Rat liver fibrosis regresses better with pegylated interferon alpha2b and ursodeoxycholic acid treatments than spontaneous recovery.

BACKGROUND/AIMS: Fibrosis and cirrhosis are common complications of chronic liver diseases. An imbalance between fibrogenesis and fibrolysis results in scarring of the liver parenchyma. We aimed to investigate the possible antifibrotic effectiveness of a newly modified interferon molecule peginterferon alpha2b (PEG-IFNalpha2b) which has better antiviral activity, and ursodeoxycholic acid (UDCA). METHODOLOGY: Liver fibrosis was established on 60 male Sprague Dawley rats with CCl4 in 12 weeks. After cessation of CCl4 Group I was left for spontaneous recovery. Group II was treated with PEG-IFN 1.5 microg/kg/week, Group III with UDCA 25 mg/kg/day and Group IV with combination of both drugs. All rats were killed at week 16. Histopathologic fibrosis scores, tissue hydroxyproline, TIMP-1 and MMP-13 levels were determined. Hepatic stellate cell apoptosis was detected by dual staining with TUNEL technique and anti-alpha smooth muscle actin. RESULTS: Fibrosis scores were lower in Group II, III and IV than Group I (p<0.05 for group I vs. II and III; p<0.01 for group I vs. IV). Tissue hydroxyproline levels were significantly decreased in Group II, III and IV when compared to Group I (p<0.05 for group I vs. II, p<0.01 for group I vs. III and IV). Lower liver TIMP-1 and higher MMP-13 levels were measured in Group II, III, and Group IV than Group I (p<0.01 for TIMP-1 and p<0.01, for MMP). Activated HSC apoptosis was significantly increased in Group II, III and IV when compared to Group I (p<0.01, for all). There was significantly higher apoptosis in Group II than Group III and IV (p<0.01). CONCLUSION: Treatment with both PEG-IFNalpha2b and UDCA improved CCl4 induced rat liver fibrosis. Significantly higher effects were obtained using these agents in combination.     

Tumor necrosis factor-alpha and transforming growth factor-beta reflect severity of liver damage in primary biliary cirrhosis

BACKGROUND AND AIMS: The pathogenesis of primary biliary cirrhosis (PBC) is unknown. The role of cytokines such as tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta), and the effect of ursodeoxycholic acid (UDCA) in modifying the cytokine environment in patients with PBC has remained largely unstudied. Our aims were to determine: (i) the relationship between serum levels of TNF-alpha and TGF-beta and the severity of PBC; and (ii) the effects of UDCA therapy on TNF-alpha and TGF-beta levels in patients with PBC. METHODS: We studied 90 patients who had been treated with UDCA (53 patients) or placebo (37 patients) for 2 years as part of a randomized, double-blind, controlled trial. Patients were divided into histological stage I/II or stage III/IV disease. Serum TNF-alpha and TGF-beta levels were quantified by enzyme-linked immunoabsorbent assay. RESULTS: Baseline levels of TNF-alpha were significantly greater in patients with stage III/IV compared to stage I/II disease. After 2 years of treatment with UDCA, patients showed a significantly greater decrease in TNF-alpha levels and progression risk score compared to placebo-treated patients. TNF-alpha and TGF-beta levels were significantly reduced compared to baseline levels in the UDCA-treated group after 2 years, while there was no significant change in the levels of placebo-treated patients. CONCLUSIONS: Serum TNF-alpha and TGF-beta levels may reflect severity of disease in patients with PBC. The beneficial effects of UDCA therapy may be explained by lowering serum levels of these two cytokines.     

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.     

Methotrexate improves biochemical tests in patients with primary biliary cirrhosis who respond incompletely to ursodiol.

