Alpha-1 antitrypsin deficiency

Alpha-1 antitrypsin deficiency (AATD) is a genetic condition in which low levels of the alpha-1 antitrypsin (A1AT) protein predispose affected individuals to hepatic dysfunction and early-onset lung disease.

AATD can present at any age and should be considered in individuals with:

• hepatic dysfunction:
  • neonatal cholestasis with raised liver enzymes; or
  • progressive fibrosis and cirrhosis in adulthood (more common in men);
• lung disease:
  • emphysema (in individuals above 30 years old);
  • bronchiectasis;
  • childhood-onset lung disease (though this is extremely rare); or
  • individuals who smoke or who are exposed to occupational dust; or
• panniculitis (though this is uncommon).

AATD is caused by pathogenic variants in the SERPINA1 gene. SERPINA1 encodes A1AT, a protease inhibitor that protects the lungs from the elastase released by neutrophils.

AATD is inherited in an autosomal codominant manner with three common SERPINA1 alleles:

• M: the most common allele, which produces normal levels of A1AT;
• S: produces moderately low levels of A1AT; and
• Z: produces very little A1AT.

The most common genotypes are MM (present in 90% of North Europeans), MS, MZ, SS, SZ and ZZ, with MM being unaffected and ZZ being the most severe.

Heterozygosity for the Z-allele may be relevant for patients without an identified cause of liver disease, highlighting the potential value of SERPINA1 genotyping in individuals with cryptogenic cirrhosis.

The age of onset and symptoms are highly variable and are dependent on the genotype. The genotype-to-phenotype correlation of AATD is shown below.

• MM: Associated with a normal serum concentration of A1AT and no increased risk of liver or lung disease.
• MS: Not usually associated with an increased risk of disease. May be associated with an offspring risk, depending on the partner’s genotype.
• MZ: Serum A1AT levels are usually lower but sufficient. Not usually associated with an increased risk of disease. May be associated with an offspring risk, depending on the partner’s genotype.
• SS: Not usually associated with an increased risk of disease. May be associated with an offspring risk, depending on the partner’s genotype.
• SZ: Serum A1AT levels are usually below the protective threshold value, which means that these individuals are at 60% increased risk of developing early onset chronic obstructive pulmonary disease and an increased risk of liver disease.
• ZZ: Individuals with this genotype have serum A1AT levels that are approximately 10%–20% of the normal level and are at high risk of developing both lung and liver disease. This genotype is present in 95% of individuals with clinical manifestations of AATD.

Individuals with suspected alpha-1 antitrypsin deficiency have their diagnosis confirmed by a combination of:

• Phenotyping: iso-electric focussing (IEF) based gel electrophoresis (performed in a specialized laboratory following clinician request); and
• Genotyping: sequencing of the SERPINA1 gene (see R191 Alpha-1-antitrypsin deficiency in the National Genomic Test Directory).
• For information about testing, including genomic testing, for AATD:
  • where testing in primary care see Presentation: Patient with abnormal liver screen (suspected alpha-1 antitrypsin deficiency); or
  • where testing in secondary care see Presentation: Patient with alpha-1-antitrypsin deficiency.

AATD is inherited in an autosomal codominant manner, which means that both alleles contribute to the phenotype, with different variants contributing different amounts of A1AT protein (see the Genomics section, above).

It is important to note that 10% of the European population are carriers for the S or Z variant. The parents of most affected individuals are carriers for the condition and therefore have a 25% chance of having another affected child.

Management of individuals with AATD depends on the clinical manifestations that present (such as emphysema or liver cirrhosis). Individuals may require referral to specialist services (such as respiratory and/or hepatology), depending on the severity of their manifestations.

All patients should be strongly advised to avoid smoking, which greatly accelerates lung disease and significantly reduces life expectancy.

Patients should also be advised against excessive alcohol consumption, which can not only accelerate liver disease but also has been associated with the exacerbation of chronic obstructive pulmonary disease in individuals with AATD.

For clinicians

• GeneReviews: Alpha-1 antitrypsin deficiency
• MedlinePlus: Alpha-1 antitrypsin deficiency
• NHS England: National Genomic Test Directory
• North Bristol NHS Trust: Alpha-1 antitrypsin fact sheet for primary care (PDF, three pages)

References:

• Chen VL, Burkholder DA, Moran IJ and others. ‘Hepatic decompensation is accelerated in patients with cirrhosis and alpha-1 antitrypsin Pi*MZ genotype‘ JHEP Reports 2022: volume 4, issue 6, article number 100483. DOI: 10.1016/j.jhepr.2022.100483
• Fromme M, Schneider CV, Guldiken N and others. ‘Alcohol consumption and liver phenotype of individuals with alpha-1 antitrypsin deficiency‘. Liver International 2024: volume 44, issue 10, pages 2,660–2,671. DOI: 10.1111/liv.16044
• McElvaney GN, Sandhaus RA, Miravitlles M and others. ‘Clinical considerations in individuals with α₁-antitrypsin PI*SZ genotype‘. European Respiratory Journal 2020: volume 55, issue 6, article number 1902410. DOI: 10.1183/13993003.02410-2019
• Sandford AJ, Weir TD, Spinelli JJ and Paré P. ‘Z and S mutations of the α₁-antitrypsin gene and the risk of chronic obstructive pulmonary disease‘. American Journal of Respiratory Cell and Molecular Biology 1999: volume 20, issue 2, pages 287–291. DOI: 10.1165/ajrcmb.20.2.3177

For patients

• Alpha-1 Foundation
• Asthma and Lung UK: Alpha-1-antitrypsin deficiency