Alpha-1 Antitrypsin Deficiency

Normal Alpha-1 Antitrypsin Physiology (see Serum Alpha-1 Antitrypsin, [[Serum Alpha-1 Antitrypsin]])

Synthesis and Circulation of Alpha-1 Antitrypsin

  • A1AT is Mainly Synthesized by the Liver: some A1AT is also synthesized locally in the lung by macrophages and bronchial epithelial cells
  • A1AT is a 52 kD (394 AA) Glycoprotein Serine Protease Inhibitor (From the “Serpin” Family)
    • “Serpinopathies”: collection of neurodegenerative diseases, angioedema-related disorders, and coagulation disorders
  • A1AT Synthesized in the Liver Reaches the Lungs Via Diffusion from the Circulation

Normal Alpha-1 Antitrypsin Level

  • Normal Serum A1AT Level: 100-300 mg/dL (20-60 µM)
  • Threshold (Protective) Serum A1AT Level Below Which There is an Increased Risk of Emphysema: <80 mg/dL (<11 µM)

Normal Biologic Functions of Alpha-1 Antitrypsin

  • Inhibition of Pancreatic Trypsin/Chymotrypsin
  • Inhibition of Elastase/Granulocytic Elastase: the main site of action is neutrophil elastase
  • Inhibition of Collagenase/Synovial and Skin Collagenases
  • Inhibition of Microorganism Proteases

Etiology of Elevated Alpha-1 Antitrypsin

  • General Comments: A1AT is an acute phase reactant, which is increased in a variety of conditions
  • Active Vasculitis (see Vasculitis, [[Vasculitis]])
  • Following Intravenous Typhoid Vaccine Administration (see Typhoid Fever, [[Typhoid Fever]])
  • Infection
  • Malignancy
  • Pregnancy (see Pregnancy, [[Pregnancy]])
  • Severe Burns (see Burns, [[Burns]])
  • Tobacco Use (see Tobacco, [[Tobacco]]): smoking elevates the A1AT level approximately 20%

Interactive Effect of Tobacco Smoke Exposure

  • Smokers Have Increased Neutrophils and Increased A1AT: however, the A1AT is inactivated by smoke
  • There is Greater Desmosine Excretion (Derived from Elastin Cross-Links) in Smokers with More Rapid Decline in Lung Function (as Compared to Smokers with Normal Rates of Decline): this supports the role of elastin degradation in the decline in lung function
  • Basilar-Predominance of Lung Disease: likely related to greater blood flow to lung bases, with more neutrophil elastase-mediated damage in this region of the lung

Genetics

General Information

  • SERPINA1 Gene is Located on the Long Arm of Chromosome 14 and Encodes for A1AT
    • At Least 150 Different Alleles of SERPINA1 Have Been Identified the alleles have letter codes based on the electrophoretic mobility of the protein which is produced
      • M Allele: normal allele
        • M Migrates in the “Middle” on Isoelectric Focusing
      • S Allele: single amino acid substitution of valine for glutamic acid at position 264 -> enhanced intracellular degradation of A1AT protein
        • S Migrates “Slowly” on Isoelectric Focusing
      • Z Allele: point mutation Glu342Lys (substitution of lysine for glutamic acid at position 342) -> increased polymerization and aggregation of A1AT protein
        • Z Migrates the Most Slowly on Isoelectric Focusing: “Z” was used to designate that it was “last”
  • Autosomal Co-Dominant Transmission: affected patients inherit an abnormal gene from each parent