BACKGROUND & AIMS: Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of presumed autoimmune etiology. Ursodeoxycholic acid (UDCA), methotrexate, and colchicine each have shown promise in its treatment. The value of combining 2 or 3 of these drugs is uncertain. The aim of this study was to determine whether addition of methotrexate to the treatment regimen improves results of liver biochemical tests in patients with antimitochondrial antibody-positive PBC who responded incompletely to treatment with UDCA and colchicine. METHODS: Methotrexate was added to the treatment regimen of 10 consecutive patients with antimitochondrial antibody-positive PBC who had an incomplete response to therapy with UDCA alone or in combination with colchicine. The primary end point was biochemical response. Symptoms and histological changes were also recorded. RESULTS: Addition of methotrexate to the UDCA plus colchicine regimen was associated with a significant reduction in serum alkaline phosphatase (ALP) levels beyond those found with UDCA and colchicine alone or in combination. Median ALP concentration was 389 IU (range, 247-1013 IU) at baseline, 300 IU (range, 155-467 IU) after treatment with UDCA plus colchicine, and 120 IU (range, 66-351 IU) after treatment with methotrexate. CONCLUSIONS: Addition of methotrexate to a regimen of UDCA and colchicine may be beneficial for patients with PBC who respond incompletely to treatment with UDCA and colchicine.     

The efficacy of ursodeoxycholic acid and bezafibrate combination therapy for primary biliary cirrhosis: A prospective, multicenter study.

Aim: Treatment with ursodeoxycholic acid (UDCA) improves the survival of stage I and II primary biliary cirrhosis (PBC) patients. However, new therapeutic options are needed for patients who are refractory to UDCA and for those whose disease is at an advanced stage. Bezafibrate could be useful in PBC treatment, since it increases phospholipid output into the bile and reduces the cytotoxicity of hydrophobic bile acids, which are increased with cholestasis. Methods: We conducted two prospective, multicenter randomized open studies in non-cirrhotic patients with PBC to evaluate the efficacy of bezafibrate. One study compared UDCA and bezafibrate monotherapy (study 1: 45 patients [37 females], mean age 55.9 years), and the other evaluated the addition of bezafibrate to patients who were refractory to UDCA (study 2: 21 patients [18 females], mean age 54.1 years). Results: Study 1 demonstrated that bezafibrate monotherapy was as effective as UDCA and study 2 revealed that bezafibrate combined with UDCA was effective in improving and maintaining biliary enzymes where the ineffectiveness of long-term treatment with UDCA was confirmed. Conclusion: This multicenter, randomized, open study revealed that combination therapy of bezafibrate and UDCA improved biliary enzymes in non-cirrhotic Japanese patients with PBC refractory to UDCA. Further studies are needed to evaluate whether combination therapy improves histological staging and prognosis.     

Primary biliary cirrhosis: incidence and predictive factors of cirrhosis development in ursodiol-treated patients

BACKGROUND & AIMS: Ursodeoxycholic acid (UDCA) slows the progression of primary biliary cirrhosis (PBC). However, some UDCA-treated patients escape and progress toward cirrhosis and end-stage disease. This study aimed to assess the incidence of cirrhosis in UDCA-treated patients with PBC and to determine the predictive factors of cirrhosis development under this treatment. METHODS: A Markov model was used to describe the progression toward cirrhosis in 183 UDCA-treated patients with PBC. A total of 254 pairs of liver biopsy specimens collected during 655 patient-years were studied. RESULTS: The incidence of cirrhosis after 5 years of UDCA treatment was 4%, 12%, and 59% among patients followed-up from stages I, II, and III, respectively. At 10 years, the incidence was 17%, 27%, and 76%, respectively. The median time for developing cirrhosis from stages I, II, and III was 25 years, 20 years, and 4 years, respectively. The independent predictive factors of cirrhosis development were serum bilirubin greater than 17 mumol/L, serum albumin less than 38 g/L, and moderate to severe lymphocytic piecemeal necrosis. CONCLUSIONS: This study provides new data about the time course of PBC under UDCA and constitutes a rationale for the design and evaluation of clinical trials aimed to assess the efficacy of drugs associated with UDCA.     

