Alpha-1 Antitrypsin Deficiency: An Underrecognized Cause of Chronic Obstructive Pulmonary Disease

1. A CME Presentation Alpha-1 Antitrypsin Deficiency: An Underrecognized Cause of Chronic Obstructive Pulmonary Disease

2. Outline Chronic Obstructive Pulmonary Disease (COPD) Alpha-1 Antitrypsin (AAT) Deficiency Epidemiology of AAT Deficiency Pathophysiology of AAT Deficiency Genetics of AAT Deficiency Diagnosis of AAT Deficiency Diagnostic Tests Treatment of AAT Deficiency

3. Changing Face of COPD Historically, COPD has been diagnosed late and more often in men1 COPD was recognized as impaired lung function thatwas clinically apparent and moderately advanced Men were more likely than women to die from COPD COPD is now recognized earlier and in more women1 Individuals with impaired lung function that is not clinically apparent are now recognized as having COPD In the year 2002, for the first time, more women than men died from COPD (64,103 vs. 60,713)2 1American Lung Association. www.lungusa.org. 2CDC. National Vital Statistics Reports. 2005;53.

4. Unsuspected COPD Courtesy of H. Ari Jaffe, MD

5. Percent Change in Age-Adjusted Death Rates, US, 1965-1998 Proportion of 1965 Rate 3.0 Coronary Heart Disease Stroke Other CVD COPD All Other Causes 2.5 2.0 1.5 1.0 0.5 –59% –64% –35% +163% –7% 0 1965 –1998 1965 –1998 1965 –1998 1965 –1998 1965 –1998 GOLD teaching slide set. www.goldcopd.com

6. Risk Factors for COPD Exposure Tobacco smoke Occupational dusts and chemicals Air pollution Host factors Airway hyperresponsiveness Stunted lung development Alpha-1 antitrypsin (AAT) deficiency Pauwels RA. Lancet. 2004;364:613.

7. Prevalence of AAT Deficiency in Patients With COPD Estimated prevalence of severe AAT deficiency in patients with COPD is approximately 2% to 3%1–5 “…all subjects with COPD or asthma characterized by incompletely reversible airflow obstruction should be tested once for quantitative AAT determination.” ATS/ERS Standards 1Lieberman J. Chest. 1986;89:370. 2Alvarez-Granda L. Thorax. 1997;52:659. 3Cox DW. Am Rev Respir Dis. 1976;113:601. 4Morse JO. NEJM. 1977;296:1190. 5Wencker M. Eur Respir J. 2002;20:319. 6ATS/ERS Standards. Am J Respir Crit Care Med. 2003;168:181.

8. Therapy at Each Stage of COPD Old (2001) 0: At Risk I: Mild II: Moderate IIA IIB III: Severe New (2003) 0: At Risk I: Mild II: Moderate III: Severe IV: Very Severe Characteristics • Chronic Symptoms • Exposure to risk factors • Normal spirometry • FEV1/FVC <70% • FEV1 80% • With or without symptoms • FEV1/FVC <70% • 50% < FEV1 <80% • With or without symptoms • FEV1/FVC <70% • 30% < FEV1 <50% • With or without symptoms • FEV1/FVC <70% • FEV1 <30% or FEV1 <50% predicted plus chronic respiratory failure Avoidance of risk factor(s); influenza vaccination Add short-acting bronchodilator when needed Add regular treatment with one or more long-acting bronchodilators; Add rehabilitation Add inhaled glucocorticosteroids if repeated exacerbations Add long-term oxygen if chronic respiratory failure; Consider surgical treatments GOLD. Pocket Guide to COPD Diagnosis, Management, and Prevention. 2004.

9. Management of AAT Deficiency COPD Symptom management is the same as typical COPD1 Emphysema associated with AAT deficiency can also be treated with infusion of purified human AAT (AAT augmentation therapy)2 Indicated for use in patients with congenital AAT deficiency AND clinically evident emphysema3-5 Only treatment besides smoking cessation shown to slow disease progression and improve survival6 1GOLD. Pocket Guide to COPD Diagnosis, Management, and Prevention. 2004. 2ATS/ERS Standards. Am J Respir Crit Care Med. 2003;168:181. 3Prolastin prescribing information. 4Aralast prescribing information. 5Zemaira prescribing information. 6AAT Deficiency Study Group.Am J Respir Crit Care Med. 1998;158:49.