Genotypes

  • General Information
    • Pi: stands for protease inhibitor
  • Pi-MM (Heterozygosity for Normal Allele): genotype present in 90% of European descendants
    • A1AT Level: 1800-2000 mg/L (Normal Levels)
    • Risk of Disease: no risk of disease
  • Pi-SS
    • A1AT Level: usually 15-33 µM (Mean: 52% of Normal)
    • Risk of Disease: no risk of disease
  • Pi-SZ (Compound Heterozygosity = Carries Two Different Mutations of the Gene)
    • A1AT Level: usually 8-19 µM (mean: 37% of Normal)
      • Approximately 10% of Pi-SZ Cases Have A1AT levels <80 mg/dL (<11 µM)
    • Risk of Disease: rarely develop emphysema -> this group provides the basis for the serum level cut-off of 11 µM
  • Pi-MZ: genotype present in 2-3% of caucasians in the US
    • A1AT Level: usually 12-35 µM (mean level: 57% of Normal)
      • Pi-MZ Cases Rarely Have A1AT Levels Below the Serum Cut-Off Level of 80 mg/dL (<11 µM)
    • Risk of Lung Disease
      • From Family Study Data: minimally increased risk of lung disease
      • From Population Study Data: probably no increased risk of lung disease
    • Risk of Liver Disease: associated with cryptogenic cirrhosis in adults (Hepatology, 1998) [MEDLINE]
  • Pi-ZZ
    • A1AT Level: usually 2.5-7.0 µM (Mean level: 16% of Normal)
    • Risk of Disease: see below
  • Pi-Null
    • A1AT Level: undetectable
  • Pi-Null-Null
    • A1AT Level: decreased
  • PiZ-Null
    • A1AT Level: decreased
  • Dysfunctional A1AT
    • A1AT Level: normal levels of dysfunctional A1AT

End-Organ Dysfunction in Alpha-1 Antitrypsin Deficiency

  • Lung Disease: results from an imbalance between neutrophil elastase in the lung (which destroys elastin) and the elastase inhibitor A1AT (which protects against the proteolytic degradation of elastin)
  • Liver Disease: results from an accumulation of unsecreted variant A1AT protein within the hepatocyte

Diagnosis

Pulmonary Function Tests (PFT’s) (see Pulmonary Function Tests, [[Pulmonary Function Tests]])

  • Obstructive Pattern (see Obstructive Lung Disease, [[Obstructive Lung Disease]])
    • FEV1: decreased
    • FVC: normal
    • FEV1/FVC Ratio: decreased

Perfusion (Q) Scan (see Ventilation-Perfusion Scan, [[Ventilation-Perfusion Scan]])

  • Demonstrates that Earliest Involvement Occurs in the Lung Bases

Bronchoscopy (see Bronchoscopy, [[Bronchoscopy]])

  • Usually Not Necessary
  • Bronchoalveolar Lavage (BAL): A1AT present in normals

Video-Assisted Thoracoscopic Surgery (VATS) with Lung Biopsy (see Video-Assisted Thoracoscopic Surgery, [[Video-Assisted Thoracoscopic Surgery]])

  • Usually Not Necessary: panlobular basilar-predominant emphysema

Chest X-Ray/Chest CT Pattern (see Chest X-Ray, [[Chest X-Ray]] and Chest Computed Tomography, [[Chest Computed Tomography]])

  • Hyperinflation with Basilar-Predominant Emphysema: this is strongly suggestive, but not necessary, for the diagnosis
    • This is in contrast to normal (Pi-MM) COPD, which typically has upper lobe predominance
    • Pi-ZZ patients typically have more evidence of emphysema than PI-MM patients with COPD
    • 85% of Pi-ZZ cases have some radiologic evidence of emphysema (of these, 99.8% have some basilar emphysema, while 24% have emphysema confined to the lung bases)

Serum Alpha-1 Antitrypsin Level (see Serum Alpha-1 Antitrypsin, [[Serum Alpha-1 Antitrypsin]])

