Treatment of ursodeoxycholic acid with glucocorticoids and immunosuppressants may improve the long-term survival rate in primary biliary cholangitis patients

Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease. The clinical effectiveness of ursodeoxycholic acid (UDCA) plus glucocorticoids and/or immunosuppressants remains controversial in PBC patients. The study aimed to compare the efficacy of monotherapy and combination therapy in patients with PBC and to assess the factors affecting the efficacy. In this retrospective study, 266 patients diagnosed with PBC were divided into monotherapy group (UDCA), double therapy group (UDCA plus glucocorticoids or immunosuppressants), and triple therapy group (UDCA plus glucocorticoids and immunosuppressants) according to different treatments. Demographic characteristics, immune parameters, biochemistry profiles, and other indicators were evaluated at baseline, 6 months, and 1 year following treatment. The prognosis was evaluated using the Paris II standard. The liver transplant-free survival at 3, 5, 10, and 15 years was predicted by GLOBE score. All statistical analyses were conducted using SPSS (version 24) software (SPSS Inc, Chicago, IL). The long-term survival rate of the triple therapy group was significantly improved compared with the monotherapy group (P = .005). In addition, multivariate analysis showed that abnormal platelet count, alkaline phosphatase, and albumin levels were risk factors for poor response. When IgG levels were elevated but below twice the upper limit of normal, the clinical benefit was not significant compared with monotherapy (P > .05). Compared with monotherapy and double therapy, triple therapy may improve the long-term survival rate of PBC patients. Abnormal platelet count, alkaline phosphatase, and albumin levels were associated with a poor prognosis.     

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.     

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.     

Rate of non-response to ursodeoxycholic acid in a large real-world cohort of primary biliary cholangitis patients in Italy

Abstract

Background and aim: Response to ursodeoxycholic acid (UDCA) is crucial for the prediction of primary biliary cholangitis (PBC) prognosis, and different response criteria were validated and proposed by reference centers for PBC. To date, rates of non-response to UDCA from real-world series are lacking.

Methods: Hepatology/Gastroenterology centers belonging to ‘Club Epatologi Ospedalieri’ (CLEO) and ‘Associazione Italiana Gastroenterologi Ospedalieri’ (AIGO) were invited to participate in the study, and asked to extract all patients followed for PBC, without any selection or exclusion, and fill in the database provided.

Results: Thirty-four centers were enrolled throughout Italy, for a total of 713 patients. None of these centers, except one, had a hepatology outpatient clinic devoted to the care of patients with autoimmune liver diseases. After excluding 79 cases of PBC/autoimmune hepatitis overlaps, 634 patients were analyzed: mean age, 64.4?±?12.0 years; 91.2% females; F/M 10.3/1. For patients with at least 1?year of UDCA treatment (583), rates of non-response to UDCA were evaluated according to the Paris-I/-II, Toronto and GLOBE criteria, and compared with those in the original cohorts: 27% vs 39% in Paris-I cohort; 39.6% vs 52% in Paris-II; 20.1% vs 43.5% in Toronto; 15.7% vs 30% in GLOBE (age-specific cutoffs). Mean alkaline phosphatase levels on UDCA treatment, and the age-adjusted prevalence of F3/F4 fibrosis, appeared lower in this PBC population than in reference cohorts.

Conclusions: A mean ～15% better response to UDCA is observed in a real-world PBC population, probably due to migration of some of most severe/advanced cases to PBC referral centers.     

Combination therapy of bezafibrate and ursodeoxycholic acid for primary biliary cirrhosis: A meta‐analysis

