Alpha – 1 Antitrypsin Deficiency

1. Alpha – 1 Antitrypsin Deficiency Jorge Mera, MD Presbyterian Hospital of Dallas

2. Alpha – 1 – Antitrypsin Deficiency • Mechanism of Alpha-1- Antitrypsin Deficiency (AATD) • Clinical Case (Presentation) • Lung Disease • Pathogenesis • Clinical Presentation • Treatment • Extra-Pulmonary Disease • Hepatic Disease • Pathogenesis • Clinical Presentation • Other • Clinical Case (Resolution)

3. Serpin • These are inhibitors of proteolytic enzymes with a serine residue at the active site • AAT, Antithrombin, C1-inhibitor and alpha 1 antichymotrypsin • When they bind to its target proteinase it undergoes a conformational change • The advantage • Is that the conformational change stabilizes the complex • It allows the modulation of inhibitory activity • The disadvantage of conformational mobility is their vulnerability to mutations which can : • Decrease its activity • Allow inappropriate changes that lead to polymerizations

4. Protein Folding and Function Elastase AAT AAT

5. AATD is a Protein Folding Disease • Protein folding is the process by which an unfolded polypeptide chain folds in to a specific native and functional structure • Defective protein folding is an important mechanism underlying the pathogenesis of many diseases

6. Protein Folding and Disease ER: Endoplasmic Reticulum

7. Abnormal Folding and Polymerization of AAT • The most common and severe form of AAT deficiency is caused by e Z mutation, a single base substitution (Glu-342-lys) in the AAT gene. • This slows the rate of protein folding in the cell • Allowing the accumulation of an intermediate which polymerizes Impeeding its release • Leading to plasma deficiency AAT Polymer

8. Electron Microscopy of AAT Polymers in the Liver

9. Clinical Case • CC: 45 yowm comes to your office with a CC of Dyspnea on mild exercise. • PMH: Is unremarkable, and he never smoked • Family Hx: His Father was a smoker and died of Emphysema at 43 years of age and his mother is 73 yo and in good health. He has 2 sons 19 and 21 years old, his older son has a 3 pack/year smoking Hx and the 19 yo has IgA deficiency • PE: Vital signs reveal BP 120/74 HR: 88 RR: 20/min. The only positive findings are diminished bilateral breath sounds and an emphysematous type Chest wall.

10. Clinical Case • His Chest X ray shows bullous images in both LL • His Chest CT • His PFT reveal a FEV1 48% of predicted with a 35% increase on inhaled bronchodilators. • CBC and Chem 14 are normal. His AAT level is 45 mg/dL.

11. Clinical Case • Does he have a AAT deficiency ? • What other tests should you order? • What is his prognosis? • What information regarding treatment should you give him? • Is he a candidate for AAT augmentation therapy? • If so, what precautions should you take before starting treatment? • Should his siblings be tested for AATD and Phenotype? • What will you do with the results if they are abnormal?

12. AATD • Described in 1963 by Laurell and Erikson1 • Underrecognized Disorder that may affect • Lungs • Liver • Skin (rarely) • AAT • Inhibitor of proteolytic enzyme elastase • Member of the Serpins Family (Serine Protease Inhibitors) • 90 Alleles Identified 1. Laurell, C-B,Eriksson, A. Scand J Clin Lab Invest 1963: 15:32

13. AATD Lung Disease

14. AAT Phenotypes

15. What is the minimum Level of AAT necessary for lung protection? 11 umol/L or 80 mg/dL (NV: 20-53 umol/L or 150 300 mg/dL) Based on population studies

16. Pathogenesis of Lung Damage in AATD AAT Clinical Case

17. Epidemiology • USA: 80,000 – 100,000 • Worldwide 3,000,000 Worldwide racial and ethnic distribution of alpha(1)-antitrypsin deficiency. Chest 2002;122:1818

18. Prevalence • Based on a US population of 250 million • COPD screening1: 2 - 3 % of 965 COPD patients screened1 • If in the USA there are 2.1 million patients with Emphysema, 40,000-60,000 would be expected to be AAT Deficient • Direct population screening studies2 • 1:1575 – 1:5097 are positive 80,000 - 100,000 would be expected to be AAT Deficient 1. Chest 1986;89:370 2. N Eng J Med 1976;294:1316

