Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease that occurs in the setting of insulin resistance and increased adiposity. It has rapidly evolved into the most common liver disease seen in the pediatric population and is a management challenge for general pediatric practitioners, subspecialists and for health systems. In this guideline, the expert committee on NAFLD (ECON) reviewed and summarized the available literature, formulating recommendations to guide screening and clinical care of children with NAFLD.

Context Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in US children and adolescents and can present with advanced fibrosis or non-alcoholic steatohepatitis (NASH). No treatment has been established. Objective To determine whether children with NAFLD would improve from therapeutic intervention with vitamin E or metformin. Design, Setting, and Patients Randomized, double-blind, double-dummy, placebo-controlled clinical trial conducted at 10 university clinical research centers in 173 patients (aged 8–17 years) with biopsy-confirmed NAFLD conducted between September 2005 and March 2010. Interventions Daily dosing of 800 IU of vitamin E (58 patients), 1000 mg of metformin (57 patients), or placebo (58 patients) for 96 weeks. Main Outcome Measures The primary outcome was sustained reduction in alanine aminotransferase (ALT) defined as 50% or less of the baseline level or 40 U/L or less at visits every 12 weeks from 48 to 96 weeks of treatment. Improvements in histological features of NAFLD and resolution of NASH were secondary outcome measures. Results Sustained reduction in ALT level was similar to placebo (10/58; 17%; 95% CI, 9% to 29%) in both the vitamin E (15/58; 26%; 95% CI, 15% to 39%; P=.26) and metformin treatment groups (9/57; 16%; 95% CI, 7% to 28%; P=.83). The mean change in ALT level from baseline to 96 weeks was −35.2 U/L (95% CI, −56.9 to −13.5) with placebo vs −48.3 U/L (95% CI, −66.8 to −29.8) with vitamin E (P=.07) and −41.7 U/L (95% CI, −62.9 to −20.5) with metformin (P=.40). The mean change at 96 weeks in hepatocellular ballooning scores was 0.1 with placebo (95% CI, −0.2 to 0.3) vs −0.5 with vitamin E (95% CI, −0.8 to −0.3; P=.006) and −0.3 with metformin (95% CI, −0.6 to −0.0; P=.04); and in NAFLD activity score, −0.7 with placebo (95% CI, −1.3 to −0.2) vs −1.8 with vitamin E (95% CI, −2.4 to −1.2; P=.02) and −1.1 with metformin (95% CI, −1.7 to −0.5; P=.25). Among children with NASH, the proportion who resolved at 96 weeks was 28% with placebo (95% CI, 15% to 45%; 11/39) vs 58% with vitamin E (95% CI, 42% to 73%; 25/43; P=.006) and 41% with metformin (95% CI, 26% to 58%; 16/39; P=.23). Compared with placebo, neither therapy demonstrated significant improvements in other histological features. Conclusion Neither vitamin E nor metformin was superior to placebo in attaining the primary outcome of sustained reduction in ALT level in patients with pediatric NAFLD. Trial Registration clinicaltrials.gov Identifier: NCT00063635

Adult nonalcoholic fatty liver disease (NAFLD) is characterized by absent or mild portal chronic inflammation (CI); in children, portal CI may be predominant. This study correlated clinical features with portal CI. Centrally-graded biopsies and temporally-related clinical parameters from 728 adults and 205 children. From the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) were evaluated. Mild, more than mild and no portal CI were found in 60%, 23% and 16% of adult biopsies and 76%, 14% and 10% of pediatric biopsies. Autoantibodies, and elevated alanine aminotransferase were not associated with portal CI. Clinical features associated with "more than mild" in adults were older age (P < 0.0001), female gender (P ‫؍‬ 0.001), higher body mass index (P < 0.0001), elevated insulin levels (P ‫؍‬ 0.001), higher homeostasis model assessment of insulin resistance score (HOMA-IR) (P < 0.0001), and medications used for NAFLD (P ‫؍‬ 0.0004), diabetes (P < 0.0001), and hypertension (P < 0.0001). "More than mild" in the pediatric biopsies correlated with younger age (P ‫؍‬ 0.01), but not with body mass index, insulin or HOMA-IR. In both groups, lobular and portal inflammation scores had no association, but there was an association with definite steatohepatitis (P < 0.0001). Features associated in the adult biopsies with "more than mild" were steatosis amount (P ‫؍‬ 0.01) and location (P < 0.0001), ballooning (P < 0.0001), and advanced fibrosis (P < 0.0001). In the pediatric biopsies, "more than mild" was associated with steatosis location (P ‫؍‬ 0.0008) and fibrosis score (P < 0.0001), specifically, the portal/periportal fibrosis or greater fibrosis) (P < 0.01). Conclusion: Increased portal CI is associated with many clinical and pathologic features of progressive NAFLD in both adults and children, but not with ALT, autoantibodies, or lobular inflammation. More than mild portal CI in liver biopsies of untreated NAFLD may be considered a marker of advanced disease. (HEPATOLOGY 2009;49:809-820.)

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the UnitedStates. The association between NAFLD and quality of life (QOL) remains unclear. These data are important to estimate the burden of illness in NAFLD. The aim was to report QOL scores of adults with NAFLD and examine the association between NAFLD severity and QOL. QOL data were collected from adults with NAFLD enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network using the Short Form 36 (SF-36) survey, and scores were compared with normative U.S. population scores. Liver biopsy histology was reviewed by a central pathology committee. A total of 713 subjects with NAFLD (male ‫؍‬ 269, female ‫؍‬ 444) were included. Mean age of subjects was 48.3 years; 61% had definite nonalcoholic steatohepatitis (NASH), and 28% had bridging fibrosis or cirrhosis. Diabetes was present in 27% of subjects. Subjects with NAFLD had worse physical (mean, 45.2) and mental health scores (mean, 47.6) compared with the U.S. population with (mean, 50) and without (physical, 55.8; mental, 52.5) chronic illness. Subjects with NASH reported lower physical health compared with subjects with fatty liver disease without NASH (44.5 versus 47.1, P ‫؍‬ 0.02). Subjects with cirrhosis had significantly (P < 0.001) poorer physical health scores (38.4) than subjects with no (47.6), mild (46.2), moderate (44.6), or bridging fibrosis (44.6). Cirrhosis was associated with poorer physical health after adjusting for potential confounders. Mental health scores did not differ between participants with and without NASH or by degree of fibrosis. Conclusion: Adults with NAFLD have a significant decrement in QOL. Treatment of NAFLD should incorporate strategies to improve QOL, especially physical health. (HEPATOLOGY 2009;49:1904-1912