alpha-1-antitrypsin deficiency
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Alpha-1-Antitrypsin Deficiency
Mark Brantly, M.D.Professor & Chief
Division of Pulmonary, Critical Care & Sleep MedicineUniversity of Florida College of Medicine
Objectives
1. Learn about the clinical and molecular features of Alpha-1-Antitrypsin deficiency
2. Learn who should be screened for Alpha-1-Antitrypsin deficiency
3. Learn about current and new therapies for Alpha 1-Antitrypsin Deficient Individuals
Alpha-1-Antitrypsin Deficiency
• AAT level 5.75 M PI*Z (>95%)• PI*Z Glu to Lys at 342• Clinical Presentation
– Asthma– Bronchiectasis– Pneumonia– COPD– Cirrhosis
• Rapid decline in lung function• Premature disability and death• Smokers die 20 years before
non-smokers• Passive Smoking is especially
risk for Deficient Children
51 y/o AAT Deficient Individual Chest CT Coronal View
1-Antitrypsin
• 52 kDa glycoprotein• Acute phase reactant “anti-
inflammatory”• Secreted in large amount
from hepatocytes, but also express in many other tissues
• At least 100 different alleles• 34 alleles associated with
deficiency or dysfunction• Mutations may affect the
amount secreted and/or its function
• The frequency of the Z allele suggest a selective advantage
Met 358
Our Genetic LegacyVariation is the Spice of Life
• “Insanity is hereditary-you get it from your kids”, MBrantly, father to 14, 16 and 28 year old children
• Alleles are the result of genetic variation on the same gene
• Not all alleles are associated with increased risk of disease
• Genetic Load: 5-15 “lethal” genes• Genes are not absolutely
predictive for the development of disease
• Risk (lung disease) MM=1, MZ~1.5-3, SZ~4-8, ZZ~18
Active SiteZ MutationGlu to Lys 342
1-Antitrypsin Deficiency
• AAT level 5.75 M PI*Z (>95%)• Common genetic disease, 75-100,000
homozygous individuals in USA (1:2500-4000)
• Frequency of S and Z alleles in Turkey is unknown
• COPD and Liver disease• Rapid decline in lung function often
associated with lung infections• Asthma is common presenting feature• Carriers are at increased risk for COPD• Most common inherited risk factor for
COPD (~10% are MZ, SZ or ZZ)• Early diagnosis and preventive care
translate into health benefits
5000
~95,000
The Problem
WHO-ATS-ERS-ACCP Recommendations
• All individuals with COPD should be tested once with PI/genotyping plus an AAT level
• All individuals with asthma and a non-reversible component
• Family members of individuals with Alpha-1-antitrypsin deficiency
• Individuals with “cryptogenic” cirrhosis
1-Antitrypsin-Neutrophil Elastase Docking
1-antitrypsin
Neutrophilelastase
Met358
Asn46
Asn83
Asn247
Asp46
Asn144
Asn95
His46
Ser195
Protease-Antiprotease Balance
Normal AAT Deficiency
Neutrophil Elastase Burden
Anti-Neutrophil Elastase Protection
Neutrophil Elastase Burden
AAT
AAT
• Lung damage is the result of both a burden of neutrophils and its toxic products and a lack of sufficient AAT in the lower lung.
Anti-Neutrophil Elastase Protection
Lung Injury in AAT Deficient Individuals
Oxidants
Proteases
-Defensins
Effectsof
Injury
Propagation
andMaintenancePro-Inflammatory Cells (PMN, Mast Cells, Lymphocytes &AM)
InitiationSmoking
Infections
Polymers of Z AAT
Cellular Response to UPR
Pro-Inflammatory Molecules (LTB4 & IL8)
Recruitment-Expansion-ActivationFibrosis
AATAirwayAlveolus
1-Antitrypsin is More than an Antiprotease
• 52 kDa glycoprotein• Acute phase reactant “anti-
inflammatory”• Secreted in large amount from
hepatocytes, but also expressed in macrophages & bronchial epithelium
• Broad spectrum anti-protease• Inhibits -defensin cytotoxicity
and pro-inflammatory properties• Anti-oxidant with 9 methionines
Met 358
AAT Gene
SERPIN Cluster
AAT Gene Coding Region
AAT Normal Alleles
AAT Null Variants
Active Site
Active Site
AAT Deficiency Alleles
AAT Z Protein
Active Site
Z MutationGlu to Lys 342
Active Site
The Spectrum of Lung Disease AAT Deficiency
• Normal Lung Function with CT Evidence of Emphysema
• Emphysema• Bronchiectasis• Rapid decline in lung function often
associated with lung infections• Asthma is common presenting
feature• Accelerated Rate of Decline in Lung
Function– FEV1 35-80% -ROD 83.5ml/year– Increase ROD in BDR+
Individuals• Evidence that Lung Inflammation
Begins Early
