Alpha-1 Antitrypsin Deficiency

It is an autosomal recessive disease characterized by liver dysfunction and chronic obstructive pulmonary disease. Its severity depends on which pathogenic variants in the SERPINA1 gene are involved and how much alpha-1 antitrypsin activity is reduced.

Alpha-1 antitrypsin deficiency (AATD) is an autosomal recessive genetic disorder caused by mutations in the SERPINA1 gene, which result in decreased serum alpha-1 antitrypsin protease inhibitory activity and predispose affected patients to the development of pulmonary emphysema and liver cirrhosis. It is one of the most common autosomal recessive genetic disorders in Northern Europe and affects approximately 1:2000 to 1:5000 individuals.

Symptoms

The severity of the symptoms will depend on the pathogenic variant causing the disease and the consequences they have on the levels and activity of alpha-1 antitrypsin. Symptoms mainly occur at the pulmonary and hepatic level:

There is an increased risk of pulmonary emphysema and of patients developing chronic obstructive pulmonary disease or COPD. It is estimated that 1 in 850 cases of COPD in Europe are due to AATD.
Liver dysfunction that may appear in newborns in the form of neonatal cholestasis (decreased bile formation and/or excretion) or with the course of the disease.

Another less frequent symptom is panniculitis or cutaneous, inflammatory and tender nodules that may ulcerate on the legs and lower abdomen.

Disease management

AATD has no cure, but there are some measures that can help reduce the risk of pulmonary emphysema, such as:

Quitting smoking and avoiding exposure to tobacco smoke.
Reducing exposure to air pollutants or irritants.
Wear protective equipment at work if you are exposed to irritants or toxins.
It is important to follow healthy lifestyle habits. A balanced diet, adequate weight and physical activity adapted to the patient's level of fatigue should be maintained.

The only specific treatment available for AATD-associated lung disease is periodic, lifelong intravenous administration of alpha-1 antitrypsin obtained from blood donors, called augmentation therapy. Patients with COPD may also be treated with bronchodilator medications and inhaled steroids. It is essential to control lung infections to preserve lung integrity.

In some more severe cases, liver or lung transplantation may become necessary.

Genes analyzed

SERPINA1

Bibliography

Craig TJ, Henao MP. Advances in managing COPD related to α1 -antitrypsin deficiency: An under-recognized genetic disorder. Allergy. 2018 Nov;73(11):2110-2121. doi: 10.1111/all.13558.

Greulich T, Albert A, Cassel W, et al . Opinions and Attitudes of Pulmonologists About Augmentation Therapy in Patients with Alpha-1 Antitrypsin Deficiency. A Survey of the EARCO Group. Int J Chron Obstruct Pulmon Dis. 2022 Jan 5;17:53-64.

Ferrarotti I, Carroll TP, Ottaviani S, et al . Identification and characterisation of eight novel SERPINA1 Null mutations. Orphanet J Rare Dis. 2014 Nov 26;9:172.

Jardim JR, Casas-Maldonado F, Fernandes FLA, et al . Update on and future perspectives for the diagnosis of alpha-1 antitrypsin deficiency in Brazil. J Bras Pneumol. 2021 May 31;47(3):e20200380.

Ortega VE, Li X, O'Neal WK, et al . The Effects of Rare SERPINA1 Variants on Lung Function and Emphysema in SPIROMICS. Am J Respir Crit Care Med. 2020 Mar 1;201(5):540-554.

Stoller JK, Hupertz V, Aboussouan LS. Alpha-1 Antitrypsin Deficiency. 2006 Oct 27 [updated 2020 May 21]. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022.