Alpha-1-Antitrypsin (AAT) deficiency is frequently under recognized or misdiagnosed by clinicians.  AAT deficiency is the most common genetic cause of liver disease in children and the second most common hereditary disease in Caucasians after Cystic Fibrosis.  It is one of the most common fatal genetic disordes in people of European decent and has an estimated prevalence of 1 in 1600 newborns. 


AAT deficiency is an inherited condition caused by a defective gene on chromosome 14.  Over 70 different variants of AAT have been identified and the normal is labeled M.  The two most important abnormal variants are called S and Z.  Both result from mutations of the Alpha-1-Antitrypsin gene.  Individuals may have two normal genes, (PiMM), two abnormal genes (PiSS, PiZZ or PiSZ) or one of each (PiMS or PiMZ).  AAT genes are co-dominant, so each gene of a pair contributes 50% of the alpha-1-antitrypsin produced. The PiZ gene makes only about 10% of the Alpha-1-Antitrypsin produced by the normal PiM gene while the PiS produces 30-35%. PiZZ people have only 15-20% of normal blood Alpha-1-Antitrypsin levels and can suffer severe liver and lung disease.  PiMZ people have Alpha-1-Antitrypsin levels round 60% (PiM 50% PiZ 10%) of normal levels, which is usually enough to prevent disease.  People with two PiS genes (PiSS) are less severely affected with Alpha-1-Antitrypsin levels 60-70% of normal.  This can cause lung complications but usually not liver disease. Lack of Alpha-1-Antitrypsin causes progressive lung damage, especially when combined with other factors like smoking, usually leading to panacinar emphysema. Occasionally bronchiectasis may develop. In PiZZ people, defective Alpha-1-Antitrypsin molecules clump together in liver cells producing toxic effects. AAT is one of the most common genetic causes of liver disease in infants.  First signs are jaundice, pale stools and an enlarged liver – “neonatal hepatitis syndrome”, which usually begins between four days and six weeks after birth. Adult liver disease has symptoms similar to those in children, nl. cirrhoses, jaundice, abdominal swelling, bleeding into the gut and ultimately coma.

Disease in Carriers:

Reduced Alpha-1-Antitrypsin may worsen or increase susceptibility to liver disease due to other causes e.g. infection or alcohol.

Patient with symptoms of AAT-deficiency can be tested to confirm the diagnosis.  After counseling, family screening can be offered to identify relatives at risk.  Prenatal diagnosis is possible, but may not predict the future