Nonalcoholic Fatty Liver Disease (NAFLD)

Nonalcoholic Fatty Liver Disease (NAFLD) is a topic covered in the 5-Minute Clinical Consult.

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  • A spectrum of fatty liver diseases not due to excess alcohol consumption ranging from nonalcoholic fatty liver (NAFL), to nonalcoholic steatohepatitis (NASH), to cirrhosis with hepatocyte injury with/without fibrosis
  • Leading cause of chronic liver disease; implicated in up to 90% of patients with asymptomatic, mild aminotransferase elevation not caused by alcohol, viral hepatitis, or medications


  • NAFL (1)
    • Reversible condition in which large vacuoles of triglyceride fat accumulate in hepatocytes
    • Liver biopsy: fatty deposits in >30% of cells, no hepatocyte ballooning, no necrosis, no fibrosis
    • Alanine aminotransferase/aspartate aminotransferase (ALT/AST) enzymes usually normal but may be elevated, rarely >3 to 4 times ULN
    • Minimal risk of progressing to cirrhosis or liver failure
    • Synonym: steatosis
  • NASH: progressive form of NAFL (1)
    • Liver biopsy: fatty deposits in >50% of cells with ballooning, acute/chronic inflammation, ± fibrosis
    • ALT and AST elevated, generally <3 to 4 times ULN
    • 30% with NASH may progress to fibrosis over 5 years, may progress to cirrhosis, liver failure, and rarely hepatocellular cancer
  • NASH cirrhosis (1)
    • Presence of cirrhosis with current or previous histologic evidence of steatosis or steatohepatitis


  • Nonalcoholic fatty liver disease (NAFLD): most common chronic liver disease globally; usually benign, asymptomatic
  • Predicted to become the most frequent indication for liver transplantation by 2030 (2)
  • NASH may be symptomatic with progressive inflammation and fibrosis.
    • Predominant age: 40s to 50s; can occur in children
    • Predominant sex: male > female (slight)

Estimates vary widely from 31 to 86 cases of NAFLD per 10,000 person-years to 29/100,000 person-years (1).

  • United States estimate: 30–40%
  • Worldwide: 6–33%, median 20–25% (1)
  • Present in 58–74% of obese persons (BMI >30) and 90% of morbidly obese persons (BMI >39) (1)
  • Among individuals with type 2 diabetes mellitus, rate of 69–87%; in patients with dyslipidemia, rate of 50% (1)

Etiology and Pathophysiology

Primary mechanism is thought to be insulin resistance, leading to increased lipolysis, triglyceride synthesis, and increased hepatic uptake of fatty acids.

  • NAFLD: excessive triglyceride accumulation in the liver and impaired ability to remove fatty acids
  • NASH: multiple hit theory that inflammation precedes steatosis in environmentally and genetically predisposed people. Multiple insults, including insulin resistance, hormones from adipose tissue, nutritional factors, endotoxins released by the gut microbiota, oxidative stress damage, and genetic factors. These “hits” act on liver parenchymal cells via toll-like receptors to lead to the progression of NASH (3).

Largely unknown: Some familial clustering and increased heritability. NAFL: more first-degree relatives with cirrhosis than matched controls; NASH: 18% with affected first-degree relative. Carriers of hemochromatosis gene are more likely to be affected. Patatin-like phospholipase (PNPLA3) polymorphism implicated in NAFLD, hypertriglyceridemia, and insulin resistance (1,2).

Risk Factors

  • Obesity (BMI >30), visceral obesity (waist circumference >102 cm for men or >88 cm for women), hypertension, dyslipidemia, high serum triglycerides and low serum high-density lipoprotein (HDL) levels, metabolic syndrome
  • Type 2 diabetes mellitus, cardiovascular disease, and chronic kidney disease (2)
  • Possible associations with hypothyroidism, hypopituitarism, hypogonadism, obstructive sleep apnea, pancreaticoduodenal resection, osteoporosis, psoriasis, and polycystic ovary syndrome (2)
  • Increasing age associated with increased prevalence, severity, advanced fibrosis, and mortality
  • High fructose intake linked to intestinal dysbiosis and metabolic stress (4)
  • Protein–calorie malnutrition; total parenteral nutrition (TPN) >6 weeks
  • Severe weight loss (starvation, bariatric surgery)
  • Organic solvent exposure (e.g., chlorinated hydrocarbons, toluene); vinyl chloride; hypoglycin A
  • Gene for hemochromatosis/other conditions with increased iron stores
  • Smoking
  • Drugs: tetracycline, glucocorticoids, tamoxifen, methotrexate, amiodarone, antiretroviral agents for HIV, valproic acid, fialuridine, many chemotherapy regimens, and nucleoside analogues
Pregnancy Considerations
Acute fatty liver of pregnancy: rare but serious complication in 3rd trimester. 50% of cases are associated with preeclampsia.
  • Symptoms: nausea, vomiting, headache, fatigue, right upper quadrant or epigastric pain, jaundice
  • Elevated ALT and AST >300 IU/L but usually <1,000 IU/L; elevated bilirubin
  • Liver biopsy confirms diagnosis (do not delay treatment for biopsy).
  • Early recognition and prompt delivery is key.
  • Recurrence is rare.
Pediatric Considerations
  • Increasing prevalence of NAFLD among children parallels rise in pediatric obesity.
  • Reports of NAFLD as early as age 2 years and NASH-related cirrhosis as early as age 8 years
  • Treat with intensive lifestyle modification.
  • Vitamin E of possible benefit.
  • Reye syndrome: fatty liver syndrome with encephalopathy usually following viral illness
    • Vomiting with dehydration
    • Confusion, progressive CNS damage
    • Hepatomegaly with extensive fatty vacuolization
    • Hypoglycemia
  • Etiology unknown; viral URIs and drugs (especially salicylates) have been implicated; mortality rate: 50%
  • Treat with mannitol, IV glucose, and FFP.

General Prevention

  • Avoid excess alcohol: ≤2 standard drinks per day (men); ≤1 standard drink per day (women)
  • Maintain appropriate BMI.
  • Prevention and optimal management of diabetes
  • Avoid hepatotoxic medications.
  • HAV and HBV vaccination if not immune
  • Pneumococcal and annual influenza vaccinations

Commonly Associated Conditions

Central obesity; hypertension; type 2 diabetes; insulin resistance; hyperlipidemia; preeclampsia in pregnancy; CVD and arrhythmias; hypothyroidism; hypogonadism; OSA (2)

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