Plasma Fibroblast Growth Factor 21 Is Associated With Severity of Nonalcoholic Steatohepatitis in Patients With Obesity and Type 2 Diabetes

Abstract

Context The relationship between plasma fibroblast growth factor 21 (FGF21), insulin resistance, and steatohepatitis has not been systematically assessed. Objective To determine if higher plasma FGF21 is associated with worse steatohepatitis on liver biopsy in patients with nonalcoholic fatty liver disease (NAFLD). Design and Setting Cross-sectional study in a university hospital. Patients Interventions and Main Outcome Measures Patients with a body mass index >25 (n = 187) underwent: (i) euglycemic hyperinsulinemic clamp to assess tissue-specific insulin resistance (IR); (ii) liver magnetic resonance spectroscopy for intrahepatic triglyceride quantification, (iii) liver biopsy (if NAFLD present; n = 146); and (iv) fasting plasma FGF21 levels. Methods and Results Patients were divided into three groups: (i) No NAFLD (n = 41); (ii) No nonalcoholic steatohepatitis (NASH) (patients with isolated steatosis or borderline NASH; n = 52); and (iii) NASH (patients with definite NASH; n = 94). Groups were well-matched for age/sex, prevalence of type 2 diabetes mellitus, and hemoglobin A1c. During euglycemic hyperinsulinemic insulin clamp, insulin sensitivity in skeletal muscle and adipose tissue worsened from No NAFLD to NASH (both P < 0.001). Plasma FGF21 levels correlated inversely with insulin sensitivity in adipose tissue (r = −0.17, P = 0.006) and skeletal muscle (r = −0.23, P = 0.007), but not with liver insulin sensitivity. Plasma FGF21 was higher in patients with NASH (453 ± 262 pg/mL) when compared with the No NASH (341 ± 198 pg/mL, P = 0.03) or No NAFLD (325 ± 289 pg/mL, P = 0.02) groups. Plasma FGF21 increased with the severity of necroinflammation (P = 0.02), and most significantly with worse fibrosis (P < 0.001), but not with worsening steatosis (P = 0.60). Conclusions Plasma FGF21 correlates with severity of steatohepatitis, in particular of fibrosis, in patients with NASH. Measurement of FGF21 may help identify patients at the highest risk of disease progression.

Relationship between Heart Disease and Liver Disease: A Two-Way Street

“…In recent years, novel hepatic tissue-specific molecules known as hepatokines have been described to determine cardiovascular effects. Fibroblast growth factor 21 (FGF-21) is a peptide predominantly produced and secreted by the liver and correlates with hepatic fat content and the severity of NAFLD [110]. Elevated FGF-21 serum levels have been shown to be associated with atherosclerosis [111], and coronary heart disease [112].…”

Novel Combinatorial Regimen of Garcinol and Curcuminoids for Non-alcoholic Steatohepatitis (NASH) in Mice

“…5A). Serum FGF21 levels and hepatic mRNA of FGF21 are known to be elevated in human and mice models of NASH, due to FGF21 resistance 41,42 . The mice treated with curcuminoids and the combination of GIE and curcuminoids showed a decrease in FGF21 levels in serum and liver compared to the untreated control, while GIE had no impact on FGF21 levels (Fig.…”

Decrease in fasting insulin secretory function correlates with significant liver fibrosis in Japanese non‐alcoholic fatty liver disease patients

“…Fibroblast growth factor-21 (FGF21), which is expressed in fat, skeletal muscle, and liver, increases glucose-induced ISF in rodent islets, 33 and the plasma FGF21 increases with the severity of liver fibrosis in NAFLD. 34 Clinical trials of FGF21 administration to NAFLD patients showed improvements in liver steatosis and fibrosis. 35,36 In addition, the concentration of circulating betatrophin, which increases in NAFLD patients according to the extent of their hepatic steatosis, 37,38 was higher in patients with liver fibrosis than in healthy controls.…”