  • Techniques: normal values differ for each test
    • Immune Turbidimetry
    • Immunodiffusion
    • Nephelometry
    • Rocket Immunoelectrophoresis
  • Cautions
    • A1AT is an Acute Phase Reactant: increases during acute illness (perhaps into the normal range for patients with PiSZ and PiMZ phenotypes)
      • For This Reason, Testing Should Be Deferred Until Resolution of the Acute Illness
  • Interpretation
    • Normal Level: 150-350 mg/dL (20-48 µM)
    • Threshold Level for “Deficiency” (by Immunodiffusion): <80 mg/dL (<11 µM) -> represents a level of about 35% of normal
      • Most Patients Below this Level are Homozygous for the Z Allele (PiZZ Phenotype)
  • Clinical Data
    • Small Dutch Study Evaluating Alpha-1 Antitrypsin Phenotypes in Severe Asthma (Respir Med, 2006) [MEDLINE]
      • A1AT Heterozygosity Does Not Seem to Be an Important Risk Factor of Persistent Airflow Limitation in Patients with Asthma
  • Targeted Testing for Alpha-1 Antitrypsin Deficiency is Recommended for the Following Indications (Canadian Thoracic Society Alpha-1 Antitrypsin Testing and Alpha-1 Antitrypsin Replacement Guidelines, 2012) (Can Respir J, 2012) [MEDLINE]
    • Patient with COPD Diagnosed Before Age <65
    • Patient with COPD Diagnosed with a <20 Pack-Year Smoking History
  • Targeted Testing is Not Recommended for the Following Indications (Canadian Thoracic Society Alpha-1 Antitrypsin Testing and Alpha-1 Antitrypsin Replacement Guidelines, 2012) (Can Respir J, 2012) [MEDLINE]
    • Patients with Bronchiectasis or Asthma (Grade 2C Recommendation)

Genetic Testing

  • Isoelectric Focusing: assesses distinct protein migration speed of the various A1AT variants (S migrates “slowly”; M migrates in the “middle”; Z migrates most slowly -> “Z” was used to designate that it was “last”)
    • Gold Standard Blood Test for Identifying A1AT Variants
  • Genotype PCR (or Restriction Fragment Length Polymorphism, RFLP): detects the most common A1AT alleles (F, I, S, Z)
  • Gene Sequencing: used when PCR and RFLP fail to detect the more rare variants or null alleles

Liver Biopsy (see Liver Biopsy, [[Liver Biopsy]])

  • PAS-Positive Granules in Hepatocytes: probably represent unsecreted incompletely glycosylated Z-protein

Clinical Manifestations: Pi-SZ Genotype

Epidemiology

  • Rare Phenotype

Diagnosis

  • A1AT Level: usually 8-19 µM (mean level: 37% of normal)
    • Approximately 10% of Pi-SZ Cases Have A1AT Level <80 mg/dL (<11 µM)

Clinical Manifestations

  • Emphysema: rarely occurs in this population
    • This Group Provides the Basis for the Serum Level Cut-Off

Clinical Manifestations: Pi-MZ Genotype

Epidemiology

  • Phenotype Present in 2-3% of Caucasians in US

Diagnosis

  • A1AT Level: usually 12-35 µM (mean level: 57% of normal)
    • Since this Group of Patients Rarely Have A1AT Level <80 mg/dL (<11 µM), They are Not Considered Candidates for A1AT Replacement Both for the Reasons Related to Their A1AT Level and Because They are Not Believed to Be at Increased Risk for Lung Disease

Clinical Manifestations

  • Risk of Lung Disease
    • From Family Study Data: minimally increased risk of lung disease
    • From Population Study Data: probably no increased risk of lung disease
  • Cryptogenic Cirrhosis (in Adults) (Hepatology, 1998) [MEDLINE]
  • Necrotizing Panniculitis (see Panniculitis, [[Panniculitis]]): cases have been reported

Clinical Manifestations: Pi-ZZ (and Other Rare A1AT Deficient Phenotypes)

