Alpha-1 antitrypsin deficiency

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Alpha-1 antitrypsin is produced mainly by hepatocytes and inhibits neutrophil elastase in lung tissue. SERPINA1 variants are described by protease-inhibitor phenotypes and genotype; the common M allele produces usual amounts, while Z and some null alleles can produce marked deficiency. Disease expression varies with genotype, smoking, occupational exposure, infections and other modifiers, so a result predicts risk rather than an inevitable clinical course.

Pulmonary disease classically causes premature panlobular emphysema with lower-zone predominance, but upper-zone, mixed and airway-predominant patterns occur. Some people have asthma-like reversibility or bronchiectasis. Hepatic polymer accumulation may cause neonatal cholestasis, fibrosis, cirrhosis and hepatocellular carcinoma despite no lung symptoms. Rare manifestations include necrotising panniculitis, and testing may arise through family screening rather than illness.

The diagnostic sequence is serum concentration, confirmation of the protein or gene variant, then organ staging and counselling. Concentrations depend on assay and rise during inflammation, pregnancy or oestrogen exposure. A genuinely deficient result therefore needs laboratory-specific interpretation and genotype or phenotype correlation. Care should join respiratory medicine, clinical genetics or genomic services, hepatology when needed, and primary care prevention rather than treating the laboratory label alone.

Key points

AAT deficiency is an inherited SERPINA1 disorder in which reduced or dysfunctional circulating antiprotease permits accelerated elastin injury, particularly when tobacco smoke adds oxidant and neutrophil burden.
Think of it in early-onset emphysema, COPD with little smoking exposure, basal-predominant panlobular destruction, an affected relative, or otherwise unexplained liver disease with compatible pulmonary features.
Serum AAT is the screening test, but it is an acute-phase protein; measure inflammatory context and confirm a low or suspicious value with phenotype or genotype rather than reporting a concentration alone.
Inheritance is codominant, so each allele contributes to the circulating phenotype; severe deficiency is commonly associated with two high-risk alleles, but genotype–risk relationships are not perfectly binary.
Lung injury reflects insufficient antiprotease activity, whereas liver disease is driven principally by retention of misfolded protein within hepatocytes; this explains why augmentation cannot treat the hepatic mechanism.
Complete smoking avoidance is the highest-value intervention, including support to stop smoking and practical reduction of occupational dust, fume and second-hand smoke exposure.
Manage airflow obstruction, exacerbations, hypoxaemia and rehabilitation according to standard COPD or bronchiectasis guidance while maintaining specialist surveillance for an unusually rapid trajectory.
Human AAT augmentation has a UK marketing authorisation for selected severe deficiency, but NICE NG115 does not recommend routine AAT replacement therapy for COPD; eligibility and access require specialist commissioning review, not ad hoc prescribing.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

SERPINA1 variants

Pathogenic inherited variants reduce circulating functional alpha-1 antitrypsin through impaired production, abnormal folding or polymer retention within hepatocytes.

Smoking and inhaled injury

Tobacco smoke, dusts and fumes accelerate lung damage by increasing neutrophil elastase activity and functionally impairing the remaining protective protein.

Family risk

Autosomal codominant inheritance means siblings and offspring may carry deficient alleles, with clinical severity shaped by genotype and environmental exposure.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Protease imbalance
Low or dysfunctional circulating alpha-1 antitrypsin leaves neutrophil elastase insufficiently opposed during pulmonary inflammation, with effects that increase as the pathological process progresses.
2
Alveolar destruction
Unchecked protease activity damages elastin and alveolar walls, producing emphysema that often has basal predominance, which helps produce the characteristic physiological impairment.
3
Airflow limitation
Loss of elastic recoil permits expiratory small-airway collapse, gas trapping and progressive obstructive physiology, thereby altering ventilation, gas transfer or respiratory mechanics.
4
Hepatocyte injury
Certain misfolded protein variants accumulate within liver cells, causing inflammation, fibrosis and a separate risk of cirrhosis or liver cancer.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Premature emphysema

Persistent airflow obstruction or emphysema at an unusually young age, particularly below about 45 years or after limited tobacco exposure, should prompt AAT measurement even if the radiological distribution is not textbook.

Basal panlobular pattern

Lower-lobe-predominant, diffuse acinar destruction is a classic clue and contrasts with the upper-lobe centrilobular pattern often associated with smoking, but overlap is common and imaging cannot provide the genotype.

Family signal

A first-degree relative with severe deficiency, early emphysema or unexplained cirrhosis justifies counselling and a structured testing offer. Record the proband's confirmed variant rather than relying on family recollection.

Liver presentation

Unexplained transaminitis, fibrosis, cirrhosis or hepatocellular carcinoma can be the dominant phenotype. Normal lung function does not remove hepatic risk, and severe breathlessness should not lead clinicians to neglect liver assessment.

