Colchicine for primary biliary cirrhosis: a Cochrane Hepato-Biliary Group systematic review of randomized clinical trials

OBJECTIVES: Colchicine is used for patients with primary biliary cirrhosis due to its immunomodulatory and antifibrotic potential. The results from randomized clinical trials have, however, been inconsistent. We conducted a systematical review to evaluate the effect of colchicine for primary biliary cirrhosis. METHODS: We identified randomized clinical trials comparing colchicine with placebo/no intervention. We analyzed effects by fixed and random effects model. We investigated heterogeneity by subgroup and sensitivity analyses. RESULTS: We included 10 trials involving 631 patients, four of which were high-quality trials. No significant differences were detected between colchicine and placebo/no intervention regarding mortality (relative risk (RR), 1.21; 95% confidence interval (CI), 0.71-2.06), mortality or liver transplantation (RR = 1.00; 95% CI, 0.67-1.49), liver complications, liver biochemical variables, liver histology, or adverse events. Regarding mortality, an extreme case analysis favoring colchicine did not demonstrate beneficial effects of colchicine, whereas an extreme case analysis favoring placebo/no intervention demonstrated a detrimental effect of colchicine (RR = 2.28; 95% CI, 1.17-4.44). The number of patients without improvement of pruritus significantly decreased in the colchicine group (RR = 0.75; 95% CI, 0.65-0.87). However, this estimate was based on only 156 patients from three trials. CONCLUSIONS: There is insufficient evidence to support the use of colchicine for patients with primary biliary cirrhosis. As we are unable to exclude a risk of increased mortality, we recommend to use colchicine only in randomized clinical trials.     

Ursodeoxycholic acid in primary sclerosing cholangitis: meta-analysis of randomized controlled trials

Aims:  The effect of ursodeoxycholic acid (UDCA) treatment on survival and liver histological progression of primary sclerosing cholangitis (PSC) remains uncertain. The aim of the present study was to evaluate the effect and safety of UDCA in PSC.
Methods:  Electronic databases including Medline, Embase, Cochrane controlled trials register, Web of Science and PubMed (updated to January 2009) and manual bibliographical searches were carried out. A meta-analysis of all randomized controlled trials (RCT) comparing UDCA with placebo or no treatment was carried out.
Results:  Eight RCT including 465 patients were assessed. UDCA could significantly improve liver biochemistry, but had no effect on pruritus and fatigue. Meta-analysis of the included RCT showed UDCA had no significant effect on the incidence of death, liver transplantation, and death and/or liver transplantation. However, a significant difference for the incidence of histological improvement was found between the two groups (odds ratio [OR], 9.19; 95% CI: 0.98, 86.15; P  = 0.05). Meta-analysis also indicated a reduction trend of histological deterioration and an improvement trend of cholangiographic changes. These trends were constant in the sensitivity analyses.
Conclusion:  The meta-analysis found that UDCA can improve liver biochemistry and there is a trend towards improvement in liver histology and cholangiography, but has no effect on survival free of transplantation.     

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.     

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.     

Clopidogrel and aspirin after ischemic stroke or transient ischemic attack: an updated systematic review and meta-analysis of randomized clinical trials

Journal of Thrombosis and Thrombolysis - Patients with primary or secondary antiphospholipid syndrome (APS) have an increased risk of recurrent venous, arterial thrombosis and pregnancy...     

Long-term effects of mid-dose ursodeoxycholic acid in primary biliary cirrhosis: a meta-analysis of randomized controlled trials

OBJECTIVES: The effect of ursodeoxycholic acid (UDCA) treatment on survival and liver histological progression of primary biliary cirrhosis (PBC) remains uncertain. The aim of this study is to assess the long-term efficacy of mid-dose UDCA treatment for PBC. METHODS: Electronic databases including Medline, Embase, Cochrane controlled trials register, Science Citation Index, and PUBMED (updated to Nov 2005), and manual bibliographical searches were conducted. A meta-analysis of all long-term randomized controlled trials (RCTs) comparing mid-dose UDCA with placebo or no treatment was performed. RESULTS: Seven RCTs and six reports of their extended follow-up including 1,038 patients were assessed. UDCA could significantly improve liver biochemistry, but had no effect on pruritus and fatigue. UDCA could delay the progression of PBC, especially for early-stage patients. Meta-analysis of the seven RCTs including their extended follow-up showed a significant reduction of the incidence of liver transplantation (OR 0.65, p = 0.01), and a marginally significant reduction of the rate of death or liver transplantation (fixed-effect model: OR 0.76, p = 0.05; random-effect model: OR 0.77, p = 0.3) in the UDCA group, except death (OR 1.01, p = 1). In the sensitivity analyses, which included studies administrating placebo as control, long-term studies (> or = 48 months), or large size studies (total number of patients > or = 100), we all found long-term treatment with UDCA could significantly reduce the incidence of liver transplantation, and death or liver transplantation. CONCLUSIONS: Long-term treatment with mid-dose UDCA can improve liver biochemistry and survival free of liver transplantation in patients with PBC. In addition, UDCA therapy can delay the histological progression in the early-stage patients.     

