Alpha-1 antitrypsin deficiency

• Alpha-1 antitrypsin deficiency (AATD) is an inherited condition in which the liver makes too little, or a badly folded form, of alpha-1 antitrypsin (AAT), a protein that blocks neutrophil elastase.
• Loss of this brake lets neutrophil elastase chew up alveolar walls, producing the panlobular basal emphysema that is the hallmark of AATD lung disease.
• The same badly folded protein piles up inside hepatocytes and damages the liver, so liver disease can appear from the newborn period to old age.
• Servicing all of this is a single gene, SERPINA1 on chromosome 14, inherited in an autosomal codominant pattern; PiZZ is the genotype behind severe disease.
• Testing is recommended in every person with COPD, in adults with unexplained bronchiectasis, and in adult-onset asthma that develops persistent airflow obstruction.
• Intravenous augmentation therapy with pooled human AAT at 60 mg/kg once weekly is the only disease-modifying treatment for the lung disease, and it is reserved for selected patients.

By the end of this page you should be able to:

1. Explain the two separate mechanisms by which AATD damages the lung and the liver.
2. Read a genotype (PiMM, PiMZ, PiSZ, PiZZ, and null) and predict the likely serum AAT level and disease risk.
3. Describe the clinical picture of pulmonary and hepatic AATD, including panniculitis and vasculitis.
4. Work through the testing algorithm: serum AAT with C-reactive protein (CRP), then phenotyping or genotyping, with the correct cut-offs.
5. State the criteria and dose for augmentation therapy, and say when it is not used. ^[2]
6. Outline the monitoring, complications, prognosis, and low-resource approach.

Alpha-1 antitrypsin deficiency (AATD) is a genetic condition in which circulating levels of the protein alpha-1 antitrypsin (AAT) are reduced, or the protein that is present does not work properly, increasing the risk of pulmonary emphysema and liver disease throughout life.^[1][2] AAT is a serine protease inhibitor made mainly by liver cells; its principal job in the lung is to inhibit neutrophil elastase, a protease released by neutrophils during inflammation.

AATD is not a single mutation but a family of variants of the SERPINA1 gene, which sits on chromosome 14q31-32.3 and encodes AAT.^[2][5] Variants are named by letters that reflect how the protein migrates during isoelectric focusing, the laboratory method used for phenotyping. The normal allele is called M, and the deficient alleles most often met in practice are S and Z. Two alleles combine to give a genotype; because inheritance is autosomal codominant, both alleles are expressed, and the lower the plasma AAT falls, the greater the clinical risk.^[2]

The common genotypes form the backbone of the topic:

• PiMM is the normal pattern, with full protection.
• PiMZ and PiSZ give partial deficiency.
• PiZZ gives severe deficiency.
• Rare alleles and null alleles (written Q0 plus the city of the index case, for example Q0bellingham) also occur; null alleles make no protein at all and therefore cause severe lung disease but no liver disease, because there is no polymer to accumulate in hepatocytes.^[2][5]

Severe AATD is far commoner than its reputation suggests, but most affected people remain undiagnosed. A PiZZ genotype is estimated to occur in roughly 1 in every 2000 to 5000 individuals in Northern and Western Europe, where the Z allele frequency is 0.014 to 0.02.^[1] A worldwide systematic review estimates about 235,000 people have PiZZ, half of them in Europe.^[1] Taking all genotypes together, PiZZ and PiSZ are estimated to affect about 1.5 million people worldwide, with roughly 120,000 PiZZ individuals in Europe, and about one in every 800 people with COPD in Europe is affected.^{[6] [4]}

On a population level the incidence is quoted as 1 in 1600 to 1 in 3500 live births, comparable with cystic fibrosis.^[5] Only an estimated 3.8% of severely deficient individuals are identified, and diagnosis is delayed on average by 5.6 years.^[5] Around 15 to 30% of cases are diagnosed in European countries.^[6]

There is no modifiable cause in the ordinary sense. AATD is inherited in an autosomal codominant fashion at the SERPINA1 locus, so the main risk factor is carrying deficient alleles, compounded by a family history of COPD or AATD.^[1][2] Environmental insults decide much of the phenotype. Cigarette smoke both increases neutrophil elastase load and inactivates the anti-elastase capacity of AAT in vitro and in vivo, which is why genetically identical relatives can fare very differently.^[4] Occupational dust, fumes and air pollution, and repeated exacerbations accelerate decline.^[1] Liver disease is worsened by cofactors such as obesity, alcohol excess and viral hepatitis.^[5]

In the lung AATD is a loss-of-function disorder. Neutrophil elastase and related serine proteases, especially proteinase 3, are released during inflammation and normally kept in check by AAT. When AAT is scarce or defective, elastase digests elastin and other matrix components in alveoli unchecked, producing emphysema.^[1][4] The clinical emphysema is usually panlobular and basal, which is the mirror image of the (often upper-lobe predominant) centrilobular emphysema of smoking, although the two can coexist.