Incomplete response to ursodeoxycholic acid in primary biliary cirrhosis: is a double dosage worthwhile?

OBJECTIVE: The aim of this study was to assess the safety and efficacy of high-dose ursodeoxycholic acid (UDCA, 28-32 mg/kg/day) in patients with primary biliary cirrhosis (PBC) who had shown an incomplete response to the standard dose (13-15 mg/kg/day). METHODS: A total of 25 patients with PBC who had been on UDCA (13-15 mg/kg/day) therapy for 24-141 months and had shown persistent elevation of ALP activity at least two times the upper limit of normal were enrolled. The dose of UDCA was increased to 30 (28-32) mg/kg/day and given for 1 yr. RESULTS: A significant but marginal improvement in serum ALP activity (707+/-52 vs 571+/-32, p = 0.001) was noted at 1 yr of treatment with high-dose UDCA. However, levels of total bilirubin (1.1+/-0.2 vs 1.0+/-0.2, p = 0.1), AST (58+/-9 vs 54+/-1, p = 0.1), albumin (4.1+/-0.7 vs 4.0+/-0.08, p = 0.1), or Mayo risk score (4.13+/-0.3 vs 4.12+/-0.3, p = 0.2) remained essentially unchanged. Normalization of liver tests did not occur in any patient, and adverse events were not recorded in any case. CONCLUSIONS: Although UDCA at a dose of 28-32 mg/kg/day is well tolerated, this dosage does not seem to benefit most patients with PBC responding incompletely to a dose of 13-15 mg/kg/day. The results of this pilot study would seem to discourage further controlled trials of high-dose UDCA in suboptimal responders to the standard dose of UDCA.     

Pharmacokinetics and pharmacodynamic action of budesonide in early- and late-stage primary biliary cirrhosis

Budesonide has been discussed as a potential treatment option in primary biliary cirrhosis (PBC). Therefore, we studied the pharmacokinetics and pharmacodynamics of budesonide in patients with PBC stage I/II and stage IV. Twelve patients with early PBC stage I/II and 7 patients with PBC stage IV under continuous treatment with ursodeoxycholic acid (UDCA) were enrolled in an exploratory trial. Each patient received oral budesonide for 3 weeks at weekly increasing dosages of 3 mg once to thrice per day. Budesonide and cortisol plasma levels, urinary cortisol excretion, serum liver tests, and immunoglobulins were determined on days 1, 7, and 21 of the study. Patients with PBC stage IV showed significantly higher peak plasma concentrations (4.9 +/- 3.5 vs. 1.5 +/- 0.4 ng/mL; P <.05) and areas under the plasma concentration-time curves (AUC) (23.2 +/- 16.8 vs. 5.1 +/- 1.4 hours. ng/mL, P <.01, total AUC extrapolated to infinity [AUC(0- infinity )]) after a single dose of 3 mg budesonide when compared with patients with PBC stage I/II. Equally, AUC of budesonide were significantly increased under a multiple dose regimen on day 21 (14.0 +/- 11.6 vs. 5.0 +/- 1.9 hours. ng/mL, P <.01, AUC at steady state from dosing time to 8 hours [AUC(ss,0-8 h)]). Higher levels of budesonide were related to a significant decrease in plasma cortisol and reduction of urinary cortisol excretion in patients with stage IV disease. Two patients with stage IV disease developed portal vein thrombosis (PVT). In conclusion, administration of budesonide leads to markedly elevated plasma levels in cirrhotic patients with PBC associated with serious adverse drug reactions. Thus, further evaluation of combined treatment with UDCA may be considered in early-stage PBC but not in cirrhotic patients with PBC.     

Ursodeoxycholic acid treatment in primary biliary cirrhosis with the emphasis on late stage disease.

