Non-Alcoholic Fatty Liver Disease (NAFLD)

Non-Alcoholic Fatty Liver Disease (NAFLD)

1 Overview

Summary and Quick Facts

  • Fat can build up in the liver. When this happens in people who do not drink alcohol, it is called non-alcoholic fatty liver disease, or NAFLD. Over time, NAFLD can progress to an inflammatory condition called non-alcoholic steatohepatitis (NASH), which can cause many health problems.
  • In this protocol, learn about the causes of fatty liver, and how to take steps to prevent, and potentially reverse the condition before it causes major problems.
  • Supplementation with milk thistle and a specialized form of lipid compound called PPC can support liver health by several mechanisms.

What is Non-Alcoholic Fatty Liver Disease?

Non-alcoholic fatty liver disease (NAFLD) is a condition where fat deposits build up in the liver in patients with little or no alcohol intake and with no other known cause. NAFLD is closely associated with obesity. While poor dietary choices are often to blame, genetic factors may also contribute.

As the condition is generally asymptomatic or has very mild symptoms initially, many people do not know they have it unless a blood test detects abnormal levels of liver enzymes. NAFLD may progress to nonalcoholic steatohepatitis (NASH), which can then progress to cirrhosis, fibrosis, liver failure, and even liver cancer.

Natural interventions such as vitamin E and milk thistle may help protect the liver and even halt or reverse disease progression.

What are the Risk Factors for Non-Alcoholic Fatty Liver Disease?

  • Obesity
  • Insulin resistance/diabetes
  • Metabolic syndrome
  • Increased fructose consumption

What are Conventional Treatments for Non-Alcoholic Fatty Liver Disease?

Note: NAFLD is generally treated with dietary and lifestyle changes, not pharmaceutical interventions. Health practitioners may encourage patients with NAFLD to:

  • Engage in slow and steady weight loss
  • Engage in regular physical activity
  • Refrain from drinking alcohol

What are Emerging Therapies for Non-Alcoholic Fatty Liver Disease?

  • Metformin, a drug generally used to treat diabetes, has been shown in several studies to dramatically improve liver blood flow, reduce markers of liver cell death, and reduce the prevalence and severity of fatty liver.

What Natural Interventions May Be Beneficial for Non-Alcoholic Fatty Liver Disease?

  • Vitamin E. People with fatty liver disease and NASH have depressed levels of vitamin E. Vitamin E has been shown to reduce levels of liver cell-injury markers, liver fat levels, and inflammation, and improve the appearance of liver tissue on biopsies.
  • Omega-3 fatty acids. People with insufficient dietary intake of omega-3 fatty acids are more prone to NAFLD. A clinical trial revealed that supplementation decreased serum markers of liver cell damage, triglyceride levels, and fasting glucose. Supplemented patients also showed improvement of their livers’ appearance and blood flow.
  • S-adenosylmethionine (SAMe). Oxidative damage depletes liver glutathione levels. Supplementation with SAMe increased glutathione levels in patients with NAFLD and prevented relatively mild NAFLD from progressing to NASH.
  • N-acetylcysteine (NAC). NAC boosts glutathione levels. The combination of NAC with metformin improved liver appearance and reduced fibrosis in patients with NAFLD.
  • Milk thistle. Milk thistle has long been used for protecting the liver. Silymarin, an extract of milk thistle, combined with vitamin E and phospholipids (like phosphatidylcholine), improved insulin resistance, reduced liver fat accumulation, and decreased markers of liver scarring.
  • Phosphatidylcholine. Higher amounts of phosphatidylcholine in cell membranes help limit the progression of NAFLD to NASH. A rich source of phosphatidylcholine derived from soybeans, polyenylphosphatidylcholine (PPC) supplements in animals attenuated nonalcoholic liver fibrosis and even accelerated its regression.
  • Resveratrol. Resveratrol can protect liver tissue from alcoholic fatty liver disease, and its mechanisms may also apply to NAFLD. In animal studies, resveratrol reduced liver fat accumulation and insulin resistance.

2 Introduction

Roughly one-third of the American population suffers from non-alcoholic fatty liver disease or NAFLD.1-3 Many of its victims do not know they have it. NAFLD can go undetected for years and may eventually progress to inflammation and scarring of the liver (cirrhosis) and, in some cases, full-blown liver failure.

