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.     

Characterization of overlap syndrome between primary biliary cirrhosis and autoimmune hepatitis according to antimitochondrial antibodies status

AIMS: Codification of variant forms between Primary Biliary Cirrhosis (PBC) and Autoimmune Hepatitis (AIH) has not been definitively standardized. The aim of this study was to compare among 102 consecutive patients, 2 subsets of overlap syndrome (OS, N=21) with and without antimitochondrial antibody (AMA) to two groups of patients with typical PBC (N=43) or AIH (N=38). METHODS: OS was defined by the presence in the same patient of at least 2 of 3 accepted criteria of PBC and AIH. Twelve patients with OS were AMA negative and 9 were AMA positive. RESULTS: A lower level of alanine transaminase (139+/-48 vs 269+/-154 IU/L, P<0.05) and a trend towards a higher level of alkaline phosphatase or gamma-glutamyl transpeptidase was observed in OS without AMA than in OS with AMA (693+/-200 vs 544+/-124 IU/L; 370+/-66 vs 241+/-77 IU/L, respectively). All AMA-negative patients with OS had antinuclear and/or anti-smooth muscle antibodies. OS without AMA differed from those with AMA in that they had more severe bile duct damage including destructive cholangitis (P<0.05), ductopenia (P<0.05), ductular hyperplasia (P<0.05) and a higher METAVIR fibrosis score (2.5+/-0.3 vs 1.3+/-0.3, P<0.05). The response to therapy was not different between PBC, AIH and OS. CONCLUSIONS: According to the presence of AMA, 2 homogeneous subgroups of patients with overlap syndrome between PBC and AIH may be identified. AMA status affects clinical presentation and liver disease severity of OS.     

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.     

Efficacy of colchicine in patients with primary biliary cirrhosis poorly responsive to ursodiol and methotrexate

OBJECTIVE: Approximately 20-30% of patients with primary biliary cirrhosis (PBC) respond fully to treatment with ursodeoxycholic acid (UDCA). The rest have progressive disease and eventually develop cirrhosis and liver failure. More effective treatment is needed. Methotrexate improved biochemical tests of liver function and liver histology in patients with PBC who had failed to respond to UDCA in one report and induced sustained biochemical and histological remission in another. The role of colchicine in PBC is unclear. We describe three patients with symptomatic PBC who responded very well to the addition of colchicine after they had failed to respond to UDCA alone and in combination with methotrexate. We suggest that colchicine should be tried in PBC patients who clearly fail to respond to UDCA. METHODS: Three patients with symptomatic biopsy-proven, antimitochondrial antibody-positive PBC failed to respond to UDCA and then to the addition of methotrexate. Colchicine was eventually added to the regimen. Symptoms, biochemical tests of liver function, and percutaneous liver biopsies were done at baseline, after treatment with UDCA, UDCA plus methotrexate, and UDCA plus methotrexate plus colchicine. RESULTS: All three patients responded after colchicine was added to UDCA and methotrexate. Symptoms, biochemical tests of liver function, and liver histology improved in all, and blood tests normalized in two. CONCLUSIONS: Colchicine may be effective treatment in some symptomatic patients with PBC who respond incompletely to UDCA alone or in combination with methotrexate. Colchicine may be tried in such patients.     

Mycophenolate mofetil for the treatment of primary biliary cirrhosis in patients with an incomplete response to ursodeoxycholic acid

