Is vitamin E beneficial in chronic liver disease?
Authors: Ingrid Hickman, Graeme Macdonald
Journal: Hepatology (2007)

Oxidative stress is implicated as a cause of liver injury in a range of liver diseases including viral hepatitis, alcoholic liver disease, and nonalcoholic steatohepatitis (NASH). Vitamin E is the most widely studied antioxidative, particularly in NASH. In the current issue of HEPATOLOGY, Soden et al.1 have examined the role of vitamin E in an animal model of liver disease. GCDC, glycochenodeoxycholic acid; NASH, nonalcoholic steatohepatitis; ROS, reactive oxygen species. Oxidative stress is mediated by reactive oxygen species (ROS) generated in the liver by a number of mechanisms involving induction of microsomal CYP2E12 and H2O2 production from peroxisomal β-oxidation of fatty acids, consequently resulting in cytokine release as well as recruitment of activated inflammatory cells.3 ROS react with a range of molecules in the cell, leading to impaired nucleotide and protein synthesis, which in turn injure organelles and activate hepatic stellate cells.4 ROS are responsible for inducing apoptosis and cell death and interfere with repair mechanisms. Polyunsaturated fatty acids are major constituents of cell membranes. They are particularly susceptible to free-radical-mediated oxidation which results in lipid peroxidation and disturbances in membrane structure and function. Oxidative stress and lipid peroxidation may change the physical state of plasma membranes and impair membrane function, including insulin signaling.5 In patients with NASH, markers of lipid peroxidation are positively correlated with insulin resistance.6 There are a number of protective mechanisms that ameliorate or attenuate the effect of ROS including the up-regulation of a range of endogenous antioxidants, such as coenzyme Q10 and ubiquinones. There is also a range of exogenous antioxidants including vitamins E and C, carotenoids (beta carotene and lycopene), and polyphenols (flavonoids). Vitamin E is of particular interest because it can limit membrane injury by ROS. There are 8 naturally occurring vitamin E compounds, 4 tocopherol homologs and 4 tocotrienols, which are synthesized by plants from homogenistic acid. The 4 tocopherol homologs (dα-, dβ-, dγ-, dδ-) have a saturated 16-carbon phytol side chain, whereas the tocotrienols (dα-, dβ-, dγ-, dδ-) have 3 double bonds on the side chain. All are derivatives of 6-chromanol and differ in the number and position of the methyl groups on the ring structure (Fig. 1). The term vitamin E can be used to describe any combination of compounds; however, α-tocopherol is the most abundant in nature and in human plasma, and the most widely used in supplements and biomedical research studies. The chemical structure of naturally occurring (A) tocopherols and (B) tocotrienols. The tocotrienols differ from the tocopherols in that the 16-carbon phytol chain contains 3 unsaturated double bonds. The number and position of the methyl groups on the chromanol ring (R1 and R2) denotes the different homologs (dα-, dβ-, dγ-, dδ-). The hydroxyl group on the ring structure is involved in antioxidant activity.24 The structure of vitamin E makes it a highly effective antioxidant, readily donating the hydrogen from the hydroxyl group on the ring structure to free radicals, and rendering them inactive. Vitamin E is fat soluble and is primarily located within the phospholipid bilayer of the cell membranes where it has a major biological role in protecting polyunsaturated fats and other components of the cell membranes from oxidation by free radicals. Obesity has been linked to insulin resistance, hepatic steatosis, and liver injury in a range of conditions. These factors appear particularly important in the pathogenesis of NASH. Hyperinsulinemia and hyperglycemia have been linked with increased oxidant stress5 and a decrease in α-tocopherol independent of body weight.7 Central obesity is associated with depletion of the body's endogenous antioxidants.8 As a consequence, the liver may be more vulnerable to injury. Vitamin E supplementation with d1-α-tocopherol (900 mg/day for 4 months) improves total body glucose disposal and nonoxidative glucose metabolism in lean subjects, and in type 2 diabetes.9 Vitamin E may have dual benefits by decreasing oxidative stress and improving insulin sensitivity and is an attractive therapeutic agent for NASH and other liver diseases. Despite the encouraging in vitro work, results from clinical studies have been mixed. In population studies, there seems to be a lack of benefit from vitamin E in preventing cardiovascular disease.10, 11 Randomized trials of supplemental vitamin E to date have been small and have not shown substantial beneficial effects on mortality endpoints. A recent meta-analysis suggested there may be a small increase in the risk of all-cause mortality with high-dose α-tocopherol supplementation (>400 IU/day).12 A number of studies have examined the role of supplemental vitamin E in liver disease. A recent Cochrane review concluded that data was too limited