We studied the effect of ursodeoxycholic acid in 19 patients with primary biliary cirrhosis, mainly stages III and IV. The dose of UDCA employed was 10-15 mg/kg body weight per day. After 1 yr, 17 patients were still using UDCA, and the mean values of serum alkaline phosphatase, gamma-glutamyltranspeptidase and alanine-aminotransferase had fallen significantly. Serum bilirubin, initially elevated in 7 of the 13 late-stage (III and IV) patients, showed a further increase in 3 of the 7 patients. In 2 of these 3 patients, UDCA had to be withdrawn (dose reduction had no effect). One patient developed a decompensated cirrhosis in spite of UDCA withdrawal. Pruritus worsened in 4 patients, all of whom were late stage patients. Ten late-stage (III-IV) patients showed improvement in liver biochemistry and clinical findings as did all early-stage PBC patients. Thus, UDCA treatment is not beneficial for all PBC patients. Special care should be taken in the early phase of UDCA therapy in later-stage (III-IV) patients: frequent biochemical checks should be carried out, for instance every 2 weeks in the first 2 months after starting UDCA, especially the estimation of bilirubin.     

A 35‐year follow‐up of a large cohort of patients with primary biliary cirrhosis seen at a single centre

Background: The natural history of primary biliary cirrhosis (PBC) is still debated. Aims: To evaluate: (i) long‐term survival in a large cohort of PBC patients observed prospectively at a single centre and (ii) mortality in relation to baseline characteristics and ursodeoxycholic acid (UDCA) treatment. Methods: We considered all consecutive patients between 1973 and 2007 (327 subjects; 310 females, 17 males). Results: The mean follow‐up was 9.1±7.7 years. The patients' age at diagnosis for representative periods (1973–1980, 1981–1990, 1991–2000, 2001–2007) increased progressively from 47.7±1.5 to 53.2±1.2, to 65.2±2.1 and then 63.6±2.9 years. The proportion of asymptomatic patients at diagnosis increased from 30 to 48% in the last decade, while associated symptoms of extrahepatic autoimmunity remained unchanged. Eighty patients (24.4%) died, 74 of them because of liver failure (12 patients developed hepatocellular carcinoma); nine patients underwent liver transplantation. From 1988 onwards, all patients were treated with UDCA (n=288). The mean age at death for the sample as a whole was 67.2±1.3 years. The survival probability at 20 years was 82% for patients with histological stages I–II at entry, 64% for those with stage III and 42% for those with stage IV (P=0.0007). Mortality was significantly reduced in patients treated with UDCA (P=0.012), whereas it was independently associated with oesophageal varices (P=0.015). Patients treated with UDCA had a better prognosis than those untreated, irrespective of the histological stage. Early treated subjects with a good response to UDCA have an 85% chance of survival at 20 years. Conclusions: The clinical presentation of PBC has been changing over the years. Its early detection and early treatment improve the related survival rates.     

Additive improvement induced by bezafibrate in patients with primary biliary cirrhosis showing refractory response to ursodeoxycholic acid

Background and Aim: Ursodeoxycholic acid (UDCA) has been widely used in the treatment of patients with primary biliary cirrhosis (PBC). However, some patients are refractory to UDCA. The aim of this study is to clarify the additive improvement induced by bezafibrate in patients refractory to UDCA. Methods: This study was a prospective analysis of 37 consecutive PBC patients. All patients were treated first for 6 months with UDCA, and then with bezafibrate, if their alkaline phosphatase (ALP) levels did not decrease more than 40% or within the normal range after 6 months' treatment with UDCA. Clinical parameters were monitored for the subsequent 24 months. Result: Twenty‐two patients (59%) achieved improvement of ALP levels after the treatment with UDCA. Those patients (Group A) had significantly lower levels of ALP at diagnosis than those with abnormal ALP levels after 6 months' treatment with UDCA (Group B; P = 0.020). They continued UDCA monotherapy, and maintained normal ALP levels at subsequent follow ups. However, immunoglobulin M (IgM) levels remained abnormal in eight patients, whose IgM levels at the time of diagnosis were significantly higher than those whose IgM were normalized after 6 months' treatment with UDCA (P = 0.026). Those in Group B were treated additionally with bezafibrate, and 12 patients (80%) achieved normal ALP and IgM levels within 12 months of commencement of therapy. Conclusion: Higher ALP level at diagnosis is one of the predictors for UDCA failure. Combination treatment of bezafibrate in addition to UDCA may be an effective treatment for PBC patients refractory to UDCA.     