Epidemiology

  • Frequency of Z Allele in US and Europe: 1 in 1600 to 1 in 4000
    • Usually Whites of European Descent: as the Z allele is rare in asians and blacks
  • Relationship of Pi-ZZ Genotype to Disease
    • Pi-ZZ Genotype Accounts for <10% of COPD Cases in North America
    • Pi-ZZ Genotype Accounts for >95% of Severely Deficient A1AT Deficiency Patients
    • Homozygous Pi-ZZ Disease is the Most Common Genetic Liver Disease in Children: occurs in 1:1600 to 1:2800 infants in the US
    • Approximately 10-20% of Pi-ZZ Cases Have Significant Liver Disease During Childhood
    • Family History of COPD is Usually Present in Pi-ZZ Cases, Due to the Genetic Basis of A1AT Deficiency

Diagnosis

Clinical Manifestations

General Comments

  • Clinical Features Which Should Raise the Suspicion of Alpha-1 Antitrypsin Deficiency (American Thoracic Society, ATS/European Respiratory Society, ERS, Alpha-1 Antitrypsin Deficiency Guidelines, 2003) (Am J Respir Crit Care Med, 2003) [MEDLINE]
    • Anti-Proteinase 3-Positive Vasculitis (C-ANCA-Positive Vasculitis)
    • Early-Onset Emphysema (Age ≤45 y/o)
    • Emphysema in the Absence of a Recognized Risk Factor (Smoking, Occupational Dust Exposure, etc)
    • Emphysema with Prominent Basilar Hyperlucency
    • Family History of Any of the Following
    • Necrotizing Panniculitis (see Panniculitis, [[Panniculitis]])
    • Unexplained Bronchiectasis (see Bronchiectasis, [[Bronchiectasis]])
    • Unexplained Liver Disease (see Cirrhosis, [[Cirrhosis]])

Dermatologic Manifestations

  • Necrotizing Panniculitis (see Panniculitis, [[Panniculitis]])
    • Epidemiology
      • Rare: <50 cases reported
      • Mean Age of Onset: 40 y/o (Am J Respir Crit Care Med, 2003)* [MEDLINE]
    • Clinical
      • Hot, Painful, Erythematous Nodules or Plaques
        • Typically Located on Thighs or Buttocks
        • May Have an Oily, Yellow Discharge

