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Background and Aims: The are geographic variations in the incidence and prevalence of primary biliary cholangitis (PBC). The aim was to explore whether clinical outcomes of patients within Western Europe differ according to geographical region., Methods: Ursodeoxycholic acid-treated patients from European centers from the Global PBC database diagnosed from 1990 onwards were included. Patients with a time lag > 1 year from diagnosis to start of follow-up were excluded. Differences in baseline characteristics were studied according to North/South and East/West, whereas outcomes (transplant-free survival and decompensation) were studied with center latitude and longitude. Cox regression analyses were adjusted for age, sex, diagnosis year, biochemical markers, and cirrhosis as a time-dependent covariate., Results: One thousand eight hundred seventy-eight patients were included, and there were no geographical differences in age or sex, with a mean age of 54 years and 89% female patients. Those in North Europe were more often of a moderately advanced/advanced Rotterdam biochemical stage (28.4%) compared with South Europe (20.6%). Additionally, they exhibited higher median alkaline phosphatase (2.0 ×ULN vs. 1.4 ×ULN) and transaminases. In multivariable analysis, there was a significant interaction between center latitude and longitude for decompensation (P < 0.001) and a trend for transplant-free survival, in which the Northwestern area demonstrated an increased risk for poor outcomes as compared to the reference (Paris)., Conclusion: We describe geographic variations in outcomes for patients across Europe from specialist centers in the Global PBC Study Group. Further study is important to explore the potential individual, environmental, and healthcare-related factors that may be contributors., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

In patients with cirrhosis with severe thrombocytopenia (platelet count [PC] <50 × 10 9 /L) and undergoing invasive procedures, it is common clinical practice to increase the PC with platelet transfusions or thrombopoietin receptor agonists to reduce the risk of major periprocedural bleeding. The aim of our study was to investigate the association between native PC and perioperative bleeding in patients with cirrhosis undergoing surgical procedures for the treatment of hepatocellular carcinoma (HCC). We retrospectively evaluated 996 patients with cirrhosis between 1996 and 2018 who underwent surgical treatments of HCC by liver resection (LR) or radiofrequency ablation (RFA) without prophylactic platelet transfusions. Patients were allocated to the following three groups based on PC: high (>100 × 10 9 /L), intermediate (51-100 × 10 9 /L), and low (≤50 × 10 9 /L). PC was also analyzed as a continuous covariate on multivariable analysis. The primary endpoint was major perioperative bleeding. The overall event rate of major perioperative bleeding was 8.9% and was not found to differ significantly between the high, intermediate, and low platelet groups (8.1% vs. 10.2% vs. 10.8%, P = 0.48). On multivariable analysis, greater age, aspartate aminotransferase, lower hemoglobin, and treatment with LR (vs. RFA) were found to be significant independent predictors of major perioperative bleeding, with associations with disease etiology and year of surgery also observed. After adjusting for these factors, the association between PC and major perioperative bleeding remained nonsignificant. Conclusion: Major perioperative bleeding was not significantly associated with PC in patients with cirrhosis undergoing surgical treatment of HCC, even when their PC was <50 × 10 9 /L. With the limit of a retrospective analysis, our data do not support the recommendation of increasing PC in patients with severe thrombocytopenia in order to decrease their perioperative bleeding risk., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: Primary biliary cirrhosis (PBC), a chronic cholestatic liver disease, is frequently associated with severe hypercholesterolaemia but the clinical significance of this finding is unclear., Aims: To characterise changes in serum lipid profile over time and to assess the risk of cardiovascular disease in PBC., Subjects and Methods: We studied a cohort of 400 PBC patients for 6.2 years (range 4 months to 24 years) by serial determinations of serum lipid levels and registration of all cardiovascular events. Subjects included in an Italian prospective population based study served as controls., Results: At presentation, 76% of patients had serum cholesterol levels >5.2 mmol/l. Hyperbilirubinaemic patients had higher total cholesterol and lower high density lipoprotein (HDL) cholesterol levels (p<0.001). With time, disease progression was associated with a reduction in total (p<0.001) and HDL (p<0.05) cholesterol. The incidence of cardiovascular events was similar to that of the general population (cerebrovascular events: standardised ratio 1.4; 95% confidence interval 0.5-3.7; coronary events: 2.2; 0.9-4.3). Hypertension was associated with an increased risk of cardiovascular events (3.8; 1.6-8.9). Association with moderate hypercholesterolaemia was of borderline significance (3.8; 0.9-17) whereas severe hypercholesterolaemia was not associated with increased risk (2.4, 0.5-11)., Conclusions: In PBC, serum cholesterol levels markedly increase with worsening of cholestasis, and decrease in the late disease stages, despite a severe reduction in biliary secretion. Marked hypercholesterolaemia, typical of severe longstanding cholestasis, is not associated with an excess risk of cardiovascular disease while less advanced patients with moderate hypercholesterolaemia are exposed to an increased cardiovascular risk. Putative protective factors in PBC patients with severe hypercholesterolaemia should be assessed.

