Statins, antidiabetic medications and liver histology in patients with diabetes with non-alcoholic fatty liver disease

Background: Type-2 diabetes mellitus (T2DM) is a risk factor for progressive non-alcoholic fatty liver disease (NAFLD). Drugs commonly prescribed in patients with T2DM may affect liver histology by interfering with lipid metabolism and insulin resistance/secretion. Aim: We studied if statins or antidiabetic agents were associated with non-alcoholic steatohepatitis (NASH) and significant fibrosis (SF). Methods: We performed a cross-sectional study of 346 diabetics with biopsy-proven NAFLD. T2DM was defined as fasting glucose ≥7 mmol/L or glycated haemoglobin ≥6.5% and/or use of antidiabetics. NASH was defined according to the FLIP algorithm and SF as F2-4 Kleiner's stages. Results: 84% of patients were on antidiabetic therapy and 45% on statins. NASH and SF were present in 57% and 48% of patients. Statin-treated patients were older, more frequently male and with poorer glycaemic control despite more frequent antidiabetic therapy than those without statins; however, the prevalence of NASH (57%vs56%, p=0.868) and SF (48%vs48%, p=0.943) was not different between statin users and non-users. NASH was more common in patients on metformin or insulin than in those not treated with these drugs (60% vs47%, p=0.026; 68%vs53%, p=0.017). SF was more common in those treated with sulfonylureas (57% vs44%, p=0.030). Multivariate analyses confirmed that use of statins was independently and negatively associated with both NASH (OR (95% CI) 0.57 (0.32 to 1.01), p=0.055) and SF (OR (95% CI) 0.47 (0.26 to 0.84), p=0.011). Moreover, we found independent associations between insulin use and NASH (OR (95% CI) 2.24 (1.11 to 4.54), p=0.025) and sulfonylureas use and SF (OR (95% CI) 2.04 (1.11 to 3.74), p=0.022). Conclusions: Several medications used in patients with diabetes are differently associated with NAFLD histology. Statin use is negatively associated, while insulin and sulfonylureas are positively associated with NASH and SF. A wider use of statins may be warranted in this high-risk population

Noninvasive Markers of Hepatic Fibrosis in Chronic Hepatitis B

A serum biomarker (FibroTest; Biopredictive, Paris, France; FibroSure; LabCorp, Burlington, USA) and liver stiffness measurement (LSM) by Fibroscan (Echosens, Paris, France) have been extensively validated in chronic hepatitis C. This review updates the clinical validation of serum biomarkers and LSM in patients with chronic hepatitis B (CHB). One meta-analysis combined all published studies and another used a database combining FibroTest individual data. Sensitivity analysis assessed the impact of several factors, including authors’ independence, length of biopsy, ethnicity, hepatitis B early antigen status, viral load, and alanine aminotransferase value. Only two biomarkers had several validations: FibroTest (8 studies, 1,842 patients), and Fibroscan (5 studies, 618 patients). For the diagnosis of advanced fibrosis, the standardized area under the receiver operating curve was 0.84 (0.79–0.86) for FibroTest and 0.89 (0.83–0.96) for LSM, without significant difference. No significant factors of variability were identified for FibroTest’s performance. In conclusion, FibroTest and LSM were the most validated biomarkers of fibrosis in CHB. However, the reliability of Fibroscan must be better assessed

Applicability and precautions of use of liver injury biomarker FibroTest. A reappraisal at 7 years of age

<p>Abstract</p> <p>Background</p> <p>FibroTest (FT) is a validated biomarker of fibrosis. To assess the applicability rate and to reduce the risk of false positives/negatives (RFPN), security algorithms were developed. The aims were to estimate the prevalence of RFPN and of proven failures, and to identify factors associated with their occurrences.</p> <p>Methods</p> <p>Four populations were studied: 954 blood donors (P1), 7,494 healthy volunteers (P2), 345,695 consecutive worldwide sera (P3), including 24,872 sera analyzed in a tertiary care centre (GHPS) (P4). Analytical procedures of laboratories with RFPN > 5% and charts of P4 patients in with RFPN were reviewed.</p> <p>Results</p> <p>The prevalence of RFPN was 0.52% (5/954; 95%CI 0.17-1.22) in P1, 0.51% (38/7494; 0.36-0.70) in P2, and 0.97% (3349/345695; 0.94-1.00) in P3. Three a priori high-risk populations were confirmed: 1.97% in P4, 1.77% in HIV centre and 2.61% in Sub-Saharan origin subjects. RFPN was mostly associated with low haptoglobin (0.46%), and high apolipoproteinA1 (0.21%). A traceability study of a P3 laboratory with RFPFN > 5% permitted to correct analytical procedures.</p> <p>Conclusion</p> <p>The mean applicability rate of Fibrotest was 99.03%. Independent factors associated with the high risk of false positives/negatives were HIV center, subSaharan origin, and a tertiary care reference centre, although the applicability rate remained above 97%.</p

An Accurate Definition of the Status of Inactive Hepatitis B Virus Carrier by a Combination of Biomarkers (FibroTest-ActiTest) and Viral Load

