Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease. The increasing prevalence of NAFLD in recent years is thought to be closely associated with similar rises in metabolic syndrome and obesity. There is no cure at present for NAFLD, but changes in eating habits can be beneficial, such as lowering your calorie intake, adhering to a Mediterranean diet, and consuming pre- and probiotics. Specifically, the antioxidant function of vitamin E when consumed in high doses appears to play a useful role in preventing further liver damage. Further, vitamin D has antifibrotic effects, which may prove an effective intervention in future NAFLD studies.
In recent years, there has been a substantially greater incidence of non-alcoholic fatty liver disease (NAFLD). It has been suggested that the global increases in the prevalence of obesity and metabolic syndrome, themselves due to diet and lifestyle changes, are the cause of this. The NAFLD patient faces the risk of progressing to non-alcoholic steatohepatitis (NASH), caused by inflammation of the liver (though people with NAFLD may also remain asymptomatic for many years). NASH is defined by fat accumulation in the liver exceeding 5% of its own weight. NASH can then progress to liver fibrosis, cirrhosis, and hepatocellular carcinoma – conditions for which a transplant may become the only available treatment. At present, there is no effective therapy for NAFLD patients in the general population.
The pathogenesis behind NAFLD development and progression remains unclear. However, imbalances between pro- and antioxidant mechanisms and between pro- and anti-inflammatory cytokines are thought to be important. Hence, the degree of oxidative stress is likely to be an important factor in the progression of NAFLD (1).
The insulin resistance (IR) found in NAFLD and metabolic syndrome leads to esterified free fatty acids and triglycerides being stored inappropriately in non-adipose tissue, particularly in the liver. Attempts to find an effective pharmacological intervention have concentrated on insulin sensitizers, particularly Metformin and thiazolidinediones (TZDs).
It is possible that our level of oxidative stress increases as a result of oxidized metabolites from the adipose tissue surrounding the gut. Therefore, one interesting area of research would be to optimize the proper transit function of the gut by using pre- and probiotics in order to beneficially modify the gut microbiota (2).
A modest weight loss of just 7–10% can result in improved liver histology for NASH patients (1). Sticking to a Mediterranean diet is known to have a beneficial effect on metabolic syndrome and thus is also likely to be beneficial for NAFLD patients. Consequently, it seems evident that they should also avoid refined sugars, particularly fructose. Following the same logic, it is likely that marine omega-3 fatty acids could also be beneficial (3).
Naturally occurring antioxidants are showing promise. Indeed, the Chilean Hepatological Association has suggested that a combination of the TZD Pioglitazone with vitamin E is a good treatment option for NASH that offers proven histological benefits. However, they have also stated that further evidence is required as to its efficacy and long-term safety (4).
Oxidative stress and reduced antioxidant levels are thought to be a key mechanism behind the progression of NASH/NAFLD. Fat-soluble vitamin E is a highly effective, chain-breaking antioxidant and free radical scavenger. It is particularly effective in preventing lipid peroxidation. Specifically, vitamin E is also believed to downregulate a number of metabolic factors involved in the promotion of liver fibrosis, including peroxisome proliferator-activated receptor gamma (PPARγ), transforming growth factor beta-1, and apoptosis-regulating genes.
While vitamin E has often been used in the treatment of NAFLD/NASH, the magnitude of response associated with vitamin E in improving liver function and histology in NAFLD/NASH has not yet been quantified systematically. In 2010, Sanyal et al reported on a 96-week, double-blind, multicenter, randomized trial to determine the effect of 800 IU /day vitamin E and pioglitazone on the hepatic histology of NASH patients (the PIVENS trial) without diabetes (5). The vitamin E arm of the trial received an intake of 800 IU /day. The result was an improvement in liver histological features in 43% of the cohort, with reductions in hepatic steatosis and lobular inflammation. Pioglitazone only achieved an improvement in 34% of cases. No benefit was derived from combining the two treatments. In addition, serum alanine and aspartate aminotransferase levels were reduced in the vitamin E arm of the trial.
In the 2011 TONIC trial, again a daily dose of 800 IU vitamin E for 96 weeks achieved histological resolution in 58% of children with NASH, which compared favourably with the 41% improvement achieved with Metformin (both measured against a placebo).
The meta-analysis conducted by Sato (7), which examined five studies, concluded that vitamin E therapy can result in decreased levels of liver damage caused by hepatitis and cirrhosis in children and adults with NAFLD and NASH. Specifically, vitamin E therapy significantly reduces levels of key liver enzymes that are elevated in people with NAFLD and NASH (e.g., aspartate transaminase, alanine aminotransferase, and alkaline phosphatase).
From the point of view of cell pathology, vitamin E was shown to reduce steatosis (abnormal retention of lipids in the cell, which distorts the nucleus), lobular inflammation, and even hepatocellular ballooning in the liver. Professor Sato and his team concluded from the meta-analysis that “vitamin E significantly improved liver function and histological changes in patients with NAFLD/NASH.”
On a separate note, as well as being important for bone formation, vitamin D has key immunomodulatory, anti-inflammatory and antifibrotic properties (8). Vitamin D insufficiency is often a characteristic of metabolic syndrome. Vitamin D is mainly synthesized in the liver, producing the active metabolite 25(OH)D. Thus, it is not surprising that vitamin D deficiency is also found in patients with chronic liver disease. Vitamin D appears to be capable of preventing the progression of fibrosis in NAFLD. Vitamin D receptors act by depositing a destructive extracellular matrix, which damages normal liver structure (9). As such, vitamin D could be an interesting target for future therapeutic NASH/NAFLD studies.