Background: Combined medical treatment may provide further benefit to primary biliary cirrhosis (PBC) patients administered ursodeoxycholic acid (UDCA)., Aim: To evaluate the long-term effects of colchicine and UDCA in symptomatic PBC patients., Patients/methods: We extended up to 10 years the double-blind treatment of 44 symptomatic PBC patients originally included in a 3-year multicentre study comparing UDCA and colchicine (U + C) versus UDCA and placebo (U + P). Outcome measures were death or liver transplantation; incidence of clinically relevant events; clinical and quantitative variables retaining prognostic information., Results: Mean follow-up was 7 +/- 3 years. One patient was lost, three withdrew because of jaundice (U + P); two patients stopped colchicine but remained on UDCA. Eleven patients (two for liver-unrelated reasons, U + P) and six patients (U + C) died, three and two patients, respectively, were transplanted (incidence rate difference, five cases per 100 patient-years; 95% CI, -1 to 11). Hepatocellular carcinoma developed in one (U + P) and four (U + C) patients (difference, -2; CI, -5 to 1), portal hypertension complications in nine patients from each group (difference, 1; CI, -5 to 6). Trends of serum bilirubin, Mayo score, antipyrine clearance were similar among treatment groups., Conclusions: In cirrhotic PBC patients, colchicine does not offer additional benefits to UDCA. In this population, UDCA does not obviate disease progression.

The clinical effectiveness of ursodeoxycholate in the treatment of liver disease may be limited by its poor absorption and extensive biotransformation. Because in vitro and in vivo studies suggest that the more hydrophilic bile acid tauroursodeoxycholate has greater beneficial effects than ursodeoxycholate, we have compared for the first time the absorption, metabolism, and clinical responses to these bile acids in patients with primary biliary cirrhosis (PBC). Twelve female patients with PBC were sequentially administered tauroursodeoxycholate and ursodeoxycholate (750 mg/d for 2 months) in a randomized, cross-over study. Bile acids were measured in serum, duodenal bile, urine, and feces by gas chromatography-mass spectrometry (GC-MS). Biliary ursodeoxycholate enrichment was higher during tauroursodeoxycholate administration (32.6% vs. 29.2% during ursodeoxycholate; P <.05). Lithocholic acid concentration was consistently higher in all biological fluids during ursodeoxycholate administration. Fecal bile acid excretion was the major route of elimination of both bile acids; ursodeoxycholate accounted for 8% and 23% of the total fecal bile acids during tauroursodeoxycholate and ursodeoxycholate administration, respectively (P <.05). Tauroursodeoxycholate was better absorbed than ursodeoxycholate, and, although it was partially deconjugated and reconjugated with glycine, it underwent reduced biotransformation to more hydrophobic metabolites. This comparative study suggests that tauroursodeoxycholate has significant advantages over ursodeoxycholate that may be of benefit for long-term therapy in PBC.

Antibody to carbonic anhydrase II, an enzyme abundantly present in biliary epithelium, has been proposed as a diagnostic marker for antimitochondrial antibody-negative PBC. In this study we determine its prevalence and clinical significance in a large series of patients with antimitochondrial antibody-positive and -negative PBC. Reactivity to carbonic anhydrase II was sought by Western immunoblotting in sera from 215 consecutive patients with PBC (26 antimitochondrial antibody-negative), 13 with autoimmune hepatitis, 25 with primary Sjögren's syndrome (pSS), 12 with systemic sclerosis, 19 with systemic lupus erythematosus and 73 healthy subjects. The prevalence of antibody to carbonic anhydrase II (titre 1:100) in PBC was 8%. No specific reactivity to carbonic anhydrase II was found in antimitochondrial antibody-negative PBC (7% versus 8% in antimitochondrial antibody-positive PBC). Ascites (P = 0.006) and Sjögren's syndrome (SS) (P = 0.022) in PBC were significantly associated with presence of the antibody. In patients with SS associated with PBC, the prevalence (19%) was similar to that observed in pSS (16%). At a serum dilution of 1:40, the prevalence of positive sera in PBC rose to 27% but disease specificity was reduced. Our findings in a large population of PBC patients rule out a relation between presence of antibody to carbonic anhydrase II and lack of antimitochondrial antibody. The higher prevalence of ascites found in positive patients warrants further evaluation.

