• Deficiency of a-1 antitrypsin, a serum protease inhibitor, a glycoprotein of approximately 52 kD, which inhibits the activity of elastase, an enzyme involved in the remodeling of connective tissue.
• In the absence of regulated protease activity, alteration in the structure of end organs, lung, and liver can develop and cause disease.

• Most common metabolic cause of emphysema in adults and liver disease in children, for which they receive orthotopic liver transplantation.
• Incidence and prevalence change with the population studied, ranging from 1:1639 live births in Sweden to 1:2000 individuals in the United States.

• Autosomal recessive inheritance
• Multiple structural forms of the a-1 antitrypsin protein are encoded on chromosome 14.
• 75 Different alleles with the most common phenotypes are characterized as Pi, protease inhibitors, by gel electrophoresis.
• The most common normal variant is referred to as M.
• Individuals with the most severe deficiency have an a-1 antitrypsin alleleic variant, referred to as Z.

• Cirrhosis and emphysema are common
• Individuals expressing the homozygous ZZ alleles
• Infants are often diagnosed with neonatal hepatitis and jaundice and may develop one of three patterns of disease in the future: death, continuing evidence of liver damage, possibly necessitating liver transplantation for development of normal liver function.
• In adults with cirrhosis and chronic active hepatitis, the heterozygous alleleic variant, MZ, may be detected.

Question: Was there jaundice in the newborn?
Significance: Neonatal hepatitis and jaundice may be the first signs of a-1 antitrypsin deficiency

Question: Was there prolonged jaundice?
Significance: Common to see persistent elevation of neonatal bilirubin level, often within the first 4 months of life

Question: What is the significance of resolved cholestasis in infants?
Significance: May then have long asymptomatic periods

Question: What is adult presentation?
Significance: Adulthood present with cirrhosis and ascites

Finding: Jaundice and hepatosplenomegaly
Significance: Evidence of chronic liver disease in older children and adults

Test: The diagnosis of the alleleic variants is made by serum protein electrophoresis, which characterizes the most common of the protein forms.
Significance: The most common variants are the normal alleleic variant, M; deficient variant, Z and S, the latter leading to lung disease and the former leading to both liver and lung disease; and the null and dysfunctional variants.

Test: MM
Significance: Gives a serum a-1 antitrypsin level of 20 to 53 mmol/L, the normal state.

Test: PiZZ
Significance: Gives a low concentration of 2.5 to 7 mmol/L.

Test: Pinull/nul
Significance: Gives zero levels.

Test: PiSZ
Significance: Gives a mildly increased risk.

• No appropriate drug therapy currently exists for the deficient state.
• Ursodeoxycholic acid, a choleretic agent, is used in doses of 20 to 30 mg/kg/day in one or divided doses for management of cholestasis and pruritus.
• Other medications for treatment of complications of chronic liver disease may be necessary.
• Future treatment options will include definitive gene therapy for ZZ and possibly other genotypes.

• Lifelong expectant management and treatment of complications

• Only definitive therapy is orthotopic liver transplantation

• One-fourth of children will need a future liver transplantation as a result of worsening liver function and evidence of cirrhosis and portal hypertension.
• One-fourth will stabilize and liver function will normalize.
• One-fourth will slowly develop chronic liver disease and cirrhosis.
• One-fourth will have less severe liver function and live into adulthood.

Q: What is the usual course for my child with this problem?
A: In general, one-fourth of children will need future liver transplantation as a result of worsening liver function and evidence of cirrhosis and portal hypertension; one-fourth will stabilize and liver function will normalize; one-fourth will slowly develop chronic liver disease and cirrhosis; and one-fourth will have less severe liver function and live into adulthood.

Q: Is there a cure for my daughter at present?
A: Yes; at present treatment options range from treating for complications and definitively performing a liver transplantation to remove the affected organ. Since prognosis can change for children, we wait until the liver is no longer functioning before it is replaced.

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Balistreri W. Neonatal cholestasis. J Pediatr 1987;106:171.

Balistreri W. Liver disease associated with a a-antitrypsin deficiency. In: Balistreri W, Stocker J, eds. Pediatric hepatology. New York: Hemisphere, 1990:159–175.

Marcus N, Teckman JH, Perlmutter DH. a-Antitrypsin deficiency in childhood disease. J Pediatr Gastroenterol Nutr 1998;27(1):65–74.

Perlmutter DH. a-Antitrypsin deficiency. In: Walker WA, Durie PR, Hamilton JR, Walker-Smith JA, Watkins J, eds. Pediatric gastrointestinal disease. Philadelphia: BC Decker, 1991:976–991.