中等剂量熊去氧胆酸治疗原发性胆汁性肝硬化的系统评价

目的评价长期应用中等剂量熊去氧胆酸治疗原发性胆汁性肝硬化的疗效及安全性。方法对全世界关于中等剂量(13～15mg·kg-1·g-1)熊去氧胆酸与安慰剂对照治疗原发性胆汁性肝硬化的随机对照试验进行系统评价。结果共纳入7项随机对照试验,累计1038例患者。熊去氧胆酸能显著改善患者的肝功能生化检测指标,但不能改善疲劳和瘙痒等症状。病程Ⅰ至Ⅱ期的患者治疗2年后肝脏组织学显著好于对照组(P=0.03),但分析所有患者时差异无统计学意义(P=0.08)。荟萃分析显示治疗组与对照组间死亡率(OR0.99,95%可信区间0.62～1.58)、肝病相关死亡率(1.05,0.53～2.05)、肝移植率(0.87,0.53～1.41)、死亡和(或)肝移植率(0.92,0.64～1.31)和肝功能失代偿率(0.94,0.60～1.49)差异无统计学意义。结论熊去氧胆酸能有效改善肝功能,但不能改善症状,也无足够证据支持熊去氧胆酸能延长患者的生存期。早期患者及早并长期应用熊去氧胆酸可能延缓肝脏组织学进展。     

Ursodeoxycholic acid therapy and the risk of colorectal adenoma in patients with primary biliary cirrhosis: an observational study

Ursodeoxycholic acid (UDCA) is the first-line treatment for primary biliary cirrhosis (PBC). The long-term administration of UDCA might indirectly favor colon carcinogenesis by increasing the fecal excretion of secondary bile acids or, in contrast, it might inhibit colon carcinogenesis, as demonstrated in animal models. In patients with PBC, we examined the effect of prolonged UDCA administration on the prevalence and recurrence of colorectal adenoma and on the proliferation of colon epithelial cells. One hundred fourteen patients (103 women, 11 men; mean age, 55 years) with PBC, were enrolled in a colonoscopic surveillance program. The prevalence of colon adenoma was compared in patients already treated with UDCA (mean duration 46 months) at the time of colonoscopy (treated group, n = 52) and in patients undergoing colonoscopy just prior to treatment initiation (untreated group, n = 62). The recurrence of adenoma following removal (mean follow-up, 35 months) was compared between UDCA-treated patients and appropriate age- and gender-matched controls (2/1) selected from a cohort of 205 patients undergoing polypectomy. Epithelial cell proliferation was assessed using anti-Ki67 antibodies on colon biopsies from both treated and untreated patients. Treated and untreated patients displayed similar demographic characteristics. The prevalence of colorectal adenomas was 13% in the treated group versus 24% in the untreated group (P =.16). The colon epithelial cell proliferation index was significantly lower in treated patients than in untreated patients (P =.001). Following removal of the adenoma, the probability of recurrence was significantly lower in patients treated with UDCA than in controls (7% vs. 28% at 3 years, P =.04). In conclusion, this study suggests that, in patients with PBC, the prolonged administration of UDCA (1) is not associated with an increased prevalence of colorectal adenomas, and (2) significantly decreases the probability of colorectal adenoma recurrence following removal. These results are strengthened by the significant reduction in colon epithelial cell proliferation seen in patients treated with UDCA.     

