Alpha 1 Antitrypsin Deficiency Two basic functional changes: Mark - PDF document

What is the physiology of emphysema? Alpha 1 Antitrypsin Deficiency Two basic functional changes: Mark D. Wewers, M.D. Ohio State University 1. Loss of elastic recoil and 2. Loss of membrane surface area Charlie Strange, M.D. Medical University of South Carolina Pulmonary Emphysema Normal Emphysema • Permanent enlargement of airspaces distal to the terminal respiratory bronchioles which involves destructive changes in alveolar walls • Affects as many as 5-10% of adults in U.S. 1

Elastic Recoil Important for Normal Emphysema Airway Patency Normal Airway Emphysematous Airway Spirometry Doubles Tennis Court Alveolar Capillary Membrane Alveolar capillary membrane Volume Liters Normal 4 Obstruction 3 2 Restriction FVC FEV1 1 0 Red blood cell 0 1 2 3 4 5 6 Seconds 2

Alveolar Capillary Membrane Emphysema Emphysema Normal How Does It Happen? Lessons from alpha 1-antitrypsin deficiency Symptomatic at minimal exertion Smoking Effects on Lung Function A1AT Genetic Defect 14q32 Fletcher, Peto, Tinker, Speizer. Oxford Press, 1976 3

Serum Protein Electrophoresis Z Mutation for Alpha 1-Antitrypsin Glu342 (GAG) Lys342 (AAG) Ia Ib Ic II III IV V 3’ 5’ Alpha 1-Antitrypsin Gene Alpha 1 and Emphysema Monomeric Forms Polymeric Forms • 5 patients found to have deficient alpha 1 peaks on their serum protein electrophoresis • 3 of the 5 had severe emphysema M or normal type Z or deficient type Laurell, C.-B. and Eriksson S. The electrophoretic alpha1-globulin pattern of serum in alpha 1-antitrypsin deficiciency. Scandinav. J. Clin. and Lab. Investigation . 15:1320140, 1963. 4

Protease-Antiprotease Imbalance Hypothesis How does this defect protection danger injury cause disease? proteases Anti-proteases • Infection • A1AT • Smoking • Inherited Type • Dust A Few Case Histories: Patients Protease/Antiprotease with A1AT Deficiency Hypothesis Laurell and Eriksson, Gross P. et al., 1965, • • 1963, Scand.J.Clin.Lab.Invest . Arch.Environ.Health. � Papain into silicotic � 3/5 cases had rats emphysema � “Some connection � Induced emphysema between degenerative pulmonary disease and α 1-antitrypsin deficiency is suggested.” Fletcher, Peto, Tinker, Speizer. Oxford Press, 1976 5

Alpha 1 a Rare AATD: Recommendations from the AAT Deficiency Task Force Disease? • Genetic testing is recommended for 1972-1974 All newborns in Sweden screened finding 127 of 200,000 with Pi ZZ. � Absent alpha-1 peak on SPEP 1 in 1600 � Early onset pulmonary emphysema (regardless of smoking history) Oregon 1 in 5097 St. Louis 1 in 2857 � Family members of known AATD patients New York 1 in 3694 � Dyspnea and cough occurring in multiple family members in same or different ~ 1 in 3000 generations in US Sveger, Pediatrics 1978; 62:22 O’Brien J Pediat 1978; 92:1006 AATD, alpha-1 antitrypsin deficiency. Silverman ARRD 1989; 140:961 American Thoracic Society, European Respiratory Society. Am J Respir Crit Care Med. 2003;168:818-900. Colp Chest 1993; 103:812 AATD Individuals AATD: Recommendations from the AAT Deficiency Task Force Identified • Genetic testing is recommended for � Liver disease of unknown cause < 5000 Identified � All subjects with COPD � Adults with bronchiectasis without evident etiology 95,000 � Patients with asthma whose spirometry Unidentified fails to return to normal with therapy � Unexplaned panniculitis and anti- proteinase 3 vasculitis AATD, alpha-1 antitrypsin deficiency. American Thoracic Society, European Respiratory Society. Am J Respir Crit Care Med. 2003;168:818-900. 6

