Serum biomarkers for nonalcoholic fatty liver disease: Are we there yet?

Nonalcoholic fatty liver disease (NAFLD) is already the most common liver disease in the Western world, where overweight or obese adults make up the growing majority. Its comparable impact in other regions, such as Asia, is increasingly being recognized. As we enter into an era of improving global hepatitis B vaccination coverage and effective therapies to either control or eradiate chronic viral hepatitis, the proportional burden of NAFLD is set to rise dramatically and demand our attention. Accordingly, NAFLD has already become the second-leading indication for liver transplantation in the United States. Distinguishing between nonalcoholic fatty liver (NAFL) and the more-progressive nonalcoholic steatohepatitis (NASH) is clinically important given that NASH is currently the target for pharmacological treatment. Routine imaging techniques, such as ultrasound scan, computed tomography, and magnetic resonance imaging, can accurately detect NAFLD and even quantify hepatic steatosis in the case of magnetic resonance spectroscopy. However, these investigations cannot diagnose NASH or liver fibrosis. Currently, the gold standard for diagnosing and differentiating the NAFLD spectrum is a liver biopsy. Its invasiveness, cost, and low patient acceptance make it unfeasible to be used for routine screening, much less for repeated assessments to monitor disease progression or response to treatment. Even when a liver biopsy is successfully performed, its shortcomings attributed to sampling error or interand intraobserver variability are well documented. Hence, noninvasive tests, such as serum biomarkers, are clearly needed to prioritize “atrisk” patients who require liver biopsy or ideally replace liver biopsy all together. Opportunities exist for biomarkers to make an impact across the whole NAFLD spectrum, such as diagnosing NAFL, diagnosing NASH, and assessing fibrosis (Fig. 1). In this issue of HEPATOLOGY, Ajmera et al. evaluate 32 potential plasma biomarkers of disease activity and severity in a large, well-characterized cohort of adult patients with biopsy-proven NAFLD. The 648 patients were recruited from two multicenter studies conducted by the NASH Clinical Research Network: the NAFLD database study and the pioglitazone or vitamin E for nonalcoholic steatohepatitis (PIVENS) trial. All participants underwent robust confirmation and phenotyping of NAFLD by baseline liver histology, which was reviewed centrally by a group of nine blinded hepatopathologists. Plasma samples drawn within 6 months of the liver biopsy were then analyzed using a Luminex-based biomarker multiplex assay. Given that all biomarkers evaluated were chosen based on a priori knowledge, the positive findings in this study have largely been demonstrated previously. However, the investigators were seeking to find the most impactful biomarkers in NAFLD and their intercorrelation—a feat only achieved with a large sample size and biomarker panel as in the current study. Diagnosis of definite NASH, which was present in 58% of patients, was the primary outcome. Its individual histological components (steatosis, lobular inflammation, and hepatocyte ballooning) were also studied. Abbreviations: IL-8, interleukin-8; NAFL, nonalcoholic fatty liver; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; PAI-1, plasminogen activator inhibitor 1; PIVENS, pioglitazone or vitamin E for nonalcoholic steatohepatitis.