19. Why is AAT Deficiency Underdetected ? • Many patients are asymptomatic despite severe deficiency • Lack of recognition of symptomatic patients by physicians • In a cohort of 304 AAT deficient patients • Mean time to diagnosis was 7.2 years • Number of physicians seen before diagnosis was made • 3 (43% of the patients) • 6 – 10 (12 % of the patients) Cleve Clin J Med 1994;61:461

20. Why is it important to detect AATD • Treatment is available • Counseling • Of the patient to avoid other risk factors • Of the siblings for screening and

21. Clinical Presentation • Emphysema • Pathogenesis: • Imbalance between neutrophil elastase in the lung which destroys elaste and elastase inhibitor AAT which protects against proteolytic degradation of elastin • Risk factors: • Phenotypes associated with a AAT levels below the “Protective threshold” of 11umol/L • Smoking • Parental Hx of o COPD • Bronchiectasis ? • Asthma ?

22. Lung Related Clinical Manifestations • Emphysema • Presenting Symptoms: • Dyspnea (most common symptom) • Cough, phlegm production and wheezing • Bronchodilator responsiveness • Differences with patients w usual COPD • Earlier Age • Bullous changes prominent in lung bases • > 90 % of ZZ phenotype have lung bases involved • Limited to lung bases in 24 %Found exclusively in • Asthma and Bronchiectasis: • Relationship not proven

23. Diagnosis • Measure AAT level • Phenotype by isoelectric focusing • Genotype

24. AAT Phenotypes Am Rev Respir Dis 1989;140:1494

25. Risk for developing lung disease • Smoking: • Age of onset of Dyspnea in AAT (ZZ) Deficient Non-smokers Vs Smoker1:32 - 40 vs 48 – 54 • In heterozygous SZ phenotype, COPD rarely occurs unless smoking is present2 • Family History: • MZ phenotypes have increased risk of COPD only when they have a symptomatic first degree relative3 • Airway irritants: • Risk of other irritants in disease progression is controversial 1. Lancet 1985;1:152 2. Am J Respir Crit Care Med 1996;154:1718 3. Am J Respir Crit Care Med 2000;161:81

26. Survival in AAT according to FEV1 Seersholm N et al. Eur Respir J 1994;7:1985

27. Treatment • Augmentation Therapy • Intravenous (only one FDA approved) • Aerosolized • Enhancement of endogenous AAT • Gene Therapy

28. IV Augmentation Therapy • FDA approved IV AAT based on clinical studies that proved that the infusion: • Increase plasma and ELF levels of AAT • Increase Levels anti-neutrophil elastase activity in ELF recovered by BAL • Is Safe and well tolerated • There are no randomized clinical trials that prove clinical efficacy in change in natural history of emphysema • Indication of IV AAT is based on observational studies

29. IV Augmentation Therapy: Concerns • The true protective threshold value (AAT level) • Is not available • It is estimated from values that separate affected from unaffected individuals • Some severely deficient patients have normal lung function • Plasma levels alone do not predict disease they only assign risk • The proportion of individuals with ZZ phenotype that do not develop clinically significant emphysema is not known

30. Observational Studies • National Registry of Patients with Severe AATD conducted a prospective cohort study1 • Survival was enhanced in recipients of augmentation therapy • The subset with FEV1 35 % – 49 % of predicted had a slower decline of FEV1 over time • Study comparing Ex- German Smokers (198) with treatment (3.2 years) with Ex Danish smokers (98) without treatment2 • Lower FEV1 decline in treatment group (53ml vs 75ml per year, P= 02) • Study evaluating 96 patients with severe AAT before and after treatment3 • Showed a lower FEV1 only in those with mild airflow obstruction 1. Am J Respir Crit Care Med 1998;158:49. 2. Eur Respir J 1997;10:2260 3. Chest 2001;119:737

31. Selection Criteria for Treatment • High – risk phenotype (ZZ or Null) • Plasma AAT level below 11 umol/L • Airflow obstruction by Spirometry • American Thoracic Society: < 80 % of predicted • Canadian Thoracic Society: 35% - 50 % of predicted • Patient compliance to treatment • Age equal to or greater than 18 • Nonsmoker or ex-smoker

32. Selection Criteria for Treatment • Not recommended for • Heterozygous Phenotypes • AAT > 11umol/L • Unknown • Fixed severe obstruction • Normal airflow but radiographic evidence of Emphysema

33. Goals of IV Infusion • Maintain a through level above the protective threshold • Diffusion of AAT in lung tissue (ELF) • In vivo anti neutrophil elastase activity after infusion