BACKGROUND & AIMS: Despite evidence for therapeutic efficacy with ursodeoxycholic acid (UDCA) in primary biliary cirrhosis (PBC), only 30-50% of patients achieve complete biochemical remission within 1 year of therapy. Mycophenolate mofetil (MMF) is an immunosuppressive medication that inhibits T and B lymphocyte proliferation. The aim of this investigation was to determine the safety and estimated efficacy of MMF in patients with PBC. METHODS: Twenty-five patients with incomplete responses to UDCA (defined as persistent elevation of serum alkaline phosphatase > or =2 times the upper limit of normal) received MMF 1 g daily to a maximum of 3 g daily with UDCA (13-15 mg/kg per day) for 1 year. Liver biochemistries were determined at 3-month intervals with Mayo Risk Score calculated at baseline and end of therapy. RESULTS: Nineteen (76%) patients completed 1 year of therapy. Despite improvements in serum alkaline phosphatase (920 +/- 308 vs. 709 +/- 242 IU/L, P = 0.001) and AST (65 +/- 31 vs. 51 +/- 19 IU/L, P = 0.007) levels, these findings were clinically insignificant. Exploratory analysis revealed a strong correlation between advanced PBC defined by higher Mayo Risk Score and reduction in serum alkaline phosphatase levels (r = -0.74, P = 0.006). Six patients (24%) did not complete therapy; adverse drug events were responsible for study withdrawal in 3 individuals. Adverse reactions that resolved spontaneously or by dose reduction occurred in 13 patients. CONCLUSIONS: MMF is not associated with important clinical benefits in PBC based on the results of this pilot investigation.     

Primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is an idiopathic chronic autoimmune liver disease that primarily affects women. It is believed that the aetiology for PBC is a combination between environmental triggers in genetically vulnerable persons. The diagnosis for PBC is made when two of the three criteria are fulfilled and they are: (1) biochemical evidence of cholestatic liver disease for at least 6 month's duration; (2) anti-mitochondrial antibody (AMA) positivity; and (3) histologic features of PBC on liver biopsy. Ursodeoxycholic acid (UDCA) is the only FDA-approved medical treatment for PBC and should be administered at a recommended dose of 13-15 mg/kg/day. Unfortunately despite adequate dosing of UDCA, approximately one-third of patients does not respond adequately and may require liver transplantation. Future studies are necessary to elucidate the role of environmental exposures and overall genetic impact not only in the development of PBC, but on disease progression and variable clinical response to therapy.     

Decrease in the prevalence of IL-4-producing CD4+ T cells in patients with advanced stage of primary biliary cirrhosis

OBJECTIVE: To elucidate the precise immunological features in primary biliary cirrhosis (PBC), we examined the relative prevalence of CD4+ T cells in either symptomatic PBC (sPBC) or asymptomatic PBC patients (aPBC), and furthermore, these results were compared with their histological features. METHODS: Cytokine synthesis of peripheral blood mononuclear cells obtained from 24 PBC patients (9 sPBC and 15 aPBC) were examined by intracellular staining method. The relative prevalence of three distinct CD4+ T cells, gamma-interferon (IFN-gamma)-producing cells (Th1), interleukin-4 (IL-4)-producing cells (Th2), and the cells producing both IL-4 and IFN-gamma (Th0), was analyzed by FACScan and compared with those of closely age-matched healthy and disease controls. RESULTS: The results demonstrated that although a significant difference was not observed in the prevalence of Th1 or Th0, a remarkable difference was observed in the prevalence of Th2 (1.2+/-0.7 in sPBC, 4.1+/-1.3 in healthy subjects, 4.1+/-2.1 in aPBC, 3.4+/-1.3 in chronic hepatitis C, and 3.6+/-2.3 in cirrhosis secondary to CH-C; p < 0.05 for sPBC vs all others). Histological examination of these patients showed that all aPBC patients belonged to relatively early stage (stage I-II) and 7 of 8 sPBC patients belonged to late stage (stage III-IV). Thus, our results suggest that, mainly as a result of the decline of Th2, a predominance of Th1 may exist in advanced stage PBC. CONCLUSIONS: The present results demonstrated that a slight elevation of Th1 prevalence, as well as a significant decline of Th2 prevalence, was observed in peripheral blood of advanced stage PBC.     

