The diagnosis of nonalcoholic steatohepatitis (NASH) is defined by the presence and pattern of specific histological abnormalities on liver biopsy. A separate system of scoring the features of nonalcoholic fatty liver disease (NA) called the NAFLD Activity Score (NAS) was developed as a tool to measure changes in NAFLD during therapeutic trials. However, some studies have used threshold values of the NAS, specifically NAS ≥ 5, as a surrogate for the histologic diagnosis of NASH. To evaluate whether this unintended use of the NAS is valid, biopsy and clinical data from the 976 adults in NASH CRN studies were reviewed. Biopsies were evaluated centrally by the NASH CRN Pathology Committee. Definite steatohepatitis (SH) was diagnosed in 58.1%, borderline SH in 19.5% and “not SH” in 22%. The NAS was ≥ 5 in 50% and ≤ 4 in 49%; in this cohort only 75% of biopsies with definite SH had a NAS ≥ 5, while 28% of borderline SH and 7% of "not SH" biopsies had NAS ≥ 5. Of biopsies with a NAS ≥ 5, 86% had SH and 3% "not SH". NAS ≤ 4 did not indicate benign histology; 29% had SH and only 42% had "not SH". Higher values of the NAS were associated with higher levels of ALT and AST, while the diagnosis of SH was associated with features of the metabolic syndrome. Conclusions The diagnosis of definite SH or the absence of SH based on evaluation of patterns as well as individual lesions on liver biopsies does not always correlate with threshold values of the semiquantitative NAS. Clinical trials and observational studies should take these different performance characteristics into account.

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Serum ferritin (SF) levels are commonly elevated in patients with nonalcoholic fatty liver disease (NAFLD), due to 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 a serum ferritin measurement within six months of their liver biopsy. A threshold SF>1.5XULN (i.e. >300 ng/ml in women and >450 ng/ml in men) was significantly associated with male sex, elevated serum ALT, AST, iron, transferrin-iron saturation, iron stain grade and decreased platelets (p<0.01). Histologic features of NAFLD were more severe among patients with SF>1.5XULN including steatosis, fibrosis, hepatocellular ballooning and diagnosis of NASH (p<0.026). On multiple regression analysis, SF>1.5XULN was independently associated with advanced hepatic fibrosis (OR, 1.66, 95% 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 >1.5XULN 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 serum ferritin is useful to identify NAFLD patients at risk for NASH and advanced fibrosis.

Previous studies have shown familial aggregation of insulin resistance and nonalcoholic-fatty-liver-disease (NAFLD). Therefore, we aimed to examine whether family history of diabetes-mellitus (DM) is associated with nonalcoholic steatohepatitis (NASH) and fibrosis in patients with NAFLD. This is a cross-sectional analysis in participants of the NAFLD Database Study and PIVENS Trial who had available data on family history of DM. 1069 patients (63% women) with mean age of 49.6 (± 11.8) years and BMI of 34.2 (± 6.4) kg/m2, were included. 30% had DM and 56% had family history of DM. Both personal history of DM and family history of DM were significantly associated with NASH with an odds ratio (OR) of 1.93 (95% CI, 1.37–2.73; p-value <0.001) and 1.48 (95% CI, 1.11–1.97; P=0.01), and any fibrosis with an OR of 3.31 (95% CI, 2.26–4.85; p-value <0.001) and 1.66 (95% CI, 1.25–2.20; P<0.001), respectively. When the models were adjusted for age, sex, BMI, ethnicity, and metabolic traits, the association between diabetes and family history of DM, with NASH showed an increased adjusted-OR of 1.76 (95% CI, 1.13–2.72, p-value <0.001) and 1.34 (95% CI, 0.99–1.81; P=0.06), respectively, and with any fibrosis with an significant adjusted-OR of 2.57 (95% CI, 1.61–4.11; p-value < 0.0001) and 1.38 (95% CI, 1.02–1.87; P=0.04), respectively. After excluding patients with personal history of diabetes, family history of DM was significantly associated with presence of NASH and any fibrosis with adjusted OR of 1.51 (95% CI, 1.01–2.25; P=0.04), and 1.49 (95% CI, 1.01–2.20; P=0.04), respectively. Conclusions: Diabetes is strongly associated with risk of NASH, fibrosis and advanced fibrosis. Family history of diabetes especially among non-diabetics is associated with NASH and fibrosis in NAFLD.