| Background:Primary biliary cholangitis(PBC)is a chronic autoimmune liver disease characterized by chronic non-suppurative destruction and inflammation of small intrahepatic bile ducts.The progression of PBC will lead to cholestasis and liver fibrosis,and eventually lead to cirrhosis.The etiology and pathogenesis of PBC are not completely clear.Some studies have reported that its etiology may be related to the disorder of autoimmune system mediated by environmental factors and family genetic factors.Fatigue and pruritus are the most common clinical manifestations of PBC patients.The increase of alkaline phosphatase(ALP),gamma-glutamyl transferase(GGT),and immunoglobulin M(Ig M)levels is the main feature of blood biochemical indicators in PBC patients,and non-suppurative destructive cholangitis is its pathological feature.Ursodeoxycholic acid(UDCA)is the only therapeutic drug that has been proved safe and effective for PBC by large-scale clinical trials,and is also the only drug approved by the Food and Drug Administration(FDA)for PBC treatment.The results of several randomized controlled trials(RCT)and meta-analysis showed that UDCA could effectively reduce the serum total bilirubin(TBIL),ALP,GGT,aspartate aminotransferase(AST)and cholesterol(CHO)levels in PBC patients.60%~70% of PBC patients can obtain good biochemical response and treatment effect after receiving UDCA treatment.Their disease progression is relatively slow and their prognosis is good.However,there are still 30%~40% of PBC patients who can not benefit even after taking the maximum recommended dose of UDCA regularly,and their risk of progression to end-stage liver disease is significantly increased,with poor prognosis.Therefore,we define these PBC patients with poor UDCA biochemical response or UDCA intolerance as UDCA-refractory PBC patients.At present,there is no unified treatment method for UDCA-refractory PBC patients.Fibrates can be used to treat hypertriglyceridemia and mixed hyperlipidemia,and play a role in anti-inflammatory,anti-fibrosis and reducing cholestasis.Although many observational studies have been published,the mechanism of reducing biochemical markers of cholestasis by fibrates and whether the use of fibrates can improve the survival rate of patients with these diseases are still unclear.As a member of the fibrates family,fenofibrate belongs to a class of receptors activated by activating peroxisome proliferatorsα(PPARα)Drugs that are often used to treat hypercholesterolemia and hypertriglyceridemia in clinic.In recent years,more and more evidences have shown that fenofibrate has anti-cholestasis,anti-inflammatory and anti-fibrosis effects,and its combined treatment with UDCA has significant clinical benefits in UDCA-refractory PBC.Therefore,our work intends to verify the therapeutic effect of fenofibrate combined with UDCA in refractory PBC through meta-analysis and cohort study,and enrich its clinical evidence-based medical evidence,which is of great significance.Method:Using "ursodeoxycholic acid","UDCA","fenofibrate","PBC","primary billiary cholangitis","primary billiary cirrhosis" and "randomized controlled trial" as search words,the included literature is determined by searching the published relevant research in Pub Med,Embase,The Cochrane Library and other English databases(the publication time is up to December 2021).The retrieved documents were screened and their quality was evaluated.This cohort study included PBC patients who were diagnosed in the Department of Gastroenterology of the First Affiliated Hospital of the Air Force Military Medical University from February 2010 to November 2020 and received UDCA monotherapy for six months and had poor or intolerable UDCA biochemical response.The patients were divided into "UDCA group" and "UDCA+FF group" according to the follow-up treatment of UDCA single drug or the combination treatment of fenofibrate and UDCA.The clinical information and relevant data of patients at the time of treatment and each follow-up were collected systematically,and the biochemical response rate,serum biochemical indicators and liver histopathological data of the two groups of patients after treatment were compared and analyzed.At the same time,we explored the influencing factors related to the response after treatment with fenofibrate and the safety evaluation of fenofibrate.Meta analysis was processed with Rev Man5.4 software,and clinical research data was analyzed with SPSS 26.0 software.Bilateral P<0.05 was considered statistically significant.Result:9 studies was finally included in the updated meta-analysis,and all met the requirements of meta-analysis after quality evaluation.In this analysis,there were 389 patients with UDCA-refractory PBC,of whom 216 were treated with UDCA alone and 173 were treated with fenofibrate combined with UDCA.The follow-up time was 3~24 months.The daily dose of UDCA is 13-15mg/kg,and the daily dose of fenofibrate is 100-200 mg.Meta-analysis results showed that the combination therapy was more effective than the UDCA monotherapy in reducing the main clinical biochemical indexes(such as ALP,GGT,Ig M and TG)of patients with refractory PBC(P<0.05).However,the incidence of pruritus and adverse events in the combined treatment group was slightly higher than that in the UDCA monotherapy group.A total of 156 patients with UDCA-refractory PBC were enrolled in this cohort study.Among them,68 patients were treated with UDCA alone,and 88 patients were treated with fenofibrate combined with UDCA.Among patients with UDCA-refractory PBC,the combination of fenofibrate and UDCA significantly increased the ALP normalization rate of patients with UDCA-refractory PBC(P<0.001)and decreased the incidence of liver deterioration events(P<0.05).And the combined use of fenofibrate did not bring significant hepatorenal toxicity.The increase of serum total bilirubin is an independent risk factor for poor biochemical response in fenofibrate combined with UDCA treatment group.Conclusion:1.The updated meta-analysis results confirmed that the combined treatment of fenofibrate and UDCA could improve the main serum biochemical indexes of patients with UDCA-refractory PBC;2.The combined treatment of fenofibrate and UDCA can significantly improve the biochemical response rate of UDCA-refractory PBC patients and reduce the occurrence of liver-related deterioration events,but it can not significantly improve the liver histopathological progress;3.The combined use of fenofibrate and UDCA in this cohort did not significantly increase the levels of serum urea nitrogen,creatinine and e GFR.The incidence of serious liver-related adverse events did not significantly increase,and there was no significant hepatorenal toxicity.However,the safety of its long-term use needs to be proved by long-term follow-up and further research;4.The clinical research method combined with cohort study and meta-analysis will further strengthen the evidence-based medicine application of fenofibrate combined with UDCA in patients with UDCA-refractory PBC. |
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