45例原发性胆汁性肝硬化的临床特征

目的　分析原发性胆汁性肝硬化患者的临床特征 ,以指导对该病的诊断。方法　对 4 5例原发性胆汁性肝硬化患者的一般资料、病程、临床表现、生物化学、免疫学及病理学等改变进行分析。结果　本组患者中女性 4 2例 ,确诊时的平均年龄为 (5 0 8± 8 1)岁 ,初诊至确诊的时间平均为 2年 (2个月～ 12年 )。临床症状以乏力最为多见 (6 6 7% ,30 / 4 5 ) ,其次为黄疸 (5 5 6 % ,2 5 / 4 5 )和皮肤瘙痒 (40 % ,18/ 4 5 ) ,9例患者 (2 0 % )无症状 ,9例患者 (2 0 % )合并其他自身免疫性疾病 [干燥综合征和(或 )类风湿关节炎 ]。所有患者血清碱性磷酸酶及γ 谷氨酰转肽酶水平明显升高 [分别为 (498 5±36 9 8)IU/L和 (5 95 2± 5 18 4 )IU/L],而血清ALT、AST水平仅轻中度升高 [分别为 (83 9± 5 8 8)IU/L和(10 0 8± 4 8 8)IU/L],5 5 6 % (2 5 / 4 5 )的患者血清总胆红素水平≥ 34 2 μmol/L ,88 9% (40 / 4 5 )患者血清IgM升高 ,95 6 %患者 (43/ 4 5 )线粒体抗体和 (或 )线粒体抗体M2亚型阳性。结论　在中国 ,原发性胆汁性肝硬化可能并非少见 ,主要累及中年女性 ,最常见的症状为乏力 ,部分早期患者可无症状 ,血清碱性磷酸酶及γ 谷氨酰转肽酶水平升高及抗线粒体抗体和 (或 )线粒体抗体M2亚型阳性有助于诊断     

Primary biliary cirrhosis with additional features of autoimmune hepatitis: response to therapy with ursodeoxycholic acid

Patients with primary biliary cirrhosis (PBC) may have additional features of autoimmune hepatitis (AIH). Corticosteroids usually contraindicated in PBC have been advocated for these patients. Patients with antimitochondrial antibody (AMA)-positive PBC from two previous randomized, controlled trials were assessed for features of AIH. Their biochemical, immunologic, and histologic responses to ursodeoxycholic acid (UDCA) versus placebo were compared with those without AIH features. The survival of patients testing positive or negative for antinuclear antibodies (ANA) was also examined. Features of AIH were defined by the presence of 2 or more of the following: 1) alanine transaminase (ALT) > 5 x the upper limit of normal (ULN); 2) immunoglobulin G (IgG) > 2 x ULN or positive anti-smooth muscle antibody (ASMA); and 3) moderate to severe lobular inflammation on pretreatment liver biopsy. Testing for AMA, ASMA, and ANA was done by immunofluorescence. The change in serum bilirubin, alkaline phosphatase (ALP), transaminases, IgM, and IgG from baseline to 2 years was compared. Of the 331 patients randomized, 16 (4.8%) had features of AIH (12 UDCA, 4 placebo). The median percent change in serum biochemistry and immunoglobulin values were similar in patients with PBC +/- features of AIH after 2 years of therapy with UDCA. Over 2 years, little change in histologic features of AIH was observed. Survival was similar for patients with PBC with and without ANA. In conclusion, features of AIH in PBC may be transient and response to UDCA therapy similar to patients with PBC without features of AIH.     

An electron microscopic and morphometric study of ursodeoxycholic effect in primary biliary cirrhosis

