Alpha-1 Antitrypsin (AAT) Deficiency

Alpha-1 antitrypsin deficiency is a genetic disorder caused by inherited genetic mutations of the SERPINA1 gene, causing the defective production of the protease inhibitor alpha-1 antitrypsin (AAT). These mutations can lead to deficiency of the enzyme causing lung disease, production of an abnormal form of the enzyme leading to liver dysfunction, or both. Patients commonly present with emphysema, spontaneous pneumothorax, cirrhosis, hepatitis, or hepatocellular carcinoma. There is no known cure. Management is supportive and includes infusion of AAT, treatment of comorbidities, and liver transplantation. Prognosis may vary based on the form of disease contracted and the severity of symptoms.

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  • Single-chain glycoprotein produced by hepatocytes, phagocytes, and lung epithelial cells
    • Chain of 394 amino acids that demonstrate various glycoforms
    • Mass of 52 kDa
  • Belongs to a superfamily of proteases called serpins:
    • SERine Protease INhibitor
    • A group of proteins with similar structures
    • Irreversibly inactivate chymotrypsin-like proteases: cause a conformational change in structure of the protease → inhibit binding of active site to ligand

Protective functions

  • Alpha-1 antitrypsin inhibits action of many serine proteases.
    • Neutrophil elastase
    • Cathepsin G
    • Proteinase 3
  • These proteases are usually produced by neutrophils during inflammatory processes.
  • Absence of AAT is known to have deleterious effects on the liver and lungs, as well as on small to medium-sized blood vessels.


  • Rare disease, but thought to be severely underrecognized
  • Approximately 1 in 1600–2000 live births 
  • Most common genetic causative factor for juvenile liver problems
  • Highest incidence among Caucasians of European descent
  • Lowest incidence in Asian populations


  • Only known etiology is inherited genetic mutation of the SERPINA1 gene.
    • Gene found on chromosome 14 and is pleomorphic 
    • ≥ 150 known alleles 
  • Autosomal codominant inheritance:
    • A mutated allele must be inherited from each parent for pathologic phenotype to be expressed:
      • M allele is normal.
      • S allele causes moderately decreased production of protein.
      • Z allele causes dramatically decreased production of protein.
      • MM and MS individuals → normal
      • MZ individuals → increased risk for lung disease
      • ZZ individuals → accumulation of nonfunctional protein in liver and high rates of lung disease
      • Homozygous for null mutations → no detectable plasma AAT, lung disease but no liver disease


Liver disease:

  • Single amino acid mutation replacement (e.g., E342K) results in abnormal folding of protein:
    • Resulting abnormality in structure leads to impairment in the mobility of protein out from the secretory cell (e.g., hepatocytes).
    • Lead to liver inflammation damage as accumulated protein polymerizes and aggregates
    • Toxicity to liver (resulting in inflammation) predisposes to liver cancer.
  • Environmental factors play a key role in the development of the disease
  • Single nucleotide polymorphisms in downstream flanking region of the endoplasmic reticulum; mannosidase I can affect the degree of AAT deficiency and liver damage.

Lung disease: 

  • In healthy individuals:
    • Neutrophils use elastase to degrade mucus and bacteria.
    • Excess elastase activity degrades lung tissue, making it less compliant.
    • Alpha-1 antitrypsin blocks elastase activity.
  • Patients affected by AAT: 
    • No balancing of elastase activity
    • Cigarette smoking and lung infection increase elastase burden in pulmonary tissue: loss of lung compliance, leading to emphysema

Clinical Presentation


  • Disease diagnosed early in childhood and manifests as early as 2 months of age 
  • Neonatal symptoms:
    • Impaired vitamin K synthesis causing bleeding at:
      • Umbilical stump
      • GI tract
      • Intracranial space
      • Unexplained bruising
    • Neonatal hepatitis with cholestatic jaundice
  • Childhood/teenage symptoms:
    • Hepatomegaly
    • Splenomegaly
    • Ascites
    • Bleeding esophageal varices
    • Scleral icterus
  • Manifestations associated with cirrhosis in adults: hepatocellular carcinoma


  • Onset of lung manifestation begins in the 3rd or 4th decade of life.
  • Common symptoms 
    • Coughing 
    • Difficulty breathing
    • Chronic sputum production
    • Wheezing
  • External factors such as occupational exposure to irritants and smoking accelerate progression of disease.

