Description

• Clinical diagnosis of non-alcoholic fatty liver disease (NAFLD) requires that (1) there is hepatic steatosis by imaging/histology, (2) no significant alcohol consumption, (3) no competing etiologies for hepatic steatosis, and (4) no coexisting causes for chronic liver disease.
• Most patients with nonalcoholic steatohepatitis (NASH) are asymptomatic.
• Increased aminotransferase activities are the most common abnormality reported in patients with NASH.
• NASH is the most severe form of NAFLD; both are the hepatic manifestations of metabolic syndrome.

Epidemiology

• NAFLD and NASH have a worldwide distribution.
• NAFLD is the most common form of chronic liver disease in the Western world.
• NAFLD affects ∼6.3–33%, and NASH, 3–17%, of people in the US and other Western countries:
  • 25–35% of NASH patients develop fibrosis.
  • 9–20% of NASH patients develop cirrhosis.
  • 22–33% of cirrhotics die of complications of liver failure or require orthotopic liver transplantation.
• This increasing prevalence parallels epidemic obesity and diabetes mellitus (DM).
• Predominant age: 5th–6th decades

• Obesity is also increasing in prevalence in children. The overall prevalence of NAFLD in children is estimated at 3–10%, but it may be much higher in obese children.
• Reye syndrome: Fatty liver with encephalopathy; characterized by vomiting with dehydration, progressive CNS damage, hypoglycemia, and signs of hepatic injury
• Mortality rate is 50%.
• Treatment: Mannitol, IV glucose, and fresh frozen plasma

Risk Factors

• NAFLD is composed of individuals who have associated metabolic syndrome/insulin resistance.
• The presence of metabolic syndrome increases the risk of future development of NAFLD by 4–11-fold (1)[A].
• The 3 most important risk factors are closely related to metabolic syndrome and insulin resistance (1)[A]:
  • Obesity: Associated in 25–93% of patients with NAFLD
  • DM: Present in 30–50% of patients with NAFLD
  • Dyslipidemia: Found in up to 92% of patients with NAFLD
• Insulin resistance is associated strongly with metabolic syndrome and plays a central role in the pathogenesis of NAFLD.
• Other risk factors:
  • Data suggest that hypothyroidism, hypopituitarism, sleep apnea, and polycystic ovary syndrome, independent of obesity, are important risk factors for the presence of NAFLD.
  • Small bowel resections, gastric bypass, and jejunal bypass operations often lead to rapid weight loss, which may increase risk of NAFLD.
  • Medications: Corticosteroids, synthetic estrogens, amiodarone, tamoxifen, methotrexate
  • Other conditions: Wilson disease, hemochromatosis, abetalipoproteinemia, galactosemia, glycogen storage diseases

Genetics
There may be a genetic component.

General Prevention

• Maintain ideal weight and normal cholesterol and blood sugar levels.
• Avoid alcohol.
• Avoid hepatotoxic substances.

Pathophysiology

• NAFLD is closely linked to obesity, insulin resistance, and metabolic syndrome.
• When insulin resistance develops, free fatty acids are inappropriately shifted to nonadipose tissue, including the liver.
• Insulin resistance increases free fatty acid flux to the liver by decreased inhibition of lipolysis and also increased de novo lipogenesis.
• Insulin resistance and visceral obesity also result in decreased levels of adiponectin. Adiponectin inhibits liver gluconeogenesis and suppresses lipogenesis. Thus, decreased adiponectin hinders fatty acid oxidation and increases fat accumulation in the liver.
• Apoptosis and oxidative stress also may contribute to the development and progression of NASH.

Etiology

• Cause is unknown, but is closely linked to obesity, insulin resistance, and metabolic syndrome.
• Of these, insulin resistance may be the most important trigger of simple fatty liver (steatosis) and NASH.
• Since both these conditions can remain stable for many years, causing little harm, a second hit to the liver may trigger a progression to cirrhosis.
• Triggers may include cytokine-mediated inflammation, lipid peroxidation, and apoptosis.

Commonly Associated Conditions

Preeclampsia
Pregnancy Considerations

• A severe complication of 3rd trimester is acute fatty liver of pregnancy. It presents as an abrupt onset of confusion and restlessness with possible jaundice and right upper quadrant pain.
• Alanine aminotransferase/aspartate aminotransferase (ALT/AST) elevated, usually >1,000 U/L
• Emergency liver biopsy confirms.
• Prompt delivery corrects the liver disease. In most cases, the fetus has an inborn error of lipid metabolism blocking, the same as in the mother.
• Recurrence is rare in subsequent pregnancies.