Definition
- Alpha-1 antitrypsin deficiency (AATD) is an autosomal codominant genetic disorder caused by mutations in the SERPINA1 gene, which encodes alpha-1 antitrypsin (AAT), a key protease inhibitor responsible for neutralising neutrophil elastase in the lungs.
- A deficiency or dysfunction of AAT leads to uncontrolled proteolytic damage, predisposing affected individuals to chronic obstructive pulmonary disease (COPD), emphysema, and liver disease, including cirrhosis and hepatocellular carcinoma.
Aetiology
Genetic Basis
- AATD is caused by mutations in the SERPINA1 gene, which is located on chromosome 14q32.1.
- The condition follows an autosomal codominant inheritance pattern, meaning that both alleles contribute to the clinical phenotype.
- The Pi locus is highly polymorphic, with over 100 known allelic variants.
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Genotypes and Clinical Impact:
- PI*MM (Normal): Produces normal levels of AAT.
- PI*ZZ (Severe Deficiency): The most common genotype associated with disease. Individuals have only 10–15% of normal AAT levels and are at high risk for early-onset emphysema and liver disease.
- PI*SZ (Intermediate Deficiency): Serum AAT levels are reduced but less severely than in PI*ZZ individuals; carries 20–50% increased risk of emphysema compared to MM homozygotes.
- PI*MZ (Heterozygous Carrier): Generally asymptomatic but can develop COPD with significant environmental exposures (e.g., smoking, pollution).
- PI*Null (Complete Absence of AAT): Leads to 100% risk of emphysema by age 30 but does not cause liver disease, as no abnormal AAT is produced to accumulate in hepatocytes.
Environmental and Lifestyle Modifiers
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Cigarette Smoking:
- Smoking accelerates disease progression by increasing neutrophil elastase release and inactivating residual AAT through oxidative modification.
- In smokers with PI*ZZ, emphysema onset occurs 10 years earlier than in non-smokers.
- PI*MZ individuals who smoke exhibit more severe lung disease and lower FEV1/FVC ratios compared to PI*MM smokers.
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Occupational and Environmental Exposures:
- Exposure to dust, fumes, and airborne pollutants can increase neutrophilic inflammation, leading to accelerated lung function decline.
- A study on New York City Fire Department (FDNY) rescue workers post-9/11 found that those with AATD had significantly greater declines in lung function compared to those without.
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Infections:
- Recurrent respiratory infections can accelerate pulmonary inflammation and tissue damage in AATD patients.
- Viral and bacterial infections drive neutrophil recruitment, exacerbating elastase-mediated destruction of lung parenchyma.
Pathophysiology
Genetic Basis and Protein Function
- Alpha-1 antitrypsin (AAT) is a serine protease inhibitor (serpin) primarily synthesised in the liver and secreted into circulation to neutralise neutrophil elastase and other proteases in the lungs.
- The SERPINA1 gene, located on chromosome 14q32.1, encodes AAT. Over 120 allelic variants have been identified, with three main categories:
- Normal allele (M) – Produces sufficient functional AAT.
- Deficient alleles (Z, S, and others) – Lead to reduced circulating AAT levels.
- Null alleles – Result in complete absence of AAT, leading to severe lung disease but no liver disease.
Molecular Pathogenesis
The primary mechanisms of AATD-related disease are:
- Loss of antiprotease protection in the lungs → Emphysema.
- Toxic gain of function in hepatocytes → Liver disease.
1. Pulmonary Disease: Protease-Antiprotease Imbalance
- Normally, AAT inhibits neutrophil elastase, preventing excessive degradation of elastin and collagen in the alveoli.
- In AAT deficiency, unopposed neutrophil elastase activity leads to destruction of alveolar walls, causing panacinar emphysema.
- Z allele pathology:
- The Glu342Lys mutation causes beta-sheet polymerisation, reducing secretion into circulation.
- Only 10–15% of normal AAT levels reach the lung, leaving alveoli vulnerable.
- S allele pathology:
- A Val264Glu substitution leads to defective post-translational processing, resulting in moderate deficiency.