Other inflammatory disease manifestations

  • Necrotizing panniculitis
  • Wegner’s granulomatosis
  • Membranoproliferative glomerulonephritis
  • IgA nephropathy
  • Other vasculitis syndromes


  • Alpha-1 antitrypsin deficiency should be suspected in patients with history of:
    • Chronic liver disease, especially at young age 
    • Emphysema at age < 45 years
    • Emphysema in a nonsmoker
    • Family history of emphysema or liver disease and panniculitis
  • Diagnosis of AAT deficiency can be confirmed by:
    • Measuring serum levels of AAT:
      • Patients with < 20 µmol/L (100 mg/dL) serum levels should be evaluated further.
      • Alpha-1 antitrypsin is elevated in inflammatory processes.
      • Elevated serum measurement should not be used as the sole basis for the exclusion of AAT deficiency
    • Targeted genetic testing:
      • PCR testing to determine what alleles are present
      • Isoelectric focusing gel electrophoresis to determine what protein variants are present
  • Chest X-ray:
    • Nondiagnostic but has characteristic pattern
    • Basilar dominant emphysematous bullae
  • Liver biopsy: 
    • Can help determine extent of liver damage and presence of hepatocellular carcinoma
    • Presence of PAS-positive and diastase-resistant inclusions is diagnostic of the disease

Management, Prognosis, and Complications


  • Supportive treatment is indicated in milder forms or early stages of disease.
    • Oxidative stress to hepatocytes and bile stasis can be prevented by administering vitamin E and ursodeoxycholic acid, respectively.
    • Health education, smoking cessation
    • Vaccination against influenza, pneumococcus, and hepatitis A and B indicated to reduce progression of disease
  • Pulmonary form only: replacement therapy with plasma containing AAT usually indicated
  • Severe forms:
    • Liver transplantation
    • Lung transplantation

Prognosis and complications

  • Liver involvement in AAT deficiency progresses slowly but can be accelerated in the presence of comorbidities and infections.
  • Manifestations develop into severe forms, much like those seen in other chronic liver diseases.
  • Complications include:
    • Severe bleeding, especially among newborns
    • Malnutrition
    • Malabsorption caused by cholestasis
  • Patients with AAT deficiency may continue to live without any liver-related complications.
  • In advanced cases, liver transplantations have demonstrated favorable results.

Differential Diagnosis

  • Bronchiectasis: chronic condition in which there is bronchial dilation and destruction as a result of inflammation and infection. Symptoms of bronchiectasis include dyspnea, chronic cough, and purulent sputum. The diagnosis is with imaging, including X-ray and CT. Management includes bronchodilators and antibiotics for acute exacerbations
  • Chronic obstructive pulmonary disease (COPD): lung disease characterized by progressive, largely irreversible airflow obstruction. Symptoms of COPD include progressive dyspnea and chronic cough. Prolonged expiration, wheezing, or diminished breath sounds may be noted on exam. The diagnosis is confirmed with pulmonary function testing. Management includes smoking cessation, pulmonary rehabilitation, and pharmacotherapy.
  • Autoimmune hepatitis: liver inflammation that occurs when the body’s immune system turns against liver cells. Clinical presentation ranges from asymptomatic to symptoms of acute liver failure. Diagnosed by testing for serum anti–smooth muscle antibodies and liver biopsy. Treatment is with corticosteroids and azathioprine. With early treatment, the prognosis is favorable. If left untreated, half of patients die in the 1st few years.
  • Viral hepatitis: infection from a virus causing acute liver disease. Viral hepatitis presents with jaundice, fever with hepatomegaly, and the transaminase elevation is often > 500. Further differentiation can be established by detecting viral antigens and antibodies in the serum. Treatment is based on cause, and for certain types, can be prevented by vaccination.


  1. Stoller JK, Aboussouan LS. (2012). A review of α1-antitrypsin deficiency. Am J Respir Crit Care Med. 
  2. Miravitlles M, Dirksen A, Ferrarotti I, et al. (2017). European Respiratory Society statement: diagnosis and treatment of pulmonary disease in α1-antitrypsin deficiency. Eur Respir J. 
  3. Strnad P, McElvaney NG, Lomas DA. (2020). Alpha1-antitrypsin deficiency. N Engl J Med. 
  4. Adapted from Hawkey CJ, Bosch J, Richter JE, Tsao GG, Chan FKL (Eds.). (2012). Textbook of Clinical Gastroenterology and Hepatology, 2nd ed. Wiley-Blackwell.

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