Nonalcoholic Fatty Liver Disease
Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum of conditions characterized by hepatic fat accumulation in the absence of primary causes, including alcohol abuse. Nonalcoholic steatohepatitis (NASH), in which fat accumulation is accompanied by inflammation, is the most common type of NAFLD and the most common form of liver disease in the United States. Clinically, NASH may be indistinguishable from alcoholic hepatitis, but it is most often a subclinical disease.
The progressive accumulation of triglycerides in hepatic tissue results from increased delivery of fatty acids to the liver, decreased export of fatty acids from the liver, or impaired oxidation of fatty acids within the liver. Insulin resistance is thought to play a key role in disease development by causing alterations in lipid metabolism, leading to increased uptake of fatty acids by the liver and increased oxidation of lipids within it.
Most patients remain asymptomatic, although nonspecific symptoms, such as fatigue, malaise, and tenderness of the upper-right abdomen, may occur. In more serious cases, the pathologic features resemble those of alcoholic liver disease and may include fibrosis, inflammation, necrosis, and cirrhosis. Hepatocellular carcinoma can develop from cirrhosis caused by NASH.
Fatty liver disease is particularly prevalent among Latin Americans. Other risk factors include:
Obesity, especially abdominal obesity.
States of insulin resistance (typically related to obesity, diabetes mellitus, and the metabolic syndrome).
Hyperlipidemia, especially hypertriglyceridemia.
Other conditions that may be associated with NAFLD include: polycystic ovarian syndrome, hypothyroidism and obstructive sleep apnea. A history of a cholecystectomy, independent of risk factors for gallstones, increases risk of NAFLD.
Primary conditions that can lead to hepatic steatosis (and therefore are not necessarily considered NAFLD) include:
Hepatitis C infection.
Severe or rapid weight loss.
Total parenteral nutrition.
Drugs (e.g., glucocorticoids, synthetic estrogens, and certain pesticides).
Pregnancy. Acute fatty liver of pregnancy is a life threatening condition that requires immediate medical attention.
The diagnosis of NAFLD requires: documentation of hepatic steatosis on imaging or by biopsy, exclusion of overconsumption of alcohol, and exclusion of other causes of hepatic steatosis. Alcoholic liver disease should be ruled out by history, physical examination, and laboratory testing, as necessary.
Laboratory studies that may be helpful in the evaluation include complete blood count (CBC), blood chemistry, liver function tests, and coagulation studies.
NASH differs from alcoholic hepatitis in that the alanine aminotransferase (ALT) is generally greater than the aspartate aminotransferase (AST). The bilirubin level is generally not elevated, but alkaline phosphatase may be up to 2-3 times the upper limit of normal. However, liver function testing is not sufficient to make the diagnosis as these enzymes may be normal even with significant histologic pathology.
It is important to rule out other causes of hepatic steatosis and hepatic inflammation including: infection with hepatitis A, B, or C; autoimmune hepatitis; and hemochromatosis.
Ultrasound, CT scan, and MRI may be diagnostic. These tests can identify fatty liver and evaluate for other disorders, including biliary tract disease.
Liver biopsy may be useful if the cause of fatty liver is unclear. Biopsy will also reveal the grade and stage of disease to guide management and estimate prognosis.
Weight loss is essential for overweight patients with NAFLD. Even modest weight loss (~ 5% of body weight) may have significant beneficial effects by alleviating diabetes and hypertension.
Exercise may be beneficial, with or without associated weight loss. Use of pharmacologic weight loss agents may be beneficial. Morbidly obese patients (BMI > 35 kg/m 2) may consider surgical options, such as gastric bypass.
Diabetes mellitus in NAFLD patients should be treated as appropriate. Insulin-sensitizing drugs, t hiazolidinediones in particular, reduce steatosis. However, this class of medications has significant side effects and is not indicated in the routine treatment of NAFLD. While it does help modulate blood sugar, metformin has not been found to improve NASH. Treatment of hyperlipidemia with statins is safe in NASH and may decrease the progression of disease.