Clinical Manifestations AAT Genetics • Panacinar Emphysema MZ MZ � Early onset � Most common in current or past smokers • Bronchiectasis � Atypical Mycobacterial Disease MZ MM MZ ZZ • Hepatic insufficiency � Both Infant and after age 50 predominant 25% 50% 25% Clinical Manifestations AAT Genetics MM ZZ MM MZ • Panniculitis • Association with Anti-proteinase 3 vasculitis MZ MZ MZ MZ MM MM MZ MZ • Association with Connective Tissue Diseases MZ MZ ZZ ZZ • Poorly responsive HIV • Association with Lung Cancer MM MZ MZ ZZ ZZ ZZ ZZ ZZ 7

Alpha-1 Registry Respondents AAT Is Normally Secreted by the Liver Reporting Liver Disease 18 AAT To all Other/Unknown Liver 16 PiSZ tissues Respondents (n) 14 PiMZ Pi*ZZ 12 10 8 6 4 2 0 Hepatocytes 5 8 2 6 0 4 8 2 6 0 4 8 2 6 0 4 8 2 6 < - 1 1 2 2 2 3 3 4 4 4 5 5 6 6 6 7 7 5 - - - - - - - - - - - - - - - - - 9 3 7 1 5 9 3 7 1 5 9 3 7 1 5 9 3 1 1 2 2 2 3 3 4 4 4 5 5 6 6 6 7 Blood vessel Age (y) Alpha-1 Liver Disease 139 Liver Affected 30 Diagnosed before Age 18 109 Adults 15 Transplants 84 Non-transplant 25 Transplant More Alcohol Use More Obesity And Viral Hepatitis 8

Protease-Antiprotease Imbalance Hypothesis What are the protection danger injury treatment options? proteases Anti-proteases • A1AT • infection • smoking • dust • inherited type First Infusions of Alpha Protease-Antiprotease 1-antitrypsin Imbalance Hypothesis • Gadek JE, J Clin Invest . 68:1158, 1981. � 5 patients for 4 weeks protection danger injury proteases Anti-proteases • A1AT • infection • Wewers, MD. NEJM 316:1055, 1986. • smoking � 21 patients for 6 months • inherited type • dust 9

A1AT Infusion Therapy p value 0.71 0.03 0.50 0.09 0.40 AM J RESPIR CRIT CARE MED 1998;158:49–59. NEJM 1987; 316:1055-62. A1AT Trough Levels Over 6 Months of Therapy Protease-Antiprotease Imbalance Hypothesis Amount of Protein protection danger injury proteases Anti-proteases Elastase Inhibitory Capacity • A1AT • infection • inherited type • smoking • dust NEJM 1987; 316:1055-62. 10

Protease-Antiprotease Treatment Options Imbalance Hypothesis • Smoking cessation protection danger • Avoid dusty occupational exposures and injury passive smoking • Preventive measures: handwashing; proteases Anti-proteases vaccines for influenza and pneumonia • A1AT • infection • Treat infections early • inherited type • smoking • Augmentation therapy with alpha 1 antitrypsin ($$) • dust Smoking Cessation and FEV1 Future Hopes for in A1AT Deficiency Therapy • Genetic manipulation to remove the PiZZ gene from hepatocytes and replace with functioning PiMM gene • Enhanced antitobacco legislation to help prevent institution of tobacco habit AM J RESPIR CRIT CARE MED 1998;158:49–59. 11

Some of the Not For Profit Faces Registry Newsletter Alpha-1 Alpha-1 AlphaNet Association Foundation Research-focused Member-based Health management organization: organization: organization: Health maintenance and Increase research Support and Education disease prevention Improve health Outcome studies Advocacy Worldwide detection Clinical research Genetic Counseling Center Cure for Alpha-1 Health Management Coordinators Registry Not-for-Profit DNA and Tissue Bank but revenue generating Alpha-1 Registry Why should we detect Participants (N=2021) individuals with AATD? • Assist in smoking cessation • Assist in occupational decisions • Meaningful genetic data to family members • Disease specific support • Allow therapy specific for AATD Blue = 1 participant Purple = 2 participants Yellow = 3 participants Red = 4 participants 12