Download Alpha – 1 Antitrypsin (AAT) Deficiency

Alpha – 1 Antitrypsin
Deficiency
Jorge Mera, MD
Presbyterian Hospital of Dallas
Alpha – 1 – Antitrypsin Deficiency
Mechanism of Alpha-1- Antitrypsin Deficiency (AATD)
Clinical Case (Presentation)
Lung Disease
– Pathogenesis
– Clinical Presentation
– Treatment
Extra-Pulmonary Disease
– Hepatic Disease
Pathogenesis
Clinical Presentation
– Other
Clinical Case (Resolution)
Serpin
These are inhibitors of proteolytic enzymes with a serine
residue at the active site
– AAT, Antithrombin, C1-inhibitor and alpha 1 antichymotrypsin
When they bind to its target proteinase it undergoes a
conformational change
The advantage
– Is that the conformational change stabilizes the complex
– It allows the modulation of inhibitory activity
The disadvantage of conformational mobility is their
vulnerability to mutations which can :
– Decrease its activity
– Allow inappropriate changes that lead to polymerizations
Protein Folding and Function
Elastase
AAT
AAT
AATD is a Protein Folding Disease
Protein folding is the process by which an
unfolded polypeptide chain folds in to a
specific native and functional structure
Defective protein folding is an important
mechanism underlying the pathogenesis
of many diseases
Protein Folding and Disease
Disease
Protein Affected
Molecular Defect
Cystic fibrosis
transmembrane regulator
(CFFTR)
Misfolding and retention
in the ER, leading to
degradation
Marfan Syndrome
Fibrillin
Misfolding
Nephrogenic
Diabetes Insipidus
Vasopressin receptor or
aquaporin water channel
Misfolding and retention
in the ER
Alfa -1- Antitrypsin
Deficiency
Alfa -1- Antitrypsin
Misfolding and retention
in the ER leading to
aggregation in cells of
synthesis
Creutzfeldt-Jakob
Disease
Prion protein
Aggregation in brain
(after protein release)
Alzheimer’s Disease
Beta-amyloid
Aggregation in brain
(after protein release)
Cystic Fibrosis
ER: Endoplasmic Reticulum
Abnormal Folding and
Polymerization of AAT
The most common and severe
form of AAT deficiency is
caused by e Z mutation, a
single base substitution (Glu342-lys) in the AAT gene.
This slows the rate of protein
folding in the cell
Allowing the accumulation of
an intermediate which
polymerizes Impeeding its
release
Leading to plasma deficiency
AAT Polymer
Electron Microscopy of AAT Polymers
in the Liver
Clinical Case
CC: 45 yowm comes to your office with a CC of Dyspnea on mild
exercise.
PMH: Is unremarkable, and he never smoked
Family Hx: His Father was a smoker and died of Emphysema at 43
years of age and his mother is 73 yo and in good health. He has 2
sons 19 and 21 years old, his older son has a 3 pack/year smoking
Hx and the 19 yo has IgA deficiency
PE: Vital signs reveal BP 120/74 HR: 88 RR: 20/min. The only
positive findings are diminished bilateral breath sounds and an
emphysematous type Chest wall.
Clinical Case
His Chest X ray shows
bullous images in both LL
His Chest CT
His PFT reveal a FEV1
48% of predicted with a
35% increase on inhaled
bronchodilators.
CBC and Chem 14 are
normal. His AAT level is
45 mg/dL.
Clinical Case
Does he have a AAT deficiency ?
What other tests should you order?
What is his prognosis?
What information regarding treatment should you give
him?
Is he a candidate for AAT augmentation therapy?
If so, what precautions should you take before starting
treatment?
Should his siblings be tested for AATD and Phenotype?
What will you do with the results if they are abnormal?
