Liver-related and extrahepatic events in patients with non-alcoholic fatty liver disease: a retrospective competing risks analysis.

Background & Aim: Non-alcoholic fatty liver disease (NAFLD), and especially fibrotic non-alcoholic steatohepatitis, is associated with high risks of liver-related events (LRE) and extrahepatic events (EHE). We evaluated the competitive risk occurrence of LRE and EHE in a large cohort of biopsy-proven NAFLD stratified according to baseline severity of fibrosis. Methods: Two thousand one hundred thirty-five patients with biopsy-proven NAFLD were enrolled. Observed cumulative incidence functions (CIFs) were used to evaluate the risk of LRE and EHE; cause-specific Cox model and predicted CIFs were fitted to identify predictors of LRE and EHE. A replication cohort of NAFLD patients with live…

Metabolic syndrome and severity of fibrosis in nonalcoholic fatty liver disease: An age-dependent risk profiling study

Background & Aims: Metabolic syndrome (MS) and its individual components are associated with the severity and progression of nonalcoholic fatty liver disease (NAFLD). We sought to evaluate the relationship between MS components and the risk of severe hepatic fibrosis in NAFLD patients discriminated by age. Methods: We considered 863 consecutive patients with biopsy-proven NAFLD, who had been fully evaluated for components of MS. Results: Multivariate logistic regression analysis showed that F3-F4 was associated with visceral obesity, IFG/diabetes, and low high-density lipoprotein (HDL) cholesterol, but not triglycerides >150 or arterial hypertension. A significant interaction was found betw…

Caucasian lean subjects with non-alcoholic fatty liver disease share long-term prognosis of non-lean: Time for reappraisal of BMI-driven approach?

[Objective] The full phenotypic expression of non-alcoholic fatty liver disease (NAFLD) in lean subjects is incompletely characterised. We aimed to investigate prevalence, characteristics and long-term prognosis of Caucasian lean subjects with NAFLD.

Genetic variation in the TLL1 gene is not associated with fibrosis in patients with metabolic associated fatty liver disease.

Metabolic associated fatty liver disease (MAFLD) is the most prevalent liver disease in Western nations, with high heritability. A recent study of Japanese patients with the disease suggested that TLL1 rs17047200 is associated with fibrosis; whether a similar association is observed in Caucasian patients with MAFLD is unknown. We investigated the association of the TLL1 rs17047200 polymorphism with liver fibrosis in a cohort of Caucasian patients with MAFLD (n = 728). We also investigated whether TLL1 expression is altered during liver injury in humans, in murine models of fibrosis, and in in-vitro. While TLL1 expression is upregulated in the liver of humans with MAFLD and in mice, the rs17…

Fibrosis is not just fibrosis - basement membrane modelling and collagen metabolism differs between hepatitis B- and C-induced injury

BACKGROUND: While morphological patterns differ, the molecular phenotype of liver fibrosis is considered a stereotypical response to chronic liver injury. However, with different cellular triggers and networks regulating fibrosis, the molecular responses of the injured liver may not be identical.AIM: To investigate whether differences in extracellular matrix (ECM) composition of the liver during fibrogenesis in two seemingly similar types of viral hepatitis could be reflected by differences in ECM turnover.METHODS: Utilising a cross-sectional design, we measured specific ECM protein fragments in plasma from 197 chronic hepatitis B (CHB) patients and 403 chronic hepatitis C (CHC) patients ma…

<i>NR1H4</i> rs35724 G>C Variant Modulates Liver Damage in Nonalcoholic Fatty Liver Disease

Background and Aims: Farnesoid X receptor (FXR) plays a key role in bile acid and lipid homeostasis. Experimental evidence suggests that it can modulate liver damage related to nonalcoholic fatty liver disease (NAFLD). We examined the impact of the NR1H4 rs35724 variant, encoding for FXR, on liver damage in a large cohort of patients at risk of steatohepatitis. Methods: We considered 2,660 consecutive individuals at risk of steatohepatitis with liver histology. The rs35724 G>C polymorphisms was genotyped by TaqMan assays. Gene expression was evaluated by RNASeq in a subset of patients (n=124). Results: The NR1H4 rs35724 variant was protective against severity of steatosis (OR 0.89, 95% C.I.…

Collagen biology and non‐invasive biomarkers of liver fibrosis

There is an unmet need for high-quality liquid biomarkers that can safely and reproducibly predict the stage of fibrosis and the outcomes of chronic liver disease (CLD). The requirement for such markers has intensified because of the high global prevalence of diseases such as non-alcoholic fatty liver disease (NAFLD). In particular, there is a need for diagnostic and prognostic tools, as well as predictive biomarkers that reflect the efficacy of interventions, as described by the BEST criteria (Biomarkers, EndpointS, and other Tools Resource). This review covers the various liver collagens, their functional role in tissue homeostasis and delineates the common nomenclature for biomarkers bas…