Vitamin E is an antioxidant and has been found to improve histologic score and liver transaminase levels in patients with NASH. A joint statement issued in 2012 American Association for the Study of Liver Diseases, the American Gastroenterological Association, and the American College of Gastroenterology suggests vitamin E (800 mg daily) as first-line pharmacotherapy for nondiabetic patients with biopsy-proven NASH.
Rarely, patients with advanced disease may require liver transplantation.
All patients without documented immunity should receive hepatitis A and hepatitis B vaccinations, along with the pneumococcal vaccine, which is indicated for all individuals with chronic liver disease.
NAFLD is in most cases the result of obesity, particularly the abdominal variety known to be involved in the promotion of insulin resistance. Although this can occur with excessive weight gain from any cause (except for lean body mass) NAFLD is more easily promoted with diets high in saturated fat and refined carbohydrates (e.g., high fructose corn syrup). Healthful dietary patterns and the intake of unsaturated fats are protective against NAFLD, while a Western diet increases the risk for this disease due to its high content of bioavailable iron and saturated fat content. Certain dietary supplements (omega-3 fatty acids, probiotics, vitamin E, and milk thistle) may be helpful as well.
Excess Weight and Weight Loss
Between 20% and 60% of obese adults have NAFLD, and this number is even greater for obese children. According to a number of investigations, consumption of an excess of fructose (as is found in beverages sweetened with high fructose corn syrup) is a suspected contributor to NAFLD, as well as being associated with a greater degree of fibrosis in patients with extant NAFLD. Through its metabolism to uric acid, fructose ultimately depletes hepatocyte ATP, causing enhanced hepatic lipogenesis, mitochondrial generation of oxygen radicals, endothelial dysfunction, and pro-inflammatory cytokine secretion. High fructose corn syrup may also contribute to de novo lipogenesis.
Nevertheless, the current consensus states that excess weight gain per se is responsible for causing NAFLD, rather than an excess of specific macronutrients.
Weight loss of at least 7% is sufficient to reduce hepatic inflammation and steatosis;, however, a loss of 10% or more provides the greatest degree of improvement. 5 Improvement in NAFLD has been shown with weight loss regardless of what type of diet regimen was used, although a combination of diet and exercise may be more effective because the latter reduces intrahepatic fat regardless of weight loss. Previous concerns that rapid weight loss (exceeding ~ 1 lb per week in children and ~ 3.5 lbs per week in adults) could worsen NAFLD symptoms appear to be unfounded for the overwhelming majority of patients. Although the American College of Gastroenterology, the American Gastroenterological Association, and the American Association for the Study of Liver Diseases do not yet consider weight loss surgery an established option for NASH treatment, r eviews have concluded that nearly all bariatric surgery patients have consistent improvement of steatosis, inflammation, fibrosis, and no disease progression.
Studies of isocaloric diets have favored low-fat, high-carbohydrate regimens over low-carbohydrate, high-fat diets, showing a decrease in liver fat in the former and an increase in the latter. While studies of hypocaloric diets initially found a benefit of very-low-carbohydrate (i.e., ketogenic) regimens over standard low calorie diets in terms of reduced steatosis, these benefits were not maintained roughly three months later.
Replace saturated fats with polyunsaturated and monounsaturated types.
Various types of diets have been compared with regard to both the causes and treatment for NAFLD. Saturated fat clearly had a significantly greater ability to promote NAFLD when compared with unsaturated fats, while both polyunsaturated and monounsaturated fats reduced liver fat content. 8 Differences between how these fats affect the liver are thought to derive in part from the fact that the unsaturated fats more easily undergo beta-oxidation while suppressing lipogenic genes.
A healthy dietary pattern. Although research in this area needs further clarification, existing data have shown two trends. The first is the ability of a Western dietary pattern high in saturated fat and refined carbohydrates to significantly increase the risk for NAFLD (by roughly 60%). The second pertains to the association of healthy diets (high in whole grains, fruits, vegetables, and legumes) with a significantly lower risk for this disease. 5,
Although clinical trials have not yet evaluated the effect of low-fat, high-fiber vegetarian diets on NAFLD, these diets nevertheless can help achieve the aims required to prevent or improve this disease. Plant-based diets typically cause weight loss and can lower the concentrations of blood fats (e.g., triglycerides) that contribute to NAFLD and are also associated with reduced insulin resistance and greater antioxidant protection, compared with omnivorous diets. , Plant-based diets have somewhat less iron bioavailability, and vegetarians have lower body-iron stores. This is important in that excess iron storage has been found in roughly one third of NAFLD patients, and evidence suggests that this worsens the clinical course in these individuals.
