α₁-Antitrypsin Deficiency Liver Disease

Key Features

Essentials of Diagnosis

• Serum α₁-antitrypsin level < 50–80 mg/dL

• Identification of a specific protease inhibitor (PI) phenotype (PIZZ, PISZ) or genotype

• Detection of diastase-resistant glycoprotein deposits in periportal hepatocytes

• Histologic evidence of liver disease

• Family history of early-onset pulmonary disease or liver disease

General Considerations

• Caused by a deficiency in α₁-antitrypsin, a protease inhibitor (Pi) system, predisposing patients to chronic liver disease and an early onset of pulmonary emphysema

• Liver disease is associated only with the Pi phenotypes ZZ and SZ

• Accumulation of misfolded aggregates of α₁-antitrypsin protein in the liver causes the liver injury by unclear mechanisms

Clinical Findings

Symptoms and Signs

• Most affected children are completely asymptomatic

• Neonatal cholestasis is present in about 10%–20% of affected infants

• Jaundice, acholic stools, and malabsorption may also be seen

• Infants are often small for gestational age

• Hepatosplenomegaly may be present

• In older children who have hepatomegaly or physical findings suggestive of cirrhosis and portal hypertension, α₁-antitrypsin deficiency should be suspected

Differential Diagnosis

• Biliary atresia

• Hepatitis B, hepatitis C, autoimmune hepatitis

• Wilson disease

• Cystic fibrosis

• Glycogen storage disease

Diagnosis

Laboratory Findings

• Serum α₁-antitrypsin level is low (< 50–80 mg/dL) in homozygotes (PiZZ)

• Specific Pi phenotyping or genotyping should be done to confirm the diagnosis

• Liver function tests often reflect underlying hepatic pathologic changes

• Hyperbilirubinemia (mixed) and elevated aminotransferases, alkaline phosphatase, and GGT are present early

• Hyperbilirubinemia generally resolves, while aminotransferase and GGT elevation may persist

• Signs of cirrhosis and hypersplenism may develop even when liver function tests are normal

• Liver biopsy findings after age 6 months show diastase resistant, periodic acid–Schiff staining intracellular globules, particularly in periportal zones

Treatment

• No specific treatment for the liver disease of this disorder

• Replacement of the protein by infusion therapy is used to prevent or treat pulmonary disease in affected adults

• Choleretics, medium-chain triglyceride–containing formula, and water-soluble preparations of fat-soluble vitamins are given to infants with neonatal cholestasis

• Hepatitis A and B vaccines should be given to children with α₁-antitrypsin deficiency

• Liver transplantation

  • Cures the deficiency with excellent long-term survival

  • Prevents the development of pulmonary disease

Outcome

Complications

• Portal hypertension

• Cirrhosis

• Chronic cholestasis

• Paucity of interlobular bile ducts

• Early-onset pulmonary emphysema occurs in young adults (age 30–40 years), particularly in smokers

• An increased susceptibility to hepatocellular carcinoma has been noted in cirrhosis associated with α₁-antitrypsin deficiency

Prognosis

• Of all infants with PiZZ α₁-antitrypsin deficiency, liver disease develops in only 15–20%; many have clinical recovery

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