BACKGROUND/AIMS: Primary biliary cirrhosis (PBC) is a chronic liver disease that results in cholestasis and bile duct loss. Ursodeoxycholic acid (UDCA) has been shown to reduce hepatocellular damage in PBC. The study attempted to quantify perisinusoidal collagenization and the number of apoptotic bodies in PBC liver biopsies from patients in a randomized control trial treated with UDCA compared to those who received placebo. METHODS: Twenty-eight patients with PBC (10 cirrhotic, 18 non-cirrhotic; 13 treated with UDCA, 15 treated with placebo) were compared with 32 controls with normal hepatic histology on light microscopy. Liver biopsies were examined for degree of perisinusoidal fibrosis and apoptotic activity using electron microscopy. RESULTS: The degree of perisinusoidal fibrosis and apoptotic activity was similar in pretreatment biopsies of UDCA and placebo-treated patients. After two years of placebo, patients showed a significant increase in fibrosis (P < 0.001). In contrast, there were no changes in non-cirrhotic and a decrease in fibrosis in cirrhotic patients given UDCA. At baseline, PBC patients had higher numbers (apoptotic cells/100 hepatocytes +/- SE) of apoptotic cells (7 +/- 3), than controls (2 +/- 0.5) (P < 0.05), with no difference between cirrhotic and non-cirrhotic patients in the two groups of patients. After two years, the numbers of apoptotic cells in UDCA-treated patients decreased significantly compared to baseline (3 +/- 2) (P < 0.05); with placebo patients the number of apoptotic cells increased (12 +/- 5) (P < 0.05). CONCLUSION: Treatment with UDCA prevents the deposition of perisinusoidal collagen and reduces the apoptotic activity in PBC patients after 2 years of therapy.     

Fenofibrate enhances urate reduction in men treated with allopurinol for hyperuricaemia and gout

OBJECTIVE: To assess the short-term urate-lowering effect of fenofibrate in men on long-term allopurinol therapy for hyperuricaemia and gout. METHODS: Ten male patients (38-74 yr) with a history of chronic tophaceous or recurrent acute gout with hyperuricaemia and on established allopurinol at 300-900 mg/day for > or =3 months were studied in an open-crossover study of fenofibrate therapy. Allopurinol at the established dose was continued throughout the study. Clinical and biochemical assessments (serum urate and creatinine, 24-h urinary excretion of urate and creatinine, liver function tests, creatine kinase and fasting serum lipids) were undertaken at: (i) baseline, (ii) after 3 weeks of once-daily therapy with micronized fenofibrate (Lipantil Micro) at 200 mg and (iii) 3 weeks after fenofibrate was withdrawn. RESULTS: Fenofibrate was associated with a 19% reduction in serum urate after 3 weeks of treatment (mean+/-S.E. 0.37+/-0.04 vs 0.30+/-0.02 mM/l; P=0.004). The effect was reversed after a 3-week fenofibrate withdrawal period (0.30+/-0.02 vs 0.38+/-0.03 mM/l). There was a rise in uric acid clearance with fenofibrate treatment of 36% (7.2+/-0.9 vs 11.4+/-1.6 ml/min, normal range 6-11; P=0.006) without a significant change in creatinine clearance. Both total cholesterol and serum triglycerides were also reduced. No patient developed acute gout whilst taking fenofibrate. CONCLUSIONS: Fenofibrate has a rapid and reversible urate-lowering effect in patients with hyperuricaemia and gout on established allopurinol prophylaxis. Fenofibrate may be a potential new treatment for hyperuricaemia and the prevention of gout, particularly in patients with coexisting hyperlipidaemia or those resistant to conventional therapy for hyperuricaemia.     

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.     

Treatment with ursodeoxycholic acid is associated with weight gain in patients with primary biliary cirrhosis

