Nonalcoholic fatty liver disease (NAFLD) is strongly associated with obesity. Because of the current obesity epidemic, NAFLD is currently one of the most prevalent liver diseases in the world and a major cause of cirrhosis and liver-related mortality.1 Fortunately, only some of the many individuals with NAFLD will ever develop progressive liver injury that results in steatohepatitis (SH), cirrhosis, or primary liver cancer. Therefore, efficient, accurate identification of patients who are most likely to develop progressive liver damage is crucial so that such individuals can be targeted for more aggressive surveillance and therapeutic interventions to optimize the outcomes and minimize the costs of the NAFLD epidemic. Success has been stymied by our relatively poor understanding of the processes that regulate the outcomes of fatty liver injury.
Research involving experimental animals is often used to delineate key mechanisms and pilot therapies for human diseases with long and/or seemingly idiosyncratic natural histories. In NAFLD, however, this approach has been hampered by the lack of small animal models of SH and progressive liver fibrosis that also mimic the typical metabolic perturbations of human NAFLD.2 Nonetheless, recent studies in mice demonstrated that the development of SH and fibrosis correlated strongly with the intensity and duration of Hedgehog (HH)-pathway activation that developed during fatty liver injury.3 Other work in cultured cells demonstrated that HH ligands stimulate quiescent hepatic stellate cells to become myofibroblastic, promote proliferation of liver myofibroblasts and progenitors, inhibit apoptosis of these cell types, and up-regulate the production of chemokines for various types of immune cells.4, 5 Therefore, it is conceivable that interindividual differences in HH-pathway activity contribute to the variable outcomes of fatty liver injury in NAFLD patients. This concept was supported by immunohistochemical (IHC) staining of liver-biopsy samples from a small number of NAFLD patients.3 The resultant data showed that the hepatic content of HH-ligand–producing cells, as well as the burden of HH-responsive liver cells, increased in parallel with fibrosis stage. However, the fact that the analysis was performed in only a small number of patients from a single institution raised valid concerns among clinicians who questioned whether the selected cohort was representative of the general NAFLD population. Further investigation of this issue is warranted, and therefore the aim of the present study was to evaluate the relationship between the level of HH-pathway activity and severity of liver inflammation and fibrosis in a large, representative cohort of NAFLD patients.