Etiology, possible causes, and treatment considerations for NAFLD
Nonalcoholic fatty liver disease (NAFLD) is subdivided into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). In the United States, prevalence of NAFLD is 10% to 46% of the population. Worldwide prevalence is 6% to 35% (median 20%). There is a need to increase understanding of liver disease and its many causes, which will help to improve patient outcomes and reduce the stigma many patients experience. This article discusses epidemiology, etiologies, suspected pathogenesis, and risk factors, along with conventional and naturopathic therapeutic treatment options.
The frequency of hepatic steatosis varied significantly with ethnicity (45% in Hispanics; 33% in whites; 24% in blacks) and sex (42% in white men; 24% in white women). The higher prevalence of hepatic steatosis in Hispanics was due to the higher prevalence of obesity and insulin resistance in this ethnic group.6
Nonalcoholic Fatty Liver Disease
“In clinical reality, nonalcoholic fatty liver disease typically comes to the attention of the healthcare practitioner because laboratory testing reveals elevated liver aminotransferases.”
- Weight loss for patients who are overweight or obese;
- Hepatitis A and B vaccinations, except in those with serologic evidence of immunity21;
- Treatment of risk factors for cardiovascular disease; and
- Abstention from alcohol.
- Tocotrienols: 200 mg twice daily with food.34 Gamma-tocotrienol, but not alpha-tocopherol, attenuates triglycerides accumulation by regulating fatty acid synthase and carnitine palmitoyltransferase enzymes, leading to a reduction of hepatic inflammation and endoplasmic reticulum stress.35
- N-acetyl-cysteine (NAC): 600 mg twice daily, best taken on an empty stomach.36 NAC blocks the propagation of lipid peroxidation.37
- Omega 3 essential fatty acids: 2 g to 4 g daily.38 Omega 3 polyunsaturated fatty acids are known to downregulate sterol regulatory element binding protein 1c and upregulate peroxisome proliferator activated receptor α, which would favor fatty acid oxidation and reduce steatosis.39
- Silybum marianum (milk thistle): 280 mg to 360 mg daily.40 Phytosomes provide the greatest bioavailability.41 Silymarin interferes with leukotriene formation in Kupffer cell cultures, thus inhibiting hepatic stellate cell activation.42
- L-carnitine: 1 g twice daily.43 L-carnitine plays a critical role in fatty acid oxidation of energy regulation. It serves as a carrier to facilitate the transport of long-chain fatty acids through the mitochondrial membrane and to undertake free fatty acid b-oxidation.44
- Choline: 250 mg to 1,000 mg daily.45 The precise mechanism of choline is unknown, except for its methyl donor properties and the observation that those with genetic polymorphisms involved in choline biosynthesis are associated with an increased risk of developing fatty liver.46
- Betaine: 20 g daily (1-6 g/d may beneficial if used in conjunction with other therapies).47 Betaine, when used in rats with alcohol-induced steatohepatitis, led to an increase in S-adenosyl-l-methionine, which in turn led to a reduction in hepatic steatosis.47
- Vitamin E (as RRR-α-tocopherol): 400 IU twice daily with food.48 Although well studied, I don’t utilize this treatment by itself due to increased risk for adverse cardiovascular events49 and gamma-tocopherol depletion50 at this dose. Mixed tocopherols have also shown efficacy in NAFL.35 Vitamin E is an effective defense mechanism against lipid peroxidation.51 Lipid peroxidation is increased in NAFLD and can promote inflammation and tissue damage.52
Given the relatively high US prevalence of non-alcoholic fatty liver disease, along with its strong correlation in conditions such as metabolic syndrome, types I and II diabetes, obesity and dyslipidemia, evidence-based naturopathic strategies and interventions lay the framework for these treatments to take center stage.
- Sazci A, Ergul E, Aygun C, Akpinar G, Senturk O, Hulagu S. Methylenetetrahydrofolate reductase gene polymorphisms in patients with nonalcoholic steatohepatitis (NASH). Cell Biochem Funct. 2008;26(3):291-296.
- Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology. 1999;29(3):664-669.
- Caldwell SH, Crespo DM. The spectrum expanded: cryptogenic cirrhosis and the natural history of non-alcoholic fatty liver disease. JHepatol. 2004;40(4):578-584.
- Lazo M, Hernaez R, Eberhardt MS, et al. Prevalence of nonalcoholic fatty liver disease in the United States: the Third National Health and Nutrition Examination Survey, 1988-1994. Am J Epidemiol. 2013;178(1):38-45.
