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A decline of LAMP- 2 predicts ursodeoxycholic acid response in primary biliary cirrhosis.

ABSTRACT: Biochemical response to ursodeoxycholic acid (UDCA) in patients with primary biliary cirrhosis (PBC) is variable. We have previously reported that augmented expression of lysosome-associated membrane protein 2 (LAMP-2) was correlated with the severity of PBC. This study aimed to determine whether serum LAMP-2 could serve as a predictor of biochemical response to UDCA. The efficiency of serum LAMP-2 to predict biochemical response was assessed after 1 year of UDCA treatment in PBC patients by a retrospective analysis. We found that the basal serum LAMP-2 level was increased in PBC, especially in patients with stage III-IV (p = 0.010) or TBIL > 1 mg/dL (p = 0.014). Baseline serum LAMP-2 was higher in non-responders than that in responders, but the difference was statistically insignificant. However, after UDCA treatment, serum LAMP-2 level decreased prominently in the first 3 months, which was more obvious in responders. Further studies showed that the 35% decline of LAMP-2 after treatment for 3 months could be stated as an indicator of UDCA response with the sensitivity of 62.9% and specificity of 75.0% by Paris criteria. Meanwhile the specificity and sensitivity were identified as 63.5% and 64.1% by Barcelona criteria. Together, a decline in LAMP-2 might help to predict the response to UDCA.

SUBMITTER: Wang L

PROVIDER: S-EPMC4403591 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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Project description:BackgroundTreatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after 12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted using pretreatment clinical parameters.MethodsWe did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less than 1·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy. Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury and fibrosis, on liver biopsy samples.Findings2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with lower probability of UDCA response: higher alkaline phosphatase concentration (p<0·0001), higher total bilirubin concentration (p=0·0003), lower aminotransferase concentration (p=0·0012), younger age (p<0·0001), longer interval from diagnosis to the start of UDCA treatment (treatment time lag, p<0·0001), and worsening of alkaline phosphatase concentration from diagnosis (p<0·0001). Based on these variables, we derived a predictive score of UDCA response. In the external validation cohort, 460 patients diagnosed with primary biliary cholangitis were treated with UDCA, with follow-up data until May 31, 2016. In this validation cohort, the area under the receiver operating characteristic curve for the score was 0·83 (95% CI 0·79-0·87). In 20 liver biopsy samples from patients with primary biliary cholangitis, the UDCA response score was associated with ductular reaction (r=-0·556, p=0·0130) and intermediate hepatocytes (probability of response was 0·90 if intermediate hepatocytes were absent vs 0·51 if present).InterpretationWe have derived and externally validated a model based on pretreatment variables that accurately predicts UDCA response. Association with histological features provides face validity. This model provides a basis to explore alternative approaches to treatment stratification in patients with primary biliary cholangitis.FundingUK Medical Research Council and University of Milan-Bicocca.

Project description:IntroductionAbout one-third of primary biliary cholangitis (PBC) patients do not exhibit complete response to ursodeoxycholic acid (UDCA). Some of these patients were reported to benefit from the combination therapy of fibrates and UDCA, but more clinical evidence is required. In this study, we conducted a randomized, controlled trial on the safety and efficacy of fenofibrate in the treatment of patients with PBC.MethodsForty-eight PBC patients with incomplete response to UDCA were enrolled and randomly assigned to two groups (24 in the experiment group and 24 in the control group). For the experimental group, the patients were administered 13-15 mg/kg/day UDCA in combination with 200 mg/day fenofibrate. For the control group, the patients continued to receive UDCA at 13-15 mg/kg/day. The patients were followed up for at least 12 months. The serum levels of alkaline phosphatase (ALP), gamma-glutamyl transferase (γ-GT), aspartate aminotransferase (AST), and other biochemical parameters were measured at 3, 6, and 12 months during the trial to assess patient conditions.ResultsAt 12 months, 20.8% of the patients in the experimental group had all three indexes of serum ALP, γ-GT, and total bilirubin normalized, while 0% of patients in the control group reached the primary outcome (difference, 20.8 percentage points; 95% CI, 4.6-37.0). 54.2% of the patients had normal ALP levels in the experimental group and 4.2% in the control group (difference, 50 percentage points; 95% CI, 28.5-71.5). The experimental group had greater improvement of ALP (p < 0.001) and IgG (p = 0.026) than the control group. The biochemical indexes of the patients in the experimental group also significantly improved during the treatment of fenofibrate.ConclusionAddition of fenofibrate can improve biochemical indexes of PBC patients who had an incomplete response to UDCA. Reversible elevation of serum creatine and transaminases is observed in some patients.The trial was registered in the Chinese Clinical Trial Registry (ChiCTR) as ChiCTR1800020160 (protocol available online: http://www.chictr.org.cn/showproj.aspx?proj=32443).

Project description:Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic liver disease with a slowly progressive course. Without treatment, most patients eventually develop fibrosis and cirrhosis of the liver and may need liver transplantation in the late stage of disease. PBC primarily affects women (female preponderance 9-10:1) with a prevalence of up to 1 in 1,000 women over 40 years of age. Common symptoms of the disease are fatigue and pruritus, but most patients are asymptomatic at first presentation. The diagnosis is based on sustained elevation of serum markers of cholestasis, i.e., alkaline phosphatase and gamma-glutamyl transferase, and the presence of serum antimitochondrial antibodies directed against the E2 subunit of the pyruvate dehydrogenase complex. Histologically, PBC is characterized by florid bile duct lesions with damage to biliary epithelial cells, an often dense portal inflammatory infiltrate and progressive loss of small intrahepatic bile ducts. Although the insight into pathogenetic aspects of PBC has grown enormously during the recent decade and numerous genetic, environmental, and infectious factors have been disclosed which may contribute to the development of PBC, the precise pathogenesis remains enigmatic. Ursodeoxycholic acid (UDCA) is currently the only FDA-approved medical treatment for PBC. When administered at adequate doses of 13-15 mg/kg/day, up to two out of three patients with PBC may have a normal life expectancy without additional therapeutic measures. The mode of action of UDCA is still under discussion, but stimulation of impaired hepatocellular and cholangiocellular secretion, detoxification of bile, and antiapoptotic effects may represent key mechanisms. One out of three patients does not adequately respond to UDCA therapy and may need additional medical therapy and/or liver transplantation. This review summarizes current knowledge on the clinical, diagnostic, pathogenetic, and therapeutic aspects of PBC.

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A decline of LAMP- 2 predicts ursodeoxycholic acid response in primary biliary cirrhosis.

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