Alpha-1 Antitrypsin Deficiency

Presented by

David A. Solomon, MD

The Information herein was :

Developed by D. Kyle Hogarth, MD, FCCP Assistant Professor of Medicine, University of Chicago

Edited by James M. Stocks, MD Professor of Pulmonary Medicine, University of Texas Health Science Center at Tyler

Approved by Alpha-1 Foundation Educational Material Working Group 3/28/14

Objectives

• Recognize the many ways Alpha-1 Antitrypsin Deficiency (Alpha-1) presents clinically

• Improve your understanding of the disease and the genetic background of the disorder

• Examine the data supporting augmentation therapy and how to manage these patients

“Chance favors the prepared mind”

Louis Pasteur - 1854

History of AAT

• 1962: Dr. Carl-Bertil Laurell (1919-2001) at the University of Lund, Sweden discovered the absence of the alpha-1 band in 2 serum electrophoresis gels.

• Further investigation by Dr. Sten Eriksson demonstrated 4 more.

• 4 of the 6 patients had emphysema.

Laurell and Eriksson,1963

Normal AAT Protein

• Normal AAT protein phenotype “M” • 95% is made in the liver • Main function is to neutralize/control

neutrophil elastase, a potent proteolytic enzyme able to damage the elastin matrix of the lung.

• Autosomal Co-dominant inheritance

Alpha-1-antitrypsin – Z Protein

• PiZ results from a point mutation that encodes a single Amino Acid substitution.

• Z protein misfolds/polymerizes & accumulates in the liver • secretion from liver is impaired.

• Low secretion results in “deficient” serum level.

• Z phenotype accounts for 95% of clinical illness.

Carrell and Lomas, 2002

Other Deficient Variants

• S allele : • Variant is associated with milder

deficiency • Not associated with AAT accumulation

within hepatocyte

• Null allele – No AAT production • Zero serum level • Earlier lung but no liver disease

• More than 100 other rare mutations exist

De Serres, 2002 and 2007

PresenterPresentation NotesDeficient variants can be further divided into 3 groups.The first is denoted by the letter Z. In this type, AAT cannot be released effectively from liver cells, and as a result, the levels in the blood are low and the retained AAT in the liver cells may cause injury.Slightly more prevalent than the Z allele is the S allele, which is associated with mild deficiency. Despite having deficient genes, it is not conclusive that people with an S allele are at increased risk of deficiency due to accumulation of AAT within liver cells.The last variation is the presence of the Null alleles, which indicates no production of AAT.

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Genetic PI Type Risk of lung disease “normal” low low low moderate high high

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11 µM threshold

Inheritance – Diagnostic Levels

PresenterPresentation NotesTwo specific blood tests determine the diagnosis of inherited emphysema. The first test measures the concentration of alpha1-antiproteinase inhibitor in the plasma or serum. �A second blood test can be done to determine the type of the actual gene-expressed protein. Healthy individuals have MM genetic pattern, which leads to normal levels of alpha1-antiproteinase inhibitor in the blood.There are 7 major protein variants that impact serum AAT levels. Each of these has a different degree of impact on the individual’s risk for lung disease. The PI*M phenotype generally has a serum level of AAT that ranges from 20 micromole to 53 micromole with no risk of lung disease. The PI*MS, PI*SS, and PI*MZ phenotypes have a low risk of lung disease. The PI*SZ phenotype may have an increased potential for developing lung disease. The greatest risk for lung disease is in the individual with a PI*Z or PI* (null) (null) phenotype. These individuals also have the lowest alpha1-antitrypsin levels with a range of 3.4 – 7 micrograms or a 0 level for nulls.PI*MM - Normal serum AAT values 20 - 48 M.PI*MZ - Normal or slightly decreased values PI*ZZ - Severely deficient values 2.5 - 7 M (mean 16% normal)Moderately deficient values PI*SS - 15 - 33 M (mean 52% normal)PI*SZ - 8 - 19 M (mean 35% normal)

Population Screening Studies

• 200,000 neonates screened in Sweden • Pi*ZZ in 127, or 1 in 1575

• 20,000 blood donors tested in St. Louis • Pi*ZZ : 1 in 2857

• 965 consecutive emphysema patients

• 1.9% were Pi*ZZ • 8.0% were Pi*MZ

Sveger, 1976; Silverman et al, 1989; ATS/ERS AATD Standards, 2003

Prevalence of Alpha-1

• The most prevalent potentially fatal genetic disorder of adult Caucasians in the United States.

