Predictors of Nonalcoholic Steatohepatitis and Significant Fibrosis in Non-obese Nonalcoholic Fatty Liver Disease

Donghee Kim; Won Kim; Sae Kyung Joo; Jung Ho Kim; Stephen A. Harrison; Zobair M. Younossi; Aijaz Ahmed

Disclosures

Liver International. 2019;39(2):332-341. 

In This Article

Results

Demographic, Clinical and Biochemical Characteristics of Non-obese NAFLD Compared to Non-obese Controls or Obese NAFLD

Among the 542 subjects (mean age 52.6 ± 15.6 years; men 51.3%) with biopsy-proven NAFLD, 132 non-obese subjects were classified as the non-obese NAFLD, and the remaining 410 obese subjects were classified as the obese NAFLD. Eighty-one non-obese subjects without NAFLD were enrolled as non-obese controls and 41 obese subjects without NAFLD as obese controls. The baseline characteristics of this cohort are shown in Table 1. In terms of gender, the three groups were similar. Non-obese NAFLD were in between non-obese controls and obese NAFLD with regard to BMI, waist circumference, SAD, aminotransferase levels, HOMA-IR and VAT area. These differences demonstrate that both non-obese and obese NAFLD groups harbour components of metabolic syndrome with higher frequency than non-obese controls.

Histological Characteristics in Non-obese Compared to Obese Subjects With NAFLD

Table 2 presents the comparison of the histological features between the non-obese and obese subjects with NAFLD. The lobular inflammation, hepatocyte balloon degeneration, presence of NASH and prevalence of significant fibrosis (≥F2) were similar between the non-obese and obese NAFLD subjects. In contrast, compared to obese subjects with NAFLD, non-obese subjects with NAFLD had lesser degrees of hepatic steatosis. The NAS was lower in non-obese subjects with NAFLD than in obese subjects with NAFLD (3.5 ± 1.5 vs 3.8 ± 1.4, P = 0.021), which was mainly derived from difference in hepatic steatosis. Regarding fibrosis stage and advanced fibrosis, non-obese subjects with NAFLD had higher stage of hepatic fibrosis (P = 0.012) and higher prevalence of advanced fibrosis (P = 0.058) compared to obese subjects with NAFLD.

Histological Characteristics in Non-obese Compared to Obese Subjects With NASH

Table 3 shows the comparison of the histological features between the non-obese and obese subjects with NASH (n = 224). Between the non-obese and obese NASH subjects, lobular inflammation and ballooning degeneration were similar apart from the obese NASH subjects having higher hepatic steatosis grade. In contrast, compared to obese subjects with NASH, non-obese NASH subjects had higher stage of hepatic fibrosis and higher prevalence of significant fibrosis (P = 0.040) and advanced fibrosis (P = 0.011).

Risk Factors for NASH in Non-obese and Obese Populations

We analysed our data to identify characteristic features that may be associated with the presence of NASH in the non-obese population. Independent predictors of NASH among non-obese population determined from multivariable-adjusted backward stepwise logistic regression analyses were females (OR 2.49, 95% CI 1.04-5.96), higher ALT value (OR 1.03, 95% CI: 1.01-1.04), lower HDL cholesterol levels (OR 0.96, 95% CI 0.92-0.998), higher prevalence of diabetes (OR 3.65, 95% CI 1.53-8.73) and higher VAT area (OR 1.63 per SD increase of VAT, 95% CI 1.06-2.52; Table 4). On the contrary, the independent determinants of NASH in the obese population included female (OR 2.21, 95% CI 1.38-3.52), higher AST (OR 1.02, 95% CI 1.01-1.03) and ALT levels (OR 1.01, 95% CI 1.00-1.02) and higher VAT area (OR 1.38 per SD increase of VAT, 95% CI 1.11-1.72) (Table 6). Increased VAT area demonstrated a stronger association with NASH in non-obese subjects compared to obese subjects (63% increased risk of NASH in non-obese vs 38% increased risk of NASH in obese [per SD increase of VAT]).

Risk Factors for Significant Fibrosis in Non-obese and Obese Populations

We investigated the risk factors associated with significant fibrosis in non-obese population (Table 5). When the models were adjusted for age, gender, BMI, aminotransferase, HDL cholesterol, triglycerides, HOMA-IR, diabetes, hypertension and VAT and SAT areas, age (OR 1.04, 95% CI 1.00-1.07), higher AST value (OR 1.02, 95% CI 1.01-1.04), diabetes (OR 2.76, 95% CI 1.30-5.88) and higher VAT area (OR 1.57 per SD increase of VAT, 95% CI 1.08-2.29) were associated with significant fibrosis in non-obese population. On the contrary, the independent determinants of significant fibrosis in obese population included age (OR 1.06, 95% CI 1.04-1.08), diabetes (OR 1.76, 95% CI 1.07-2.91), HOMA-IR level (OR 1.08, 95% CI 1.01-1.15), higher AST value (OR 1.02, 95% CI 1.01-1.03) and higher BMI (OR 1.08, 1.00-1.07, Table 6). In terms of body fat distribution, non-obese subjects with 1-SD increase of VAT had 57% greater odds of significant fibrosis; however, general obesity, not VAT area, was associated with significant fibrosis in obese population.

Ability of Anthropometric Measures to Predict NASH or Significant Fibrosis

We investigated whether SAD as a surrogate marker of VAT is independently associated with NASH or significant fibrosis. When we analysed multivariable analyses adjusted for SAD and transverse abdominal diameter instead of VAT and SAT areas, SAD demonstrated a significant association with 37% increased risk of NASH (OR 1.37 per 1 cm increase, 95% CI 1.08-1.73) and significant fibrosis (OR 1.37 per 1 cm increase, 95% CI 1.07-1.75) in non-obese population respectively (Table 4 and Table 5). Among obese subjects, SAD was associated with 19% increased risk of NASH (OR 1.19 per 1 cm increase, 95% CI 1.08-1.32), but not significant fibrosis (Table 6). We compared the diagnostic accuracy of anthropometric measures for detecting NASH and significant fibrosis. As shown in Table 7, SAD was the best in detecting NASH (AUROC 0.653 for non-obese vs 0.639 for obese) and significant fibrosis (AUROC 0.705 for non-obese vs 0.544 for obese), especially for non-obese NAFLD subjects. SAD was significantly superior to BMI among non-obese subjects (AUROC 0.653 vs 0.538, P = 0.030 for NASH; 0.705 vs 0.578, P = 0.015 for significant fibrosis).

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