The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis

BACKGROUND AND AIMS: We used a multistate modeling approach to assess the effect of ursodeoxycholic acid (UDCA) therapy on the natural course of primary biliary cirrhosis (PBC), which remains controversial. METHODS: Our population included 262 patients with PBC who had received 13-15 mg/kg UDCA daily for a mean of 8 years (range, 1-22 years). Data were analyzed using a multistate Markov model, with histologic stage progression, death, and orthotopic liver transplantation (OLT) as main end points. Survival without OLT was compared with that predicted by the updated Mayo model and with the expected survival in the control population. RESULTS: Forty-five patients developed cirrhosis, 20 underwent OLT, and 16 died by the censor date. Ten deaths were due to liver disease. The overall survival rates were 92% at 10 years and 82% at 20 years. Survival rates without OLT were 84% and 66% at 10 and 20 years, respectively, which were slightly lower than the survival rate of an age- and sex-matched control population (relative risk [RR], 1.4; P = .1) but better than the spontaneous survival rate as predicted by the updated Mayo model (RR, .5; P < .01). The survival rate of patients in stage 1 and 2 was similar to that in the control population (RR, .8; P = .5), whereas the probability of death or OLT remained significantly increased in treated patients in late histologic stages (RR, 2.2; P < .05). CONCLUSIONS: Treatment with UDCA alone normalizes the survival rate of patients with PBC when given at early stages. However, there is a continued need for new therapeutic options in patients with advanced disease.     

The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis

Ursodeoxycholic acid (UDCA) is the only approved treatment for primary biliary cirrhosis (PBC). However, the benefit from UDCA therapy on the progression of PBC from its early stage towards extensive fibrosis and cirrhosis has not been clearly shown. The aim of this study was to assess the effect of UDCA therapy on liver fibrosis progression in PBC. A Markov model was used to analyze the progression rates between early and late histologic stages in 103 patients with PBC enrolled in a randomized, double-blind, placebo-controlled trial of UDCA. Early stage was defined by the presence of portal and periportal lesions without extensive fibrosis, whereas late stage was defined by the presence of numerous septa, bridging fibrosis, or cirrhosis. A total of 162 pairs of liver biopsy specimens were studied. The model accurately described the observed data. UDCA therapy was associated with a 5-fold lower progression rate from early stage disease to extensive fibrosis or cirrhosis (7% per year under UDCA vs. 34% per year under placebo, P <.002), but was not associated with a significant difference in regression rates (3% per year under both UDCA and placebo). At 4 years, the probability of UDCA-treated patients to remain in early stage disease is 76% (95% confidence interval: 58%-88%), as compared with 29% (15%-52%) in placebo-treated patients. In conclusion, UDCA therapy significantly delays the progression of liver fibrosis in PBC. Markov modeling should prove useful in assessing the efficacy of future medical treatments in clinical trials involving histologic endpoints.     

Gene expression profiling of early primary biliary cirrhosis: possible insights into the mechanism of action of ursodeoxycholic acid

Objectives: Primary biliary cirrhosis (PBC) is a poorly understood disease, both in terms of its pathogenesis and the mechanism of action of its most common treatment, ursodeoxycholic acid (UDCA). We used gene expression profiling to compare liver tissue from treatment‐naïve and UDCA‐treated patients in order to outline some of the molecular changes associated with PBC and its treatment. Patients and Experimental Design: Liver biopsy specimens from non‐cirrhotic, treatment‐naïve (n=11) patients were compared with biopsies from UDCA‐treated patients (n=20) and with 10 normal, healthy female controls. Gene expression was determined using a 19K cDNA microarray. In order to determine whether the observed changes in gene expression levels were specific to PBC or generic to liver damage overall, PBC samples were also compared with chronically diseased [48 hepatitis C virus (HCV), 18 hepatitis B virus (HBV)] and acutely stressed liver tissue (25 liver biopsies taken after reperfusion of liver transplant grafts). Results: We found a gene signature specific to PBC (P≤0.012), containing biologically plausible genes (221 genes with adjusted P≤0.05). Differences in the expression of selected genes were confirmed using real‐time polymerase chain reaction. When gene expression from non‐cirrhotic UDCA‐treated (n=20) and UDCA‐naïve liver tissue was compared, we found a striking downregulation of a number of genes involved in protein biosynthetic pathways. Conclusions: These studies highlight the genes associated with both treatment‐naïve and UDCA‐treated PBC, and suggest that the effects of UDCA are mediated, at least in part, via a modulation of protein biosynthesic pathways.     