34. AAT Infusion: Side Effects • Low grade self limited fever • Anaphylaxis with IgE antibody formation to AAT (rare) • Syndrome of • Transient fever • Chest and low back pain • Biological hazard • Anaphylaxis in IgA deficient patients

35. Weekly Infusions of AAT 60 mg/Kg Am J Med 1988;84(supp; 6A):52.

36. Monthly Infusion of 250mg/Kg of AAT AAT protective level JAMA 1988;260:1259

37. Efficacy of aerosolized AAT Normal range Hubbard, RC et al. Ann Intern Med 1989;111:206

38. Pre- Treatment Testing Respiratory Function: Spirometry DLCO Laboratory: Hepatitis profile LFT’s HIV Titer Immunization Hepatitis B vaccine IVIG immunoglobulin Supportive Therapy Cessation Smoking Respiratory irritants Non-Specific Treatments Bronchodilators Pulmonary Rehab Oxygen Therapy Early treatment of respiratory infections Vaccines: Pneumococcal Influenza Management of Candidates for Augmentation Therapy

39. Extra-pulmonary AAT Deficiency • Hepatic Disease (most frequent) • Skin Disease • Panniculitis (1:1000 of AATD) • More inflammatory • More “oily discharge” • More acute inflammation in histology • Vascular disease • Aneurysms • Fibromuscular displasia • AAT Pittsburg mimics effects of antithrombin III • Glomerulonephritis • Prolipherative GN • IgA GN • Inflammatory Bowel disease • AATD patients have more severe Colitis

40. Hepatic Disease • Liver Diseases associated with AAT phenotypes • Neonatal hepatitis • Elevated transaminases in young adults • Cirrhosis in children and adults • Hepatocellular carcinoma • “Null” Phenotype has no risk of hepatic disease and a High risk of Emphysema

41. Pathogenesis of Liver Disease Intra-hepatocyte Polymerization of AAT variants (Z and M) Intra-hepatocyte accumulation of AAT molecules in the endoplasmic reticulum (ER) Decreased degradation of the AAT polymers in the ER Cell engorgement due to increase mass and release of lysosomal enzymes Increase risk of viral mediated hepatitis

42. Polymerization of AAT in the Hepatocyte • Intra-hepatocyte accumulation of AAT molecules in the endoplasmic reticulum (ER) • PAS positive granules AAT polymers

43. Natural History of Hepatic Disease of ZZ Phenotype

44. Natural History of Hepatic Disease • 15 % neonatal hepatitis • 5% Cirrhosis in the 1st year of life • 10 % • 25% Resolution of hepatitis by ages 3 to 10 • 25% Cirrhosis between age 6 mo and 17 years • 25% Histological evidence of cirrhosis with survival through the first decade • 25% Elevated LFT’s without Cirrhosis • 85% Asymptomatic at childhood • Cirrhosis in 11.8 % • Hepatocellular carcinoma in 3.3 % • 85% No Disease

45. Clinical Case Resolution • Does he have a AAT deficiency ? • YES • What other tests should you order? • PHENOTYPE ZZ • What is his prognosis? • According to FEV1 15 % in 2 years • What information regarding treatment should you give him? • That he is a candidate for Augmentation therapy but that there are no clinical trials to assure him improvement • Is he a candidate for AAT augmentation therapy? • Yes, his age, FEV1, AAT level and phenotype and non-smoker status making him a good candidate

46. Clinical Case Resolution • If so, what precautions should you take before starting treatment? • Hep B vaccination, HIV testing, Influenza and Pneumococcal vaccines • Should his siblings be tested for AATD and Phenotype? • Yes • What will you do with the results if they are abnormal? • His 21 year old son is ZZ phenotype, FEV1 is normal • Stop smoking and control of FEV1 • His 19 year old son is ZM phenotype (probably like his mother) and FEV1 is also normal • Avoid smoking • No treatment warranted since AAT infusion can cause anaphylaxis in IgA deficiency

47. Situations to Suspect Severe Deficiency of AAT • Emphysema in a young individual (less than 45 years old) • Emphysema in a non smoker • Emphysema characterized by predominant basilar changes on the chest x-ray • Family History of Emphysema and/or liver disease (unexplained cirrhosis or hepatoma) • Clinical findings or history of panniculitis • Clinical findings or history of unexplained chronic liver disease

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