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

A CME Presentation. Alpha-1 Antitrypsin Deficiency: An Underrecognized Cause of Chronic Obstructive Pulmonary Disease. Outline. Chronic Obstructive Pulmonary Disease (COPD) Alpha-1 Antitrypsin (AAT) Deficiency Epidemiology of AAT Deficiency Pathophysiology of AAT Deficiency

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

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A cme presentation

A CME Presentation

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


Outline

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


Changing face of copd

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.


A f ffffffffffffffff ff

Unsuspected COPD

Courtesy of H. Ari Jaffe, MD


Percent change in age adjusted death rates us 1965 1998

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


Risk factors for copd

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.


Prevalence of aat deficiency in patients with copd

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.


A f ffffffffffffffff ff

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.


Management of aat deficiency copd

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.


Outline1

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


Aat deficiency

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.


A f ffffffffffffffff ff

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.


Mechanism of neutrophil elastase inhibition

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.


Mechanism of neutrophil elastase inhibition1

Mechanism of Neutrophil Elastase Inhibition

Courtesy of James A. Huntingon, PhD; University of Cambridge.


Mechanism of neutrophil elastase inhibition2

Mechanism of Neutrophil Elastase Inhibition

Courtesy of James A. Huntingon, PhD; University of Cambridge.


Mechanism of neutrophil elastase inhibition3

Mechanism of Neutrophil Elastase Inhibition

Courtesy of James A. Huntingon, PhD; University of Cambridge.


Mechanism of neutrophil elastase inhibition4

Mechanism of Neutrophil Elastase Inhibition

Courtesy of James A. Huntingon, PhD; University of Cambridge.


Mechanism of neutrophil elastase inhibition5

Mechanism of Neutrophil Elastase Inhibition

Courtesy of James A. Huntingon, PhD; University of Cambridge.


Mechanism of neutrophil elastase inhibition6

Mechanism of Neutrophil Elastase Inhibition

Courtesy of James A. Huntingon, PhD; University of Cambridge.


Mechanism of neutrophil elastase inhibition7

Mechanism of Neutrophil Elastase Inhibition

Courtesy of James A. Huntingon, PhD; University of Cambridge.


Mechanism of neutrophil elastase inhibition8

Mechanism of Neutrophil Elastase Inhibition

Courtesy of James A. Huntingon, PhD; University of Cambridge.


Mechanism of neutrophil elastase inhibition9

Mechanism of Neutrophil Elastase Inhibition

Courtesy of James A. Huntingon, PhD; University of Cambridge.


Mechanism of neutrophil elastase inhibition10

Mechanism of Neutrophil Elastase Inhibition

Courtesy of James A. Huntingon, PhD; University of Cambridge.


Mechanism of neutrophil elastase inhibition11

Mechanism of Neutrophil Elastase Inhibition

Courtesy of James A. Huntingon, PhD; University of Cambridge.


Mechanism of neutrophil elastase inhibition12

Mechanism of Neutrophil Elastase Inhibition

Courtesy of James A. Huntingon, PhD; University of Cambridge.


Aat alleles

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.


Outline2

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


Prevalence of aat deficiency

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.


Prevalence in the us vs genetic disorders and certain cancers

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.


Gene frequency

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.


Outline3

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


Lung disease associated with aat deficiency

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.


Pathogenesis of lung destruction due to aat deficiency

Pathogenesis of Lung Destruction Due to AAT Deficiency


Pathogenesis of lung destruction due to aat deficiency1

Pathogenesis of Lung Destruction Due to AAT Deficiency


Risk factors of lung disease associated with aat deficiency

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.


Other diseases that may be associated with aat deficiency

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.


Liver disease associated with aat deficiency

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.


Aat is secreted by the liver

AAT is Secreted by the Liver

AAT

To all

tissues

Liver

Blood vessel

Hepatocytes

Blood vessel


Mutant aat is not secreted efficiently

Mutant AAT is not Secreted Efficiently

AAT

To all

tissues

Liver

Blood vessel

Sequestered AAT

polymers

Hepatocytes

Blood vessel


Inclusion bodies in hepatocytes of a patient with aat deficiency

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


Panniculitis

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.