to assess the effectiveness of Vitamin E in NAFLD,13 and the only study to assess the histological effect of α-tocopherol supplementation in NASH showed no histological improvement compared to placebo.14 In patients with chronic hepatitis C, high-dose α-tocopherol significantly reduced oxidative stress but did not affect liver enzymes or histological features of liver injury,15 whereas in a randomized, placebo-controlled study of alcoholic hepatitis, there was no beneficial effect with 1000 IU/day.16 Vitamin E appears more promising in hepatitis B, where it was associated with improved alanine aminotransferase levels and suppressed viral replication in nearly half the patients treated17; however, these studies have not been repeated in larger cohorts. Why might vitamin E supplementation not translate into clinical benefit? First, the term vitamin E is used collectively for 8 compounds, each potentially with its own biological effects. Most research used tocopherol (99% of vitamin E papers on PubMed relate to α-tocopherol)18 rather than tocotrienols. However, tocotrienols exhibit powerful neuroprotective, anticancer, and some cholesterol-lowering properties that are not necessarily shared by tocopherols.18 Second, the method of administration has been predominantly oral supplementation. This approach is straightforward and allows greater dosage than is possible from dietary sources. However, the oral bioavailability of supplemental tocopherols are not precisely known and high-dose α-tocopherol may reduce the plasma concentrations of other vitamin E analogs such as γ-tocopherol and δ-tocopherol due to competition for uptake and transfer in key tissues.19 The changes to bioavailability of other tocopherols and tocotrienols may in part account for the null effects in studies of supplemental α-tocopherol. Finally, the production of ROS in different disease states may overwhelm the ability of supplemental vitamin E to ameliorate lipid peroxidation and cellular injury. In this issue of HEPATOLOGY, Soden et al.1 report the results of subcutaneous administration of α-tocopherol in an animal model of steatocholestasis. This group has a long history of studying toxicity of bile acids and the effects of vitamin E and other antioxidants.20-22 They recently extended their studies to the Zucker fatty rat, an animal model of hyperphagia, obesity, and hepatic steatosis that occurs as a consequence of a mutation in the leptin receptor.22 These animals develop hepatic steatosis without inflammation or fibrosis. Hepatocytes isolated from these animals and exposed to glycochenodeoxycholic acid (GCDC) undergo necrosis, which is mediated in part by ROS. The isolated hepatocytes could be protected from necrosis by exposure to antioxidants, including α-tocopherol. In their current study, the effects of GCDC and vitamin E were studied in vivo. Animals were loaded with α-tocopherol by parenteral administration for a week prior to exposure to GCDC. Treatment with the bile acid resulted in necrosis and inflammation, particularly in the obese animals. This was associated with evidence of lipid peroxidation, but there was no histological evidence of apoptosis. Pretreatment with α-tocopherol led to a significant increase in vitamin E concentration in the liver, and a significant reduction in hepatocyte necrosis and inflammation. There was no beneficial effect on lipid peroxidation, although in their earlier in vitro studies, the authors were able to show a beneficial effect of α-tocopherol on generation of ROS.22 The first observation from this study is that hydrophobic bile acids can stimulate necroinflammation in an animal model of hepatic steatosis, at least with short-term exposure. Thus, these bile acids may be an important "second hit" in the evolution of NASH. An important caveat is that leptin signaling has been shown to be relevant in hepatic responses to injury23 and leptin resistance may play a role in this model. The second observation is that pretreatment with α-tocopherol can ameliorate, but not abrogate, this liver injury. Although not shown in the current study, this may be mediated through reduction in ROS and lipid peroxidation. In summary, a range of experimental studies have shown that vitamin E can play a role in protecting cells from injury caused by ROS and lipid peroxidation. ROS and depleted antioxidants have been implicated in insulin resistance and obesity and may play a role in the pathogenesis of disease such as NASH. However, to date there is little data to support the use of supplemental vitamin E in treating liver disease. The possible therapeutic utility is made complex because vitamin E is a group of compounds, and issues related to bioavailability and interactions between these related compounds need to be resolved. Soden and colleagues have shown that parenteral vitamin E ameliorates liver injury in an animal model of obesity and hepatic steatosis, by protecting animals from hydrophobic bile acid. These observations provide support for further exploration of the role of vitamin E supplementation in liver disease.