The aim of this study was to assess the efficiency and safety of combination therapy of ursodeoxycholic acid (UDCA) and bezafibrate for primary biliary cirrhosis. A meta‐analysis of all long‐term randomized controlled trials comparing the combination of UDCA and bezafibrate with UDCA monotherapy was performed via electronic searches. Seven trials, which included 177 patients, were assessed. Combination therapy with UDCA and bezafibrate was more effective than UDCA monotherapy in improving liver biochemistry, alkaline phosphatase (mean difference [MD], ?146.15 IU/L; 95% confidence interval [CI], ?193.58 to ?98.72; P < 0.00001), γ‐glutamyltransferase (MD, ?20.64 IU/L; 95% CI, ?30.86 to ?10.43; P < 0.0001), immunoglobulin M (MD, ?90.96 mg/dL; 95% CI, ?137.36 to ?44.56; P = 0.0001) and triglycerides (MD, ?15.49 mg/dL; 95% CI, ?30.25 to ?0.74; P = 0.04). However, their effects on pruritus (odds ratio [OR], 0.82; 95% CI, 0.30–2.24; P = 0.70) and alanine aminotransferase (MD, ?8.41 IU/L; 95% CI, ?22.57 to 5.75; P = 0.24) did not differ significantly. This meta‐analysis revealed no significant differences in the incidence of all‐cause mortality (OR, 0.72; 95% CI, 0.10–5.49; P = 0.75) and adverse events (OR, 0.35; 95% CI, 0.07–1.84; P = 0.22) between patients treated with combination therapy and those treated with monotherapy. In this meta‐analysis, combination therapy with UDCA and bezafibrate was more effective than UDCA monotherapy. Combination therapy improved liver biochemistry, but did not improve clinical symptoms, incidence of death or adverse events more effectively than monotherapy.     

Old and new treatments for primary biliary cholangitis

Primary biliary cholangitis (formerly primary biliary cirrhosis) is a rare progressive cholestatic liver disease, whose hallmark features include a persistently elevated alkaline phosphatase level, presence of anti‐mitochondrial antibodies and characteristic histology. Since 1998, ursodeoxycholic acid (UDCA), a bile acid, has been the only available therapeutic agent. Primary biliary cholangitis is associated with the development of end‐stage liver disease, increased morbidity and mortality. UDCA has been shown to improve serum biochemistries, histology and delay the need for liver transplantation. The clinical issue is that approximately 25%‐40% of patients do not respond to this standard therapy. In recent years, many trials have investigated alternative and adjunctive treatments, leading to the recent approval of obeticholic acid, an analogue of chenodeoxycholic acid, which has shown significant and sustained reductions in alkaline phosphatase levels in combination with UDCA. Obeticholic acid has rapidly been embraced as a new agent to improve the biochemical profile in refractory patients, in addition to being approved for use as monotherapy in patients who cannot tolerate UDCA. There are several other studies and targets which are being investigated. This review is intended to highlight the benefits of UDCA, educate the reader on the newly available obeticholic acid, and to summarize the many ongoing trials and therapeutic targets being investigated in attempts to control and cure primary biliary cholangitis.     

柳氮磺吡啶联合熊脱氧胆酸治疗原发性硬化性胆管炎的有效性探讨

[目的]探讨柳氮磺吡啶(SASP)联合熊脱氧胆酸(UDCA)治疗原发性硬化性胆管炎的有效性。[方法]将30例原发性硬化性胆管炎患者分别纳入联合组、UDCA组、SASP组,每组10例;联合组口服UDCA联合SASP治疗,UDCA组单独口服UDCA治疗,SASP组单独口服SASP治疗。评价指标为治疗12周后,血清碱性磷酸酶、谷酰转肽酶、血清总胆红素的降低程度,以及1年后胆道镜下病变进展情况。[结果]30例中有29例完成全部治疗,联合组与UDCA组患者治疗后血清碱性磷酸酶、谷酰转肽酶、总胆红素较治疗前均明显下降,差异均有统计学意义(P0.05~0.01);SASP组治疗前后血清碱性磷酸酶、谷酰转肽酶差异具有统计学意义(P0.01),而总胆红素治疗前后差异无统计学意义(P0.05)。联合组血清各项指标均较UDCA组、SASP组降低更明显(P0.05~0.01)。1年后各组患者病变进展情况相比差异无统计学意义(P0.05)。[结论]单独或联合应用SASP与UDCA治疗原发性硬化性胆管炎有一定的短期临床效果,且联合应用效果可能更好。     