BACKGROUND: Ursodeoxycholic acid (UDCA) is the established treatment of primary biliary cirrhosis (PBC) and is a safe and well-tolerated medication. Nevertheless, patients often anecdotally complain of weight gain while on this drug. GOALS: We compared weight changes in patients treated with UDCA and those on placebo to characterize this potential side effect. STUDY: One-hundred eighty patients with PBC who were enrolled into a randomized, controlled trial received either UDCA (13-15 mg/kg/d) or an identical placebo. Changes from baseline weight were calculated at 12, 24, 36, and 48 months. Other markers of disease activity, including liver biochemistries, serum lipids, histologic stage, and Mayo Risk Score were evaluated in both groups. RESULTS: The proportion of patients who gained weight during the first 12 months of therapy was significantly greater in the UDCA than placebo group (67/86 [78%] versus 43/73 [57%] respectively, P = 0.005). Patients in the UDCA group gained an average of 3.6 +/- 6.5% kg (2.2 +/- 5.1 kg) which was significantly greater than the average of 0.6 +/- 6.9% kg (0.6 +/- 4.9 kg) gained in the placebo group (P = 0.04). The biggest change in weight occurred in the first 12 months of treatment (P < 0.001); after this, weight was maintained for the 4-year duration of treatment. There was no significant correlation between initial body mass index (BMI) and weight change or changes in disease activity and weight. CONCLUSION: UDCA treatment in patients with PBC is associated with a significant weight gain that occurs in the first 12 months of treatment, persists for the duration of treatment, and occurs independent of baseline BMI. Discussions with PBC patients beginning UDCA treatment should include the beneficial effects this medication has on disease outcome, but should also mention weight gain as a possible side effect.     

Ursodeoxycholic acid for primary biliary cirrhosis: final results of a 12-year,prospective, randomized,controlled trial

OBJECTIVES: The aim of this study was to evaluate whether ursodeoxycholic acid (UDCA) has any effect on the development of liver decompensation and on survival of patients with primary biliary cirrhosis (PBC). METHODS: A total of 86 patients with compensated PBC were randomly assigned to receive UDCA (n = 43) or to remain untreated (controls, n = 43). There was no significant difference in the baseline characteristics between the two groups. Mean follow-up was 7.3 +/- 3.0 yr in the UDCA and 8.1 +/- 3.1 yr in the control group. Fourteen control patients were crossed-over to UDCA therapy after a median of 3.5 yr (range 2-8 yr), at their own request. RESULTS: Liver decompensation developed in 41 patients (22 in the UDCA and 19 in the control group) and liver death or transplantation in 33 (19 in the UDCA and 14 in the control group) patients. There was no significant difference in the probability of development of liver decompensation, liver death, or transplantation (by log-rank test) between UDCA-treated and control patients, whether by an intention-to-treat or by treatment-as-received analysis. CONCLUSIONS: UDCA was not found to have any demonstrable effect on the long-term outcome of PBC and did not improve the survival of PBC patients.     

Primary biliary cirrhosis and hepatitis C virus infection

OBJECTIVE: The aim of this study was to describe the clinical characteristics of hepatitis C virus (HCV)-infected patients with primary biliary cirrhosis (PBC) by comparison to patients with both antimitochondrial (AMA) positive and AMA negative PBC. METHODS: All patients consecutively diagnosed as having PBC between 1973 and 1999 who had a regular follow-up of at least 2 yr were prospectively included in the study. The mean follow-up was 8.3 +/- 5.7 yr. Survival was calculated according to Kaplan-Meier curves. RESULTS: A total of 170 patients with PBC were considered. The syndrome with PBC and HCV infection (HCV-infected PBC patients) was recorded in 14 patients (13 women and one man), whereas 135 patients had AMA positive PBC and 18 had AMA negative PBC. Only three patients fulfilled the criteria for overlap syndrome involving PBC and autoimmune hepatitis. At presentation, the HCV-infected PBC group had significantly lower levels of ALP, gamma-glutamyl transpeptidase, and IgM than the AMA positive or AMA negative PBC patients (p < 0.01). With regard to the autoantibody profile, there was a significant association with LKM and HCV-infected PBC patients (21.4%), whereas ANA was significantly higher in AMA negative PBC patients than in the other two groups (83% vs 21.4% in the HCV-infected PBC patients and 38.5% in the AMA positive PBC group). No differences were found regarding the association with autoimmune conditions. During follow-up, hepatocellular carcinoma (HCC) developed more frequently in the PBC/HCV overlap group (i.e., three of 14 vs four of 135 patients with AMA positive PBC, p < 0.05). Survival curves were similar in HCV-infected PBC patients and AMA positive PBC, whereas the AMA negative group had a significantly slower decline (relative risk (RR) = 2.44, p < 0.05). CONCLUSION: HCV-infected PBC patients are characterized by a biochemical profile with a modest rise in cholestatic enzymes but a high risk of developing HCC during follow-up.     

