Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + Download Section PDF Listen ++ For further information, see CMDT Part 16-10: Nonalcoholic Fatty Liver Disease + Key Features Download Section PDF Listen +++ +++ Essentials of Diagnosis ++ Often asymptomatic Elevated serum aminotransferase levels, hepatomegaly, and/or steatosis on ultrasonography Predominantly macrovesicular steatosis with or without inflammation and fibrosis on liver biopsy +++ General Considerations +++ Nonalcoholic fatty liver disease (NAFLD) ++ Causes include obesity (present in ≥ 40%), diabetes mellitus (in ≥ 20%), and hypertriglyceridemia (in ≥ 20%) in association with insulin resistance as part of the metabolic syndrome; the risk of NAFLD in persons with metabolic syndrome is 4 to 11 times higher than that of persons without insulin resistance Nonobese persons (more frequently Asians) account for 3–30% of persons with NAFLD and have metabolic profiles characteristic of insulin resistance Persons with NAFLD are at increased risk for cardiovascular disease, chronic kidney disease, and colorectal cancer The frequency and severity of NAFLD is greater in men than in women during reproductive age, but after menopause the frequency is higher in women than men, suggesting that estrogen is protective +++ Nonalcoholic steatohepatitis (NASH) ++ Results from progression of macrovascular steatosis to steatohepatitis and fibrosis Characterized histologically by the macrovesicular steatosis of NAFLD with Focal infiltration by polymorphonuclear neutrophils Mallory hyaline Histologic features are indistinguishable from alcoholic hepatitis Histologic severity is increased in women who take synthetic hormones (oral contraceptives and hormone replacement therapy) +++ Other causes of fatty liver disease ++ Cushing syndrome and hypopituitarism Excessive dietary fructose consumption Starvation and refeeding syndrome Hypobetalipoproteinemia Polycystic ovary syndrome Hypothyroidism Obstructive sleep apnea Total parenteral nutrition Psoriasis (NAFLD) Soft drink consumption (NAFLD) Cholecystectomy (NAFLD) Medications: corticosteroids, amiodarone, diltiazem, tamoxifen, irinotecan, oxaliplatin, and antiretroviral therapy Toxins: vinyl chloride, carbon tetrachloride, yellow phosphorus +++ Causes of microvesicular steatosis ++ Reye syndrome Medications: didanosine, stavudine, linezolid, valproic acid, tetracycline Acute fatty liver of pregnancy Women in whom fatty liver of pregnancy develops often have a defect in fatty acid oxidation due to reduced long-chain 3-hydroxyacyl-CoA dehydrogenase activity + Clinical Findings Download Section PDF Listen +++ +++ Symptoms and Signs ++ Most patients with NAFLD are asymptomatic or have only mild right upper quadrant discomfort Hepatomegaly is present in 75% of patients with NASH, but the stigmas of chronic liver disease are uncommon Signs of portal hypertension generally signify advanced liver fibrosis or cirrhosis but occasionally occur in patients with mild or no fibrosis and severe steatosis +++ Differential Diagnosis ++ Alcoholic fatty liver disease Hepatitis, eg, viral, alcoholic, toxic Cirrhosis Heart failure Hepatocellular carcinoma or metastatic cancer + Diagnosis Download Section PDF Listen +++ +++ Laboratory Tests ++ There may be mildly elevated serum aminotransferase and alkaline phosphatase levels However, laboratory values may be normal in up to 80% of persons with hepatic steatosis In contrast to alcoholic liver disease, Ratio of serum alanine aminotransferase (ALT) to aspartate aminotransferase (AST) is almost always > 1 in NAFLD However, it decreases to < 1 as advanced fibrosis and cirrhosis develop Antinuclear or smooth muscle antibodies and an elevated serum ferritin level may each be detected in 30% of patients with NASH Elevated serum ferritin levels May signify so-called dysmetabolic iron overload syndrome and mildly increased body iron stores May play a causal role in insulin resistance and oxidative stress in hepatocytes and correlate with advanced fibrosis The frequency of mutations in the HFE gene for hemochromatosis is not increased in patients with NAFLD +++ Imaging Studies ++ Macrovascular steatosis may be demonstrated on ultrasonography, CT, or