A formerly rare condition, its rapid emergence has been linked to skyrocketing rates of metabolic syndrome and “diabesity,” the term many experts use for co-occurring diabetes and obesity.3-5

While poor dietary choices are often to blame, cutting-edge research suggests that hidden genetic factors may also play a role, as some people do not metabolize polyunsaturated fats properly, resulting in fatty deposits in the liver.6

As mainstream medicine continues to struggle in the search for drugs to manage this widespread condition, emerging scientific evidence has shed light on effective natural interventions that may halt or even reverse its progress.

3 Fat Overload, Liver Damage, and the Inflammatory Storm

NAFLD is defined as deposition of fat in the liver cells of patients with minimal or no alcohol intake and with no other known cause.7 The term “NAFLD” refers to a group of related and progressive conditions closely associated with overweight and obesity.2

NAFLD usually does not cause symptoms, but some people with NAFLD report feeling tired or experiencing mild discomfort in their upper-right abdominal quadrant.8 Early NAFLD can ultimately progress to a more serious condition, non-alcoholic steatohepatitis or NASH.9 About a third of people with NAFLD will develop NASH,8 and about 20% of people with NASH will go on to liver fibrosis and cirrhosis, with its accompanying risk of liver failure and even liver cancer.2,8,10 Overall, people with NAFLD stand a 12% increased risk of liver-related death over 10 years.8

NAFLD has multiple interrelated causes. Primary mechanisms include obesity leading to steadily increasing insulin resistance coupled with an overabundance of circulating fatty acids. These factors fuel one another in a destructive cycle.4 Together with advanced glycation end-products (AGEs), these events lead to increased oxidant stress and ultimately inflammation, cell death, and fibrous destruction of liver tissue.3,4,8

An overload of fatty acids and abnormal lipid profiles factor so heavily in the onset of NAFLD that they’re now referred to as “lipotoxicity” because of the ways they directly poison liver tissue.9,11,12 And as fat builds inside liver cells, they begin churning out a storm of fat-related cytokines known as adipokines, which fan the inflammatory flames of the metabolic syndrome and NAFLD.1

Of course, what we eat is as important as the calories it contains. One of the major bad actors in today’s world is fructose, found in high quantities in high-fructose corn syrup.13 Fructose promotes formation of new fat molecules in the liver, blocks breakdown of existing fats, stimulates free radical production, and promotes insulin resistance.14 An increasing number of studies are linking increased fructose consumption with NAFLD, and even with its deadlier consequence, non-alcoholic steatohepatitis (NASH).15 Patients with NAFLD consume 2‒3 times as much fructose as do control patients, even corrected for body weight.16

4 Diagnosis of NAFLD

In order to make a diagnosis of NAFLD, a physician considers both clinical data about the patient, and, when appropriate, data from a liver biopsy (for definitive diagnosis). The first indication that NAFLD might be present is rarely a symptom, but rather a finding of elevated levels of liver enzymes in the blood, indicating early liver cell damage. Other treatable causes of liver disease must be ruled out by appropriate testing (eg, hepatitis B or C), and other liver functional parameters (eg, blood clotting factors) should also be measured. Some physicians will do an imaging study such as a liver ultrasound, but normal appearance of the liver does not rule out NAFLD. Alcoholic fatty liver, which can closely resemble NAFLD, must be ruled out. This can be done by reliably establishing the absence of substantial alcohol intake (less than 20‒40 grams of alcohol per day, equivalent to 2‒3 drinks). If and when there is concern that the more dangerous condition, NASH, is present, then liver biopsy must be performed to establish a definitive diagnosis.17

5 Treatment of NAFLD

Despite a growing understanding of the pathology of NAFLD, scientists have been persistently baffled in their attempts to prevent and treat it with drug therapies. Lifestyle interventions such as steady, gentle weight loss and regular exercise have been the only interventions that offered any hope at all.2,9 Insulin-sensitizing drugs, while theoretically of value, have proved disappointing in clinical trials.18,19

The only successful pharmaceutical intervention for dealing with NAFLD has been metformin, which is examined further in this section.