Background: Results from animal studies and preliminary data from pilot studies in patients with primary biliary cirrhosis suggest that tauro-ursodeoxycholic acid has metabolic properties that may favour its long-term use as an alternative to ursodeoxycholic acid for patients with chronic cholestatic liver diseases. No direct comparison of tauro-ursodeoxycholic and ursodeoxycholic acids have yet been carried out in primary biliary cirrhosis., Methods: The effects of ursodeoxycholic and tauro-ursodeoxycholic acids were compared in 23 patients with primary biliary cirrhosis according to a crossover design. Both drugs were administered at the daily dose of 500 mg. in a randomly assigned sequence for two 6-month periods separated by a 3-month wash-out period., Results: Serum liver enzymes related to cholestasis and cytolysis consistently improved, as compared to baseline values, during the administration of both ursodeoxycholic and tauro-ursodeoxycholic acids, but no significant difference between these two bile acids was found. Both treatments were well tolerated and no patient complained of side effects., Conclusion: In the short-term, tauro-ursodeoxycholic acid appears to be safe and at least as effective as ursodeoxycholic acid for the treatment of primary biliary cirrhosis.

Cystic fibrosis is the most common, potentially lethal genetic defect in the Caucasian population. During recent years it has been increasingly associated with a number of hepatic and biliary abnormalities, of which chronic cholestatic liver disease is by far the most relevant. Plugging of intrahepatic bile ducts with inspissated secretions is thought to play a major role in the pathogenesis. Attempts have been made to provide uniform criteria to identify patients with early, possibly reversible, hepatic lesions, as well as to assess severity of liver disease. It has been estimated that bout 13% of cystic fibrosis patients present serum liver enzyme abnormalities, but prevalence of liver involvement is likely to be higher. Due to decreasing mortality from extrahepatic causes in cystic fibrosis and to the widespread use of laboratory tests and ultrasound examination, patients with minor degree of liver involvement will be increasingly represented in future. Oral bile acid therapy is promising, but its long-term benefits in terms of survival and prevention of major complications of liver cirrhosis remain to be established. Liver transplantation is the only potentially curative treatment for patients with advanced stage liver disease and mild pulmonary involvement.

Tauroursodeoxycholic acid, a highly hydrophilic bile acid, may be of therapeutic value for chronic cholestatic liver diseases. We performed a dose-response study on 24 patients with primary biliary cirrhosis who were randomly assigned to receive 500, 1000, or 1500 mg daily of tauroursodeoxycholic acid for six months. Biliary enrichment with ursodeoxycholic acid ranged from 15% to 48% and was not related with the dose. Serum liver enzyme levels decreased significantly after the first month of treatment with all the three doses. No significant difference among the three doses was found, although further reduction over time occurred with 1000 and 1500mg daily. Plasma total and HDL cholesterol significantly decreased in patients administered the two higher doses. Diarrhea was the only side effect. In conclusion, a dose of about 10mg/kg body wt/day of tauroursodeoxycholic acid should be used for long-term studies in patients with primary biliary cirrhosis.

A review is made of the literature regarding the present status of ursodeoxycholic acid in the treatment of primary biliary cirrhosis, focusing on the difficulties encountered in establishing the efficacy of this and any other therapy in the management of the disease. It is concluded that further studies or, at least, an updated meta-analysis including the final data emerging from the multicentre, long-term, randomised, double-blind, controlled trials currently under way are needed to establish the clinical importance of ursodeoxycholic acid as a therapeutic agent in primary biliary cirrhosis.

