The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis.
A pilot study of a 48-week course of pioglitazone demonstrated significant improvements in the biochemical and histological features of nonalcoholic steatohepatitis (NASH). The aim of the study was to assess the effects of stopping pioglitazone. Twenty-one patients with NASH were treated with pioglitazone (30 mg/day) for 48 weeks and underwent baseline and end-of-treatment evaluation including liver biopsy. Thirteen patients were followed for at least 48 weeks after stopping therapy and 9 underwent repeat liver biopsy. Statistical comparisons were made to evaluate whether discontinuation of pioglitazone resulted in a reversal of improvements seen on therapy. Stopping pioglitazone was associated with subsequent elevation in serum alanine aminotransferase levels (from 34 +/- 13 to 70 +/- 39 IU/l), decrease in adiponectin (from 9.7 +/- 9.1 to 5.1 +/- 4.5 microg/ml), worsening insulin sensitivity (HOMA Index: from 2.9 +/- 1.8 to 5.5 +/- 5.4), and increase in total hepatic fat (from 30% +/- 32% to 71% +/- 33%) despite no change in average body weight compared to the end of treatment. Repeat liver biopsy in 9 patients revealed significant worsening of parenchymal inflammation (from 1.2 +/- 0.7 to 2.9 +/- 1.1) and steatosis (from 0.9 +/- 0.6 to 2.1 +/- 1.3) but no change in fibrosis (from 1.1 +/- 1.2 to 1.2 +/- 1.3). NASH was again present on liver biopsy in 7 patients.


CONCLUSIONS
These findings suggest that long-term therapy with pioglitazone may be necessary to maintain improvements in disease activity in patients with NASH, although weight gain during treatment may ultimately limit its beneficial effects.
Lutchman
Glen
G
Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA.
Modi
Apurva
A
Kleiner
David E
DE
Promrat
Kittichai
K
Heller
Theo
T
Ghany
Marc
M
Borg
Brian
B
Loomba
Rohit
R
Liang
T Jake
TJ
Premkumar
Ahalya
A
Hoofnagle
Jay H
JH
D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D005234:Fatty Liver / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D008099:Liver / Q000473:pathology; D008297:Male; D008875:Middle Aged; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000009:adverse effects / Q000627:therapeutic use*; D015430:Weight Gain / Q000187:drug effects
D047495:PPAR gamma; D045162:Thiazolidinediones; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000077205:Pioglitazone