Ursodeoxycholic acid administration on bile acid metabolism in patients with early stages of primary biliary cirrhosis

Ursodeoxycholic acid has been proposed for the treatment of primary biliary cirrhosis. The aim of this study was to evaluate the effect of ursodeoxycholic acid administration on bile acid metabolism in patients with early-stage primary biliary cirrhosis. Biliary bile acid composition, primary bile acid pool sizes, synthesis, and fractional turnover rate were measured before and after four weeks of ursodeoxycholic acid administration (600 mg/day) in nine patients with biopsy-proven primary biliary cirrhosis (stages I-III). Molar percentages of chenodeoxycholic, cholic, and deoxycholic acids in bile were significantly decreased by ursodeoxycholic acid administration, while its biliary concentration increased to 34.2% at the end of the same four-week period. The cholic and chenodeoxycholic acid pools decreased, although not significantly, while the deoxycholic acid pool was reduced by 60% (from 0.7±0.12 to 0.29±0.07 mmol,P<0.002). Primary bile acid synthesis was slightly increased, and fractional turnover rate was significantly increased. The conversion rate of cholic to deoxycholic acid was measured and found to be significantly increased (P<0.05) after ursodeoxycholic acid administration; however, serum levels of both free and conjugated deoxycholic acid were significantly decreased (from 23.2±9.7 to 3.8±1.9 μmol/liter,P<0.001). We conclude that in patients with primary biliary cirrhosis, ursodeoxycholic acid administration replaces endogenous bile acids in the enterophepatic circulation by increasing bile acid fractional turnover rate without significant increments of their hepatic synthesis.     

Risk factors for recurrent primary biliary cirrhosis after liver transplantation: A systematic review and meta-analysis

BackgroundRecurrent primary biliary cirrhosis (PBC) is frequently observed in patients with PBC after liver transplantation (LT). We performed a meta-analysis to evaluate the risk factors for PBC recurrence.MethodsWe searched the EMBASE, PubMed and the Cochrane Library databases for studies published before August 2020. Studies that identified the risk factors of PBC recurrence were eligible for inclusion. We extracted the hazard ratio (HR) data with 95% confidence intervals (CI) for the risk factors.ResultsOur meta-analysis included 6 studies, which comprised 3184 patients (88.5% females) who underwent liver transplantation from 1982 to 2017, and of these patients, 935 (29.4%) developed PBC recurrence. The use of tacrolimus (HR = 2.62, 95% CI = 1.35, 5.09) and preventive ursodeoxycholic acid (UDCA) (HR = 0.40, 95% CI = 0.28, 0.57) were significantly associated with the risk of PBC recurrence based on the pooled analysis of the results obtained from the multivariate analysis.ConclusionsThe use of tacrolimus is associated with an increased risk of PBC recurrence. Preventive UDCA after LT for PBC can help to prevent disease recurrence.     

熊去氧胆酸治疗老年原发性胆汁性肝硬化的临床研究

目的探讨老年原发性胆汁肝硬化（PBC）的临床特征、诊断和治疗效果。方法将66例诊断为PBC的病人分为老年组40例,中年组26例,比较两组的临床表现、生化免疫指标（碱性磷酸酶：ALP、谷氨酰转肽酶：GGT、抗线粒体抗体：AMA）。两组病例均给予口服熊去氧胆酸（UDCA：优思弗）治疗,服药8W后比较疗效。结果90％病人因体检发现ALP、GGT升高就诊,治疗前两组患者的ALP、GGT升高程度差异无统计学意义（P〉0．05）。非特异性皮肤瘙痒是老年PBC患者的主要表现,中年组患者中88．5％无症状,明显高于老年组的37．5％;口服优思弗8W后,两组ALP、GGT均较治疗前明显程度降低（P〈0．05）。老年组中3例肝硬化患者服用优思弗后,其症状、体征及ALP、GGT均无改善,2例死亡。服药后两组患者乏力、皮肤瘙痒症状均无改善,影像学也无变化。结论：（1）PBC早期缺乏特异症状;（2）AMA对PBC诊断有重要意义,ALP、GGT的升高早于黄疸、肝肿大出现。（3）应重视体检中无法解释的ALP、GGT异常升高。（4）UDCA对早期原发性胆汁肝硬化疗效满意。（5）老龄可能是影响PBC患者预后的因素之一。     

Evaluation of urate-lowering therapy in hyperuricemia patients: a systematic review and Bayesian network meta-analysis of randomized controlled trials

Clinical Rheumatology - Hyperuricemia is a strong precursor of gout, which deteriorates patients’ health and quality of life. Sustained adherence to urate-lowering therapies (ULTs) is crucial...