William F. Balistreri, MD

Disclosures

April 05, 2016

In This Article

The Economical Treatment of NAFLD/NASH

There is a need to develop inexpensive yet effective therapies that improve both liver/cardiac risks and outcomes in obese patients. Because vitamin E is known to improve NASH—but only in certain patients—a method to predict response would be of considerable value, allowing clinicians to target these strategies to those most likely to benefit.

Vitamin E in NASH

Kowdley and coworkers[9] presented nonrandomized safety and efficacy estimates for vitamin E in diabetic patients with NASH. Vitamin E treatment was associated with similar significant improvement in NASH histology in diabetic and nondiabetic patients. There was no association of vitamin E use with important adverse safety measures, and no significant differences were noted from baseline in serum levels of total cholesterol, HDL cholesterol, low-density lipoprotein (LDL) cholesterol, or triglycerides. These preliminary findings offer promising safety and efficacy data regarding the use of vitamin E in diabetic patients with NASH.

The question remains: Which patients are most likely to benefit from treatment? It is known that the genotype 2 allele for the antioxidant haptoglobin is associated with improved cardiac outcomes after vitamin E treatment.

Asgharpour and colleagues[10] therefore hypothesized that this allele would also serve as a biomarker for enhanced liver and metabolic response to vitamin E treatment for patients with NASH. They reported that the genotype 2 allele was associated with an increased response to vitamin E compared with genotype 1. When all patients were pooled, genotype 2 had significantly better end-of-treatment adjusted mean changes from baseline in the NAS, steatosis, and lobular inflammation. Patients with genotype 2 also had larger decreases in ALT, AST, and total cholesterol. Thus, the haptoglobin genotype 2 allele can be used to identify patients with NASH who are more likely to have improved liver histology and reduced cardiometabolic risks after treatment with vitamin E.

Obeticholic Acid in NASH

In the multicenter, double-blind FLINT trial, conducted by the NASH CRN, treatment with the farnesoid X receptor ligand obeticholic acid (OCA) led to improvement in fibrosis in patients with noncirrhotic NASH. Fibrosis is the best predictor of liver-related mortality in patients with NASH.

Chalasani and colleagues[11] evaluated the performance of a commonly used noninvasive scoring algorithm for fibrosis, FIB-4, in monitoring the improvement in fibrosis due to OCA treatment. Among 200 patients treated with OCA, 32% had stage III fibrosis, 29% had stage II fibrosis, and 26% had stage I fibrosis as determined by biopsy at baseline. FIB-4 was measured over time and correlated with fibrosis stage according to the histologic scoring system. OCA treatment led to a significant reduction in FIB-4 scores compared with placebo; a significantly greater proportion of patients receiving OCA (35% vs 19% placebo) improved by one stage or more. A 10% improvement of FIB-4 at 24 weeks was associated with a histologic improvement in fibrosis by one stage or more at 72 weeks. FIB-4 may be a noninvasive surrogate for fibrosis monitoring.

Hameed and coworkers[12] assessed the role of weight loss and OCA treatment in improving the clinical and metabolic features of NASH. Weight loss occurred in 42% of OCA vs 30% of placebo recipients. The NAS improved more with OCA treatment in patients who lost weight than in those who did not. ALT also improved more with weight loss in both OCA and placebo recipients. Weight loss in patients receiving OCA was associated with a lesser decrease in waist circumference and an increase vs a decrease in waist/hip ratio compared with placebo.

Weight loss had additive beneficial effects on some biochemical and histologic features of disease activity in patients with NASH treated with OCA. However, other metabolic beneficial effects of weight loss, such as those on LDL cholesterol, HDL cholesterol, and insulin resistance, are absent or reversed on OCA treatment. This is in contrast to the consistent and expected benefit of weight loss achieved in the placebo group with improved lipid profile and insulin resistance. These findings stress the importance of assessing concomitant metabolic effects and long-term safety of new therapies of NASH.

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