Background/aims: The density of total IgG-bearing cells and the distribution of their subclasses were studied in the liver of patients with primary biliary cirrhosis., Methods: Immunohistochemistry and computerized image analysis were used to compare liver specimens from 18 patients with primary biliary cirrhosis and 28 with chronic hepatitis of different etiology., Results: The density of total IgG-bearing cells was similar in the two groups. However, in patients with primary biliary cirrhosis the proportion of IgG3-positive cells was significantly higher than in patients with chronic hepatitis (53 +/- 7% vs. 7.5 +/- 2.4%) (p < 10(-8)). Conversely, IgG1-positive cells were significantly less prevalent in patients with primary biliary cirrhosis than in chronic hepatitis patients (27 +/- 6.9% vs. 68 +/- 7.2%, p < 10(-8)). Stratification of patients with primary biliary cirrhosis according to histology did not show any difference in the distribution of IgG subclasses associated with the progression of disease., Conclusion: These data suggest a pathogenetic role of local IgG3-bearing cells in primary biliary cirrhosis.

No satisfactory treatment is available for metabolic bone disease associated with primary biliary cirrhosis. On the basis of the similarities to postmenopausal osteoporosis, the rationale exists for calcitonin to be tested in clinical studies in patients with primary biliary cirrhosis-associated osteoporosis. We evaluated the effect of calcitonin on bone metabolism and mineral density in 25 women with primary biliary cirrhosis and severe osteopenia. After 6 mo of observation, patients received a synthetic calcitonin or a control treatment consisting of less than one hundredth of the recommended dose of porcine calcitonin. The two treatments were administered in sequence to each patient for two 6-mo periods, with a 3-mo washout between them, according to a crossover design. After the observation period, oral calcium supplementation was started. Bone mineral density was measured by dual-photon absorptiometry of the lumbar spine at study entry and at the beginning and the end of each treatment period. During the observation period bone mineral density fell by 3.5% whereas during the following 6 mo it increased in both the patients who received calcitonin (4.3%) and those who received the control treatment (4.9%). Conversely, after the crossover, bone mineral density decreased during both calcitonin (-2.7%) and control treatment (-2.9%). A significant difference was observed between the two periods but not between the two treatments or between the two sequences of treatment administration. In conclusion, our findings indicate that parenterally administered calcitonin for 6 mo is ineffective in halting bone loss in patients with primary biliary cirrhosis-associated metabolic bone disease, whereas calcium supplementation may have a transient beneficial effect.

To evaluate cost-effectiveness and response predictors of treatment with recombinant interferon alpha-2a in chronic non-A, non-B hepatitis, 263 consecutive patients were enrolled in a multicenter long-term study. A pre-planned analysis aimed at identifying predictors of early response was carried out when all patients had completed the initial 3 months of treatment with 6 MU thrice weekly. Sixty-three percent of the patients enrolled were classified as responders. At multivariate logistic regression analysis, baseline gamma-glutamyltranspeptidase levels and cirrhosis were the only independent variables significantly associated with response. The risk of no response after 3 months of treatment was 3.9 times higher (95% confidence interval, 1.6 to 7.2) in patients with high baseline levels of gamma-glutamyltranspeptidase as compared with patients showing low baseline levels, and it was 2.0 times higher (1.1 to 3.8) in patients with cirrhosis as compared with those without it. We expect that results from this and other studies on large patient populations may help to select those patients who are more likely to benefit from interferon administration.

