Because of the central role of insulin resistance in development of NAFLD and NASH, it makes sense to evaluate insulin-sensitizing drugs for their prevention.36,37 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.38,39
Studies of metformin for NAFLD and NASH have multiplied in the past few years with almost uniform success. Metformin in the amount of 500 mg three times daily for 6 months produced dramatic improvements in liver blood flow and velocity as detected by Doppler ultrasound exams.40 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, though the improvement lasted only 3 months.41 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.36,42 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, an extremely challenging group of patients.43
Metformin is an ideal drug for combination studies because of its safety and compatibility with other therapies. A 2008 study revealed that the combination of metformin with the potent antioxidant N-acetyl cysteine (NAC) for 12 months improved both liver chemistry results and measurements of insulin resistance.44 Liver tissue evaluated by biopsy also showed improved appearance for the earlier signs of disease.
Finally, in 2010 we learned of an entirely new mechanism by which metformin fights fatty liver disease. In addition to triggering insulin resistance, the excessive supply of fatty acids to the liver also contributes to cellular stresses. Those stresses result in liver cell death by apoptosis, accelerating conversion of NAFLD to NASH.45 Korean laboratory researchers have now shown that metformin blocked the induction of cellular stress proteins in cultured liver cells, protecting them from death induced by fatty acids.45 This novel mechanism adds to metformin’s already impressive array of multitargeted effects on metabolism and fatty liver disease.
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.46,47 The nutrient S-adenosylmethionine (SAMe) is one of a small group of molecules that can replenish GSH levels and restore liver cell protection to normal.48 In individuals with alcoholic or non-alcoholic liver disease, supplementation with 1,200 mg SAMe daily increased liver glutathione levels.49 Studies using agents that increase SAMe levels are known to reduce severity of NAFLD.46,50
A number of studies have demonstrated improvement in liver enzymes, an early marker of cell damage, resulting from treatment with SAMe and other liver antioxidants.51 SAMe supplements also produce improvements in microscopic features of NAFLD associated with fatty degeneration, inflammation, and tissue death.48 And SAMe also down-regulated damaging proinflammatory genes in a rat model of NAFLD.48
A major discovery about SAMe, however, is its ability to directly stop the 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.52 This has led to interest in using SAMe to prevent NASH from developing in people who already have NAFLD, thereby protecting them from the full fury of the disease.53
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 was first used to prevent liver damage following acetaminophen poisoning.54 It rapidly restores depleted glutathione to normal levels, sparing liver cells from the effects of oxidant damage, which is considered a “second hit” following development of NAFLD.55-57
A NAC derivative called SNAC was recently shown to prevent onset of NAFLD in rats fed a liver disease-inducing diet.58 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.44 And stunning findings in 2009 revealed that NAC, given to rats with NAFLD, could stimulate regeneration of healthy liver cells in animals that had had part of their livers removed!59 The researchers in that study observed that NAC supported glutathione levels, and postulated that the resulting reduction in oxidative stress accounted for the good outcome.
Silymarin (Milk Thistle)
Extracts of milk thistle have long been used for liver protection. It is estimated that 30-40% of American liver disease patients use the active ingredient, silymarin.60 Silymarin is itself composed of six major active molecules such as silybin, which are known as flavolignans, with exceptional antioxidant and anti-inflammatory activity.60,61 Modern science is rediscovering the use of milk thistle extracts for reduction of the impact of NAFLD and preventing its progression to NASH.
One very effective combination is silymarin plus vitamin E and phospholipids (such as phosphatidylcholine); this approach improves the overall antioxidant activity of the compound.62 In animal studies the combination limited liver depletion of the natural antioxidant glutathione, and reduced mitochondrial stress damage.63 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.22,23,64 Open studies have shown that silymarin also significantly increased survival rates in patients with alcohol-induced liver cirrhosis.61
Phosphatidylcholine and PPC
Phospholipids—fat molecules with phosphate groups attached—are major constituents of cell membranes in mammals.65 One of the most important phospholipids in humans is phosphatidylcholine (PC), which is available in small amounts in the diet. Higher ratios of PC to other phospholipids 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.65
A particularly rich source of PC molecules is a mixture called polyenylphosphatidylcholine (PPC), which is derived from soybeans.66 PPC supplements in animals help to attenuate nonalcoholic liver fibrosis and even accelerate its regression.67 PPC appears to exert this effect in part by blocking oxidant damage to cell membranes.68-70 A separate mechanism is reduction in the high cholesterol levels that precede NAFLD formation.71 PPC also prevents proliferation of scar tissue-forming liver cells in NAFLD and other forms of liver toxicity.72 And PPC restores liver cell levels of SAMe, providing additional liver protection.73 Finally, PPC attenuates liver cell death by apoptosis following chronic alcohol exposure.74
We are unknowingly in the midst of a full-blown liver disease epidemic. Fully one in three Americans suffers from the potentially life-threatening early-stage condition known as nonalcoholic fatty liver disease or NAFLD. Left undetected, it can progress to inflammation and scarring of the liver (cirrhosis) and full-blown liver failure. While an overload of fatty acids and abnormal lipid profiles (“lipotoxicity”) are the chief culprits, genetic factors may also play a role. Cutting-edge researchers have uncovered a handful of effective preventive therapies. Vitamin E confers resistance to oxidative stress, prevents inflammation, and improves insulin sensitivity, in some cases outperforming prescription drugs. Omega-3 fatty acids attack lipotoxicity—the other source of NAFLD-related liver damage. Metformin directly lowers fasting glucose, enhances insulin sensitivity, and improves appearance of liver tissue by ultrasound and biopsy. Recent studies reveal that metformin also prevents the impact of stress proteins produced under the stress of lipotoxicity. Finally, antioxidant supplements such as SAMe, NAC, and silymarin provide additional protection through different mechanisms, while PPC stabilizes liver cell membranes and also boosts SAMe levels.
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