NASH and thiazolidinediones: Not to be taken lightly☆
Article Outline
Following the recent report of Belfort et al. in the New England Journal of Medicine showing an improvement of non-alcoholic steatophepatitis (NASH) with pioglitazone [1], more and more patients diagnosed with this disorder will be offered treatment with a peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist. As the study of Balas et al. in this issue of the Journal reminds us, one has to weigh the benefits against the risks of these drugs [2].
A liver biopsy is a prerequisite for the diagnosis of NASH. Histological signs, suggestive of alcohol consumption – macrovesicular steatosis, hepatocellular ballooning and parenchymal inflammation – in a subject drinking little or no alcohol, are diagnostic of NASH, even if formal criteria are still missing. Accumulated evidence shows that about 20% of NASH patients develop, over time, full-blown cirrhosis with all its complications including hepatocellular carcinoma [3]. We do not yet have the means to identify those patients in whom the disease will progress. Several factors have been implicated in the pathogenesis of NASH. Among these factors, oxidative stress and insulin resistance are currently the focus of intense scrutiny. Binding of insulin to its receptor results in the phosphorylation of an effector protein, which activates intracellular signalling pathways [4]. Oxidative stress through activation of the NF-κB and JNK pathways may disrupt the signal by phosphorylation of the insulin-receptor substrates [5]. Normally, insulin activates PPAR-γ, a transcription factor promoting adipogenesis and lipid storage [6]. In the case of insulin resistance, PPAR-γ is not activated. Pharmacological agonists of PPAR-γ such as thiazolidinediones, which bypass this impaired step, have been developed for their potential to treat insulin resistance. These drugs effectively decrease plasma glucose levels and lower plasma triglyceride and free fatty acid levels. Caldwell et al. was the first to test a thiazolidinedione in patients with NASH. He treated 10 patients with troglitazone for 6
months and documented an improvement of circulating aminotransferase levels and a mild amelioration of the histology [7]. This study was completed before withdrawal of troglitazone from the market due to cases of idiosyncratic hepatitis. This withdrawal raised concerns regarding the use of this class of drugs to treat NASH. Two subsequent pilot studies treating patients with rosiglitazone [8] and pioglitazone [9], respectively, also reported an amelioration of the aminotransferases and an improvement of the histological lesions without major toxicity. These studies lead to a placebo-controlled trial, first performed by Belfort et al. [1], which confirmed the positive effects of pioglitazone on plasma aminotransferase levels, insulin sensitivity and histology. Fatigue and lower extremity oedema were the only side effects mentioned. Ratziu et al. led a larger and longer randomized placebo-controlled study with rosiglitazone and presented similar findings [10].
In these studies, administration of a thiazolidinedione did not improve the body mass index, but rather worsened it. In Belfort’s study, 6months of treatment with pioglitazone resulted in an average of 2.5kg weight gain [1], whereas in Ratziu’s study, 1year of treatment with rosiglitazone resulted in an average of 1.5kg weight gain (personal communication). The work of Balas et al. published in this issue of the Journal investigates the nature of this weight gain. Is it water retention, consistent with reports of oedema of the lower extremities and even congestive heart failure [11] or rather an increase in body fat? The Balas study group consisted of 35 patients originally included in Belfort’s study, of whom 21 patients received pioglitazone and 14 received placebo, as well as 10 additional lean healthy subjects. Total body fat content and lean body mass were determined by dual energy X-ray absorptiometry, total body water was measured with tritiated water and its distribution between intracellular and extracellular compartments was measured by bioelectric impedance. The study demonstrates that the weight gain in the patients who took pioglitazone for 6months was exclusively related to an increase in body fat content without water retention. This is hardly surprising given that none of the 35 patients included in the study developed oedema and that a drug ameliorating insulin sensitivity will promote fat storage. Taken together, the Belfort and the Balas studies show that pioglitazone treatment is not only associated with a redistribution of fat from the liver into adipose tissue but also with a net increase in body fat. This effect is especially unappealing to individuals who are overweight, a consistent characteristic of NASH patients.
The Balas study raises important questions. Is the weight gain associated with thiazolidinedione limited? Drug trials involving NASH are short lived, whereas in practice patients with NASH will undergo long treatments. Where is pioglitazone-induced fat deposited? Intra-abdominal fat is considered more harmful than subcutaneous fat. Magnetic resonance imaging and spectroscopy in 10 patients with non-alcoholic fatty liver disease receiving nutritional counselling found that the improvement of serum aminotransferase activities correlated with the reduction in abdominal adipose tissue, but not with the diminution of intrahepatic lipids [12]. In a group of patients with type 2 diabetes, pioglitazone decreased visceral fat and increased the ratio of subcutaneous fat to visceral fat assessed by magnetic resonance imaging [13]. The work of Balas et al. did not localize the fat deposition. Does this weight gain impact negatively on other, liver-unrelated health issues like cardiovascular events? Since the publication of the Belfort trial considerable controversy has ignited regarding the possibility that long-term treatment with rosiglitazone might increase the risk of cardiovascular events [14], although this is still uncertain [15], [16], [17]. While changes in plasma lipids induced by pioglitazone are different from those induced by rosiglitazone, it cannot be excluded that the absence of protection or, worse, the yet to be proven increase of cardiovascular-related death could be a class effect of thiazolidinediones. Indeed, a long-term prospective randomized controlled trial of pioglitazone in patients with type 2 diabetes failed to confirm a protective effect on the primary outcome, a composite outcome defined as overall cardiovascular events and mortality [18]. This is worrisome since patients with NASH are not only at risk of developing liver cirrhosis but also of cardiovascular-related deaths [19].
This demonstration of pioglitazone-induced fat deposition should not be taken lightly and emphasizes the need to explore other therapeutic options. Physical activity even if it does not lead to weight loss may affect the fat distribution in the body and in particular mobilize the intra-abdominal fat [20]. Ursodeoxycholic acid is safer than thiazolidinediones and may have some insulin sensitizing effect [21]. Notwithstanding one large placebo-controlled randomized negative trial [22], ursodeoxycholic acid either at a higher dose or in combination with vitamin E [23] merits further investigation.
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☆ The author declares that he has a relationship with the manufacturers, of rosiglitazone Avandia®. He is the principle investigator of an investigation-initiated study testing rosiglitazone in NASH. Furthermore, he declares he received funding from GlaxoSmithKline to carry out his study.
PII: S0168-8278(07)00408-4
doi:10.1016/j.jhep.2007.07.012
© 2007 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