• An estimated 25 million individuals carry deficient genes

• Over 100,000 Americans have severe Alpha-1 deficiency

• Less than 10% yet diagnosed

Stoller et al, 2005

PresenterPresentation NotesThis figure translates to approximately 25 million individuals who carry such deficient genes, with an estimated 100,000 Americans demonstrating AAT deficiency. Of these 100,000, less than 10% have actually been diagnosed, with even fewer receiving specific treatment for their AAT deficiency. In light of these data, the question becomes why is this disorder so infrequently diagnosed?

Comparison of PI*ZZ Prevalence Disorder Prevalence

AAT deficiency (PI*ZZ) Over 100,000

Cystic Fibrosis 30,000

Huntington’s Disease 30,000

Spina Bifida 166,000

Idiopathic Pulmonary Fibrosis 128,000

Testicular Cancer 196,000

Ovarian Cancer 177,000

Hodgkin’s Lymphoma 164,000

Cervical Cancer 243,884

Clinical Presentation of Alpha-1

Clinical Pulmonary Presentation

• Results from 2 patient registries regarding prior diagnosis before Alpha-1:

• 54% had emphysema • The mean FEV1 among 1129 participants in the NHLBI registry

was 43% of predicted with a mean age of 45. • 72% had respiratory symptoms • 42-46% with chronic bronchitis • 35% had a diagnosis of asthma.

• 30% of NHLBI patients had FEV1 reversibility when tested with spirometry.

• Clinical presentation does NOT ID AATD!

NIH-AATD Registry Group, 1998; Silverman and Sandhaus, 2009, Campos et al, 2005

Normal Emphysema

Why do those with Alpha-1 get Lung Disease?

• Uncontrolled proteolytic attack on lung tissue because of low circulating levels of AAT.

• The Z protein is less effective at inhibiting neutrophil elastase than the M protein.

• Cigarette smoke can inactivate the patient’s own AAT in the lungs.

• Normal AAT levels function to suppress inflammatory chemoattraction.

Elastase Burden

Elastase

AAT (MM)

Elastase protection

Normal Balance of Neutrophil Elastase & AAT

PresenterPresentation NotesAs a built-in defense mechanism, the liver releases AAT, which travels up to the lungs where it ultimately neutralizes the excess neutrophil elastase. If the body is unable to produce adequate levels of AAT to neutralize the neutrophil elastase, the balance is shifted, which may cause damage to the lung.

Balance of Neutrophil Elastase & AAT in a Deficient Patient

Breakdown of lung tissue

Elastase

AAT (not MM)

Elastase protection

Elastase Burden

Radiology

• A review of chest radiographs from 165 consecutive ZZ alpha patients: • 15% were normal • Only 20% showed the “classic” finding of emphysema at

the bases

• A review of 102 CTs of ZZ alpha patients • 64% showed basal predominance • 36% had predominant apical disease

• HRCT often finds bronchiectasis

Chest x-rays and CT scans can NOT identify AATD.

Yamashiro et al, 2009

Average Age at Diagnosis

Based on 302 patients with PiZZ out of 26,520 patients tested. M Brantly, U of Florida

47%

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Not just “young” with COPD

AATD and Survival

• Median survival in smokers = 49 years • In non-smokers = 69 years

• In non-smokers lung disease often

develops after age 50

Seersholm et al, 1995

Missed Clinical Recognition

• Average Alpha-1 patient has symptoms for 7.2 to 8.3 years before diagnosis is made.

• 44% of Alpha-1 patients see at least 3 doctors

(PCP or specialist) before a diagnosis is made.

Campos et al, 2009

• Why do many physicians (including pulmonary specialists) presume that SOB, cough, and wheezing is asthma or caused by smoking…

• But gastroenterologists never presume that

liver dysfunction is due to alcohol?

Missed Clinical Recognition

Alpha-1 Liver Disease

Synthesis Synthesis Secretion Secretion

Degradation Degradation

Wild Type M Mutant Z

ER ER

AAT Protein Processing

Proteasomal and autophagic degradative pathways may govern hepatic risk

Human ZZ Liver

PAS + intracellular inclusions are polymerized AAT ‘Z’

Highly Variable Hepatic Risk

• Risk of life threatening liver disease in childhood is about 5%. • 2nd most common reason for liver transplant

• Risk of any liver disease or dysfunction in childhood is 15-50% (depends on testing).

• The majority of ZZ infants with problems at birth are well by age 18y.

• Significant, but possibly silent liver disease in older adults likely over 50%.

Eriksson, 1985 and 1987

Liver Management

• Regular contact with a doctor who is familiar with alpha-1 liver disease.

• A combination of asking about new symptoms, physical examination monitoring, blood tests, and x-ray/ultrasound exams.