In the liver the problem is the opposite: a toxic gain of function. PiZ (p.Glu342Lys) misfolds and polymerizes in the rough endoplasmic reticulum of hepatocytes, where the polymers accumulate as periodic acid-Schiff-positive, diastase-resistant globules.^[2][5] This accumulation drives chronic hepatocyte injury, mitochondrial damage, fibrosis, cirrhosis and an increased risk of hepatocellular carcinoma. Cumulative liver risk is bimodal: fulminant disease in infancy, and slowly progressive cholestasis, fibrosis and cirrhosis in adults. Only an estimated 8 to 10% of PiZZ homozygotes develop severe liver disease in the first four decades, which implies powerful but still poorly understood modifying factors.^[5]

Null alleles, which make no protein, produce severe lung disease but no liver disease at all, because there are no polymers to trap in hepatocytes.^[2] That contrast is the clearest proof that lung and liver disease in AATD are caused by two different mechanisms.^[4]

Neutrophilic panniculitis presents as painful recurring nodules that can ulcerate and drain, and granulomatosis with polyangiitis has also been associated with AATD.^[1][2]

On liver biopsy the characteristic finding is the intracellular globule described above, which stains with periodic acid-Schiff after diastase and is highlighted by antibody to human AAT.^[5] Autopsy and imaging studies show the basal, panlobular destruction of the lung. AAT proteins polymerized in the lung are also pro-inflammatory and may add to pulmonary damage.^[4]

Lung disease is often labelled asthma or COPD for years before the true cause is recognized. Symptoms are those of chronic airflow obstruction: exertional breathlessness, chronic cough with sputum, wheeze and reduced exercise tolerance. Clues that should prompt testing are early-onset COPD in someone under 40 to 45 years, COPD with minimal smoking, basal panlobular emphysema on imaging, and unexplained bronchiectasis.^[3][4] Unlike classic smoker's emphysema, symptoms can be present with a relatively preserved forced expiratory volume in 1 second (FEV1), and full lung function testing (volumes, transfer factor) may be needed to show the extent of parenchymal destruction.^[4]

Hepatic presentation ranges from silent abnormalities of liver enzymes to neonatal cholestasis and jaundice in the first weeks of life, through adolescence with persistently raised transaminases, to cirrhosis and hepatocellular carcinoma in adulthood.^[5][4] Two thirds or more of adults requiring liver transplantation for AATD are male, pointing to sex-influenced expression.^[5] Many adults have transient elevations of transaminases, but synthetic function (albumin, coagulation) and signs of portal hypertension are the more specific indicators of serious disease.^[4]

Necrotizing panniculitis produces tender nodules and ulceration, often on the trunk and thighs, and can precede the diagnosis of AATD. Granulomatosis with polyangiitis should also raise the possibility.^[4]

The first task is to separate AATD from the far more common causes of COPD and chronic bronchitis. The second is to distinguish AATD-related liver disease from other chronic liver conditions.

Testing starts with a serum AAT level, but it must be interpreted with C-reactive protein (CRP) measured at the same time, because AAT is an acute-phase reactant. In heterozygotes and compound heterozygotes its concentration can double during inflammation and remain raised for one to several weeks.^[2] In PiZZ individuals the level barely rises, because the defective protein is trapped in hepatocytes and little is secreted. Measuring CRP together prevents a deficient patient being classed as normal on a transiently raised value.^[2]

Normal AAT is roughly 100 to 200 mg/dL. The 2026 Spanish guideline proposes a two-step pathway that begins with serum AAT (by immunonephelometry) plus CRP, using a first-step cut-off of under 116 mg/dL to move on to phenotyping or genotyping; this value came from a healthy PiMM reference interval of 116 to 232 mg/dL.^[2] The Canadian guideline uses an equivalent threshold of under 23 micromol/L (under 1.2 g/L) for the same decision in people with moderate suspicion.^[3] Converting, 116 mg/dL of AAT is about 22.3 micromol/L using the Spanish guideline's factor of 0.1923.^[2] Severe deficiency is defined everywhere at under 11 micromol/L, roughly 57.2 mg/dL.^[2][3] (One contemporary review renders the same 11 micromol/L as approximately 80 mg/dL, an inconsistency between sources that reflects different conventions in converting molar to mass units; the molecular-weight conversion gives 57.2 mg/dL.)^[1]

