Alpha-1 antitrypsin deficiency (AATD) is a rare genetic condition characterized by liver and obstructive lung disease. AATD is considered one of the more common rare diseases, affecting 1 in every 3000 to 5000 people.1 AATD is listed alongside cystic fibrosis and Down syndrome as one of the 3 most common potentially lethal rare diseases among Caucasians.
Mutations in the SERPINA1 gene disrupt the normal production of the protein, alpha-1 antitrypsin (AAT), or more accurately named alpha-1 antiprotease. Normally, AAT is synthesized in the liver and released into the bloodstream. Once in the lungs, AAT forms a protective screen to protect the alveolar wall. It accounts for 95% of all the antiprotease activity in the alveoli of human lungs.1
The primary purpose of AAT is to inhibit the neutrophil elastase protease enzyme.1 This powerfully destructive protease enzyme is a part of the immune system’s response to frequently inhaled airborne foreign materials that become trapped in the lungs. Neutrophil elastase participates in the phagocytosis of these foreign substances, but it does not discriminate between healthy lung tissue and foreign pathogens. These neutrophils also release cytokines as part of the inflammatory process.1,2
In AATD, these mutations in the SERPINA1 gene either result in no AAT production at all OR production of an abnormally structured AAT protein which becomes trapped in the liver.2 This entrapment results in scarring and damage to the hepatocytes, contributing to the development of liver disease.
When the AAT is trapped in the liver, not enough is released into the bloodstream to protect the lungs from neutrophil elastase which begins to destroy the alveoli. This eventually manifests as an obstructive lung disease like emphysema, chronic obstructive pulmonary disease (COPD), or chronic bronchitis. AAT also demonstrates anti-inflammatory effects that are separate from its anti-neutrophil elastase role.3
The SERPINA1 gene, formerly known as Pi, is located on the long arm of chromosome 14 with variants for more than 100 alleles.1,3 The different alleles on the SERPINA1 gene are classified by the amount of functional serum alpha-1 antitrypsin protein they express. Researchers have recorded over 150 different mutations in the SERPINA1 gene.3 There are 24 different variants of the alpha1-antitrypsin protein discovered so far.1
Variants can be categorized into four groups: normal, deficient, null, and dysfunctional. The normal variant is the M allele with two M alleles presenting as the normal genotype without AATD. Deficient alleles which produce less than 35% of the normal level of AAT plasma protein include the most common type, the Z allele, and the S allele. Null alleles result in no detectable serum levels of the AAT protein. Individuals with the null-null genotype, while the least common of the genotypes, are at highest risk for severe lung disease associated with AATD. Dysfunctional allele variants produce a normal serum concentration of AAT protein, but the protein itself is not properly functional.4
Types of AATD
The M alleles are the most common, normal variant found 90% of the time in individuals who produce normal amounts of AAT resulting in serum levels of 20-53 µmol/L or 150-350 mg/dL. Patients who typically present with clinical symptoms of AATD usually have one or two of the abnormal alleles Z or S. These individuals are either homozygous ZZ or SS, or heterozygous MZ, MS, or SZ.1
The most common form of AATD is found in individuals with homozygous ZZ (also known as PiZ) alleles. These individuals produce extremely low amounts, about 10% to 15% of normal serum levels of AAT at around 3.4-7 µmol/L. They typically develop emphysema. Those with S allele mutations produce moderately low serum levels of AAT.3
More severe presentations of AATD are affiliated with genotypes PiSZ, PiNull, PiZ/Null. Patients with PiSZ produce serum levels of AAT around 75-120 mg/dL and are 20-50% more predisposed to develop emphysema.1 When a patient is found with the null gene for AAT, they do not produce any AAT at all. 100% of these individuals develop emphysema by the time they reach 30 years of age. Unlike other genotypes with AATD who present with both liver and lung disease, the interesting characteristic about those with the null gene is these individuals do not develop liver disease due to complete lack of production of AAT. No abnormally shaped AAT proteins are accumulating within or inflaming the liver cells.1
Carriers who have one normal M allele and one abnormal allele (Z, S, or Null) typically produce 35% of normal levels of AAT, which is enough to prevent alveolar destruction and development of AATD.1
Mode of Inheritance of AATD
AATD is classified as a rare autosomal codominant genetic condition. Codominant indicates 1 abnormal gene comes from each parent, who either have the disorder themselves or are each a carrier of 1 abnormal gene, but do not develop AATD. The likelihood of 2 carrier parents having a child with AATD is 25% with each pregnancy. There is a 50% risk that this child may also be a carrier like the parents. Of course, there is also a 25% chance that the child born to carrier parents may have normal alleles and not develop AATD.1 This is not a sex-linked mode of inheritance, so the risk of inheriting AATD is equal among men and women.3
- Anariba DEI. Etiology of alpha1-antitrypsin deficiency. Medscape. Accessed June 1, 2021.
- Kawabata K, Hagio T, Matsuoka S. The role of neutrophil elastase in acute lung injury. Eur J Pharmacol. 2002; 451(1):1-10. doi:10.1016/s0014-2999(02)02182-9
- Alpha-1 antitrypsin deficiency. National Organization for Rare Diseases (NORD). Accessed June 1, 2021.
- Meseeha M, Attia M. Alpha 1 antitrypsin deficiency. In: StatPearls. StatPearls Publishing; 2021. Accessed June 24, 2021.
Article reviewed by Michael Sapko, MD, on July 1, 2021.