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Vitamin E and changes in serum alanine aminotransferase levels in patients with non-alcoholic steatohepatitis

Vitamin E and changes in serum alanine aminotransferase levels in patients with non-alcoholic steatohepatitis

Alimentary Pharmacology & Therapeutics

J. H. Hoofnagle1,*, M. L. Van Natta2, D. E. Kleiner3, J. M. Clark2, K. V. Kowdley4, R. Loomba5, B. A. Neuschwander-Tetri6, A. J. Sanyal7, J. Tonascia2, the Non-alcoholic Steatohepatitis Clinical Research Network (NASH CRN)
Article first published online: 29 MAY 2013 DOI: 10.1111/apt.12352

Volume 38, Issue 2, pages 134–143, July 2013

Discussion Only

Full Text Available @ Alimentary Pharmacology & Therapeutics

Discussion
Non-alcoholic fatty liver disease has become the most common cause of liver test abnormalities adults in the Western world and is estimated to affect up to 30% of the adult population.[17-19] This condition is also increasing in frequency among children and adolescents.[20] NAFLD is often benign and nonprogressive and associated with few, if any, symptoms. On the other hand, a proportion of patients with NAFLD develop progressive liver disease that can result in cirrhosis, end-stage liver disease, need for liver transplantation, hepatocellular carcinoma and death.[21-25] Patients with progressive disease usually have NASH on liver biopsy with the typical findings of centrizonal (zone 3) cellular injury (also called ballooning degeneration), inflammation, and fibrosis in addition to steatosis.[22] The separation of simple steatosis from NASH non-invasively can be difficult and is not predicted by serum aminotransferase levels, thus leading to the need for liver biopsy to decide upon interventions.[26, 27] These findings suggest that serum ALT and AST are unreliable markers for the degree of activity or severity, stage or degree of fibrosis and ultimate progression of NASH to end-stage liver disease.
 
In this secondary analysis of the PIVENS trial, however, serum ALT levels, if elevated at baseline, were found to have reasonable reliability in detecting improvement in the underlying liver disease, at least as assessed by liver biopsy and a validated histological scoring system. Over 80% of patients treated with vitamin E whose serum ALT levels fell to 40 U/L or less and by at least 30% of baseline had histological improvement. Importantly, none of these patients had evidence of worsening. In contrast, patients who did not achieve this degree of improvement in serum liver biochemical tests were less likely to show histological improvement and a significant proportion worsened.
This reanalysis of the PIVENS trial also showed the important and confounding effects of weight change on serum ALT levels as well as histological features of disease. Indeed, in patients who lost weight (using a cut point of only 2 kg over a 2-year period), the proportion of patients with histological improvement was similar in vitamin E and placebo groups (71% vs. 64%), although the quantitative degree of improvement in NAS score was greater with vitamin E than placebo (−2.8 vs. −1.9 points). Perhaps more strikingly, patients who gained weight were less likely to improve with vitamin E therapy, and those receiving placebo were likely to worsen. Weight gain was indeed associated with significant worsening of hepatic fibrosis in the placebo-treated patients. In contrast, patients who received placebo and who lost or did not gain weight and those who received vitamin E were unlikely to demonstrate progression of fibrosis scores over the 2-year period of this study whether or not ALT levels improved. These results provide strong and evidence-based support for dietary recommendations in patients with NASH. A first priority should be weight loss. But, perhaps more important is strict avoidance of further weight gain, which is closely associated with worsening of fibrosis, a surrogate, but convincing marker for disease progression.
 
The demonstration that vitamin E resulted in decreases in ALT levels and histological improvements in NASH was shown in the initial publication of the PIVENS trial [13] and was reinforced by several features in this study. First, there was a rapid and statistically significant decline in ALT levels in the vitamin E-, but not placebo-treated patients. The proportion of patients with an ALT response was three or more times higher in the vitamin E than placebo group, both at 24 weeks (39% vs. 7%) and 96 weeks (48% vs. 16%). Improvements in ALT levels were associated with improvements in histology scores and this was most evident in the vitamin E-treated subjects. Finally, discontinuation of vitamin E was followed by a prompt relapse and loss of the ALT response in 42% of patients.
Shortcomings of this post hoc analysis include the small sample size of the controlled study, which was adequate to assess the primary endpoint, but was somewhat limited for extensive secondary analyses. In addition, the definitions of ALT and histological responses were made a priori with only limited analysis of the dataset. However, both definitions are based upon clinical understanding of NAFLD and were easy to apply. The numbers of patients in the study were too few to attempt to generate statistically based algorithms for defining an ALT or histological responses; however, in preliminary analyses, modification of the criteria, such as dropping the requirement for a 30% decline in ALT from baseline, decreasing the criteria for an ALT response from ≤40 to ≤30 U/L, and using AST rather than ALT values did not improve the area under the curve in predicting histological responses (Table S1). Finally, this study was carried out in nondiabetic patients and the findings may not be applicable to patients with diabetes, who typically have more severe disease. Furthermore, only half of patients (48%) responded to vitamin E therapy and most relapsed when it was stopped.
In summary, these results show that vitamin E therapy is associated with improvements in serum aminotransferase levels, and that decreases of ALT values into the normal range (to ≤40 U/L and by 30% of baseline) are usually associated with histological improvement in disease activity (steatosis, inflammation, cell injury). Weight loss can also achieve these endpoints, but importantly weight gain has definite negative implications for the natural history and outcome of this common and increasingly important form of liver disease. The effects of vitamin E and weight loss on both ALT and histological responses were separate and independent, so that even patients who lost weight benefitted from vitamin E therapy.

Clinical Trial Number: NCT00063622.

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