing cholangitis (PSC) dominant stenoses are frequently associated with bacterial, and in part, also fungal infections of the bile ducts. In the present study, the influence of dominant stenoses and of biliary infections on the long-term outcome was studied. METHODS In a prospective study, 171 patients were followed up for 20 years. All patients were treated with ursodeoxycholic acid. Dominant stenoses were treated endoscopically and during endoscopic procedures, bile was obtained for microbiologic analysis. RESULTS Of the 171 patients, 97 had or developed major bile duct stenoses and 96/97 were treated endoscopically. In the 55/97 patients with dominant stenosis, bile samples were obtained and of these, 41/55 had bacteria, five had also Candida and 2/55 had only Candida in their bile. Survival free of liver transplantation in patients without dominant stenosis at 18 years was 73.1% and of patients with dominant stenosis was 25.0% (p=0.011). Bacteria in bile had no effect on survival whereas Candida in bile was associated with reduced survival (p=0.025). CONCLUSIONS In patients with dominant stenosis, survival free of liver transplantation is reduced. Bacteria in bile do not worsen the outcome if dominant stenoses are opened endoscopically and infection is adequately treated with antibiotics. Candida in bile is associated with a poor prognosis and these patients need liver transplantation relatively soon.

Endoscopic dilation of dominant stenoses in primary sclerosing cholangitis: outcome after long-term treatment

BACKGROUND Primary sclerosing cholangitis is characterized by progressive fibrotic inflammation and obliteration of intra- and/or extrahepatic bile ducts. Total or subtotal stenoses of major bile ducts are associated with reduced survival. OBJECTIVE To evaluate the outcome after long-term endoscopic treatment. DESIGN Prospective, single-center study. SETTING Tertiary care academic medical center. PATIENTS A total of 171 patients treated with ursodeoxycholic acid were followed for as long as 20 years. At entry, 20 patients had dominant stenoses, and during a median follow-up period of 7.1 years, dominant stenosis developed in another 77. INTERVENTIONS Ninety-six patients with dominant stenoses were treated by repeated balloon dilation; 5 patients with complete obstruction with bacterial cholangitis were stented. MAIN OUTCOME MEASUREMENTS Survival free of liver transplantation, number of procedures, complications. RESULTS In total, 500 balloon dilations were performed and 5 stents were placed. Complications were pancreatitis (2.2%), bacterial cholangitis (1.4%), and bile duct perforation (0.2%); there were no deaths. Repeated endoscopic interventions allowed the preservation of a functioning common bile duct and of at least 1 hepatic duct up to 2 cm above the bifurcation in all patients. Progression of intrahepatic bile duct and liver disease led to the need for liver transplantation in 22 of 96 patients. Five years after the first dilation of a dominant stenosis, the survival free of liver transplantation rate was 81%, and after 10 years, it was 52%. LIMITATIONS Single-center study, no control group, primary end-stage liver disease excluded. CONCLUSION Repeated endoscopic balloon dilations of dominant stenoses allow the preservation of a functioning common bile duct for many years.

Effect of high-dose ursodeoxycholic acid on its biliary enrichment in primary sclerosing cholangitis

Ursodeoxycholic acid (UDCA) has beneficial effects in cholestatic liver diseases. In primary sclerosing cholangitis (PSC), there is evidence that high doses (±20 mg/kg) of UDCA may be more effective than average doses. Biliary enrichment of UDCA at such high doses may represent the decisive factor for its beneficial effect. Up to now it is not clear how high‐dose UDCA correlates with its biliary enrichment and whether bacterial degradation of large amounts of UDCA may lead to an increased bacterial formation of more toxic hydrophobic bile acids. We determined the biliary bile acid composition in 56 patients with PSC including 30 patients with repeat bile samples treated with various doses of UDCA. At a UDCA dose of 10–13 mg/kg/d (n = 18) biliary UDCA represented 43.1% + 0.3% (mean + SD) of total bile acids; at a UDCA dose of 14–17 mg/kg (n = 14), its biliary content increased to 46.9% + 0.3%, at 18–21 mg/kg (n = 34) to 55.9% + 0.2%, at 22–25 mg/kg (n = 12) to 58.6% + 2.3%, and at 26–32 mg/kg (n = 8) to 57.7% + 0.4%. During UDCA treatment, the biliary content of all other bile acids was unchanged or decreased. In conclusion, biliary enrichment of UDCA increases with increasing dose and reaches a plateau at 22–25 mg/kg. There was no increase of toxic hydrophobic bile acids. If biliary enrichment of UDCA represents the decisive factor for its clinical effect, it seems likely that UDCA doses of up to 22–25 mg/kg may be more effective than lower doses. (HEPATOLOGY 2004;40:693–698.)