Vasculitis associated with aat deficiency

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.


Outline4

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


Inheritance of aat alleles

Inheritance of AAT Alleles

MM (25%)

MZ (50%)

ZZ (25%)

MZ

MZ


Third generation inheritance prior to clinical disease

Third Generation Inheritance Prior to Clinical Disease

F2

F1

F2

F3


Aat phenotypes

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.


Range of serum levels by phenotype

Range of Serum Levels by Phenotype

Adapted from The Alpha-1 Foundation slide set. www.alphaone.org.

Courtesy of H. Ari Jaffe, MD


Range of serum levels by phenotype1

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


Range of serum levels by phenotype2

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


Outline5

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


Aat deficiency is underdiagnosed

AAT Deficiency is Underdiagnosed

Only ~5% of individuals with PI*ZZ in the US are currently diagnosed

80,000–100,000 PI*ZZ,1,2 only ~5,000 diagnosed

Misdiagnosed as COPD

Average time from first pulmonary symptom to initial diagnosis is 7.2 years4

44% of patients with pulmonary symptoms saw >3 physicians before initial diagnosis4

Early diagnosis can allow for treatment that can slow lung disease progression4

1Colp C. Chest. 1993;103:812.

2O’Brien ML. J Pediatr. 1978;92:1006.

3Silverman EK. Am Rev Respir Dis. 1989;140:961.

4Stoller JK. Cleve Clin J Med. 1994;61:461.


Aat deficiency is misdiagnosed

AAT Deficiency is Misdiagnosed

Misdiagnosed as:

COPD due to smoking/environmental/occupational exposure

Asthma

Allergies

Bronchitis

Clinical recognition confounded by symptoms typical in patients with COPD

Clinician must differentiate AAT deficiency from other causes of lung disease

Definitive diagnosis is simple via a blood test

1Brantly ML. Am Rev Respir Dis. 1988;138:327.

2McElvaney NG. Chest. 1997;111:394.


A f ffffffffffffffff ff

Pulmonary Signs and Symptoms

COPD Only1-4

COPD &AAT Deficiency1-4

AAT Deficiency Only1-4

  • Panacinar emphysema

  • Early onset (< 50 years)of symptoms in patientswith smoking history

  • Airflow obstruction not reversible with treatment

  • Family history of COPD

  • Onset > 50 years

  • Airflow obstructionreversible withtreatment

  • Centriacinar or paraseptal emphysema

  • Chronic cough

  • Shortness of breath with activity

  • Wheezing

  • Increased sputum production

  • Increased lower respiratory infections

1McElvaney NG. Chest. 1997;111:394.

2Brantly ML. Am Rev Respir Dis. 1988;138:327.

3Janus ED. Lancet. 1985;1:152.

4Larsson C. Acta Med Scand. 1978;204:345.


Ats ers range of recommendations for testing

ATS/ERS Range of Recommendations for Testing

Type A

Testing is recommended

Type B

Testing should be discussed, could be reasonably accepted or declined

Type C

Testing should not be encouraged

Type D

Testing should be discouraged

ATS/ERS Standards. Am J Respir Crit Care Med. 2003;168:818.


Who should be tested type a recommendations

Who Should Be Tested?Type A Recommendations

Adults with COPD or emphysema

Adults with asthma not reversible with treatment

Asymptomatic individuals with persistent obstructive pulmonary dysfunction with smoking or occupational exposure

Newborn, child, or adult with unexplained liver disease

Adults with necrotizing panniculitis

Siblings of individual with AAT homozygosity

ATS/ERS Standards. Am J Respir Crit Care Med. 2003;168:818.


