Nonalcoholic steatohepatitis in nonobese patients (2016)

Nonalcoholic fatty liver disease (NAFLD) is usually associated with obesity and a metabolic environment of “lipotoxicity,” insulin resistance, and abnormal glucose metabolism.1 However, relatively little attention has been given to NAFLD in nonobese individuals, and many clinicians have a (false) perception of it being rare or more “benign” in nature. Few studies are available on the subject (Table 1).2-9 Studies reveal the overlooked fact that such patients are usually insulin-resistant and have higher plasma triglycerides when compared to matched controls without NAFLD, although admittedly both abnormalities are usually less severe than in obese NAFLD patients. In the setting of NAFLD plasma triglycerides become a surrogate marker for a metabolic state of lipotoxicity, where diminished sensitivity of adipose tissue to insulin results in higher rates of lipolysis and increased fatty acid flux to the liver, promoting hepatic steatosis and increased very low-density lipoprotein secretion.1 Of note, while the vast majority of patients are insulin-resistant, only a minority of nonobese patients with NAFLD have manifestations of the metabolic syndrome (MetS) (Table 1). Less clear is whether nonobese compared to obese patients with nonalcoholic steatohepatitis (NASH) have a lower risk of cirrhosis and a better overall long-term prognosis. One would suspect so as the metabolic environment that appears to drive the disease is frequently less adverse than in obesity. Unfortunately, the evidence available is limited to a handful of cross-sectional and retrospective studies (Table 1); but in this issue of Hepatology, Leung et al.9 report on their efforts to address this important question. To this end, they recruited 307 consecutive patients of Chinese ethnicity at a tertiary-level hospital in Hong Kong referred for evaluation of NAFLD. The obese and nonobese (23.5% of all patients) groups were well matched for major clinical parameters, including prevalence of diabetes, fasting plasma glucose, and lipids.9 As expected, more patients in the obese group had MetS (70% versus 43%; P < 0.001); but this was largely driven by the higher body mass index and hypertension. Nonobese patients with NAFLD had somewhat less steatosis (mean grade 1.7 versus 2.0, P = 0.01) and fibrosis (mean stage 1.3 versus 1.7, P = 0.004), although a similar degree of lobular inflammation.9 Also, fewer nonobese patients had ballooning (60.9% versus 73.4%, P = 0.045) and fibrosis (55% versus 80%, P < 0.001). However, similar proportions of obese and nonobese patients had NASH (51.9% versus 43.5%, P = 0.217). Once NASH developed, there were no significant differences in histology, with advanced fibrosis (F3-F4) being comparable between the two groups, although there was a trend toward less steatosis and ballooning degeneration in nonobese patients with NASH.9 Was the prognosis better for nonobese compared to obese NAFLD patients? There was a trend for obese patients to have more progression to advanced fibrosis (1/21 [6.3%] versus 12/61 [31.6%], P = 0.079), a finding confounded by ∼50% more advanced fibrosis at baseline in obese patients (23.8 versus 37.7%, P = 0.25), a major determinant of future poor outcomes.10 Only 18% of all events (liver-related and extrahepatic) happened in nonobese subjects. Six patients died, 2 who developed hepatocellular carcinoma and 1 liver failure, all of whom belonged to the obese group. Taken together, the authors concluded that nonobese NAFLD patients may have a better prognosis than obese ones. The detailed cross-sectional and longitudinal data linking baseline clinical characteristics with long-term outcomes were a major strength of the study. However, definite conclusions are difficult to make as follow-up was relatively short (mean of 49 months) and only a total of 21 nonobese and 61 obese patients had a repeat liver biopsy (27% of the entire cohort).9 There were also few events: 11% of all patients (34 out of 307 patients) and events occurred at a similar rate, 11.9% in obese compared to 8.3% in nonobese patients (P = 0.190). More importantly and consistent with three prior studies (see Table 1),2, 3, 5 the proportion of patients with advanced fibrosis at baseline, taking into account either all 307 patients or only those with a repeat liver biopsy, was not different between obese and nonobese subjects. This suggests that the risk of cirrhosis for nonobese patients may not be that different after all and that once NASH is established, obesity (lipotoxicity) may not be the main driver of fibrosis progression. Patients with versus without major clinical outcomes had the same waist circumference and waist-to-hip ratio (body mass index was not reported but would likely be the same; see their Supporting Table S4a) and no major differences in liver histology (percentage with NASH as well as severity of NASH and of fibrosis; Supporting Table S4b). Again, overall