- LaBrecque D, Abbas Z, Anania, F, et al. World Gastroenterology Organisation Global Guidelines: Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. June 2012. Available at:http://www.worldgastroenterology.org/assets/export/userfiles/2012_NASH%20and%20NAFLD_Final_long.pdf. Accessed July 14, 2014.
- Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40(6):1387-1395.
- Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980;55(7):434-438.
- Osorio Calixtro L, Patiño Trinidad T, Tagle Arróspide M, Huayanay Falconi L. Perceptions, knowledge and attitudes about liver disease in healthy adults attending health facilities in stratum A, B and C [in Spanish]. Rev Gastroenterol Peru. 2010;30(2):126-132.
- Younossi ZM, Stepanova M, Afendy M, et al. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol. 2011;9(6):524-530.e1; quiz e60.
- Alberti KG, Eckel RH, Grundy SM, et al; International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation.2009;120:1640-1645.
- Meigs James. Metabolic syndrome and the risk for type 2 diabetes. Expert Rev Endocrin Metab. 2006;(1): 1:57-66.
- Viganò M, Vergani A, Trombini P, Paleari F, Piperno A. Insulin resistance influence iron metabolism and hepatic steatosis in type II diabetes. Gastroenterology. 2000;118(5):986-987.
- Angulo P, Alba LM, Petrovic LM, Adams LA, Lindor KD, Jensen MD. Leptin, insulin resistance, and liver fibrosis in human nonalcoholic fatty liver disease. J Hepatol. 2004;41(6):943-949.
- Baskol G, Baskol M, Kocer D. Oxidative stress and antioxidant defenses in serum of patients with non-alcoholic steatohepatitis. Clin Biochem. 2007;40(11):776-780.
- Miele L, Valenza V, La Torre G, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease.Hepatology. 2009;49(6):1877-1887.
- Bacon BR, Farahvash MJ, Janney CG, Neuschwander-Tetri BA. Nonalcoholic steatohepatitis: an expanded clinical entity.Gastroenterology. 1994;107(4):1103-1109.
- Charatcharoenwitthaya P, Lindor KD, Angulo P. The spontaneous course of liver enzymes and its correlation in nonalcoholic fatty liver disease. Dig Dis Sci. 2012;57(7):1925-1931.
- Mofrad P, Contos MJ, Haque M, et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology. 2003;37(6):1286-1292.
- Banderas DZ, Escobedo J, Gonzalez E, Liceaga MG, Ramírez JC, Castro MG. γ-glutamyl transferase: a marker of nonalcoholic fatty liver disease in patients with the metabolic syndrome. Eur J Gastroenterol Hepatol. 2012;24(7):805-810.
- Irie M, Sohda T, Iwata K, et al. Levels of the oxidative stress marker γ-glutamyltranspeptidase at different stages of nonalcoholic fatty liver disease. J Int Med Res. 2012;40(3):924-933.
- US Centers for Disease Control and Prevention. Vaccines that might be indicated for adults based on medical and other indications. 2014. Available at: http://www.cdc.gov/vaccines/schedules/hcp/imz/adult-conditions.html. Accessed July 14, 2014.
- Gaunt IF, Grasso P, Gangolli SD. Brominated maize oil. I. Short-term toxicity and bromine-storage studies in rats fed brominated maize oil. Food Cosmet Toxicol. 1971;9(1):1-11.
- Leamy AK, Egnatchik RA, Young JD. Molecular mechanisms and the role of saturated fatty acids in the progression of non-alcoholic fatty liver disease. Prog Lipid Res. 2013;52(1):165-174.
- Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol. 2013;10(11):686-690.
- Freedman ND, Cross AJ, McGlynn KA, et al. Association of meat and fat intake with liver disease and hepatocellular carcinoma in the NIH-AARP Cohort. J Natl Cancer Inst. 2010;102(17): 1354-1365.
- Tetri LH, Basaranoglu M, Brunt EM, Yerian LM, Neuschwander-Tetri BA. Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent. Am J Physiol Gastrointest Liver Physiol. 2008;295(5):G987-G995.
- US Environmental Protection Agency. What you need to know about mercury in fish and shellfish. Available at:http://water.epa.gov/scitech/swguidance/fishshellfish/outreach/advice_index.cfm. Accessed July 18, 20014.
- Whitfield JB. Gamma glutamyl transferase. Crit Rev Clin Lab Sci. 2001;38(4):263-355.
- American Institute for Cancer Research. AICR’s foods that fight cancer: broccoli and cruciferous vegetables. http://www.aicr.org/foods-that-fight-cancer/broccoli-cruciferous.html. Accessed July 14, 2014.