Gastrointestinal/Hepatic Manifestations

  • General Comments
    • Hepatic Manifestations May Occur in Infancy in Pi-ZZ Cases, But Usually Resolve: may progress to cirrhosis by time of mid-late adulthood
    • Approximately 10-20% of Pi-ZZ Cases Have Significant Liver Disease During Childhood
    • Homozygous Pi-ZZ Disease is the Most Common Genetic Liver Disease in Children: occurs in 1:1600 to 1:2800 infants in the US
    • Approximately 10-15% of Adults with A1AT Deficiency Develop Liver Disease (Am J Respir Crit Care Med, 2003) [MEDLINE]
    • Approximately 40% of Adults with Pi-ZZ Phenotype (or M[malton] Phenotype) Have Histologically-Significant Liver Injury or Cirrhosis (Best Pract Res Clin Gastroenterol, 2010) [MEDLINE]
      • Prevalence of Liver Disease at Death in A1AT Deficiency is Even Higher in Never Smokers: 28% (Thorax, 2008) [MEDLINE]
  • Chronic Hepatitis/Elevated LFT’s (see Elevated Liver Function Tests, [[Elevated Liver Function Tests]])
    • Physiology: pathologic polymerization of the variant form of A1AT, resulting in intrahepatocyte accumulation (inclusions stain positively with periodic acid-Schiff (PAS) reagent, but resist digestion by diastase)
    • Clinical: may occur in adults without antecedent childhood hepatitis
  • Cholestasis
    • Physiology: pathologic polymerization of the variant form of A1AT, resulting in intrahepatocyte accumulation (inclusions stain positively with periodic acid-Schiff (PAS) reagent, but resist digestion by diastase)
    • Clinical
      • Disproportionate Elevation in the Alkaline Phosphatase, as Compared to the Serum Aminotransferases
      • Variable Elevation in the Serum Bilirubin
      • Variable Abnormalities in Tests of Synthetic Function
  • Cirrhosis (see Cirrhosis, [[Cirrhosis]])
    • Epidemiology: in patients with Pi-ZZ related lung disease, 63.2% had a history or clinical findings suggestive of liver disease or had liver function/ultrasound abnormalities [MEDLINE]
      • 17.5% of the patients had severe fibrosis/cirrhosis on liver biopsy: this subset of patients was more likely to have higher body mass index (BMI), elevated alanine transaminase, elevated alkaline phosphatase, elevated prothrombin time, maximal vital capacity, thrombocytopenia, and abnormal liver echogenicity/splenomegaly on liver ultrasound
    • Physiology: pathologic polymerization of the variant form of A1AT, resulting in intrahepatocyte accumulation (inclusions stain positively with periodic acid-Schiff (PAS) reagent, but resist digestion by diastase)
    • Recommended Diagnostic Screening: liver function tests (LFT’s), platelet count, and hepatic ultrasound
      • Liver Biosynthetic Activity is Usually Preserved
      • Bilirubin May Be Normal
  • Hepatocellular Carcinoma (Hepatoma) (see Hepatocellular Carcinoma, [[Hepatocellular Carcinoma]])
    • Physiology: pathologic polymerization of the variant form of A1AT, resulting in intrahepatocyte accumulation (inclusions stain positively with periodic acid-Schiff (PAS) reagent, but resist digestion by diastase)
  • Hepatosplenomegaly (see Hepatomegaly, [[Hepatomegaly]] and Splenomegaly, [[Splenomegaly]])
    • Physiology: pathologic polymerization of the variant form of A1AT, resulting in intrahepatocyte accumulation (inclusions stain positively with periodic acid-Schiff (PAS) reagent, but resist digestion by diastase)

Pulmonary Manifestations

  • General Comments
    • Pi-ZZ Genotype Accounts for <10% of COPD Cases in North America
    • Pi-ZZ Genotype Accounts for >95% of Severely Deficient A1AT Deficiency Patients
    • Family History of COPD is Usually Present in Pi-ZZ Cases, Due to the Genetic Basis of A1AT Deficiency
    • Pi-ZZ Patients Manifest a Highly Variable Extent of Lung Disease: rate of decline in Pi-ZZ patients varies from 23-316 mL per year
      • Premature Emphysema: hallmark of A1AT deficiency
      • Onset of Dyspnea (see Dyspnea, [[Dyspnea]])
        • Non-Smokers: median age of onset of dyspnea is 53 y/o
        • Smokers: median age of onset of dyspnea is 40 y/o
      • Symptoms of Lung Disease: rarely develop before age 25
    • Risk Factors for Decline in FEV1 (Development of Lung Disease) in the Setting of A1AT Deficiency
      • Age 30-44 y/o
      • Atopy: possible, but unproven, risk factor
      • Bronchodilator Responsiveness
      • Decreased Serum A1AT Level (see Serum Alpha-1 Antitrypsin, [[Serum Alpha-1 Antitrypsin]])
      • FEV1 35-79% Predicted
      • Gas/Fume Exposure
      • Interleukin-10 (IL-10) Gene Polymorphisms: maybe be associated with development of COPD in the setting of severe A1AT deficiency
      • Lower Respiratory Infections
      • Male Sex
      • Occupational Exposure to Siliceous Dusts, Metal Gases, Ozone, Pollution, Particulate Matter <10 um, and Welding
      • Recurrent Respiratory Infections
      • Tobacco Smoke Exposure (see Tobacco, [[Tobacco]]): severity of obstruction and age of onset are most strongly related to smoking
        • Non-Smoker Pi-ZZ Patients Rarely Develop Symptoms Prior to Age 40
        • Non-Smoker Pi-ZZ Patients Rarely Develop Obstruction Prior to Age 50’s-60’s
  • Bronchiectasis (see Bronchiectasis, [[Bronchiectasis]])
    • Epidemiology: present in 2/5 cases first reported in 1963 and in some later studies
  • Chronic Bronchitis (see Chronic Obstructive Pulmonary Disease, [[Chronic Obstructive Pulmonary Disease]]): present in about 50% of symptomatic cases
    • Clinical
      • Bronchospasm: 27% of cases have bronchial hyperresponsiveness (asthma-like symptoms occur in 4-34% of cases)
      • Chronic Sputum Production
  • Emphysema (see Chronic Obstructive Pulmonary Disease, [[Chronic Obstructive Pulmonary Disease]])
    • Clinical: premature emphysema is the hallmark of A1AT deficiency