Silymarin in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid

Ursodeoxycholic acid (UDCA) is a safe and effective medical therapy for most patients with primary biliary cirrhosis (PBC), but some patients show an incomplete response. Silymarin is a potent antioxidant with immunomodulatory and antifibrotic properties. The aim of this study was to evaluate the safety and assess the efficacy of silymarin in patients with PBC who had shown a suboptimal response to UDCA. Twenty-seven patients with PBC who had been on UDCA (13-15 mg/kg/day) therapy for 7 to 221 months and had shown a persistent elevation of alkaline phosphatase activity at least 2 times the upper limit of normal for more than 6 months were enrolled. Oral silymarin, 140 mg 3 times daily was given for 1 year, and patients continued on the same dosage of UDCA. No significant changes in serum alkaline phosphatase activity (897 +/- 84 vs. 876 +/- 95, P =.5), total bilirubin (0.9 +/- 0.1 vs. 1 +/- 0.1, P =.07), aspartate transaminase (AST) (58 +/- 5 vs. 56 +/- 6, P =.4), albumin (4.0 +/-.06 vs. 4.1 +/-.06, P =.4), or Mayo risk score (3.82 +/- 0.2 vs. 3.88 +/- 0.2, P =.4) were noted after 1 year of treatment with combination therapy. Transitory gastrointestinal adverse events occurred in 2 patients. In conclusion, although silymarin was well tolerated, this medication did not provide benefit to patients with PBC responding suboptimally to UDCA. The results of this pilot study would seem to discourage further controlled trials of silymarin in patients with PBC.     

Long-term ursodeoxycholic acid delays histological progression in primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a progressive cholestatic liver disease frequently leading to development of cirrhosis and its complications. Ursodeoxycholic acid (UDCA) is a beneficial medical therapy for patients with PBC. Improvement in some histological features, but not in histological stage, has been reported after 2 years of UDCA therapy. Thus, longer follow-up may be necessary to determine whether UDCA has a favorable effect on histological stage of disease and progression to cirrhosis. Our aim was to determine the long-term effects of UDCA therapy on histological stage and progression to cirrhosis in patients with PBC. Sixteen unselected patients with noncirrhotic PBC who had been on long-term UDCA therapy (13-15 mg/kg/d) for 6.6 +/- 0.4 years (range, 5-9 years) were identified and their histological finding during treatment compared with that of 51 noncirrhotic patients with PBC who had received ineffective therapy (D-penicillamine [DPCA] or placebo) for 5.6 +/- 0.07 years (range, 5-8 years). Histological stage was determined using the Ludwig classification. The rate of progression to cirrhosis (stage 4) was significantly less in the UDCA group than in the control group (13% vs. 49%; P =.009). Although the overall rate of progression of histological stage was less in the UDCA group than in the control group (50% vs. 71%), this difference was not significant (P =.1). A marked improvement in liver biochemistries and Mayo risk score was noted in all patients during UDCA therapy; however, this improvement was not significantly different between patients who progressed and those who did not. In conclusion, long-term UDCA therapy appeared to delay the development of cirrhosis in PBC.     

Clinical features and treatment outcomes of primary biliary cholangitis in a highly admixed population

