ALPHA-1 ANTITRYPSIN DEFICIENCY

Background
- AAT – serine protease inhibitor that is produced by hepatocytes
- AAT def – autosomal co-dominant inheritance of mutations in A1AT gene
Risk factors for lung disease
- Plasma AAT levels below 11microcmol/L are considered to have severe def. of AAT and
are at risk for emphysema
Clinical manifestations
1. Lung – SOB, cough, phlegm, wheeze, younger age of onset and basilar predominant
pattern of emphysema – toxic loss of function (destruction of elastin by elastase because of
the deficiency of the elastase inhibitor AAT)
a. CXR changes – bullous changes more prominent at lung bases than at apices
2. Liver – adult onset chronic hepatitis, cirrhosis, HCC
a. Accumulation of ATT in hepatocytes
b. Pathogenesis: pathologic polymerization of variant AAT, resulting in intrahepatocytes
accumulation of AAT “toxic gain of function)
c. Intrahepatocyte accumulation of Z-type molecule occurs within RER and results from
abnormal folding and aggregation of variant AAT molecules in loop-sheet
polymerization + decreased degradation of Z-type molecules within ER
d. Unclear how accumulation of Z-type protein within RER causes liver cell injury –
possibly simple cell engorgement related to mass build-up release of lysosmal
enzymes cause by cell engorgement with resultant cell damage
e. Routine – LFTs
f. No specific Tx has been identified as mechanism of liver injury is accumulation of
mutant Z protein in hepatocytes
g. Mx – supportive to prevent or reduce complications
3. Skin – panniculitis (hot, painful, red nodules or plaques on thigh or buttocks0, necrotizing,
systemic vasculitis, psoriasis, urticarial, angioedema
a. Dx: deep excision biopsy
b. Tx: Dapsone, Doxycycline (scavenging ROS produced by neutrophils a/o slowing
breakdown of matrix proteins by elastase

Evaluation and diagnosis

- Adults with persistent airflow obstruction on spirometry
- Indicative symptoms
o Emphysema in young
o Emphysema in non-smoker
o Emphysema – predominant basilar changes on chest radiograph
o FHX of emphysema
o Panniculitis
o Unexplained chronic liver disease
Diagnosis
- Severe deficiency = serum level <11microcol
- Isoelectric focusing – GOLD standard for ID AAT variants – AAT variants migrate differently
at different rates under isoelectric focusing
- Genotyping
- Gene sequencing
- PFTS – assess presence and severity of lung disease
o Spirometry and reversibility
o Lung volumes
o DLCO

PiZZ – intracellular accumulation, defective inhibition of neutrophil elastase – liver and lung
Treatment
Supportive care
1. Smoking cessation
2. Bronchodilators and ICS/POS – follow COPD guidelines
3. Pulmonary rehabilitation – for decreased exercise tolerance
4. Nutritional support – maintain healthy body weight
5. Assessed for resting hypozemia and supplemental O2 prescibed if SpO2 <88% at rest
6. Prompt treatment of LRTIS to minimize inflammatory cell burden
7. Preventive vaccines – influenza and pneumococcal

IV augmentation
- Infusion of pooled human Alpha-1 proteinase inhibitor
- Goal to slow progression of emphysema
- Not recommended for patients who are heterozygous and how plasma AAT levels
>11micromol
- Obtains baseline serum IgA as all commercial preps for AAT augmentation contain some
IgA and patients with severe deficiency of IGG are at risk fo anaphylaxis with infusion of
pooled human and baseline spirometry and DLCO
- Side effects: flu-ike symptoms, hypersensitivity, potential volume overload, transmission of
infectious agents
- RAPID randomized trial – lower rate of loss of CT density significantly lower but no effect on
exacerbations, QoL,

Lung transplantation
- Improved survival and has a comparable survival to transplantation in nonA1At deficient
COPD
- Inhaled A1AT – direct delivery of AAT to lung – no long-term clinical studies have been
published – the aerosolized protein was shown to be functionally intact as evidence by
normalisaiton of ELF antineutrophil elastase

DDx:
1. COPD - emphysema
2. Bronchiectasis
3. Asthma
4. TB
5. Pulmonary vasculitis??