Siegfried Walker

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.

Effect of ursodeoxycholic acid on liver and bile duct disease in primary sclerosing cholangitis. A 3-year pilot study with a placebo-controlled study period.

Primary sclerosing cholangitis is a cholestatic disease of the liver characterized by progressive fibrotic inflammation and obliteration of the extra- and/or intrahepatic bile ducts. There is no effective therapy. We, therefore, studied the safety and efficacy of ursodeoxycholic acid in patients with primary sclerosing cholangitis with or without additional ulcerative colitis. In a 1-year ursodeoxycholic acid treatment period, which preceded the controlled study period, ursodeoxycholic acid was well tolerated in 22 of 24 patients with ulcerative colitis and in all three patients without ulcerative colitis. In two patients with ulcerative colitis the dose of 750 mg ursodeoxycholic acid/day led to diarrhea, but following reduction of the dose to 500 and 250 mg/day ursodeoxycholic acid was well tolerated. After 1 year of ursodeoxycholic acid treatment, 20 patients were randomly assigned to receive either ursodeoxycholic acid 750 mg/day or placebo. All of them finished a double-blind, placebo-controlled study period. During ursodeoxycholic acid treatment, the liver enzymes improved markedly. The difference in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and gamma-glutamyltransferase between the placebo and ursodeoxycholic acid group was significant (p < 0.05). Following ursodeoxycholic acid treatment, pruritus and fatigue improved in half of the patients but the difference between the placebo and ursodeoxycholic acid group was not significant. According to the ethical guidelines, after 3 months of placebo treatment, the controlled study had to be discontinued because of a more than twofold increase of serum transaminases in 8/10 patients on placebo. After the end of the controlled study, all patients were continuously treated with ursodeoxycholic acid for up to 4 years.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Analysis of bile acid glucuronides in urine: group separation on a lipophilic anion exchanger

A chromatographic separation of glucuronidated bile acids using the anion exchanger diethylaminohydroxypropyl Sephadex LH-20 (DEAP LH-20) is described. Group separation of non-sulfated, non-glucuronidated bile acids, bile acid glucuronides, bile acid monosulfates, and bile acid disulfates was obtained. The method allowed analysis of all these bile acid derivatives in the urine of 15 patients with cirrhosis of the liver and cholestasis. The patients excreted in mean 30.4 mumol/24 h non-sulfated, non-glucuronidated bile acids, 90.3 mumol bile acid monosulfates, and 10.2 mumol bile acid glucuronides. Glycine- or taurine-conjugated were 68% of the non-sulfated, non-glucuronidated bile acids, 96% of bile acid sulfates, and 81% of bile acid glucuronides.

Absorption of Urso- and Chenodeoxycholic Acid and Their Taurine and Glycine Conjugates in Rat Jejunum, Ileum, and Colon

Chenodeoxycholic acid (cheno) and ursodeoxycholic acid (urso) dissolve cholesterol gallstones in man. Comparative studies of the absorption of cheno and urso are not available. The absorption of urso and cheno and their glycine and taurine conjugates in jejunum, terminal ileum, and colon of the rat were therefore determined in an open in situ perfusion system. Absorption of unconjugated urso and cheno in jejunum, ileum, and colon was similar. In the jejunum conjugated urso and cheno were absorbed only in minimal amounts. In the ileum glycine-conjugated urso was absorbed to a lower extent than glycine-conjugated cheno (6.5 +/- 0.4 vs. 8.6 +/- 0.6 nmol/cm X h at 25 mumol/l bile acid concentration, p less than 0.05) and taurine-conjugated urso was absorbed less than taurine-conjugated cheno (6.4 +/- 0.5 vs. 8.1 +/- 0.7 nmol/cm X h, p less than 0.05). In the colon glycourso and taurourso were not absorbed, while glycocheno and taurocheno were absorbed in small amounts. The low reabsorption rates of urso conjugates in ileum and colon may contribute to the relatively low urso content in bile during urso treatment.