- Null allele pathology:
- No AAT is produced, leading to severe protease-antiprotease imbalance and early-onset, rapidly progressive emphysema.
- No AAT is produced, leading to severe protease-antiprotease imbalance and early-onset, rapidly progressive emphysema.
2. Liver Disease: Intracellular Accumulation of Misfolded AAT
- The Z allele mutation leads to misfolded AAT polymers being retained in hepatocytes instead of being secreted.
- This ER accumulation triggers:
- Hepatocyte apoptosis.
- Liver inflammation, fibrosis, and cirrhosis.
- Hepatocellular carcinoma (HCC) in some cases.
- Key observations:
- PI*ZZ homozygotes are at high risk for liver disease.
- PI*Null/Null individuals do not develop liver disease, as no toxic polymer accumulates in hepatocytes.
- PI*SZ individuals have lower hepatic polymer burden but may still develop fibrosis.
Modifiers of Disease Progression
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Cigarette Smoking:
- Major accelerant of emphysema in AATD.
- Inactivates residual AAT through oxidation.
- Induces neutrophilic inflammation, worsening elastin degradation.
- PIMZ smokers have significantly worse lung function than non-smoking PIMZ individuals.
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Environmental and Occupational Exposures:
- Dust, fumes, air pollutants, and toxins exacerbate lung disease by increasing oxidative stress and inflammation.
- WTC-exposed rescue workers with AATD had significantly higher rates of lung function decline.
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Respiratory Infections:
- Recurrent bacterial and viral infections lead to increased neutrophil elastase activity, accelerating lung damage.
- Chronic bronchitis and exacerbations are common in AATD patients.
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Genetic and Epigenetic Factors:
- Heterozygous PI*MZ individuals have an increased risk of COPD but only in the presence of additional risk factors (e.g., smoking).
- Some studies show increased alveolar apoptosis independent of neutrophilic inflammation.
Epidemiology
Global Prevalence
- AATD is present worldwide but has variable prevalence depending on geographical and ethnic backgrounds.
- Estimated to affect 1 in 2000 to 6000 individuals, AATD is most commonly observed in populations of European descent, particularly in Northern and Western Europe.
- It is significantly less common in individuals of Asian, African, and Indigenous American descent.
- Northern and Western European populations have the highest rates of AATD, with prevalence estimates of 1 in 1600 to 1 in 5000.
- The Iberian Peninsula (Spain and Portugal) also exhibits a relatively high carrier frequency.
- Global estimates suggest that 117 million individuals are carriers and 3.4 million people worldwide have severe AAT deficiency (PI*ZZ).
- Scandinavian countries have contributed to major newborn screening studies, demonstrating that AATD occurs in 1 in 1575 to 1 in 5097 newborns.
United States
- AATD is one of the most common lethal genetic disorders in white populations, with an estimated 70,000–100,000 individuals having severe AAT deficiency (PI*ZZ).
- Approximately 25 million Americans are carriers of at least one deficient allele, but less than 10% of severely affected individuals are identified.
- Direct-to-consumer genetic testing has estimated the prevalence of PI*ZZ at 1 in 3846 Americans.
- Clinical under-recognition is a significant issue, with studies estimating that many PI*ZZ individuals remain undiagnosed.
Race and Ethnicity
- White individuals of European descent make up the largest affected group, with the highest prevalence of Z and S alleles.
- Non-European populations have a lower prevalence, though specific regions in Asia and Africa have reported rare pathogenic variants.
- Data on African, Indigenous American, and South Asian populations suggest a much lower prevalence, though screening studies remain limited.
Sex Distribution
- Men and women are equally affected, as the SERPINA1 gene follows autosomal codominant inheritance.
- Some studies suggest earlier onset and more severe disease in men, potentially due to higher rates of smoking and environmental exposure.
Age-Related Manifestations
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Bimodal distribution of symptoms:
- Neonatal Period: AATD can cause neonatal jaundice, cholestatic hepatitis, and liver dysfunction.
- Childhood: Some children develop hepatic fibrosis or cirrhosis, making AATD a leading genetic cause of pediatric liver transplantation.
