Changes in serum and hepatic levels of immunoreactive prolyl hydroxylase in two models of hepatic fibrosis in rats

Changes in serum and hepatic levels of immunoreactive prolyl hydroxylase (IRPH) as well as cellular localization of the enzyme were studied in 2 models of hepatic fibrosis, which was induced in male rats either by subcutaneous administration of CCl4 (Group A) or by intraperitoneal injection of porcine serum (Group B). Hepatic fibrosis appeared at the 8th week in Group A and at the 12th week in Group B, and liver cirrhosis developed at the 16th week in both models. Although tissue contents of hydroxyproline (HP) and IRPH increased in both models, only HP levels correlated with the degree of fibrosis. Serum IRPH levels and serum asparate aminotransferase (AST) activities increased, showing a significant positive correlation, in group A, whereas both remained in a control range in Group B. Moreover, in another model which received a single intraperitoneal injection of CCl4, serum IRPH showed a marked increase and then a rapid decrease in parallel with the change in serum AST. Immunohistochemical analysis also showed a difference between the two fibrosis models: in group A, IRPH was positive mainly in parenchymal cells in the peripheral zone of the pseudolobulus, while in group B the staining was diffuse. These results indicate that the elevation of serum IRPH is, at least in part, due to the parenchymal cell damage, and that IRPH levels should be carefully evaluated when being used as a parameter to estimate the activity of fibrogenesis in the liver.     

Hepatic copper in primary biliary cirrhosis: biliary excretion and response to penicillamine treatment.

Excessive hepatic copper accumulation occurs in long-lasting cholestatic liver disorders especially in primary biliary cirrhosis. As in Wilson's disease, penicillamine has recently been introduced for the treatment of primary biliary cirrhosis. In Wilson's disease there is decreased biliary excretion of copper. The present study shows that as compared with controls the biliary excretion of copper is not decreased in primary biliary cirrhosis; instead it may be increased in some patients. However, when compared with high hepatic copper concentration biliary copper excretion was low. In contrast with copper, biliary secretion of bile acids was decreased in eight of the 17 patients. Treatment with oral penicillamine (600 mg/day) for one year resulted in a significant decrease of hepatic copper concentration, but had no consistent effect on the biliary excretion of copper or on the amount of histologically stainable orcein-positive copper-binding protein. The results suggest that excessive hepatic copper accumulation in primary biliary cirrhosis may not be primarily caused by a decreased biliary excretion, or that a new equilibrium is achieved in advanced primary biliary cirrhosis. D-penicillamine appears to improve significantly the biliary excretion of bile acids.     

Low therapeutic value of D-penicillamine in a short-term prospective trial in primary biliary cirrhosis

A small double-blind controlled trial to evaluate the short-term effects of D-penicillamine therapy was carried out in 24 patients with primary biliary cirrhosis (PBC). The daily dose of D-penicillamine was increased monthly by 250 mg until a total of 1 g daily was reached. Two out of 11 patients (18%) were withdrawn because of side-effects, as also were 4 out of 13 (31%) patients receiving the placebo. Transient improvement in symptoms was observed in 4 of 11 patients on D-penicillamine, but also in 5 of 13 patients from the placebo group. The proportion of patients showing a fall in serum IgM, IgG and hepatic copper was significantly larger for the D-penicillamine group than for the placebo group. No improvement in liver tests was observed, but the progression of inflammatory periportal liver cell destruction (piecemeal necrosis) was retarded in patients on D-penicillamine (p = 0.02). Data analysis within the D-penicillamine group showed that lowering the dose of D-penicillamine to 500 mg daily abolished the effect on the serum immunoglobulins and hepatic copper. The beneficial effect of D-penicillamine therapy appears to be small and dose-related; side effects should not prevent its use, provided the drug is introduced slowly.     

