1. health and fitness
2. disease

Alpha-1 Antitrypsin
Deficiency: Dispelling
Myths
Ronald Reilkoff, MD
Staff Physician, HealthEast St.Paul, Mn
Assistant Professor (Adjunct)
University of Minnesota
Disclosures
 Speakers Bureau for CSL Behring,
Grifols and Boehringer Ingleheim
Goal
Raise awareness regarding the prevalence and
diagnosis of Alpha-1 Antitrypsin Deficiency (A1AD)
Top Myths - Misconceptions
regarding A1AD
Myth 1 – A1AD is rare (so why worry)
Myth 2 – A1AD has a distinct presentation
Myth 3 – A1AD testing is complicated
Myth 4 – There is no effective therapy for
A1AD
1.Stoller and Aboussouan Arch Int Med 169: 6 2009
A1AD is the Major Genetic Risk
Factor for COPD
 ~15 million individuals have been diagnosed
with COPD*1
 10M office visits
 1.5M ED visits
 700K hospital discharges
 3rd leading cause of death in United States2
 $50 Billion in 2010 direct cost of COPD2
* Self reported diagnosis
1.
2.
3.
4.
Ford. Chronic Obstructive Pulmonary Disease Surveillance. 1999-2011 Chest 2013
GOLD 2011 Guidelines
Kosacz Morbidity and Mortality Weekly, 2012;61(46) 938
NIH website
Alpha-1 Antitrypsin
 Alpha-1 antitrypsin (A1AT) is a protein
predominantly produced by liver cells and
released into the bloodstream
 Broad spectrum anti-protease activity
 Broad Spectrum antioxidant
 Modulates inflammation and lymphocyte
proliferation
 Body normally produces 32mg/kg A1AT per
day
 Serum levels 150-350mg/dL
 Variability in levels as it is an acute phase
reactant
1. ATS/ERS Guidelines. Am J Respir Crit Care Med 2003; 168:818-900
Deficiency of Alpha-1 Antitrypsin =
Risk of Lung Disease
 Hereditary condition characterized by low
(or dysfunctional) levels of A1AT in
plasma.
 < 11µM/L or <80 mg/dL*
 PiZZ phenotype
*Theoretic protective threshold
Alpha-1 Antitrypsin Deficiency
 A1AT protects the lungs from digestion by
neutrophil elastase (NE) (protease)
 NE is released by white blood cells in response to
infection/irritation
 A1AT accounts for >90% anti-neutrophil elastase
Normal Protection
Neutrophil
elastase
burden
Antineutrophil
protection
 If left unchecked NE may attack healthy
AAT
lung tissue
 A1AT binds NE, neutralizing the elastase
and preventing lung damage
AAT Deficient
Neutrophil
elastase
burden
Antineutrophil
protection
AAT
Molecular Genetics of A1AT1
 Two alleles that genetically code for the A1AT
protein = “genotype”
 PI = protease inhibitor “MM” = phenotype
 >100 alleles for A1AT
 >30 alleles result in deficiency or dysfunction
 98% of human population carries M, S or Z
 M allele – Normal variant (95% of US)
 Z allele - Found in 95% with clinically recognized AATD
 S allele (slightly more common than Z)
 Variant causing mildly decreased A1AT levels
 Null allele
 Interrupted A1AT synthesis due to transcriptional or translational
errors
1. ATS/ERS Guidelines. Am J Respir Crit Care Med 2003; 168:818-900
2. Stoller JK & Aboussouan LS. Am J Respir Crit Care Med 2012; 185:246-259
Heterozygous
• 2 different alleles
• Expressed as:
• PI*MZ
• PI*SZ
Homozygous
• 2 same alleles
• Expressed as:
• PI*ZZ
A1AD and Risk of COPD
Development
Range of serum levels and risk of deficiency by A1AT phenotype 1,2
