Alpha 1-antitrypsin deficiency natural history, complications, and prognosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mazia Fatima, MBBS [2]

If left untreated, not all patients with deficient gene develop symptomatic emphysema or cirrhosis. In symptomatic patients, the median time between observation of symptoms and diagnosis is approximately 8 years. The symptoms of alpha1-antitrypsin deficiency (AATD) in the first two decades of life are mainly of associated liver disease progressing to pulmonary manifestations appear later in life. Emphysema is seen in non-smokers in the fifth decade of life and during the fourth decade of life in smokers. Less common associations are panniculitis and cytoplasmic antineutrophil cytoplasmic antibody‒positive vasculitis. The most common cause of death is emphysema. Chronic liver disease is the second most common cause of death. Common complications of AATD include pneumothorax, pneumonia, acute exacerbation of airflow obstruction, respiratory failure. Prognosis depends on how patients are identified. Patients identified as a result of screening often have excellent prognosis. Those identified because of their symptoms have poor prognosis.

• If left untreated, not all patients with deficient gene develop symptomatic emphysema or cirrhosis.
• In symptomatic patients, the median time between observation of symptoms and diagnosis is approximately 8 years.^[1][2][3]
• The symptoms of alpha1-antitrypsin deficiency (AATD) in the first two decades of life are mainly of associated liver disease progressing to pulmonary manifestations appear later in life.
• Emphysema, is seen in nonsmokers in the fifth decade of life and during the fourth decade of life in smokers.
• Less common associations are panniculitis and cytoplasmic antineutrophil cytoplasmic antibody‒positive vasculitis.
• FEV1 decreases in patients with PiZZ genotype at 51-317 mL per year compared to an estimated decline in healthy individuals at 30 mL/y.
• AATD can be seen in neonates as a cause of neonatal jaundice and hepatitis.
• It may present in infants as cholestatic jaundice and in children as liver cirrhosis or hepatic failure.
• AATD is the leading condition requiring liver transplantation in children.
• PiZZ patients have a 16% likelihood of surviving to age 60 years compared to an 85% likelihood for the general US population.
• The most common cause of death is emphysema. Chronic liver disease is the second most common cause of death.
• Respiratory failure accounts for about 62% of deaths, and complications of chronic liver disease for approximately 13%.
• The mean age of death is 50 years old for nonsmokers and 40 years old for smokers, with only 16% surviving to 60 years old compared to about 85% surviving to 65 years old in the general population.
• Mortality is directly related to FEV1 (forced expiratory volume), and rises exponentially as FEV1 falls below 35% predicted.

Common complications of AATD include:^[3]

• Pneumothorax
• Pneumonia
• Acute exacerbation of airflow obstruction
• Respiratory failure
• Bronchiectasis
• Cirrhosis or liver failure
• Emphysema
• Liver cancer

Prognosis depends on how patients are identified. Patients identified as a result of screening often have excellent prognosis. Those identified because of their symptoms have poor prognosis.^[1][2][3]

Features associated with poor prognosis include:

• Severe degree of airflow obstruction:
  • FEV1 >50% has a  5-year mortality rate at 4%
  • FEV1  within range 35-49% has  5-year mortality rate at 12%
  • FEV1 <35 has a 5-year mortality rate at 50%
• A bronchodilator response greater than >12%
• Smoking
• Male sex

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