Joel E. Lavine

Non-alcoholic fatty liver disease is a multifaceted disease that progresses through multiple phases; it involves metabolic as well as structural changes. These alterations can be measured directly or indirectly through blood, non-invasive imaging, and/or tissue analyses. While some studies have evaluated the correlations between two sets of measurements (e.g., histopathology with cross-sectional imaging or blood biomarkers), the interrelationships, if any, among histopathology, clinical blood profiles, cross-sectional imaging, and metabolomics in a pediatric cohort remain unknown. We created a multiparametric clinical MRI–histopathologic NMR network map of pediatric NAFLD through multimodal correlation networks, in order to gain insight into how these different sets of measurements are related. We found that leptin and other blood markers were correlated with many other measurements; however, upon filtering out the blood biomarkers, the network was decomposed into three independent hubs centered around histopathological features, each with associated MRI and plasma metabolites. These multi-modality maps could serve as a framework for characterizing disease status and progression and could potentially guide medical interventions.

Context Sex hormones have been linked with presence and severity of nonalcoholic fatty liver disease (NAFLD) in adults, but it is unknown if they affect severity of pediatric NAFLD. Objective To examine associations of circulating SHBG, estrogens, and androgens with key histologic features of pediatric, biopsy-confirmed NAFLD. Design Baseline assessment of longitudinal cohorts and randomized clinical trials. Setting Nonalcoholic Steatohepatitis Clinical Research Network. Patients Children and adolescents ≤18 years with liver biopsy-confirmed NAFLD in the United States. Main Outcome Measures We assayed SHBG, estrone, estradiol, dehydroepiandrosterone (DHEAS), androstenedione, and testosterone in relation to grade/stage of steatosis, portal inflammation, hepatic ballooning, fibrosis, and nonalcoholic steatohepatitis (NASH) severity using linear regression. Results Mean age of 573 children at the time of biopsy was 13.1 years (SD 2.8). Lower SHBG was inversely associated with steatosis severity in boys and girls (P = 0.001), and with portal inflammation in girls only (P for sex interaction P for sex interaction = 0.003 and 0.01, respectively) in boys, but detrimental in girls. In boys and girls, higher estrone, estradiol, and testosterone were associated with lower portal inflammation grade; higher estradiol was positively associated with hepatic ballooning severity; DHEAS was inversely associated with hepatic ballooning and NASH severity (all P < 0.05). Androstenedione was not associated with NAFLD features. Conclusions Largely consistent with findings in adults, sex hormones are associated with distinct histologic features of NAFLD in children and adolescents. These hormone levels relate to differences with gender and pubertal change.

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of disease that can range from isolated macrovesicular hepatocellular steatosis to nonalcoholic steatohepatitis (NASH) with or without fibrosis to cirrhosis. The prevalence of NAFLD has increased over several decades, mirroring the global obesity pandemic. NAFLD currently represents the most common etiology of chronic liver disease in children and adolescents worldwide. Disease presentation in childhood strongly suggests that these children may have unique susceptibilities and more severe long-term consequences. Emerging data demonstrate that the pathogenesis of early-onset NAFLD is secondary to a complex interplay involving genetic, metabolic, environmental, and microbiological factors. Such influences may begin in utero. Dietary and lifestyle modifications remain the primary effective therapeutic interventions, although long-term efficacy is limited by poor adoption or adherence. Advances in the development and validation of non-invasive biomarkers and imaging modalities will facilitate diagnosis for affected children and adolescents and facilitate long-term natural history studies and the development of therapeutic interventions.

BACKGROUND: Magnetic resonance imaging-estimated proton-density-fat-fraction (MRI-PDFF) has been shown to be a noninvasive, accurate and reproducible imaging-based biomarker for assessing steatosis and treatment response in nonalcoholic steatohepatitis (NASH) clinical trials. However, there are no data on the magnitude of MRI-PDFF reduction corresponding to histologic response in the setting of a NASH clinical trial. The aim of this study was to quantitatively compare the magnitude of MRI-PDFF reduction between histologic responders versus histologic nonresponders in NASH patients. METHODS: This study is a secondary analysis of the MOZART trial, which included 50 patients with biopsy-proven NASH randomized to ezetimibe 10 mg/day orally or placebo for 24 weeks. The primary aim was to perform a head-to-head comparative analysis of histologic responders [defined as a ⩾2-point reduction in the nonalcoholic fatty liver disease (NAFLD) Activity Score (NAS) without worsening fibrosis] versus nonresponders, and the corresponding quantitative change in liver fat content measured via MRI-PDFF. RESULTS: Of the 35 patients who underwent paired liver biopsy and MRI-PDFF assessment at the beginning and end of treatment, 10 demonstrated a histologic response. Compared with histologic nonresponders, histologic responders had a statistically significant reduction in MRI-PDFF of -4.1% ± 4.9 versus -0.6 ± 4.1 (p < 0.04) with a mean relative percent change of -29.3% ± 33.0 versus +2.0% ± 24.0 (p < 0.004), respectively. CONCLUSIONS: Utilizing paired MRI-PDFF and liver histology data, we demonstrate that a relative reduction of 29% in liver fat on MRI-PDFF is associated with a histologic response in NASH. After external validation by independent research groups, these results can be incorporated into designing future NASH clinical trials, especially those utilizing change in hepatic fat quantified by MRI-PDFF, as a treatment endpoint.