Units
PI*MM
PI*MS
PI*SS
PI*MZ
PI*SZ
PI*ZZ
Null/
null
20-48
18-48
15-33
17-33
8-16
2.5-7
0
150-350
140-350
100-200
90-210
75-120
20-45
0
Normal
Low
Low
Moderate
High
High
High
µmol/
L
mg/dL
Risk
Protective Threshold
~ 80mg/dL
1.
2.
Rachelefsky G, Hogarth K. J Allergy Clin Immunol 2008;121: 833-838
ATS/ERS A1AD AJRCCM 2003; 168(7):818-900
Myth 1 – A1AD is Rare
Studies of the Prevalence of A1AD
 Two conclusions:
 Relatively Common disease
 Under-recognized
 A1AD thought to comprise 3% of all COPD cases worldwide1
 ~ 1in 2500 individuals in US affected2
 A1AD can affect multiple ethnicities
 PIZ most prevalent in Northern Europeans, least in Asian
and Hispanic
 Prevalence of S and Z alleles is worldwide3,4
1.
2.
3.
4.
ATS/ERS A1AD AJRCCM 2003; 168(7):818-900
www.alpha1.org/newly-diagnosed
de Serres FJ. Environ Health Perspect 2003; 111:1851-1854
de Serres.Ther Adv Resp Disease 2012: 6:5 277-95
Origins of Alpha (S, Z)
Gene Frequencies of PiZ in Europe
 Screening studies show
highest prevalence of PiZ in
NorthernEuropean
populations (founder
population)
 Originated 2000-7000 years
ago
 PiS highest in southern
Europe (Iberian pennisula)
 Originated 10-50000 years
ago
Vikings/Norse Migration 5th to 10th Centuries
Worldwide Indirect Estimates of
Predominant PI types1*
1. de Serres.Ther Adv Resp Disease 2012: 6:5 277-95
* Based on epidemiological surveys (indirect) – low estimates
Higher Prevalence of Alpha-1 vs US
Population: Kentucky Study
Observed
Genotype
Prevalence
in KY Cohort
Prevalence in
Caucasian
US Population
(N)
(%)
(%)
MM
3948
91.64
94.0 to 96.0
MZ
113
2.62
2.0
MS
174
4.04
5.0
SZ
12
0.28
0.05
ZZ
12
0.28
0.01
SS
5
0.12
0.05
Rare M subtypes
32
0.7
Rare, deficiency-related
12
0.28
4308
100.00
Genotype
Total
Koura F. Poster presented at: American Thoracic Society International Conference; May 18-23, 2012; San Francisco, CA.
Screening for Alpha-1
Population based Screening:
PiZZ1,2-5 ~ 1:1600 (Sweden)  1:4500
(US) ~ avg 1:2500
WorldWide estimate:
• 116,000,000 PiMZ
• 1,100,000 PiZZ
In the US 100,000 individuals are
affected 4-5
• AATD diagnosed in approximately
7,000 US individuals or <10%4
• ~10 Milliion Americans with
deficient alleles (heterozygous)
1. Sveger T. NEJM 1976;294:1316:1321
2. Sveger T. Acta Paediatr Scand 1988; 77:847-851
3. Silverman EK, et al. Am Rev Respir Dis 1989; 140:961-966
4. de Serres FJ. Chest 2002; 122:1818-1829
5. Stoller JK & Aboussouan LS. Am J Respir Crit Care Med 2012; 185:246-259
6. de Serres, Blanco Ther Adv Resp Disease 2012; (6) 5:277-95
Myth 2 – A1AD has a Classic
Presentation
Myth 2 – A1AD has a Classic
Presentation
Textbook definition:
“early onset emphysema in a nonsmoker with LL predominant
emphysema”
Original case series in 1963 by Laurel
and Erickson with 5 patients1:
 3 with obstructive lung disease
(chronic bronchitis, emphysema and
bronchiectasis)
 2 without obvious signs of
obstructive lung disease
1. Laurell and Erickson Scand J Clin Lab Invest 1963; 15 : 132-140
A1AD – Clinical Manifestations1
 Lung disease
 Emphysema
 Chronic Bronchitis
 Bronchiectasis
 Childhood and adult liver disease