Advancing the global public health agenda for NAFLD: a consensus statement

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Effects of IL28B rs12979860 CC Genotype on Metabolic Profile and Sustained Virologic Response in Patients With Genotype 1 Chronic Hepatitis C

Patients with genotype 1 chronic hepatitis C (G1 CHC) frequently develop steatosis and insulin resistance (IR), caused by metabolic and viral factors. These accelerate the progression of liver disease and reduce the response to therapy. A sustained virologic response (SVR) to therapy in patients with G1 CHC is associated strongly with polymorphisms near the interleukin-28B (IL28B) gene, but the interaction between IL28B genotype and IR, and their combined effects on SVR, have not been defined. We tested the association between the IL28B rs12979860 single-nucleotide polymorphism and metabolic features, including IR, and evaluated their effects on SVR.We performed genotype analysis of IL28B r…

Endotrophin, a pro-peptide of Type VI collagen, is a biomarker of survival in cirrhotic patients with hepatocellular carcinoma

Aim: Type VI collagen, is emerging as a signaling collagen originating from different types of fibroblasts. A specific fragment of Type VI collagen, the pro-peptide, is also known as the hormone endotrophin. We hypothesized that this fibroblast hormone would be of particular relevance in cancer types with a high amount of fibrosis activity, namely for outcome in hepatocellular carcinoma (HCC) cirrhotic patients. Patients & methods: Plasma C6M, PRO-C6 and alphafeto-protein (AFP) were assessed in 309 patients with mixed etiologies (hepatitis C, hepatitis B, alcohol and nonalcoholic fatty liver) diagnosed as cirrhotics, cirrhotics with HCC, noncirrhotics and healthy controls. Progression-f…

Lean NAFLD: A Distinct Entity Shaped by Differential Metabolic Adaptation

Background and Aims: Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the adult population. A significant subset of patients are lean, but their underlying pathophysiology is not well understood. Approach and Results: We investigated the role of bile acids (BAs) and the gut microbiome in the pathogenesis of lean NAFLD. BA and fibroblast growth factor (FGF) 19 levels (a surrogate for intestinal farnesoid X receptor [FXR] activity), patatin-like phospholipase domain containing 3 (PNPLA3), and transmembrane 6 superfamily member 2 (TM6SF2) variants, and gut microbiota profiles in lean and nonlean NAFLD were investigated in a cohort of Caucasian patients with biopsy-proven NAFLD (n …

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

© 2019 Elsevier Ltd. All rights reserved.

PNPLA3 rs738409 I748M is associated with steatohepatitis in 434 non-obese subjects with hepatitis C

Summary Background The PNPLA3/Adiponutrin rs738409 C/G single nucleotide polymorphism is associated with the severity of steatosis, steatohepatitis and fibrosis in patients with non-alcoholic fatty liver disease, as well as the severity of steatosis and fibrosis in patients with chronic hepatitis C (CHC). Aim To test in genotype 1(G1)-CHC patients, the putative association between the PNPLA3 variant and histological features of steatohepatitis, as well as their impact on the severity of fibrosis. Methods Four hundred and thirty-four consecutively biopsied Caucasian G1-CHC patients were genotyped for PNPLA3 rs738409, its effect evaluated by using an additive model. Histological features of s…

IFNL3/4 genotype is associated with altered immune cell populations in peripheral blood in chronic hepatitis C infection

Single-nucleotide polymorphisms near the interferon lambda 3 (IFNL3) gene predict outcomes to infection and anti-viral treatment in hepatitis C virus (HCV) infection. To identify IFNL3 genotype effects on peripheral blood, we collected phenotype data on 400 patients with genotype 1 chronic hepatitis C (CHC). The IFNL3 responder genotype predicted significantly lower white blood cells (WBCs), as well as lower absolute numbers of monocytes, neutrophils and lymphocytes for both rs8099917 and rs12979860. We sought to define the WBC subsets driving this association using flow cytometry of 67 untreated CHC individuals. Genotype-associated differences were seen in the ratio of CD4CD45RO+ to CD4CD4…

NR1H4 rs35724 G>C variant modulates liver damage in nonalcoholic fatty liver disease