AATD
Described in 1963 by Laurell and Erikson1
Underrecognized Disorder that may affect
– Lungs
– Liver
– Skin (rarely)
AAT
– Inhibitor of proteolytic enzyme elastase
– Member of the Serpins Family (Serine Protease Inhibitors)
– 90 Alleles Identified
1. Laurell, C-B,Eriksson, A. Scand J Clin Lab Invest 1963: 15:32
AATD Lung Disease
AAT Phenotypes
Normal
Deficient
Null
Dysfunctional
Phenotype
AAT Levels
AAT Function
MM
Normal
Normal.
ZZ
(most common)
Under 35 % of
normal level
Normal
Null Null
0%
NA
varies
Normal
Abnormal
What is the minimum Level of AAT
necessary for lung protection?
11 umol/L or 80 mg/dL
(NV: 20-53 umol/L or 150 300 mg/dL)
Based on population studies
Pathogenesis of Lung Damage in AATD
AAT
Clinical Case
Epidemiology
USA:
Worldwide
80,000 – 100,000
3,000,000
Worldwide racial and ethnic distribution of alpha(1)-antitrypsin
deficiency. Chest 2002;122:1818
Prevalence
Based on a US population of 250 million
– COPD screening1: 2 - 3 % of 965 COPD patients screened1
If in the USA there are 2.1 million patients with Emphysema,
40,000-60,000 would be expected to be AAT Deficient
– Direct population screening studies2
1:1575 – 1:5097 are positive 80,000 - 100,000 would be expected to
be AAT Deficient
1. Chest 1986;89:370
2. N Eng J Med 1976;294:1316
Why is AAT Deficiency
Underdetected ?
Many patients are asymptomatic despite
severe deficiency
Lack of recognition of symptomatic patients by
physicians
– In a cohort of 304 AAT deficient patients
Mean time to diagnosis was 7.2 years
Number of physicians seen before diagnosis was made
– 3
(43% of the patients)
– 6 – 10 (12 % of the patients)
Cleve Clin J Med 1994;61:461
Why is it important to detect AATD
Treatment is available
Counseling
– Of the patient to avoid other risk factors
– Of the siblings for screening and
Clinical Presentation
Emphysema
– Pathogenesis:
Imbalance between neutrophil elastase in the lung which destroys
elaste and elastase inhibitor AAT which protects against proteolytic
degradation of elastin
– Risk factors:
Phenotypes associated with a AAT levels below the “Protective
threshold” of 11umol/L
Smoking
Parental Hx of o COPD
Bronchiectasis ?
Asthma ?
Lung Related Clinical Manifestations
Emphysema
– Presenting Symptoms:
Dyspnea (most common symptom)
Cough, phlegm production and wheezing
Bronchodilator responsiveness
– Differences with patients w usual COPD
Earlier Age
Bullous changes prominent in lung bases
– > 90 % of ZZ phenotype have lung bases involved
– Limited to lung bases in 24 %Found exclusively in
Asthma and Bronchiectasis:
– Relationship not proven
Diagnosis
Measure AAT level
Phenotype by isoelectric focusing
Genotype
AAT Phenotypes
Phenotype
Risk for
Emphysema
True Plasma
level (umol/L)
Commercial
Standard (mg/dL)
MM
No increase
20-53
150-350
MZ
Possible mild
increase
12-35
90-210
SS
No increase
15-30
100-140
SZ
Mild Increase
(20 -50%)
8-19
75-120
ZZ
High Risk
(80 – 100%)
2.5-7
20-45
Null
High Risk
(100% by age 30)
0
0
Am Rev Respir Dis 1989;140:1494
Risk for developing lung disease
Smoking:
– Age of onset of Dyspnea in AAT (ZZ) Deficient Non-smokers Vs
Smoker1: 32 - 40 vs 48 – 54
– In heterozygous SZ phenotype, COPD rarely occurs unless
smoking is present2