Biliary secretion of bile acids and lipids in primary sclerosing cholangitis.Influence of cholestasis and effect of ursodeoxycholic acid treatment

In patients with primary sclerosing cholangitis cholestasis is a prominent feature of the disease. We studied the effect of cholestasis and of ursodeoxycholic acid treatment on the biliary secretion of bile acids and lipids in ten patients with primary sclerosing cholangitis. Ursodeoxycholic acid treatment for 3 months led to an increase in the biliary secretion rates of total bile acids from 0.91 mmol/h to 1.47 mmol/h, mainly due to an increase in urosodeoxycholic acid, which represented 31% of biliary bile acids. With increasing cholestasis, the biliary enrichment of the bile acid pool with urosodeoxycholic acid decreased. Biliary output of endogenous bile acids on average was unchanged, but in patients with cholestasis and diminished output before treatment, it increased after ursodeoxycholic acid. Phospholipid secretion increased from 0.26 mmol/h to 0.43 mmol/h without correlation to the degree of cholestasis. Biliary cholesterol secretion on average was unchanged after ursodeoxycholic acid (0.1 versus 0.09 mmol/h) but, in patients with cholestasis and diminished output before treatment, it increased after ursodeoxycholic acid. The decreasing enrichment of the bile acid pool with ursodeoxycholic acid with increasing cholestasis may be related to its slight effect in advanced disease. The increase in biliary phospholipid secretion may represent another mechanism of action of urosodeoxycholic acid responsible for its beneficial effect in cholestatic liver disease.

In PSC with dominant bile duct stenosis, IBD is associated with an increase of carcinomas and reduced survival

BACKGROUND & AIMS In patients with primary sclerosing cholangitis (PSC) treated with ursodeoxycholic acid (UDCA), dominant stenoses are associated with reduced survival free of liver transplantation and the role of inflammatory bowel disease (IBD) in such patients is unclear. In the present study the influence of IBD on the outcome in patients with and without dominant stenosis has been evaluated. METHODS In a prospective study, 171 patients were followed for up to 20 years. All patients were treated with ursodeoxycholic acid; patients with dominant stenosis in addition were treated endoscopically. RESULTS A total of 97 out of 171 patients had or developed dominant bile duct stenoses and 96 out of 97 were treated endoscopically. In patients with dominant stenosis without IBD, no carcinoma was found whereas all six bile duct and two gallbladder carcinomas and 6/7 colo-rectal carcinomas were found in patients with dominant stenosis with IBD (p=0.012). In patients without dominant stenosis but with IBD, 1 out of 7 had colo-rectal carcinoma. In patients with dominant stenosis without IBD (n=30), actuarial survival free of liver transplantation at 18 years was 77.8% and in those with dominant stenosis and inflammatory bowel disease (n=67) it was 23.0% (p=0.045). In PSC patients without dominant stenosis and without IBD (n=21), actuarial survival free of liver transplantation at 18 years was 68.2% and in those with inflammatory bowel disease (n=53) it was 78.4% (n.s.). CONCLUSIONS In patients without dominant stenosis, IBD had no effect on the incidence of carcinomas and survival. Only patients with dominant stenosis with additional IBD had an increased carcinoma rate. This may contribute to the reduced survival free of liver transplantation in such patients.

Ileal excretion of bile acids: Comparison with biliary bile composition and effect of ursodeoxycholic acid treatment

The amount of bile acid excreted via an ileostomy at the end of the ileum should give an estimate of the amount of bile acid transported to the colon. In the present study, 8 patients with ileostomies at the end of the ileum but without disease or resection of the small intestine excreted 1690 +/- 205 mumol/day (mean +/- SEM) of bile acids from the ileostomies. In comparison with duodenal bile, cholic acid was increased at the end of the ileum and chenodeoxycholic acid decreased; in addition, bile acid sulfates were increased and bile acid glucuronides were decreased. When ursodeoxycholic acid, a bile acid that decreases biliary cholesterol saturation and dissolves gallstones, was administered at a dose of 500 mg to each subject, 59% +/- 8% (mean +/- SEM) of this bile acid was excreted within 24 h from the ileostomies. It is apparent from these studies that absorption of ursodeoxycholic acid from the small intestine is slower than previously anticipated and involves the entire small intestine and probably also the colon.

The incidence of cholangiocarcinoma in primary sclerosing cholangitis after long-time treatment with ursodeoxycholic acid.

Background/Aims Cholangiocarcinoma represents a serious complication of primary sclerosing cholangitis. Ursodeoxycholic acid may possibly influence the incidence of cholangiocarcinoma in man. The aim of this study was to evaluate the incidence rate of cholangiocarcinoma in a large group of primary sclerosing cholangitis patients after long-time treatment with ursodeoxycholic acid. Patients and methods From May 1987 up to May 2005 a total of 150 patients with primary sclerosing cholangitis but without evidence of cholangiocarcinoma at entry were included in the study. All patients were treated with ursodeoxycholic acid and controls were performed in at least yearly intervals. Results The median treatment time of the 150 patients was 6.4 years. Altogether five patients developed a cholangiocarcinoma during treatment yielding a rate of 3.3%. The patients developed 0.58 cholangiocarcinoma per 100 patient-years in years 0–2.5, 0.59 cholangiocarcinoma in years 2.5–8.5, and no cholangiocarcinoma thereafter up to 18 years after entry into the study. The Kaplan–Meier estimate of cholangiocarcinoma incidence during ursodeoxycholic acid treatment reached a plateau after 8.3 years. Summary and conclusion The annual incidence rate of cholangiocarcinoma in primary sclerosing cholangitis treated with ursodeoxycholic acid is lower than expected and decreases with time of treatment.