Previous studies from our groups have demonstrated improvements in biochemical markers of liver function when cystic fibrosis patients with associated liver disease were administered oral ursodeoxycholic acid. The magnitude of the response was somewhat less than that found when comparable doses (10 to 15 mg/kg body wt/day) of ursodeoxycholic acid are given to other liver disease patients; this may be explained by the bile acid malabsorption that is characteristic of the disease. For this reason a dose-response study was carried out in nine cystic fibrosis patients with liver disease to establish whether improved efficacy could be obtained with higher doses. Ursodeoxycholic acid in doses of 5, 10 and 15 mg/kg body wt/day was given orally for consecutive 2-mo periods in a replicated Latin-square design. After this, all patients received 20 mg/kg body wt/day. Liver function, individual serum bile acids and biliary bile acid composition were determined at entry and at the end of each treatment period. Our data demonstrate that the magnitude of the biochemical improvement in serum liver enzymes was significantly greater with higher doses of ursodeoxycholic acid; at 20 mg/kg body wt/day it was similar to that reported for patients with other liver diseases administered lower doses. Biliary ursodeoxycholic acid enrichment increased with increasing doses, attaining 42% +/- 6% of the total biliary bile acids with the highest dose. Fasting serum ursodeoxycholic acid concentrations increased during ursodeoxycholic acid administration but were variable and correlated poorly with the dose of ursodeoxycholic acid administered, whereas no correlation was found between serum ursodeoxycholic acid concentration and the proportion of ursodeoxycholic acid in bile.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: To compare the effectiveness and safety of spontaneous ascites filtration and reinfusion and total paracentesis plus intravenous albumin infusion in cirrhotic patients with tense ascites., Design: Randomised trial of the two treatments., Setting: Teaching hospital and district general hospital in Milan., Patients: 45 consecutive cirrhotic patients with recurrent tense ascites and urinary sodium excretion rate less than 20 mmol/day. 35 fulfilled admission criteria and completed the study. 17 received spontaneous ascites filtration and 18 paracentesis plus albumin infusion., Main Outcome Measures: Body weight; urinary volume; serum and urinary electrolyte, serum fibrinogen, and plasma aldosterone concentrations; and plasma renin activity before the procedure and 24 hours and eight days afterwards., Results: Both procedures were effective in all patients. Weight decreased in both groups and showed no substantial increase after eight days. In patients receiving ascites filtration, values decreased significantly (p less than 0.01) after 24 hours for platelet count (mean relative change 0.92; 99% confidence interval 0.86 to 0.98) and serum fibrinogen concentration (0.92; 0.88 to 0.98) but returned to pretreatment values after eight days; no laboratory and clinical signs of disseminated intravascular coagulation were noted. Three patients in this group had fever, which receded spontaneously. One patient in each group had dilutional hyponatraemia., Conclusions: Spontaneous ascites filtration and reinfusion is an effective treatment for tense ascites. Reinfusion of the patient's concentrated proteins provides savings without compromising safety.

We retrospectively investigated anti-HCV prevalence in a series of 160 consecutive patients with primary biliary cirrhosis who presented between 1980 and 1989. Of these, 19 (12%) were positive for anti-HCV by C-100 ELISA. Serum IgG levels were significantly higher in anti-HCV-positive patients and correlated to optical density values. A serum sample was again collected from all the patients from the same series who were seen in 1990 for follow-up, after a median period of 32 months. Anti-HCV positivity was found to be substantially unchanged in this subgroup of patients when the freshly drawn blood samples were retested with C-100 ELISA, while it increased from 10% to 17% when second generation ELISA was used. Three of the C-100 ELISA positive samples were C-100 RIBA reactive, and six of the second generation ELISA positive samples were 4-RIBA reactive. The HCV genome was not detected in any of the seven anti-HCV C-100 ELISA and second generation ELISA positive sera which were studied by polymerase chain reaction, including four cases confirmed by 4-RIBA. Life expectancy, as determined by survival analysis, did not differ significantly between anti-HCV-positive and -negative patients. These findings suggest that anti-HCV positivity does not influence the clinical presentation and course of primary biliary cirrhosis.

Liver-cell dysplasia is a well known histological entity with preneoplastic significance in experimental hepatic carcinogenesis. However, while the association of liver-cell dysplasia with hepatitis B virus can be considered as established, it is still controversial whether this lesion represents a premalignant condition in cirrhotic patients. Efforts have been made to render its morphological assessment more reliable, but no firm conclusions can be drawn from the available clinical studies, which are mainly retrospective or based on autopsy series. Preliminary results from a prospective study argue that liver-cell dysplasia is associated with an increased risk to hepatocellular carcinoma. The emergence of liver-cell dysplasia as a preneoplastic lesion in cirrhotic patients will have some impact in the future on their management, including selection for closer monitoring in early detection of hepatocellular carcinoma and for liver transplantation.

We investigated the prevalence of anti-HCV in 160 consecutive patients with primary biliary cirrhosis. By ELISA, 19 (12%) were positive, as compared to a 68% prevalence in 135 patients with chronic non-A, non-B hepatitis. Serum IgG levels were significantly higher in the anti-HCV positive group. By RIBA, seropositivity was confirmed for 4 patients, whereas 7 were indeterminate. A slight, non-significant reduction of life expectancy was found in anti-HCV positive patients. Until reliable and independent confirmatory tests become available, definitive conclusions on the importance of anti-HCV positivity in primary biliary cirrhosis are improper.