Who should be tested type b recommendations

Who Should Be Tested?Type B Recommendations

Adults with bronchiectasis of unknown cause

Adolescents with persistent obstructive pulmonary dysfunction

Asymptomatic persistent obstructive pulmonary dysfunction with no risk factors

Family history of lung or liver disease

Adults with multisystemic vasculitis (anti-PR-3-positive vasculitis)

Relatives of individual with AAT homozygosity or heterozygosity

Adults and adolescents in areas where prevalence of AAT deficiency and smoking rates are high

ATS/ERS Standards. Am J Respir Crit Care Med. 2003;168:818.


Why aren t patients tested for aat deficiency

Why Aren’t Patients Tested for AAT Deficiency?

Issue

Answer

  • Misconception that deficiency is rare

  • AAT deficiency is the most common, potentially fatal hereditary disease

  • Misconception that testing is invasive, expensive, and time consuming

  • Testing is quick and noninvasive, and screening may be free

  • Lack of awareness of efficacy of AAT augmentation therapy

  • Treatment can slow progression of lung disease and improve survival

  • Misconception that deficiency is only found in one ethnic group

  • Studies show that deficiency is found in ALL ethnic groups


Advantages of detection of aat deficiency

Advantages of Detection of AAT Deficiency

Lifestyle changes to prevent/slow disease progression can be implemented:

Smoking cessation or prevention

Exercise

Nutrition

Occupational decisions

Influenza and hepatitis vaccinations

Disease-specific therapy (e.g., AAT augmentation therapy) can slow progression of lung disease and decrease mortality

Disease-specific support

Meaningful genetic data to family members

ATS/ERS Standards. Am J Respir Crit Care Med. 2003;168:818.


Outline6

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


Diagnostic tests for aat deficiency quantitative testing

Diagnostic Tests for AAT Deficiency: Quantitative Testing

Method

Normal range

Protective threshold

Radial immunodiffusion

150/220–350/400 mg/dL*

80 mg/dL*

Nephelometry

83/120–200/220 mg/dL*

50 mg/dL*; 11 µM†

  • Immunoassay to determine serum AAT levels

*Value obtained by commercially available standards. †Value obtained by NIH standard.

1ATS/ERS Standards. Am J Resp Crit Care Med. 2003;168:818.

2Brantly M. Chest. 1991;100:703.

3Brantly M. Am J Med. 1988;84(suppl 6A):12.

4Dati LF. Eur J Clin Chem Clin Biochem. 1996;34:517.


Range of serum levels and risk of disease by aat phenotype

Range of Serum Levels and Risk of Disease by AAT Phenotype

Phenotype

Units

PI*MM

PI*MS

PI*SS

PI*MZ

PI*SZ

PI*ZZ

null/null

µmol/L

20–48

18–48

15–33

17–33

8–16

2.5–7

0

mg/dL

150–350

140–350

100–200

90–120

75–120

20–45

0

Risk

Normal

Low

Low

Mod

High

High

High

Table adapted from ATS/ERS Standards. Am J Respir Crit Care Med. 2003;168:818.

Data from Brantly M. Am J Med. 1988;84:13 and Fagerhol MK. Adv Hum Genet. 1981;11:1371.


Diagnostic tests for aat deficiency qualitative testing

Diagnostic Tests for AAT Deficiency: Qualitative Testing

Phenotyping

Isoelectric focusing (IEF) is used to determine the AAT protein type(s)1

Genotyping

Identifies the AAT allele(s) present at the PI locus of chromosome 14

PCR with allele-specific amplification of genomic DNA1

Direct sequencing2

1ATS/ERS Standards. Am J Respir Crit Care Med. 2003;168:818.

2Brantly M. In: Crystal RG, ed. Alpha 1-Antitrypsin Deficiency: Biology, Pathogenesis, Clinical Manifestations, Therapy. New York, NY: Marcel Dekker, Inc.;1996.