Treatment of primary biliary cirrhosis with ursodeoxycholic acid, budesonide and fibrates

Long-term treatment with ursodeoxycholic acid (UDCA; 13-15 mg/kg/day) in patients with primary biliary cirrhosis (PBC) improves biochemical liver tests, delays histological progression and prolongs survival without liver transplantation. UDCA monotherapy appears sufficient for many patients as suggested by long-term observational data. However, the transplant-free survival rate of UDCA-treated patients remains significantly lower than that of an age- and sex-matched control population. Therefore, there is a continued need for new therapeutic options in PBC. In this article we review and discuss the following issues: the appropriate selection of patients requiring new therapeutic options, the role of budesonide in the management of these patients, and the emerging place of peroxisome proliferator-activated receptor-α ligands as anti-inflammatory and immunomodulating agents in PBC.     

Serological markers for monitoring disease progression in noncirrhotic primary biliary cirrhosis on ursodeoxycholic acid therapy

Background/Aim: Liver biopsy has so far been the only method to accurately follow the progression of primary biliary cirrhosis (PBC). The stage and the severity of lymphocytic piecemeal necrosis (LPN) have been shown to be an independent factor for the development of cirrhosis. In this 3‐year prospective study, we evaluated the diagnostic value of several liver function tests, surrogate markers of fibrogenesis, hyaluronic acid (HA), procollagen III N‐terminal peptide (S‐PIIINP), cholestanol and plant sterols in noncirrhotic PBC patients treated with ursodeoxycholic acid (UDCA) or with UDCA and budesonide to assess the stage, inflammation and fibrosis. Methods: Seventy‐seven stage I–III PBC patients were included into the study, with control biopsy at 36 months. Serum liver enzymes, bile acids (BA), HA, PIIINP, immunoglobulins, lipids and cholesterol precursors and plant sterols were measured at baseline and at 36 months. Results: Aspartate aminotransferase (AST), HA, BA and PIINP were significantly different between stages I to III and differentiated mild (F0F1) from moderate (F2F3) fibrosis. The combination of these variables (PBC score) exhibited best sensitivity and specificity, compared with AST/platelet ratio, Forns' score and fibrosis index. Using a cut‐off value of 66 for the PBC score, the sensitivity was 81.4% and specificity was 65.2% for classifying the stage of PBC, regarding the stage the and fibrosis in noncirrhotic PBC. Conclusions: Serum HA, BA, PIIINP and AST may serve as valuable simple tools to monitor the treatment response to UDCA in early stages of PBC. Combinations of these biomarkers into a single index further potentiate the diagnostic value of such measurements.     

Biochemical response to ursodeoxycholic acid among PBC patients: a nationwide population-based study

Objective: To assess the proportion of PBC patients with a biochemical response to ursodeoxycholic acid (UDCA) in a population-based cohort and the association of biochemical response with outcomes.

Methods: All patients diagnosed with PBC in Iceland from 1991–2015 were identified. Patients taking UDCA for an adequate period of time were analyzed for treatment response according to the Barcelona, Paris I, Paris II and Toronto criteria and outcomes.

