Nonalcoholic Fatty Liver Disease (NAFLD)


  • A spectrum of fatty liver diseases ranging from nonalcoholic fatty liver (NAFL), to nonalcoholic steatohepatitis (NASH), to fibrosis and cirrhosis, not due to other cause of fatty infiltration of liver (such as alcohol use)
  • Most common chronic liver disease in the United States and other industrialized nations; 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 cells without hepatocellular injury (no hepatocyte ballooning, no necrosis, no fibrosis)
    • ALT and AST normal or <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 cells with hepatocellular injury (ballooning, acute/chronic inflammation, ± fibrosis); may be histologically indistinguishable from alcoholic steatohepatitis
    • ALT and AST elevated, generally <3 to 4 times ULN
    • 30% with NASH may progress to fibrosis over 5 years and may progress to cirrhosis, liver failure, and rarely hepatocellular cancer.
  • NASH cirrhosis—presence of cirrhosis with current or previous histologic evidence of steatosis or steatohepatitis


  • Most common chronic liver disease in industrialized Western countries
  • Predicted to become the most frequent indication for liver transplantation by 2030 (2)
  • Predominant age: 40s to 50s; can occur in children
  • Predominant sex: male = female

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: 10–40%
  • Present in 58–74% of obese (BMI ≥30 kg/m2); 90% of morbidly obese (BMI ≥40 kg/m2); 69–87% with type 2 diabetes mellitus (DM); 50% with dyslipidemia (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. Thus, there is an international momentum to rename this condition to metabolic-associated fatty liver disease (MAFLD).

  • NAFL: excessive triglyceride accumulation in the liver and impaired ability to remove fatty acids
  • NASH: multiple hit theory (insulin resistance, adipose tissue hormones, oxidative stress damage, genetic factors, intestinal bacteria) that causes inflammation and acts on liver parenchymal cells leading to steatohepatitis


  • 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 (1)

Risk Factors

  • Obesity (BMI >30 kg/m2), visceral obesity (waist circumference >102 cm for men or >88 cm for women), hypertension, high triglycerides and low high-density lipoprotein (HDL) levels, metabolic syndrome
  • Type 2 DM, cardiovascular disease (CVD), and chronic kidney disease
  • 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, nucleoside analogues
  • History of cholecystectomy
  • Increasing age associated with increased prevalence, severity, advanced fibrosis, and mortality

Pregnancy Considerations
Acute fatty liver of pregnancy: rare but serious complication in 3rd trimester—50% of cases are associated with preeclampsia

Pediatric Considerations

  • Pediatric NAFLD
    • Increasing prevalence of NAFLD among children parallels rise in pediatric obesity, with prevalence of 9.6% (1).
    • Vitamin E of possible benefit
  • Reye syndrome: fatty liver syndrome with encephalopathy usually following viral illness

General Prevention

  • Avoid excess alcohol: ≤2 units per day (men); ≤1 unit 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 (1)

There's more to see -- the rest of this topic is available only to subscribers.