10. Outline Chronic Obstructive Pulmonary Disease (COPD) Alpha-1 Antitrypsin (AAT) Deficiency Epidemiology of AAT Deficiency Pathophysiology of AAT Deficiency Genetics of AAT Deficiency Diagnosis of AAT Deficiency Diagnostic Tests Treatment of AAT Deficiency

11. AAT Deficiency AAT deficiency is an autosomal, codominant, hereditary disorder characterized by low serum and lung levels of AAT AAT gene resides at the proteinase inhibitor (PI) locus on chromosome 14 The most common mutant AAT allele (PI*Z) produces an abnormal protein that is polymerized and sequestered in hepatocytes AAT deficiency predisposes affected individuals to lung, liver, and other diseases Tobin MJ. Br J Dis Chest. 1983;77:14.

12. AAT 51 KDa glycoprotein made predominantly in the liver Secreted to blood, permeates all tissues Circulating serum levels in normal individuals range from 150–350 mg/dL (20–48µM) Protease inhibitor Primary target is the white blood cell protease, neutrophil elastase (NE) 1Crystal RG. Hosp Pract (Off Ed). 1991;26:81. 2Crystal RG. Chest. 1989;95:196.

13. Mechanism of Neutrophil Elastase Inhibition Reaction results in destruction of both AAT and NE Reactive loop AAT flings the tethered NE to the opposite end of the AAT molecule NE cleaves the AAT reactive loop AAT This distorts the NE active site and alters its structure so it can be destroyed Cleavage triggers AAT to snap NE backwards NE Courtesy of James A. Huntingon, PhD; University of Cambridge.

14. Mechanism of Neutrophil Elastase Inhibition Courtesy of James A. Huntingon, PhD; University of Cambridge.

15. Mechanism of Neutrophil Elastase Inhibition Courtesy of James A. Huntingon, PhD; University of Cambridge.

16. Mechanism of Neutrophil Elastase Inhibition Courtesy of James A. Huntingon, PhD; University of Cambridge.

17. Mechanism of Neutrophil Elastase Inhibition Courtesy of James A. Huntingon, PhD; University of Cambridge.

18. Mechanism of Neutrophil Elastase Inhibition Courtesy of James A. Huntingon, PhD; University of Cambridge.

19. Mechanism of Neutrophil Elastase Inhibition Courtesy of James A. Huntingon, PhD; University of Cambridge.

20. Mechanism of Neutrophil Elastase Inhibition Courtesy of James A. Huntingon, PhD; University of Cambridge.

21. Mechanism of Neutrophil Elastase Inhibition Courtesy of James A. Huntingon, PhD; University of Cambridge.

22. Mechanism of Neutrophil Elastase Inhibition Courtesy of James A. Huntingon, PhD; University of Cambridge.

23. Mechanism of Neutrophil Elastase Inhibition Courtesy of James A. Huntingon, PhD; University of Cambridge.

24. Mechanism of Neutrophil Elastase Inhibition Courtesy of James A. Huntingon, PhD; University of Cambridge.

25. Mechanism of Neutrophil Elastase Inhibition Courtesy of James A. Huntingon, PhD; University of Cambridge.

26. AAT Alleles There are more than 100 distinct AAT alleles, with varying clinical significance1 Deficiency alleles encode abnormal protein that is not secreted normally, resulting in decreased circulating levels of AAT1,2 Most common alleles1,2 PI*M (normal) PI*S (moderately deficient) PI*Z (severely deficient) The null allele (rare), which produces no protein, results in the most severe deficiency1,2 1Crystal RG. Chest. 1989;95:196. 2Tobin MJ. Br J Dis Chest. 1983;77:14.