We describe a detailed study of the effects of ursodeoxycholic acid administration on bile acid composition of the serum and bile of patients with primary biliary cirrhosis. Gas chromatography-mass spectrometry was used to analyze bile acids from 10 patients with primary biliary cirrhosis before and during ursodeoxycholic acid administration (500 mg/day, corresponding to approximately 8 mg/kg body wt), after group separation of the unconjugated and conjugated fractions by lipophilic anion exchange chromatography. These studies were directed at assessing whether the beneficial role of ursodeoxycholic acid in primary biliary cirrhosis was the consequence of a shift in the hydrophobic/hydrophilic balance of the bile acid pool and whether the hypercholeresis might result from the cholehepatic circulation of unconjugated ursodeoxycholic acid in bile. In basal conditions, the unconjugated bile acids accounted for only 5.5% and 2.5%, respectively, of the total bile acids of serum and bile; cholic acid was the major component of the conjugated fraction of serum and bile (56.0% +/- 4.0%, mean +/- S.E.M.), and ursodeoxycholic acid was present in only trace amounts. The conjugated fraction contained many unusual bile acids (representing 16.5% +/- 1.3% of total) including C25 bile acids, iso-chenodeoxycholic acid and several oxo-bile acids. After ursodeoxycholic acid administration biochemical indices of liver function all improved, but the proportions of the unconjugated bile acids in serum and bile did not significantly change.(ABSTRACT TRUNCATED AT 250 WORDS)

Ursodeoxycholic acid was administered to a patient with benign recurrent intrahepatic cholestasis to prevent cholestatic episodes. A detailed study of bile acid metabolism in this patient was carried out in the anicteric and icteric phases before and after ursodeoxycholic acid (750 mg/day) administration. Urinary, biliary and serum bile acids were measured by gas chromatography-mass spectrometry and by high-performance liquid chromatography techniques. During the anicteric phase the daily urinary excretion and serum concentrations of bile acids were within normal ranges, indicating normal hepatic uptake and secretion of bile acids during the cholestasis-free period. Only slight qualitative differences from normal individuals were observed; the relative proportions of deoxycholic acid in the bile and serum were higher, and 12-oxo-lithocholic acid was the predominant urinary bile acid. During the icteric phase a marked increase in the urinary excretion of primary bile acids and C-1, C-2, C-4 and C-6 hydroxylated metabolites was found. Serum bile acid concentrations increased before the rise in bilirubin, suggesting an acute disturbance in bile acid transport at the onset of the cholestatic attack. After ursodeoxycholic acid administration in the anicteric phase, bile became enriched with the exogenous bile acid, but little qualitative change was found in the other metabolites present in the urine, serum or bile during the anicteric or icteric phases. Prolonged administration of ursodeoxycholic acid failed to prevent recurrence of a cholestatic episode, suggesting that in benign recurrent intrahepatic cholestasis, oral ursodeoxycholic acid may be of little benefit in the treatment or prevention of cholestasis despite marked enrichment of the bile acid pool with this hydrophilic bile acid.

The effect of ursodeoxycholic acid administration on liver function tests and on bile acid metabolism was investigated in 18 patients with chronic active hepatitis. Three different doses of ursodeoxycholic acid--250 mg, 500 mg and 750 mg--were administered daily to each patient for consecutive 2-mo periods. The order of doses was randomly assigned according to a replicated Latin-square design. A significant decrease in serum transaminases and gamma-glutamyl transpeptidase occurred with the lowest dose of ursodeoxycholic acid, which corresponded to 4 mg/kg body wt/day, and no further significant decrease with the higher doses was seen. Biliary bile acid composition was determined by high-performance liquid chromatography and gas chromatography-mass spectrometry. At entry the relative proportions of major bile acids were similar to those observed in normal individuals. During treatment the mean percentage of ursodeoxycholic acid in bile (22% with the 250 mg dose, 32% with the 500 mg dose and 34% with the 750 mg dose) was lower than values previously reported for patients with gallstones and normal liver function. The major bile acids were cholic, chenodeoxycholic and deoxycholic acids. A number of unusual bile acids were identified by gas chromatography-mass spectrometry, but these accounted for only 3% to 5% of the total and did not change during ursodeoxycholic acid therapy. No correlation between the improvement in liver function tests and the percentage of ursodeoxycholic acid in bile existed. These data suggest that even a slight enrichment of bile with ursodeoxycholic acid, as is attained with 250 mg/day, is effective in improving biochemical markers of liver function in patients with chronic active hepatitis.