Pulmonary function tests

Pulmonary Function Tests

Spirometry (pre- and postbronchodilator)

Considered “fifth vital sign”

Reduced FEV1, FVC, and FEV1/FVC ratio1,2

Fixed airflow obstruction1,2

In contrast to asthma, spirometry in patients with AAT deficiency does not return to normal with treatment3

Should be included in yearly follow-up1

1ATS/ERS Standards. Am J Respir Crit Care Med. 2003;168:818.

2McElvaney NG. In: Crystal RG, ed. Alpha 1-Antitrypsin Deficiency: Biology, Pathogenesis, Clinical Manifestations, TherapyNew York, NY:Marcel Dekker;1996.

3Eden E. Am J Respir Crit Care Med. 1997;156:68.


Spirometry normal vs aat deficiency

Spirometry: Normal vs. AAT Deficiency

FVC % Pred

FEV1 % Pred

FVC

FEV1

FEV1/FVC

Normal

4.150

96%

92%

5.20

80%

COPD

52%

72%

2.350

3.90

60%

Adapted from GOLD. Pocket Guide to COPD Diagnosis, Management, and Prevention. 2004.


Radiology

Radiology

Upper lung zone

Lower lung zone

  • Computed tomography1–4

    • Most definitive assessment of emphysema

    • Panacinar emphysema

    • Basilar hyperlucency

    • Reduced lung markings

    • Bullae formation

*Images from reference 2; used with permission.

1ATS/ERS Standards. Am J Respir Crit Care Med. 2003;168:818.

2Wilson JS. Chest. 2000;118:867.

3Beinert T. Chest. 1995;108:998.

4Schwaiblmair M. Eur J Med Res. 1998;3:527.


Radiology1

Radiology

Chest radiography

Not sufficient to use as a diagnostic tool

Recommended as an initial test for emphysema1

Advanced disease may show1–3:

Hyperinflation

Basilar hyperlucency

Reduced lung markings

Bullae formation

1ATS/ERS Standards. Am J Respir Crit Care Med. 2003;168:818.

2Brantly ML. Am Rev Respir Dis. 1988;138:327.

3Foster WL. Radiographics. 1993;13:311.


Radiology2

Radiology

lower zone disease

higher zone disease

lower zone disease


Radiology3

Radiology

Normal Chest X-ray

lower zone disease

higher zone disease

When AAT Deficiency Should Be Diagnosed


Liver function studies

Liver Function Studies

Standard liver function tests

Aspartate aminotransferase (AST)

Alanine aminotransferase (ALT)

Alkaline phosphatase

Total and direct bilirubin

Additional blood testing

Albumin, clotting studies (PT, INR, PTT)

Alpha fetoprotein

Imaging

Liver ultrasound

ATS/ERS Standards. Am J Respir Crit Care Med. 2003;168:818.


Outline7

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


Aat deficiency specific therapy for lung disease

AAT Deficiency–Specific Therapy for Lung Disease

IV augmentation therapy

Purified human AAT concentrate

60 mg/kg weekly maintains serum AAT levels above protective threshold (11 µM/80 mg/dL)1–3

Increases AAT levels in lung epithelial lining fluid (ELF)1–3

Goal is to slow progressive lung tissue destruction

1Gadek JE. J Clin Invest. 1981;68:889.

2Wewers MD. NEJM. 1987;316:1055.

3Schmidt EW. Am J Med. 1988;84(6A):63.


Ats ers recommendations for use of augmentation therapy

ATS/ERS Recommendations for Use of Augmentation Therapy

Patients with AAT serum level <11 µM with obstructive lung disease, independent of phenotype

Patients with FEV1 30% to 65% predicted have greatest benefit

Benefits for severe or mild airflow obstruction less clear

Possible benefit in post-lung transplant during respiratory tract inflammation or acute or chronic rejection

1ATS/ERS Standards. Am J Respir Crit Care Med. 2003;168:818.


