The metabolomic window into hepatobiliary disease

J Hepatol. 2013 Oct;59(4):842-58. doi: 10.1016/j.jhep.2013.05.030. Epub 2013 May 25.


The emergent discipline of metabolomics has attracted considerable research effort in hepatology. Here we review the metabolomic data for non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cirrhosis, hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), alcoholic liver disease (ALD), hepatitis B and C, cholecystitis, cholestasis, liver transplantation, and acute hepatotoxicity in animal models. A metabolomic window has permitted a view into the changing biochemistry occurring in the transitional phases between a healthy liver and hepatocellular carcinoma or cholangiocarcinoma. Whether provoked by obesity and diabetes, alcohol use or oncogenic viruses, the liver develops a core metabolomic phenotype (CMP) that involves dysregulation of bile acid and phospholipid homeostasis. The CMP commences at the transition between the healthy liver (Phase 0) and NAFLD/NASH, ALD or viral hepatitis (Phase 1). This CMP is maintained in the presence or absence of cirrhosis (Phase 2) and whether or not either HCC or CCA (Phase 3) develops. Inflammatory signalling in the liver triggers the appearance of the CMP. Many other metabolomic markers distinguish between Phases 0, 1, 2 and 3. A metabolic remodelling in HCC has been described but metabolomic data from all four Phases demonstrate that the Warburg shift from mitochondrial respiration to cytosolic glycolysis foreshadows HCC and may occur as early as Phase 1. The metabolic remodelling also involves an upregulation of fatty acid β-oxidation, also beginning in Phase 1. The storage of triglycerides in fatty liver provides high energy-yielding substrates for Phases 2 and 3 of liver pathology. The metabolomic window into hepatobiliary disease sheds new light on the systems pathology of the liver.

Keywords: Cirrhosis; Core metabolomic phenotype; Hepatocellular carcinoma; Metabolic remodelling; Metabolomics; NAFLD; NASH; Warburg effect.

Publication types

  • Review

MeSH terms

  • Animals
  • Bile Duct Neoplasms / metabolism
  • Biliary Tract Diseases / etiology
  • Biliary Tract Diseases / metabolism*
  • Carcinoma, Hepatocellular / metabolism
  • Chemical and Drug Induced Liver Injury / metabolism
  • Cholangiocarcinoma / metabolism
  • Cholecystitis / metabolism
  • Cholestasis / metabolism
  • Disease Progression
  • Fatty Liver / metabolism
  • Hepatitis B, Chronic / metabolism
  • Hepatitis C, Chronic / metabolism
  • Humans
  • Liver Cirrhosis / metabolism
  • Liver Diseases / etiology
  • Liver Diseases / metabolism*
  • Liver Diseases / surgery
  • Liver Diseases, Alcoholic / metabolism
  • Liver Neoplasms / metabolism
  • Liver Transplantation
  • Metabolomics
  • Models, Biological
  • Non-alcoholic Fatty Liver Disease