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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

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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.

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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

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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.

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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

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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

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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

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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

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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

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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