Family History:
– MZ phenotypes have increased risk of COPD only when they
have a symptomatic first degree relative3
Airway irritants:
– Risk of other irritants in disease progression is controversial
1. Lancet 1985;1:152
2. Am J Respir Crit Care Med 1996;154:1718
3. Am J Respir Crit Care Med 2000;161:81
Survival in AAT according to FEV1
0.6
0.5
0.4
Mortality rate 0.3
0.2
0.1
0
15
20
25
30
35
% of predicted FEV 1
2 year Mortality
Seersholm N et al. Eur Respir J 1994;7:1985
60
Treatment
Augmentation Therapy
– Intravenous (only one FDA approved)
– Aerosolized
Enhancement of endogenous AAT
Gene Therapy
IV Augmentation Therapy
FDA approved IV AAT based on clinical studies that
proved that the infusion:
– Increase plasma and ELF levels of AAT
– Increase Levels anti-neutrophil elastase activity in ELF
recovered by BAL
– Is Safe and well tolerated
There are no randomized clinical trials that prove
clinical efficacy in change in natural history of
emphysema
Indication of IV AAT is based on observational studies
IV Augmentation Therapy: Concerns
The true protective threshold value (AAT level)
– Is not available
– It is estimated from values that separate affected from unaffected
individuals
Some severely deficient patients have normal lung
function
– Plasma levels alone do not predict disease they only assign risk
The proportion of individuals with ZZ phenotype that do
not develop clinically significant emphysema is not
known
Observational Studies
National Registry of Patients with Severe AATD
conducted a prospective cohort study1
– Survival was enhanced in recipients of augmentation therapy
– The subset with FEV1 35 % – 49 % of predicted had a slower
decline of FEV1 over time
Study comparing Ex- German Smokers (198) with
treatment (3.2 years) with Ex Danish smokers (98)
without treatment2
– Lower FEV1 decline in treatment group (53ml vs 75ml per year,
P= 02)
Study evaluating 96 patients with severe AAT before and
after treatment3
– Showed a lower FEV1 only in those with mild airflow obstruction
1. Am J Respir Crit Care Med 1998;158:49. 2. Eur Respir J 1997;10:2260
3. Chest 2001;119:737
Selection Criteria for
Treatment
High – risk phenotype (ZZ or Null)
Plasma AAT level below 11 umol/L
Airflow obstruction by Spirometry
– American Thoracic Society: < 80 % of predicted
– Canadian Thoracic Society: 35% - 50 % of predicted
Patient compliance to treatment
Age equal to or greater than 18
Nonsmoker or ex-smoker
Selection Criteria for
Treatment
Not recommended for
– Heterozygous Phenotypes
– AAT > 11umol/L
Unknown
– Fixed severe obstruction
– Normal airflow but radiographic evidence of
Emphysema
Goals of IV Infusion
Maintain a through level above the
protective threshold
Diffusion of AAT in lung tissue (ELF)
In vivo anti neutrophil elastase activity
after infusion
AAT Infusion: Side Effects
Low grade self limited fever
Anaphylaxis with IgE antibody formation to
AAT (rare)
Syndrome of
– Transient fever
– Chest and low back pain
Biological hazard
Anaphylaxis in IgA deficient patients
Weekly Infusions of AAT 60 mg/Kg
400
350
350
350
350
350
350
Concentration of AAT in mg/dL
300
250
200
150
150
150
150
150
100
50
0
0
-7
0
2
7
9
14
Days
Am J Med 1988;84(supp; 6A):52.