Pathologic analysis of liver transplantation for primary biliary cirrhosis

A retrospective histopathologic review of all pathologic specimens from 394 adult liver transplant patients was undertaken with clinical correlation to determine if primary biliary cirrhosis has affected the posttransplant course compared to all other indications for liver transplantation and if recurrent primary biliary cirrhosis has occurred after liver transplantation. We also compared the histopathologic features seen in native livers with primary biliary cirrhosis to failed allografts with chronic rejection. One hundred six of the 394 adult patients transplanted during this time (1981 to July, 1986) fulfilled clinicopathologic criteria for a diagnosis of primary biliary cirrhosis. Neither the incidence nor any qualitative pathologic feature of histologically documented acute cellular rejection differentiated subjects transplanted for primary biliary cirrhosis vs. other diseases. No correlation between the titers of antimitochondrial antibody and the presence of posttransplant hepatic dysfunction based on liver enzyme profiles or the development of chronic rejection was seen in patients transplanted for primary biliary cirrhosis. Minor differences noted in the posttransplant course of primary biliary cirrhosis patients as compared to other conditions (higher incidence of chronic rejection as a cause of graft failure) was seen, but this did not significantly affect graft or patient survival. Recurrent primary biliary cirrhosis could not be diagnosed with certainty in any patient. A comparison of failed chronically rejected allografts vs. native hepatectomies obtained from patients with primary biliary cirrhosis revealed the presence of chronic obliterative vasculopathy, centrilobular cholestasis, and lack of granulomas, cirrhosis, cholangiolar proliferation, copper-associated protein deposition and Mallory's hyalin in specimens with chronic rejection.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum lysyl oxidase activity in chronic liver disease in comparison with serum levels of prolyl hydroxylase and laminin.

Lysyl oxidase was partially purified from serum by a diethylaminoethyl batch procedure in the presence of 6 mol/L urea and dialyzed against 3 mol/L KSCN. Using this method, we determined serum lysyl oxidase activity in 52 patients with liver disease and in 14 healthy controls, and we examined usefulness of serum lysyl oxidase in assessing liver fibrogenesis. For this purpose, serum lysyl oxidase activity in chronic liver disease was compared with serum levels of prolyl hydroxylase and laminin P1. As compared with controls, serum lysyl oxidase activity increased 1.6-fold in chronic persistent hepatitis, 4.4-fold in chronic active hepatitis and 11.8-fold in cirrhosis, indicating an increase in concert with the development of liver fibrosis. In hepatocellular carcinoma, the serum activity, although significantly increased, was lower than that in cirrhosis. Serum prolyl hydroxylase was significantly increased in chronic active hepatitis, in liver cirrhosis and in hepatocellular carcinoma. Serum laminin P1 was significantly increased in chronic active hepatitis, in cirrhosis and in hepatocellular carcinoma. Serum lysyl oxidase activity did not correlate significantly with serum levels of prolyl hydroxylase and laminin P1 in any subject or in any subgroup. The magnitude of the increase and the abnormal percentage of serum lysyl oxidase activity were larger than those for serum prolyl hydroxylase and laminin P1. These results suggest that serum lysyl oxidase activity is a more sensitive indicator of liver fibrosis than serum prolyl hydroxylase and laminin P1.     

A prospective clinical trial of D-penicillamine in the treatment of primary biliary cirrhosis

We conducted a prospective clinical trial to assess the relative efficacy and safety of high- vs. low-dose D-penicillamine in patients with primary biliary cirrhosis. Following clinical tests and liver biopsy diagnostic of primary biliary cirrhosis, 56 patients were randomized to receive either 250 or 750 mg D-penicillamine daily. Patients were monitored with clinical tests and annual liver biopsy. Randomization produced two groups without differences in demographic, clinical or histologic characteristics. During the trial, no differences were seen between the mean change in liver test results in patients in either treatment group. The 11% per year rise of bilirubin in the 750 mg dose group during the first 3 years was not significantly different from the 18% per year rise in the 250 mg dose group. No patient showed improvement on liver biopsy although patients on 750 mg D-penicillamine deteriorated more slowly. Side effects, particularly rash and dysgeusia, were more common in the 750 mg dose group. The frequency and severity of side effects were responsible for the early conclusion of our trial. Twenty-six patients experienced side effects necessitating discontinuation of D-penicillamine. No evidence of increased efficacy was demonstrated by high-dose D-penicillamine therapy, and side effects were observed in patients on 250 mg D-penicillamine daily. With the severity of adverse effects and continued progression of disease, D-penicillamine is not a clinically useful therapy in primary biliary cirrhosis.     

HLA-DR antigens in primary biliary cirrhosis: lack of association.

