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Visceral obesity raises risk for NASH in lean, obese patients with NAFLD

In a comparative study of overweight-to-obese patients vs. lean patients with nonalcoholic fatty liver disease, researchers found an association between waist circumference and nonalcoholic steatohepatitis in both groups. They also observed an association among a variant in the PNPLA3 gene and both NASH and fibrosis in lean patients.

“In the present study, we analyzed in a large series of Caucasian patients with biopsy-proven NAFLD the possible differences between lean NAFLD, which reflects ‘normal weight obesity,’ and overweight/obese NAFLD and investigated the role of visceral obesity,” Anna Ludovica Fracanzani, MD, from the University of Milan, Italy, and colleagues wrote. “In lean NAFLD, the only independent variable associated with NASH and significant fibrosis ... was the GG PNPLA3 polymorphism, confirming the role of genetic predisposition in patients with only minor metabolic alterations.”

The retrospective study comprised data from 143 lean patients with NAFLD (BMI < 25 kg/m²) and 526 overweight or obese patients with NAFLD (BMI 25 kg/m²).

Compared with the overweight-to-obese patients, the lean patients were younger (46 vs. 49 years; P = .04) and had lower waist circumference (89.3 vs. 105.1 cm; P < .0001). They also had a lower prevalence of diabetes (11% vs. 26%; P = .0001), hypertension (20% vs. 37%; P = .001), metabolic syndrome (14% vs. 39%; P = .0001), constraint induced movement therapy (0.74 vs. 0.84 mm; P = .0009), carotid Plaques (27% vs. 39%; P = .03), NASH (17% vs. 40%; P = .0001) and fibrosis score 2 or higher (17% vs. 42%; P = .0001).

Prevalence of NASH

Data revealed an association between higher waist circumference — over 88 cm in women and over 102 cm in men — and NASH in both the lean patients with NAFLD (OR = 2.7; 95% CI, 1.3-2.5) and the overweight-to-obese patients (OR = 1.7; 95% CI, 1.06-2.8).

For lean patients with NAFLD, data further showed a significant association between the PNPLA3 GG genotype and both NASH (OR = 4.5; 95% CI, 1.1-20) and fibrosis (OR = 2.8; 95% CI, 1.1-7.6). Additionally, lean patients had a significantly higher prevalence of the TM6SF2 167KK variant of the genotype than the overweight to obese patients (4% vs. 0.3%; P = .02).

The role of visceral obesity

Researchers defined visceral obesity by measuring waist circumference. Lean male patients with waist circumference between 94 cm and 102 cm and female lean patients between 80 cm and 88 cm had a significantly higher risk for diabetes (OR = 11; 95% CI, 1.2-133) vs. overweight-to-obese patients with waist circumference in the same range. Both lean and overweight patients with NAFLD who had a waist circumference over 88 cm in women or 102 cm in men had a higher relative risk for diabetes (P = .03 and P = .02), hypertension (P = .04 and P = .0001), carotid Plaques (P = .03 for both) and fibrosis score 2 or higher (P = .004 and P = .0001), vs. patients with lower waist circumferences.

Compared with lean patients with lower waist circumferences, those with visceral obesity had a higher prevalence of NASH (44% vs. 12%; P = .005), fibrosis score 2 or higher (44% vs. 15%; P = .008) metabolic syndrome (41% vs. 10%; P = .003) and carotid Plaques (50% vs. 24%; P = .04).

“It is well known that abdominal visceral obesity, which represents ectopic fat accumulation, is associated with insulin resistance, proinflammatory cytokines, and endothelial dysfunction,” the researchers wrote. “In addition, in lean NAFLD patients we also found a significantly higher prevalence of carriers of the TM6SF2 E167K variant, reported to be associated with a reduced secretion of very–low-density lipoproteins, lower circulating lipids, more severe steatosis, inflammation, and NASH. However, because we could type only a limited number of cases, we cannot draw sound conclusions on the role of the TM6SF2 E167K variant in lean subjects and on the possible synergistic role of the two gene polymorphisms in this subset of patients.” – by Talitha Bennett

Disclosure: The researchers report no relevant financial disclosures.