Nelson et al, 2012

Treatment

• There are no specific treatments to prevent alpha-1 liver damage.

• There are effective treatments used for liver disease in general.

• Liver transplantation : trading one disease for another?

• Augmentation therapy has no effect on liver disease.

Liver Management

• Avoid or limit alcohol: Controversially means less than one drink per day.

• Avoid obesity (fatty liver disease). • Occasional Tylenol in ordinary doses. • NSAIDS may have potential to increase

hepatic injury. (experimental data) • Consider hepatitis vaccination

Pearls

• Liver biopsy not required for diagnosis. • Patients with cirrhosis may remain

stable without transplantation for 10y or more.

• The majority of ZZ children will do well with minimal intervention.

• Genetic and environmental disease modifiers are likely important, but poorly understood.

• Typical liver disease supportive care or transplant are the only recommended therapies at this time.

Time to Test

Who Should Be Tested?

• All subjects with COPD or unexplained bronchiectasis regardless of smoking Hx

• All adults with asthma characterized by incompletely reversible airflow

• Subjects with unexplained chronic liver disease

• Necrotizing panniculitis (1 in 1000 ZZ) • Anti-proteinase 3-positive vasculitis

(C-ANCA-positive vasculitis) • 5.6 to 17.6% of c-ANCA+ individuals are ZZ

ATS/ERS AATD Standards, 2003

Lab Testing

• Serum blood test that measures the concentration of circulating AAT- ‘levels’ • An acute phase reactant • Heterozygous/normal overlap but • Not between ZZ and normal levels

• “Phenotyping” or Pi-typing of the protein • Determine whether the patient is a carrier of the

deficiency or homozygous • Done by isoelectric focus gel analysis

• Genotyping • DNA testing that determines the Pi genes from

extracted DNA Stoller and Brantly, 2013

PresenterPresentation NotesWhile there are a variety of tests and procedures that may occur leading up to the diagnosis of AATD, there are 2 tests that may help confirm diagnosis.The first is a blood test to measure the amount of circulating AAT. The second is a phenotype test which can be performed on either a finger-stick or venipuncture. This will determine whether the patient is a carrier of the deficiency or a sufferer. Note to representative – The Alpha community refers to this as phenotype when it is technically genotype.The normal range for circulating AAT is 20-48 µM/L.Testing can be performed on a blood sample obtained either from a �finger-stick or venipuncture.

Testing via Finger Stick

• Testing for AAT levels and genotype via a single finger-stick of blood

• Can be mailed into a central lab

So you found an Alpha.

Now What ?!?!?

Treatment Options

• Standard Therapies in COPD Treatment • Smoking cessation • Pulmonary Rehab • Bronchodilators (rescue/LABA) • Inhaled steroids • Oxygen • Lung transplant

• Management/Evaluation of Liver disease • Augmentation Therapy

PresenterPresentation NotesNot all Alpha-1 patients are managed in the same manner. Of those definitively diagnosed, more than 90% are receiving augmentation therapy.

Quit Smoking!

Augmentation Therapy

• Augmentation therapy is used to increase serum and lung epithelial lining fluid (ELF) levels of AAT

• Plasma derived treatment for adults with AATD and emphysema

PresenterPresentation NotesThe purpose of augmentation therapy is to increase the levels of AAT in the serum and lung epithelial linings.It is the recommended treatment for adult patients with AATD, where emphysema is evident.

Augmentation Therapy

• Augmentation therapy was first approved 25 years ago.

• Four approved drugs – Aralast, Glassia, Prolastin, Zemaira

• Original approval based on pharmacokinetic and biochemical data.

• Subsequent approval same criteria. • None based on therapeutic efficacy.

PresenterPresentation NotesThe purpose of augmentation therapy is to increase the levels of AAT in the serum and lung epithelial linings.It is the recommended treatment for adult patients with AATD, where emphysema is evident.

AATD Imbalance of Neutrophil Elastase & AAT

Breakdown of lung tissue

Elastase

AAT

Elastase protection

Elastase Burden

Lung Tissue Protected

Elastase burden

Elastase protection

Elastase AAT +

AAT Augmentation

+

Role of Augmentation Therapy

Why Augmentation Therapy?

Wewers, 1987

Importance of Weekly Dosing

N=56

AAT Serum Levels During Biweekly Infusions

AAT Serum Levels During Monthly Infusions

Soy at al, 2006

PresenterPresentation Notes It is recommended that alpha1-antitrypsin infusions are administered weekly. In a double-blind, randomized, prospective multicenter study, alpha1-antitrypsin infusions (250mg/kg) were given every 4 weeks. After 23 days, alpha1-antitrypsin levels fall below the protective threshold of 11 microM (p

Does Augmentation Clinically Work?

