Ultra-high-field magnetic resonance spectroscopy in non-alcoholic fatty liver disease: Novel mechanistic and diagnostic insights of energy metabolism in non-alcoholic steatohepatitis and advanced fibrosis

Liver Int. 2017 Oct;37(10):1544-1553. doi: 10.1111/liv.13451. Epub 2017 May 20.

Abstract

Background & aims: With the rising prevalence of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) non-invasive tools obtaining pathomechanistic insights to improve risk stratification are urgently needed. We therefore explored high- and ultra-high-field magnetic resonance spectroscopy (MRS) to obtain novel mechanistic and diagnostic insights into alterations of hepatic lipid, cell membrane and energy metabolism across the spectrum of NAFLD.

Methods: MRS and liver biopsy were performed in 30 NAFLD patients with NAFL (n=8) or NASH (n=22). Hepatic lipid content and composition were measured using 3-Tesla proton (1 H)-MRS. 7-Tesla phosphorus (31 P)-MRS was applied to determine phosphomonoester (PME) including phosphoethanolamine (PE), phosphodiester (PDE) including glycerophosphocholine (GPC), phosphocreatine (PCr), nicotinamide adenine dinucleotide phosphate (NADPH), inorganic phosphate (Pi), γ-ATP and total phosphorus (TP). Saturation transfer technique was used to quantify hepatic ATP flux.

Results: Hepatic steatosis in 1 H-MRS highly correlated with histology (P<.001) showing higher values in NASH than NAFL (P<.001) without differences in saturated or unsaturated fatty acid indices. PE/TP ratio increased with advanced fibrosis (F3/4) (P=.002) whereas GPC/PME+PDE decreased (P=.05) compared to no/mild fibrosis (F0-2). γ-ATP/TP was lower in advanced fibrosis (P=.049), while PCr/TP increased (P=.01). NADPH/TP increased with higher grades of ballooning (P=.02). Pi-to-ATP exchange rate constant (P=.003) and ATP flux (P=.001) were lower in NASH than NAFL.

Conclusions: Ultra-high-field MRS, especially saturation transfer technique uncovers changes in energy metabolism including dynamic ATP flux in inflammation and fibrosis in NASH. Non-invasive profiling by MRS appears feasible and may assist further mechanistic and therapeutic studies in NAFLD/NASH.

Keywords: saturation transfer; adenosine triphosphate flux; fatty liver; lipotoxicity; mitochondrial function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Adult
  • Biomarkers / metabolism
  • Biopsy
  • Body Mass Index
  • Energy Metabolism*
  • Fatty Acids / metabolism
  • Feasibility Studies
  • Female
  • Humans
  • Lipase / genetics
  • Liver / diagnostic imaging
  • Liver / metabolism*
  • Liver / pathology
  • Liver Cirrhosis / diagnosis*
  • Liver Cirrhosis / etiology
  • Liver Cirrhosis / genetics
  • Liver Cirrhosis / metabolism
  • Male
  • Membrane Proteins / genetics
  • Metabolomics / methods*
  • Middle Aged
  • Non-alcoholic Fatty Liver Disease / diagnosis*
  • Non-alcoholic Fatty Liver Disease / etiology
  • Non-alcoholic Fatty Liver Disease / genetics
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Obesity / complications
  • Obesity / diagnosis
  • Polymorphism, Single Nucleotide
  • Predictive Value of Tests
  • Prospective Studies
  • Proton Magnetic Resonance Spectroscopy / methods*
  • Ultrasonography

Substances

  • Biomarkers
  • Fatty Acids
  • Membrane Proteins
  • TM6SF2 protein, human
  • Adenosine Triphosphate
  • Lipase
  • adiponutrin, human