Alpha-1 Antitrypsin Deficiency



  • α1-antitrypsin (AAT) deficiency is an autosomal codominant genetic disorder that causes lung, liver, and skin disease.
  • Lung disease in AAT deficiency can develop after the 3rd decade of life and progress to emphysema.
  • Liver disease may present as jaundice in infants or as elevated liver enzymes, portal hypertension, or cirrhosis in older patients.
  • Skin disease is more rare and presents as necrotizing panniculitis in adults (mean age of onset is 40 years).
  • AAT deficiency is caused by a deficiency of AAT, which is a serine protease inhibitor (Pi), comprised of a 55-kDa glycoprotein that is primarily synthesized in the liver and released into the circulation.
  • AAT is the main inhibitor of neutrophil proteases.
  • Classic PiZZ AAT deficiency is caused by homozygosity for Z mutant allele of AAT.


Most common genetic cause of liver disease in children and of emphysema in adults


  • Incidence of the PiZZ genotype is highest in Caucasians in North America, Australia, and Europe, particularly in Scandinavia, British Isles, Northern France, and the Tyrol region of Italy.
  • In the United States, the PiZ allele is found in ~14.5 per 1,000 people, with higher frequency in Caucasians and lower frequency in Asians, blacks, and Hispanics.
  • The incidence of classic AAT deficiency (PiZZ) is 1 in 1,800 to 2,000 live births.


  • It has been estimated that approximately 70,000 to 100,000 individuals are affected in the United States.
  • Of these genetically affected individuals, fewer than 10% are estimated to have been diagnosed with AAT deficiency.
  • Approximately 25 million people in the United States are thought to be carriers of a mutant allele.

Risk Factors


  • AAT is a serine Pi encoded by the SERPINA1 gene, which is located on the long arm of chromosome 14.
  • The normal allele is M, with >100 variant alleles identified.
  • The classic PiZZ genotype is the result of a point mutation at position 342 in the AAT gene, which encodes a substitution of lysine for glutamate.
  • The S allele (second most common mutation) occurs from a substitution of valine for glutamate at position 246.
  • Patients with PiZZ alleles have serum AAT levels, which are < 15% of normal.
  • Heterozygous carriers of the Z allele are found in 1.5–3% of the population. In and of itself, this genetic mutation is not a cause of liver disease, but it may contribute to pathophysiology of other liver diseases.
  • PiMS, PiMZ, and PiSS are also not directly associated with liver disease, although referral center data reports patients with chronic liver disease having a higher frequency of PiMZ than would be predicted by chance.
  • The mutant S protein, when coexpressed with Z-protein, can form abnormal polymers leading to liver disease, which is identical to PiZZ patients.
  • Because ~10% of affected PiZZ or PiSZ individuals have clinically significant liver disease, there may be other genetic or environmental factors that are important modifiers of AAT.


  • Lung disease in patients with PiZZ results from inadequate levels of AAT to protect the lungs from destructive enzymes, such as elastase, leading to early emphysema.
    • This process is further worsened by exposure to cigarette smoke and environmental pollutants.
  • Liver disease occurs from accumulation of the abnormal Z mutant protein within liver cells.
    • The mutant Z gene is transcribed, translated, and then translocated into the endoplasmic reticulum (ER).
    • Some molecules undergo proteolytic degradation, others aggregate to form large protein polymers, and few are secreted, leading to intrahepatocyte accumulation and thereby resulting in low AAT serum levels.
    • ER-associated degradation of mutant Z-protein is less efficient, leading to a great burden of protein in the liver and increased liver injury.
    • Autophagy degradation has also been proposed as an important route for degradation of the AAT mutant Z polymers.
  • Panniculitis involves inflammation of the fat underneath the skin, causing hardening in lumps and patches, likely due to the unrestrained, destructive action of neutrophil elastase.


Mutations in the SERPINA1 gene result in lung disease through unopposed protease activity and in liver disease by intracellular retention of mutant AAT.

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