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Key Features

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Essentials of Diagnosis
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  • 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

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General Considerations
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  • 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

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Clinical Findings

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Symptoms and Signs
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  • 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

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Differential Diagnosis
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  • Biliary atresia

  • Hepatitis B, hepatitis C, autoimmune hepatitis

  • Wilson disease

  • Cystic fibrosis

  • Glycogen storage disease

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Diagnosis

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Laboratory Findings
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  • 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

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Treatment

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  • 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

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Outcome

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Complications
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  • 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

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

  • Of those patients with neonatal cholestasis,

    • Liver transplantation will be necessary in 10–25% during the first 5 years of life ...

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