Cholesterol-lowering drugs like statins have no proven benefit to date.4 Further studies are needed to determine if bariatric surgery to induce weight loss benefits patients with NAFLD.9,20

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.21,22 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.23,24

Studies of metformin for NAFLD and NASH have multiplied in the past few years. Metformin, 500 mg three times daily for six months, produced dramatic improvements in liver blood flow and velocity as detected by Doppler ultrasound exams.25 A similar dose of metformin (20 mg/kg body weight for one year, or approximately 1,450 mg/day for a 160-lb individual) produced reductions in blood markers of liver cell death.26 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.21,27 And a recent study showed significant reduction in the prevalence and severity of fatty liver after six months’ treatment with 850 mg metformin twice daily in obese adolescents.28

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.29

Recent evidence shows that metformin blocks the induction of cellular stress proteins in cultured liver cells, protecting them from death induced by fatty acids.30 This novel mechanism adds to metformin’s already impressive array of multitargeted effects on metabolism and fatty liver disease.

What You Have Learned So Far

  • One in three Americans now suffers from the stealth condition known as non-alcoholic fatty liver disease or NAFLD.
  • NAFLD may go undetected for years, and may progress to liver inflammation and scarring (cirrhosis) or full-blown liver failure.
  • While chiefly driven by poor dietary choices linked to metabolic syndrome and “diabesity,” genetic factors can also play a role in NAFLD’s progress.
  • Medical science has proved relatively helpless at preventing or treating NAFLD and NASH, leaving millions of Americans vulnerable to their effects.

6 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 seven integrative 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.31

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.32 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.33 People with fatty liver disease and NASH have depressed levels of vitamin E in their blood, the result of increased oxidation.34,35 Even relatively low-dose vitamin E (450 IU/day) can reduce circulating liver enzymes, a chemical marker of liver cell injury.36,37

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.38 Another study demonstrated a vitamin E-related reduction in oxidative damage and tissue levels of the inflammatory mediator tumor necrosis factor-alpha (TNF-α), while beneficially reducing PPAR-gamma activity.39 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.12 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.12,40-42

Increasing the amount of unsaturated fats like omega-3s in cell membranes is associated with improved insulin sensitivity.43 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.44 Omega-3s also contribute to improved insulin sensitivity, a reduction in serum triglycerides, and stimulation of fat utilization in liver tissue and skeletal muscle.45

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.46 Another study found that supplementation with 751 mg eicosapentaenoic acid (EPA) and 527 mg docosahexaenoic acid (DHA) three times daily for 24 weeks decreased triglyceride levels in individuals with NAFLD.47 Olive oil also decreases accumulation of triglycerides in the liver during NAFLD, but fish oil provided better antioxidant activity.48 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.49 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.50

Clearly the omega-3 fatty acids have earned their designation as an innovative therapy for NAFLD.51

S-Adenosylmethionine

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.52,53 The nutrient S-adenosylmethionine (SAMe) can replenish GSH levels and restore liver cell protection to normal.54 In individuals with alcoholic or non-alcoholic liver disease, supplementation with 1,200 mg SAMe daily increased liver glutathione levels.55 Studies using agents that increase SAMe levels are known to reduce severity of NAFLD.52,56

SAMe and other liver antioxidants improve levels of liver enzymes, an early marker of cell damage.57 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.54

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.58 This has led to interest in using SAMe to prevent NASH from developing in people who already have NAFLD.59

N-Acetyl Cysteine

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.60 It rapidly restores depleted glutathione levels, sparing liver cells from the effects of oxidant damage.61-63

A NAC derivative, called SNAC, was recently shown to prevent onset of NAFLD in rats fed a liver disease-inducing diet.64 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.29 And, given to rats with NAFLD, NAC stimulates regeneration of healthy liver cells in animals that have part of their livers removed.65

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 flavonolignans, having exceptional antioxidant and anti-inflammatory activity.66,67

One very effective combination is silymarin plus vitamin E and phospholipids (such as phosphatidylcholine); this approach improves the overall antioxidant activity of the compound.68 In animal studies the combination limited liver depletion of the natural antioxidant glutathione, and reduced mitochondrial stress damage.69 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.70,71

Phosphatidylcholine and Polyenylphosphatidylcholine (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. Higher amounts of phosphatidylcholine 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.72

A particularly rich source of phosphatidylcholine molecules is a mixture called polyenylphosphatidylcholine (PPC), derived from soybeans.73 PPC supplements in animals attenuate non-alcoholic liver fibrosis and even accelerate its regression.74 PPC appears to exert this effect in part by blocking oxidant damage to cell membranes.75-77 A separate mechanism is reduction in the high cholesterol levels that precede NAFLD formation.78 PPC also prevents proliferation of scar tissue in NAFLD and other forms of liver toxicity.79 And PPC restores liver cell levels of SAMe, providing additional liver protection.80