A study of HLA-DR antigen in 75 patients with primary biliary cirrhosis has been carried out in order to test the hypothesis that genetic factors related to genes controlling immune responses might be important in the pathogenesis of primary biliary cirrhosis. The frequencies of HLA-DR locus antigens was not significantly different from those in 200 normal controls, nor were those of tissue antigens on the A and B loci. No HLA-DR antigen was significantly associated with the appearance of granulomata on liver biopsy (possibly good prognosis) or with raised serum bilirubin (possibly bad prognosis); nor was there any association between any HLA-DR antigen and adverse reactions to D-penicillamine treatment in 17 patients with such adverse reactions. It is concluded that genetic traits related to HLA antigens studied are probably not important in the aetiology of the disease.     

Clinical significance of hepatic iron deposition and serum iron values in patients with chronic hepatitis C infection

OBJECTIVES: To assess the potential association between hepatic iron deposition or serum iron values and hepatic fibrosis and inflammatory activity in patients with chronic hepatitis C virus infection. METHODS: In 100 consecutive patients with hepatitis C virus infection, tissue iron deposition was assessed by quantifying iron stain on liver biopsy specimens. Serum iron, ferritin, and transferrin saturation were determined by standard laboratory procedures. Statistical analyses incorporated potential confounders associated with hepatic fibrosis. RESULTS: Twenty-one patients had no fibrosis (stage 0), 13 had portal fibrosis (stage 1), 31 had periportal fibrosis (stage II), 10 had bridging fibrosis (stage III), and 25 had cirrhosis (stage IV). Positive iron stain found in liver biopsy specimens of 19 patients was associated with stage III or IV fibrosis (p = 0.004). No significant difference was found between the iron concentration or the hepatic iron index in patients with stage III or IV fibrosis compared with patients with stage I or II fibrosis. At least 1 of 3 serum iron values assessed was abnormal in 55 patients. In univariate analysis, elevated serum iron (p = 0.01), serum ferritin (p < 0.001), and transferrin saturation (p = 0.002) were associated with stage III or IV fibrosis. In multivariate analysis, the only independent predictive factor of severe hepatic fibrosis was serum ferritin (p < 0.02; odds ratio = 11.35). The serum ferritin value and tissue iron stain had a significant positive correlation (p < 0.001). CONCLUSIONS: Increased hepatic iron deposition may be associated with more advanced hepatic fibrosis in patients with chronic hepatitis C virus infection. The serum ferritin value, an independent predictor of severe hepatic fibrosis in patients with chronic hepatitis C virus infection, may predict hepatic iron deposition and severity of fibrosis.     

Hepatic prolyl hydroxylase and collagen synthesis in patients with alcoholic liver disease

Hepatic prolyl hydroxylase activity and collagen synthesis were measured in patients with alcoholic liver disease to determine the feasibility of using the enzyme prolyl hydroxylase as a marker of hepatic fibrogenesis. Alcoholic patients with liver histopathology consistent with normal, steatosis, alcoholic hepatitis, early cirrhosis, or advanced cirrhosis were analysed for liver prolyl hydroxylase activity and in vitro collagen synthesis. Prolyl hydroxylase activity and the rate of in vitro collagen synthesis were correlated when these parameters were measured in samples of the same liver biopsy. Mean prolyl hydroxylase activity was significantly raised in all groups of alcoholic patients with alcoholic liver disease, except those with steatosis, when compared with alcoholic patients with normal morphology. Alcoholic patients with early cirrhosis had enzyme activity (mean ± SE: 1·367 ±0·162 mU/mg protein) significantly raised over all other groups. Mean enzyme activity was less raised (0·985 ± 0·097 mU/mg protein) in patients with advanced cirrhosis. The percentage of collagen synthesis in patients with early or advanced cirrhosis was also raised compared with alcoholic patients with normal morphology. Prolyl hydroxylase activity and the rate of collagen synthesis are significantly correlated (r=0·62). These findings suggest that hepatic prolyl hydroxylase activity is a useful indicator of hepatic fibrogenesis and its measurement on available liver biopsy tissue should be a potent diagnostic tool reflecting active fibrogenesis and predicting progression of alcoholic liverdisease.     

Markers of collagen and basement membrane metabolism in sera of patients with progressive systemic sclerosis.