- Adulthood: The most common presentations are chronic liver disease (fifth decade) and early-onset emphysema (fourth to fifth decade in smokers, fifth to sixth decade in non-smokers).
Underdiagnosis and Delayed Recognition
- AATD is widely underdiagnosed, despite its genetic prevalence and clinical impact.
- Studies suggest an average diagnostic delay of 5 to 8 years after symptom onset.
- Primary reasons for under-recognition:
- Lack of clinician awareness.
- Misdiagnosis as COPD or asthma.
- Absence of routine screening in patients with chronic lung disease.
- One study in St. Louis found that only 4% of expected PI*ZZ individuals had been identified, indicating a major gap in diagnosis.
- Despite guideline recommendations, many symptomatic individuals remain untested.
History
General Considerations
- Not all individuals with AATD develop clinically significant disease.
- The presentation and severity of symptoms depend on the specific mutation and environmental exposures, particularly cigarette smoking and occupational pollutants.
- The most common manifestations are chronic lung disease (emphysema, COPD) and liver disease (cirrhosis, hepatitis, hepatocellular carcinoma).
- Less common associations include panniculitis and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.
- Due to symptom overlap with more common conditions such as asthma and smoking-related COPD, AATD is often underdiagnosed or misdiagnosed.
Key Historical Features
Respiratory Symptoms
- Cough (50%) – May be chronic and productive, meeting criteria for chronic bronchitis (≥3 months of cough per year for 2 successive years).
- Dyspnea (84%) – Initially exertional, progressing over years to limitation with mild activities.
- Wheezing – Often mistaken for asthma, though bronchodilator response is incomplete compared to classic asthma.
- Frequent respiratory infections – Patients often require multiple antibiotic courses due to chronic bronchitis and bacterial exacerbations.
- Spontaneous pneumothorax – Occurs in some cases as a presenting feature or complication of established disease.
- Bronchiectasis – Reported in 2% to 43% of patients, often co-existing with emphysema.
Liver Symptoms
- Jaundice and scleral icterus – More common in neonates and adults with cirrhosis.
- Hepatomegaly – May indicate chronic liver disease.
- Ascites and portal hypertension – Seen in advanced cirrhosis.
- Hepatic encephalopathy (confusion, asterixis) – Suggests decompensated liver failure.
- History of liver transplantation – AATD is a leading cause of pediatric liver transplantation.
Demographic Risk Factors
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Age at symptom onset:
- Pulmonary disease: Typically presents in the fourth to fifth decade in non-smokers but third to fourth decade in smokers.
- Liver disease: May present in infancy (neonatal jaundice) or as adult-onset cirrhosis in the fifth decade.
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Sex:
- Men and women are affected equally, though males may have earlier and more severe pulmonary symptoms, potentially due to higher smoking rates.
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Family history:
- Presence of early-onset emphysema, COPD, unexplained liver disease, or spontaneous pneumothorax in first-degree relatives should raise suspicion for AATD inheritance.
Environmental and Lifestyle Factors
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Cigarette smoking:
- The strongest risk factor for early and severe lung disease in AATD.
- Smokers with AATD develop symptoms 10 years earlier than non-smokers.
-
Occupational exposures:
- Inhaled toxins (dust, fumes, chemicals, kerosene heaters, biomass fuels) can accelerate pulmonary function decline.
- Studies in firefighters and rescue workers suggest increased susceptibility to occupational lung injury in AATD.
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Air pollution and passive smoking:
- May exacerbate lung inflammation, contributing to accelerated emphysema progression.
- May exacerbate lung inflammation, contributing to accelerated emphysema progression.
Diagnostic Delays and Misdiagnosis
- Average delay from symptom onset to diagnosis: 5 to 8 years.
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Frequent misdiagnosis as:
- Asthma – Due to wheezing and variable bronchodilator response.
- COPD – Often attributed solely to smoking rather than genetic factors.
- Recurrent respiratory infections – Some patients undergo multiple evaluations for sinusitis, postnasal drip, or gastroesophageal reflux before AATD is considered.
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High index of suspicion is required in:
- Young non-smokers with early emphysema or unexplained dyspnea.