Rheumatologic Manifestations

  • Wegener’s Granulomatosis (see Wegener’s Granulomatosis, [[Wegeners Granulomatosis]])
    • Epidemiology
      • Due to the Strong Association Between c-ANCA Positive Vasculitis and A1AT Deficiency, It Has Been Suggested that All Wegener’s Granulomatosis Patients Be Tested for A1AT (Phenotyping or Genotyping May Be Required, Since A1AT is an Acute Phase Reactant Which Increases During Active Vasculitis)*

Disease Manifestations with Unclear Association with A1AT Deficiency

  • Bladder Cancer (see Bladder Cancer, [[Bladder Cancer]])
  • Celiac Disease (see Celiac Disease, [[Celiac Disease]])
  • Chronic Pancreatitis (see Chronic Pancreatitis, [[Chronic Pancreatitis]])
  • Colorectal Cancer (see Colorectal Cancer, [[Colorectal Cancer]])
  • Glomerulopnephritis
    • IgA Nephropathy (see IgA Nephropathy, [[IgA Nephropathy]])
    • Proliferative Glomerulonephritis
  • Inflammatory Bowel Disease
  • Vascular Manifestations
    • Fibromuscular Dysplasia
    • Intraabdominal Aneurysm
    • Intracranial Aneurysm (see Intracranial Aneurysm, [[Intracranial Aneurysm]])
  • Lung Cancer (see Lung Cancer, [[Lung Cancer]])

Treatment

Usual Therapies for Chronic Obstructive Pulmonary Disease (COPD)

General Measures

Bronchodilators

Tobacco Smoking Cessation (see Tobacco, [[Tobacco]])

  • Crucial to Slow Progression of Disease

Alpha-1 Antitrypsin Replacement Therapy (see Alpha-1 Antitrypsin, [[Alpha-1 Antitrypsin]])

Mechanism of Action

  • Purified Heat-Treated Human A1AT: isolated from human plasma

Commercially-Available Agents

  • Aralast
  • Aralast-NP
  • Glassia
  • Prolastin
  • Prolastin-C
  • Zemaira

Indications for A1AT Replacement

  • A1AT Level <80 mg/dl (<11 µM) with Associated Lung Disease: note that the serum A1AT level of 80 mg/dL (11 µM) is considered the threshold level below which there is an increased risk of emphysema
    • A1AT Level <80 mg/dl (<11 µM) with Normal Lung Function: it is recommended to follow patient annually and start replacement only if pulmonary function tests deteriorate
  • Recommendations for Alpha-1 Antitrypsin Replacement (American Thoracic Society, ATS/European Respiratory Society, ERS, Alpha-1 Antitrypsin Deficiency Guidelines, 2003) (Am J Respir Crit Care Med, 2003) [MEDLINE]
    • Evidence of Airflow Obstruction Attributable to Alpha-1 Antitrypsin Deficiency
      • Greatest Benefit from Alpha-1 Replacement Has Been Demonstrated in Patients with FEV1 35-60% Predicted: benefit in more mild or severe disease is unclear
      • Alpha-1 Replacement is Not Recommended for Patients without Emphysema
    • Alpha-1 Anitrypsin Deficiency Patients Who Have Undergone Lung Transplant and are Experiencing Acute Rejection and Infection (see Lung Transplant, [[Lung Transplant]]): replacement therapy is probably recommended during these episodes
  • Recommendations for Alpha-1 Antitrypsin Replacement (Canadian Thoracic Society Alpha-1 Antitrypsin Testing and Alpha-1 Antitrypsin Replacement Guidelines, 2012) (Can Respir J, 2012) [MEDLINE]
    • Alpha-1 Antitrypsin Replacement May Be Considered in Non-Smoking/Ex-Smoking Patients with with COPD (FEV1 25-80% Predicted) Attributable to Emphysema and A1AT Level Level <80 mg/dl (<11 µM) Who are Receiving Optimal Pharmacologic and Non-Pharmacologic Therapy (Including Comprehensive Case Management and Pulmonary Rehabilitation) Because of Benefits in CT Scan Lung Density (Grade 2B Recommendation) and Mortality (Grade 2C Recommendation)

