Description

• Fatty liver:
  • Reversible condition where large vacuoles of triglyceride fat accumulate in hepatocytes; liver biopsy usually shows fatty deposits in >30% of liver cells; no necrosis, no fibrosis
  • Alanine aminotransferase/aspartate aminotransferase (ALT/AST) enzymes usually normal, but may be elevated, rarely >3–4× the upper limit of normal
• NAFLD:
  • Fatty liver not due to excess alcohol consumption, and so forth (see definition)
  • Risk factors: Obesity, metabolic syndrome, dyslipidemia, insulin resistance, and type 2 diabetes
  • Emerging associations: Polycystic ovary, hypothyroidism, obstructive sleep apnea, hypopituitarism, hypogonadism, pancreatic resection
• NASH:
  • Progressive form of NAFLD; liver biopsy: Fatty deposits in >50% of liver cells with acute and chronic inflammation, fibrosis
  • Asymptomatic; ALT and AST elevated, generally <3–4× upper limit of normal
  • Disease may progress to cirrhosis and/or liver cancer; incomplete data to assess natural history, although some evidence indicates that 30% with NASH have progression of fibrosis over 5 years.
• Both diseases usually identified in the 4th and 5th decade; may occur at any age
• Associated with obesity, type 2 diabetes mellitus (T2DM), dyslipidemia, and metabolic syndrome.
• Synonym(s): Steatosis; steatonecrosis; NAFLD; steatohepatitis; NASH

• Acute fatty liver of pregnancy: Severe complication of 3rd trimester. May be associated with pre-eclampsia
• Abrupt onset of confusion and restlessness with possible jaundice and right upper quadrant pain
• ALT, AST always elevated, >300 IU/L, but usually <1,000 IU/L
• Emergency liver biopsy confirms diagnosis.
• Prompt delivery corrects the liver disease.
• Recurrence rare in subsequent pregnancies

Epidemiology

NAFLD: Most common chronic liver disease globally, usually benign, asymptomatic fatty liver. NASH may be symptomatic with progressive inflammation and fibrosis; increases with age, slight male predominance (1)

• Present in up to ⅔ of obese (body mass index [BMI] >30) and in 90% of morbidly obese (BMI >39) persons
• Present in 5–10% patients with T2DM
• Predominant age: 40s–50s; does occur in children
• Predominant sex: Male = Female

Prevalence
US prevalence: Estimated at 6–24%. NAFLD: Worldwide prevalence of 6.3–33%; increases to 58–74% in obesity (2), to 69–87% in T2DM, and 50% of individuals with dyslipidemia (1).

Risk Factors

• Obesity: BMI >30 and visceral obesity, T2DM, dyslipidemia: High serum triglycerides and low serum high-density lipoprotein (HDL) levels, metabolic syndrome
• New data suggest hypothyroidism, hypopituitarism, hypogonadism, sleep apnea, and polycystic ovary syndrome are risk factors for NAFLD.
• Protein–calorie malnutrition; total parenteral nutrition (TPN) >6 weeks
• Increasing age associated with increased prevalence, severity, advanced fibrosis, or mortality
• Severe acute weight loss (starvation, bariatric surgery)
• Organic solvent (e.g., chlorinated hydrocarbons, toluene) exposure; vinyl chloride; hypoglycin A
• Gene for hemochromatosis/other conditions with increased iron stores
• Drugs: Tetracycline, glucocorticoids, tamoxifen, methotrexate, valproic acid, fialuridine, many chemotherapy regimens, and nucleoside analogues

• Reye syndrome: Fatty liver with encephalopathy:
  • Vomiting with dehydration; usually postviral URI
  • Progressive CNS damage
  • Signs of hepatic injury: Extensive fatty vacuolization
  • Hypoglycemia

• Etiology unknown; viral agents and drugs, especially salicylates, are implicated.
• Mortality rate: 50%
• Tx: Mannitol, IV glucose, and FFP

Genetics
Largely unknown: Data suggest familial clustering, slight increased heritability. NAFL: More 1st-degree relatives with cirrhosis than matched controls; NASH: 18% had an affected 1st-degree relative (1). Carriers of hemochromatosis gene are more likely to be affected; possible genetic variants in apolipoprotein C3 gene may play a role in fatty liver, insulin resistance, hypertriglyceridemia.

General Prevention

• Avoid excess alcohol: >30 g/d (men); >20 g/d (women).
• Maintain/Attain appropriate BMI.
• Optimize prevention and management of diabetes.
• Avoid hepatotoxic medications.
• Obtain HAV and HBV vaccination if not immune.
• Obtain Pneumovax and yearly influenza vaccination.

Pathophysiology

Primary derangement is insulin resistance, which leads to increased lipolysis, triglyceride synthesis, and increased hepatic uptake of fatty acids (3).

Etiology

• NAFLD: Most commonly an impaired ability of the liver to remove fatty acids
• NASH: “2-hit” hypothesis involving macrovesicular steatosis due to increased hepatic lipid synthesis, reduced hepatic transfer of lipids, increasing insulin resistance with increased hepatic oxidative stress (3). Mitochondrial damage leading to impaired restoration of ADT stores, lipid peroxidation, and increased iron stores each are found in 25–40% of NASH patients.

Commonly Associated Conditions

Preeclampsia in pregnancy, central obesity, type 2 diabetes, insulin resistance, hyperlipidemia, hypertension; possible increased risk in hypothyroidism, hypogonadism, sleep apnea