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.     

Combination therapy with ursodeoxycholic acid and colchicine for primary biliary cirrhosis

Twelve patients with primary biliary cirrhosis (PBC), stages I to III, received long-term therapy with a combination of 600 mg ursodeoxycholic acid (UDCA) and 1 mg colchicine given daily for more than 2 years. Drug toxicity was mild; one patient experienced diarrhoea that was probably due to colchicine. Serum levels of bilirubin, alkaline phosphatase (ALPase), gamma-glutamyl transpeptidase and alanine aminotransferase decreased by more than 50% of the initial values. Serum albumin and cholesterol levels also improved, but immunoglobulins and anti-mitochondrial antibody titre did not change. Histologic features in the eight patients who received serial liver biopsies before and 2 years after the beginning of treatment were evaluated. Piecemeal necrosis and portal inflammation were improved, but there was no change in portal fibrosis. Patients were divided into two groups; the first received both drugs from the outset, and the second group were started on UDCA for 3 months followed by the addition of colchicine. After 3 months, the improvement in serum bilirubin and ALPase in the first group was greater than in the second. However, in the second group, the ALPase levels had decreased significantly when measured at 6 and 9 months after the treatment compared with the levels at 3 months. These findings suggest that UDCA and colchicine may have a synergistic effect. This combination therapy appears to be safe and effective, both clinically and histologically, for treating PBC.     

加味茵陈蒿汤联合熊去氧胆酸治疗原发性胆汁性肝硬化的临床研究

目的:观察加味茵陈蒿汤联合熊去氧胆酸治疗30例原发性胆汁性肝硬化临床分期为早中期患者的临床疗效。方法:60例患者随机分为对照组和治疗组各30例。两组均给予基础治疗,对照组患者同时口服熊去氧胆酸胶囊15～20mg.kg-1.d-1;治疗组患者在对照组基础上加服加味茵陈蒿汤,1剂/d,疗程均为24周。观察治疗前后两组患者的临床疗效、肝功能(γ-GT、ALP、ALT、AST、TBil)、免疫指标(IgM、IgG及IgA)的变化。结果:治疗结束时,治疗组26例(86.7%)患者得到完全反应,与对照组19例(63.3%)比较差异有显著性意义(P<0.05);两组患者治疗后肝功能(γ-GT、ALP、ALT、AST、TBil)均较治疗前明显下降(P<0.05),治疗组治疗后肝功能下降明显优于对照组(P<0.05或P<0.01);治疗后两组患者免疫指标IgM、IgG、IgA均较前有所下降,经比较差异无统计学意义(P>0.05)。结论:加味茵陈蒿汤联合熊去氧胆酸治疗原发性胆汁性肝硬化,较单用熊去氧胆酸疗效更好,并能明显改善患者的肝功能。     

Similar anti-mitochondrial antibody reactivity profiles in familial primary biliary cirrhosis.

AIMS:: Familial accumulation of primary biliary cirrhosis (PBC) has been documented. To examine the importance of genetic factors, we carried out family study of the disease with a particular focus on the reactivity profiles of anti-mitochondrial antibodies (AMA). PATIENTS AND METHODS:: Eighty-five patients with PBC that we experienced in the period of 1982-2003 were investigated, retrospectively. Twelve patients from a total of six families were investigated clinically and immunologically. RESULTS:: Of the 85 patients, 5 (5.9%) were found to have a family history of PBC. The six PBC family relationships consisted of four cases of sisters and two cases of a mother and daughter. HLA haplotypes were identical in two cases and were half-similar in the other cases. AMA titers were almost the same in three families and in five of the six families, sera from individual members within the family showed similar AMA-reactive bands in immunoblotting. CONCLUSION:: The prevalence of PBC is strikingly increased in family members (frequency of 5.9%). Sera from PBC patients of the same family showed the same AMA reactivity profile, suggesting that development of AMA may be greatly influenced by certain underlying genetic factors. Large-scale genomic studies of familial PBC will be critical to identify mechanisms of disease susceptibility.     

