Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease

Abstract

Serum ferritin (SF) levels are commonly elevated in patients with nonalcoholic fatty liver disease (NAFLD) because of systemic inflammation, increased iron stores, or both. The aim of this study was to examine the relationship between elevated SF and NAFLD severity. Demographic, clinical, histologic, laboratory, and anthropometric data were analyzed in 628 adult patients with NAFLD (age, ≥ 18 years) with biopsy-proven NAFLD and an SF measurement within 6 months of their liver biopsy. A threshold SF >1.5 × upper limit of normal (ULN) (i.e., >300 ng/mL in women and >450 ng/mL in men) was significantly associated with male sex, elevated serum alanine aminotransferase, aspartate aminotransferase, iron, transferrin-iron saturation, iron stain grade, and decreased platelets (P < 0.01). Histologic features of NAFLD were more severe among patients with SF >1.5 × ULN, including steatosis, fibrosis, hepatocellular ballooning, and diagnosis of NASH (P < 0.026). On multiple regression analysis, SF >1.5 × ULN was independently associated with advanced hepatic fibrosis (odds ratio [OR], 1.66; 95% confidence interval [CI], 1.05-2.62; P = 0.028) and increased NAFLD Activity Score (NAS) (OR, 1.99; 95% CI, 1.06-3.75; P = 0.033).

Conclusions: A SF >1.5 × ULN is associated with hepatic iron deposition, a diagnosis of NASH, and worsened histologic activity and is an independent predictor of advanced hepatic fibrosis among patients with NAFLD. Furthermore, elevated SF is independently associated with higher NAS, even among patients without hepatic iron deposition. We conclude that SF is useful to identify NAFLD patients at risk for NASH and advanced fibrosis.

Figure 1. Histogram of distribution of serum ferritin values according to sex, above and below the threshold SF>1.5XULN

The relative proportion of subjects by serum ferritin values are shown for each of the four categories: A) SF≤1.5XULN, male; B) SF≤1.5XULN, female; C) SF>1.5XULN, male; D) SF>1.5XULN, female. Each bin corresponds to a range of SF values of 100ng/ml. The density estimation plot is shown by the smooth line.

Figure 2. Relationship between NAS, level of serum ferritin and presence and pattern of iron staining among subjects

The mean NAS values are shown for subjects above and below SF 1.5XULN according to each hepatic iron deposition pattern including subjects without iron deposition; HC, RES and mixed HC/RES groups. Significant differences between groups, determined using multivariate ordinal regression modeling after controlling for the covariates BMI, age, sex, type 2 diabetes and serum ALT level, are indicated by arrows. Standard deviations are indicated by the error bars.