Resveratrol

Resveratrol protects liver tissue against the ravages of alcoholic fatty liver disease through its antioxidant effects, buffering the impact of alcohol.81 It also activates two critical signaling molecules, SIRT1 and AMPK, which are inhibited by alcohol, and are also dysfunctional in metabolic syndrome.82-85 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.86-88

Note: NAFLD and NASH are progressive conditions that require patient collaboration with a qualified physician. Because the liver metabolizes many nutrients and drugs, it is important that liver patients not add any substances to their regimen without cooperation and close monitoring by a qualified physician. The goals of therapy are:

  • Reduce the accumulation of fat in liver tissue by decreasing new fat synthesis and increasing utilization of existing fat stores in the liver.
  • Minimize free radical production, and enhance free radical scavenging in liver tissue
  • Reduce or eliminate the inflammatory responses of fat-infiltrated liver tissue to prevent progression of NAFLD to the more-deadly NASH, which is a precursor of liver failure.

References

  1. Polyzos SA, Kountouras J, Zavos C, Tsiaousi E. The role of adiponectin in the pathogenesis and treatment of nonalcoholic fatty liver disease. Diabetes Obes Metab. 2010 May;12(5):365-83.
  2. Schuppan D, Gorrell MD, Klein T, Mark M, Afdhal NH. The challenge of developing novel pharmacological therapies for nonalcoholic steatohepatitis. Liver Int. 2010 Jul;30(6):795-808.
  3. Younossi ZM. Review article: current management of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Aliment Pharmacol Ther. 2008 Jul;28(1):2-12.
  4. Kaser S, Ebenbichler CF, Tilg H. Pharmacological and non-pharmacological treatment of nonalcoholic fatty liver disease. Int J Clin Pract. 2010 Jun;64(7):968-83.
  5. Bondini S, Younossi ZM. Nonalcoholic fatty liver disease and hepatitis C infection. Minerva Gastroenterol Dietol. 2006 Jun;52(2):135-43.
  6. Puri P, Wiest MM, Cheung O, et al. The plasma lipidomic signature of nonalcoholic steatohepatitis. Hepatology. 2009 Dec;50(6):1827-38.
  7. Lirussi F, Azzalini L, Orando S, Orlando R, Angelico F. Antioxidant supplements for nonalcoholic fatty liver disease and/or steatohepatitis. Cochrane Database Syst Rev. 2007 Jan 24(1):CD004996.
  8. Raszeja-Wyszomirska J, Lawniczak M, Marlicz W, Miezynska-Kurtycz J, Milkiewicz P. Nonalcoholic fatty liver disease--new view. Pol Merkur Lekarski. 2008 Jun;24(144):568-71.
  9. Musso G, Gambino R, Cassader M. Nonalcoholic fatty liver disease from pathogenesis to management: an update. Obes Rev. 2010 Jun;11(6):430-45.
  10. Mark N, de Alwis W, Day CP. Current and future therapeutic strategies in NAFLD. Curr Pharm Des. 2010 Jun;16(17):1958-62.
  11. Schaffer JE. Lipotoxicity: when tissues overeat. Curr Opin Lipidol. 2003 Jun;14(3):281-7.
  12. Perez-Martinez P, Perez-Jimenez F, Lopez-Miranda J. n-3 PUFA and lipotoxicity. Biochim Biophys Acta. 2010 Mar;1801(3):362-6.
  13. Parker-Pope T. A New Name for High-Fructose Corn Syrup. The New York Times. September 14, 2010, 2010;Well.
  14. Lim JS, Mietus-Snyder M, Valente A, Schwarz JM, Lustig RH. The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol. 2010 May;7(5):251-64.
  15. Abdelmalek MF, Suzuki A, Guy C, et al. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. Hepatology. 2010 Jun;51(6):1961-71.
  16. Ouyang X, Cirillo P, Sautin Y, et al. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol. 2008 Jun;48(6):993-9.