Results: Overall 182 females and 40 males were diagnosed with PBC and 135 patients were treated with UDCA. Overall 99 (73%) patients had adequate data on UDCA treatment and results of liver tests to assess biochemical response according to the Barcelona criteria, 95 (70%) according to the Toronto criterion and 85 (63%) according to the Paris I and II criteria. In all 74% (n?=?63), 67% (n?=?64), 54% (n?=?53) and 46% (n?=?39) responded to treatment according to the Paris I, Toronto, Barcelona and Paris II criteria. Among nonresponders according to the Paris I, Toronto, Paris II and Barcelona criteria, 50%, 39%, 33% and 30% developed cirrhosis versus 10%, 6%, 5% and 11% of responders, HR 5.36 (p?=?.002), 6.61 (p?=?.002), 10.94 (p?=?.003) and 2.21(p?=?.11), respectively. Age-adjusted mortality was significantly lower among responders according to the Paris I and Paris II criteria, HR 0.33 (p?=?.02) and 0.31 (p?=?.02), respectively.

Conclusion: Development of cirrhosis and higher mortality was significantly associated with a lack of biochemical response to UDCA. Frequent development of cirrhosis and increased mortality in nonresponders underlines the need for a more effective therapy than UDCA for this sizeable subgroup of patients.     

A Comparative Study Between Laparoscopic Findings and Histological Stages in Primary Biliary Cirrhosis

Abstract: Histopathologically, early lesions of primary biliary cirrhosis (PBC) are focal within the liver and there is segmental involvement of the bile ducts. In addition, the development of PBC is variable within the liver. PBC is characterized by the following laparoscopic findings: reddish patch, mesh-like white marking and gentle undulation, etc. In the present study, we analyzed the correlation between the laparoscopic findings and the histological stage as per Scheuer's classification in 22 patients with PBC. The results of this study are summarized as follows: 1) Reddish patch was frequently observed in the early stage of PBC. 2) Mesh-like white marking was observed in cases of stage I, II and III. 3) Gentle undulation was seen in stage II and III. The absence of this finding is useful in the diagnosis of stage I. 4) In stage IV, these three findings were not observed. 5) From these three findings, it was difficult to differentiate stage II or III. But the presence of portal hypertension and increased vascularity of the liver capsule were observed in accordance with the progression of the disease. Indications of portal hypertension were seen even in the early stage and in some asymptomatic cases of PBC. In conclusion, the laparoscopic findings such as reddish patch, mesh-like white marking, gentle undulaion and portal hypertension are very valuable for stage diagnosis and the evaluation of prognosis in patients with PBC.     

Medical treatment of primary biliary cirrhosis and primary sclerosing cholangitis.

Treatment of primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) with ursodeoxycholic acid (UDCA) has been in common use since 1985. In PBC, treatment with UDCA improves laboratory data, liver histology, enables a longer transplantation-free interval and prolongs disease survival. Because UDCA is unable to cure the disease newer drugs or combination therapies are still needed. Studies with UDCA and immunosuppressants such as prednisone, budesonide and azathioprine have shown that in selected patients combination therapy may be superior to UDCA monotherapy. PSC is treated successfully with UDCA and endoscopic dilatation of the bile duct strictures. Treatment of extrahepatic manifestations of cholestatic liver disease such as pruritus, fatigue, osteoporosis and steatorrhea can be problematic and time-consuming.     

Ursodeoxycholic acid inhibits eosinophil degranulation in patients with primary biliary cirrhosis.