MRI Magnetic resonance spectroscopy or MRI-proton density fat fraction allows hepatic fat content to be quantitated and appears to correlate with the risk of fibrosis progression However, imaging does not distinguish steatosis from steatohepatitis or detect fibrosis Elastography Used to measure liver stiffness measurement by assessing the fibrosis stage In general, results are less accurate in obese than in nonobese subjects +++ Diagnostic Procedures ++ Percutaneous liver biopsy Diagnostic Only way to assess the degree of inflammation and fibrosis Risks of the procedure must be balanced against the impact of the added information on management decisions and assessment of prognosis + Treatment Download Section PDF Listen +++ +++ Medications ++ Metformin, thiazolidinediones, and pentoxifylline may reverse fatty liver and are under study Vitamin E, 800 international units/day (to reduce oxidative stress) Appears to be of benefit if patients do not have comorbid diabetes mellitus May increase the risk of prostate cancer in men (controversial) Other agents under study include Orlistat Recombinant human leptin Glucagon-like protein-1-receptor agonists Probucol Losartan Iron depletion therapy Obeticholic acid Liraglutide Sitagliptin Canagliflozin L-carnitine Omega-3 fatty acids Selective caspase inhibitors Aramchol Cenicriviroc Pegbelfermin +++ Surgery ++ Bariatric surgery may be considered in patients with a body mass index (kg/m2) > 35 Liver transplantation is indicated in appropriate candidates with advanced cirrhosis caused by NASH +++ Therapeutic Procedures ++ Fatty liver is readily reversible with discontinuation of alcohol or treatment of other underlying conditions Weight loss, dietary fat restriction, and moderate exercise can often improve liver chemistries and steatosis in obese patients with fatty liver + Outcome Download Section PDF Listen +++ +++ Complications ++ Risk factors for advanced hepatic fibrosis and cirrhosis Older age Obesity Diabetes mellitus +++ Prognosis ++ NASH may be associated with hepatic fibrosis in 40% of cases; cirrhosis develops in 9–25%; and decompensated cirrhosis occurs in 30–50% of patients over a period of 10 years Hepatocellular carcinoma can occur in cirrhosis caused by NASH NASH may account for many cases of cryptogenic cirrhosis and can recur following liver transplantation Mortality in patients with fatty liver is more likely to result from malignancy or cardiovascular disease than from liver disease +++ Prevention ++ Avoid alcohol Maintain ideal weight Exercise Treat hypertriglyceridemia +++ When to Refer ++ For liver biopsy + References Download Section PDF Listen +++ + +Castera L et al. Noninvasive assessment of liver disease in patients with nonalcoholic fatty liver disease. Gastroenterology. 2019 Apr;156(5):1264–81. [PubMed: 30660725] + +Chalasani N et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018 Jan;67(1):328–57. [PubMed: 28714183] + +Cheung A et al. Nonalcoholic fatty liver disease: identification and management of high-risk patients. Am J Gastroenterol. 2019 Apr;114(4):579–90. [PubMed: 30839326] + +Hajifathalian K et al. Effect of alcohol consumption on survival in nonalcoholic fatty liver disease: a national prospective cohort study. Hepatology. 2019 Aug;70(2):511–21. [PubMed: 30125379] + +Konerman MA et al. Pharmacotherapy for NASH: current and emerging. J Hepatol. 2018 Feb;68(2):362–75. [PubMed: 29122694] + +Lee Y et al. Complete resolution of nonalcoholic fatty liver disease after bariatric surgery: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2019 May;17(6):1040–60. [PubMed: 30326299] + +Pelusi S et al. Prevalence and risk factors of significant fibrosis in patients with nonalcoholic fatty liver without steatohepatitis. Clin Gastroenterol Hepatol. 2019 Oct;17(11):2310–19. [PubMed: 30708111] + +Younes R et al. NASH in lean individuals. Semin Liver Dis. 2019 Feb;39(1):86–95. [PubMed: 30654392] + +Younossi ZM. Non-alcoholic fatty liver disease—a global public health perspective. J Hepatol. 2019 Mar;70(3):531–44. [PubMed: 30414863] + +Younossi ZM et al. Current and future therapeutic regimens for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology. 2018 Jul;68(1):361–71. [PubMed: 29222911]