27. Outline Chronic Obstructive Pulmonary Disease (COPD) Alpha-1 Antitrypsin (AAT) Deficiency Epidemiology of AAT Deficiency Pathophysiology of AAT Deficiency Genetics of AAT Deficiency Diagnosis of AAT Deficiency Diagnostic Tests Treatment of AAT Deficiency

28. Prevalence of AAT Deficiency 3.4 million individuals with mutant AAT allele combinations worldwide1 PI*ZZ = 175,268 PI*SZ = 929,014 PI*SS = 2,260,801 Based on direct population screening studies,prevalence of PI*ZZ in the US may be 80,000–100,0002-4 Only approximately 5,000 individuals in the US are currently diagnosed with PI*ZZ 95% undiagnosed 1de Serres FJ. Chest. 2002;122:1818. 2Colp C. Chest. 1993;103:812; 3O’Brien ML. J Pediatr. 1978;92:1006; 4Silverman EK. Am Rev Respir Dis. 1989;140:961.

29. Prevalence in the US vs. Genetic Disorders and Certain Cancers Disorder Prevalence Disease Prevalence7 AAT deficiency (PI*ZZ) 80,000–100,0001-3* Adult leukemias 85,000 Cervical cancer 50,000 Spina bifida 70,0004 Testicular cancer 37,000 Huntington’s disease 30,0005 Hodgkin’s lymphoma 35,000 Cystic fibrosis 30,0006 *Based on US population of 260M. Only ~5,000 have been diagnosed. 1Colp C. Chest. 1993;103:812; 2O’Brien ML. J Pediatr. 1978;92:1006; 3Silverman EK. Am Rev Respir Dis. 1989;140:961. 4www.sbaa.org, 5www.hdsa.org, 6www.cff.org, 7SEER Cancer Statistics Review 1975-2001.

30. Gene Frequency • PI*S and PI*Z found in ALL ethnicities worldwide1 • PI*Z • Highest in Northern Europe, where it may have originated2–4 • PI*S • Highest on Iberian Peninsula, where it may have originated2 • In the US, PI*Z frequency is highest in individuals of Northern and Western European descent5 PI*Z PI*S 1de Serres FJ. Chest. 2002;122:1818. 2Hutchison DC. Respir Med. 1998;92:367. 3Cox DW. Nature. 1985;316:79. 4Seixas S. Hum Genet. 2001;108:20. 5Dykes DD. Hum Hered. 1984;34:308.

31. Outline Chronic Obstructive Pulmonary Disease (COPD) Alpha-1 Antitrypsin (AAT) Deficiency Epidemiology of AAT Deficiency Pathophysiology of AAT Deficiency Genetics of AAT Deficiency Diagnosis of AAT Deficiency Diagnostic Tests Treatment of AAT Deficiency

32. Lung Disease Associated with AAT Deficiency A common manifestation of AAT deficiency Defining characteristics1,2: Panacinar emphysema Early-onset of disease (35–50 years of age) in presence of additional risk factors Airway obstruction not completely reversible with treatment 1Larsson C. Acta Med Scand. 1978;204:345. 2Wittes J. In: Crystal RG, ed. Alpha-1 Antitrypsin Deficiency: Biology, Pathogenesis, Clinical Manifestations, Therapy. New York, NY:Marcel Dekker, Inc.;1996.

33. Pathogenesis of Lung Destruction Due to AAT Deficiency

34. Pathogenesis of Lung Destruction Due to AAT Deficiency

35. Risk Factors of Lung Disease Associated with AAT Deficiency AAT deficiency has a highly variable clinical course of disease In absence of additional risk factors, individuals with AAT deficiency can have an almost normal life span1,2 Risk factors3: Smoking Passive smoking Occupational/environmental exposures Lung infections 1Seersholm N. Thorax. 1994;49:695. 2Larsson C. Acta Med Scand. 1978;204:345. 3ATS/ERS Standards. Am J Respir Crit Care Med. 2003;168:181.

36. Other Diseases That May Be Associated With AAT Deficiency Liver disease is another primary manifestation of AAT deficiency Childhood and adult liver disease1,2 AAT deficiency is also more rarely associated with: Panniculitis3 C-ANCA–positive vasculitis4,5 Wegener’s granulomatosis 1Larsson C. Acta Med Scand. 1978;204:345. 2Sharp HL. J Lab Clin Med. 1969;73:934. 3Hendrick SJ. J Am Acad Dermatol. 1988;18:684. 4Elzouki AN. J Intern Med. 1994;236:543. 5Griffith ME. Nephrol Dial Transplant 1996;11:438.

