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Definition, Etiology, PathogenesisTop
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of liver diseases where there is excessive fat accumulation in the liver (hepatic steatosis) in patients without significant alcohol consumption, without long-term use of a steatogenic medication, and without monogenic hereditary disorders. Hepatic steatosis is defined as fat in ≥5% of hepatocytes of a liver specimen or liver fat content >5.6% in proton magnetic resonance spectroscopy (MRS) or phase-contrast magnetic resonance imaging (MRI). NAFLD can be further categorized into:
1) Nonalcoholic fatty liver (NAFL): There is no evidence of hepatocyte damage or fibrosis. The risk of progression to cirrhosis is negligible.
2) Nonalcoholic steatohepatitis (NASH): There is hepatocyte injury such as ballooning and inflammation with or without fibrosis. If untreated, NASH can be associated with a risk of developing cirrhosis, liver failure, and possibly hepatocellular carcinoma (HCC).
NAFLD is associated with metabolic syndrome and with an increased risk of premature atherosclerosis and death from cardiovascular causes. Its pathogenesis includes insulin resistance, abnormal adiponectin regulation, and oxidative stress in patients with overweight or obesity that develop due to a high-calorie diet (particularly in the case of high fructose intake), physical inactivity, and genetic factors.
The key risk factors for NAFLD include obesity (particularly visceral obesity), type 2 diabetes mellitus, dyslipidemia, and male sex. Other factors showing a weaker correlation with the development of NAFLD include polycystic ovary syndrome (PCOS), hypothyroidism, hypopituitarism, hypogonadism, and obstructive sleep apnea (OSA). Risk factors for the development of fibrosis and cirrhosis in patients with NAFLD remain unclear but may include NASH histologic subtype (the greatest risk factor), type 2 diabetes mellitus, hyperlipidemia, obesity, hypertension, genetic polymorphism (PNPLA3, TM6SF2), and age. NASH develops in 15% to 20% of patients with NAFLD. Cirrhosis develops in <5% of patients with NAFLD and in 12% to 35% of patients with NASH.
Clinical Features and Natural HistoryTop
1. Symptoms: The disease is usually asymptomatic, but it may cause fatigue, weakness, malaise, and upper right abdominal discomfort. It is often diagnosed incidentally by ultrasonography performed for another reason or after finding abnormal liver enzyme levels (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) in serum.
2. Signs: Usually obesity, hepatomegaly (up to 75% of patients), splenomegaly (<25%), or other features of portal hypertension (rarely). Liver fibrosis usually progresses slowly over decades (faster in NASH than in NAFL), but in 20% of patients the progression of fibrosis is rapid. In patients with NASH the risk of developing cirrhosis and HCC is increased, but the main cause of death is cardiovascular disease, with liver-related mortality being the second or third cause of death among patients with NAFLD.
1. Blood biochemical tests: There may be mild to moderate elevations in the serum levels of ALT, AST, and gamma-glutamyl transferase (GGT) (~50%). Normal ALT and AST levels do not exclude the diagnosis of NAFLD. Bilirubin is rarely increased. Dyslipidemia and hyperglycemia (or impaired glucose tolerance) may be present. Iron, transferrin saturation, and ferritin are commonly elevated, but if iron studies are suggestive of hemochromatosis, this diagnosis should be excluded with HFE genetic testing. Autoantibodies (antinuclear antibody [ANA], smooth muscle antibody [SMA]) may be positive, although their significance is unclear. In patients who develop cirrhosis, there may be hyperbilirubinemia, hypoalbuminemia, prolonged international normalized ratio (INR), thrombocytopenia, and neutropenia.
2. Imaging studies: Ultrasonography (the first-line diagnostic modality) reveals hyperechogenic liver (due to fatty infiltration) and occasional hepatomegaly. In patients with cirrhosis signs of portal hypertension can be observed. Of note, in obese patients ultrasonography can be difficult to perform and cannot detect mild hepatic steatosis or differentiate between simple steatosis and NASH (but it can still assess moderate and severe steatosis). Computed tomography (CT) is useful for evaluating the liver and other organs but not recommended for routine use due to ionizing radiation. MRI allows for an accurate assessment of mild steatosis (5%-10% of hepatocytes). Proton MRS is the only verified method for quantifying fat content in the liver.
3. Noninvasive assessments of liver fibrosis: These may be used to identify patients with less severe fibrosis (F0-F1) in whom liver biopsy may be omitted:
1) Elastography (the accuracy of FibroScan in patients with obesity is limited), magnetic resonance elastography.
2) Scores based on serum biomarkers: NAFLD fibrosis score (available at nafldscore.com), FIB-4 index (available at mdcalc.com), Enhanced Liver Fibrosis (ELF) test (currently available in Europe only), FibroTest.
