Noninvasive indices of fibrosis in NAFLD: starting to think about a three-hit (at least) phenomenon.

NAFLD is a highly prevalent, phenotypically diverse condition. A small minority of patients with NAFLD progress to clinically important stages of fibrosis. Identifying patients at risk for progressive disease is one of the great challenges of hepatology. There are an increasing number of models that have been reported to provide noninvasive indices of histological severity of NAFLD, including a new report by Gholam et al. in this issue of the Journal. All models estimating risk of severity of NAFLD lack predictivity for future progression of fibrosis. Although conceptually considered to be a "two-hit" phenomenon, the combination of steatosis, necroinflammation, and progressive fibrosis is likely to be much more complex. Because the phenotypic expression of NAFLD, like so many liver diseases, is an interaction among genes, behavior, and environment, predicting future outcomes for patients with NAFLD (and liver diseases in general) will likely require models that combine genetic susceptibility, biological environment, and behavior. Emerging data are reviewed that suggest that it will not be long before studies like that of Gholam et al. are combined with those of clinical genomics to deliver tools that we can apply to the individual patient.