The concentrations of the amino terminal propeptide of type III procollagen, the 7S domain of type IV collagen, and the fragment P1 of laminin (PIIINP, 7S, and P1 respectively) and the activity of galactosylhydroxylysyl glucosyltransferase (GGT) in serum were evaluated as indicators of disease activity in a cross sectional study of 84 patients with progressive systemic sclerosis. The mean values of PIIINP, P1, and GGT were raised in progressive systemic sclerosis, 19-32% of patients having abnormal values of the various tests. PIIINP, measured with two different assays, and P1 were associated with active, acute, or subacute disease. GGT also correlated positively with some acute phase proteins in the whole group, without a clear association with the course of the disease. Arthritis was associated with increased PIIINP concentrations as well as with an increased activity of GGT. Kidney disease led to raised concentrations of the degradation products of PIIINP. Raynaud's phenomenon in the hands was related to increased PIIINP concentrations.     

Diagnostic Value of Serum γ-Glutamyl-Transferase Activity and Mean Corpuscular Volume in Alcoholic Patients with or without Cirrhosis

In an attempt to assess the diagnostic values of serum gamma-glutamyltransferase (GGT) and mean corpuscular volume (MCV) variations as markers of liver disease and of abstinence in alcoholic patients, we compared 174 patients with alcoholic cirrhosis, 175 with noncirrhotic alcoholic liver disease and 67 patients with nonalcoholic cirrhosis. GGT and MCV values were checked three times, the day of admission, 7 days later, and on the last sample available during follow-up (1 to 12 months), and were compared according to the liver disease and abstinence. A decrease of GGT activity during the 1st week of hospitalization was noted in alcoholics with (-9 IU/liter) or without (-13 IU/liter) cirrhosis and not in nonalcoholic cirrhosis (+8 IU/liter), without MCV variations. During follow-up, median GGT activity was strikingly different in abstinent patients with (27 IU/liter) or without (21 IU/liter) cirrhosis and in nonabstinent patients (99 IU/liter and 123 IU/liter, respectively) (p less than 0.001). MCV decrease was noted in alcoholics whatever their abstinence or not, contrasting with the absence of decrease in nonalcoholic patients. For the diagnosis of alcoholism in cirrhotic patients, the positive predictive value (PPV) of a GGT or a MCV decrease during the 1st week of hospitalization was 0.82 and 0.78, respectively, and the negative predictive value (NPV) was 0.33 and 0.70, respectively. For abstinence during follow-up, the PPV of a GGT activity less than 50 IU/liter was 0.92 and the NPV was 0.65.(ABSTRACT TRUNCATED AT 250 WORDS)     

Detection of male DNA in the liver of female patients with primary biliary cirrhosis

BACKGROUND/AIMS: Primary biliary cirrhosis is a chronic cholestatic liver disease characterized by progressive inflammatory destruction of bile ducts, with eventual hepatic fibrosis and cirrhosis. Since primary biliary cirrhosis affects predominantly middle-aged women and has pathological similarities to hepatic graft-versus-host-disease, we investigated whether fetal cell microchimerism might be involved in the development of this disease. METHODS: The presence of Y-chromosome-specific sequences was analyzed by polymerase chain reaction using peripheral blood mononuclear cells from women with primary biliary cirrhosis (n=18) and healthy (control) women (n=18), and by in situ hybridization of liver biopsy sections from women with primary biliary cirrhosis (n=19) and women with chronic hepatitis C or alcoholic liver disease (n=20). RESULTS: Male cells were detected in liver biopsy specimens of 8 of 19 patients (42%) with primary biliary cirrhosis. Y-chromosome-containing cells were not seen in any of the liver biopsy specimens from women with chronic hepatitis C or alcoholic liver disease. Male cells were detected in peripheral blood mononuclear cells from one healthy control at a level of 1 male cell per 10(6) female cells, but were not detected in peripheral blood mononuclear cells of women with primary biliary cirrhosis. CONCLUSIONS: The presence of male cells in the liver of women with primary biliary cirrhosis raises the possibility that fetal cell microchimerism may be involved in the pathogenesis of this chronic liver disease.     

The serum concentrations of the aminoterminal propeptide of procollagen type III and the hepatic content of mRNA for the alpha 1 chain of procollagen type III in carbon tetrachloride-induced rat liver fibrogenesis.