Human aat preparations

Human AAT Preparations

3 human AAT preparations are approved in the US for use in patients with AAT deficiency who have lung disease

Pasteurized only1

Solvent-detergent (SD)-treated and nanofiltered2

Pasteurized and ultrafiltered3

Clinical studies suggest that all 3 preparations are bioequivalent and have similar safety profiles2,4

1Prolastin prescribing information.

2Aralast prescribing information.

3Zemaira prescribing information.

4Stoller JK. Chest. 2002;122:66.


Safety of augmentation therapy

Safety of Augmentation Therapy

Relatively few side effects reported

Most frequent:

Headaches

Myalgias

Arthralgias

Low back pain

No treatment or occasional analgesic use required

1Seersholm N. Eur Respir J. 1997;10:2260.

2AAT Deficiency Study Group.Am J Respir Crit Care Med. 1998;158:49.

3Dirksen A. Am J Respir Crit Care Med. 1999;160:1468.

4Wencker M. Chest. 2001;119:737.

5Stoller JK. Chest. 2002;122:66.


Augmentation therapy efficacy studies

Augmentation Therapy Efficacy Studies

Two registry studies (Danish and National Heart, Lung and Blood Institute [NHLBI]) demonstrated decreased annual decline in FEV1 in treated vs. untreated registry patients1,2

A mortality benefit was demonstrated with treatment in the NHLBI Registry study2

A randomized study demonstrated decreased loss of lung tissue in treated vs. untreated patients3

A longitudinal study demonstrated a slower decline in FEV1 in patients after vs. before they received augmentation therapy4

1Seersholm N. Eur Respir J. 1997;10:2260.

2AAT Deficiency Study Group.Am J Respir Crit Care Med. 1998;158:49.

3Dirksen A. Am J Respir Crit Care Med. 1999;160:1468.

4Wencker M. Chest. 2001;119:737.


Study of efficacy of augmentation therapy in danish registry

Study of Efficacy of Augmentation Therapy in Danish Registry

Inclusion Criteria

Danish group

PI*ZZ or AAT serum level <12 µM, ex-smokers, ≥2 spirometries ≥1 year apart, 5.8 years follow-up, no augmentation therapy

German group

PI*ZZ, AAT serum level <12 µM, ex-smokers, ≥2 spirometries ≥1 year apart, 3.2 years follow-up, augmentation therapy (60 mg/kg weekly) ≥1 year

Seersholm N. Eur Respir J. 1997;10:2260.


Study of efficacy of augmentation therapy in danish registry1

Study of Efficacy of Augmentation Therapy in Danish Registry

Treated (German)

Untreated (Danish)

n

ΔFEV1

n

ΔFEV1

Diff

P

Initial FEV1

≤30% pred

75

-24.2

27

-30.9

6.7

0.6

31%–65% pred

112

-61.8

58

-82.8

21

0.04

>65% pred*

11

-162.0

12

-140.0

22

0.7

Total

198

-53

97

-74.5

21.5

0.02

*In the treated group, these patients were required to have a decline in FEV1>120 mL/yr

Seersholm N. Eur Respir J. 1997;10:2260.


Study of efficacy of augmentation therapy in nhlbi registry

Study of Efficacy of Augmentation Therapy in NHLBI Registry

Study Design

Annual decline in FEV1 of 650 treated patients on registry compared with 277 untreated patients

Followed 3.5 to 7 years

Spirometry measured pre- and post-bronchodilator every 6 to 12 months

AAT Deficiency Study Group. Am J Respir Crit Care Med. 1998;158:49.


Study of efficacy of augmentation therapy in nhlbi registry1

Study of Efficacy of Augmentation Therapy in NHLBI Registry

AAT Deficiency Study Group. Am J Respir Crit Care Med. 1998;158:49.


Study of efficacy of augmentation therapy in nhlbi registry2

Study of Efficacy of Augmentation Therapy in NHLBI Registry*

*Patients with FEV1 <50% predicted

AAT Deficiency Study Group. Am J Respir Crit Care Med. 1998;158:49.


