Fatty Liver Disease, Nonalcoholic

Essentials of Diagnosis

• Often asymptomatic

• Elevated serum aminotransferase levels, hepatomegaly, and/or steatosis on ultrasonography

• Predominantly macrovesicular steatosis with or without inflammation and fibrosis on liver biopsy

General Considerations

Nonalcoholic fatty liver disease (NAFLD)

• Causes include obesity (present in ≥ 40%), diabetes mellitus (in ≥ 20%), and hypertriglyceridemia (in ≥ 20%) in association with insulin resistance as part of the metabolic syndrome; the risk of NAFLD in persons with metabolic syndrome is 4 to 11 times higher than that of persons without insulin resistance

• Nonobese persons (more frequently Asians) account for 3–30% of persons with NAFLD and have metabolic profiles characteristic of insulin resistance

• Persons with NAFLD are at increased risk for cardiovascular disease, chronic kidney disease, and colorectal cancer

• The frequency and severity of NAFLD is greater in men than in women during reproductive age, but after menopause the frequency is higher in women than men, suggesting that estrogen is protective

Nonalcoholic steatohepatitis (NASH)

• Results from progression of macrovascular steatosis to steatohepatitis and fibrosis

• Characterized histologically by the macrovesicular steatosis of NAFLD with

  • Focal infiltration by polymorphonuclear neutrophils

  • Mallory hyaline

  • Histologic features are indistinguishable from alcoholic hepatitis

• Histologic severity is increased in women who take synthetic hormones (oral contraceptives and hormone replacement therapy)

Other causes of fatty liver disease

• Cushing syndrome and hypopituitarism

• Excessive dietary fructose consumption

• Starvation and refeeding syndrome

• Hypobetalipoproteinemia

• Polycystic ovary syndrome

• Hypothyroidism

• Obstructive sleep apnea

• Total parenteral nutrition

• Psoriasis (NAFLD)

• Soft drink consumption (NAFLD)

• Cholecystectomy (NAFLD)

• Medications: corticosteroids, amiodarone, diltiazem, tamoxifen, irinotecan, oxaliplatin, and antiretroviral therapy

• Toxins: vinyl chloride, carbon tetrachloride, yellow phosphorus

Causes of microvesicular steatosis

• Reye syndrome

• Medications: didanosine, stavudine, linezolid, valproic acid, tetracycline

• Acute fatty liver of pregnancy

• Women in whom fatty liver of pregnancy develops often have a defect in fatty acid oxidation due to reduced long-chain 3-hydroxyacyl-CoA dehydrogenase activity

Symptoms and Signs

• Most patients with NAFLD are asymptomatic or have only mild right upper quadrant discomfort

• Hepatomegaly is present in 75% of patients with NASH, but the stigmas of chronic liver disease are uncommon

• Signs of portal hypertension generally signify advanced liver fibrosis or cirrhosis but occasionally occur in patients with mild or no fibrosis and severe steatosis

Differential Diagnosis

• Alcoholic fatty liver disease

• Hepatitis, eg, viral, alcoholic, toxic

• Cirrhosis

• Heart failure

• Hepatocellular carcinoma or metastatic cancer

Laboratory Tests

• There may be mildly elevated serum aminotransferase and alkaline phosphatase levels

  • However, laboratory values may be normal in up to 80% of persons with hepatic steatosis

• In contrast to alcoholic liver disease,

  • Ratio of serum alanine aminotransferase (ALT) to aspartate aminotransferase (AST) is almost always > 1 in NAFLD

  • However, it decreases to < 1 as advanced fibrosis and cirrhosis develop

• Antinuclear or smooth muscle antibodies and an elevated serum ferritin level may each be detected in 30% of patients with NASH

• Elevated serum ferritin levels

  • May signify so-called dysmetabolic iron overload syndrome and mildly increased body iron stores

  • May play a causal role in insulin resistance and oxidative stress in hepatocytes and correlate with advanced fibrosis

• The frequency of mutations in the HFE gene for hemochromatosis is not increased in patients with NAFLD

Imaging Studies

• Macrovascular steatosis may be demonstrated on ultrasonography, CT, or MRI

• Magnetic resonance spectroscopy or MRI-proton density fat fraction allows hepatic fat content to be quantitated and appears to correlate with the risk of fibrosis progression

• However, imaging does not distinguish steatosis from steatohepatitis or detect fibrosis

• Elastography

  • Used to measure liver stiffness measurement by assessing the fibrosis stage

  • In general, results are less accurate in obese than in nonobese subjects

Diagnostic Procedures

• Percutaneous liver biopsy

  • Diagnostic

  • Only way to assess the degree of inflammation and fibrosis

  • Risks of the procedure must be balanced against the impact of the added information on management decisions and assessment of prognosis

Medications

• Metformin, thiazolidinediones, and pentoxifylline may reverse fatty liver and are under study

• Vitamin E, 800 international units/day (to reduce oxidative stress)

  • Appears to be of benefit if patients do not have comorbid diabetes mellitus

  • May increase the risk of prostate cancer in men (controversial)

• Other agents under study include

  • Orlistat

  • Recombinant human leptin

  • Glucagon-like protein-1-receptor agonists

  • Probucol

  • Losartan

  • Iron depletion therapy

  • Obeticholic acid

  • Liraglutide

  • Sitagliptin

  • Canagliflozin

  • L-carnitine

  • Omega-3 fatty acids

  • Selective caspase inhibitors

  • Aramchol

  • Cenicriviroc

  • Pegbelfermin

Surgery

• Bariatric surgery may be considered in patients with a body mass index (kg/m²) > 35

• Liver transplantation is indicated in appropriate candidates with advanced cirrhosis caused by NASH

Therapeutic Procedures

• Fatty liver is readily reversible with discontinuation of alcohol or treatment of other underlying conditions

• Weight loss, dietary fat restriction, and moderate exercise can often improve liver chemistries and steatosis in obese patients with fatty liver

Complications

• Risk factors for advanced hepatic fibrosis and cirrhosis

  • Older age

  • Obesity

  • Diabetes mellitus

Prognosis

• NASH may be associated with hepatic fibrosis in 40% of cases; cirrhosis develops in 9–25%; and decompensated cirrhosis occurs in 30–50% of patients over a period of 10 years

• Hepatocellular carcinoma can occur in cirrhosis caused by NASH

• NASH may account for many cases of cryptogenic cirrhosis and can recur following liver transplantation

• Mortality in patients with fatty liver is more likely to result from malignancy or cardiovascular disease than from liver disease

Prevention

• Avoid alcohol

• Maintain ideal weight

• Exercise

• Treat hypertriglyceridemia

When to Refer

• For liver biopsy