Hepatitis
Cirrhosis (37%)
Hepatocellularcarcinoma
Fulminant liver failure
 Occasional systemic manifestations
 Necrotizing panniculitis
 Inflammation of the subcutaneous fibro-fatty layer that underlies the skin
usually over buttocks and thighs
 Red, painful nodular lesions, with weeping oily discharge
 C-ANCA Vasculitis (Wegener’s Granulomatosis)
1. Ranes J & Stoller JK. Semin Respir Crit Care Med 2005; 26:154-166
No Unique Presenting Features
Majority (72%) of patient with A1AD present with symptoms1
 Family member with A1AD (20%)
 Abnormal imaging (8%)
In a survey of patients enrolled in the NHLBI registry of A1AD1,
symptoms at enrolment included:
 Dyspnea (84%)
 Wheezing:


With upper respiratory tract infection (76%)
Without upper respiratory tract infection (65%)
 Cough (42%)
 Excess sputum production (46%)
1. McElvaney NG et al. Chest 1997; 111:394-403
Variable Imaging in AATD
 Chest X-rays from 165 ZZ Alpha-1
patients:¹
 15% were normal
 Only 20% showed classic “emphysema”
at bases
 CTs from 102 ZZ Alpha-1 patients:²
 64% showed basal predominance
 36% had predominant apical disease
 Some individuals with A1AD (PiZZ)
never develop emphysema
 Bronchiectasis
1.
2.
Gishen. Clin Radiol 1982; 33: 371-377
Parr D. Am J Respir Crit Care Med 2004; 170:1172-1178
21
Myth 3 – A1AD testing is
Complicated
It’s Not.
 Can be simple as a fingerstick
 It can be done for free and anonymously.
 Free testing kits available from Pharma
 Free testing in state of Florida
 Alpha-1 Coded Testing Study (ACT) through
Medical University of South Carolina
1. Brantley M, Clin Chem. 2006;52 (12):2180-2181
2. Wall. J Pediatr. 1990;116:248-251
3. ATS/ERS Guidelines. Am J Respir Crit Care Med 2003;168:818-900
4. Carpenter MJ, et al. Ann Behav Med. 2007;33(1):22-28
Serologic testing of A1AD
 A1AT serum level test*
 Determines A1AT levels in blood or serum
 May not identify heterozygotes
 A1AT genotyping*
 Identifies abnormal A1AT gene
 Typically performed using polymerase chain reaction
 Identifies if a patient has S or Z allele(s), but may miss rare alleles
 A1AT Pi-typing (ie, phenotyping)
 Determines type of A1AT protein in the blood via isoelectric focusing
on polyacrylamide gels
 Can identify virtually all mutations
 Requires a high level of expertise to read; more costly; limited
number of experts available for reading tests
*Free testing via fingerstick kits
Diagnosing A1AD
 To make A1AD diagnosis = Laboratory Diagnosis
 Positive deficient genotype (PiZZ, PiSZ, null or rare)
 Clinically compatible disease (COPD, liver disease,
panniculitis)
 Serum levels of A1AT are not sufficient to make
diagnosis
 Acute phase reactant
 Does not identify heterozygotes
Barriers to Testing
 Misconceptions:
 Rare disease
 Easy to detect
 No effective treatment (“therapeutic nihilism”)
 Technical barriers:
 Introduction of A1AD testing in routine hospital laboratories
 Patient reservations regarding testing
 Discrimination: Health and Life Insurance
 Provider remembering to test
 Testing fatigue
1. Bazzi K & Rahaghi F. US Resp Dis 2010; 6:47-51
Discrimination Concerns
Genetic Information Nondiscrimination Act 20081
 Bars discrimination of health insurance companies
and employers on basis of genetic information
Life Insurance
 A1AD itself is not considered a sole factor in denial
of Life Insurance2
1. www.govtrack.us
2.Gomez AJRCCM 185:2012:A4364
Importance of Testing:
Delay in Diagnosis
 Average delay in diagnosis 8.3 +/- 6.9 years
between onset of symptoms and diagnosis1
 Patients often evaluated by 2-3 providers
before diagnosis
 Average age of 45.5+/- 9.5
 ‘Asthma’ is often initial diagnosis
1. Campos, MA et al Chest 2005;128(3)
Implications in Delay of A1AD
Diagnosis
The estimated annual rate of
FEV1 decline1
Normal lung function declines at
approximately 30 mL/yr
PI*ZZ A1AD non-smokers = 4060 mL/yr
PI*ZZ A1AD smokers = 113
mL/yr
Predictors of greater FEV1
decline
Smokers, males, aged 30-44
years, FEV1 35-79% predicted
value, decreased serum A1AT
levels and bronchodilator
response2
1. Piitulainen E & Eriksson S. Eur Respir J 1999; 13:247-251
2. Stoller JK & Aboussouan LS. Lancet 2005; 365:2225-2236
Reasons to Test
 Early detection of subjects is crucial to apply
effective preventive measures and early
institution of therapy!
 Lifestyle implications:
 Patients who are tested more likely to attempt to quit
smoking2,4
 Increases potential for family testing and genetic
counseling3
 Raises awareness to avoid hazards of
occupational/environmental respiratory pollutants
1. Brantley M, Clin Chem. 2006;52 (12):2180-2181
2. Wall. J Pediatr. 1990;116:248-251
3. ATS/ERS Guidelines. Am J Respir Crit Care Med 2003;168:818-900
4. Carpenter MJ, et al. Ann Behav Med. 2007;33(1):22-28
ATS Diagnostic Testing Guidelines
*No definitive physical conditions that confirm A1AD although
certain clinical features should prompt suspicion of A1AT
deficiency1
Type A – Recommend
• Symptomatic adults with:
•
•
•
•
-Emphysema
-COPD
Incompletely reversible asthma
Asymptomatic individuals with:
-Persistent obstruction on PFT
and identifiable risk factors
(patients with FEV1< 80%
predicted and FEV1/FVC less
than 0.70)
All individuals with unexplained liver
disease
Adults with necrotizing panniculitis
Type B – Consider
• Adults with bronchiectasis of
•
•
•
1. ATS/ERS Guidelines. Am J Respir Crit Care Med 2003;168:818900
unknown source
Adolescents with persistent airflow
obstruction
Asymptomatic individuals with
persistent airflow obstruction and no
identifiable risk factors
Adult C-ANCA-positive vasculitis
Myth 4- There are no Effective
Therapies for A1AD
Treating Alpha-1 Antitrypsin






