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.

Figure 1.

Plasma FGF21 levels in patients without NAFLD (No NAFLD group, n = 41), isolated steatosis or steatosis with minimal inflammation (No NASH group, n = 52), and NASH (n = 94). Data are shown as mean ± SE. *P < 0.05 when compared with the No NAFLD group. †P < 0.05 when compared with the No NASH group.

Figure 2.

Tissue-specific measures on insulin sensitivity during the euglycemic insulin clamp studies in the three groups: No NAFLD (n = 41), No NASH (n = 52), and NASH (n = 94). (A) Hepatic insulin sensitivity (i.e., suppression of EGP by low-dose insulin infusion) was not significantly different among the three groups. (B) Skeletal muscle (Rd) and (C) adipose tissue (suppression of plasma FFA by low-dose insulin infusion) insulin sensitivity worsened from the No NAFLD to NASH group. Higher values indicate greater insulin sensitivity. Data are shown as mean ± SE. LBM, lean body mass. *P < 0.05 when compared with the No NAFLD group.

Figure 3.

Plasma FGF21 level in relationship to quartiles of insulin sensitivity: from most insulin sensitive to most insulin resistant. (A) FGF21 levels by quartiles of liver insulin sensitivity measured as suppression of EGP by low-dose insulin infusion. (B) FGF21 levels by quartiles of skeletal muscle insulin sensitivity shown as Rd. (C) FGF21 levels by quartiles of adipose tissue insulin sensitivity measured as suppression of FFA by low-dose insulin infusion. Data are shown as mean ± SE. N = 187. P values represent the comparisons among the four quartiles by ANOVA.

Figure 4.

Plasma FGF21 level in relationship to severity of liver histology in patients with NASH (n = 94). (A) FGF21 levels by severity of liver steatosis. Grade 1 represents between 5% and 33% of liver fat; grade 2 = 34% to 66%; and grade 3 ≥66%. (B) FGF21 levels by severity of necroinflammation, a combined lobular inflammation, and hepatocellular ballooning scores (grades 2 through 4). (C) FGF21 by severity of liver fibrosis, stages 0 through 4. Data are shown as mean ± SE. *P < 0.05 by Bonferroni post hoc analysis compared with first column. NASH was defined based on presence of at least grade 1 for each of the following three components: steatosis, lobular inflammation, and hepatocellular ballooning.