Serum levels vary by genotype in ways that overlap between groups, so a blood level alone rarely decides the diagnosis:

Phenotyping by isoelectric focusing identifies the protein isoforms present in serum and separates normal from deficient variants by their migration. It is an expert technique, rare variants can be missed, and null alleles cannot be detected at all, because no protein is produced.^[2][4] Genotyping is more definitive. The 2026 Spanish panel recommends genotyping of the 14 most common alleles using the REDAAT-Progenika pathway on saliva, dried blood or whole blood, with a step up to SERPINA1 sequencing when AAT levels and genotype do not agree.^[2] The Canadian guideline goes further and suggests DNA sequencing of the coding regions (exons 2 to 5) as the gold standard, because targeted genotype panels miss rare or novel variants, reserved for people with high clinical suspicion; for moderate suspicion, sequencing is added only if the level falls under the threshold.^[3] The US adult guideline (Alpha-1 Foundation, Sandhaus 2016) recommends genotyping at least the S and Z alleles for symptomatic testing, with confirmatory Pi-typing, level testing or expanded genotyping as needed.^[4]

Whom to test

• Every individual with COPD, regardless of age, severity or smoking history.^[2][4]
• Adults with unexplained bronchiectasis.^[2][3][4]
• Adult-onset asthma that develops persistent airflow obstruction or has associated emphysema (systematic testing of all asthma is not recommended).^[2][3]
• All individuals with unexplained chronic liver disease.^[4]
• Neonatal cholestasis; liver disease of unknown cause.^[2]
• Necrotizing panniculitis, granulomatosis with polyangiitis.^[2][4]
• First-degree relatives of a confirmed case, with genetic counselling.^[3][4]

The Canadian risk-stratification table is useful at the bedside: high suspicion applies to early-onset COPD under 40 years, COPD with a smoking history under 10 pack-years, basal panlobular emphysema, a family history of COPD or AATD, and a history of perinatal jaundice; moderate suspicion applies to COPD, unexplained bronchiectasis, adult-onset asthma with persistent obstruction, liver cirrhosis, and GPA or panniculitis.^[3]

Complete pulmonary function testing, including static volumes and transfer factor, is recommended at baseline because spirometry alone can look normal even when emphysema is substantial.^[4] A baseline chest CT is recommended for symptomatic or abnormal patients.^[4] Both guidelines advise against routine serial CT during follow-up, because no study has shown that it improves outcomes, and radiation must be justified.^[2][4] A 2024 European Delphi consensus (EARCO) adds detailed routine monitoring (annual spirometry, body plethysmography, transfer factor, baseline high-resolution CT) and a negative consensus that augmentation therapy should not be initiated after a successful lung transplant.^[6]

Baseline liver biochemistry (AST, ALT, GGT, albumin, bilirubin, INR, platelets), physical examination for liver disease, liver ultrasound, and, where available, elastography are recommended, with annual liver function testing thereafter.^[4][6] Referral to a hepatologist should follow the diagnosis.^[6] Suspicious results warrant hepatology referral and, when appropriate, biopsy.

Severe AATD is defined at AAT under 11 micromol/L, roughly 57.2 mg/dL.^[2][3] Severe AATD is PiZZ in 96% of cases, with occasional combinations of Z, S, rare or null alleles.^[2]

Management of AATD has two pillars: standard care of COPD and liver disease (nothing in AATD exempts a patient from evidence-based COPD management), and removing the specific trigger that drives accelerated decline.^[1] Smoking cessation is the single most effective intervention, with data showing that birth identification of AATD lowers smoking uptake and that adult diagnosis improves quit rates.^[4] Avoidance of occupational dust, fumes and pollutants, vaccination against influenza and pneumococcus, prompt treatment of exacerbations, pulmonary rehabilitation, supplemental oxygen for chronic hypoxaemia, bronchodilators and inhaled corticosteroids guided by the usual criteria all apply.^[1] COPD recommendations, e.g. the GOLD strategy, should always be followed in patients with AATD in relation to the use of LABA, LAMA and ICS.^[6]

Inhaled therapy plays the same role as in other COPD. One PiZZ study found that adding inhaled corticosteroid to a long-acting beta-agonist and oxitropium improved lung function and symptoms, and a post-hoc analysis found less FEV1 decline in PiZZ patients whose eosinophil count exceeded 0.2 x 10^9/L and who received inhaled corticosteroids.^[1] Evidence beyond this is limited, so these are modest refinements rather than a separate COPD playbook.