Introduction and objectivesLittle is known about primary biliary cholangitis (PBC) in non-whites. The purpose of this study was to evaluate clinical features and outcomes of PBC in a highly admixed population.Material and methodsThe Brazilian Cholestasis Study Group multicentre database was reviewed to assess demographics, clinical features and treatment outcomes of Brazilian patients with PBC.Results562 patients (95% females, mean age 51 ± 11 years) with PBC were included. Concurrent autoimmune diseases and overlap with autoimmune hepatitis (AIH) occurred, respectively, in 18.9% and 14%. After a mean follow-up was 6.2 ± 5.3 years, 32% had cirrhosis, 7% underwent liver transplantation and 3% died of liver-related causes. 96% were treated with ursodeoxycholic acid (UDCA) and 12% required add-on therapy with fibrates, either bezafibrate, fenofibrate or ciprofibrate. Response to UDCA and to UDCA/fibrates therapy varied from 39%-67% and 42-61%, respectively, according to different validated criteria. Advanced histological stages and non-adherence to treatment were associated with primary non-response to UDCA, while lower baseline alkaline phosphatase (ALP) and aspartate aminotransferase (AST) levels correlated with better responses to both UDCA and UDCA/fibrates.Conclusions: Clinical features of PBC in highly admixed Brazilians were similar to those reported in Caucasians and Asians, but with inferior rates of overlap syndrome with AIH. Response to UDCA was lower than expected and inversely associated with histological stage and baseline AST and ALP levels. Most of patients benefited from add-on fibrates, including ciprofibrate. A huge heterogeneity in response to UDCA therapy according to available international criteria was observed and reinforces the need of global standardization.     

Ursodeoxycholic acid reduces CpG-induced IgM production in patients with primary biliary cirrhosis

Aim:  Ursodeoxycholic acid (UDCA) treatment reduces IgM serum levels in patients with primary biliary cirrhosis (PBC) without affecting serum antimitochondrial antibody (AMA) titers. We previously reported that PBC-associated hyper-IgM is secondary to a disease-specific hyperproduction following bacterial stimulation by B cells.
Methods:  We isolated peripheral blood mononuclear cells (PBMC) from patients with PBC and controls and evaluated whether bacterial CpG challenge in the presence of UDCA at concentrations consistent with those achieved in treated patients led to changes in total IgM, IgG-AMA, and IgM-AMA production. Further, p65 phosphorylation and CD38 cell expression were analyzed as measures of activation of the NF-kB signaling pathway and B cell subsets, respectively.
Results:  UDCA significantly reduced CpG-induced total IgM and IgM-AMA production, but had no impact on IgG-AMA production. UDCA also significantly reduced the activation ofnaïve and IgM memory, but not IgG memory, B cells, as represented by CD38 expression levels. Further, p65 phosphorylation was significantly reduced in the presence of UDCA.
Conclusion:  UDCA reduces total and IgM-AMA production in PBMC from patients with PBC by downregulating B cell activation and NF-kB signaling. These data ultimately suggest novel mechanisms of action for UDCA in chronic autoimmune cholestasis.     

Fenofibrate is effective in treating hypertriglyceridemia associated with HIV lipodystrophy

OBJECTIVE: To determine the effectiveness of fenofibrate in treating hypertriglyceridemia associated with highly active antiretroviral therapy-associated HIV lipodystrophy syndrome (HLS). METHODS: The authors recruited from their HIV metabolic clinic 55 adult patients with anthropomorphic changes consistent with HLS together with hypertriglyceridemia. The patients had no prior history of taking lipid-lowering medications and were free of liver and renal disease. They were on various highly active antiretroviral therapy regimens, and these regimens were not altered during the course of the study. Fenofibrate was started at 54 mg a day and the dose increased every 2 weeks to a maximum of 162 mg/day. Fasting lipid concentrations were measured at baseline and 6 months after the intervention. RESULTS: At baseline, the fasting plasma concentrations of total cholesterol, triglyceride, and high-density lipoprotein (HDL) cholesterol were 259 +/- 11, 886 +/- 172, and 35.7 +/- 2.3 (mean +/- SEM) mg/dL, respectively. After 6 months of fenofibrate treatment, the fasting plasma concentrations were as follows: total cholesterol, 243 +/- 13; triglycerides, 552 +/- 104, and HDL cholesterol, 35.7 +/- 1.8 mg/dL. The decrease in fasting plasma triglyceride concentration was statistically significant (P < 0.05). Fenofibrate was well tolerated, and no subjects dropped out of the study. CONCLUSION: Fenofibrate is an effective, well-tolerated treatment for hypertriglyceridemia associated with HLS.