alpha 1 anitrypsin deficiency - osu center for continuing ... - pdf of slides.pdf · deficiency is...
TRANSCRIPT
1
Alpha 1 Antitrypsin DeficiencyMark D. Wewers, M.D.Ohio State University
and Charlie Strange, M.D.
Medical University of South Carolina
Pulmonary Emphysema
• Permanent enlargement of airspaces distal to the terminal respiratory bronchioles which involves destructivechanges in alveolar walls
• Affects as many as 5-10% of adults in U.S.
What is the physiology of emphysema?
Two basic functional changes:
1. Loss of elastic recoil2. Loss of membrane surface area
Normal Emphysema
2
Normal Airway Emphysematous Airway
Elastic Recoil Important for Airway Patency
Spirometry
0 1 2 3 4 5 6Seconds
VolumeLiters
4
3
2
1
0
FEV1FVCRestriction
Normal
Obstruction
Normal Emphysema
Doubles Tennis Court Alveolar Capillary Membrane
Red blood cell
Alveolar capillary membrane
3
Alveolar Capillary Membrane
Symptomatic at minimal exertion
Emphysema Normal
Smoking Effects on Lung Function
Fletcher, Peto, Tinker, Speizer. Oxford Press, 1976
How Does It Happen?
Lessons from alpha 1-antitrypsin deficiency
Emphysema
14q32
A1AT Genetic Defect
4
Z Mutation for Alpha 1-Antitrypsin
Glu342 (GAG) Lys342 (AAG)
5’ 3’
Ia Ic IIIIb II IV V
Alpha 1-Antitrypsin Gene
M or normal type Z or deficient type
Monomeric Forms Polymeric Forms
Serum Protein Electrophoresis
Alpha 1 and Emphysema
• 5 patients found to have deficient alpha1 peaks on their serum proteinelectrophoresis
• 3 of the 5 had severe emphysema
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.
5
How does this defect cause disease?
Protease/Antiprotease Hypothesis
• Gross P. et al., 1965, Arch.Environ.Health.
Papain into silicoticrats
Induced emphysema
• Laurell and Eriksson, 1963, Scand.J.Clin.Lab.Invest.
3/5 cases had emphysema“Some connection between degenerative pulmonary disease and α1-antitrypsin deficiency is suggested.”
protection
danger
injury
proteases Anti-proteases• A1AT
• InheritedType
• Infection
• Smoking
• Dust
Protease-AntiproteaseImbalance Hypothesis
A Few Case Histories: Patients with A1AT Deficiency
Fletcher, Peto, Tinker, Speizer. Oxford Press, 1976
6
Alpha 1 a Rare Disease?
1972-1974 All newborns in Sweden screened finding 127 of 200,000 with Pi ZZ.
1 in 1600Oregon 1 in 5097St. Louis 1 in 2857New York 1 in 3694
~ 1 in 3000in US
Sveger, Pediatrics 1978; 62:22O’Brien J Pediat 1978; 92:1006Silverman ARRD 1989; 140:961Colp Chest 1993; 103:812
AATD Individuals Identified
< 5000 Identified
95,000 Unidentified
AATD: Recommendations from the AAT Deficiency Task Force• Genetic testing is recommended for
Absent alpha-1 peak on SPEPEarly onset pulmonary emphysema (regardless of smoking history)Family members of known AATD patientsDyspnea and cough occurring in multiple family members in same or different generations
American Thoracic Society, European Respiratory Society. Am J Respir Crit Care Med. 2003;168:818-900.
AATD, alpha-1 antitrypsin deficiency.
AATD: Recommendations from the AAT Deficiency Task Force• Genetic testing is recommended for
Liver disease of unknown causeAll subjects with COPDAdults with bronchiectasis without evident etiologyPatients with asthma whose spirometry fails to return to normal with therapyUnexplaned panniculitis and anti-proteinase 3 vasculitis
American Thoracic Society, European Respiratory Society. Am J Respir Crit Care Med. 2003;168:818-900.
AATD, alpha-1 antitrypsin deficiency.