  17. Nugent C and Younossi ZM. Evaluation and management of obesity-related nonalcoholic fatty liver disease. Nature Clinical Practice Gastroenterology & Hepatology (2007) 4, 432-441
  18. Adams LA and Lindor KD. Nonalcoholic fatty liver disease. Ann Epidemiol. 2007 17(11): 863-9.
  19. Park, SH. Nonalcoholic steatohepatitis: pathogenesis and treatment. Korean J Hepatol. 2008 14(1): 12-27.
  20. Chavez-Tapia NC, Tellez-Avila FI, Barrientos-Gutierrez T, Mendez-Sanchez N, Lizardi-Cervera J, Uribe M. Bariatric surgery for nonalcoholic steatohepatitis in obese patients. Cochrane Database Syst Rev. 2010 Jan 20(1):CD007340.
  21. Uygun A, Kadayifci A, Isik AT, et al. Metformin in the treatment of patients with nonalcoholic steatohepatitis. Aliment Pharmacol Ther. 2004 Mar 1;19(5):537-44.
  22. Idilman R, Mizrak D, Corapcioglu D, et al. Clinical trial: insulin-sensitizing agents may reduce consequences of insulin resistance in individuals with nonalcoholic steatohepatitis. Aliment Pharmacol Ther. 2008 Jul;28(2):200-8.
  23. Hadden DR. Goat's rue - French lilac - Italian fitch - Spanish sainfoin: gallega officinalis and metformin: the Edinburgh connection. J R Coll Physicians Edinb. 2005 Oct;35(3):258-60.
  24. Rotella CM, Monami M, Mannucci E. Metformin beyond diabetes: new life for an old drug. Curr Diabetes Rev. 2006 Aug;2(3):307-15.
  25. Magalotti D, Marchesini G, Ramilli S, Berzigotti A, Bianchi G, Zoli M. Splanchnic haemodynamics in nonalcoholic fatty liver disease: effect of a dietary/pharmacological treatment. A pilot study. Dig Liver Dis. 2004 Jun;36(6):406-11.
  26. Nair S, Diehl AM, Wiseman M, Farr GH, Jr., Perrillo RP. Metformin in the treatment of nonalcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther. 2004 Jul 1;20(1):23-8.
  27. Schwimmer JB, Middleton MS, Deutsch R, Lavine JE. A phase 2 clinical trial of metformin as a treatment for non-diabetic paediatric nonalcoholic steatohepatitis. Aliment Pharmacol Ther. 2005 Apr 1;21(7):871-9.
  28. Nadeau KJ, Ehlers LB, Zeitler PS, Love-Osborne K. Treatment of nonalcoholic fatty liver disease with metformin versus lifestyle intervention in insulin-resistant adolescents. Pediatr Diabetes. 2009 Feb;10(1):5-13.
  29. de Oliveira CP, Stefano JT, de Siqueira ER, et al. Combination of N-acetylcysteine and metformin improves histological steatosis and fibrosis in patients with nonalcoholic steatohepatitis. Hepatol Res. 2008;38(2):159-65.
  30. 30. Kim DS, Jeong SK, Kim HR, Chae SW, Chae HJ. Metformin regulates palmitate-induced apoptosis and ER stress response in HepG2 liver cells. Immunopharmacol Immunotoxicol. 2010 Jun;32(2):251-7.
  31. Sanyal AJ, Mofrad PS, Contos MJ, et al. A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2004 Dec;2(12):1107-15.
  32. Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010 May 6;362(18):1675-85.
  33. Medina J, Moreno-Otero R. Pathophysiological basis for antioxidant therapy in chronic liver disease. Drugs. 2005;65(17):2445-61.
  34. Bell H, Bjorneboe A, Eidsvoll B, et al. Reduced concentration of hepatic alpha-tocopherol in patients with alcoholic liver cirrhosis. Alcohol Alcohol. 1992 Jan;27(1):39-46.
  35. Bahcecioglu IH, Yalniz M, Ilhan N, Ataseven H, Ozercan IH. Levels of serum vitamin A, alpha-tocopherol and malondialdehyde in patients with nonalcoholic steatohepatitis: relationship with histopathologic severity. Int J Clin Pract. 2005 Mar;59(3):318-23.
