Alpha 1-Antitrypsin Deficiency (AATD)

Definition

Alpha 1-Antitrypsin Deficiency (AATD) is an autosomal recessive, genetic disorder characterised by a reduction in the serum level of alpha-1 antitrypsin. In adults, AATD manifests primarily as pulmonary emphysema; in children, it can present as liver disease (orpha.net n.d.)

Alpha-1-antitrypsin (AAT) is a protease inhibitor, plasma protein, produced by the liver and circulated in the blood.  AAT protects tissues from the body's immune response to microbes and noxious agents.  AATD raises the risk of chronic obstructive pulmonary disease, liver disease, skin problems, and inflammation of the blood vessels (GARD n.d.).   AATD is the leading genetic cause of liver disease among children (Mitchell 2017).

Frequency

Alpha-1 antitrypsin deficiency occurs worldwide, but its prevalence varies by population. This disorder affects about 1 in 1,500 to 3,500 individuals with European ancestry. It is uncommon in people of Asian descent. Many individuals with alpha-1 antitrypsin deficiency are likely misdiagnosed, particularly people diagnosed chronic obstructive pulmonary disease (COPD). COPD can be caused by alpha-1 antitrypsin deficiency; however, the alpha-1 antitrypsin deficiency is often never diagnosed. Some people with alpha-1 antitrypsin deficiency are misdiagnosed with asthma (NLM 2021).

Etiology

Mutations in the SERPINA1 gene cause AATD . More than 100 variants in the SERPINA1 gene have been associated with AATD. These gene variations alter the structure of the AAT protein. Two of the more common gene variations occur at the Z allele and the S allele.

• The Z allele produces an AAT protein that has a conformation conducive to forming large polymers of the AAT protein.  The polymers become too large to be secreted by the hepatocyte. Accumulation of the AAT protein causes inflammation, fibrosis, cirrhosis, and increased risk of hepatocellular carcinoma (NLM 2021).  AAT associated liver disease is more prevalent in children but may be exacerbated in adults by external liver insults.
• The S allele produces an AAT protein that is quickly broken down in the liver. Still other gene variants prevent the production of any alpha-1 antitrypsin protein.  As a result, little or no alpha-1 antitrypsin is available in the lungs. While the liver remains healthy in individuals with S allele variants, the lungs are left unprotected from neutrophil elastase (NLM 2021).  "Neutrophil elastase is an powerful neutrophil protease that is critical for the host immune response to infection, but NE is also a major instigating factor for inflammation and airway injury in chronic inflammatory lung diseases" (Voynow 2021).

Treatment

Options include

• IV infusion of purified, pooled human plasma-derived AAT protein indicated for adults with emphysema due to severe hereditary alpha1-antitrypsin deficiency (AATD)
• Appropriate use of antibiotics to infection induced neutrophil elastase
• Appropriate vaccines e.g., SARS-CoV-2, viral hepatitis, influenza, etc
• Elimination of environmental risks, i.e., air pollutants, fungal spores and allergenic pollens
• Lung or liver transplants are reserved for end-stage disease resistant to conservative treatment. Liver transplantation replaces abnormal liver cells with donor tissue that produces normal AAT. Gene therapy is also being studied as a form of treatment.
  

References

Alpha-1 antitrypsin deficiency. (n.d.). Retrieved November 10, 2021, from https://www.orpha.net/data/patho/Pro/en/Emergency_Alpha1Antitrypsin-enPro194.pdf.

Mitchell, E. L., & Khan, Z. (2017). Liver Disease in Alpha-1 Antitrypsin Deficiency: Current Approaches and Future Directions. Current pathobiology reports, 5(3), 243–252. https://doi.org/10.1007/s40139-017-0147-5

U.S. National Library of Medicine (NLM). (2021). Serpina1 Gene: Medlineplus genetics. MedlinePlus. Retrieved November 10, 2021, from https://medlineplus.gov/genetics/gene/serpina1/#conditions.

U.S. Department of Health and Human Services. (n.d.). Alpha-1 antitrypsin deficiency. Genetic and Rare Diseases Information Center (GARD n.d.). Retrieved November 10, 2021, from https://rarediseases.info.nih.gov/diseases/5784/alpha-1-antitrypsin-deficiency.

Voynow, J.A.; Shinbashi, M. Neutrophil Elastase and Chronic Lung Disease. Biomolecules 2021, 11, 1065. https://doi.org/10.3390/ biom11081065