- Patients with COPD and basilar-predominant emphysema on imaging.
- Individuals with unexplained liver disease, particularly cirrhosis without known risk factors.
Physical Examination
General Considerations
- No single physical examination finding is specific for AATD, but characteristic signs develop as the disease progresses.
- Lung and liver involvement are the primary features, though cutaneous and vascular manifestations may also be present.
- Examination should assess for signs of emphysema, airflow obstruction, liver dysfunction, and systemic effects.
Respiratory Examination
Signs of Increased Work of Breathing
- Tachypnea
- Tripod positioning (leaning forward with arms braced)
- Use of accessory muscles (scalene, intercostal muscle retractions)
Airflow Obstruction
- Pursed-lip breathing – Increases airway pressure to prevent collapse.
- Prolonged expiratory phase – Indicative of air trapping.
- Wheezing – May be bronchodilator-responsive but not fully reversible (unlike asthma).
- Pulsus paradoxus – Exaggerated drop in systolic blood pressure during inspiration, seen in severe airflow limitation.
Hyperinflation and Structural Changes
- Barrel chest – Increased anteroposterior diameter due to lung hyperexpansion.
- Increased percussion note – Hyperresonance due to air trapping.
- Diminished breath sounds – Reduced lung sounds due to alveolar destruction.
- Distant heart sounds – Secondary to hyperinflated lungs.
Late-Stage Pulmonary Findings
- Cyanosis – Suggests advanced respiratory failure.
- Digital clubbing – Rare, but may indicate concomitant bronchiectasis.
- Peripheral edema – Suggestive of cor pulmonale (right heart failure secondary to pulmonary disease).
Liver Examination
- Hepatomegaly – Common in early-stage liver disease.
- Splenomegaly – May indicate portal hypertension in cirrhotic patients.
- Ascites – Fluid accumulation due to decompensated cirrhosis.
- Jaundice and scleral icterus – Seen in hepatic dysfunction.
- Asterixis (flapping tremor) – Suggests hepatic encephalopathy.
Cutaneous Manifestations
- Panniculitis – Painful, erythematous nodules or plaques, particularly on the thighs or buttocks.
- Purpuric or ulcerating skin lesions – May indicate vasculitis, which has been linked to ANCA-positive disease in AATD.
Additional Systemic Features
- Unexplained weight loss – Common in advanced COPD or cirrhosis.
- Muscle wasting – Seen in cachexia of severe lung disease.
- Signs of spontaneous pneumothorax:
- Sudden pleuritic chest pain.
- Absent breath sounds on the affected side.
- Hyperresonance on percussion.
Investigations
Biochemical Testing
Serum Alpha-1 Antitrypsin (AAT) Levels
- Indication: First-line screening in patients with early-onset lung disease, cryptogenic liver disease, or a family history of AATD.
- Method: Measured using nephelometry or radial immunodiffusion.
- Diagnostic Thresholds:
- Normal range: 100–300 mg/dL (varies by lab).
- <80 mg/dL (~11 µmol/L): Suggests insufficient lung protection.
- <20 µmol/L: Indicates severe deficiency and high disease risk.
- Considerations:
- AAT is an acute-phase reactant and may be falsely elevated during inflammation.
- Borderline levels require further testing (phenotyping/genotyping).
Liver Function Tests (LFTs)
- Indication: Assess hepatic involvement, even in asymptomatic individuals.
- Findings:
- Elevated ALT and AST (hepatocellular injury).
- Increased bilirubin and alkaline phosphatase (cholestasis).
- Low albumin and prolonged INR (advanced liver dysfunction).
Alpha-Fetoprotein (AFP)
- Indication: Surveillance for hepatocellular carcinoma (HCC) in cirrhotic AATD patients.
- Elevated AFP: Suggests possible malignancy.
Pulmonary Function and Functional Assessments
Pulmonary Function Tests (PFTs)
- Indication: Evaluates lung disease severity in symptomatic patients.
- Key Findings:
- Obstructive pattern: Reduced FEV1, FVC, and FEV1/FVC ratio.
- Hyperinflation: Increased total lung capacity (TLC) and residual volume (RV).
