17 begins to shed some light in this area. They found that patients who improved their insulin sensitivity by 40% or greater had a significant improvement in hepatocyte find more ballooning. Alternatively, those with less of a response did not do as well, corroborating the experience seen in the bariatric surgery field.24 These findings highlight the particular need to better characterize patients who may or may not respond to TZD therapy, similar to how we characterize patients with hepatitis C prior to initiating therapy with pegylated interferon and ribavirin. Does gender, ethnicity, or the presence or absence of diabetes

mellitus among patients with NASH influence the degree of insulin sensitivity improvement seen with the TZDs? Does the degree of baseline insulin resistance influence histopathologic response rates? Is there more to the story than simply improving insulin resistance? The TZDs clearly do not improve histology in every patient. With further knowledge of response factors, clinicians may be able to distinguish or even predict responders from nonresponders

FXR agonist prior to initiating therapy with a TZD or within a few weeks to months of starting therapy depending on the insulin response curve. Finally, the results from the PIVENS trial presented at the recent 60th annual meeting of the American Association for the Study of Liver Diseases suggest that treatment strategies other than insulin sensitivity improvement may also improve histopathology.15 The multiple mechanisms leading to NASH may require that more than one therapeutic approach be considered in the treatment of this disease. The future may involve either targeted monotherapy based on specific patient demographics and baseline laboratory data or combination therapy that is aimed at improving key pathogenic abnormalities

seen MCE in patients with NASH, such as oxidative stress, insulin resistance, apoptosis, or other, as-yet clarified, manifestations of lipotoxicity. For now, lifestyle intervention remains the cornerstone of therapy for NAFLD. However, for those patients who are unable to exercise or lose weight through diet, or for those patients with more advanced NASH, studies with adjuvant pharmacologic therapy targeting insulin resistance appears indicated. More recent data suggest that patients with NAFLD are not just at risk for progression to cirrhosis and hepatocellular carcinoma, but also are at significant risk for progression to diabetes and cardiovascular disease. Given this information, it may be myopic for Hepatologists to simply focus on the histopathologic effects of NASH therapies. The beneficial effects of the TZDs to prevent or delay the progression to diabetes and the potential beneficial effects of pioglitazone on cardiovascular disease should be considered concurrently with the potential for histopathologic improvement.