  36. Hasegawa T, Yoneda M, Nakamura K, Makino I, Terano A. Plasma transforming growth factor-beta1 level and efficacy of alpha-tocopherol in patients with nonalcoholic steatohepatitis: a pilot study. Aliment Pharmacol Ther. 2001 Oct;15(10):1667-72.
  37. Bernal-Reyes R, Escudero RB. Treatment of nonalcoholic steatohepatitis (NASH). A comparative study of ursodeoxycholic acid and alpha-tocopherol. A preliminary report. Rev Gastroenterol Mex. 2002 Apr-Jun;67(2):70-5.
  38. Nan YM, Wu WJ, Fu N, et al. Antioxidants vitamin E and 1-aminobenzotriazole prevent experimental nonalcoholic steatohepatitis in mice. Scand J Gastroenterol. 2009;44(9):1121-31.
  39. Raso GM, Esposito E, Iacono A, et al. Comparative therapeutic effects of metformin and vitamin E in a model of nonalcoholic steatohepatitis in the young rat. Eur J Pharmacol. 2009 Feb 14;604(1-3):125-31.
  40. Pachikian BD, Neyrinck AM, Cani PD, et al. Hepatic steatosis in n-3 fatty acid depleted mice: focus on metabolic alterations related to tissue fatty acid composition. BMC Physiol. 2008;8:21.
  41. Zelber-Sagi S, Nitzan-Kaluski D, Goldsmith R, et al. Long term nutritional intake and the risk for nonalcoholic fatty liver disease (NAFLD): a population based study. J Hepatol. 2007 Nov;47(5):711-7.
  42. Cortez-Pinto H, Jesus L, Barros H, Lopes C, Moura MC, Camilo ME. How different is the dietary pattern in nonalcoholic steatohepatitis patients? Clin Nutr. 2006 Oct;25(5):816-23.
  43. Martin de Santa Olalla L, Sanchez Muniz FJ, Vaquero MP. N-3 fatty acids in glucose metabolism and insulin sensitivity. Nutr Hosp. 2009 Mar-Apr;24(2):113-27.
  44. Larter CZ, Yeh MM, Cheng J, et al. Activation of peroxisome proliferator-activated receptor alpha by dietary fish oil attenuates steatosis, but does not prevent experimental steatohepatitis because of hepatic lipoperoxide accumulation. J Gastroenterol Hepatol. 2008 Feb;23(2):267-75.
  45. Ukropec J, Reseland JE, Gasperikova D, et al. The hypotriglyceridemic effect of dietary n-3 FA is associated with increased beta-oxidation and reduced leptin expression. Lipids. 2003 Oct;38(10):1023-9.
  46. Capanni M, Calella F, Biagini MR, et al. Prolonged n-3 polyunsaturated fatty acid supplementation ameliorates hepatic steatosis in patients with nonalcoholic fatty liver disease: a pilot study. Aliment Pharmacol Ther. 2006 Apr 15;23(8):1143-51.
  47. Hatzitolios A, Savopoulos C, Lazaraki G, et al. Efficacy of omega-3 fatty acids, atorvastatin and orlistat in nonalcoholic fatty liver disease with dyslipidemia. Indian J Gastroenterol. 2004 Jul-Aug;23(4):131-4.
  48. Hussein O, Grosovski M, Lasri E, Svalb S, Ravid U, Assy N. Monounsaturated fat decreases hepatic lipid content in non-alcoholic fatty liver disease in rats. World J Gastroenterol. 2007 Jan 21;13(3):361-8.
  49. Assy N, Nassar F, Nasser G, Grosovski M. Olive oil consumption and non-alcoholic fatty liver disease. World J Gastroenterol. 2009 Apr 21;15(15):1809-15.
  50. Sofi F, Giangrandi I, Cesari F, et al. Effects of a 1-year dietary intervention with n-3 polyunsaturated fatty acid-enriched olive oil on non-alcoholic fatty liver disease patients: a preliminary study. Int J Food Sci Nutr. 2010 May 13.
  51. Xin YN, Xuan SY, Zhang JH, Zheng MH, Guan HS. Omega-3 polyunsaturated fatty acids: a specific liver drug for nonalcoholic fatty liver disease (NAFLD). Med Hypotheses. 2008 Nov;71(5):820-1.
  52. Kwon do Y, Jung YS, Kim SJ, Park HK, Park JH, Kim YC. Impaired sulfur-amino acid metabolism and oxidative stress in nonalcoholic fatty liver are alleviated by betaine supplementation in rats. J Nutr. 2009 Jan;139(1):63-8.