- Reduced diffusing capacity (DLCO): Suggests alveolar destruction.
- Bronchodilator response: Often incomplete (helps differentiate AATD from asthma).
Exercise Testing with Arterial Blood Gas (ABG)
- Indication: Assess hypoxemia during exertion.
- Findings:
- Reduced PaO₂ with increased alveolar-arterial gradient.
- Exercise-induced oxygen desaturation in advanced cases.
Imaging Studies
Chest X-ray
- Indication: Initial assessment of structural lung abnormalities.
- Findings Suggestive of AATD:
- Basilar-predominant emphysema (as opposed to apical in smoking-related COPD).
- Hyperinflation with flattened diaphragms.
- Bullae formation in severe cases.
High-Resolution Chest CT (HRCT)
- Indication: More sensitive than chest X-ray for detecting early lung disease.
- Key Features:
- Panacinar emphysema – More prominent in the lower lobes.
- Bronchiectasis, which often coexists with emphysema.
- Reduced vascular markings and alveolar airspace enlargement.
Liver Imaging
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Liver Ultrasound:
- Recommended annually in patients at risk for AATD-associated liver disease.
- Detects cirrhosis, hepatomegaly, and portal hypertension.
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Abdominal CT/MRI:
- Assesses fibrosis, cirrhosis, and hepatocellular carcinoma.
- More sensitive than ultrasound for detecting malignancy.
Confirmatory Genetic Testing
Phenotyping (Isoelectric Focusing)
- Indication: When serum AAT levels are low or borderline.
- Purpose: Identifies specific AAT protein variants, distinguishing between normal, deficient, and dysfunctional forms.
Genotyping (PCR-Based DNA Testing)
- Indication: If phenotyping does not align with clinical suspicion.
- Purpose: Confirms SERPINA1 gene mutations (e.g., PIZZ, PIMZ, PI*SZ).
Whole Gene Sequencing
- Indication: When rare or null alleles are suspected.
- Findings: Confirms uncommon pathogenic variants.
Additional Investigations
Hepatic Biopsy (Rarely Indicated)
- Indication: When liver disease is suspected but imaging is inconclusive.
- Findings:
- PAS-positive diastase-resistant globules in hepatocytes (suggests AATD).
- Variable fibrosis and cirrhosis depending on disease severity.
Histological Features (Lung Biopsy, Rarely Indicated)
- Findings:
- Panacinar emphysema with destruction of alveolar walls.
- Uniform acinar involvement, predominantly in the lung bases.
Differential Diagnosis
Pulmonary Differentials
1. Chronic Obstructive Pulmonary Disease (COPD)
- Key similarities:
- Progressive dyspnea.
- Airflow obstruction on spirometry (non-reversible post-bronchodilator).
- Increased risk in smokers.
- Key distinguishing features:
- AATD-associated emphysema is basilar predominant, whereas smoking-related COPD is apical predominant.
- Earlier onset of disease (30s-50s in AATD vs. 50s-70s in smoking-related COPD).
- Family history of early-onset COPD suggests AATD.
2. Asthma
- Key similarities:
- Dyspnea, cough, and wheezing.
- Key distinguishing features:
- Asthma is fully reversible with bronchodilators, while AATD-related airflow obstruction is only partially reversible.
- Eosinophilic inflammation predominates in asthma, whereas neutrophilic inflammation is more prominent in AATD-related lung disease.
- No emphysema on imaging in asthma.
3. Bronchiectasis
- Key similarities:
- Chronic cough with mucopurulent sputum production.
- Recurrent respiratory infections.
- CT scan findings of airway wall thickening.
- Key distinguishing features:
- AATD patients often have coexisting emphysema, which is uncommon in primary bronchiectasis.
- Cystic fibrosis, primary ciliary dyskinesia, or immune deficiencies should be ruled out if bronchiectasis is isolated.
- CFTR gene mutations and ciliary dysfunction tests differentiate other causes of bronchiectasis.
4. Cystic Fibrosis (CF)
- Key similarities:
- Chronic cough, frequent infections, and bronchiectasis.