Serum concentrations of the aminoterminal propeptide of procollagen type III (PIIIP) are elevated in fibrogenic diseases of the liver, but the mechanism of elevation is not fully understood. To investigate the mechanism, we compared serum concentrations of PIIIP with total liver content of mRNA for the pro alpha 1 (III) chain, in rats with carbon tetrachloride (CCl4)-induced liver fibrosis. Adult male rats received CCl4 in mineral oil twice weekly for 8 weeks and were compared with age-matched controls. Serum concentrations of PIIIP were measured by a specific radioimmunoassay; molecular sizes of PIIIP in serum were also determined. Pro alpha 1 (III) mRNA content in the liver was quantitated by RNA slot-blot hybridization and chemical measurement of total hepatic RNA content. Total collagen content of the liver was estimated by hydroxyproline measurement. All CCl4-treated animals had septal fibrosis after 4 weeks, and evidence of cirrhosis (regenerative nodules, ascites) was seen after 7 weeks of treatment. Serum concentrations of PIIIP and pro alpha 1 (III) mRNA content in the liver were correlated well until cirrhosis has established. They increased simultaneously after 3 weeks of treatment, 1 week before any elevation of hepatic hydroxyproline could be detected. After cirrhosis has established, pro alpha 1 (III) mRNA content in the liver decreased markedly, but serum PIIIP levels continued to be elevated. Hepatic hydroxyproline plateaued after 5 weeks. The molecular sizes of serum PIIIP indicate the release of intact native procollagen peptide during the development of cirrhosis. In conclusion, at least in CCl4-induced liver fibrosis in the rats, serum PIIIP levels can be used as a fibrogenic marker for the period progressing to cirrhosis. But the use of the serum PIIIP levels in cirrhosis seems to be limited by factors other than liver fibrogenesis.     

Clinical and statistical analyses of new and evolving therapies for primary biliary cirrhosis

Primary biliary cirrhosis is a chronic, progressive, cholestatic liver disease thought to be related to abnormalities in immune regulation. The disease is associated with granulomatous bile duct destruction, cholestasis, hepatic copper overloading and the development of hepatic fibrosis or cirrhosis or both. There have been numerous therapeutic trials evaluating immunosuppressive, antifibrotic and cupruretic agents. Prednisolone, D-penicillamine, azathioprine, colchicine and chlorambucil have been evaluated in controlled clinical trials, and biochemical improvement of liver function has been noted with all of the agents, except D-penicillamine. Improved survival has also been reported in patients treated long-term with azathioprine and colchicine. However, none of the therapeutic agents has been demonstrated to halt histologic progression of the disease or to induce a complete clinical, biochemical and histologic remission as has been reported in patients with autoimmune chronic active hepatitis treated with corticosteroids. Many of the trials did not use a double-blind design, failed to use the "intent to treat" rule or failed to define an objective time to analyze results. Many of the studies involved small numbers of patients with short-term follow-up and thus potentially were inadequate to appreciate drug effects that might be of clinical benefit. Currently, there is no totally effective therapy for primary biliary cirrhosis. We believe that well-designed clinical trials can provide important information to better understand this disease until a totally effective therapy is available. New clinical trials should use well-established methodologic guidelines in study design and well-accepted statistical standards in the analysis and interpretation of results.     

Hepatic prolyl hydroxylase activity in human liver disease

The activity of prolyl hydroxylase was measured in liver tissue obtained from a small series of patients with a variety of liver disease. Enzyme levels were marginally elevated in patients with fatty liver and viral hepatitis, conditions not normally associated with progressive fibrosis. In some patients with alcoholic hepatitis and in all patients with cirrhosis and chronic active hepatitis, there was a marked increase in enzyme activity. Patients with conditions characterised by high liver prolyl hydroxylase levels showed histological evidence of extensive hepatic fibrosis and also significant increases in the serum values of glutamate dehydrogenase and gamma-glutamyl-transpeptidase. Prolyl hydroxylase activity was not detected in serum.     

Effects of malotilate treatment on the serum markers of hepatic fibrogenesis in liver cirrhosis

Malotilate, a hepatotropic agent, was given to 39 cirrhotic patients for more than 32 weeks. The serial changes in the serum levels of hepatic fibrogenesis markers, such as procollagen type III N-terminal peptides (P-III-N-P) and immunoreactive prolyl hydroxylase beta-subunit (IR-BPH) were analyzed. Serum albumin levels, transaminase and choline esterase activities and the Normotest values were found to be significantly improved by malotilate treatment. The levels of both serum markers of hepatic fibrogenesis were also significantly reduced by malotilate. The prognoses of the decompensated liver cirrhosis patients treated with malotilate were significantly better than those who did not receive malotilate. These results indicate that the effects of malotilate on chronic liver diseases are not simply biocosmetic, but rather are related to an improvement in the basal changes of the liver, including a decrease in the fibrogenetic stimulus. These effects of malotilate improved the prognosis of liver cirrhosis.     

