Abstract
BackgroundWorldwide, over 350 million people are chronically infected with the hepatitis B virus (HBV) and are at increased risk of developing progressive liver diseases. The confinement of HBV replication to the liver, which also acts as the central hub for metabolic and nutritional regulation, emphasizes the interlinked nature of host metabolism and the disease. Still, the metabolic processes operational during the distinct clinical phases of a chronic HBV infection—immune tolerant, immune active, inactive carrier, and HBeAg-negative hepatitis phases—remains unexplored.MethodsTo investigate this, we conducted a targeted metabolomics approach on serum to determine the metabolic progression over the clinical phases of chronic HBV infection, using patient samples grouped based on their HBV DNA, alanine aminotransferase, and HBeAg serum levels.ResultsOur data illustrate the strength of metabolomics to provide insight into the metabolic dysregulation experienced during chronic HBV. The immune tolerant phase is characterized by the speculated viral hijacking of the glycerol-3-phosphate–NADH shuttle, explaining the reduced glycerophospholipid and increased plasmalogen species, indicating a strong link to HBV replication. The persisting impairment of the choline glycerophospholipids, even during the inactive carrier phase with minimal HBV activity, alludes to possible metabolic imprinting effects. The progression of chronic HBV is associated with increased concentrations of very long chain triglycerides together with citrulline and ornithine, reflective of a dysregulated urea cycle peaking in the HBV envelope antigen-negative phase.ConclusionsThe work presented here will aid in future studies to (i) validate and understand the implication of these metabolic changes using a thorough systems biology approach, (ii) monitor and predict disease severity, as well as (iii) determine the therapeutic value of the glycerol-3-phosphate–NADH shuttle.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-016-0318-8) contains supplementary material, which is available to authorized users.
Highlights
Worldwide, over 350 million people are chronically infected with the hepatitis B virus (HBV) and are at increased risk of developing progressive liver diseases, including fibrosis, liver failure, or hepatocellular carcinoma (HCC), over the course of several decades [1, 2]
Definition of chronic HBV clinical phases Serum alanine aminotransferase (ALT) was measured on an automated analyzer, qualitative serum HBV surface antigen (HBsAg), HBV envelope antigen (HBeAg), and anti-HBeAg antibodies were measured on an Architect Abbott analyzer, and serum HBV DNA levels were measured using the COBAS AmpliPrep-COBAS Taq-Man HBVv2test (CAP-CTM; Roche Molecular Systems, Indianapolis, IN, USA)
Baseline characteristics of the study population For the metabolomics characterization of chronic HBV infection, a cohort of treatment-naïve patients was chosen and patients with other comorbidities and/or advanced liver fibrosis were excluded from the study
Summary
Over 350 million people are chronically infected with the hepatitis B virus (HBV) and are at increased risk of developing progressive liver diseases. Chronic HBV infection can be divided into four progressively distinct clinical phases based upon serum levels of HBV DNA, alanine aminotransferase (ALT), and HBV envelope antigen (HBeAg). These four phases are the immune tolerant (IT), immune active (IA), inactive carrier (IC), and HBeAg-negative (ENEG) phases. The increased ALT levels in the IA and ENEG phases reflect hepatic injury due to viral activity and immune activity Even though these phases are used in clinical practice for deciding on therapeutic interventions [3], not much is known about the underlying metabolic mechanisms associated with each and/or the progressive nature of the disease. The use of material obtained from patients is crucial to study and understand chronic HBV infection
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