- Key distinguishing features:
- CF presents in childhood, whereas AATD-related bronchiectasis is more common in adults.
- Sweat chloride test and CFTR gene testing confirm CF.
- Pancreatic insufficiency is common in CF but absent in AATD.
5. Primary Ciliary Dyskinesia (Kartagener Syndrome)
- Key similarities:
- Chronic bronchiectasis and recurrent infections.
- Key distinguishing features:
- Dextrocardia or situs inversus (in Kartagener syndrome).
- Nasal nitric oxide test and ciliary function studies differentiate primary ciliary dyskinesia from AATD.
Hepatic Differentials
1. Chronic Viral Hepatitis (Hepatitis B, C)
- Key similarities:
- Chronic liver disease, cirrhosis, and hepatocellular carcinoma risk.
- Key distinguishing features:
- Positive viral hepatitis serology (HBV DNA, HCV RNA).
- Absence of AAT accumulation in hepatocytes on liver biopsy.
2. Hereditary Hemochromatosis
- Key similarities:
- Genetic liver disease with cirrhosis.
- Key distinguishing features:
- Elevated serum ferritin and transferrin saturation.
- HFE gene mutation testing confirms diagnosis.
- Iron deposition in hepatocytes on liver biopsy.
3. Wilson Disease
- Key similarities:
- Genetic liver disease that presents with cirrhosis.
- Key distinguishing features:
- Neurological symptoms (tremor, dystonia, psychiatric changes) are common in Wilson disease.
- Low serum ceruloplasmin, high urinary copper.
- Kayser-Fleischer rings on slit-lamp examination.
4. Non-Alcoholic Steatohepatitis (NASH)
- Key similarities:
- Liver fibrosis and cirrhosis in the absence of alcohol abuse.
- Key distinguishing features:
- Obesity, diabetes, and metabolic syndrome are common risk factors.
- Elevated liver enzymes (ALT > AST) but no AAT accumulation.
- Liver biopsy showing macrovesicular steatosis.
5. Autoimmune Hepatitis
- Key similarities:
- Hepatitis, cirrhosis, and possible hepatocellular carcinoma.
- Key distinguishing features:
- Positive autoimmune markers: ANA, SMA, anti-LKM-1.
- Elevated IgG levels.
- Interface hepatitis on liver biopsy.
6. Alcohol-Related Liver Disease
- Key similarities:
- Liver cirrhosis and hepatocellular carcinoma.
- Key distinguishing features:
- History of heavy alcohol consumption.
- Elevated gamma-GT, AST > ALT (2:1 ratio).
- Carbohydrate-deficient transferrin (CDT) testing.
Management
General Approach
- Smoking cessation: The most critical intervention to slow disease progression.
- Environmental exposure reduction: Avoidance of air pollutants, occupational fumes, and secondhand smoke to prevent worsening lung disease.
- Vaccination: Hepatitis A and B vaccines to reduce the risk of viral liver injury.
- Lifestyle modifications: Pulmonary rehabilitation and nutritional optimisation to maintain function and reduce complications.
- Routine monitoring: Annual lung function (FEV1) and liver function (LFTs) tests to track disease progression.
Pulmonary Management
Standard COPD Treatment
AATD-related emphysema is treated similarly to COPD from other causes, incorporating:
- Bronchodilators (short- and long-acting).
- Inhaled corticosteroids (for frequent exacerbators).
- Antibiotic therapy (for exacerbations with increased sputum production).
- Oxygen therapy (for chronic hypoxemia).
- Pulmonary rehabilitation to improve endurance and reduce dyspnea.
- Annual influenza and pneumococcal vaccines.
Augmentation Therapy (Intravenous AAT)
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Indications:
- Recommended for PIZZ or PIZ/null individuals with FEV1 ≤65%.
- Not beneficial for heterozygous carriers (PI*MZ) unless significant COPD is present.
- Patients with low AAT levels but normal lung function are not candidates.
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Evidence:
- Studies suggest a 23-26% reduction in the rate of FEV1 decline.
- Meta-analyses show improvement in lung density on CT, but no clear mortality benefit.
