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Alpha-1-Antitrypsin Deficiency

Alpha-1-Antitrypsin Deficiency. Mark Brantly, M.D. Professor & Chief Division of Pulmonary, Critical Care & Sleep Medicine University of Florida College of Medicine. Objectives. Learn about the clinical and molecular features of Alpha-1-Antitrypsin deficiency

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Alpha-1-Antitrypsin Deficiency

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  1. Alpha-1-Antitrypsin Deficiency Mark Brantly, M.D. Professor & Chief Division of Pulmonary, Critical Care & Sleep Medicine University of Florida College of Medicine

  2. Objectives Learn about the clinical and molecular features of Alpha-1-Antitrypsin deficiency Learn who should be screened for Alpha-1-Antitrypsin deficiency Learn about current and new therapies for Alpha 1-Antitrypsin Deficient Individuals

  3. Alpha-1-Antitrypsin Deficiency • AAT level 5.75 M PI*Z (>95%) • PI*Z Glu to Lys at 342 • Clinical Presentation • Asthma • Bronchiectasis • Pneumonia • COPD • Cirrhosis • Rapid decline in lung function • Premature disability and death • Smokers die 20 years before non-smokers • Passive Smoking is especially risk for Deficient Children 51 y/o AAT Deficient Individual Chest CT Coronal View

  4. 1-Antitrypsin • 52 kDa glycoprotein • Acute phase reactant “anti-inflammatory” • Secreted in large amount from hepatocytes, but also express in many other tissues • At least 100 different alleles • 34 alleles associated with deficiency or dysfunction • Mutations may affect the amount secreted and/or its function • The frequency of the Z allele suggest a selective advantage Met 358

  5. Our Genetic LegacyVariation is the Spice of Life • “Insanity is hereditary-you get it from your kids”, MBrantly, father to 14, 16 and 28 year old children • Alleles are the result of genetic variation on the same gene • Not all alleles are associated with increased risk of disease • Genetic Load: 5-15 “lethal” genes • Genes are not absolutely predictive for the development of disease • Risk (lung disease) MM=1, MZ~1.5-3, SZ~4-8, ZZ~18 Active Site Z Mutation Glu to Lys 342

  6. 1-Antitrypsin Deficiency The Problem • AAT level 5.75 M PI*Z (>95%) • Common genetic disease, 75-100,000 homozygous individuals in USA (1:2500-4000) • Frequency of S and Z alleles in Turkey is unknown • COPD and Liver disease • Rapid decline in lung function often associated with lung infections • Asthma is common presenting feature • Carriers are at increased risk for COPD • Most common inherited risk factor for COPD (~10% are MZ, SZ or ZZ) • Early diagnosis and preventive care translate into health benefits 5000 ~95,000

  7. WHO-ATS-ERS-ACCP Recommendations • All individuals with COPD should be tested once with PI/genotyping plus an AAT level • All individuals with asthma and a non-reversible component • Family members of individuals with Alpha-1-antitrypsin deficiency • Individuals with “cryptogenic” cirrhosis

  8. a1-Antitrypsin-Neutrophil Elastase Docking Asn95 1-antitrypsin Asp46 Asn46 His46 Ser195 Met358 Asn144 Asn247 Neutrophil elastase Asn83

  9. Protease-Antiprotease Balance Normal AAT Deficiency Anti-Neutrophil Elastase Protection Neutrophil Elastase Burden Neutrophil Elastase Burden Anti-Neutrophil Elastase Protection AAT • Lung damage is the result of both a burden of neutrophils and its toxic products and a lack of sufficient AAT in the lower lung. AAT

  10. Lung Injury in AAT Deficient Individuals Propagation and Maintenance Effects of Injury Initiation Smoking Oxidants Pro-Inflammatory Cells (PMN, Mast Cells, Lymphocytes &AM) Infections Polymers of Z AAT Cellular Response to UPR Proteases Recruitment-Expansion-Activation Fibrosis Pro-Inflammatory Molecules (LTB4 & IL8) a-Defensins AAT Airway Alveolus

  11. 1-Antitrypsin is More than an Antiprotease • 52 kDa glycoprotein • Acute phase reactant “anti-inflammatory” • Secreted in large amount from hepatocytes, but also expressed in macrophages & bronchial epithelium • Broad spectrum anti-protease • Inhibits a-defensin cytotoxicity and pro-inflammatory properties • Anti-oxidant with 9 methionines Met 358