Liver immunoreactive prolyl hydroxylase protein in human primary hepatocellular carcinoma

Total prolyl hydroxylase protein was measured in hepatic tissues of 8 patients with primary hepatocellular (PHC), 5 with acute viral hepatitis, and 5 with cirrhosis (3 alcoholic and 2 with secondary biliary cirrhosis). The mean values were compared with the mean value of 10 normal hepatic tissues. The mean values were all highly significantly elevated (P less than 0.001) in PHC, acute viral hepatitis and the cirrhotic patients, respectively. The mean L-IRPH value in PHC was about 9.50 times the control mean, while in acute viral hepatitis, and cirrhosis the mean L-IRPH values were about 3.00 and 2.30 times the control mean respectively. The mean level of L-IRPH in PHC was 4.06 times the mean level of L-IRPH in cirrhosis and 3.14 times the mean value in acute viral hepatitis. The findings of this study provide a basis for the elevated serum values of this intracellular enzyme of collagen synthesis in patients with primary hepatocellular carcinoma and the data indicate that this enzyme may be elevated to compensate for an increased rate of collagen synthesis in the malignant liver tissue.     

Serum bile acids in primary biliary cirrhosis

Serum bile acid classes have been studied in 15 patients with primary biliary cirrhosis in five patients with cholestasis, and in five patients who had cirrhosis without cholestatic features. Conjugated monohydroxy bile acids (12-35% serum total bile acids) were found in eight of 11 sera from patients with primary biliary cirrhosis, in sera from four patients with cholestasis but not in any of the five patients with cirrhosis. The glycine conjugates/taurine conjugates (G/T) ratio in eight of 11 patients with primary biliary cirrhosis and two of four patients with cholestasis was <1.0.Bile acid concentrations in seven patients with primary biliary cirrhosis were measured before and during cholestyramine therapy. Decreases in serum total bile acid concentrations were observed which were accompanied by small increases in the trihydroxy/dihydroxy ratio and also in the G/T ratio in six of the seven patients. No association was found between the concentration of any particular conjugated or free bile acid and the presence or absence of pruritus.     

熊去氧胆酸治疗原发性胆汁性胆管炎患者疗效及对血清Nrf2和HO-1水平的影响

目的 探讨熊去氧胆酸(UDCA)治疗原发性胆汁性胆管炎和肝硬化(PBC)患者疗效及对血清核因子相关因子2(Nrf2)和血红素加氧酶-1(HO-1)水平的影响.方法 2017年1月～2020年1月我院诊治的原发性胆汁性胆管炎患者31例和原发性胆汁性肝硬化患者34例(Child A级15例,Child B级12例,Chil...     

Different response to ursodeoxycholic acid (UDCA) in primary biliary cirrhosis according to severity of disease

To evaluate the effect of ursodeoxycholic acid (UDCA) treatment according to the severity of primary biliary cirrhosis, a long-term prospective open trial in 54 consecutive PBC patients, 19 with histological stage I–II, 24 stage III, and 11 stage IV was carried out. UDCA was administered at a dosage of 250 mg twice a day. Clinical and biochemical assessment (AST, ALT, alkaline phosphatase, GGT, bilirubin) were done initially and every six months. Serum hyaluronate (HY) and type III procollagen amino propeptide (PIIIP) were also evaluated, as they are considered markers of fibrosis and prognosis. All patients were followed-up for at least two years (24–36 months); results were analyzed at 24 months after treatment. The composite pruritus score failed to show significant changes during UDCA treatment, while intensity score demonstrated a significant reduction from the 6th month. Patients with histological stage I–II disease had a significant decrease of liver enzymes (AST, ALT, alkaline phosphatase, GGT) after six months and maintained the levels up to 24 months. The patients with histological stage III disease showed a significant decrease of AST, ALT, alkaline phosphatase (but not GGT) up to month 18; subsequently AST and ALT serum levels increased, reaching values comparable to baseline by 24 months. In patients with histological stage IV disease no significant change in liver enzymes was observed during the follow-up. HY and PIIIP serum levels failed to show significant changes during UDCA treatment in the three groups of patients. In conclusion, although well tolerated in all patients with PBC, UDCA seems to improve itching and liver enzymes only in the pre cirrhotic stage. A long-term remission of the disease is maintained only in the early histological stages.