Randomized trial of augmentation therapy

Randomized Trial of Augmentation Therapy

Study Design

56 ex-smokers with FEV1 30% to 80% predicted and PI*ZZ phenotype randomized to 250 mg/kg IV AAT (n = 28) or albumin (n = 28) every 4 weeks for 3 years

Self-administered spirometry performed twice daily and lung density measured by annual CT

Dirksen A. Am J Respir Crit Care Med. 1999;160:1468.


Randomized trial loss of lung tissue slower with treatment

Randomized Trial: Loss of Lung Tissue Slower With Treatment

Treated

Untreated

Diff

P

ΔFEV1*

-26.5

-25.2

-1.3

0.96

ΔFEV1†

-2.11

-1.47

-0.64

0.20

CT, whole lung, g/L

-1.50

-2.57

1.07

0.07

*Obtained by daily, patient-administered serial spirometry.

†Obtained from FVC maneuvers every 3 months.

Dirksen A. Am J Respir Crit Care Med. 1999;160:1468.


Longitudinal study

Longitudinal Study

Study design

96 patients with AAT serum levels below the protective threshold and reduced lung function

Patients were used as their own controls

Decline in FEV1 ≥1 year before they received treatment was compared with decline in FEV1 ≥1 year after receiving treatment (60 mg/kg weekly)

Wencker M. Chest. 2001;119:737.


Longitudinal study decline in fev 1 significantly slower with treatment

Longitudinal Study: Decline in FEV1 Significantly Slower With Treatment

Pre-treatment

Post-treatment

Initial FEV1*

n

Diff

P

<30% pred

25

-15.3

-19.0

-3.7

ns

30–65% pred

60

-49.3

-37.8

11.6

0.066

>65% pred

11

-122.5

-48.9

73.6

0.045

Total

96

-49.2

-34.3

14.8

0.019

Results

*FEV1 was < 65% predicted or decline in FEV1 was >120 mL/yr.

Wencker M. Chest. 2001;119:737.


Change in fev 1 slowed with treatment in rapid decliners

Change in FEV1 Slowed With Treatment in Rapid Decliners

Wencker M. Chest. 2001;119:737.


Change in fev 1 slowed with treatment in rapid decliners1

Change in FEV1 Slowed With Treatment in Rapid Decliners

Wencker M. Chest. 2001;119:737.


Surgical treatment for aat associated lung disease

Surgical Treatment for AAT-Associated Lung Disease

Lung transplantation

For patients who do not respond to more conservative therapy or who have extensive lung damage1

5% to 10% of lung transplants performed in the US each year are performed due to AAT deficiency2

5-year survival is approximately 50%3

Lung volume reduction surgery

May improve dyspnea and lung function

Not recommended due to lack of evidence1

1ATS/ERS. Am J Respir Crit Care Med. 2003;168:818.

2UNOS OPTN data, 1988-2004.

3UNOS OPTN data, 1995-2002.


Treatment for aat associated liver disease

Treatment for AAT-Associated Liver Disease

No specific treatment

Avoidance of alcohol

Hepatitis A and B vaccinations

Liver transplantation

For patients who do not respond to more conservative therapy or who have extensive liver damage

ATS/ERS. Am J Respir Crit Care Med. 2003;168:818.


Conclusions

Conclusions

AAT deficiency is underdiagnosed

Some of your COPD patients have AAT deficiency

Early onset of COPD (<50 years of age)

Emphysema in the absence of risk factors or with prominent basilar hyperlucency

Asthma not completely reversible with treatment

Family history of emphysema, bronchiectasis, liver disease, or panniculitis

Unexplained liver disease or panniculitis or vasculitis

Bronchiectasis


Conclusions continued

Conclusions (continued)

AAT augmentation therapy can slow the annual decline in FEV1 and possibly slow the loss of lung tissue

If you don’t test, you can’t:

Test family members

Initiate interventions (smoking prevention or cessation, occupational decisions)

Treat with augmentation therapy

Affect mortality associated with AAT deficiency


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