Eosinophilia is a distinctive feature of primary biliary cirrhosis (PBC), especially in its early stages. Intriguingly, treatment with ursodeoxycholic acid (UDCA) ameliorates eosinophilia as well as liver tests in patients with PBC. It remains unknown, however, whether eosinophils in PBC patients are functionally activated and whether UDCA inhibits eosinophil activation. In the present study, we systematically examined eosinophil dynamics in the blood and liver in patients with stage I to II PBC before and after UDCA treatment. We determined serum concentrations of eosinophil granule proteins (major basic protein [MBP] and eosinophil-derived neurotoxin [EDN]) by radioimmunoassay and quantitated eosinophil degranulation using computer-assisted morphometry after MBP immunohistochemistry. Before UDCA treatment, patients with PBC (n = 25) showed significantly higher circulating eosinophil counts (P <. 05) and serum concentrations of MBP (P <.0005) and EDN (P <.02) compared with patients with chronic viral hepatitis (n = 22), autoimmune hepatitis (n = 10), and obstructive jaundice (n = 12). Four-week UDCA treatment significantly reduced blood eosinophil counts (P <.0001) and serum MBP (P <.0001) and EDN (P <.0001) levels in PBC patients. MBP immunohistochemistry and computer-assisted quantitative morphometry showed infiltration and degranulation of eosinophils in the portal tract in patients with PBC and significant reductions in the number of sites and the area occupied by extracellular MBP deposits after UDCA treatment for 2 years (P <.02) but not in placebo-treated patients. Our results suggest that eosinophils in patients with PBC are not only increased in number, but also release granule proteins, and that UDCA treatment inhibits this eosinophil activation/degranulation.     

Efficacy of fenofibrate in Chinese patients with primary biliary cirrhosis partially responding to ursodeoxycholic acid therapy

OBJECTIVE: To investigate the efficacy of fenofibrate combination therapy in Chinese patients with primary biliary cirrhosis (PBC) who had a partial response to standard dose of ursodeoxycholic acid (UDCA) for at least one year. METHODS: PBC patients were treated with UDCA (13–15 mg/kg/day) for more than one year. The biochemical response to UDCA treatment was evaluated after treatment. Fenofibrate (200 mg/day) was added to 22 patients with partial response to UDCA. RESULTS: In patients with partial response to UDCA, serum alkaline phosphatase (ALP) and γ‐glutamyl transpeptidase levels significantly decreased after 3‐month combination therapy of UDCA and fenofibrate, 68% of these patients even reached normal ALP level. Serum triglyceride (TG) and cholesterol levels were improved, and alanine transaminase (ALT) and aspartate transaminase (AST) were also decreased during the combination therapy. However, fenofibrate had no significant effect on serum bilirubin levels. The improvement of liver biochemical tests was maintained in some patients with long‐term therapy (at least 6 months). No obvious adverse effects were observed in patients taking fenofibrate. CONCLUSIONS: Fenofibrate is effective for improving liver biochemical tests in patients who have partial response to UDCA monotherapy. It is worth exploring the efficacy of fenofibrate on histological changes in PBC patients.     

Portal hypertension in primary biliary cirrhosis (PBC): A reversible condition? Yes,but not in all UDCA treated patients

Portal hypertension is not a rare complication of PBC, but there are no useful clinical predictors of its severity. In fact, in PBC patients, the evaluation of portal hypertension needs a direct access to the portal vein in order to measure the real porto-hepatic gradient (PHG), mainly because of a possible pre-sinusoidal component. The severity of portal hypertension, as measured by the PHG using a thin needle, correlated significantly with the long-term survival of PBC patients, but the initial Mayo score remained the best predictor of survival. In addition to the well-known effects on biological parameters, ursodeoxycholic acid (UDCA) treatment has been associated with a stabilization or improvement of portal hypertension but this effect was not observed in all patients: "responders" and "non-responders" to the UDCA could be identified according to changes in PHG and aspartate aminotransferase (AST) levels observed 2 years after UDCA therapy and had significantly different long-term survivals. This notion of "responders" and "non-responders" is new and may well explain the conflicting data found in the literature concerning the effects of UDCA in PBC patients as reported in various clinical trials. These findings are of interest when considering the emerging non-invasive methods aimed at evaluating liver fibrosis, particularly elastography that may prove useful in the indirect assessment of portal hypertension in the near future, therefore avoiding the need for the invasive measurement of the PHG.