4. Histologic examination of liver biopsy specimens: This is the diagnostic gold standard for NASH, but it carries a risk of complications. Histologic features are as in alcoholic hepatitis. Biopsy may be indicated in case of diagnostic uncertainty (eg, in patients with high serum iron levels, positive autoantibodies [ANA, SMA, antimitochondrial antibodies, or AMAs], drug abuse) or in patients with another coexisting liver disease.
1. Features of hepatic steatosis on imaging studies or histologic examination in a person without a history of significant alcohol consumption (defined in a consensus meeting of the National Institute of Alcohol Abuse and Alcoholism [NIAAA] in 2016 as <21 standard drinks/wk in men and <14 standard drinks/wk in women, each standard drink defined as containing 14 g of pure alcohol).
2. Exclusion of other causes of hepatic steatosis (including hepatitis C, Wilson disease, lipodystrophy, starvation, parenteral nutrition, abetalipoproteinemia, drugs; Table 6.2-7).
3. Exclusion of other causes of chronic liver disease (particularly viral hepatitis B or C, autoimmune hepatitis, hemochromatosis, Wilson disease, alpha1-antitrypsin deficiency, drug-induced liver injury).
Of note: Differentiation between NAFL and NASH is currently not possible without liver biopsy.
In the diagnostic process, consider alcohol intake; presence and family history of diabetes, hypertension, and cardiovascular diseases; body mass index, lipid levels, thyroid disease, PCOS, and OSA.
1. Lifestyle changes: Sustained weight loss, either by diet alone or in combination with exercise. In patients with obesity a reduction in body weight by 3% to 5% may be sufficient to reduce liver steatosis, and a weight loss of 7% to 10% may improve necrotic inflammatory changes and fibrosis.
1) Diet: There is no specific diet composition. A hypocaloric diet (decrease daily calorie intake by 30% or 750-1000 kcal/d) allowing sustained weight loss is recommended. The Mediterranean diet has been shown to improve steatosis.
2) Exercise: An increase in physical activity (150 min/wk or an increase by >60 min/wk) is associated with a reduction in serum transaminases and body weight in NAFL patients. The effects on NASH and fibrosis are less clear.
2. Treatment of the underlying condition (eg, metabolic syndrome).
3. Bariatric surgery: According to guidelines from the American Association for the Study of Liver Diseases (AASLD), this may be considered in patients who have other indications for bariatric surgery. There is not enough evidence to consider this as an option strictly for NASH. According to guidelines from the European Association for the Study of the Liver (EASL), this is an option for patients not responding to lifestyle changes and pharmacotherapy.
4. Liver protection treatment: This may be considered in patients with NASH documented by liver biopsy. The use of vitamin E (not in cirrhosis or diabetes mellitus) or pioglitazone is suggested by some authorities.
5. Symptomatic treatment of complications of cirrhosis.
6. Liver transplantation may be considered in patients with decompensated cirrhosis or HCC.
As in alcoholic fatty liver disease. Screening is currently not recommended even in populations at increased risk of NAFLD.
– Drugs: Antibiotics (tetracycline, bleomycin, puromycin), cytotoxic agents (methotrexate, asparaginase), vitamins (high-dose vitamin A), other drugs (amiodarone, estrogens, glucocorticoids, hydralazine, salicylates, sodium valproate, warfarin)
– Chemicals: Chlorinated hydrocarbons, tetrachloromethane, carbon disulfide, phosphate, barium salts
– Mushroom toxins (alfa-amanitin)
Metabolic conditions and nutritional factors
– Overweight, obesity, starvation, protein malnutrition (kwashiorkor)
– Diabetes mellitus
– Cushing syndrome
– Zinc deficiency
– Parenteral nutrition that is long-term or total (or both; choline and carnitine deficiency)
– Diseases of pancreas
– Intestinal resection
– Intestinal anastomoses (eg, jejunoileal anastomosis)
– Celiac disease
– Inflammatory bowel disease (ulcerative colitis, Crohn disease)
Inherited metabolic disorders
– Storage diseases involving cholesterol esters (Wolman disease), sphingomyelin (Niemann-Pick disease), gangliosides (Tay-Sachs disease), glucocerebroside (Gaucher disease), copper (Wilson disease), iron (hemochromatosis), glycogen (glycogenoses), galactose, fructose, tyrosine, homocysteine, phytate (Refsum disease)
– Inherited urea cycle abnormalities
– Viral hepatitis C
– Fulminant viral hepatitis D
– Effects of endotoxins
– Reye syndrome
– Complications of pregnancy: Acute hepatic steatosis in pregnancy, eclampsia, HELLP syndrome (hemolysis, elevated liver enzyme [aminotransferase] levels, low platelet levels [thrombocytopenia])