poor outcomes could not be clearly attributed to excess adiposity or NASH severity at baseline in such patients. Diabetes was not related either to the severity of steatohepatitis or to outcomes, in contrast to reports in other ethnic groups,1 perhaps because hyperglycemia is more often associated with insulin secretion defects than insulin resistance in Chinese populations. Finally, only a minority of nonobese patients had MetS. This is consistent with prior reports where the prevalence of MetS in this population has ranged between 2% and 48% and in contrast to the higher rates observed in NAFLD associated with obesity (22%-64%).2-8 To further highlight the limited value of MetS in identifying liver disease, NASH developed in 40% of patients without MetS. That nonobese patients with NAFLD are insulin-resistant has been known for ∼20 years.11 In an elegant study by Bugianesi et al.12 that included only nonobese patients, many having NASH with fibrosis, none had any features of MetS. This emphasizes the low sensitivity of the clinical manifestations of MetS as an indicator of NAFLD or NASH, particularly in nonobese patients. While insulin-resistance measurements were not provided in the study by Leung et al.,9 a recent report from this group including patients from this cohort did reveal that among nonobese subjects without impaired fasting glucose or diabetes, insulin resistance was an independent risk factor associated with NAFLD.6 Therefore, it is more accurate to say that the liver in NAFLD is a “metabolic mirror” of insulin resistance and “lipotoxicity” and to avoid stating that NAFLD “is the hepatic manifestation of the metabolic syndrome” as clinical manifestations of MetS are heterogenous and age-related (i.e., often absent in insulin-resistant younger adults)13 and depend on many other poorly understood factors (especially true when considering the diverse mechanisms causing hypertension).14 What are the clinical implications of this study? The most provocative finding is the similar rate of steatohepatitis and of severe fibrosis between obese and nonobese patients, although consistent with earlier reports.2, 3, 5 In addition, lean compared to overweight patients had the same high prevalence of NASH (40.7% versus 45.2%, P = 0.71) and severity of liver disease (Supporting Table S2b),9 which was not that different from that of the obese, which questions the perception among clinicians that NASH is rare in lean patients. While this could be, at least in part, due to patient selection from referral to a tertiary medical center, it does challenge current dogma and a certain disregard in screening for NASH in patients without obesity. It also calls for urgent confirmation in larger cohorts of patients and across other ethnic groups. The work by Leung et al.,9 and that of others in the field (Table 1),2-8 also suggests that the pathophysiology of NAFLD and NASH in nonobese patients is closely linked to insulin resistance/lipotoxicity and that it is not all that different from that observed in obese patients. This is supported by the finding that only elevated plasma triglycerides stood as an independent predictor of hepatic steatosis and overall disease severity (odds ratio, 1.64; 95% confidence interval, 1.079-2.502; P = 0.021) and that more patients with increased triglycerides had hepatocyte ballooning (70.8% versus 45.7%, P = 0.045).9 Steatosis and atherogenic dyslipidemia from elevated plasma triglycerides are a reflection of adipose tissue insulin resistance.1, 15, 16 Finally, cardiovascular events accounted for about two thirds of all major events, suggesting that nonobese NAFLD patients may also be at relatively high risk for the same comorbidities observed in their obese NAFLD counterparts. In summary, the study by Leung et al.9 is a step forward in our understanding of NAFLD in nonobese patients but should not be misinterpreted as NASH being a “more benign” condition in this population. At least in lean or overweight patients referred to hepatology clinics in tertiary academic centers for evaluation of NAFLD (as in this work), NASH develops often (in 38%-55% of patients)2-9 and does not make them immune from developing advanced fibrosis. This study also suggests that the pathogenesis of NASH is not all that different from that observed in insulin-resistant obese patients, with steatosis behaving as the “metabolic mirror” of insulin resistance and a state of lipotoxicity. The lack of a role of type 2 diabetes mellitus in nonobese NAFLD will need confirmation in other ethnic groups. Taken together, the current findings are a call for more studies to understand the natural history of the disease but also for greater awareness among practitioners about the potential health risks associated with NAFLD in nonobese patients. Kenneth Cusi, M.D., F.A.C.P., F.A.C.E. Division of Endocrinology, Diabetes and Metabolism University of Florida Malcom Randall Veterans Affairs Medical Center Gainesville, FL