Augmentation means infusing pooled, purified human AAT derived from donor plasma. It can raise serum AAT above the protective threshold and restore anti-elastase activity in the epithelial lining fluid.^[2][4] It is the only disease-modifying, approved intervention for the lung disease of AATD.^[1] It does not cure emphysema: destroyed parenchyma does not recover, which is why timing matters.^[2]

Dose and regimen

• The licensed and trialled dose is 60 mg/kg body weight intravenously once weekly, independent of product presentation.^[2][4]
• This maintains serum AAT above the 11 micromol/L protective threshold across the whole inter-dose interval.^[2]
• Weekly doses above 60 mg/kg are not recommended.^[4]
• Doubling to 120 mg/kg every 14 days or 180 mg/kg every 21 days keeps protective levels in most patients (over 90% and around 85% of the interval respectively), but no trial has tested these schedules on emphysema progression, so they should only be discussed with experienced centres and the patient.^[2]
• Extended-interval dosing is accepted practice in European consensus (biweekly infusions).^[6]

Indications (all must be met for the Spanish criteria)

• Age over 18 years.
• Severe AATD with AAT under 57.2 mg/dL (under 11 micromol/L).
• Emphysema with abnormal pulmonary function tests and CT evidence.
• Documented genotype or phenotype of severe deficiency.
• Non-smoker or ex-smoker for at least the last 6 months.
• Receiving optimal pharmacological and non-pharmacological COPD therapy.
• No IgA deficiency.
• Willingness to accept regular infusions.^[2]

The Canadian guideline expresses the same idea as a conditional recommendation for patients with COPD who are never or former smokers, have FEV1 under 80% predicted, documented emphysema, documented SERPINA1 deficiency genotypes, severely reduced AAT under 11 micromol/L (under 0.57 g/L), and optimal COPD therapy.^[3] The US guideline (Sandhaus 2016) recommends augmentation for FEV1 between 30 and 65% predicted, suggests it below 30%, and recommends an informed discussion above 65% (factors such as age, rapid FEV1 decline, falling transfer factor and progressive emphysema on imaging inform the decision).^[4] These three documents disagree on where the spirometric threshold should sit, and that disagreement should be settled by local protocol rather than by memorisation. ^[2][6]

When not to use augmentation

• Liver disease due to AATD: the mechanism is intracellular accumulation, not circulating deficiency, so augmentation is not recommended.^[4]
• After successful liver transplantation: donor liver makes normal AAT, so augmentation adds nothing.^[2][4]
• MZ genotype with COPD: augmentation is not recommended.^[4]
• Continued smoking: not recommended, because cigarette smoke both inactivates AAT and drives elastase release.^[4]
• Bronchiectasis without airflow obstruction: not recommended on current evidence.^[4]
• Post-lung transplantation: the EARCO consensus explicitly recommends against initiating augmentation after a successful transplant.^[6]

Necrotizing panniculitis is the one non-pulmonary exception where intravenous augmentation is recommended, sometimes at higher doses.^[4]

Evidence summary

• Randomised trials totalling a few hundred patients over two to three years show slower loss of CT lung density at total lung capacity with weekly 60 mg/kg versus placebo.^[2]
• The RAPID trial randomised 180 patients for 2 years; the open-label extension showed that delayed starters lost lung density less quickly once switched, from minus 2.26 g/L per year to minus 1.26 g/L per year.^[1]
• Mortality data from large registries suggest a survival benefit (adjusted hazard ratio about 0.64) and an estimated gain of 5.6 to 5.8 years before end-stage failure or transplant; FEV1 change has never reached statistical significance in trials.^[2]
• Quality of life and exacerbation frequency have not been shown to improve.^[2]

There is, at present, no licensed therapy for AATD-associated liver disease; orthotopic liver transplantation is the only curative treatment, and it restores normal circulating AAT so lung disease stops progressing.^[1][5] Medical care therefore means removing cofactors (alcohol, hepatotoxic drugs, obesity management, vaccination against hepatitis), monitoring, screening for hepatocellular carcinoma, and treating complications of portal hypertension in the usual way.^[4][5] A 2024 European consensus among experts recommended annual liver function testing and hepatology referral for all AATD patients.^[6]

