Clinical Features

  • Alpha-1 antitrypsin (A1AT) is produced by the liver and protects lung airways (and other tissues) from the proteolytic enzyme elastase. Autosomal recessive genetic deficiency of A1AT (due to decreased level or function) can lead to early onset COPD/emphysema, liver disease, and less commonly skin disease (panniculitis)
    • During the first 20-30 years of life some patients with severe A1AT deficiency may present with liver disease (i.e. chronic elevation of liver enzymes or cirrhosis), beyond 20-30 years old most patients begin to develop COPD with accelerated lung function decline (especially with cigarette smoking and occupational exposures)
    • May be associated with bronchiectasis
    • Unclear relationship with asthma - there is an increased prevalence in asthmatics and in a large study of A1AT patients 21% met diagnostic criteria for asthma
  • Severely underdiagnosed, as 2-3% of Caucasians are carriers of severe allele;
    • The average age of diagnosis is 45.5+/-9.5 yo, with 30% of patients diagnosed >50 yo

A1AT screening recommendations.png
  • When to Consider Screening of Patients with Asthma (Hogarth)
    • Strong family history of emphysema, death from a respiratory disease, or cirrhosis
    • Asthma without evidence of atopy (negative skin and/or blood test result)
    • Asthma that has features of chronic bronchitis or emphysema by subjective or objective measurements
    • Asthma that does not improve with usual therapy, or “brittle” asthma
    • Steroid-dependent asthma or asthma that is unresponsive to steroids


Diagnosis

  • Diagnosis confirmed by both:
    1. Plasma A1AT level <50-80 mg/dL (11 μmol/L)
      • If >80 mg/dL it is unlikely that the patient has clinically important deficiency. Level <11 μmol/L is insufficient to protect lung. Depending on the lab, levels of 50-80 mg/dL correlate with 11 μmol/L.
      • A1AT is an acute phase reactant and may be elevated during acute illness
    2. A1AT genotype (usually by PCR or melting point analysis)
      • Rarely (<4% of the time), level is low but the genotype is normal, therefore protein phenotype analysis is performed by isoelectric focusing electrophoresis to identify alleles with abnormal protein migration pattern

Genotype
Risk for emphysema
True plasma level (μmol/L)----
Commercial standard plasma level (mg/dL)
MM (normal)----
No increase
20-53
150-350
NZ
Possible mild increase
12-35
90-210
SS
No increase
15-33
100-140
SZ
Mild increase (20-50%)
8-19
75-120
ZZ
High risk (80-100%)
2.5-7
20-45
null
High risk (100% by age 30)----
0
0

  • Other associated tests: LFTs, full PFT, chest X-ray, chest CT. If candidate for treatment with A1AT replacement (see below), obtain IgA level, HIV, hepatitis B titers.
  • Mayo clinic lab algorithm:
    MAYO_a1at_lab.png
  • ATS guidelines recommend obtaining consent for A1AT genetic testing



Treatment

  • IV replacement with alpha-1 proteinase inhibitor (pooled human A1AT) is expensive ($80,000/year), approved by FDA for weekly infusion (60 mg/kg/dose), but has been given monthly (250 mg/kg/dose). Formulations include Talecris Prolastin and Prolastin-C (concentrated to decrease infusion volume/time).
    • Indications
      • ATS suggests weekly A1AT for individuals who have plasma levels <11 μmol/L and FEV1 <80% predicted. Therapy not recommended if heterozygous with levels >11.
      • Additional factors supporting therapy include: high-risk genotype, patient expected to adhere to protocol, age at least 18 years old, nonsmoker or ex-smoker
      • Treatment controversial in patients with severe obstruction and patients with normal FEV1 but radiographic evidence of emphysema
    • Complications
      • Blood-borne infection - transmission of HIV or hepatitis B has not been reported, nevertheless baseline HIV and HBV titers should be obtained. Patients without anti-HBV antibodies should be immunized. If necessary to treat before an adequate antibody response to vaccination can be achieved, a single dose of HBIG (0.06 mL/kg) can be given with the first dose of hepatitis B vaccine.
      • Allergic reactions in IgA-deficient patients - pooled human A1AT contains small amounts of IgA, so the risk of anaphylaxis is increased in IgA-deficient patients with anti-IgA antibodies. IgE-mediated anaphylaxis to the actual A1AT protein is rare.

  • Liver transplant for associated liver disease is curative because donor liver produces adequate level of A1AT

  • Supportive therapy (for all patients)
    • Cigarette smoking cessation/avoidance
    • Maximal supportive therapy with bronchodilators, inhaled/oral corticosteroids, pulmonary rehabilitation, nutritional support, and oxygen (if indicated)
    • Prompt treatment of lower respiratory tract infections to minimize the inflammatory cell burden in the lung
    • Preventive vaccination (flu and pneumococcal PPSV23)



References






Alpha1.org
Alpha1 Foundation
Talecris Prolastin