Public Release Type:
Journal
Publication Year: 2010
Authors:
Kleiner DE,
Bass NM,
Brunt EM,
Chalasani NP,
Clark JM,
Diehl AM,
Donithan M,
Kowdley KV,
Lavine JE,
Loomba R,
McCullough AJ,
Neuschwander-Tetri BA,
Robuck PR,
Sanyal AJ,
Tonascia J,
Unalp A,
Van Natta M
Studies:
Nonalcoholic Steatohepatitis Clinical Research Network
The NASH CRN PIVENS trial showed that 43% of vitamin Etreated patients (800 IU/d for 96 weeks) responded with improvement in the histological features of NASH (primary endpoint) compared to 19% of placebo-treated patients (NEJM 362:1675-1685, 2010). The vitamin E benefit did not vary by patient characteristics at enrollment (BMI, age, gender, ethnicity, severity of disease and adherence to treatment). The aims of this analysis were to (1) determine if patients with lower initial blood levels of vitamin E (α-tocopherol) were more likely to benefit from vitamin E and (2) to determine whether the pattern of changes in either vitamin E blood levels or ALT during treatment differed between histological responders and non-responders in vitamin E or placebo groups. The vitamin E benefit did not vary by whether baseline vitamin E levels were above or below the 12 μg/ml median (P=0.74). There were marked increases in serum vitamin E levels at 96 weeks in the vitamin E group (P<0.0001), but the amount of increase was similar among responders (+9.8 [SD 6.7] μg/ml) and non-responders (+11.9 [9.0] μg/ml, P=0.26). Vitamin E levels did not change in the placebo group whether the criteria for histological response were met (-0.2 [2.8] μg/ml) or not (-0.2 [3.4] μg/ml, P=0.44). Serum ALT levels at 96 weeks fell markedly in the vitamin E responders (-49 [51.3] U/L) and less so in vitamin E nonresponders (-26 [49.7] U/L, P=0.05). A smaller decrease in serum ALT levels occurred in placebo group responders (-25 [30.5] U/L) and non-responders (-18.7 [45.3] U/L, P=0.59). Repeated measures analysis of all follow-up ALT levels showed that ALT levels were lower in vitamin E responders than in nonresponders (P=0.007). The amount that ALT decreased from baseline to 96 weeks increased the probability of histological improvement, but the probability did not differ between the vitamin E or placebo groups (P=0.33). For decreases in ALT of 25, 50, and 75 U/L, the probabilities of histological improvement were 0.22, 0.39, and 0.51. ALT change from baseline to 6 months was a weak discriminator of responders from nonresponders in the vitamin E group (ROC area=0.65, 95% CI: 0.52-0.77). In conclusion, histological responses to vitamin E in patients with NASH did not appear to be due to correction of unrecognized vitamin E deficiency. Improvement in serum ALT levels was associated with improved histological response as defined by the pre-specified primary endpoint. Further studies are needed to establish characteristics of patients who are likely to respond to vitamin E and to identify mediators of this response.