Approach

All patients with AAT deficiency should stop smoking and avoid pollution to help protect against respiratory manifestations. There is evidence demonstrating the rate of forced expiratory volume in the first second of expiration (FEV1) decline is worse in smokers compared with non-smokers; however, no significant difference is demonstrated between ex-smokers and non-smokers.[48]

AAT deficiency from the PI*ZZ mutations (and the rare PI*Mmalton, PI*Siiyama mutations) puts patients at risk for liver disease, these patients require hepatitis A and hepatitis B vaccination.[6][38]

AAT deficiency manifestations are treated using the same modalities as COPD/liver disease of other aetiology.

Patients with airflow obstruction and low plasma AAT levels may benefit from intravenous AAT (also known as alpha-1 proteinase inhibitor) augmentation therapy.[45]

Pulmonary manifestations

Lung disease in AAT deficiency should be treated with the same modalities as COPD of other aetiologies.[38][45][61]​​​​ Although the precise regimen is patient-specific and dependent on disease severity, therapies include short- and long-acting bronchodilators, inhaled corticosteroids, antibiotics, pulmonary rehabilitation, vaccination, smoking cessation, pollutant avoidance, oxygen, and oral corticosteroids.

Intravenous augmentation therapy for obstructive disease

Patients with plasma AAT levels <11 micromol/L have inadequate protection against inflammatory lung disease.[7] If they have coexisting airflow obstruction they may benefit from intravenous AAT augmentation therapy, although evidence examining its effectiveness is limited.[8][62][63]

Data for treating moderate obstructive disease (FEV1 31% to 65% of expected) are derived from two large observational studies (of patients >18 years with AAT deficiency) that reported reduced mortality and rate of decline in FEV among patients receiving augmentation therapy.[63][64][65] Consideration of observational studies is warranted given the low incidence of AAT deficiency; these studies have been instrumental in shaping current treatment recommendations.

One meta-analysis, that included randomised clinical studies and the observational data described above, found a reduced decline in FEV1 among all patients receiving augmentation therapy (23%); augmentation was associated with a 26% reduction in rate of FEV1 decline in the subset of patients with baseline FEV1 30% to 65% of predicted.[66] Subsequent meta-analyses of two small randomised controlled trials detected a significant difference in lung density on CT scan between AAT-treated patients (FEV1 between 25% and 80% of predicted; median 46%) and patients receiving placebo.[67][68] Neither meta-analysis reported a difference in decline in FEV1.[67][68]

Evidence suggests that augmentation therapy reduces the frequency of exacerbations and reduces total hospital cost per patient with AAT deficiency; however, the overall cost-effectiveness of therapy is unclear, given the high cost of AAT concentrates.[69]

Patient selection

Guidelines recommend intravenous augmentation therapy in those with AAT deficiency with an FEV1 less than or equal to 65% predicted, and that it should continue indefinitely.[38] However, some experts believe that individuals with mild airflow obstruction should receive augmentation therapy, citing the difficulty in detecting statistically significant efficacy in this cohort given the slow rate of decline of control patients.[70] The Global Initiative for Chronic Obstructive Lung Disease advises that never-smokers or ex-smokers with FEV1 between 35% and 60% predicted are most suitable for AAT augmentation therapy.[45] The Canadian Thoracic Society guidelines suggest that augmentation therapy may be considered for non-smoking or ex-smoking patients with COPD, with FEV1 25% to 80%, who are otherwise optimised pharmacologically and non-pharmacologically (i.e., pulmonary rehabilitation).[39]

Clinical trial and registry data are almost exclusively from patients with PI*ZZ phenotype; in clinical practice, people with PI*Z/null or PI*null/null genotypes are also evaluated for AAT augmentation. Other genotypes are not considered at risk or likely to benefit from AAT augmentation.[45] Although there is evidence that Z allele heterozygotes may have an increased risk of developing mild COPD, AAT augmentation therapy is not indicated because COPD does not develop in the absence of smoking and smoking cessation is, therefore, thought to be sufficient to prevent progression.[45]

If patients have low plasma AAT but normal lung function, they should not be treated with augmentation therapy as they have no manifestation of the disease. If patients have low plasma AAT and mild airflow obstruction (FEV1 >85%), hepatitis vaccination and lifestyle changes (smoking cessation, pollution avoidance) are encouraged, and their lung function is monitored. If they lose lung function at an accelerated rate (a change in FEV1 of >120 mL per year), or if FEV1 is <65%, augmentation therapy can be started.[38][64]

The UK National Institute for Health and Care Excellence does not recommend AAT replacement therapy for patients with AAT deficiency.[71]

The RAPID trial was a large, randomised, placebo-controlled study looking at progression of emphysema as measured by CT densitometry.[72] In this study, augmentation therapy led to less loss of lung parenchyma over time as measured at total lung capacity.

One registry study demonstrated a survival benefit of augmentation therapy in patients with severe AAT deficiency, and this was uncoupled from any effect on FEV1 stabilisation/decline.[73]​ 

Augmentation therapy regimen and adverse effects

Weekly infusions of purified AAT from pooled human plasma are sufficient for increasing AAT in lung fluid and for protective levels of plasma AAT.[74][75] Regimens of alternate doses and administration intervals have proven ineffective.[62][76][77]

The most common reactions to AAT augmentation infusion are fever, chills, dyspnoea, dizziness, and fainting.[63][64] Augmentation therapy carries a risk of anaphylaxis if an individual’s IgA level is near zero, so it is recommended that serum IgA level is measured before considering therapy.[70]

Lung transplantation

Reserved for patients with end-stage lung disease (typically when FEV1 is <25% or there are signs of chronic CO₂ retention).[10]

Around 5% of lung transplants are performed on patients with emphysema secondary to AAT deficiency.[78] A registry study conducted in the UK reported 1 year survival of 74%, 5 year survival of 53%, and 10 year survival of 45%. Lung transplantation was associated with significantly improved quality of life, but not increased survival, compared with matched controls.[79] Augmentation post-transplant may be performed in research or data-collection settings.

Hepatic manifestations

Liver disease in AAT deficiency should be treated with the same modalities as liver disease of alternate aetiologies.[6][61]

The precise regimen is patient-specific and dependent on disease severity. It may include monitoring for coagulopathy or worsening LFTs; diuretics for ascites; oesophagogastroduodenoscopy to detect and manage varices; and liver transplantation. There is no role for augmentation therapy in the treatment of liver manifestations of AAT deficiency.[38]

AAT deficiency accounts for approximately 1% of all liver transplants. A characterisation of liver transplantation in AAT-deficient patients in 3 transplant centres revealed a 5-year survival rate of 80% for patients with the ZZ phenotype and 79% for patients with the SZ phenotype.[80]

Alcohol consumption in individuals with AAT deficiency may increase the risk of liver manifestations, especially in patients with PI*ZZ phenotypes.[6] Patients with liver disease should be advised to avoid alcohol or at least limit their alcohol intake to <60 g/day (although there is no evidence that ethanol consumption affects progression of disease).[6][9]

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