Combination therapy with mycophenolate mofetil and ursodeoxycholic acid for primary biliary cirrhosis.

Evidence of autoimmunity in primary biliary cirrhosis (PBC) provides a rationale for treatment with an immunosuppressant. Such a drug should be sufficiently free from serious toxicities to enable patients with asymptomatic, but progressive, disease to be treated longterm. Mycophenolate mofetil (MMF) mediates immunosuppression by selectively and reversibly inhibiting lymphocyte function, and has a more acceptable safety profile than other immunosuppressants that have been used in the treatment of this disease. Two patients, whose response to long-term treatment with ursodeoxycholic acid (UDCA) had been inadequate, were treated with a combination of MMF 2 g daily and UDCA 1 g daily for 12 months. In both patients this regimen was associated with no clinically significant adverse events, a decrease in elevated serum alkaline phosphatase levels to values close to the upper limit of normal, and an almost complete disappearance of the chronic inflammatory cell infiltrate that had been present in pre-combination treatment liver biopsies. MMF may be an appropriate immunosuppressive drug for use in the long-term treatment of patients with PBC, including asymptomatic patients.     

原发性胆汁性肝硬化停用熊去氧胆酸治疗的前瞻性研究

目的 评价原发性胆汁性肝硬化(PBC)患者停用熊去氧胆酸(UDCA)的反应.方法 27例经UDCA治疗后肝功能正常>6个月的PBC患者分为A、B两组,A组停用UDCA,B组维持UDCA 13～15 mg·kg-1·d-1治疗,两组患者在性别、年龄、病程等方面相匹配,观察12个月.结果 随访过程中A组1例退出,B组1例失访.A组12例,B组13例.A组2例出现病情进展,占17%,均为血清胆红素升高至正常值2倍以上,分别发生在第3个月和第12个月;B组患者未出现病情进展,两组差异无统计学意义.至观察结束时,A组92%疾病复发,B组为15%,差异有统计学意义(P<0.05). A组患者丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、碱性磷酸酶(ALP)、γ-谷氨酰转肽酶(GGT)升高,差异有统计学意义(P<0.05).血清胆红素平均水平差异无统计学意义.B组上述指标均维持稳定.结论 对UDCA治疗后肝功能正常的PBC患者需要长期维持UDCA治疗.     

Effect of ursodeoxycholic acid on bile acid metabolism in primary biliary cirrhosis

We have compared the effect of ursodeoxycholic acid with placebo on the clinical state, blood liver chemistries and serum and urinary bile acids in four patients with primary biliary cirrhosis. All parameters were evaluated monthly, and bile acid composition was measured by capillary gas-liquid chromatography. At the time of admission, all patients showed intense pruritus, and their serum alkaline phosphatase, AST and ALT levels were elevated 4.3, 2.7 and 2.3 times over control values. Serum bile acids were elevated almost 38-fold with 2.5 times more cholic acid than chenodeoxycholic acid. Urinary bile acid output was elevated 28 times the control values, and 36% were 1 beta-hydroxycholic acid, 1 beta-hydroxydeoxycholic acid and hyocholic acid (3 alpha,6 alpha, 7 alpha-trihydroxy-5 beta-cholanoic acid). Three months of placebo administration did not significantly affect the clinical or biochemical presentations, and the serum and urinary bile acid composition did not change. In contrast, ursodeoxycholic acid feeding (12 to 15 mg per kg per day) for 6 months abolished pruritus in two and lessened itching in two subjects and reduced serum alkaline phosphatase, AST and ALT levels by 21, 35 and 47%, respectively. The mean values for the total serum bile acid concentrations in these patients declined 26% from the pretreatment value, but the proportion of ursodeoxycholic acid increased from 3 to 40% of the total bile acids; thus, total fasting serum endogenous bile acid levels decreased almost 50%. Similar changes were noted in the urinary bile acids, in which ursodeoxycholic acid became the major bile acid, and approximately 18% were hydroxylated at C-1, C-6 and C-21.(ABSTRACT TRUNCATED AT 250 WORDS)     

