Weight loss, with or without exercise, has been investigated as a therapy for fatty liver disease in several studies (Angulo and Lindor, 2001). Although weight loss is encouraged in overweight patients to prevent its many known complications, the data justifying its recommendation for liver disease remains unconvincing. Several difficulties with the interpretation of earlier studies have been suggested. The duration of weight loss in previous clinical trials was often relatively short and effective means of sustaining weight loss have been elusive. Adjuncts to weight reduction, such as the luminal lipase inhibitor orlistat, are now being investigated in clinical trials of NASH. One provocative observation is that early studies of weight loss as a treatment of NAFLD were associated with improved steatosis but possibly worsened fibrosis and inflammation. Because the histological characteristics of NAFLD as it improves during effective intervention are unknown, biopsy scoring systems developed for viral hepatitis may not properly identify resolving steatohepatitis.
For this reason, the previously used scoring systems that do not account for shifts in inflammation and key differences between the fibrosis of NAFLD and hepatitis C virus (HCV) may miss important changes that indicate resolution of NAFLD (Brunt EM, personal communication, 2003). Past studies may not have focused on specific his-tological abnormalities with adequate detail and their findings must be held with some circumspection. Specifically, if resolving NASH in the early weight loss trials was characterized by important shifts the inflammation and changes in the fibrosis that were missed by HCV scoring systems, such improvements would have been unnoticed. The alternate hypothesis, that weight reduction and lifestyle interventions actually worsen the underlying liver disease, especially the fibrosis, then alternative strategies must be employed to prevent progressive liver disease. Moreover, we cannot underestimate the difficulty in maintaining an altered lifestyle because of physical disabilities or societal influences, a point that further emphasizes the pragmatic need to identify effective treatment strategies besides lifestyle interventions.
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