Hepatic Secretion of Bilirubin and Biliary Lipids in Patients with Alcoholic Cirrhosis of the Liver

In patients with cirrhosis of the liver elevated bilirubin concentrations in the plasma could be the result of decreased bilirubin excretion or an overproduction of bilirubin with insufficient excretion of the increased amounts of bilirubin. Under steady state conditions with constant serum bilirubin concentrations bilirubin synthesis equals biliary and urinary bilirubin excretion. In the present study in 10 healthy volunteers and 11 patients with alcoholic cirrhosis of the liver and serum bilirubin concentrations of 7.0 +/- 1.9 mg/dl the biliary excretion of bilirubin was studied by the intestinal perfusion method and compared with the excretion of bile lipids. Biliary excretion of bilirubin in the cirrhotics was 38.7 +/- 8.8 mumol/h, the 10 healthy controls excreted 17.9 +/- 0.9 mumol/h bilirubin. Only minor amounts of bilirubin were excreted in urine. In 4 of the 11 cirrhotics 51Cr-red blood cell half-lives were studied revealing ongoing hemolysis. Bilirubin production calculated from red cell life span was identical to biliary excretion of bilirubin with an error less than 5%. The data indicate that in patients with alcoholic cirrhosis of the liver serum concentrations of bilirubin may be elevated due to overproduction of bilirubin and a concomitant decrease of the biliary transport capacity of bilirubin.

Oral Keto Analogs of Branched-Chain Amino Acids in Hyperammonemia in Patients with Cirrhosis of the Liver

Previous uncontrolled studies indicated a positive effect of keto analogs of amino acids on plasma ammonia in patients with cirrhosis of the liver and on portal-systemic encephalopathy. In the present double-blind study the influence of keto analogs of the branched chain amino acids valine, leucine and isoleucine on plasma ammonia and encephalopathy was investigated in 12 patients with cirrhosis of the liver and surgical portal systemic shunts. In addition to the usual therapy with lactulose and protein restriction (40 g protein/day) all patients received 15.24 g keto analogs and placebo orally over 4 weeks in a crossover regimen. In contrast to uncontrolled studies, plasma ammonia, which was elevated in all patients before the beginning of the study, was not significantly changed. In addition plasma amino acids, electroencephalogram, number connection test, clinical state and laboratory tests were not influenced by the therapy with keto analogs.

Colonic Absorption of Sulfated and Nonsulfated Bile Acids in Rat

Absorption of sulfated and nonsulfated chenodeoxycholic and glycochenodeoxycholic acid was studied in the colon and the data were compared with the absorption rates in the ileum. Absorption of nonsulfated chenodeoxycholic acid in the colon was in the same range of magnitude as in the ileum. Glycochenodeoxycholic acid absorption in the colon was lower than in the terminal ileum. Sulfated bile acids were not absorbed in the colon. In the ileum, absorption of sulfated bile acids was significantly (p less than 0.01) lower than the absorption of nonsulfated bile acids. Little absorption of sulfated bile acids in the ileum and lack of absorption in the colon both contribute to the rapid turnover and excretion of bile acid sulfates.

Biliary excretion of iron in healthy man and in patients with alcoholic cirrhosis of the liver.

We measured the biliary excretion of iron in 11 patients with alcoholic cirrhosis of the liver and in 10 healthy controls using an intestinal perfusion technique. In the patients with cirrhosis increased amounts of iron in liver tissue were present. The concentrations of iron in the bile samples were determined by atomic absorption spectrometry. The biliary excretion of iron in the healthy controls was 0.32 +/- 0.09 mumol/h and in the patients with cirrhosis it was 0.45 +/- 0.14 mumol/h. The biliary excretion of iron in the patients with cirrhosis was not reduced, indicating that other mechanisms than a reduced biliary excretion of iron must be responsible for the accumulation of iron in liver tissue in alcoholic cirrhosis.

Effect of Liver Adapted Amino Acids on Portosystemic Encephalopathy in Patients with Cirrhosis of the Liver and Portosystemic Shunts

Liver adapted amino acids are defined as a mixture of amino acids with a high concentration of the branched-chain type, a low concentration of the aromatic type and methionine. In uncontrolled studies, Fischer et al. (1976), Freund et al. (1979) and Reiter et al. (1978) observed an improvement of portosystemic encephalopathy after patients suffering from cirrhosis of the liver had been treated with these amino acids. In addition, Holm et al. (1978) demonstrated that liver adapted amino acids administered intravenously were capable of shifting a negative nitrogen balance induced by protein restriction towards a positive balance.