Targeted Treatments for Inflammation
Despite a rapid expansion in our understanding of this common disease, there have been very limited advances in the treatment and prevention of NASH. The recent publication of the PIVENS trial failed to demonstrate a benefit of pioglitazone in NASH. Significant benefit was observed with vitamin E (800 IU daily) versus placebo; however, there has been controversy about the safety of vitamin E at this dose, related to cardiovascular mortality as well as the validity of the predetermined primary outcome in this trial. Similarly, the combination of vitamin E and ursodeoxycholic acid was associated with improved aminotransferase levels and histological scores. Given the results of the PIVENS trial, the role of ursodeoxycholic acid is in question.
As our understanding of the pathophysiology of NASH evolves, therapeutic targets for the treatment of NASH emerge. One such potential target is NF-κB.[145,146] Selective targeting of NF-κB signaling of inflammatory cells may be crucial in therapy design, as NF-κB may also act as a hepatocellular survival factor, and its inhibition may therefore lead to enhanced apoptosis and compensatory hepatocyte proliferation, favoring HCC development. A second selective target for NASH may be modulation of the JNK pathway.[147,148] Selective blockade of JNK1 may be associated with improved hepatic steatosis, insulin resistance and inflammation; however, blockade of JNK2 may exacerbate hepatocellular injury. Alternately, modulation of the gut flora or inflammatory cytokines may prove beneficial; however, this has not been reproduced in human studies. Further work is needed to evaluate these and other potential therapeutic targets for NASH.
Expert Rev Gastroenterol Hepatol. 2011;5(2):189-200. © 2011 Expert Reviews Ltd.