熊去氧胆酸治疗原发性胆汁性胆管炎患者血清甲状腺激素水平变化*

目的 探讨应用熊去氧胆酸（UDCA）治疗原发性胆汁性胆管炎患者血清甲状腺激素水平的变化。方法 2016年1月~2017年6月我院治疗的原发性胆汁性胆管炎患者70例和原发性胆汁性肝硬化患者95例,另选20例健康人作为对照组。给予患者UDCA治疗3月,检测治疗前后血清甲状腺激素水平变化。结果 在治疗3个月末,两组患者肝功能指标得到改善,除胆管炎患者血清ALP和GGT水平仍显著高于肝硬化患者外,其他肝功能指标比较,差异无统计学意义（P>0.05）;治疗前,胆管炎患者血清总三碘甲状腺原氨酸（TT3）、总甲状腺素（TT4）、游离三碘甲状腺原氨酸（FT3）和游离甲状腺素（FT4）水平分别为1.6±0.2 nmol/L、3.2±0.4 pmol/L、95.6±28.7 nmol/L和10.3±3.6 pmol/L,肝硬化患者分别为1.1±0.2 nmol/L、3.0±0.3 pmol/L、88.2±26.7 nmol/L和9.7±2.5 pmol/L,均显著低于健康人【分别为（2.5±0.5 nmol/L、4.7±0.8 pmol/L、115.7±31.6 nmol/L和13.8±4.1 pmol/L,P<0.05】,两组患者血清促甲状腺素（TSH）水平与健康人比,差异无统计学意义【分别为（2.9±0.5 mIU/L和 2.9±0.7 mIU/L对 3.3±0.6 mIU/L,P>0.05】; 在治疗3个月末,胆管炎患者血清TT3、FT3、TT4和FT4水平分别为2.4±0.6 nmol/L、4.5±0.8 pmol/L、108.2±36.2 nmol/L和12.9±3.5 pmol/L,较治疗前显著上升,已与健康人无统计学差异（P>0.05）,而肝硬化患者血清TT3、FT3、TT4和FT4水平分别为1.2±0.3 nmol/L、3.4±0.4 pmol/L、93.7±29.8 nmol/L和9.9±3.1 pmol/L,无明显改善,仍显著低于健康人（P<0.05）。结论 原发性胆汁性胆管炎患者经熊去氧胆酸治疗后,血清甲状腺激素水平可获得改善,因此应该早期诊断、早期治疗。     

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.     

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.     

Case Report: Three paediatric cases of primary sclerosing cholangitis treated with ursodeoxycholic acid and sulphasalazine

We present here three paediatric patients with primary sclerosing cholangitis. In case 1, the serum γ-glutamyl transpeptidase was decreased only temporarily by ursodeoxycholic acid (UDCA) treatment and 34 months later, sulphasalazine was added because of microscopic colitis. The enzyme level decreased with dual therapy. Similarly, in case 3, first diagnosed as autoimmune hepatitis, the transpeptidase levels remained elevated for 18 months during treatment with UDCA, prednisolone and mizoribin. The enzyme decreased only after a diagnosis of primary sclerosing cholangitis complicated with ulcerative colitis was established and sulphasalazine was introduced. Case 2 also had Crohn's colitis and was put on UDCA and sulphasalazine from the start. The enzyme level was normalized within 1 month and has remained normal for the following 5 years. Liver biopsies were analysed repeatedly in these three patients. In case 1, periductal fibrosis remained unchanged while being treated by UDCA. There appeared to be no progression in liver cirrhosis in case 3 while being treated by UDCA, prednisolone, and mizoribin. In case 2, who has been treated with both UDCA and sulphasalazine from the start, periductal fibrosis and portal fibrosis were remarkably improved 45 months later. We suggest that sulphasalazine in addition to UDCA might be a viable treatment for children with primary sclerosing cholangitis.     

Autoimmune cholangitis with features of autoimmune hepatitis: successful treatment with immunosuppressive agents and ursodeoxycholic acid

We report a 42-year-old Chinese female with elevated serum levels of liver aminotransferases, alkaline phosphatase, gamma-glutamyl transpeptidase, cholesterol and immunoglobulin M. Serum antimitochondrial antibody was negative, but antinuclear antibody was strongly positive. Liver histology showed features of both autoimmune cholangitis and autoimmune hepatitis. Combination therapy with immunosuppressive (prednisone and azathioprine) and choleuretic agents (ursodeoxycholic acid) was given. Serum aminotransferases and biliary enzymes showed much improvement after treatment. A follow-up liver biopsy showed improvement of both hepatic necroinflammation and bile duct damage. Biliary enzymes rose after withdrawal of the immunosuppressive agents and declined again with reinstitution of prednisone. This case demonstrates that a combination of immunosuppressive agents and ursodeoxycholic acid may effectively treat patients with features of both autoimmune cholangitis and autoimmune hepatitis.