Alpha

1
Alpha 1 Antitrypsin Deficiency

• Jorge Mera, MD
• Presbyterian Hospital of Dallas

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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)

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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

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Protein Folding and Function
Elastase
AAT
AAT
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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

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Protein Folding and Disease
Disease Protein Affected Molecular Defect
Cystic Fibrosis 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)
Alzheimers Disease Beta-amyloid Aggregation in brain (after protein release)
ER Endoplasmic Reticulum
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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 (Glu-342-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
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Electron Microscopy of AAT Polymers in the Liver
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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.

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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.

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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?

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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 1532
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AATD Lung Disease
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AAT Phenotypes
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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
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Pathogenesis of Lung Damage in AATD
AAT
Clinical Case
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Epidemiology

• USA 80,000 100,000
• Worldwide 3,000,000

Worldwide racial and ethnic distribution of
alpha(1)-antitrypsin deficiency. Chest
20021221818
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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
• 11575 15097 are positive 80,000 - 100,000
  would be expected to be AAT Deficient

1. Chest 198689370 2. N Eng J Med 19762941316
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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 199461461
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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

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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 ?

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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
• gt 90 of ZZ phenotype have lung bases involved
• Limited to lung bases in 24 Found exclusively
  in
• Asthma and Bronchiectasis
• Relationship not proven

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Diagnosis

• Measure AAT level
• Phenotype by isoelectric focusing
• Genotype

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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 19891401494
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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 19851152 2. Am J Respir Crit Care
Med 19961541718 3. Am J Respir Crit Care Med
200016181
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Survival in AAT according to FEV1
Seersholm N et al. Eur Respir J 199471985
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Treatment

• Augmentation Therapy
• Intravenous (only one FDA approved)
• Aerosolized
• Enhancement of endogenous AAT
• Gene Therapy

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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

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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

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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 199815849. 2.
Eur Respir J 1997102260 3. Chest 2001119737
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Selection Criteria for Treatment

• High risk phenotype (ZZ or Null)
• Plasma AAT level below 11 umol/L
• Airflow obstruction by Spirometry
• American Thoracic Society lt 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

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Selection Criteria for Treatment

• Not recommended for
• Heterozygous Phenotypes
• AAT gt 11umol/L
• Unknown
• Fixed severe obstruction
• Normal airflow but radiographic evidence of
  Emphysema

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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

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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

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Weekly Infusions of AAT 60 mg/Kg
Am J Med 198884(supp 6A)52.
36
Monthly Infusion of 250mg/Kg of AAT
AAT protective level
JAMA 19882601259
37
Efficacy of aerosolized AAT
Normal range
Hubbard, RC et al. Ann Intern Med 1989111206
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Management of Candidates for Augmentation Therapy

• Pre- Treatment Testing
• Respiratory Function
• Spirometry
• DLCO
• Laboratory
• Hepatitis profile
• LFTs
• HIV Titer
• Immunization
• Hepatitis B vaccine
• IVIG immunoglobulin

• Supportive Therapy
• Cessation
• Smoking
• Respiratory irritants
• Non-Specific Treatments
• Bronchodilators
• Pulmonary Rehab
• Oxygen Therapy
• Early treatment of respiratory infections
• Vaccines
• Pneumococcal
• Influenza

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Extra-pulmonary AAT Deficiency

• Hepatic Disease (most frequent)
• Skin Disease
• Panniculitis (11000 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

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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

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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
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Polymerization of AAT in the Hepatocyte

• Intra-hepatocyte accumulation of AAT molecules
  in the endoplasmic reticulum (ER)
• PAS positive granules

AAT polymers
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Natural History of Hepatic Disease of ZZ Phenotype
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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 LFTs without Cirrhosis
• 85 Asymptomatic at childhood
• Cirrhosis in 11.8
• Hepatocellular carcinoma in 3.3
• 85 No Disease

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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

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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

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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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• THANK YOU