Metabolic and histological implications of intrahepatic triglyceride content in nonalcoholic fatty liver disease

Hepatology. 2017 Apr;65(4):1132-1144. doi: 10.1002/hep.28985. Epub 2017 Feb 25.


The cut-off point of intrahepatic triglyceride (IHTG) content to define nonalcoholic fatty liver disease (NAFLD) by proton magnetic resonance spectroscopy (1 H-MRS) was established based on the 95th percentile in a group of healthy individuals (i.e., ≥5.56%). Whether this threshold correlates with metabolic and histological changes and whether a further accumulation of IHTG is associated with worsening of these parameters has not been properly assessed in a large cohort of patients. In this cross-sectional study, 352 subjects were carefully characterized with the following studies: liver 1 H-MRS; euglycemic insulin clamp with measurement of glucose turnover; oral glucose tolerance test; and a liver biopsy. Hepatic insulin sensitivity (suppression of endogenous glucose production by insulin) was affected early on after IHTG content was ∼1.5% and remained uniformly impaired (∼40%-45%), regardless of further IHTG accumulation. Skeletal muscle insulin sensitivity showed a gradual impairment at low degrees of IHTG accumulation, but remained unchanged after IHTG content reached the ∼6 ± 2% threshold. A similar pattern was observed for metabolic changes typically associated with NAFLD, such as hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C). In contrast, adipose tissue insulin sensitivity (suppression of free fatty acids by insulin) showed a continuous worsening across the spectrum of IHTG accumulation in NAFLD (r = -0.38; P < 0.001). Histological severity of liver disease (inflammation, ballooning, and fibrosis) was not associated with the amount of IHTG content.

Conclusion: IHTG accumulation is strongly associated with adipose tissue insulin resistance (IR), supporting the current theory of lipotoxicity as a driver of IHTG accumulation. Once IHTG accumulation reaches ∼6 ± 2%, skeletal muscle IR, hypertriglyceridemia, and low HDL-C become fully established. Histological activity appears to have an early threshold and is not significantly influenced by increasing amounts of IHTG accumulation. (Hepatology 2017;65:1132-1144).

Publication types

  • Comparative Study

MeSH terms

  • Adult
  • Aged
  • Biomarkers / metabolism
  • Biopsy, Needle
  • Cross-Sectional Studies
  • Diabetes Mellitus, Type 2 / blood*
  • Diabetes Mellitus, Type 2 / epidemiology
  • Diabetes Mellitus, Type 2 / pathology
  • Disease Progression
  • Fatty Acids, Nonesterified / metabolism*
  • Female
  • Glucose Clamp Technique / methods
  • Humans
  • Immunohistochemistry
  • Insulin / metabolism
  • Insulin Resistance / physiology
  • Linear Models
  • Liver / metabolism*
  • Liver / pathology
  • Liver Function Tests
  • Male
  • Middle Aged
  • Non-alcoholic Fatty Liver Disease / blood*
  • Non-alcoholic Fatty Liver Disease / epidemiology
  • Non-alcoholic Fatty Liver Disease / pathology*
  • Reference Values
  • Risk Assessment
  • Severity of Illness Index
  • Triglycerides / metabolism*


  • Biomarkers
  • Fatty Acids, Nonesterified
  • Insulin
  • Triglycerides