Non-Alcoholic Fatty Liver Disease (NAFLD)
Nutritional and Supplemental Support
In contrast to the failure of most pharmacological therapies, numerous nutritional approaches show real promise in slowing the development and progression of NAFLD. In particular, Life Extension has identified eight interventions with scientifically validated effectiveness.
Vitamin E. Scientists began a series of studies on NASH (the advanced middle stage of NAFLD) and vitamin E in 2004. Based on their knowledge that NASH arises from persistent insulin resistance and oxidative stress, they examined the effects of pioglitazone (Actos®), an insulin-sensitizing drug, and vitamin E. Patients receiving both vitamin E (400 IU per day) and pioglitazone (30 mg per day) had improvements in more parameters than did patients on vitamin E alone (Sanyal et al 2004).
In a follow-up study, subjects received either vitamin E (800 IU per day) or pioglitazone (30 mg per day), or placebo, for 96 weeks.
Both treatments improved levels of liver cell-injury markers in blood, and both reduced liver fat levels and inflammation. But only vitamin E produced significant improvements in the appearance of liver tissue on biopsies (Sanyal et al 2010). Here are some clues that explain these otherwise startling results.
Vitamin E is a powerful antioxidant, and an obvious choice once the role of oxidant stress was made clear in NAFLD (Medina and Moreno-Otero 2005). People with fatty liver disease and NASH have depressed levels of vitamin E in their blood, the result of increased oxidation (Bell et al 1992, Bahcecioglu et al 2005). Even relatively low-dose vitamin E (450 IU/day) can reduce circulating liver enzymes, a chemical marker of liver cell injury (Hasegawa et al 2001, Bernal-Reyes and Escudero 2002).
Important animal studies refine our understanding of how vitamin E works. One study provided the first evidence that vitamin E can prevent NAFLD before it develops, largely by reducing oxidative stress, inflammation, and liver cell death by apoptosis (Nan et al 2009). Another study demonstrated a vitamin E-related reduction in oxidative damage and tissue levels of the inflammatory mediator TNF-alpha, while beneficially reducing PPAR-gamma activity (Raso et al 2009). This wealth of animal and now human data clearly supports daily use of 800-1,200 IU of vitamin E for prevention and treatment of NAFLD and NASH.
Omega-3 Fatty Acids. Just as vitamin E fights the oxidant and inflammatory components of NAFLD, the omega-3 fatty acids attack the problem of lipotoxicity, while contributing considerable anti-inflammatory activity of their own (Perez-Martinez 2010). People and experimental animals with insufficient omega-3 in their diets are prone to NAFLD and type 2 diabetes, suggesting that supplementation might reverse (or prevent) the process (Perez-Martinez 2010, Pachikian et al 2008, Zelber-Sagi et al 2007, Cortez-Pinto et al 2006).
Increasing the amount of unsaturated fats like omega-3s in cell membranes is associated with improved insulin sensitivity (Martin de Santa Olalla et al 2009). And supplementation with omega-3 rich fish oil results in activation of the important metabolic sensor, called PPAR-alpha, in liver cells, suppressing production of new fat molecules (Larter et al 2008). Omega-3s also contribute to improved insulin sensitivity, a reduction in serum triglycerides, and stimulation of fat utilization in liver tissue and skeletal muscle (Ukropec et al 2003).
A long-term human trial, using 1,000 mg per day of omega-3, revealed significant decreases in serum markers of liver cell damage, triglyceride levels, and fasting glucose. Most impressively, supplemented patients display improvement of their livers’ appearance and blood flow on ultrasound exams, providing graphic evidence of the supplements’ benefits (Capanni et al 2006). Another study found that supplementation with 751 mg eicosapentaenoic acid (EPA) and 527 mg docosahexaenoic acid (DHA) 3 times daily for 24 weeks decreased triglyceride levels in individuals with NAFLD (Hatzitolios et al 2004). Olive oil also decreases accumulation of triglycerides in the liver during NAFLD, but fish oil provided better antioxidant activity (Hussein et al 2007). Olive oil also independently improves postprandial triglyceride levels in blood and upregulates glucose transporter in liver. At the same time, it improves insulin resistance by decreasing liver inflammation (Assy et al 2009). And long-term consumption of olive oil enriched with omega-3 fats in patients with NAFLD is able to improve liver texture on ultrasound exams, while improving serum markers of liver injury and increasing protective adiponectin levels (Sofi et al 2010).
Clearly the omega-3 fatty acids have earned their designation as an innovative therapy for nonalcoholic fatty liver disease (Xin et al 2008).
Metformin. Because of the central role of insulin resistance in the development of NAFLD and NASH, it makes sense to evaluate insulin-sensitizing drugs for their prevention (Uygun et al 2004, Idilman et al 2008). No oral antidiabetic drug has as broad a spectrum of action, and as hefty a safety record, as the drug metformin, which is finding a host of new applications outside of diabetes itself (Hadden et al 2005, Rotella et al 2006).
Studies of metformin for NAFLD and NASH have multiplied in the past few years. Metformin, 500 mg three times daily for 6 months, produced dramatic improvements in liver blood flow and velocity as detected by Doppler ultrasound exams (Magalotti et al 2004). A similar dose of metformin (20 mg/kg body weight for one year, or approximately 1,450 mg/day for a 160-pound person) produced reductions in blood markers of liver cell death(Nair et al 2004). On the other hand, improved insulin sensitivity has repeatedly been shown in patients with NASH and NAFLD who take metformin, and many studies have now shown sustainable improvements in liver chemistry measurements (Uygun et al 2004, Schwimmer et al 2005). And a recent study showed significant reduction in the prevalence and severity of fatty liver after 6 months’ treatment with 850 mg metformin twice daily in obese adolescents (Nadeau et al 2009).