Biochemical markers for non-invasive assessment of disease stage in patients with primary biliary cirrhosis

AIM： To evaluate different biochemical markers and their ratios in the assessment of primary biliary cirrhosis （PBC） stages. METHODS： This study included 112 patients with PBC who underwent a complete clinical investigation. We analyzed the correlation （Spearman＇s test） between ten biochemical markers and their ratios with different stages of PBC. The discriminative values were compared using areas under receiver operating characteristic （ROC） curves. RESULTS： The mean age of patients included in the study was 53.88 ＋ 10.59 years, including 104 females and 8 males. We found a statistically significant correlation between PBC stage and Aspartate aminotransferase （AST）, Alanine aminotransferase （ALT） to platelet ratio （APRI）, ALT/platelet count, AST/ALT, ALT/AST and ALT/Cholesterol ratios, with the values of Spearman＇s rho of 0.338, 0.476, 0.404, 0.356, 0.351 and 0.325, respectively. The best sensitivity and specificity was shown for AST/ALT, with an area under ROC of 0.660. CONCLUSION： Biochemical markers and their ratios do correlate with different sensitivity to and specificity of PBC disease stage. The use of biochemical markers and their ratios in clinical evaluation of PBC patients may reduce, but not eliminate, the need for liver biopsy.     

Effect of ursodeoxycholic acid administration on biliary lipid secretion in primary biliary cirrhosis

Ursodeoxycholic acid (UDCA) has been reported to improve liver function tests when administered to patients with cholestatic liver diseases, such as primary biliary cirrhosis (PBC). However, its effects on biliary lipid metabolism in patients with PBC are still unknown. In this study we report the effect that UDCA (600 mg/day, for four weeks) had on biliary cholesterol saturation index, biliary bile acid pattern and pool size, and biliary lipid output in seven female patients (ages 34–58 years) with PBC, stages I to III. A significant improvement of liver function tests was observed after four weeks of treatment. Saturation index was significantly decreased from 1.23±0.1 to 0.7±0.08 (P<0.02); this effect was due to the significant decrease of biliary cholesterol concentration from 6.7±0.36 to 3.6±0.37 percent molar (P<0.02). A significant decrease of cholesterol output (from 88±9 to 55±10 μmol/hr, P<0.02) was also observed. The amount of cholic acid, the predominant bile acid in bile, significantly decreased (from 47.3±3.5 to 35.4±2.6 percent molar, P<0.02), as did amounts of chenodeoxycholic and deoxycholic acids, while the amount of UDCA rose from 1.6±1.0 to 34.0±1.3 percent molar (P<0.02). Total bile acid pool size was not affected by UDCA, but the evaluation of individual bile acid pool sizes showed an increased proportion of UDCA relative to the endogenous bile acids. The results of the study confirm the beneficial effect of UDCA on liver function tests in PBC patients and support the hypothesis that the improvement of these measurements may be due to replacement of toxic endogenous bile acids with UDCA.     

Autoimmune conditions associated with primary biliary cirrhosis: response to ursodeoxycholic acid therapy

Objectives: A variety of autoimmune conditions occur in association with primary biliary cirrhosis. Among these conditions are sicca syndrome, Raynaud's phenomenon, arthritis, and Hashimoto's thyroiditis. Information is sparse regarding the prevalence and natural history of these conditions when associated with primary biliary cirrhosis and their response to ursodeoxycholic acid treatment. We evaluated the prevalence, natural history, and response to ursodeoxycholic acid therapy of these conditions coassociated with primary biliary cirrhosis.
Methods: One hundred-eighty patients with primary biliary cirrhosis, enrolled in a prospective randomized controlled trial of ursodeoxycholic acid (13–15 mg/kg/day), were included. Patients were assessed at study entry and annually.
Results: At entry, 77/180 patients (43%) had one of the four conditions, and 18/180 patients (10%) had two or more conditions. Sicca syndrome was the most common, occurring in 58/180 patients (32%). After 2 yr, there was no difference between the treatment groups with regard to resolution or spontaneous onset of these autoimmune features. Sicca syndrome was the most common spontaneously developing condition (9% per yr). Sicca syndrome was the most common associated autoimmune condition, present in one-third of our patients. The associated conditions tended to improve over time, with a low rate of spontaneously developing these conditions. Although ursodeoxycholic acid therapy leads to improvement in the underlying liver disease, it did not appear to influence either the development or resolution of these autoimmune features.
Conclusions: Although ursodeoxycholic acid is beneficial in the treatment of primary biliary cirrhosis, it had no measurable effect on the autoimmune conditions coassociated with the disease.     