7
AAT GeneticsMZ MZ
MM MZ MZ ZZ
25% 50% 25%
AAT GeneticsMM ZZ
MZ MZ MZ MZ
MM MZ
MM MM MZ MZ
MZ MZ
MM MZ MZ ZZ
ZZ ZZ
ZZ ZZ ZZ ZZ
Clinical Manifestations• Panacinar Emphysema
Early onset
Most common in current or past smokers
• BronchiectasisAtypical Mycobacterial Disease
• Hepatic insufficiencyBoth Infant and after age 50 predominant
Clinical Manifestations• Panniculitis
• Association with Anti-proteinase 3 vasculitis
• Association with Connective TissueDiseases
• Poorly responsive HIV
• Association with Lung Cancer
8
AAT Is Normally Secreted by the Liver
AAT To alltissues
Blood vessel
Hepatocytes
Liver
Alpha-1 Registry Respondents Reporting Liver Disease
02468
1012141618
<5 5-8 9-12
13-16
17-20
21-24
25-28
29-32
33-36
37-40
41-44
45-48
49-52
53-56
57-60
61-64
65-68
69-72
73-76
Age (y)
Res
pond
ents
(n)
Other/UnknownPiSZPiMZPi*ZZ
Alpha-1 Liver Disease139 Liver Affected
30 Diagnosed before Age 1815 Transplants
84 Non-transplantMore Alcohol Use And Viral Hepatitis
25 TransplantMore Obesity
109 Adults
9
What are the treatment options?
protection
danger
injury
proteases Anti-proteases
•A1AT• inherited type
• infection
• smoking
• dust
Protease-AntiproteaseImbalance Hypothesis
protection
danger
injury
proteases Anti-proteases
•A1AT• inherited type
• infection
• smoking
• dust
Protease-AntiproteaseImbalance Hypothesis
First Infusions of Alpha 1-antitrypsin
• Gadek JE, J Clin Invest. 68:1158, 1981.5 patients for 4 weeks
• Wewers, MD. NEJM 316:1055, 1986.21 patients for 6 months
10
A1AT Infusion Therapy
NEJM 1987; 316:1055-62.
NEJM 1987; 316:1055-62.
A1AT Trough Levels Over 6 Months of TherapyAmount of Protein
Elastase Inhibitory Capacity
AM J RESPIR CRIT CARE MED 1998;158:49–59.
0.71 0.03 0.50 0.09 0.40 p value
proteases
protection
danger
injury
Anti-proteases
• A1AT
• inherited type• infection
• smoking• dust
Protease-AntiproteaseImbalance Hypothesis
11
proteases
protection
danger
injury
Anti-proteases
• A1AT
• inherited type• infection
• smoking• dust
Protease-AntiproteaseImbalance Hypothesis
Smoking Cessation and FEV1 in A1AT Deficiency
AM J RESPIR CRIT CARE MED 1998;158:49–59.
Treatment Options• Smoking cessation• Avoid dusty occupational exposures and
passive smoking• Preventive measures: handwashing;
vaccines for influenza and pneumonia• Treat infections early• Augmentation therapy with alpha 1
antitrypsin ($$)
Future Hopes for Therapy
• Genetic manipulation to remove the PiZZgene from hepatocytes and replace with functioning PiMM gene
• Enhanced antitobacco legislation to help prevent institution of tobacco habit
12
Some of the Not For Profit Faces
Alpha-1Association
Alpha-1Foundation AlphaNet
Member-based organization:
Support and EducationAdvocacy
Genetic Counseling Center
Research-focused organization:
Increase researchImprove health
Worldwide detectionCure for Alpha-1
RegistryDNA and Tissue Bank
Health management organization:
Health maintenance and disease prevention
Outcome studiesClinical research
Health Management Coordinators
Not-for-Profit but revenue generating
Alpha-1 Registry Participants (N=2021)
Blue = 1 participantPurple = 2 participantsYellow = 3 participantsRed = 4 participants
Registry Newsletter
Why should we detect 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