  12. AAT Gene SERPIN Cluster

  13. AAT Gene Coding Region

  14. AAT Normal Alleles

  15. AAT Null Variants Active Site Active Site

  16. AAT Deficiency Alleles

  17. AAT Z Protein Active Site Z Mutation Glu to Lys 342 Active Site

  18. The Spectrum of Lung Disease AAT Deficiency • Normal Lung Function with CT Evidence of Emphysema • Emphysema • Bronchiectasis • Rapid decline in lung function often associated with lung infections • Asthma is common presenting feature • Accelerated Rate of Decline in Lung Function • FEV1 35-80% -ROD 83.5ml/year • Increase ROD in BDR+ Individuals • Evidence that Lung Inflammation Begins Early

  19. Airways Disease and EmphysemaIn AAT Deficiency • Deficient individuals frequently have CT scan evidence of bronchiectasis • Greater the 65% of AAT NHLBI Registry subjects have a positive BDR • In animal models airway hyper-reactivity is reduced by AAT • Anecdotal evidence from patients on augmentation therapy • Large fraction of deficient individuals present as asthmatics

  20. Clinical Features of AAT Deficiency by Age Group

  21. Reduction in Life Span • Only 52% of 1AT Deficient Individuals with pulmonary symptoms are alive at age 50 • Only 16% of 1AT Deficient individuals with pulmonary symptoms are alive at age 62 • Most common causes of death • Emphysema • Infection • Sepsis • Liver Disease Brantly, et al Am Rev Respir Dis. 138(2): 327-36, 1988

  22. Laboratory Methods for the Detection of AAT Deficient Individuals • AAT Genotyping (typically S and Z alleles) RFLP or Taqman • AAT PI typing (Phenotype) isoelectic Focusing • AAT level-Nephelometry • High Resolution DNA Melt • Sample types: include, plasma, serum, dried blood spot and buccal swabs • Future-monoclonal AB, Amptamers, “office test” kits • AAT Deficiency Diagnosis in a LABORTORY Diagnosis

  23. a1-Antitrypsin Typing (PI Typing)

  24. Relationship Between PI Type and Serum Level 50 260 40 208 Normal Range Serum a1-Antitrypsin Level (mM) Serum a1-Antitrypsin Level (mg/dl) 30 156 104 20 10 52 MM SZ ZZ QO MS MZ a1-Antitrypsin PI Type

  25. Typical Pedigree

  26. Treatment of Lung Disease 1AT Deficiency Augment the lung AAT concentration Neutrophil Elastase Burden Anti-neutrophil Elastase Protection Reduce the burden of neutrophil products AAT

  27. Prevention of Lung Destruction • Smoking cessation*, avoidance of smoke, and dust • Pneumococcal and influenza vaccination • Aggressive antibiotic therapy • Treatment of airway disease with inhaled steriods and bronchodilators • *Children with AAT Deficiency are at great Risk of Lung Destruction when their parent Smoke

  28. Therapies of AAT Deficiency • Intravenous Augmentation Therapy • Pooled Human AAT(60mg/kg) • >$100,000/year no controlled studies but is FDA approved • Potential of viral and prion transmission • Therapies in Development • Aerosolized AAT • rAAT- nebulized • Pooled Human-dry powder (like insulin) • hAAT nebulized

  29. Specific Therapies of AATDeficiency (continued) • Therapies in Development • Gene Therapy • Muscle delivery of AAV1/2-AAT trials began in UF • Many new therapies on the horizon

  30. Dry Powder Aerosolize AAT Powder Production (Spray drying) Powder Packaging (Unit dose blisters) Replace weekly IV dosing with daily pulmonary dosing • reduced drug requirements • increased patient convenience A1PI ~ 6 mg A1PI / blister Powder Particles 1 - 2 mm Pulmonary Delivery System (Pneumatic reusable)

  31. First • It’s a Inherited Disorder--- Counseling and Family Screening

  32. AOF-UF Detection Lab Testing Algorithm Individual with Obstruction DBS Genotyping for S & Z Alleles Positive for S or Z alleles Negative for S or Z alleles (98% are MM) DBS AAT Level Stop or PI type from plasma or serum Plasma Sample Second Confirmation by PI Typing Identification of Genotype ZZ, SZ, SS, MS* & MZ* *MS & MZ with low AAT Levels are likely Null or Rare Low Level AAT Alleles and Plasma Sample is requested for PI typing & SNP scan by High Resolution DNA Melt.

  33. WHO-ATS-ERS Recommendations • All individuals with COPD should be tested once with PI/genotyping plus an a1-antitrypsin level • All individuals with asthma and a non-reversible component • Family members of individuals with a1-antitrypsin deficiency • Individuals with “cryptogenic” cirrhosis

  34. Summary: COPD Management • Spirometry • AAT Testing!!! Education Diagnose Reduce risk Education • Smoking cessation Reduce symptoms • Pharmacotherapy • Pulmonary rehabilitation Education • Immunize • Treat exacerbations • Consider oxygen Reduce complications Education

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