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About alpha1-antitrypsin (AAT) deficiency

AAT deficiency, sometimes known simply as “alpha-1”, is a genetic disease primarily affecting the lungs and liver. It is characterised by a decrease in circulating levels of a protein called alpha1 antitrypsin.1 

AAT deficiency is the major known genetic risk factor for chronic obstructive pulmonary disease (COPD), particularly emphysema with basilar predominance.2 COPD is characterised by respiratory symptoms that are persistent with a limitation of airflow due to airway or alveoli dysfunction.3

Respiratory symptoms of AAT deficiency are often indistinguishable from smoking-induced COPD or asthma, chronic bronchitis and emphysema (usually in combination), including:4,5

 

  • Wheezing
  • Cough
  • Excess sputum production
  • Severe dyspnoea on exertion

Risks associated with AAT deficiency:

  • Chronic obstructive pulmonary disease (COPD)1,6
  • Reduced life expectancy1,6
  • Cirrhosis in infants, children and adults with specific genetic variants1,6
  • Necrotising panniculitis, a rare skin disease1,6
  • Wegener's disease (vasculitis)1,6
 

There are no clinical characteristics that rule out the diagnosis of AAT deficiency, nor predictive clinical, demographic or age-related characteristics that  predict a diagnosis of AAT deficiency.7 Because AAT deficiency cannot be diagnosed on clinical presentation alone, it is underdiagnosed and should be confirmed with laboratory testing.6,8-10

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The longer AAT deficiency remains undiagnosed, the greater the risk of irreparable lung damage10,11

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What is alpha1 antitrypsin (AAT)?

La AAT (la proteína) es un inhibidor de la proteasa (IP), una enzima, que se produce principalmente en el hígado. La AAT se secreta al torrente sanguíneo y puede encontrarse en una alta concentración en los pulmones (Figura 1).12 En los casos de episodios de inflamación, infección, cáncer o durante el embarazo, aumenta la producción de AAT, por lo que se conoce como un reactante de fase aguda.13

Why is AAT critical to protect the lungs?

La función más importante de la alfa-1 antitripsina es la inactivación de las proteasas en los pulmones (Figura 2). Dichas enzimas se liberan durante una respuesta inmunológica, algo frecuente, puesto que el pulmón está continuamente expuesto a patógenos de transmisión aérea. Aunque estas proteasas son clave para destruir patógenos, si no se controlan pueden llegar a destruir el tejido pulmonar.12

Cuando hay un déficit de AAT (Figura 3), se produce un exceso de estas proteasas, en concreto la elastasa de neutrófilo, y los componentes de la matriz pulmonar, las estructuras alveolares y los vasos sanguíneos se destruyen paulatinamente. Esto se manifiesta en forma de bronquitis obstructiva crónica o enfisema.12  

AAT is critical to protect the lungs12

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What causes liver disease in AAT deficiency?

Certain genetic variants are also associated with liver disease. For example, the PiZ variant is thought to cause the AAT protein to form large polymers that accumulate in the liver cells, causing cellular injury and cell death.12

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AAT DEFICIENCY IS UNDERDIAGNOSED

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AAT: alfa1 antitripsina; COPD: chronic obstructive pulmary disease.

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References

  1. Stoller JK, Lacbawan FL, Aboussouan LS. Alpha-1 antitrypsin deficiency. In: Pagon RA, Adam MP, Ardinger HH, et al. editors. GeneReviews(R). Seattle (WA)2006 (updated 2014).
  2. World Health Organization. Alpha 1-antitrypsin deficiency: memorandum from a WHO meeting. Bull World Health Organ. 1997;75(5):397-415.
  3. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. 2020 [Updated]. Available at: http://goldcopd.org/gold-2017-global-strategy-diagnosis-management-prevention-copd/.
  4. Rachelefsky G, Hogarth DK. Issues in the diagnosis of alpha 1-antitrypsin deficiency. J Allergy Clin Immunol. 2008;121(4):833-8.
  5. Strange C, Stoller JK, Sandhaus RA, et al. Results of a survey of patients with alpha-1 antitrypsin deficiency. Respiration. 2006;73(2):185-90.
  6. ATS, ERS. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003;168(7):818-900.
  7. Sandhaus RA, Turino G, Brantly ML, et al. The diagnosis and management of alpha-1 antitrypsin deficiency in the adult (Clinical Practice Guidelines). Chronic Obstr Pulm Dis (Miami). 2016;3(3):668-82.
  8. Stockley JA, Ismail AM, Hughes SM, et al. Maximal mid-expiratory flow detects early lung disease in a1-antitrypsin deficiency. Eur Respir J. 2017;49(3).
  9. Miravitlles M, Dirksen A, Ferrarotti I, et al. European Respiratory Society statement: diagnosis and treatment of pulmonary disease in α1-antitrypsin deficiency. European Respiratory Journal. 2017;50(5).
  10. Campos MA, Wanner A, Zhang G, et al. Trends in the diagnosis of symptomatic patients with alpha1-antitrypsin deficiency between 1968 and 2003. Chest. 2005;128(3):1179-86.
  11. Vidal R, Blanco I, Casas F, et al. Guidelines for the diagnosis and management of alpha1-antitrypsin deficiency. Arch Bronconeumol. 2006;42(12):645-59.
  12. Köhnlein T, Welte T. Alpha-1 antitrypsin deficiency: pathogenesis, clinical presentation, diagnosis, and treatment. Am J Med. 2008;121(1):3-9.