Summary

Alpha-1 Antitrypsin Deficiency (AATD) is an autosomal codominant genetic disorder caused by mutations in the SERPINA1 gene, leading to reduced or dysfunctional alpha-1 antitrypsin (AAT) protein. AAT is a protease inhibitor that protects lung tissue from neutrophil elastase. Deficiency leads to early-onset emphysema, particularly in smokers. The abnormal protein also accumulates in hepatocytes, causing liver disease ranging from neonatal cholestasis to adult cirrhosis. AATD is underdiagnosed — all patients with COPD should be tested at least once. Management includes smoking cessation, standard COPD treatment, and augmentation therapy for selected patients.

Key Facts

• Prevalence: 1 in 2000-5000 Europeans; most common in Northern Europe
• Genetics: Autosomal codominant; PiZZ genotype is most severe
• Lung disease: Panacinar basilar emphysema; accelerated by smoking
• Liver disease: 15% of homozygotes develop cirrhosis
• Key management: Smoking cessation is CRITICAL; augmentation therapy in selected patients
• Screening: Test ALL COPD patients at least once

Clinical Pearls

Think Young and Basal: Classic AATD emphysema presents in patients under 45, affects the lung bases rather than apices, and may occur in non-smokers or light smokers. If the pattern doesn't fit typical smoking-related COPD, test for AATD.

The Liver Connection: AAT accumulates as PAS-positive globules in hepatocytes. Liver disease may present in infancy (neonatal cholestasis) or adulthood (cirrhosis), and can occur independently of lung disease.

One-Time Test, Lifetime Diagnosis: AATD is genetic — a single test provides a lifelong diagnosis. WHO, ATS, and ERS recommend testing ALL COPD patients at least once.

Why This Matters Clinically

AATD is the most common genetic cause of COPD and liver disease in adults. Early diagnosis allows smoking prevention/cessation (which dramatically changes prognosis), family screening, and consideration of augmentation therapy. Despite guidelines, testing rates remain low and most patients are diagnosed late.

Structured Approach

General:

• Body habitus (weight loss, muscle wasting)
• Pursed lip breathing
• Use of accessory muscles

Respiratory:

• Chest shape (hyperinflation, barrel chest)
• Expansion (reduced)
• Percussion (hyper-resonant)
• Auscultation (reduced breath sounds basally, wheeze)

Abdominal:

• Hepatomegaly
• Splenomegaly (portal hypertension)
• Ascites

Skin:

• Panniculitis (rare) — tender subcutaneous nodules

Special Tests

Natural History

• Variable expression even within same genotype
• Smokers with PiZZ: Mean age at death 50-55 years
• Non-smokers with PiZZ: Near-normal life expectancy
• Rate of FEV1 decline: 40-80 ml/year without treatment

Outcomes with Treatment

Prognostic Factors

Good Prognosis:

• Never smoked
• Diagnosed early
• Genotype other than PiZZ (e.g., PiMZ, PiSZ)
• Good baseline FEV1 at diagnosis
• Adherence to augmentation therapy

Poor Prognosis:

• PiZZ genotype
• Continued smoking
• Low FEV1 at diagnosis
• Frequent exacerbations
• Liver cirrhosis

Key Guidelines

1. ATS/ERS Statement: AATD (2003) — American Thoracic Society/European Respiratory Society. Am J Respir Crit Care Med 2003
2. Alpha-1 Foundation Clinical Practice Guidelines (2016) — Comprehensive AATD management.
3. NICE CG101 — COPD guidelines (includes AATD testing recommendation).

Landmark Trials

RAPID Trial (2015) — Augmentation therapy efficacy

• 180 patients with PiZZ AATD
• Key finding: Augmentation reduced lung density decline on CT by 34%
• Clinical Impact: Supports augmentation therapy for eligible patients

EXACTLE Trial (2009) — Augmentation and lung function

• 77 patients
• Key finding: Trend toward reduced FEV1 decline with augmentation
• Clinical Impact: Contributed to augmentation evidence base

Evidence Strength

What is Alpha-1 Antitrypsin Deficiency?

Alpha-1 antitrypsin deficiency (AATD) is an inherited condition where your body does not produce enough of a protective protein called alpha-1 antitrypsin (AAT). This protein normally protects your lungs from damage. Without enough of it, your lungs can be damaged more easily, leading to a type of lung disease called emphysema.

Why does it matter?

If you have AATD and smoke, you are at very high risk of developing emphysema at a young age. Even non-smokers with AATD can develop lung problems, though usually later in life. Some people with AATD also develop liver problems because the abnormal protein can build up in the liver.

How is it treated?

1. Stop smoking: This is by far the most important thing. Smoking with AATD can take decades off your life; not smoking can give you near-normal life expectancy.
2. Inhalers and lung treatments: Standard COPD treatments help manage symptoms.
3. Pulmonary rehabilitation: Exercise programmes help you stay as active as possible.
4. Augmentation therapy: For some patients, weekly infusions of the missing AAT protein can slow lung damage.
5. Transplantation: For severe lung or liver disease, transplantation may be an option.

What to expect

• AATD is lifelong, but outcomes depend heavily on whether you smoke
• With the right treatment and lifestyle, many people live full lives
• Family members should be tested because AATD is inherited

When to seek help

See your doctor if you:

• Are short of breath, especially with mild activity
• Have COPD and have never been tested for AATD
• Have a family history of emphysema or liver disease
• Develop worsening cough, increased sputum, or chest infections