- Data indicate fewer exacerbations and lower hospitalisation costs.
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Dosing and Administration:
- Weekly IV infusions of purified pooled human AAT to maintain protective lung levels.
- Pre-treatment IgA testing recommended (risk of anaphylaxis in IgA-deficient individuals).
Lung Transplantation
- Considered in severe cases (FEV1 <25%, chronic CO₂ retention, or frequent exacerbations).
- 5-year survival ~53%; 10-year survival ~45%.
- Does not necessarily improve life expectancy, but enhances quality of life.
Lung Volume Reduction Surgery (LVRS)
- Selective benefit for upper-lobe predominant emphysema.
- Not effective for basilar-dominant AATD emphysema.
Hepatic Management
General Treatment
- Monitor liver function regularly to detect early cirrhosis.
- Screen for hepatocellular carcinoma in patients with cirrhosis (ultrasound every 6-12 months).
- Management of complications:
- Diuretics for ascites.
- Endoscopic variceal screening and ligation.
- Liver transplantation for end-stage disease.
Liver Transplantation
- Definitive treatment for advanced liver failure.
- AATD accounts for ~1% of all liver transplants.
- Survival rates:
- 5-year: ~80% (PI*ZZ).
- 10-year: ~70%.
No Role for Augmentation Therapy
- Augmentation does not reduce liver fibrosis or improve hepatic function.
- Research into chaperone therapy and gene therapy for preventing polymer accumulation is ongoing.
Prevention and Long-Term Monitoring
Pulmonary Monitoring
- Annual lung function tests (FEV1 decline >120 mL/year suggests progression).
- Routine spirometry in first-degree relatives of diagnosed individuals.
- Pneumococcal revaccination every 5 years.
Liver Monitoring
- Regular LFTs for PI*ZZ individuals.
- Ultrasound screening every 6-12 months for hepatocellular carcinoma.
Emerging and Experimental Therapies
- Inhaled AAT therapy – Under investigation for direct pulmonary delivery.
- Gene therapy – SERPINA1 gene correction in muscle or liver cells.
- Small molecule chaperones – Designed to prevent AAT polymerisation in hepatocytes.
- Antioxidant and anti-inflammatory agents – Trials ongoing for lung tissue preservation.
Prognosis
Overall
- No cure exists for AATD, but many individuals, particularly non-smokers, have near-normal life expectancy.
- Mortality is primarily due to respiratory failure (50-72%), followed by liver disease (10-20%).
- Prognosis varies widely depending on smoking status, severity of lung disease, and genotype.
- Patients identified through screening (asymptomatic) have better outcomes than those diagnosed after symptom onset.
Lung Disease Prognosis
- Emphysema is the leading cause of death in AATD.
- Median survival age:
- Smokers: ~40 years.
- Non-smokers: ~65 years.
- FEV1 decline rates:
- Never-smokers: 47–80 mL/year.
- Ex-smokers: 41–81 mL/year.
- Current smokers: 61–316 mL/year (accelerated lung function loss).
- FEV1 as a predictor of mortality:
- FEV1 >50%: 5-year mortality ~4%.
- FEV1 35-49%: 5-year mortality ~12%.
- FEV1 <35%: 5-year mortality ~50%.
- Augmentation therapy slows lung function decline and may provide a mortality benefit.
Survival After Lung Transplant
- 5-year survival rate ~50%.
- Median post-transplant survival ~6.3 years.
Liver Disease Prognosis
- Patients with PI*ZZ who do not develop emphysema are at higher risk for liver disease.
- Fibrosis prevalence:
- 20-36% of asymptomatic PI*ZZ adults.
- Cirrhosis prevalence:
- 2-43% of AATD patients.
- Higher rates in older non-smokers.
- Primary liver cancer and cirrhosis:
- One-third of older PI*ZZ patients die from portal hypertension or hepatocellular carcinoma.
- One-third of older PI*ZZ patients die from portal hypertension or hepatocellular carcinoma.
Factors Associated with Poor Prognosis
- Smoking: Accelerates lung disease progression and shortens lifespan.
- Male sex: Linked to higher emphysema prevalence.