  53. Caballero F, Fernandez A, Matias N, et al. Specific contribution of methionine and choline in nutritional nonalcoholic steatohepatitis: impact on mitochondrial S-adenosyl-L-methionine and glutathione. J Biol Chem. 2010 Jun 11;285(24):18528-36.
  54. Oz HS, Im HJ, Chen TS, de Villiers WJ, McClain CJ. Glutathione-enhancing agents protect against steatohepatitis in a dietary model. J Biochem Mol Toxicol. 2006;20(1):39-47.
  55. Vendemiale G, Altomare E, Trizio T, et al. Effects of oral S-adenosyl-L-methionine on hepatic glutathione in patients with liver disease. Scand J Gastroenterol. 1989 May;24(4):407-15.
  56. Abdelmalek MF, Angulo P, Jorgensen RA, Sylvestre PB, Lindor KD. Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study. Am J Gastroenterol. 2001 Sep;96(9):2711-7.
  57. Chang CY, Argo CK, Al-Osaimi AM, Caldwell SH. Therapy of NAFLD: antioxidants and cytoprotective agents. J Clin Gastroenterol. 2006 Mar;40 Suppl 1:S51-60.
  58. Cave M, Deaciuc I, Mendez C, et al. Nonalcoholic fatty liver disease: predisposing factors and the role of nutrition. J Nutr Biochem. 2007 Mar;18(3):184-95.
  59. Wortham M, He L, Gyamfi M, Copple BL, Wan YJ. The transition from fatty liver to NASH associates with SAMe depletion in db/db mice fed a methionine choline-deficient diet. Dig Dis Sci. 2008 Oct;53(10):2761-74.
  60. 60. Millea PJ. N-acetylcysteine: multiple clinical applications. Am Fam Physician. 2009 Aug 1;80(3):265-9.
  61. Bajt ML, Knight TR, Lemasters JJ, Jaeschke H. Acetaminophen-induced oxidant stress and cell injury in cultured mouse hepatocytes: protection by N-acetyl cysteine. Toxicol Sci. 2004 Aug;80(2):343-9.
  62. Mehta K, Van Thiel DH, Shah N, Mobarhan S. Nonalcoholic fatty liver disease: pathogenesis and the role of antioxidants. Nutr Rev. 2002 Sep;60(9):289-93.
  63. de Oliveira CP, Simplicio FI, de Lima VM, et al. Oral administration of S-nitroso-N-acetylcysteine prevents the onset of non alcoholic fatty liver disease in rats. World J Gastroenterol. 2006 Mar 28;12(12):1905-11.
  64. Baumgardner JN, Shankar K, Hennings L, Albano E, Badger TM, Ronis MJ. N-acetylcysteine attenuates progression of liver pathology in a rat model of nonalcoholic steatohepatitis. J Nutr. 2008 Oct;138(10):1872-9.
  65. Uzun MA, Koksal N, Kadioglu H, et al. Effects of N-acetylcysteine on regeneration following partial hepatectomy in rats with nonalcoholic fatty liver disease. Surg Today. 2009;39(7):592-7.
  66. Schrieber SJ, Wen Z, Vourvahis M, et al. The pharmacokinetics of silymarin is altered in patients with hepatitis C virus and nonalcoholic Fatty liver disease and correlates with plasma caspase-3/7 activity. Drug Metab Dispos. 2008 Sep;36(9):1909-16.
  67. Feher J, Lengyel G. Silymarin in the treatment of chronic liver diseases: past and future. Orv Hetil. 2008 Dec 21;149(51):2413-8.
  68. Loguercio C, Federico A, Trappoliere M, et al. The effect of a silybin-vitamin e-phospholipid complex on nonalcoholic fatty liver disease: a pilot study. Dig Dis Sci. 2007 Sep;52(9):2387-95.
  69. Serviddio G, Bellanti F, Giudetti AM, et al. A silybin-phospholipid complex prevents mitochondrial dysfunction in a rodent model of nonalcoholic steatohepatitis. J Pharmacol Exp Ther. 2010 Mar;332(3):922-32.
  70. Trappoliere M, Federico A, Tuccillo C, et al. Effects of a new pharmacological complex (silybin + vitamin-E + phospholipids) on some markers of the metabolic syndrome and of liver fibrosis in patients with hepatic steatosis. Preliminary study. Minerva Gastroenterol Dietol. 2005 Jun;51(2):193-9.