Contraindications to A1AT Replacement

  • A1AT Deficiency with Isolated Liver Disease (Without Lung Disease)
  • Pi-MZ Phenotype: even in the presence of lung disease (note: this phenotype rarely has A1AT level <80 mg/dl, <11 µM)
  • Tobacco Abuse (see Tobacco, [[Tobacco]])

Administration

  • Dose: 60 mg/kg qweek IV (infuse over 30 min)
  • Target: aim to keep level >80 mg/dl (>11 µM)
  • Annual Cost (2011 Wholesale Prices): $93-120k annually
    • Studies Indicate that Current Prices Exceed Generally-Accepted Cost-Effectiveness Thresholds of $100k per QALY (Am J Respir Crit Care Med, 2003) [MEDLINE]: the incremental cost-effectiveness ratio was $207,841/QALY for A1AT augmentation until FEV1 is <35% predicted and $312,511/QALY for the A1AT “augmentation for life” strategy

Adverse Effects

  • Anaphylaxis (see Anaphylaxis, [[Anaphylaxis]]): occurs in <1% of cases
  • Dizziness (see Dizziness, [[Dizziness]]): occurs in up to 16.8% of cases
  • Dyspnea (see Dyspnea, [[Dyspnea]]): occurs in 3-8.5% of cases
  • Fever (see Fever, [[Fever]]): occurs in 3.8-7.4% of cases
  • Flushing (see Flushing, [[Flushing]]): occurs in up to 6.5% of cases
  • Headache (see Headache, [[Headache]]): occurs in up 47% of cases
  • Hypotension (see Hypotension, [[Hypotension]]): occurs in 0-0.3% of cases
  • Nausea/Vomiting (see Nausea and Vomiting, [[Nausea and Vomiting]]): occurs in 1.7-4.7% of cases
  • Pruritus/Urticaria (see Pruritus, [[Pruritus]] and Urticaria, [[Urticaria]]): occurs in 3.2-4.1% of cases
  • Wheezing (see Wheezing, [[Wheezing]]): occurs in 0-1.9% of cases

Clinical Efficacy

  • General Comments
    • A1AT Replacement Therapy is Not Currently Recommended for Patients without Emphysema
    • The Benefits of A1AT Therapy in Patients with Severe (FEV1 <35% predicted) or Mild (FEV1 >50–60% predicted) Airflow Obstruction are Less Clear
  • Meta-Analysis (COPD, 2009) [MEDLINE]
    • Alpha-1 Antitrypsin Replacement Therapy Slowed the Decline in Lung Function
    • Alpha-1 Antitrypsin Deficient Patients Most Likely to Benefit from Replacement Therapy were Those with FEV1 of 30-65%
  • RAPID Trial of Alpha-1 Antitrypsin Replacement Therapy (Lancet, 2015) [MEDLINE]
    • Alpha-1 Antitrypsin Replacement Therapy in A1AT Deficient Patients (With A1AT level <11 µM and FEV1 35-70% Predicted) Decreased Lung Density Loss at Total Lung Capacity (TLC), Slowing the Progression of Emphysema