Several small molecules and genetic approaches (RNA interference targeting Z-AAT, RNA editing, base editing) are in Phase 1 to 3 trials, aiming to reduce polymer load or restore normal AAT, but none is approved yet.^[1]

Lung volume reduction surgery and endobronchial valves can be offered to highly selected patients with heterogeneous upper-lobe or basal predominant disease, but results in AATD are less pronounced and shorter-lived than in AAT-replete COPD, and operative mortality may be higher.^[1][4] Transplantation is reserved for end-stage disease with BODE score 8 or above, FEV1 and DLCO usually under 25% predicted; double-lung rather than single-lung grafts are favoured, and long-term outcomes are comparable with other COPD patients.^[1][4]

• Panlobular basal emphysema, chronic bronchitis and bronchiectasis.
• Respiratory failure and chronic hypercapnia.
• Cirrhosis and hepatocellular carcinoma.
• Necrotizing panniculitis and granulomatosis with polyangiitis.
• Pneumothorax and cor pulmonale in advanced disease.
• Post-transplant complications where surgery was required.

Prognosis is driven by two variables: whether the person carries liver-risk or lung-risk variants, and how early smoke and other insults stop. Never-smoking PiZZ individuals detected without symptoms may have a near-normal expected survival.^[4] Smokers have a faster FEV1 decline and an earlier mortality, and the acceleration from smoke is well documented, although the exact annual loss varies by cohort. Registry and trial data support slowing emphysema progression with augmentation, with the greatest evidence in moderate obstruction. After liver transplantation graft and patient survival are excellent, with patient survival of 92, 90 and 90% at 1, 3 and 5 years in paediatric series, and the new liver produces normal AAT.^[5] Early diagnosis, before the decline is established, is the single biggest modifier of outcome.^{[1] [2]}

There is no agreed universal newborn screening programme; only a few countries, such as Sweden, have implemented it, and the American Academy of Pediatrics has asked for long-term data.^[1][5] Case-finding strategies target the clinical populations above. Primary prevention is anti-smoking and avoiding hepatotoxic cofactors in known families. Genetic counselling covers transmission risk for each child of an affected individual, with confidential predictive testing available for relatives.^[4][5]

Children. Liver disease dominates: AATD is the most common inherited cause of childhood liver disease, responsible for 3.51% of paediatric liver transplants, and siblings or relatives may present with cholestasis from birth.^[5] Testing of healthy infants is generally deferred or offered through parental testing; when a child presents with prolonged jaundice, AATD must be excluded.^[4][5] Lung presentation in children is rare, but severe or unusually early disease in a young person should raise the possibility of a familial (rather than sporadic) pattern and prompt family screening.^[5]

Pregnancy. AAT rises as an acute-phase reactant, which can mask deficiency, so phenotyping or genotyping rather than level alone should be used when suspicion is high. Augmentation has been continued in pregnant patients in case reports, but decisions must be individualised and shared with obstetric and respiratory specialists.

Heterozygotes. PiMZ never-smokers do not carry an increased COPD risk, so an MZ genotype should not be used to explain lung disease in a lifelong non-smoker.^[1] PiSZ confers moderate risk that rises sharply with smoking. Augmentation is not indicated for PiMZ individuals with COPD.^[4]

Older adults. AATD may be uncovered for the first time after 60; management still follows the same criteria, but treatment trade-offs and comorbidity need heavier weighting.

• Serum AAT with simultaneous CRP is the inexpensive entry test; where immunonephelometry is unavailable, levels can be measured by immunoturbidimetry, but local reference ranges must be established because cut-offs vary by method.^[2]
• Phenotyping by isoelectric focusing is widely available and remains the diagnostic fallback where gene panels are not affordable.
• Operate the same two-step logic: low level (or high suspicion) leads to phenotyping before any attempt at genotyping.
• Augmentation therapy may be unavailable or unfunded; even where diagnostic capability exists, access inequalities are real and the 11 micromol/L threshold persists in national criteria regardless.^[6] In its absence, standard COPD and liver care, strict smoking avoidance and family counselling still change outcomes.
• Pulmonary rehabilitation, vaccination and hepatology review are low-cost wins.

• Chronic obstructive pulmonary disease
• Bronchiectasis
• Liver cirrhosis and hepatocellular carcinoma
• Neonatal cholestasis
• Smoking cessation