Counseling
Family testing
Lifestyle modifications
Exercise
Avoidance of pollutants
Vaccinations
 Influenza/pneumococcus
 Hepatitis A/B
Treating A1AD with Lung
Disease
 COPD Specific therapies:






Bronchodilators
Inhaled steroids
Antibiotics
Oxygen
COPD Action Plans
Pulmonary Rehabilitation
 Augmentation therapy
 Lung Transplant
Indications for Augmentation
Therapy
 PiZZ, Null or deficient phenotypes
 Fixed airflow obstruction
 FEV1 30%-65%
 Emphysema on CT
 Nonsmoker, ex-smoker
 Adherence to medical regimen
 Rapid decline in FEV1 (>80ml/yr)
 Necrotizing panniculitis
Augmentation Therapeutic Options
 Purified Preparations:




Prolastin-C – Grifols
Zeimaira – CSL Behring
Aralast – Baxter
Glassia - Kamada
 60mg/kg weekly infusion
 Rate 0.08ml/kg as tolerated by patient
Augmentation Therapies
 Original FDA approval to raise blood and lung
levels in a genetically deficient population1
 Proving clinical efficacy is much harder
 FEV1 (rate of decline)2 traditional endpoint but poor marker
 Does not encompass all disease facet
 Diffusion impairment3




1.
2.
3.
4.
5.
6.
CT Densitometry3,6
Symptoms, exacerbations2
Mortality2
Elastin degradation products5
Gadek. J Clin Invest 1981; 68:1158-1165
A1AD NHLBI Registry AJRCCM. 1998;158:49-59
Dirksen. AJRCCM 1999;160:1468-1472
Dirksen ERJ 2009; 33(6):1345-1353
Ma. COPD 2013; 10:1-9
Stockley. Resp Res 2010;11:136
Efficacy of Augmentation
Change in FEV1 (mL/yr)
Augmentation
100
90
80
70
60
50
40
30
20
10
0
1. Chapman KR et al. COPD 2009; 6:177-184
Control
Augmentation Therapy
1. Chapman KR. COPD 2009; 6:177-184
RCT - Change in FEV1
1. Gotzche PC. Cochrane Review. 2010. Issue 7
RCT – CT Densitometry
1. Gotzche PC. Cochrane Review. 2010. Issue 7
Efficacy - Contrasting
Recommendations
Accumulated data is overwhelming in favor of augmentation
 Biologic1-2
 Observational3-4
 Epidemiologic5
ATS/ERS guidelines support6
However:
 2 Small RCT  No change in FEV17,8
 Cochrane Review  cannot recommend augmentation9
Several countries do NOT cover on this basis
Augmentation Efficacy Controversy
“Parachutes reduce the risk of injury
after gravitational challenge, but their
effectiveness has not been proved
with randomized controlled trials”
Recommend: moratorium on
parachutes until further study
Smith G BMJ 2003;327:1459
Summary
 Fact 1 - A1AD is relatively common and underrecognized by providers
 Fact 2 – A1AD can predispose to a wide range of
lung disease with a variable and non specific
clinical presentation
 Fact 3 – A1AD testing is safe, discrete and
important – and only way to rule out or in the
diagnosis
 Fact 4 – There are effective therapies for A1AD;
augmentation is efficacious.
Thank you!
 Questions?
 Contacts/Information:
 [email protected], [email protected]
 www.alpha-1foundation.org