16
21
23
28
Monthly Infusion of 250mg/Kg of AAT
ELF Antitrypsin Activity
3.5
ELF AAT Level, umol
3
2.5
Patient 1
Patient 2
Patient 3
2
1.5
1
0.5
0
0
1
2
3
AAT protective level
4
5
6
7
8
9
10
Months
JAMA 1988;260:1259
ELF antielastase capacity, mmol
Efficacy of aerosolized AAT
6
5
4
3
2
Normal range
1
0
1
2
3
4
5
6
7
Days
Line 1
Hubbard, RC et al. Ann Intern Med 1989;111:206
8
Management of Candidates for
Augmentation Therapy
Pre- Treatment Testing
– Respiratory Function:
Spirometry
DLCO
Supportive Therapy
– Cessation
Smoking
Respiratory irritants
– Non-Specific Treatments
– Laboratory:
Hepatitis profile
LFT’s
HIV Titer
– Immunization
Hepatitis B vaccine
IVIG immunoglobulin
Bronchodilators
Pulmonary Rehab
Oxygen Therapy
Early treatment of
respiratory infections
– Vaccines:
Pneumococcal
Influenza
Extra-pulmonary AAT Deficiency
Hepatic Disease (most frequent)
Skin Disease
– Panniculitis (1:1000 of AATD)
More inflammatory
More “oily discharge”
More acute inflammation in histology
Vascular disease
– Aneurysms
– Fibromuscular displasia
– AAT Pittsburg mimics effects of antithrombin III
Glomerulonephritis
– Prolipherative GN
– IgA GN
Inflammatory Bowel disease
– AATD patients have more severe Colitis
Hepatic Disease
Liver Diseases associated with AAT phenotypes
Neonatal hepatitis
Elevated transaminases in young adults
Cirrhosis in children and adults
Hepatocellular carcinoma
“Null” Phenotype has no risk of hepatic disease
and a High risk of Emphysema
Pathogenesis of Liver Disease
Intra-hepatocyte Polymerization of AAT variants (Z and M)
Intra-hepatocyte accumulation of AAT molecules
in the endoplasmic reticulum (ER)
Decreased degradation of the AAT polymers in the ER
Cell engorgement due to increase
mass and release of lysosomal
enzymes
Increase risk of viral
mediated hepatitis
Polymerization of AAT in the
Hepatocyte
Intra-hepatocyte
accumulation of AAT
molecules in the
endoplasmic reticulum
(ER)
PAS positive granules
AAT polymers
Natural History of Hepatic Disease of
ZZ Phenotype
0%
20%
40%
Neonatal Disease
60%
80%
100%
Adulthood Disease
Free of Disease
Natural History of Hepatic Disease
15 % neonatal hepatitis
– 5% Cirrhosis in the 1st year of life
– 10 %
25% Resolution of hepatitis by ages 3 to 10
25% Cirrhosis between age 6 mo and 17 years
25% Histological evidence of cirrhosis with survival through
the first decade
25% Elevated LFT’s without Cirrhosis
85% Asymptomatic at childhood
– Cirrhosis in 11.8 %
– Hepatocellular carcinoma in 3.3 %
– 85% No Disease
Clinical Case Resolution
Does he have a AAT deficiency ?
– YES
What other tests should you order?
– PHENOTYPE
ZZ
What is his prognosis?
– According to FEV1 15 % in 2 years
What information regarding treatment should you give
him?
– That he is a candidate for Augmentation therapy but that there
are no clinical trials to assure him improvement
Is he a candidate for AAT augmentation therapy?
– Yes, his age, FEV1, AAT level and phenotype and non-smoker
status making him a good candidate
Clinical Case Resolution
If so, what precautions should you take before starting
treatment?
– Hep B vaccination, HIV testing, Influenza and Pneumococcal
vaccines
Should his siblings be tested for AATD and Phenotype?
– Yes
What will you do with the results if they are abnormal?
– His 21 year old son is ZZ phenotype, FEV1 is normal
Stop smoking and control of FEV1
– His 19 year old son is ZM phenotype (probably like his mother)
and FEV1 is also normal
Avoid smoking
No treatment warranted since AAT infusion can cause anaphylaxis
in IgA deficiency
Situations to Suspect Severe
Deficiency of AAT
Emphysema in a young individual (less than 45 years old)
Emphysema in a non smoker
Emphysema characterized by predominant basilar
changes on the chest x-ray
Family History of Emphysema and/or liver disease
(unexplained cirrhosis or hepatoma)
Clinical findings or history of panniculitis
Clinical findings or history of unexplained chronic liver
disease
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