Where are we in the search for noninvasive nonalcoholic steatohepatitis biomarkers?

N onalcoholic fatty liver disease (NAFLD) is a common liver disease associated with obesity and insulin resistance. Due to the rising prevalence of obesity and diabetes, NAFLD is presently the most common cause of liver disease in the Western world, both in adults and children. The prevalence of NAFLD in Western adults is between 20% and 30%. NAFLD associates with increased hepaticrelated mortality. NAFLD ranges from the simple accumulation of triacylglycerol (TAG) in the liver (hepatic steatosis) to nonalcoholic steatohepatitis (NASH), which is characterized by steatosis, hepatocyte ballooning, scattered inflammation, fibrosis, and necrosis. A continuously changing hepatic environment—reflected in lipid metabolic changes and the lipotoxicity they generate, inflammatory cells and the paracrine mediators they release, oxidative stress, and insulin resistance—are thought to be critical in the progression from hepatic steatosis to NASH. Although TAG accumulation in steatosis is now understood as a beneficial, adaptive response to the increased exposure of the liver to fatty acids, NASH is a progressive disease that may ultimately progress to cirrhosis, liver failure, and hepatocellular carcinoma in a substantial proportion of patients. Accordingly, compared to simple hepatic steatosis, NASH has a higher liver-related mortality. The estimated prevalence of NASH in the general Western population is between 2% and 3%. Liver biopsy is the only widely accepted technique to diagnose NASH and establish the presence of fibrosis. Several systems have been proposed for the histological evaluation of NAFLD, of which the most widely used is probably the NAFLD activity score (NAS), which is based on the degree of steatosis, lobular inflammation, and hepatocyte ballooning, with an additional score for fibrosis. Although considered the ‘‘gold standard,’’ liver biopsy is an invasive, subjective, and costly procedure, associated with potential complications (risk of death of 0.01%) and prone to sampling error. Because of the limitations of liver biopsy and the increasing prevalence of NAFLD, identification of noninvasive NASH biomarkers may help physicians select subjects for further liver histology analysis, intensified life style counseling, treatment (i.e., vitamin E administration), as well as helping researchers select patients for clinical studies. The amount of TAG accumulated in the liver can be assessed noninvasively by a variety of imaging techniques, including ultrasonography (US), computed tomography, magnetic resonance imaging (MRI), and proton (H)-MRI. Compared to US and computed tomography, MRI and H-MRI perform better for the evaluation of hepatic TAG accumulation, and only these last two techniques show differences across steatosis grades. In a meta-analysis of the performance of US in the assessment of hepatic TAG, this technique showed a pooled area under the curve (AUC) of the receiver operator characteristic (ROC) of 0.93, but the performance of US is decreased in the morbidly obese population. An ideal marker would have an AUROC of 1.0 and thus a 100% sensitivity and specificity. Although imaging techniques perform as well as liver biopsy for NAFLD diagnosis, they are, however, expensive and nonspecific, because they cannot distinguish NASH from simple hepatic steatosis, or identify fibrosis. The majority of patients with NAFLD have normal alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values, and the ALT/AST ratio is often greater than one in those individuals with elevated serum aminotransferases. Bilirubin and albumin values are normal in the majority of patients who have NAFLD, whereas alkaline phosphatase and gammaglutamyl transferase (GGT) levels can be moderately elevated. A variety of scoring systems have been developed to assess NAFLD on the basis of simple laboratory test results in combination with other parameters. For instance, the fatty liver index predicts US-diagnosed NAFLD based on the combination of body Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUROC, area under the receiver operating characteristic curve; BMI, body mass index; GGT, gamma-glutamyl transferase; LC, liquid chromatography; MRI, magnetic resonance imaging; MS, mass spectrometry; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; TAG, triacylglycerol; TE, transient elastography; US, ultrasound. Address reprint requests to: José M. Mato, M.D., CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas, y Digestivas (Ciberehd), Technology, Park of Bizkaia, 48160 Derio, Bizkaia, Spain. E-mail: director@cicbiogune.es; fax: þ34 94 406 1301. CopyrightVC 2011 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.24642 Potential conflict of interest: Nothing to report.