Life Extension Magazine December 2010
The Liver Disease Epidemic You Need to Know About
By Kirk Stokel
By Kirk Stokel
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.
If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.
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. 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.
14. 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.
15. Chalasani NP, Sanyal AJ, Kowdley KV, et al. Pioglitazone versus vitamin E versus placebo for the treatment of non-diabetic patients with nonalcoholic steatohepatitis: PIVENS trial design. Contemp Clin Trials. 2009 Jan;30(1):88-96.
16. 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.
17. Medina J, Moreno-Otero R. Pathophysiological basis for antioxidant therapy in chronic liver disease. Drugs. 2005;65(17):2445-61.
18. 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.
19. 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.
20. 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.
21. 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.
22. 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.
23. 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.
24. Yakaryilmaz F, Guliter S, Savas B, et al. Effects of vitamin E treatment on peroxisome proliferator-activated receptor-alpha expression and insulin resistance in patients with nonalcoholic steatohepatitis: results of a pilot study. Intern Med J. 2007 Apr;37(4):229-35.
25. 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.
26. 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.
27. 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.
28. 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.
29. 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.
30. 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.
31. 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.
32. 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.
33. 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.
34. 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.
35. 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.
36. 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.
37. 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.
38. 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.
39. Rotella CM, Monami M, Mannucci E. Metformin beyond diabetes: new life for an old drug. Curr Diabetes Rev. 2006 Aug;2(3):307-15.
40. 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.
41. 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.
42. 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.
43. 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.
44. 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.
45. 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.
46. 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.
47. 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.
48. 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.
49. 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.
50. 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.
51. 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.
52. 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.
53. 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.
54. Millea PJ. N-acetylcysteine: multiple clinical applications. Am Fam Physician. 2009 Aug 1;80(3):265-9.
55. 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.
56. 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.
57. 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.
58. 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.
59. 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.
60. 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.
61. Feher J, Lengyel G. Silymarin in the treatment of chronic liver diseases: past and future. Orv Hetil. 2008 Dec 21;149(51):2413-8.
62. 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.
63. 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.
64. Trappoliere M, Tuccillo C, Federico A, et al. The treatment of NAFLD. Eur Rev Med Pharmacol Sci. 2005 Sep-Oct;9(5):299-304.
65. 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.
66. Lieber CS. New concepts of the pathogenesis of alcoholic liver disease lead to novel treatments. Curr Gastroenterol Rep. 2004 Feb;6(1):60-5.
67. Ma X, Zhao J, Lieber CS. Polyenylphosphatidylcholine attenuates nonalcoholic hepatic fibrosis and accelerates its regression. J Hepatol. 1996 May;24(5):604-13.
68. 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.
69. 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.
70. 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.
71. 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.
72. Brady LM, Fox ES, Fimmel CJ. Polyenylphosphatidylcholine inhibits PDGF-induced proliferation in rat hepatic stellate cells. Biochem Biophys Res Commun. 1998 Jul 9;248(1):174-9.
73. Aleynik SI, Lieber CS. Polyenylphosphatidylcholine corrects the alcohol-induced hepatic oxidative stress by restoring s-adenosylmethionine. Alcohol Alcohol. 2003 May-Jun;38(3):208-12.
74. Mi LJ, Mak KM, Lieber CS. Attenuation of alcohol-induced apoptosis of hepatocytes in rat livers by polyenylphosphatidylcholine (PPC). Alcohol Clin Exp Res. 2000 Feb;24(2):207-12.