Fatty liver disease (mainly associated with non-alcoholic fatty liver disease or NAFLD) is the most common cause of liver disorders worldwide and occurs when fat homeostasis is disrupted and too much fat accumulates in the liver. Some liver fat is normal; but, when fat makes up more than 5–10% of the liver's weight, fatty liver disease occurs.
There are two main types of fatty liver disease: alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). ALD is liver damage caused by over-consumption of alcoholic beverages. Conversely, NAFLD is the accumulation of fats/lipids in the liver in subjects who consume little or no alcohol.
Fatty liver disease is often asymptomatic. In fact, the initial stages of NAFLD may seem to be innocent and harmless. However, if NAFLD is left unchecked and not properly managed, it may progress to non-alcoholic steatohepatitis (NASH) and, eventually, end-stage liver disease (ESLD). Fatty liver disease, especially NAFLD, is on the rise, and is touted to be the silent killer of the 21st century. Worldwide, it affects 15–40% of the general population — in individuals of all ethnic groups and ages (both adults and children) — driven by unhealthy lifestyles and imbalanced diets (Figure 1).
According to CNN’s Senior Medical Correspondent, Elizabeth Cohen, about one third of the US population (100 million) has NAFLD.1 Approximately 20% of those will develop NASH. Of those, about 20–30% (4–6 million) will go on to develop cirrhosis and end-stage liver disease, for which the only real treatment is a liver transplant. Interestingly, NAFLD is a common thread that runs through a number of health conditions associated with metabolic syndrome, such as obesity, hypertension and diabetes. Many studies suggest that NAFLD as a risk factor for metabolic syndrome.2
At the moment, there is no standard treatment for non-alcoholic fatty liver disease. Instead, doctors typically treat the risk factors that contribute to the condition. For instance, a doctor can help an individual to lose weight through diet and exercise if the person is obese.
The pathogenesis of NAFLD
It’s not clear what actually causes fatty liver disease. It tends to run in families and is also more likely to occur in middle-aged people and patients afflicted with metabolic syndrome risk factors, such as obesity, high blood cholesterol, triglycerides and glucose levels. Researchers often use the 'Two-Hit' hypothesis to describe the onset of fatty liver. The 'First Hit' involves excessive lipid accumulation in the liver cells; and the 'Second Hit involves the start of inflammation-induced injury to the liver, possibly caused by oxidative stress associated with lipid peroxidation, which leads to steatohepatitis, fibrosis and cirrhosis.
Current management of NAFLD
Currently, there is no pharmacological treatment for fatty liver disease. The management of patients with NAFLD is through positive lifestyle modification such as healthy diets and regular physical exercises, as well as through dietary supplements, including vitamin E.
Management of NAFLD with tocopherols and tocotrienols
Various peer-reviewed papers have shown that vitamin E can be used as an effective managing strategy for fatty liver disease. A recent meta-analysis of five clinical studies, published in the journal Nutrition, reported that the oral supplementation of vitamin E (alpha-tocopherol) at up to 800IU daily can significantly improve liver function in patients with NAFLD.3
Conversely, however, some published studies have shown that high doses of vitamin E (400IU of alpha-tocopherol) increase all-cause mortality and the risk of prostate cancer, thereby, creating a dilemma with regard to tocopherol vitamin E supplementation.4,5 The question frequently asked by physicians is whether to recommend a daily dose of 800IU of vitamin E to NAFLD patients. In this instance, it is best to revisit the vitamin E family. It might not actually be necessary to take such high levels of tocopherol vitamin E to manage fatty liver disease!
There are eight isoforms of vitamin E in nature: four forms of tocopherols (alpha-, beta-, gamma- and delta-tocopherol) and four forms of tocotrienols (alpha-, beta-, gamma- and delta-tocotrienol). Tocotrienols differ structurally from tocopherols by having three unsaturated double bonds in their hydrocarbon side chain. In layman’s terms, tocopherols are the saturated form of vitamin E, whereas tocotrienols are the polyunsaturated form of vitamin E.
Recent research studies have shown that vitamin E isoforms share certain similar biological activities; yet, each of them has unique attributes and health benefits. Does tocotrienol help to improve liver health and can they work synergistically with tocopherol to manage NAFLD?