Acute respiratory complicationRed flag

Rapidly worsening breathlessness, hypoxaemia, pleuritic pain or unilateral reduced breath sounds may represent exacerbation, pneumonia, respiratory failure or pneumothorax and needs urgent standard assessment rather than delayed genetic discussion.

Unusual inflammatory clue

Painful ulcerating oily panniculitis is rare but strongly associated with severe deficiency. It warrants dermatology and specialist metabolic or respiratory input, biopsy where appropriate and evaluation of systemic involvement.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Serum alpha-1 antitrypsin concentrationFirst step
Why
Screen for a quantitatively deficient circulating protein level.
Interpretation and limitations
Use the reporting laboratory's method and reference range. A low result supports deficiency; an apparently normal value during inflammation can be falsely reassuring because AAT rises as an acute-phase reactant.
02
CRP and sampling context
Why
Identify inflammation or physiological factors that could distort concentration interpretation.
Interpretation and limitations
An elevated CRP makes a borderline AAT value less reassuring. Record current infection, pregnancy and exogenous oestrogen; repeat when clinically stable or proceed to molecular confirmation if suspicion is high.
03
Phenotyping and SERPINA1 genotyping
Why
Confirm the deficient protein pattern and define inherited alleles for counselling.
Interpretation and limitations
Targeted testing finds common S and Z alleles, while sequencing or deletion analysis may be required when concentration and phenotype disagree. A null allele may produce no protein and needs specialist interpretation.
04
Spirometry, lung volumes and TLCO
Why
Quantify airflow limitation, hyperinflation and gas-transfer impairment over time.
Interpretation and limitations
Obstruction with reduced TLCO supports emphysematous injury, but early disease can have preserved spirometry. Compare serial values using quality-assured testing rather than inferring progression from one visit.
05
Chest CT
Why
Define emphysema distribution, bronchiectasis and alternative structural disease.
Interpretation and limitations
Basal panlobular change is characteristic but not obligatory. CT densitometry is mainly a specialist or research outcome; repeat clinical CT should be justified by a management question and radiation exposure.
06
Liver assessment
Why
Detect polymer-related hepatic injury that may progress independently of lung disease.
Interpretation and limitations
Review LFTs, platelet count, synthetic function and ultrasound or fibrosis assessment according to risk. Normal transaminases do not exclude fibrosis; hepatology determines surveillance for cirrhosis and hepatocellular carcinoma.
07
Family cascade assessment
Why
Offer informed testing to relatives who may benefit from exposure prevention or organ follow-up.
Interpretation and limitations
Testing should follow consent and explain codominant inheritance, variable penetrance, reproductive implications and potential insurance concerns. Test the known familial variant where available.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Smoking-related COPD

Typical upper-lobe emphysema after heavy smoking may occur without inherited deficiency, but phenotype alone cannot replace serum and genotype testing.

Asthma

Variable symptoms and objective airflow variability favour asthma; alpha-1 deficiency produces persistent obstruction, though both conditions can coexist.

Bronchiectasis

Daily purulent sputum and CT bronchial dilatation suggest bronchiectasis, which can itself be associated with alpha-1 deficiency.

Other chronic liver disease

Alcohol, viral hepatitis, metabolic fatty liver and autoimmune disease require assessment because abnormal liver tests are not specific for protein polymer accumulation.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01ConfirmVerify inherited deficiencyFirst stepEarly or disproportionate COPD, a family history, suggestive liver disease or an unexpectedly low AAT level is identified.

1Measure serum AAT with CRP and relevant clinical context, repeating a borderline sample after inflammation settles when that will not delay a necessary specialist referral.
2EscalationConfirm abnormal or discordant findings through phenotype and SERPINA1 genotyping, escalating to broader molecular analysis when a very low level is not explained by common variants.
3Refer confirmed severe or clinically significant disease for respiratory and, where indicated, liver or genomic assessment, then document genotype, concentration and organ phenotype in an accessible care record.

02ProtectReduce preventable progressionA pathogenic genotype or clinically important deficient phenotype has been established.

1Prioritise complete tobacco cessation, reduce fume and dust exposure, support healthy activity and weight, and offer vaccination according to current UK age and risk schedules.
2Treat confirmed COPD or bronchiectasis using its national pathway, including inhaler review, pulmonary rehabilitation, oxygen assessment and exacerbation prevention according to phenotype rather than genotype alone.
3Assess liver risk, alcohol and metabolic cofactors, counsel against unregulated supplements, and arrange hepatology surveillance or transplant referral when fibrosis, synthetic failure or a focal lesion is suspected.

03CounselPlan specialist and family careThe result has implications for relatives, pregnancy planning, advanced disease or a request for augmentation treatment.

