Histological severity and clinical outcomes of nonalcoholic fatty liver disease in nonobese patients

Abstract

Although nonalcoholic fatty liver disease (NAFLD) is closely linked to obesity, around 10%-20% of nonobese Americans and Asians still develop NAFLD. Data on this special group are limited. We therefore studied the severity and clinical outcomes of nonobese NAFLD patients. Consecutive NAFLD patients who underwent liver biopsy were prospectively recruited. We used the NASH Clinical Research Network system to score the histology. The Asian body mass index cutoff of 25 kg/m 2 was used to define nonobese NAFLD. Among 307 recruited NAFLD patients, 72 (23.5%) were nonobese. Compared to obese patients, nonobese patients had lower NAFLD activity score (3.3 6 1.3 vs. 3.8 6 1.2; P 5 0.019), mainly contributed by steatosis (1.7 6 0.8 vs. 2.0 6 0.8; P 5 0.014) and presence of hepatocyte ballooning (60.9% vs. 73.4%; P 5 0.045). Similarly, nonobese patients had lower fibrosis stage (1.3 6 1.5 vs. 1.7 6 1.4; P 5 0.004), serum cytokeratin-18 fragments (283 vs. 404 U/L; P < 0.001) and liver stiffness measurement by transient elastography (6.3 vs. 8.6 kilopascals; P < 0.001). By multivariate analysis in nonobese patients, only elevated serum triglyceride level was independently associated with higher NAFLD activity score (adjusted odds ratio [OR], 1.644; P 5 0.021), whereas elevated creatinine level was the only factor associated with advanced fibrosis (adjusted OR, 1.044; P 5 0.025). After a median follow-up of 49 months, 6 patients died, 2 developed hepatocellular carcinoma, and 1 had liver failure, all of whom were in the obese group. Conclusion: Nonobese NAFLD patients tend to have less-severe disease and may have a better prognosis than obese patients. Hypertriglyceridemia and higher creatinine are the key factors associated with advanced liver disease in nonobese patients. (HEPATOLOGY 2017;65:54-64) SEE EDITORIAL ON PAGE 4 N onalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases in the world. (1) It can progress to nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). (2,3) Furthermore, patients with NAFLD have increased risk of cardiovascular events, other malignancies, and mortality. (4) NAFLD is strongly associated with obesity, metabolic syndrome (MetS), and cardiovascular risk factors and is more common in obese patients. (5,6) Nonetheless, a smaller, but significant, proportion of patients develop NAFLD despite having a relatively normal body mass Abbreviations: BMI, body mass index; CK-18, cytokeratin-18; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HDL, high-density lipoprotein; IQR, interquartile range; JNK, c-Jun N-terminal kinase; kPa, kilopascals; LSM, liver stiffness measurement; MetS, metabolic syndrome; NAFLD, nonalcoholic fatty liver disease; NAS, NAFLD Activity Score; NASH, nonalcoholic steatohepatitis; OR, odds ratio; PNPLA3, patatin-like phospholipase domain-containing protein 3; PPV, positive predictive value; TE, transient elastography; TM6SF2, transmembrane 6 superfamily antigen 2.

Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention

“…In a study published in 2017 (REF. 83), similar proportions of patients who were obese and non obese had NASH (51.9% versus 43.5%, respectively, P = 0.217), although the latter group had a lower degree of hepatic steatosis and hepatocyte ballooning. Consistent with a report from a decade earlier 79 , the proportion of patients with advanced fibro sis at baseline was not different between those who were obese and non obese, suggesting that once an individual has been diagnosed with NASH, obesity might not be the main driver of fibrosis progression.…”

“…Within the cohort of the National Health and Nutrition Examination Survey III 79 , mortality of patients with meta bolically normal NAFLD was similar to the cohort with out liver disease. Unfortunately, most reports are limited by the use of imaging modalities rather than liver biopsy to confirm the diagnosis of fatty liver 5,74,[79][80][81][82][83][84] . In a study conducted in Italy by Fracanzani et al 82 that included 430 cases of biopsy proven NAFLD, 55% of patients without visceral obesity had NASH and a fibrosis stage ≥F2 despite milder metabolic alterations than patients who were obese with biopsy proven NAFLD.…”

Genetic predisposition in nonalcoholic fatty liver disease

“…Nevertheless, epidemiological studies, particularly those conducted in (but not restricted to) Asia [64-66], highlight the observation that NAFLD can be also seen in lean subjects. In fact, ~10−20% of all NAFLD cases in non-obese Americans and Asians are ascribed to lean NAFLD.…”

“…There are few published reports that include well-characterized NAFLD in non-obese patients. For instance, findings of a study involving a large number of lean patients from Asia with NAFLD proven by liver biopsy have been recently published, suggesting that while the risk factors in lean and obese NAFLD are common, lean NAFLD patients tend to have less severe disease form and may have a better prognosis than obese patients [64]. Still, among lean NAFLD patients, hypertriglyceridemia and higher creatinine were significantly associated with advanced liver disease [64].…”

Developmental origins of NAFLD: a womb with a clue

“…For many decades, it was thought that NAFLD was predominantly driven by obesity in the setting of genetic susceptibility. However, this association with obesity does not explain the variable severity of illness and its outcome 6 , suggesting that NAFLD is a multifactorial disease 7 .…”