Open-label Pilot Study of Folic Acid in Patients With Nonalcoholic Steatohepatitis

Phunchai Charatcharoenwitthaya; Cynthia Levy; Paul Angulo; Jill Keach; Roberta Jorgensen; Keith D. Lindor


Liver International. 2007;27(2):220-226. 

In This Article

Abstract and Introduction

Background/Aims: Folate deficiency disturbs hepatic methionine metabolism and promotes the development of steatohepatitis in animal models. Our aims were (1) to determine the safety and efficacy of folic acid treatment in patients with nonalcoholic steatohepatitis (NASH) on changes in liver biochemistries, and (2) to investigate the presence of subclinical folate deficiency in this population.
Methods: Patients with biopsy-proven NASH were treated with folic acid 1 mg/day for 6 months. Liver enzymes and adverse events were monitored every 3 months until completion.
Results: Ten patients (one male and nine females) with a median age of 54 years were enrolled in this study. At baseline, the median steatosis grade was 2 (range 1–3), the median necroinflammatory grade was 1 (1–3), and the median fibrosis stage was 2 (0–4). The median level of red cell folate was 526 ng/ml (range 99–708); the normal level was 268–616 ng/ml. One compensated cirrhotic patient had folate deficiency. No serious adverse events occurred. After 6 months of therapy, no significant reductions in serum aspartate and alanine aminotransferase levels (60 ± 25 vs. 54 ± 29, P = 0.5 and 86 ± 29 vs. 83 ± 42, P = 0.6, respectively), were observed. Serum levels of bilirubin, alkaline phosphatase, albumin, and prothrombin time remained in the normal range during treatment in all patients.
Conclusion: Six months of therapy with folic acid at a dose of 1 mg/day, although safe and well tolerated, does not lead to a significant biochemical improvement in patients with NASH. In a small number of patients, folate deficiency was present in only a cirrhotic patient.

Nonalcoholic fatty liver disease (NAFLD) describes a clinicopathologic condition that is characterized by excessive accumulation of lipids in the liver of patients without clinical evidence of alcohol abuse.[1] NAFLD is increasingly recognized as the hepatic manifestation of insulin resistance and the systemic complex known as the metabolic syndrome.[2] Nonalcoholic steatohepatitis (NASH), the most severe form of NAFLD, is emerging as a common, clinically important type of chronic liver disease in industrialized countries and many developing countries.[3,4,5,6] Patients with NASH are at risk for the development of aggressive outcomes, such as cirrhosis, and liver cancer, and in some patients it may lead to liver transplantation.[7,8,9] No effective medical therapy is currently proven for patients with NASH. Treatment of associated conditions such as obesity, diabetes mellitus, and hyperlipidemia is generally recommended, but is not often effective in reversing NASH.

An elevated plasma homocysteine (Hcy) level has been observed in patients with nonalcoholic cirrhosis.[10,11,12] Patients with cystathionine β-synthase deficiency exhibiting severe hyperhomocysteinemia and also develop marked hepatic steatosis.[13] Recent studies described an elevated plasma Hcy level in patients with NAFLD compared with healthy subjects or patients with chronic liver disease of other etiologies.[14,15] Hyperhomocysteinemia also tends to increase in parallel with the severity of steatohepatitis.[15] Moreover, studies in animal models suggest that Hcy may be involved in hepatic fibrosis.[16,17] The relationship of hyperhomocysteinemia with pathogenesis and course of NAFLD, however, remains unclear. One potential factor may be the cellular consequence of folate insufficiency in hepatocytes.

It is well documented that the intracellular pool of folate is involved in the regulation of Hcy metabolism by supplying 5-methyltetrahydrofolate. In animal models, folate deficiency plays a causative role in hyperhomocysteinemia accompanied by a decreased concentration of hepatic S-adenosylmethionine (SAM),[18] and promotes liver injury with histologic features of steatohepatitis.[19] Folate supplementation for the folate-deficient animals leads to an increase in hepatic SAM concentration and a decrease in plasma Hcy levels.[18] On this basis, we hypothesize that folate supplementation may attenuate hepatic necroinflammation and show improvement of biochemical parameters in patients with NASH through its Hcy-lowering effect.

We therefore performed a pilot study (1) to determine the safety and potential efficacy of folic acid in untreated patients with NASH on changes in liver biochemical parameters and (2) to investigate the presence of possible subclinical folate deficiency in patients with NASH.


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