Airways Disease and EmphysemaIn AAT Deficiency
• Deficient individuals frequently have CT scan evidence of bronchiectasis
• Greater the 65% of AAT NHLBI Registry subjects have a positive BDR
• In animal models airway hyper-reactivity is reduced by AAT
• Anecdotal evidence from patients on augmentation therapy
• Large fraction of deficient individuals present as asthmatics
Adults
Age of onset; 25-45 years
Pulmonary
Dyspnea Emphysema
Chronic Bronchitis Episodic Bronchitis
Pneumonia Asthma
Hepatic Cirrhosis
Hepatosplenomegaly
Gastrointestinal Bleeding Ascites
Hepatoma
Children
Age of onset; 2 months-8 years
Hepatic
Neonatal Cholestatic Jaundice
Failure to Thrive Lethargy/Irritability
Hepatosplenomegaly Vomiting Diarrhea Cirrhosis
Gastrointestinal Bleeding Ascites
Pulmonary
Asthma Dyspnea
Other
Clinical Features of AAT Deficiency by Age Group
Reduction in Life Span
• Only 52% of 1AT Deficient Individuals with pulmonary
symptoms are alive at age 50• Only 16% of 1AT Deficient
individuals with pulmonary symptoms are alive at age 62• Most common causes of death
– Emphysema– Infection– Sepsis – Liver Disease
Brantly, et al Am Rev Respir Dis. 138(2): 327-36, 1988
Laboratory Methods for the Detection of AAT Deficient Individuals
• AAT Genotyping (typically S and Z alleles) RFLP or Taqman
• AAT PI typing (Phenotype) isoelectic Focusing
• AAT level-Nephelometry• High Resolution DNA Melt• Sample types: include,
plasma, serum, dried blood spot and buccal swabs
• Future-monoclonal AB, Amptamers, “office test” kits
• AAT Deficiency Diagnosis in a LABORTORY Diagnosis
1-Antitrypsin Typing (PI Typing)
Relationship Between PI Type and Serum Level
QO
10
20
50
40
30
MS MZMM SZ ZZ
Ser
um
1-A
ntitr
ypsi
n Le
vel (
M)
1-Antitrypsin PI Type
Ser
um
1-A
ntitr
ypsi
n Le
vel (
mg
dl)260
156
52
104
208Normal Range
Typical Pedigree
Treatment of Lung Disease
1AT Deficiency
Neutrophil Elastase Burden
Anti-neutrophil Elastase Protection
AAT
Reduce the burden of neutrophil products
Augment the lung AAT concentration
Prevention of Lung Destruction
• Smoking cessation*, avoidance of smoke, and dust
• Pneumococcal and influenza vaccination• Aggressive antibiotic therapy• Treatment of airway disease with inhaled
steriods and bronchodilators• *Children with AAT Deficiency are at great
Risk of Lung Destruction when their parent Smoke
Therapies of AAT Deficiency
• Intravenous Augmentation Therapy– Pooled Human AAT(60mg/kg)
• >$100,000/year no controlled studies but is FDA approved
• Potential of viral and prion transmission
• Therapies in Development– Aerosolized AAT
• rAAT- nebulized• Pooled Human-dry powder (like insulin) • hAAT nebulized
Specific Therapies of AAT Deficiency (continued)
• Therapies in Development– Gene Therapy
• Muscle delivery of AAV1/2- AAT trials began in UF
– Many new therapies on the horizon
Dry Powder Aerosolize AAT
Replace weekly IV dosing with daily pulmonary dosing– reduced drug requirements– increased patient convenience
A1PI
Powder Particles1 - 2 m
Powder Production(Spray drying)
Pulmonary Delivery System(Pneumatic reusable)
Powder Packaging(Unit dose blisters)
~ 6 mg A1PI / blister
First
• It’s a Inherited Disorder--- Counseling and Family Screening
AOF-UF Detection Lab Testing Algorithm
Identification of GenotypeZZ, SZ, SS, MS* & MZ*
DBS AAT Level
Positive for S or Z allelesNegative for S or Z alleles(98% are MM)
Individual with Obstruction
Stop or PI typefrom
plasma or serum Plasma Sample Second Confirmation by PI
Typing
*MS & MZ with low AAT Levels are likely Null or Rare Low Level AAT Alleles and Plasma Sample is requested for PI typing &SNP scan by High Resolution DNA Melt.
DBS Genotyping
for S & Z Alleles
WHO-ATS-ERS Recommendations
• All individuals with COPD should be tested once with PI/genotyping plus an 1-antitrypsin level
• All individuals with asthma and a non-reversible component
• Family members of individuals with 1-antitrypsin deficiency
• Individuals with “cryptogenic” cirrhosis
Summary: COPD Management
Diagnose
Reduce risk
Smoking cessation
Reduce symptoms
Reduce complications
PharmacotherapyPulmonary rehabilitation
ImmunizeTreat exacerbationsConsider oxygen
SpirometryAAT Testing!!!
Education
Education
Education
Education
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