Alpha-1 Antitrypsin Deficiency (AATD)

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.

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

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.
• PIMZ individuals who smoke exhibit more severe lung disease and lower FEV1/FVC ratios compared to PIMM smokers.

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.

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.

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

• Loss of antiprotease protection in the lungs → Emphysema.
• Toxic gain of function in hepatocytes → Liver disease.

 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.

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

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.

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.

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.

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.

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

• 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.

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

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.

Sex

• Men and women are affected equally, though males may have earlier and more severe pulmonary symptoms, potentially due to higher smoking rates.

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

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.

Air pollution and passive smoking

• May exacerbate lung inflammation, contributing to accelerated emphysema progression.

Diagnostic Delays and Misdiagnosis

• Average delay from symptom onset to diagnosis: 5 to 8 years.
• 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.
• 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.

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.

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 Ultrasound

• Recommended annually in patients at risk for AATD-associated liver disease.
• Detects cirrhosis, hepatomegaly, and portal hypertension.

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)

• Panacinar emphysema with destruction of alveolar walls.
• Uniform acinar involvement, predominantly in the lung bases.

Pulmonary Differentials

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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)

• 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.
• 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.
• 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.

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.

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.

Pulmonary Complications

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.

Chronic Bronchitis

• Defined as productive cough for ≥3 months in 2 consecutive years.
• Frequent exacerbations and recurrent infections contribute to worsening airflow limitation.

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.

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.

Spontaneous Pneumothorax

• Occurs due to rupture of emphysematous bullae.
• Sudden-onset pleuritic chest pain and dyspnea.
• Higher risk in advanced disease.

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

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.
  • Oesophagal varices.
  • Hepatic encephalopathy.

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

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.

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.

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