Optimum dose of ursodeoxycholic acid in primary biliary cirrhosis.

BACKGROUND: Ursodeoxycholic acid (UDCA) improves liver function tests and prolongs survival in primary biliary cirrhosis (PBC). The dose of 10- 15 mg/kg/day used in the large trials has largely been based on that used for gallstone dissolution. The only dose-response study of UDCA in PBC suggested that a dose of 8 mg/kg/day was the most efficacious. However, disease stage of the patients was not known, higher doses of UDCA were not tried and there was no 'washout period' between the different doses. The aim of this study was to determine the optimum dose of UDCA in early-stage PBC (stage 1 and 2). METHODS: Twenty-four biopsy-proven early-stage PBC patients (one male, 23 female) received five doses of UDCA (0, 300, 600, 900, 1200 mg/day) each for 8 weeks with 4-week washout periods between doses. Symptoms (pruritus, fatigue, diarrhoea) were assessed on a four-point scale (none, mild, moderate, severe). Liver function tests (LFTs) were performed using conventional methods, and serum bile acids were measured using gas liquid chromatography. RESULTS: The dose of 900 mg/day produced the greatest enrichment of UDCA in serum bile acids; although there was no difference in the enrichment of UDCA between the different doses. There was a trend towards normalization of the abnormal LFTs in a dose-dependent manner (for y-glutamyl transferase (yGT), alkaline phosphatase (ALP), alanine transaminase (ALT) and IgM). Multi-factorial analysis showed that UDCA treatment, irrespective of dose, was significantly better than placebo for all the variables. The 900 and 1200 mg doses were better than both 300 and 600 mg using yGT and total bilirubin as variables, better than 300 mg using ALP and IgM as variables, and better than 600 mg using albumin as a variable. No variables showed a significant difference between 900 and 1200 mg. CONCLUSION: The optimum dose of UDCA is 900 mg/day (equivalent to 13.5 mg/kg/day).     

Histopathological study of primary biliary cirrhosis and the effect of ursodeoxycholic acid treatment on histology progression

The semiquantitative histopathological analysis of the liver biopsies obtained before and after 4 years of ursodeoxycholic acid (UDCA) therapy in a cohort of primary biliary cirrhosis (PBC) patients is reported. The relationships between elementary histological lesions before treatment and their progression under therapy were assessed. At baseline, two independent groups of lesions, each of which participate in the development of fibrosis, were individualized, i.e., florid bile duct lesions and ductopenia on one hand and lymphocytic piecemeal necrosis, ductular proliferation, and lobular necroinflammatory changes on the other hand. Four years of UDCA therapy were associated with a significant decrease in the prevalence of florid interlobular bile duct (ILBD) lesions, of epithelioid granuloma (P <.001) without any aggravation in the severity of bile duct paucity. Lobular inflammation and necrosis markedly improved (P <.001) whereas the degree of severity of the lymphocytic piecemeal necrosis and ductular proliferation at entry and at 4 years were similar. Worsening of fibrosis was observed in 14 patients (12 of them had a one grade progression) whereas stabilization was noted in 30 of the remaining patients. Severity of both the lymphocytic piecemeal necrosis and lobular inflammation and necrosis at entry was significantly associated with the progression of fibrosis. The results suggest that UDCA therapy influences the process leading to bile duct destruction. Patients with severe lymphocytic piecemeal necrosis and lobular inflammation may need additional therapeutic intervention because they have increased risk of fibrosis progression.