Recent research studies have shown that vitamin E isoforms share certain similar biological activities; yet, each of them has unique attributes and health benefits
In a rat study published in 2013, a group of researchers in Japan discovered that the oral supplementation of both delta-mixed tocotrienols and alpha-tocopherol helped to improve non-alcoholic steatohepatitis (NASH), compared with alpha-tocopherol alone or individual delta-mixed tocotrienols. The study concluded that the combination of tocotrienols and alpha-tocopherol confers synergistic effects that support healthy liver function.6
A 2012 published clinical study conducted at the Ohio State University Medical Center reported that end-stage liver disease (ESLD) patients (patients on the liver transplantation list) supplemented with EVNol SupraBio (200mg, twice daily.) showed statistically significant liver protective effects. The researchers, led by Prof. Chandan Sen, observed that almost 50% of the patients supplemented with EVNol SupraBio demonstrated a reduction in MELD score (Model for End-Stage Liver Disease, a scoring system to assess the severity of chronic liver disease) of ESLD patients. Hence, it may potentially help to increase the life expectancy of patients with ESLD.7
The first ever double-blind, placebo-controlled clinical study demonstrating the efficacy of tocotrienols in managing NAFLD was published in 2013. In this groundbreaking study, a total of 64 ultrasound-diagnosed NAFLD subjects were randomised to receive either EVNol SupraBio or a placebo for 12 months. At the end of the trial, 20 patients (66.7%) out of 30 subjects in the supplemented group showed significant improvement in their fatty liver condition. Of these, 50% of the subjects had complete remission of their NAFLD. The results were statistically significant (p<0.05) compared with the control group.8
Another clinical study on the effects of tocotrienols on NAFLD was done by a group of physicians in the Philippines. Transient elastography (FibroScan) was used to measure liver stiffness. The physicians reported that NAFLD patients supplemented with 50mg of delta-mixed tocotrienol (as EVNol SupraBio), twice daily for 3 months, together with lifestyle modification, significantly improved their liver stiffness by decreasing Liver Stiffness Measurements (LSM) compared with a lifestyle modification only control group. The outcome of the liver condition in the lifestyle modification plus tocotrienol-treated group was found to be approximately four times better than the control group. This suggested the potential role of tocotrienols in preventing NAFLD at a lower dosage.9
EVNol SupraBio is a patented bioenhanced full spectrum tocotrienols/tocopherol complex, extracted from sustainably produced virgin red palm oil. The patented self-emulsifying delivery system (SupraBio) ensures a consistent and improved absorption of each individual tocotrienol into the human plasma by up to 300%.10
NAFLD is touted to be the silent killer of the 21st century. It is the common thread that connects the diseases collectively grouped as metabolic syndrome
Another groundbreaking study — the first on a tocotrienol complex — on actual human tissue distribution of tocotrienols was conducted at the Ohio State University Medical Center. Published in the Journal of Nutrition, the study reported that tocotrienols (EVNol SupraBio) were well absorbed and transported to vital human organs, including the liver. In fact, tocotrienols are reported to be preferentially distributed to the liver. This preferential distribution, along with tocotrienol’s potent antioxidant effect, helps to reduce the lipid peroxidation of fats in the liver, which is recognised as a leading factor in the pathogenesis of steatosis.
In addition, tocotrienols are potent anti-inflammatory agents that inhibit NF-kB expression and reduce triglyceride accumulation by regulating fatty acid synthase and carnitine palmitoyltransferase, thus, leading to a reduction in hepatic inflammation and endoplasmic reticulum stress.11 These mechanisms suggest the potential beneficial role of tocotrienols in hepatoprotection.
E COMPLETE for fatty liver
According to the CNN report cited above, NAFLD is touted to be the silent killer of the 21st century. It is the common thread that connects the diseases collectively grouped as metabolic syndrome (obesity, diabetes, dyslipidaemia, hypertension etc.). Owing to the rising obesity rate, the US may soon face an epidemic of NAFLD, a major cause of chronic liver disease. Researchers predict that if the current trend continues for another 20 years, the prevalence of NAFLD is expected to increase by 50% in 2030.12
The overwhelming body of science suggests that it is prudent to take both d-mixed tocopherols and d-mixed tocotrienols for their synergistic hepatoprotective effect to support liver health. As for dietary supplement companies, not only that it is scientifically substantiated, but it will also confer a unique product differentiation as well as a marketing edge to any finished product (such as reformulated vitamin E).
References
1. http://edition.cnn.com/2011/HEALTH/06/16/liver.disease.ep/.
2. A. Lonardo, et al., 'Nonalcoholic Fatty Liver Disease: A Precursor of the Metabolic Syndrome,' Dig. Liver Dis. 47(3), 181–190 (2015).
3. K. Sato, et al., 'Vitamin E Has a Beneficial Effect on Nonalcoholic Fatty Liver Disease: A Meta-Analysis of Randomized Controlled Trials,' Nutrition 31(7), 923–930 (2015).
4. E.R. Miller III, et al., 'Meta-Analysis: High-Dosage Vitamin E Supplementation May Increase All-Cause Mortality,' Ann. Intern. Med. 142, 37–46 (2005).
5. A.R. Kristal, et al., 'Baseline Selenium Status and Effects of Selenium and Vitamin E Supplementation on Prostate Cancer Risk,' J. Natl Cancer Inst. 106(3): doi: 10.1093/jnci/djt456 (2014).
6. R. Yachi, et al., 'Effects of Tocotrienol on Tumor Necrosis Factor-Alpha/D-Galactosamine-Induced Steatohepatitis in Rats,' J. Clin. Biochem. Nutr. 52(2), 146–153 (2013).
7. V. Patel, et al., 'Oral Tocotrienols are Transported to Human Tissues and Delay the Progression of the Model for End-Stage Liver Disease Score in Patients,' J. Nutr. 142(3), 513–519 (2012).
8. E. Magosso, et al., 'Tocotrienols for Normalisation of Hepatic Echogenic Response in Nonalcoholic Fatty Liver: A Randomised Placebo-Controlled Clinical Trial,' Nutr. J. 12(1), 166 (2013).
9. M. Arguillas, et al., 'The Effect of Vitamin E (Mixed Tocotrienol) on the Liver Stiffness Measurement Measured by Transient Elastography (FibroScan) Among NAFLD Patients,' presented at APASL Liver Week (6–9 June 2013, Singapore).
10. D. Ho, et al., 'Drug Delivery System: Formulation for Fat Soluble Drugs,' US Patent No. 6,596,306 (2003).
11. C. Muto, et al., 'Gamma-Tocotrienol Reduces the Triacylglycerol Level in Rat Primary Hepatocytes Through Regulation of Fatty Acid Metabolism,' J. Clin. Biochem. Nutr. 52(1), 32–37 (2013).
12. G. Vernon, et al., 'Systematic Review: The Epidemiology and Natural History of Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis in Adults,' Aliment. Pharmacol. Ther. 34, 274–285 (2011).