Although alcohol intake in obese individuals clearly increases the risk for NAFLD, the evidence is lacking in non-obese persons, in whom light to moderate drinking is associated with a lower risk for NAFLD.
Omega-3 fatty acid supplements. At a median dose of 4 g/d, omega-3 supplements reduced steatosis, insulin resistance, and inflammation, while enhancing lipid oxidation and decreasing endogenous lipid production in patients with NAFLD.
Probiotic supplementation. Intestinal dysbiosis exists in NAFLD and influences its progression to NASH. Most studies with probiotics in patients with NAFLD have found decreases in aminotransferases levels and hepatic steatosis after short-term interventions, and another review found significant decreases in insulin resistance, total cholesterol, and TNF- α.
Monitor for low vitamin D levels. Vitamin D influences free fatty acid metabolism through certain peroxisome proliferator-activated receptors (PPAR-γ) and through reducing hepatocyte inflammation. Patients with NAFLD were roughly 25% more likely to be vitamin D deficient, when compared with controls.
Vitamin E supplements. Studies in pediatric populations with NAFLD have revealed that low vitamin E intakes are associated with a higher grade of hepatic steatosis, and that vitamin E supplements led to an improvement in liver enzymes and histology. In adults, vitamin E supplements (800 IU/d) combined with either ursodeoxycholic acid or pioglitazone are an effective treatment for NAFLD,
Milk thistle. Controlled clinical trials have shown that the active ingredients in milk thistle (silymarin and silybin) reduce liver enzymes, increase the production of antioxidant enzymes, and may decrease insulin resistance,, and some of these have demonstrated increased effectiveness with the coadministration of vitamin E.
Patients on Total Parenteral Nutrition
Patients receiving total parenteral nutrition are at risk for developing fatty liver due to a lack of choline, which is now considered an essential nutrient. Choline requirements are influenced by estrogen status and genetic variation.
Hepatitis A vaccine, if not immune.
Hepatitis B vaccine, if not immune.
What to Tell the Family
In many cases fatty liver disease is responsive to diet changes, along with medications that address the elevations in weight, blood fats, and insulin resistance associated with this condition. Family members can assist the patient by participating in and encouraging a low-fat, high-fiber diet suitable for safe and gradual weight loss, along with appropriate exercise. These measures may help the patient avoid more serious liver damage. See Obesity chapter.
- 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. [PMID:21440669]
- Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al. Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis. Gastroenterology. 2015;149(2):367-78.e5; quiz e14-5. [PMID:25865049]
- Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012;142(7):1592-609. [PMID:22656328]
- Souza MR, Diniz Mde F, Medeiros-Filho JE, et al. Metabolic syndrome and risk factors for non-alcoholic fatty liver disease. Arq Gastroenterol. 2012;49(1):89-96. [PMID:22481692]
- Marcuccilli M, Chonchol M. NAFLD and Chronic Kidney Disease. Int J Mol Sci. 2016;17(4):562. [PMID:27089331]
- Yki-Järvinen H. Nutritional Modulation of Non-Alcoholic Fatty Liver Disease and Insulin Resistance. Nutrients. 2015;7(11):9127-38. [PMID:26556368]
- Hossain N, Kanwar P, Mohanty SR. A Comprehensive Updated Review of Pharmaceutical and Nonpharmaceutical Treatment for NAFLD. Gastroenterol Res Pract. 2016;2016:7109270. [PMID:27006654]