Lung Transplantation (see Lung Transplant, [[Lung Transplant]])

  • Unclear Role

Hepatic Transplantation (see Liver Transplant, [[Liver Transplant]])

  • May Be Required

Gene Therapy

  • Experimental
    • Data suggest that DNA polymorphisms in the flanking regions of the A1AT gene in patients with normal A1AT levels may increase risk for emphysema

Prognosis

  • A1AT Patients Exhibit Decreased Life Expectancy: although some patients live into their 70’s-80’s
    • Life Expectancy is Shorter in Smokers than Non-Smokers
  • Etiologies of Death in A1AT Deficiency
    • Most Common Etiology: respiratory failure (accounts for 45-72% of deaths)
    • Second Most Common Etiology: cirrhosis (accounts for 10-13% of deaths)
      • Often with associated hepatocellular carcinoma
  • Factors Associated with Increased Mortality
    • CT Assessment of Proportion of Emphysema
    • Lack of A1AT Replacement Therapy
    • Lower Education Status
    • Lower FEV1
    • Lung Transplant
    • Older Age

References

General

  • Wegener’s granulomatosis in a patient with severe PiZZ alpha-1 antitrypsin deficiency. QJM 1996;89:877 [MEDLINE]
  • Increased risk of chronic liver failure in adults with heterozygous alpha1-antitrypsin deficiency. Hepatology. 1998 Oct;28(4):1058-63 [MEDLINE]
  • The prevalence and clinical significance of alpha-1 antitrypsin deficiency (PiZ) and ANCA specificities (proteinase 3, BPI) in patients with ulcerative colitis. Inflamm Bowel Dis 1999;5: 246–252 [MEDLINE]
  • American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003 Oct 1;168(7):818-900 [MEDLINE]
  • Deficient alpha-1-antitrypsin phenotypes and persistent airflow limitation in severe asthma. Respir Med. 2006 Sep;100(9):1534-9. Epub 2006 Feb 14 [MEDLINE]
  • Clinical course and prognosis of never-smokers with severe alpha-1-antitrypsin deficiency (PiZZ). Thorax. 2008;63(12):1091 [MEDLINE]
  • Clinical practice. Alpha1-antitrypsin deficiency. N Engl J Med 2009;360(26):2749-2757 [MEDLINE]
  • Alpha-antitrypsin deficiency-related alleles Z and S and the risk of Wegener’s granulomatosis. Arthritis Rheum 2010;62:3760–3767 [MEDLINE]
  • Alpha-1-antitrypsin deficiency. Best Pract Res Clin Gastroenterol. 2010 Oct;24(5):629-33 [MEDLINE]
  • A review of alpha1-antitrypsin deficiency. Am J Respir Crit Care Med 2012;185(3):246-259 [MEDLINE]
  • Alpha-1 antitrypsin deficiency targeted testing and augmentation therapy: a Canadian Thoracic Society clinical practice guideline. Can Respir J. 2012 Mar-Apr;19(2):109-16 [MEDLINE]
  • Prevalence and risk factors for liver involvement in individuals with PiZZ-related lung disease. Am J Respir Crit Care Med 2013;187:502-508 [MEDLINE]

Treatment

  • Cost-effectiveness analysis of augmentation therapy for severe alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med 2003;167:1387–1392 [MEDLINE]
  • Augmentation therapy for alpha1 antitrypsin deficiency: a meta-analysis. COPD. 2009 Jun;6(3):177-84 [MEDLINE]
  • Alpha-1 antitrypsin deficiency targeted testing and augmentation therapy: a Canadian Thoracic Society clinical practice guideline. Can Respir J. 2012 Mar-Apr;19(2):109-16 [MEDLINE]
  • Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;386(9991):360 [MEDLINE]