BACKGROUND: The combination of transaminases (ALT), biopsy, HBeAg and viral load have classically defined the inactive status of carriers of chronic hepatitis B. The use of FibroTest (FT) and ActiTest (AT), biomarkers of fibrosis and necroinflammatory activity, has been previously validated as alternatives to biopsy. We compared the 4-year prognostic value of combining FT-AT and viral load for a better definition of the inactive carrier status. METHODS AND FINDINGS: 1,300 consecutive CHB patients who had been prospectively followed since 2001 were pre-included. The main endpoint was the absence of liver-related complications, transplantation or death. We used the manufacturers' definitions of normal FT (< = 0.27), normal AT (< = 0.29) and 3 standard classes for viral load. The adjustment factors were age, sex, HBeAg, ethnic origin, alcohol consumption, HIV-Delta-HCV co-infections and treatment. RESULTS: 1,074 patients with baseline FT-AT and viral load were included: 41 years old, 47% African, 27% Asian, 26% Caucasian. At 4 years follow-up, 50 complications occurred (survival without complications 93.4%), 36 deaths occurred (survival 95.0%), including 27 related to HBV (survival 96.1%). The prognostic value of FT was higher than those of viral load or ALT when compared using area under the ROC curves [0.89 (95%CI 0.84-0.93) vs 0.64 (0.55-0.71) vs 0.53 (0.46-0.60) all P<0.001], survival curves and multivariate Cox model [regression coefficient 5.2 (3.5-6.9; P<0.001) vs 0.53 (0.15-0.92; P = 0.007) vs -0.001 (-0.003-0.000;P = 0.052)] respectively. A new definition of inactive carriers was proposed with an algorithm combining "zero" scores for FT-AT (F0 and A0) and viral load classes. This new algorithm provides a 100% negative predictive value for the prediction of liver related complications or death. Among the 275 patients with the classic definition of inactive carrier, 62 (23%) had fibrosis presumed with FT, and 3 died or had complications at 4 year. CONCLUSION: In patients with chronic hepatitis B, a combination of FibroTest-ActiTest and viral load testing accurately defined the prognosis and the inactive carrier status

Diagnostic performance of FibroTest, SteatoTest and ActiTest in patients with NAFLD using the SAF score as histological reference

BACKGROUND: Blood tests of liver injury are less well validated in non‐alcoholic fatty liver disease (NAFLD) than in patients with chronic viral hepatitis. AIMS: To improve the validation of three blood tests used in NAFLD patients, FibroTest for fibrosis staging, SteatoTest for steatosis grading and ActiTest for inflammation activity grading. METHODS: We pre‐included new NAFLD patients with biopsy and blood tests from a single‐centre cohort (FibroFrance) and from the multicentre FLIP consortium. Contemporaneous biopsies were blindly assessed using the new steatosis, activity and fibrosis (SAF) score, which provides a reliable and reproducible diagnosis and grading/staging of the three elementary features of NAFLD (steatosis, inflammatory activity) and fibrosis with reduced interobserver variability. We used nonbinary‐ROC (NonBinAUROC) as the main endpoint to prevent spectrum effect and multiple testing. RESULTS: A total of 600 patients with reliable tests and biopsies were included. The mean NonBinAUROCs (95% CI) of tests were all significant (P < 0.0001): 0.878 (0.864–0.892) for FibroTest and fibrosis stages, 0.846 (0.830–0.862) for ActiTest and activity grades, and 0.822 (0.804–0.840) for SteatoTest and steatosis grades. FibroTest had a higher NonBinAUROC than BARD (0.836; 0.820–0.852; P = 0.0001), FIB4 (0.845; 0.829–0.861; P = 0.007) but not significantly different than the NAFLD score (0.866; 0.850–0.882; P = 0.26). FibroTest had a significant difference in median values between adjacent stage F2 and stage F1 contrarily to BARD, FIB4 and NAFLD scores (Bonferroni test P < 0.05). CONCLUSIONS: In patients with NAFLD, SteatoTest, ActiTest and FibroTest are non‐invasive tests that offer an alternative to biopsy, and they correlate with the simple grading/staging of the SAF scoring system across the three elementary features of NAFLD: steatosis, inflammatory activity and fibrosis

Diagnostic value of biochemical markers (NashTest) for the prediction of non alcoholo steato hepatitis in patients with non-alcoholic fatty liver disease

BACKGROUND: Liver biopsy is considered the gold standard for assessing histologic lesions of non-alcoholic fatty liver disease (NAFLD). The aim was to develop and validate a new biomarker of non alcoholic steato hepatitis (NASH) the NashTest (NT) in patients with NAFLD. METHODS: 160 patients with NAFLD were prospectively included in a training group, 97 were included in a multicenter validation group and 383 controls. Histological diagnoses used Kleiner et al's scoring system, with 3 classes for NASH: "Not NASH", "Borderline", "NASH"). The area under the ROC curves (AUROC), sensitivity (Se), specificity (Sp), and positive and negative predictive values (PPV, NPV) were assessed. RESULTS: NT was developed using patented algorithms combining 13 parameters: age, sex, height, weight, and serum levels of triglycerides, cholesterol, alpha2macroglobulin, apolipoprotein A1, haptoglobin, gamma-glutamyl-transpeptidase, transaminases ALT, AST, and total bilirubin. AUROCs of NT for the diagnosis of NASH in the training and validation groups were, respectively, 0.79 (95%CI 0.69–0.86) and 0.79 (95%CI 0.67–0.87; P = 0.94); for the diagnosis of borderline NASH they were: 0.69 (95%CI 0.60–0.77) and 0.69 (95%CI 0.57–0.78; P = 0.98) and for the diagnosis of no NASH, 0.77 (95%CI 0.68–0.84) and 0.83 (95%CI 0.67–0.90; P = 0.34). When the two groups were pooled together the NashTest Sp for NASH = 94% (PPV = 66%), and Se = 33% (NPV = 81%); for borderline NASH or NASH Sp = 50% (PPV = 74%) and Se = 88% (NPV = 72%). CONCLUSION: In patients with non-alcoholic fatty liver disease, NashTest, a simple and non-invasive biomarker reliably predicts the presence or absence of NASH

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

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Pet dogs exhibit social preference for people who synchronize with them: what does it tell us about the evolution of behavioral synchronization?

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