Serum biomarkers correlated with liver stiffness assessed in a multicenter study of pediatric cholestatic liver disease.

Background And Aims: Detailed investigation of the biological pathways leading to hepatic fibrosis and identification of liver fibrosis biomarkers may facilitate early interventions for pediatric cholestasis.

Approach And Results: A targeted enzyme-linked immunosorbent assay-based panel of nine biomarkers (lysyl oxidase, tissue inhibitor matrix metalloproteinase (MMP) 1, connective tissue growth factor [CTGF], IL-8, endoglin, periostin, Mac-2-binding protein, MMP-3, and MMP-7) was examined in children with biliary atresia (BA; n = 187), alpha-1 antitrypsin deficiency (A1AT; n = 78), and Alagille syndrome (ALGS; n = 65) and correlated with liver stiffness (LSM) and biochemical measures of liver disease. Median age and LSM were 9 years and 9.

Efficacy and Safety of Immunosuppression Withdrawal in Pediatric Liver Transplant Recipients: Moving Toward Personalized Management.

Background And Aims: Tolerance is transplantation's holy grail, as it denotes allograft health without immunosuppression and its toxicities. Our aim was to determine, among stable long-term pediatric liver transplant recipients, the efficacy and safety of immunosuppression withdrawal to identify operational tolerance.

Approach And Results: We conducted a multicenter, single-arm trial of immunosuppression withdrawal over 36-48 weeks.

Histologic Findings of Advanced Fibrosis and Cirrhosis in Patients With Nonalcoholic Fatty Liver Disease Who Have Normal Aminotransferase Levels.

Objectives: Patients with nonalcoholic fatty liver disease (NAFLD) and normal aminotransferase levels may have advanced liver histology. We conducted a study to characterize the prevalence of and factors associated with advanced liver histology in patients with histologically characterized NAFLD and normal aminotransferase levels.

Methods: We evaluated 534 adults with biopsy-proven NAFLD and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <40U/L within 3 months of their liver biopsy.

Evidence of Chronic Allograft Injury in Liver Biopsies From Long-term Pediatric Recipients of Liver Transplants.

Background & Aims: A substantial proportion of pediatric liver transplant recipients develop subclinical chronic allograft injury. We studied whether there are distinct patterns of injury based on histopathologic features and identified associated immunologic profiles.

Methods: We conducted a cross-sectional study of 157 stable, long-term pediatric recipients of transplanted livers (70 boys; > 6 years old at time of transplantation; mean, 8.

Vibration-Controlled Transient Elastography to Assess Fibrosis and Steatosis in Patients With Nonalcoholic Fatty Liver Disease.

Background & Aims: Vibration-controlled transient elastography (VCTE), which measures liver stiffness, has become an important tool for evaluating patients with nonalcoholic fatty liver disease (NAFLD). We aimed to determine the diagnostic accuracy of VCTE in detection of NAFLD in a multicenter cohort of patients.

Methods: We performed a prospective study of 393 adults with NAFLD who underwent VCTE within 1 year of liver histology analysis (median time, 49 d; interquartile range, 25-78 d), from July 1, 2014, through July 31, 2017.

Biliary Atresia: Clinical and Research Challenges for the Twenty-First Century.

Biliary atresia (BA) is a fibroinflammatory disease of the intrahepatic and extrahepatic biliary tree. Surgical hepatic portoenterostomy (HPE) may restore bile drainage, but progression of the intrahepatic disease results in complications of portal hypertension and advanced cirrhosis in most children. Recognizing that further progress in the field is unlikely without a better understanding of the underlying cause(s) and pathogenesis of the disease, the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) sponsored a research workshop focused on innovative and promising approaches and on identifying future areas of research.

Diagnostic accuracy of magnetic resonance imaging hepatic proton density fat fraction in pediatric nonalcoholic fatty liver disease.

Unlabelled: We assessed the performance of magnetic resonance imaging (MRI) proton density fat fraction (PDFF) in children to stratify hepatic steatosis grade before and after treatment in the Cysteamine Bitartrate Delayed-Release for the Treatment of Nonalcoholic Fatty Liver Disease in Children (CyNCh) trial, using centrally scored histology as reference. Participants had multiecho 1.5 Tesla (T) or 3T MRI on scanners from three manufacturers.