Background and Aims: Farnesoid X receptor (FXR) plays a key role in bile acid and lipid homeostasis. Experimental evidence suggests that it can modulate liver damage related to nonalcoholic fatty liver disease (NAFLD). We examined the impact of the NR1H4 rs35724 G>C, encoding for FXR, on liver damage in a large cohort of patients at risk of steatohepatitis. Methods: We considered 2,660 consecutive individuals at risk of steatohepatitis with liver histology. The rs35724 G>C polymorphisms were genotyped by TaqMan assays. Gene expression was evaluated by RNASeq in a subset of patients (n = 124). Results: The NR1H4 rs35724 CC genotype, after adjusting for clinic-metabolic and genetic conf…

A Sequential Algorithm Combining ADAPT and Liver Stiffness Can Stage Metabolic-Associated Fatty Liver Disease in Hospital-Based and Primary Care Patients.

INTRODUCTION Metabolic-associated fatty liver disease is common, with fibrosis the major determinant of adverse outcomes. Population-based screening tools with high diagnostic accuracy for the staging of fibrosis are lacking. METHODS Three independent cohorts, 2 with both liver biopsy and liver stiffness measurements (LSMs, n = 254 and 65) and a population sample (n = 713), were studied. The performance of a recently developed noninvasive algorithm (ADAPT [age, diabetes, PRO-C3 and platelets panel]) as well as aspartate aminotransferase-to-platelet ratio index, fibrosis-4, nonalcoholic fatty liver disease fibrosis score, and LSM was used to stage patients for significant (≥F2) and advanced …

Dual proteotoxic stress accelerates liver injury via activation of p62‐Nrf2

Protein accumulation is the hallmark of various neuronal, muscular, and other human disorders. It is also often seen in the liver as a major protein-secretory organ. For example, aggregation of mutated alpha1-antitrypsin (AAT), referred to as PiZ, is a characteristic feature of AAT deficiency, whereas retention of hepatitis B surface protein (HBs) is found in chronic hepatitis B (CHB) infection. We investigated the interaction of both proteotoxic stresses in humans and mice. Animals overexpressing both PiZ and HBs (HBs-PiZ mice) had greater liver injury, steatosis, and fibrosis. Later they exhibited higher hepatocellular carcinoma load and a more aggressive tumor subtype. Although PiZ and H…

Mistranslation Drives Alterations in Protein Levels and the Effects of a Synonymous Variant at the Fibroblast Growth Factor 21 Locus.

This article also appears in: Health, Medical, and Life Sciences Virtual Issue for Advanced Science.

The membrane-bound O-acyltransferase domain-containing 7 variant rs641738 increases inflammation and fibrosis in chronic hepatitis B.

Chronic hepatitis B (CHB) is characterized by hepatic inflammation that promotes progression to cirrhosis and predisposes to the development of hepatocellular carcinoma (HCC). Subtle interindividual genetic variation as well as viral and environmental factors interact to determine disease progression between individuals. Recently, the rs641738 membrane-bound O-acyltransferase domain-containing 7 (MBOAT7) polymorphism was demonstrated to influence histological liver damage in alcoholic liver disease, nonalcoholic fatty liver disease, and hepatitis C, but no data are available for CHB. We evaluated rs641738 influence on disease severity in a cohort of 1,101 patients with CHB. Forty-two patien…

A STAT4 variant increases liver fibrosis risk in Caucasian patients with chronic hepatitis B

Background Host genetic modifiers of the natural history of chronic hepatitis B (CHB) remain poorly understood. Recently, a genome-wide association study (GWAS)-identified polymorphism in the STAT4 gene that contributes to the risk for hepatocellular carcinoma (HCC) was shown to be associated with the full spectrum of hepatitis B virus (HBV) outcomes in Asian patients. However, the functional mechanisms for this effect are unknown and the role of the variant in modulating HBV disease in Caucasians has not been investigated. Aims To determine whether STAT4 genetic variation is associated with liver injury in Caucasian patients with CHB and to investigate potential mechanisms mediating this e…

P0760 : PNPLA3 rs738409 I748M is associated with steatohepatitis in non obese subjects with hepatitis C

A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement

The exclusion of other chronic liver diseases including “excess” alcohol intake has until now been necessary to establish a diagnosis of metabolic dysfunction-associated fatty liver disease (MAFLD). However, given our current understanding of the pathogenesis of MAFLD and its rising prevalence, “positive criteria” to diagnose the disease are required. In this work, a panel of international experts from 22 countries propose a new definition for the diagnosis of MAFLD that is both comprehensive and simple, and is independent of other liver diseases. The criteria are based on evidence of hepatic steatosis, in addition to one of the following three criteria, namely overweight/obesity, presence …