- Gupta V, Mah XJ, Garcia MC, et al. Oily fish, coffee and walnuts: Dietary treatment for nonalcoholic fatty liver disease. World J Gastroenterol. 2015;21(37):10621-35. [PMID:26457022]
- Orci LA, Gariani K, Oldani G, et al. Exercise-based Interventions for Nonalcoholic Fatty Liver Disease: A Meta-analysis and Meta-regression. Clin Gastroenterol Hepatol. 2016;14(10):1398-411. [PMID:27155553]
- Vander Naalt SJ, Gurria JP, Holterman AL. Surgical treatment of nonalcoholic fatty liver disease in severely obese patients. Hepat Med. 2014;6:103-12. [PMID:25378958]
- Green CJ, Hodson L. The influence of dietary fat on liver fat accumulation. Nutrients. 2014;6(11):5018-33. [PMID:25389901]
- Neuman MG, Nanau RM, Cohen LB. Nonmedicinal interventions in nonalcoholic fatty liver disease. Can J Gastroenterol Hepatol. 2015;29(5):241-52. [PMID:26076224]
- Barnard ND, Scialli AR, Turner-McGrievy G, et al. The effects of a low-fat, plant-based dietary intervention on body weight, metabolism, and insulin sensitivity. Am J Med. 2005;118(9):991-7. [PMID:16164885]
- Mach T. Fatty liver--current look at the old disease. Med Sci Monit. 2000;6(1):209-16. [PMID:11208312]
- Kuo CS, Lai NS, Ho LT, et al. Insulin sensitivity in Chinese ovo-lactovegetarians compared with omnivores. Eur J Clin Nutr. 2004;58(2):312-6. [PMID:14749752]
- Szeto YT, Kwok TC, Benzie IF. Effects of a long-term vegetarian diet on biomarkers of antioxidant status and cardiovascular disease risk. Nutrition. 2004;20(10):863-6. [PMID:15474873]
- Gawrieh S, Opara EC, Koch TR. Oxidative stress in nonalcoholic fatty liver disease: pathogenesis and antioxidant therapies. J Investig Med. 2004;52(8):506-14. [PMID:15682682]
- Hua NW, Stoohs RA, Facchini FS. Low iron status and enhanced insulin sensitivity in lacto-ovo vegetarians. Br J Nutr. 2001;86(4):515-9. [PMID:11591239]
- Aigner E, Weiss G, Datz C. Dysregulation of iron and copper homeostasis in nonalcoholic fatty liver. World J Hepatol. 2015;7(2):177-88. [PMID:25729473]
- Liangpunsakul S, Chalasani N. What should we recommend to our patients with NAFLD regarding alcohol use? Am J Gastroenterol. 2012;107(7):976-8. [PMID:22764020]
- Di Minno MN, Russolillo A, Lupoli R, et al. Omega-3 fatty acids for the treatment of non-alcoholic fatty liver disease. World J Gastroenterol. 2012;18(41):5839-47. [PMID:23139599]
- Bashiardes S, Shapiro H, Rozin S, et al. Non-alcoholic fatty liver and the gut microbiota. Mol Metab. 2016;5(9):782-94. [PMID:27617201]
- Machado MV, Cortez-Pinto H. Diet, Microbiota, Obesity, and NAFLD: A Dangerous Quartet. Int J Mol Sci. 2016;17(4):481. [PMID:27043550]
- Ma YY, Li L, Yu CH, et al. Effects of probiotics on nonalcoholic fatty liver disease: a meta-analysis. World J Gastroenterol. 2013;19(40):6911-8. [PMID:24187469]
- Wang X, Li W, Zhang Y, et al. Association between vitamin D and non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: results from a meta-analysis. Int J Clin Exp Med. 2015;8(10):17221-34. [PMID:26770315]
- Li J, Cordero P, Nguyen V, et al. The Role of Vitamins in the Pathogenesis of Non-alcoholic Fatty Liver Disease. Integr Med Insights. 2016;11:19-25. [PMID:27147819]
- Cacciapuoti F, Scognamiglio A, Palumbo R, et al. Silymarin in non alcoholic fatty liver disease. World J Hepatol. 2013;5(3):109-13. [PMID:23556042]
- Corbin KD, Zeisel SH. Choline metabolism provides novel insights into nonalcoholic fatty liver disease and its progression. Curr Opin Gastroenterol. 2012;28(2):159-65. [PMID:22134222]