Performance characteristics of vibration-controlled transient elastography for evaluation of nonalcoholic fatty liver disease.

Unlabelled: Vibration-controlled transient elastography estimates liver stiffness measurement (LSM) and controlled attenuation parameter (CAP), which are noninvasive assessments of hepatic fibrosis and steatosis, respectively. However, prior vibration-controlled transient elastography studies reported high failure rates in patients with nonalcoholic fatty liver disease. We examined the performance characteristics of the FibroScan 502 Touch with two probes, medium (M+) and extra large (XL+), in patients with nonalcoholic fatty liver disease in a multicenter setting.

Agreement Between Magnetic Resonance Imaging Proton Density Fat Fraction Measurements and Pathologist-Assigned Steatosis Grades of Liver Biopsies From Adults With Nonalcoholic Steatohepatitis.

Background & Aims: We assessed the diagnostic performance of magnetic resonance imaging (MRI) proton density fat fraction (PDFF) in grading hepatic steatosis and change in hepatic steatosis in adults with nonalcoholic steatohepatitis (NASH) in a multi-center study, using central histology as reference.

Methods: We collected data from 113 adults with NASH participating in a multi-center, randomized, double-masked, placebo-controlled, phase 2b trial to compare the efficacy cross-sectionally and longitudinally of obeticholic acid vs placebo. Hepatic steatosis was assessed at baseline and after 72 weeks of obeticholic acid or placebo by liver biopsy and MRI (scanners from different manufacturers, at 1.

Pediatric acute liver failure of undetermined cause: A research workshop.

Unlabelled: Pediatric acute liver failure (PALF) is a potentially devastating condition that occurs in previously healthy children of all ages and frequently leads to a rapid clinical deterioration. An identified cause for liver injury is lacking in approximately 30% of cases. Children with undetermined diagnosis have lower spontaneous survival and higher rates of transplantation and death than other diagnostic groups.

In Children With Nonalcoholic Fatty Liver Disease, Cysteamine Bitartrate Delayed Release Improves Liver Enzymes but Does Not Reduce Disease Activity Scores.

Background & Aims: No treatment for nonalcoholic fatty liver disease (NAFLD) has been approved by regulatory agencies. We performed a randomized controlled trial to determine whether 52 weeks of cysteamine bitartrate delayed release (CBDR) reduces the severity of liver disease in children with NAFLD.

Methods: We performed a double-masked trial of 169 children with NAFLD activity scores of 4 or higher at 10 centers.

Hepatitis B Virus--Specific and Global T-Cell Dysfunction in Chronic Hepatitis B.

Background & Aims: T cells play a critical role in viral infection. We examined whether T-cell effector and regulatory responses can define clinical stages of chronic hepatitis B (CHB).

Methods: We enrolled 200 adults with CHB who participated in the National Institutes of Health-supported Hepatitis B Research Network from 2011 through 2013 and 20 uninfected individuals (controls).

Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.

Background: The bile acid derivative 6-ethylchenodeoxycholic acid (obeticholic acid) is a potent activator of the farnesoid X nuclear receptor that reduces liver fat and fibrosis in animal models of fatty liver disease. We assessed the efficacy of obeticholic acid in adult patients with non-alcoholic steatohepatitis.

Methods: We did a multicentre, double-blind, placebo-controlled, parallel group, randomised clinical trial at medical centres in the USA in patients with non-cirrhotic, non-alcoholic steatohepatitis to assess treatment with obeticholic acid given orally (25 mg daily) or placebo for 72 weeks.

Clinical and histological determinants of nonalcoholic steatohepatitis and advanced fibrosis in elderly patients.

Unlabelled: The characteristics of nonalcoholic fatty liver disease (NAFLD) in elderly patients are unknown. Therefore, we aimed to examine the differences between elderly and nonelderly patients with NAFLD and to identify determinants of nonalcoholic steatohepatitis (NASH) and advanced fibrosis (bridging fibrosis or cirrhosis) in elderly patients. This is a cross-sectional analysis of adult participants who were prospectively enrolled in the NASH Clinical Research Network studies.

Effect of ribavirin on viral kinetics and liver gene expression in chronic hepatitis C.

