What are the typical presentation and management of an alpha-1 antitrypsin (A1AT) deficiency patient?

Clinical Presentation of Alpha-1 Antitrypsin Deficiency

Alpha-1 antitrypsin deficiency presents with two primary organ systems: pulmonary disease (most commonly early-onset emphysema) and hepatic disease (ranging from neonatal cholestasis to adult cirrhosis), with highly variable clinical manifestations even among individuals with identical genotypes. 1

Pulmonary Manifestations in Adults

Typical Age and Symptom Onset

• Symptomatic obstructive lung disease typically presents between ages 32-41 years in smokers, rarely before age 25 1
• Many nonsmokers and some smokers remain completely asymptomatic throughout life 1

Cardinal Respiratory Symptoms

• Dyspnea on exertion is the most frequent symptom (84% of patients in the NHLBI Registry) 1
• Wheezing during respiratory infections occurs in 76% of patients, with 65% experiencing wheezing independent of infections 1
• Chronic cough is present in 42% of patients, with increased cough and phlegm for at least 3 weeks per year in 50% 1
• Chronic productive cough consistent with chronic bronchitis occurs in 8-40% of patients 1
• Episodic wheezing and dyspnea mimicking asthma is commonly observed 1

Pathologic Features

• Panacinar emphysema with basal predominance is the hallmark finding at autopsy in all adult patients with severe AAT deficiency 1
• Cylindrical bronchiectasis has been reported in autopsy series and should prompt consideration of testing 1
• Large bullae preferentially in basal lung regions may be present 1

Hepatic Manifestations

Neonatal and Infant Presentation

• Liver dysfunction typically first manifests at 1-2 months of life with prolonged jaundice or hepatomegaly 1
• Laboratory findings include moderately elevated conjugated bilirubin and elevated serum transaminases 1
• All infants with conjugated hyperbilirubinemia, elevated transaminases, or "neonatal hepatitis syndrome" should be tested for AAT deficiency 1

Coagulopathy Presentation

• Some infants present with vitamin K deficiency-related bleeding: gastrointestinal bleeding, umbilical stump bleeding, easy bruising, or rarely CNS hemorrhage 1
• Timely vitamin K supplementation is potentially life-saving in these cases 1

Progressive Infantile Disease

• A small proportion develop progressive hepatosplenomegaly, ascites, liver synthetic dysfunction, poor feeding, and growth failure 1
• Fulminant hepatic failure in infancy is rare but documented 1
• Rare presentation: cholestatic pruritus with hypercholesterolemia and paucity of intrahepatic bile ducts 1

Childhood, Adolescent, and Adult Hepatic Disease

• Presentations include hepatosplenomegaly, ascites, upper GI bleeding from esophageal varices, chronic hepatitis, cirrhosis, or hepatic failure 1
• The presentation may mimic autoimmune hepatitis, drug-induced hepatitis, chronic viral hepatitis, or Wilson's disease 1
• Elevated transaminases may persist for years despite minimal clinical signs 1

Less Common Manifestations

Dermatologic

• Necrotizing panniculitis (rare) 1

Vasculitis

• Wegener's granulomatosis (anti-proteinase-3 vasculitis) shows high prevalence of PIZZ and PIMZ phenotypes 1

Who Should Be Tested: Clinical Indications

Highest Priority (Strongest Recommendations)

1. Confirmation of absent alpha-1 antitrypsin peak on serum protein electrophoresis 1
2. Early-onset pulmonary emphysema regardless of smoking history 1
3. Family members of known AAT-deficient patients 1

High Priority

1. Dyspnea and cough occurring in multiple family members across generations 1
2. Liver disease of unknown cause at any age 1
3. All subjects with COPD 1

Should Be Considered

1. Adults with bronchiectasis without evident etiology 1
2. Patients with asthma whose spirometry fails to return to normal with therapy 1
3. Unexplained panniculitis and anti-proteinase-3 vasculitis 1

Critical Diagnostic Pitfall

Alpha-1 antitrypsin is an acute phase reactant—serum levels rise during acute inflammation, infections, or exacerbations of chronic disease, potentially masking underlying deficiency with falsely normal or elevated levels. 2 Levels as high as 1.4 g/L may be reached in deficient patients during acute inflammation 2. Avoid testing during acute illness; if clinical suspicion remains high despite borderline/normal levels, proceed directly to SERPINA1 DNA sequencing rather than repeat protein measurements. 2

Management Principles

Standard COPD Therapy

• Bronchodilators provide symptomatic benefit even when objective bronchodilator responsiveness is lacking 1
• Inhaled corticosteroids for those with bronchial hyperreactivity 1
• Aggressive antibiotic treatment for purulent exacerbations and upper respiratory infections 1
• Supplemental oxygen for desaturation during exercise or severe hypoxemia 1

Augmentation Therapy Eligibility

Augmentation therapy is indicated specifically for severe hereditary AAT deficiency with clinically evident emphysema documented on CT imaging. 3, 4 The FDA label explicitly states that "the clinical efficacy of GLASSIA in influencing the course of pulmonary emphysema or the frequency, duration, or severity of pulmonary exacerbations has not been demonstrated in randomized, controlled clinical trials." 4

Strongest evidence for benefit exists in patients with FEV1 31-65% predicted (moderate emphysema), with yearly FEV1 decline of -53 mL in treated versus -75 mL in untreated groups. 3

Absolute Requirements Before Augmentation

• Current nonsmoker for at least 6 months 3
• High-resolution CT chest documenting emphysema 3
• Optimal conventional COPD therapy already in place 3
• Exclusion of IgA deficiency with anti-IgA antibodies 3

Hepatic Disease Management

• No specific medical therapy exists for AAT deficiency-related liver disease 1
• Liver transplantation is the only option for life-threatening liver failure 1, 5
• Hepatitis B vaccination is recommended for patients with overt liver disease 1

Family Screening

First-degree family members of newly diagnosed patients should be tested, with appropriate patient education and counseling, as many affected individuals are identified through family studies. 1