Changes in Serum Adipokine Levels During Pioglitazone Treatment for Nonalcoholic Steatohepatitis: Relationship to Histological Improvement

Background & Aims: Thiazolidinedione (TZD) therapy improves liver histology in nonalcoholic steatohepatitis (NASH) through a mechanism possibly related to its insulin-sensitizing or anti-inflammatory activity. This study was conducted to assess changes in serum levels of selected adipokines and proinflammatory cytokines and to relate these changes to the improved liver histology resulting from pioglitazone therapy for NASH. Methods: Serum samples from 18 patients with NASH obtained at day 0 and week 48 of therapy during an open-label study of pioglitazone were tested for adiponectin, leptin, interleukin (IL)-1a, IL-6, and tumor necrosis factor (TNF)-α levels. Paired liver biopsy specimens were scored (0–4) for steatosis, parenchymal inflammation, cell injury, and fibrosis. Results: Adiponectin levels increased from 3.7 to 10.3 μg/mL at week 48 (P < .01); the levels of the other cytokines were unchanged: TNF-α, 9.1 vs 8.8 pg/mL; IL-1a, 3.9 vs 3.4 pg/mL; IL-6, 19.4 vs 13.4 pg/mL; and leptin, 24.8 vs 29.6 ng/mL (P > .05 for all). Pioglitazone therapy was associated with improvements in steatosis (2.5 vs 1.0), parenchymal inflammation (3.3 vs 2.1), cell injury (2.2 vs 0.9), and fibrosis (2.0 vs 1.4). The change in adiponectin level was associated with the improvement in steatosis (P = .03) as well as in a summary NASH activity index score (P = .01). Changes in IL-1, IL-6, TNF-α, and leptin levels did not correlate with improvements in the histological features. Conclusions: Improvements in liver histology during TZD therapy may be modulated by an adiponectin-mediated effect on insulin sensitivity and hepatic fatty acid metabolism rather than by changes in proinflammatory cytokines.

Abbreviations used in this paper:  BMI, body mass index , ELISA, enzyme-linked immunosorbent assay , IL, interleukin , MRI, magnetic resonance imaging , NASH, nonalcoholic steatohepatitis , PPAR, peroxisome proliferation activation receptor , TNF, tumor necrosis factor