Alpha-1 antitrypsin deficiency

Board exam relevance: in 2 of 105 exam reports · rank 142

Synonyms: AATD, A1AT deficiency, alpha-1 deficiency, hereditary emphysema, AAT deficiency
Specialty: Internal medicine · Pulmonology
Images: CT 1 · Histology 2 · Gross specimen 1
Last updated: 10/2026 · Dr. Pascal Bafteh

Contents

Images (4)
Definition
Classification
Occurrence & epidemiology
Aetiopathogenesis
Clinical features
Diagnosis
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Further reading (open access)
Cross-references

Images (4)

Alpha-1 antitrypsin deficiency – CT (axial and coronal): panlobular emphysema with diffuse loss of lung parenchyma and attenuated vessels – the typical emphysema pattern in AAT deficiency — CT (axial and coronal): panlobular emphysema with diffuse loss of lung parenchyma and attenuated vessels – the typical emphysema pattern in AAT deficiencyImage: Hellerhoff (Wikimedia Commons) · CC BY-SA 4.0 · Source

Alpha-1 antitrypsin deficiency – Histology (H&E) in alpha-1 antitrypsin deficiency: panlobular emphysema with uniform destruction of alveolar walls throughout the lobule — Histology (H&E) in alpha-1 antitrypsin deficiency: panlobular emphysema with uniform destruction of alveolar walls throughout the lobuleImage: Yale Rosen from USA (Wikimedia Commons) · CC BY-SA 2.0 · Source

Alpha-1 antitrypsin deficiency – Gross specimen (lung slice): panlobular emphysema with diffuse, uniform rarefaction of lung tissue — Gross specimen (lung slice): panlobular emphysema with diffuse, uniform rarefaction of lung tissueImage: Yale Rosen from USA (Wikimedia Commons) · CC BY-SA 2.0 · Source

Alpha-1 antitrypsin deficiency – histology: Liver biopsy (PAS-diastase stain) in alpha-1 antitrypsin deficiency: diastase-resistant pink globules in hepatocytes — Liver biopsy (PAS-diastase stain) in alpha-1 antitrypsin deficiency: diastase-resistant pink globules in hepatocytesImage: Jerad M Gardner, MD (Wikimedia Commons) · CC BY-SA 3.0 · Source

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Definition

Alpha-1 antitrypsin deficiency is a hereditary deficiency of alpha-1 antitrypsin, the main antiprotease of the lung against neutrophil elastase. It leads to increased proteolytic tissue destruction with emphysema in adulthood; accumulation of misfolded molecules in the liver can cause liver disease in children and adults.

Classification

The alleles are expressed codominantly; more than 140 alleles have been described by Pi phenotype.

Phenotype	Serum level	Emphysema risk
Pi*MM	150–350 mg/dL	normal
Pi*MZ	90–210 mg/dL	minimally increased
Pi*SS	100–200 mg/dL	minimally increased
Pi*SZ	75–120 mg/dL	slightly increased
Pi*ZZ	20–45 mg/dL	high

Over 95 % of people with severe deficiency and emphysema are homozygous for the Z allele (Pi*ZZ). Null alleles (Pi*Z-null, Pi*null-null) result in undetectable serum levels.

Occurrence & epidemiology

The prevalence of the Pi*ZZ genotype in the general population is 1/2,000 to 1/10,000. Mainly people of northern European descent are affected; the Z allele is rare in people of Asian and African descent. About 1–2 % of all COPD cases are attributed to alpha-1 antitrypsin deficiency.

Aetiopathogenesis

Alpha-1 antitrypsin is produced mainly in hepatocytes and monocytes and reaches the lung via the blood, where it neutralizes neutrophil elastase.

Lung: the deficiency increases neutrophil elastase activity and leads to emphysema, especially in smokers, because cigarette smoke further increases protease activity.
Liver: certain variants change the conformation of the molecule, which polymerizes and is retained in hepatocytes. This accumulation causes neonatal cholestatic jaundice in 10–15 % of those affected and increases the risk of cirrhosis and hepatocellular carcinoma.
Other associations: panniculitis, ANCA-positive vasculitis, ulcerative colitis, aneurysms, glomerular diseases.

Clinical features

Lung: early emphysema with COPD symptoms (breathlessness, cough, wheeze, prolonged expiration); earlier in smokers than in non-smokers, but rare before the age of 25. Severity varies widely with phenotype, smoking status and other factors. Some patients have bronchiectasis.
Liver: in newborns cholestatic jaundice and hepatomegaly in the first week of life, usually resolving after 2–4 months; in about 20 % the neonatal liver involvement leads to cirrhosis in childhood. About 10 % of patients without childhood liver disease develop cirrhosis in adulthood.
Skin: panniculitis with indurated, soft, depigmented plaques or nodules, typically on the lower abdomen, buttocks and thighs.

Diagnosis

Suspicion arises in:

smokers with emphysema before the age of 45
non-smokers without occupational exposure with emphysema at any age
a positive family history of emphysema, unexplained cirrhosis or alpha-1 antitrypsin deficiency
panniculitis, unexplained bronchiectasis or liver disease
newborns with jaundice or raised liver enzymes

Laboratory tests: a serum level below 80 mg/dL (below 15 µmol/L, radial immunodiffusion) or below 50 mg/dL (below 9 µmol/L, nephelometry) supports the diagnosis; it is confirmed by genotyping or phenotyping. With rare variants, normal levels of a dysfunctional protein may be present.

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