Metformin is an ideal drug for combination studies because of its safety and compatibility with other therapies. The combination of metformin with the potent antioxidant N-acetyl cysteine (NAC) for 12 months improved liver chemistry results, measurements of insulin resistance, and liver appearance on biopsy (de Oliveira et al 2008).
Recent evidence shows that metformin blocks the induction of cellular stress proteins in cultured liver cells, protecting them from death induced by fatty acids (Kim et al 2010). This novel mechanism adds to metformin’s already impressive array of multitargeted effects on metabolism and fatty liver disease.
S-Adenosylmethionine (SAMe). Their constant exposure to oxidant and toxic stresses makes liver cells especially vulnerable to depletion of glutathione (GSH), a natural antioxidant that participates in many liver detoxification reactions (Kwon do et al 2009, Caballero et al 2010). The nutrient SAMe can replenish GSH levels and restore liver cell protection to normal (Oz et al 2006). In individuals with alcoholic or non-alcoholic liver disease, supplementation with 1,200 mg SAMe daily increased liver glutathione levels (Vendemiale et al 1989). Studies using agents that increase SAMe levels are known to reduce severity of NAFLD (Kwon do et al 2009, Abdelmalek et al 2001).
SAMe and other liver antioxidants improve levels of liver enzymes, an early marker of cell damage (Chang et al 2006). SAMe supplements improve microscopic features of NAFLD associated with fatty degeneration, inflammation, and tissue death. And SAMe also down-regulated damaging proinflammatory genes in an animal model of NAFLD (Oz et al 2006).
A major discovery about SAMe is that it directly stops progression of relatively mild NAFLD to dangerous NASH. NASH develops as the result of “second hits,” that is, additional events that damage liver cells after NAFLD has already developed; one of those “hits” is steady depletion of SAMe (Cave et al 2007). This has led to interest in using SAMe to prevent NASH from developing in people who already have NAFLD (Wortham et al 2008).
N-Acetyl Cysteine (NAC). Another molecule that supports and replenishes the natural antioxidant glutathione is N-acetyl cysteine (NAC), a versatile sulfur-rich compound that prevents liver damage following acetaminophen poisoning (Millea et al 2009). It rapidly restores depleted glutathione levels, sparing liver cells from the effects of oxidant damage (Bajt et al 2004, Mehta et al 2002, de Oliveira et al 2006).
An NAC derivative, called SNAC, was recently shown to prevent onset of NAFLD in rats fed a liver disease-inducing diet (Baumgardner et al 2008). In humans, the combination of NAC (1,200 mg/day) with metformin (850-1,000 mg/day) improved liver appearance and reduced fibrosis in patients with NAFLD (de Oliveira et al 2008). And, given to rats with NAFLD, NAC stimulates regeneration of healthy liver cells in animals that have part of their livers removed (Uzun et al 2009).
Silymarin (Milk Thistle). Extracts of milk thistle have long been used for liver protection. Silymarin is composed of six major active molecules such as silybin, which are known as flavolignans, having exceptional antioxidant and anti-inflammatory activity (Schrieber et al 2008, Feher et al 2008).
One very effective combination is silymarin plus vitamin E and phospholipids (such as phosphatidylcholine); this approach improves the overall antioxidant activity of the compound (Loguercio et al 2007). In animal studies the combination limited liver depletion of the natural antioxidant glutathione, and reduced mitochondrial stress damage (Serviddio et al 2010). Human trials have shown that a preparation providing 376 mg silybin, 776 mg phosphatidylcholine, and 360 mg vitamin E produces therapeutic effects in patients with a variety of different forms of liver damage, improving insulin resistance, reducing liver fat accumulation, and reducing blood levels of markers of liver scarring (Trappoliere et al 2005, Federico et al 2006, Trappoliere et al 2005).
Phosphatidylcholine and PPC. Phospholipids—fat molecules with phosphate groups attached—are major constituents of cell membranes in mammals. One of the most important phospholipids in humans is phosphatidylcholine (PC). Higher amounts of PC in cell membranes help to assure membrane integrity in the face of oxidative and other stresses; they also help limit the progression of NAFLD into NASH (Li et al 2006).
A particularly rich source of PC molecules is a mixture called polyenylphosphatidylcholine (PPC), derived from soybeans (Lieber 2004). PPC supplements in animals attenuate nonalcoholic liver fibrosis and even accelerate its regression (Ma et al 1996). PPC appears to exert this effect in part by blocking oxidant damage to cell membranes (Aleynik et al 1997, Lieber et al 1997, Navder et al 1999). A separate mechanism is reduction in the high cholesterol levels that precede NAFLD formation (Polichetti et al 2000). PPC also prevents proliferation of scar tissue in NAFLD and other forms of liver toxicity (Brady et al 1998). And PPC restores liver cell levels of SAMe, providing additional liver protection (Aleynik et al 2003).
Resveratrol. Resveratrol protects liver tissue against the ravages of alcoholic fatty liver disease through its antioxidant effects, buffering the impact of alcohol (Kasdallah-Grissa et al 2007). It also activates two critical signaling molecules, SIRT1 and AMPK, which are inhibited by alcohol, and are also dysfunctional in metabolic syndrome (Ajmo et al 2008, Buettner et al 2010, de Kreutzenberg et al 2010, Kraegen et al 2009). Those effects make it highly promising for prevention of NAFLD, the liver manifestation of metabolic syndrome. In animal studies, resveratrol activates AMPK, which in turn reduces liver fat accumulation, suppresses new liver fat formation, and reduces insulin resistance (Aoun et al 2010, Bujanda et al 2008, Shang et al 2008).