  71. Federico A, Trappoliere M, Tuccillo C, et al. A new silybin-vitamin E-phospholipid complex improves insulin resistance and liver damage in patients with nonalcoholic fatty liver disease: preliminary observations. Gut. 2006 Jun;55(6):901-2.
  72. Li Z, Agellon LB, Allen TM, et al. The ratio of phosphatidylcholine to phosphatidylethanolamine influences membrane integrity and steatohepatitis. Cell Metab. 2006 May;3(5):321-31.
  73. Lieber CS. New concepts of the pathogenesis of alcoholic liver disease lead to novel treatments. Curr Gastroenterol Rep. 2004 Feb;6(1):60-5.
  74. Ma X, Zhao J, Lieber CS. Polyenylphosphatidylcholine attenuates nonalcoholic hepatic fibrosis and accelerates its regression. J Hepatol. 1996 May;24(5):604-13.
  75. Aleynik SI, Leo MA, Ma X, Aleynik MK, Lieber CS. Polyenylphosphatidylcholine prevents carbon tetrachloride-induced lipid peroxidation while it attenuates liver fibrosis. J Hepatol. 1997 Sep;27(3):554-61.
  76. Lieber CS, Leo MA, Aleynik SI, Aleynik MK, DeCarli LM. Polyenylphosphatidylcholine decreases alcohol-induced oxidative stress in the baboon. Alcohol Clin Exp Res. 1997 Apr;21(2):375-9.
  77. Navder KP, Baraona E, Leo MA, Lieber CS. Oxidation of LDL in baboons is increased by alcohol and attenuated by polyenylphosphatidylcholine. J Lipid Res. 1999 Jun;40(6):983-7.
  78. Polichetti E, Janisson A, de la Porte PL, et al. Dietary polyenylphosphatidylcholine decreases cholesterolemia in hypercholesterolemic rabbits: role of the hepato-biliary axis. Life Sci. 2000 Oct 13;67(21):2563-76.
  79. Brady LM, Fox ES, Fimmel CJ. Polyenylphosphatidylcholine inhibits PDGF-induced proliferation in rat hepatic stelAleynik SI, Lieber CS. Polyenylphosphatidylcholine corrects the alcohol-induced hepatic oxidative stress by restoring s-adenosylmethionine. Alcohol Alcohol. 2003 May-Jun;38(3):208-12.
  80. Kasdallah-Grissa A, Mornagui B, Aouani E, et al. Resveratrol, a red wine polyphenol, attenuates ethanol-induced oxidative stress in rat liver. Life Sci. 2007 Feb 20;80(11):1033-9.
  81. Ajmo JM, Liang X, Rogers CQ, Pennock B, You M. Resveratrol alleviates alcoholic fatty liver in mice. Am J Physiol Gastrointest Liver Physiol. 2008 Oct;295(4):G833-42.
  82. Buettner R, Bettermann I, Hechtl C, et al. Dietary Folic Acid Activates AMPK and Improves Insulin Resistance and Hepatic Inflammation in Dietary Rodent Models of the Metabolic Syndrome. Horm Metab Res. 2010 Aug 27.
  83. de Kreutzenberg SV, Ceolotto G, Papparella I, et al. Downregulation of the longevity-associated protein sirtuin 1 in insulin resistance and metabolic syndrome: potential biochemical mechanisms. Diabetes. 2010 Apr;59(4):1006-15.
  84. Kraegen EW, Bruce C, Hegarty BD, Ye JM, Turner N, Cooney G. AMP-activated protein kinase and muscle insulin resistance. Front Biosci. 2009;14:4658-72.
  85. Aoun M, Michel F, Fouret G, et al. A polyphenol extract modifies quantity but not quality of liver fatty acid content in high-fat-high-sucrose diet-fed rats: possible implication of the sirtuin pathway. Br J Nutr. 2010 Aug 2:1-11.
  86. Bujanda LE, Hijona, et al. Resveratrol inhibits nonalcoholic fatty liver disease in rats." BMC Gastroenterol. 2008, 8: 40.
  87. Shang J, Chen LL, Xiao FX, Sun H, Ding HC, Xiao H. Resveratrol improves non-alcoholic fatty liver disease by activating AMP-activated protein kinase. Acta Pharmacol Sin. 2008 Jun;29(6):698-706.