1Explain codominant inheritance and variable expression, offer cascade testing through an appropriate service and support the patient to share an accurate laboratory-confirmed result with relatives.
2AlternativeIf augmentation is requested, distinguish the product licence from NHS recommendation: NICE does not recommend routine replacement for COPD, so only a specialist can assess exceptional commissioning, trial or alternative options.
3For progressive respiratory or hepatic failure, refer early to transplant services because candidacy assessment, exposure abstinence, rehabilitation and psychosocial preparation take time.

Key medicines and prescribing safety2 treatments · regimens, roles and cautions

Relieves airflow-obstruction symptoms and reduces exacerbations according to the person's COPD phenotype; it does not replace the missing circulating antiprotease.

Usual inhaled treatment for coexisting COPD

Select the named inhaler, device and licensed strength through the current NICE COPD pathway, then prescribe the product-specific dose only after checking inspiratory technique and comorbid asthma features.

Avoid reflex escalation without checking smoking, adherence, technique and pulmonary rehabilitation. Inhaled corticosteroid use depends on exacerbation and eosinophilic or asthmatic features and can increase pneumonia risk.

A licensed long-term augmentation product for selected adults with documented severe inherited deficiency and progressive emphysema under specialist supervision; it is not acute rescue therapy.

Human alpha-1 proteinase inhibitor augmentation

The Respreeza SmPC describes 60 mg/kg intravenously once weekly for licensed candidates, but NICE NG115 does not recommend AAT replacement therapy for routine COPD care in the UK.

Do not initiate in routine practice outside a recognised commissioning or research pathway. Confirm genotype and progression, exclude IgA-related hypersensitivity risk as directed, monitor infusion reactions, and remember that augmentation does not treat hepatic polymer accumulation.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Early emphysema

Progressive alveolar loss causes breathlessness, hyperinflation and respiratory impairment at a younger age than expected, particularly after smoking.

Respiratory failure

Advanced emphysema produces chronic hypoxaemia and sometimes hypercapnia, pulmonary vascular stress and vulnerability to exacerbations, with severity determined by its extent and the patient's underlying reserve.

Cirrhosis

Persistent hepatocyte polymer retention can lead to fibrosis, portal hypertension and decompensated chronic liver disease, with severity determined by its extent and the patient's underlying reserve.

Hepatocellular carcinoma

Severe chronic liver injury increases primary liver cancer risk, requiring surveillance according to the established hepatic diagnosis and pathway.

Rare systemic disease

Necrotising panniculitis and vasculitic associations are uncommon but clinically important manifestations in a person with confirmed deficiency.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Track smoking and occupational exposure status at every meaningful review, offering active cessation treatment rather than recording advice once.
Follow symptoms, exacerbations, exercise tolerance, weight, oxygen saturation, spirometry and TLCO at an interval proportionate to severity and rate of change.
Review inhaler technique, rehabilitation, vaccination and an exacerbation action plan as for other COPD, while avoiding unnecessary serial serum AAT measurements after genotype is established.
Monitor liver biochemistry, platelets and fibrosis risk even in a lung-dominant presentation, and use hepatology-led imaging surveillance when cirrhosis is present.
Revisit family communication, testing uptake, reproductive questions and psychosocial effects without coercing relatives or assuming that the proband has disclosed the result.
Escalate unexplained rapid decline for CT review, pulmonary vascular assessment, transplant discussion or an alternative diagnosis rather than attributing every change to AAT deficiency.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Inflammation can conceal deficiency

Because AAT rises during an acute-phase response, a borderline-normal concentration obtained with a high CRP may still be inappropriate for the person's genotype.

Lung and liver differ

The lungs are harmed by too little functional protein in plasma, while hepatocytes are injured by retained abnormal protein; one mechanistic treatment cannot be assumed to help both.

Distribution is not destiny

Lower-zone panlobular emphysema is memorable but not universal, so appropriate testing should not be withheld because CT shows upper-zone or mixed disease.

Licence is not commissioning

A medicine can hold a UK marketing authorisation while NICE advises against routine NHS use; clinicians must communicate that distinction honestly when discussing augmentation.

One diagnosis, variable outcomes

Siblings with the same variants may have very different lung and liver trajectories because smoke exposure and other modifiers substantially alter expression.

11Common pitfallsFrequent interpretation and management errors.

01
Testing only patients with a classic basal CT pattern and missing other deficient phenotypes.
02
Interpreting serum AAT without CRP or recent inflammatory context when the result is borderline.
03
Stopping after a low concentration without phenotype or genotype confirmation and family counselling.
04
Calling the condition autosomal recessive and therefore misexplaining risk to heterozygous relatives.
05
Assuming augmentation therapy is routinely commissioned because a UK product has a marketing authorisation.
06
Monitoring only lung function while silent fibrosis or other hepatic disease progresses.