- Significant bronchodilator response (>12% and >200 mL): Correlates with worse lung function decline.
- Late diagnosis: Median diagnostic delay ~8 years, leading to worse outcomes.
Complications
Pulmonary Complications
1. Emphysema
- Most common complication of AATD.
- Progressive destruction of alveolar walls, leading to air trapping and airflow obstruction.
- Basilar-predominant emphysema (distinct from smoking-related apical disease).
- Exacerbated by smoking → Accelerated FEV1 decline and early respiratory failure.
2. Chronic Bronchitis
- Defined as productive cough for ≥3 months in 2 consecutive years.
- Frequent exacerbations and recurrent infections contribute to worsening airflow limitation.
3. Asthma-like Features
- Bronchodilator-responsive airway obstruction.
- Higher prevalence of wheezing than in non-AATD COPD.
- Incomplete reversibility on spirometry differentiates it from true asthma.
4. Bronchiectasis
- Irreversible airway dilation due to chronic inflammation and infection.
- Persistent cough, sputum production, and recurrent infections.
- CT scan shows airway wall thickening and mucus plugging.
5. Spontaneous Pneumothorax
- Occurs due to rupture of emphysematous bullae.
- Sudden-onset pleuritic chest pain and dyspnea.
- Higher risk in advanced disease.
6. Pulmonary Hypertension and Cor Pulmonale
- Chronic hypoxia leads to pulmonary vasoconstriction, increasing right ventricular afterload.
- Signs of right heart failure:
- Peripheral oedema.
- Jugular venous distension.
- Hepatomegaly.
- Requires oxygen therapy and diuretics for management.
Hepatic Complications
1. Chronic Liver Disease and Cirrhosis
- Accumulation of misfolded AAT polymers in hepatocytes.
- 20-36% of asymptomatic PI*ZZ adults develop fibrosis.
- Cirrhosis prevalence: 2-43%, increasing with age.
- Complications:
- Portal hypertension.
- Esophageal varices.
- Hepatic encephalopathy.
2. Hepatocellular Carcinoma (HCC)
Increased risk in PI*ZZ individuals with cirrhosis.
- One-third of older PI*ZZ patients die from liver-related causes.
- Screening:
- Regular LFTs and alpha-fetoprotein (AFP) monitoring.
- Abdominal ultrasound every 6-12 months.
- CT/MRI if AFP levels are rising.
- Management:
- Liver transplantation for advanced cases.
- Resection or locoregional therapy in early-stage disease.
Extrapulmonary and Systemic Complications
1. Necrotising Panniculitis
- Rare (1 in 1000 AATD patients).
- Painful, erythematous, non-pruritic skin lesions.
- Lesions ulcerate with seropurulent exudate.
- Diagnosis:
- Skin biopsy (neutrophilic infiltrate, necrosis).
- Serum AAT levels and genotyping.
- Treatment:
- AAT augmentation therapy.
- Smoking cessation (critical).
- Corticosteroids and antibiotics are ineffective.
2. Granulomatosis with Polyangiitis (GPA)
- AATD is associated with c-ANCA positive vasculitis (GPA).
- Mechanism:
- AAT normally inhibits proteinase-3 (PR-3), a key target in ANCA vasculitis.
- PI*ZZ variant may exacerbate vasculitis progression.
- Clinical presentation:
- Respiratory: Sinusitis, cough, hemoptysis.
- Renal: Hematuria, proteinuria.
- Skin: Purpura, vasculitic rash.
- Diagnosis:
- ANCA serology (c-ANCA positive).
- Lung/kidney biopsy (vasculitis with necrosis).
- AAT genotyping.
- Management:
- Immunosuppressive therapy (steroids, rituximab, cyclophosphamide).
- AAT augmentation therapy may play a role.
Risk Factors for Severe Complications
- Smoking – Major risk factor for early-onset emphysema and premature death.
- Male sex – Associated with higher emphysema prevalence.
- Significant bronchodilator response (>12% and >200 mL) – Indicates faster lung function decline.
- Delayed diagnosis – Median diagnostic delay of ~8 years leads to worse outcomes.
References
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