Hydrophobic bile acids have been shown to be hepatotoxic, whereas treatment with ursodeoxycholic acid, a hydrophilic bile acid, has improved liver function indices in patients with chronic liver disease. Taurine administration has also been suggested to be useful for chronic hepatitis, taurine-conjugated bile acids being more hydrophilic than glycine-conjugated bile acids. To determine if taurine and ursodeoxycholic acid are beneficial and if their effects are additive, a double-blind, randomized trial was designed comparing the effects of ursodeoxycholic acid, taurine, and a combination of the two on indices of liver injury in 24 patients with chronic hepatitis. They were assigned at random to two of the four following treatments: ursodeoxycholic acid (600 mg/day), taurine (1.5 g/day), ursodeoxycholic acid plus taurine (600 mg + 1.5 g/day) or placebo, given in two successive cycles of 2 mo each, according to a balanced incomplete-block design. Ursodeoxycholic acid became the predominant biliary bile acid when administered alone or in combination with taurine, and taurine conjugate levels increased during taurine administration. Ursodeoxycholic acid reduced aspartate aminotransferase (35%), alanine aminotransferase (33%), and gamma-glutamyl transpeptidase (41%), whereas taurine alone did not. The addition of taurine to ursodeoxycholic acid produced only minor changes in the effects of ursodeoxycholic acid alone. Results were confirmed by the administration of ursodeoxycholic acid, in a successive open phase of the study, to the entire patient population, which was large enough for different subsets of patients to be compared. Serum bile acids were measured at entry and during the open phase: primary bile acids did not change, whereas ursodeoxycholic acid levels increased from trace amounts to very high levels, especially in patients with more severe histological disease. It is concluded that ursodeoxycholic acid, but not taurine, improves enzymatic indices of liver injury in chronic hepatitis.

In 9 CF patients with clinical and biochemical evidence of liver disease, taurine (30 mg/kg/day) was administered one month before and during the successive treatment with ursodeoxycholic acid (10-15 mg/kg/day). Standard liver function tests were determined before and after each period of treatment. Taurine administration produced only inconsistent changes of liver function tests from baseline, whereas after the addition of ursodeoxycholic acid a substantial improvement in all abnormal indices was observed. The effects of longer period of treatment are currently investigated, with purpose of establishing their clinical impact and their relationship with changes in bile acid metabolism.

Different bile acids have different effects on liver cells, depending on the degree of hydroxylation of the bile acid and the orientation of hydroxy groups. In decreasing order of hydrophobicity, and therefore hepatotoxicity, the bile acids may be ranked as follows: lithocholic greater than deoxycholic greater than chenodeoxycholic greater than cholic greater than ursodeoxycholic acid. The rationale for the use of ursodeoxycholic acid in chronic liver disease is to increase the overall hydrophilicity of the bile acid pool, which, because of cholestasis, retains potentially hepatotoxic bile acids. Recent clinical studies have indicated that ursodeoxycholic acid improves liver function indices in patients with primary biliary cirrhosis and chronic hepatitis at doses ranging between 10 and 15 mg/kg/day. These doses would be considered in the high range in the use of ursodeoxycholic acid for gallstone dissolution. In a preliminary study we found that also lower doses were effective in primary biliary cirrhosis. Two studies to determine the optimal dose of ursodeoxycholic acid for chronic hepatitis and anicteric primary biliary cirrhosis were then carried out. Eighteen patients with primary biliary cirrhosis and 12 patients with chronic hepatitis were treated with 250, 500, and 750 mg of ursodeoxycholic acid per day for three consecutive 2-month periods. Highly significant decreases in serum enzyme levels were seen with the 250 mg/day dose, which were further improved by the higher doses. The improvement roughly paralleled the enrichment of conjugated bile acids with ursodeoxycholic acid. A separate study investigating the effect of shifting the bile acid pool composition toward less detergent moieties was also done.(ABSTRACT TRUNCATED AT 250 WORDS)