What is the recommended management and treatment plan for a patient with alpha 1 antitrypsin deficiency, specifically with a genotype of PI*Z, as indicated by low alpha 1 antitrypsin level?

Management of Alpha-1 Antitrypsin Deficiency with PI*Z Genotype

For a patient with alpha-1 antitrypsin deficiency and PI*Z genotype (level 209 mg/dL, approximately 3.6 μM), the priority is confirming the diagnosis with phenotyping or DNA sequencing, implementing strict smoking cessation, screening for both lung and liver disease, and considering augmentation therapy only if clinically evident emphysema is documented. 1, 2

Diagnostic Confirmation

• Phenotyping by isoelectric focusing (IEF) is the gold standard for diagnosis, though DNA sequencing of the SERPINA1 gene surpasses IEF because it detects rare variants and provides invariant results. 3, 2

• Serum AAT levels alone should not be used as the sole basis for diagnosis, as heterozygotes often have normal plasma levels and levels may transiently increase even in PI*ZZ patients during systemic inflammation. 3

• If the patient has a PIZ genotype (either PIZZ homozygous or PI*MZ heterozygous), proceed with phenotyping plus DNA testing to definitively characterize the genotype. 2

Risk Stratification by Genotype

PI*ZZ Homozygotes (Most Severe)

• Relative risk of cirrhosis is 3% before age 18,2-5% between ages 18-50, and 20-40% after age 50, predominantly in never-smokers. 3

• PI*ZZ patients have the highest risk for both lung and liver disease due to severe AAT deficiency (typically <11 μM or <57 mg/dL). 4

PI*MZ Heterozygotes (Intermediate Risk)

• Plasma levels are often normal and may not predict disease risk accurately. 3

• Recent evidence shows PIMZ genotype increases risk of liver transplantation/liver-related death even after adjusting for liver disease severity (adjusted hazard ratio ≈1.56 vs PIMM). 5

• Heterozygotes have intermediate risk for cirrhosis (2-5% between ages 18-50). 3

Pulmonary Disease Management

Smoking Cessation (Highest Priority)

• Smoking cessation is the single most important intervention and must be the primary focus at every patient visit, as smoking dramatically accelerates emphysema progression and is associated with liver disease progression in PI*ZZ patients. 1, 6

• The risk of accelerated emphysema development is higher in smokers than ex-smokers or non-smokers. 4

Baseline Pulmonary Assessment

• Evaluate for COPD, adult-onset asthma with persistent airflow obstruction, or unexplained bronchiectasis. 1, 2

• Perform pulmonary function tests to document baseline lung function and assess for clinically evident emphysema. 1

Vaccinations and Environmental Modifications

• Vaccination against influenza and pneumococcus is mandatory. 1

• Reduction of occupational exposure to dust, smoke, gases, and air pollutants is essential. 1

Augmentation Therapy Decision-Making

Indications

• Augmentation therapy is specifically indicated only for severe hereditary AAT deficiency (PI*ZZ or rare null variants) with clinically evident emphysema documented on imaging. 1, 4

• The intended goal is to maintain serum AAT levels above 11 μM (approximately 57 mg/dL) to provide anti-neutrophil elastase protection, though this threshold has not been proven in controlled trials. 4

Absolute Contraindications

• Active smoking 1
• IgA deficiency with anti-IgA antibodies 1
• Absence of documented emphysema on imaging 1

Dosing and Administration

• The standard dose is 60 mg/kg body weight once weekly by intravenous infusion, which increases lung levels of AAT to 60-70% of normal. 1, 4

• This dosing maintains target serum AAT trough levels and increases antigenic levels in epithelial lining fluid. 4

Critical Limitations

• The clinical efficacy of augmentation therapy in influencing the course of pulmonary emphysema has not been conclusively demonstrated in adequately powered, randomized, controlled clinical trials. 4

• The clinical benefit of increased blood and epithelial lining fluid levels at the recommended dose has not been established. 4

Liver Disease Screening and Management

Diagnostic Approach

• For suspected liver disease, perform AAT phenotyping plus abdominal ultrasound—liver biopsy is not necessary to establish the diagnosis. 3, 1