37. Liver Disease Associated With AAT Deficiency A common manifestation of PI*ZZ (15%–43%) In children: Common cause of neonatal cholestasis and liver transplantation (accounts for 14%–46% of transplants)1,2 Most individuals are healthy throughout childhood3 In adults: Can cause cirrhosis and hepatic carcinoma Prevalence of cirrhosis in PI*ZZ individuals ranges from 15%–43%4-7 Prevalence of hepatoma in PI*ZZ individuals ranges from 15%–28%6,7 1ATS/ERS Standards. Am J Respir Crit Care Med. 2003;168:818. 2Sveger T. NEJM. 1976;294:1316. 3Sveger T. Hepatology. 1995;22:1316. 4Larsson C. Acta Med Scand. 1978;294:345. 5Cox DW. Am J Med. 1983;74:221. 6Eriksson S. Acta Med Scand. 1975;198:243. 7Elzouki AN. Eur J Gastroenterol Hepatol. 1996;8:989.

38. AAT is Secreted by the Liver AAT To all tissues Liver Blood vessel Hepatocytes Blood vessel

39. Mutant AAT is not Secreted Efficiently AAT To all tissues Liver Blood vessel Sequestered AAT polymers Hepatocytes Blood vessel

40. Inclusion Bodies in Hepatocytes of a Patient With AAT Deficiency The Alpha-1 Foundation slide set. www.alphaone.org. Courtesy of J. Stoller, MD, MS

41. Panniculitis • Skin disease characterized by inflammatory and necrotizing lesions of subcutaneous fat • Rare but well-recognized complication of AAT deficiency 1O’Riordan K. Transplantation. 1997;53:480. 2Smith KC. J Am Acad Dermatol. 1989;21:1192.

42. Vasculitis Associated With AAT Deficiency Relationship between AAT deficiency and anti-PR-3/C-ANCA small vessel-necrotizing vasculitides1,2 Wegener’s granulomatosis AAT inhibits proteinase-3 (PR-3)3 NE-like serine protease Protease/antiprotease imbalance may contribute to disease4 1Elzouki AN. J Intern Med. 1994;236:543. 2Griffith ME. Nephrol Dial Transplant 1996;11:438. 3Duranton J. Am J Respir Cell Mol Biol. 2003;29:57. 4Esnault VLM. Exp Clin Immunogenet. 1997;14:206.

43. Outline Chronic Obstructive Pulmonary Disease (COPD) Alpha-1 Antitrypsin (AAT) Deficiency Epidemiology of AAT Deficiency Pathophysiology of AAT Deficiency Genetics of AAT Deficiency Diagnosis of AAT Deficiency Diagnostic Tests Treatment of AAT Deficiency

44. Inheritance of AAT Alleles MM (25%) MZ (50%) ZZ (25%) MZ MZ

45. Third Generation Inheritance Prior to Clinical Disease F2 F1 F2 F3

46. AAT Phenotypes AAT phenotype refers to the AAT protein type, characterized by position of the protein on isoelectric focusing (IEF) Can define the heterozygous or homozygous states Phenotype can be confirmed with genotyping (DNA analysis) Serum levels of AAT and risk of disease vary by phenotype 1Brantly M. In: Crystal RG, ed. Alpha-1 Antitrypsin Deficiency: Biology, Pathogenesis, Clinical Manifestations, Therapy. New York: Marcel Dekker, Inc.;1996. 2Crystal RG. J Clin Invest. 1998;85:1343.

47. Range of Serum Levels by Phenotype Adapted from The Alpha-1 Foundation slide set. www.alphaone.org. Courtesy of H. Ari Jaffe, MD

48. Range of Serum Levels by Phenotype Bottom normal level Adapted from The Alpha-1 Foundation slide set. www.alphaone.org. Courtesy of H. Ari Jaffe, MD

49. Range of Serum Levels by Phenotype Bottom normal level Protective threshold Adapted from The Alpha-1 Foundation slide set. www.alphaone.org. Courtesy of H. Ari Jaffe, MD

50. Outline Chronic Obstructive Pulmonary Disease (COPD) Alpha-1 Antitrypsin (AAT) Deficiency Epidemiology of AAT Deficiency Pathophysiology of AAT Deficiency Genetics of AAT Deficiency Diagnosis of AAT Deficiency Diagnostic Tests Treatment of AAT Deficiency