Objective: Ribavirin improves treatment response to pegylated-interferon (PEG-IFN) in chronic hepatitis C but the mechanism remains controversial. We studied correlates of response and mechanism of action of ribavirin in treatment of hepatitis C.

Design: 70 treatment-naive patients were randomised to 4 weeks of ribavirin (1000-1200 mg/d) or none, followed by PEG-IFNα-2a and ribavirin at standard doses and durations.

Intravenous N-acetylcysteine in pediatric patients with nonacetaminophen acute liver failure: a placebo-controlled clinical trial.

Unlabelled: N-acetylcysteine (NAC) was found to improve transplantation-free survival in only those adults with nonacetaminophen (non-APAP) acute liver failure (ALF) and grade 1-2 hepatic encephalopathy (HE). Because non-APAP ALF differs significantly between children and adults, the Pediatric Acute Liver Failure (PALF) Study Group evaluated NAC in non-APAP PALF. Children from birth through age 17 years with non-APAP ALF enrolled in the PALF registry were eligible to enter an adaptively allocated, doubly masked, placebo-controlled trial using a continuous intravenous infusion of NAC (150 mg/kg/day in 5% dextrose in water [D5W]) or placebo (D5W) for up to 7 days.

Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy: a randomized controlled trial.

Context: The botanical product silymarin, an extract of milk thistle, is commonly used by patients to treat chronic liver disease, despite scant and conflicting evidence of its efficacy.

Objective: To determine the effect of silymarin on liver disease activity in patients with chronic hepatitis C virus (HCV) infection unsuccessfully treated with interferon-based therapy.

Design, Setting, And Participants: Multicenter, double-blind, placebo-controlled trial conducted at 4 medical centers in the United States.

Rationale, challenges, and participants in a Phase II trial of a botanical product for chronic hepatitis C.

Background: Chronic hepatitis C is associated with significant morbidity and mortality as a consequence of progression to cirrhosis, hepatocellular carcinoma, and liver failure. Current treatment for chronic hepatitis C with pegylated interferon (IFN) and ribavirin is associated with suboptimal responses and numerous adverse effects. A number of botanical products have been used to treat hepatic disorders.

Differences in the disposition of silymarin between patients with nonalcoholic fatty liver disease and chronic hepatitis C.

Silymarin, derived from the milk thistle plant Silybum marianum and widely used for self-treatment of liver diseases, is composed of six major flavonolignans including silybin A and silybin B, which are the predominant flavonolignans quantified in human plasma. The single- and multiple-dose pharmacokinetics of silymarin flavonolignans were examined in patients with nonalcoholic fatty liver disease (NAFLD) or hepatitis C virus (HCV) to determine whether the disposition of silymarin and therefore its potential efficacy vary among liver disease populations. Cohorts of eight subjects with noncirrhotic liver disease were randomized 3:1 to oral silymarin or placebo (280 or 560 mg) every 8 h for 7 days.

Hepatitis B virology for clinicians.

A basic understanding of the molecular events involved in the hepatitis B virus (HBV) life cycle is essential to better appreciate the natural history and atypical presentations of the disease and to develop individual management plans based on readily available virologic tests. With the improved knowledge gained from studying the molecular biology of HBV, novel approaches to inhibition of viral replication are being explored, such as viral entry inhibitors, nucleocapsid inhibitors, and inhibitors of viral assembly. However, the ultimate goal of therapy is to identify strategies to eliminate covalently closed circular DNA from infected hepatocytes.

Silymarin ascending multiple oral dosing phase I study in noncirrhotic patients with chronic hepatitis C.

Silymarin, derived from the milk thistle plant Silybum marianum, is widely used for self-treatment of liver diseases, including hepatitis C virus (HCV), and its antiviral activity has been demonstrated in vitro and in HCV patients administered an intravenous formulation of the major silymarin flavonolignans, silybin A and silybin B. The safety and dose-exposure relationships of higher than customary oral doses of silymarin and its acute effects on serum HCV RNA were evaluated in noncirrhotic HCV patients. Four cohorts of 8 patients with well-compensated, chronic noncirrhotic HCV who failed interferon-based therapy were randomized 3:1 to silymarin or placebo.