• Rule out other causes of chronic liver disease including viral hepatitis, hemochromatosis, Wilson's disease, alcoholic liver disease, and autoimmune hepatitis by laboratory examinations. 3

• Liver biopsy may be useful for staging severity in patients with clinically overt liver disease, but phenotyping remains the gold standard for diagnosis. 3, 2

Surveillance Protocol

• Simple liver function tests and regular ultrasound examination are necessary for follow-up of asymptomatic individuals with AAT deficiency. 3, 1

• For patients with resultant cirrhosis, periodic computed tomography scans of the liver should be considered for hepatocellular carcinoma surveillance, though this needs validation in prospective studies. 3

• Screening for primary liver cancer by CT scan is recommended due to low sensitivity and specificity of serum α-fetoprotein measurement. 3

Liver Disease Progression Factors

• Smoking history is significantly associated with liver disease progression in PI*ZZ patients with cirrhosis, whereas age and sex are not. 6

• Patients with AATD and lung disease may have delayed diagnosis of comorbid liver disease, but liver disease may progress more rapidly in patients without comorbid lung disease. 7

• The PI*Z allele is an independent risk factor for liver transplantation and liver-related death in patients with advanced chronic liver disease, even after adjusting for disease severity. 5

Hepatitis Vaccination

• The efficacy and advisability of vaccination against chronic viral infections, particularly hepatitis B, should be implemented, as the interaction between AAT deficiency and chronic viral hepatitis needs further exploration. 3

Liver Transplantation Considerations

• Liver transplantation is the only definitive treatment for PI*ZZ-associated liver disease when patients develop progressive hepatic dysfunction, cirrhosis with complications, or hepatocellular carcinoma. 3, 8

• AATD-LD-PI*ZZ patients without lung disease are more likely to undergo liver transplantation compared with those with lung disease. 7

• Restoration of plasma AAT levels after liver transplantation corrects both the liver disease and provides normal AAT protein, potentially protecting against lung disease progression. 8

Family Screening

• Family screening should be discussed with all patients, recognizing it can reasonably be accepted or declined. 1, 2

• Siblings of a PIMZ heterozygote have a 25% chance of being heterozygous; siblings of a PIZZ homozygote have a 25% chance of being homozygous. 3, 1, 2

• Offspring of a heterozygous parent have a 25% chance of being heterozygous. 1, 2

• Testing should include simultaneous serum AAT level measurement and DNA analysis of the SERPINA1 gene. 1, 2

Multiorgan Vasculitis Screening

• Approximately 2% of all patients with anti-PR-3-positive (C-ANCA) multisystemic vasculitis are PI*Z homozygotes, with the remaining PI*Z individuals being heterozygotes. 3

• There is a strong relationship between PI*Z AAT deficiency and small vessel-necrotizing vasculitides, particularly Wegener's granulomatosis and microscopic polyangiitis. 3

• The PI*Z variant may have an adverse accelerative effect on vasculitic processes once they start, potentially increasing risk of fatal outcome. 3

Rare Manifestations Requiring Awareness

Necrotizing Panniculitis

• Prevalence is less than 1 case per 1,000 AAT-deficient patients. 3

• Augmentation therapy with purified human AAT or fresh frozen plasma to restore plasma and local tissue levels appears rational, safe, and effective. 3

• Dapsone, either alone in less severe cases or combined with augmentation therapy, may provide additional benefit. 3

Pediatric Liver Disease

• Neonatal cholestasis occurs in a subset of PI*ZZ infants, with presentations ranging from transient conjugated hyperbilirubinemia to progressive liver disease. 3

• Elevated transaminases, bilirubin, and prolonged prothrombin time suggest poor prognosis in pediatric cases. 3

• Fulminant hepatic failure in infancy is rare but has been described. 3

Monitoring and Follow-Up

• Regular pulmonary function testing to monitor for emphysema progression 1

• Serial liver function tests and abdominal ultrasound for liver disease surveillance 3, 1

• Nutritional support is essential, as weight loss and malnutrition are common due to increased metabolic rate from increased respiratory work. 1

• Early recognition and aggressive treatment of depression, including loss of appetite. 1