- Zhou R, Lin J, Wu D. Sulforaphane induces Nrf2 and protects against CYP2E1-dependent binge alcohol-induced liver steatosis. Biochim Biophys Acta. 2014;1840(1):209-218.
- Gebhardt R, Fausel M. Antioxidant and hepatoprotective effects of artichoke extracts and constituents in cultured rat hepatocytes.Toxicol In Vitro. 1997;11(5):669-672.
- Kim SW, Ha KC, Choi EK, et al. The effectiveness of fermented turmeric powder in subjects with elevated alanine transaminase levels: a randomised controlled study. BMC Complement Altern Med. 2013 Mar 8;13:58.
- Krajka-Kuźniak V, Paluszczak J, Szaefer H, Baer-Dubowska W. Betanin, a beetroot component, induces nuclear factor erythroid-2-related factor 2-mediated expression of detoxifying/antioxidant enzymes in human liver cell lines. Br J Nutr. 2013;110(12):2138-2149.
- Xu R, Ye H, Sun Y, Tu Y, Zeng X. Preparation, preliminary characterization, antioxidant, hepatoprotective and antitumor activities of polysaccharides from the flower of tea plant (Camellia sinensis). Food Chem Toxicol. 2012;50(7):2473-2480.
- Magosso E, Ansari MA, Gopalan Y, et al. Tocotrienols for normalisation of hepatic echogenic response in nonalcoholic fatty liver: a randomised placebo-controlled clinical trial. Nutr J. 2013;12(1):166.
- Muto C, Yachi R, Aoki Y, Koike T, Igarashi O, Kiyose C. Gamma-tocotrienol reduces the triacylglycerol level in rat primary hepatocytes through regulation of fatty acid metabolism. J Clin Biochem Nutr. 2013;52(1):32-37.
- Khoshbaten M, Aliasgarzadeh A, Masnadi K, et al. N-acetyl-cysteine improves liver function in patients with non-alcoholic fatty liver disease. Hepatitis Mon. 2010;10(1):12-16.
- Parker HM, Johnson NA, Burdon CA, Cohn JS, O’Connor HT, George J. Omega-3 supplementation and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol. 2012;56(4):944-951.
- Pettinelli P, del Pozo T, Araya J, et al. Enhancement in liver SREBP-1c/PPAR-alpha ratio and steatosis in obese patients: correlations with insulin resistance and n-3 long-chain polyunsaturated fatty acid depletion. Biochim Biophys Acta. 2009;1792(11):1080-1086.
- Abenavoli L, Aviello G, Capasso R, Milic N, Capasso F. Milk thistle for treatment of nonalcoholic fatty liver disease. Hepatitis Mon. 2011;11(3):173-177.
- Kidd P, Head K. A review of the bioavailability and clinical efficacy of milk thistle phytosome: a silybin-phosphatidylcholine complex (Siliphos). Altern Med Rev. 2005;10(3):193-203.
- Dehmlow C, Erhard J, de Groot H. Inhibition of Kupffer cell functions as an explanation for the hepatoprotective properties of silibinin.Hepatology. 1996;23(4):749-754.
- Malaguarnera M, Gargante MP, Russo C, et al. L-carnitine supplementation to diet: a new tool in treatment of nonalcoholic steatohepatitis—a randomized and controlled clinical trial. Am J Gastroenterol. 2010;105(6):1338-1345.
- Ahmad S. L-carnitine in dialysis patients. Semin Dial. 2001;14(3):209-217.
- Nehra V, Angulo P, Buchman AL, Lindor KD. Nutritional and metabolic considerations in the etiology of nonalcoholic steatohepatitis. Dig Dis Sci. 2001;46(11):2347-2352.
- Song J, da Costa KA, Fischer LM, et al. Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD).FASEB J. 2005;19(10):1266-1271.
- 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;96(9):2711-2717.
- Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med.2010;362(18):1675-1685.
- Lonn E, Bosch J, Yusuf S, et al. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA. 2005;293(11):1338-1347.
- Jiang Q, Christen S, Shigenaga MK, Ames BN. gamma-tocopherol, the major form of vitamin E in the US diet, deserves more attention.Am J Clin Nutr. 2001;74(6):714-722.
- Sies H, Stahl W, Sundquist AR. Antioxidant functions of vitamins. Vitamins E and C, beta-carotene, and other carotenoids. Ann N Y Acad Sci. 1992 Sep 30;669:7-20.
- Dowman JK, Tomlinson JW, Newsome PN. Pathogenesis of non-alcoholic fatty liver disease. QJM. 2010;103(2):71-83.
- Gaby AR. Nutritional Medicine. Concord, NH: Fritz Perlberg; 2011.