US NHLBI Registry ‘87-95

• Prospective, non-controlled, non-randomized

• Comparison of lung function and mortality in treated versus untreated patients

• Inclusion criteria - AAT level ≤ 11µM

• n : 277 treated vs 650 untreated

NIH-AATD Registry Group, 1998

ml/yr

NHLBI Registry - Mortality

Partially: part(s) of the observation time

PresenterPresentation NotesAlpha-1 deficient patients 18 years and older with a serum Alpha-1 level 11 M or a PiZZ genotype were followed for 3.5 to 7 years with spirometry measurements every 6 to 12 months as part of a National Heart, Lung, and Blood Institute Registry of Patients with Severe Deficiency of Alpha-1. Among all 1,129 enrollees, 5 year mortality was 19%. In multivariate analyses of 1,048 subjects who had been contacted 6 months after enrolling, age and baseline FEV1 percent predicted were significant predictors of mortality. Results also showed that those patients receiving augmentation therapy (Prolastin, Alpha-1 Proteinase Inhibitor [human]) had decreased mortality (p=0.02) as compared with those not receiving therapy.

The picture shows Kaplan-Meier cumulative mortality curves based on all eligible patients and deaths, plotted for subjects with initial FEV1

Seersholm, 1997

• Number of patients • n=295; 97 control, 198 treated

• Main findings • Decline in lung function in treated group was

lower (FEV1 = 53 vs 75 mL/yr, p = 0.02) • Effect best seen with FEV1 = 31 - 65%

predicted

Lung Function

Danish Study Group

• Double-blind, randomized, prospective multicenter study (N=56 ex-smokers)

• Comparison of 250 mg/ kg monthly for at least 3 years in patients with Pi*Z.

• Endpoints – PFT and CT densitometry • No significant difference in decline of lung function

expressed in FEV1 per year between both arms

Dirksen 1999 and 2009

PresenterPresentation NotesA Randomized Clinical Trial of Alpha-1 Antitrypsin Augmentation Therapy We have investigated whether restoration of the balance between neutrophil elastase and its inhibitor, Alpha-1, can prevent the progression of pulmonary emphysema in patients with Alpha-1 deficiency. Twenty-six Danish and 30 Dutch ex-smokers with Alpha-1 deficiency of Pi*ZZ phenotype and moderate emphysema (FEV1 between 30% and 80% of predicted) participated in a double-blind trial of Alpha-1 augmentation therapy. The patients were randomized to either Alpha-1 (250 mg/kg body weight) or albumin (625 mg/kg body weight) infusion at 4-week intervals for at least 3 years. Self-administered spirometry performed every morning and evening at home showed no significant difference in decline of FEV1 between treatment and placebo. Each year, the degree of emphysema was quantified by the 15th percentile point of the lung density histogram derived from computed tomography (CT). The loss of lung tissue measured by CT was 2.6 ± 0.41 g/L/yr for placebo as compared with 1.5 ± 0.41 g/L/yr for Alpha-1 infusions (p=0.07). Power analysis showed that this protective effect would be significant in a similar trial with 130 patients. This is in contrast to calculation based on annual decline of FEV1 showing that 550 patients would be needed to show a 50% reduction of annual decline. We conclude that lung density measurements by CT may facilitate future randomized clinical trials of investigational drugs for a disease in which little progress in therapy has been made in the past 30 year.1 Reference: 1. Dirksen A et al:A Randomized Clinical Trail of Alpha-1 Antitrypsin Augmentation Therapy. Am j Respir Crit Care Med Vol 160. pp 1468-1472, 1999

Changes in Lung CT Density

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Canadian Registry 2005

• Patients receiving Alpha-1 vs untreated matched control patients

• N: 21 patients receiving Alpha-1, 42 controls

• Median observation was 5.6 years. • Median duration of augmentation

was 4.4 years.

Chapman et al, 2005

PresenterPresentation NotesChapman et al, 2005Slower Lung Function Decline During Augmentation Therapy in Patients With Alpha-1 Antitrypsin Deficiency: Results from the Canadian AIR RegistryWhile administration of exogenous Alpha-1 has proven effective in augmenting plasma and lung Alpha-1 level, the long time course of the condition has discouraged definitive clinical trials of augmentation therapy using pulmonary function outcomes. Methods: Baseline clinical and longitudinal lung function data were collected through the Canadian AIR Registry for patients receiving augmentation therapy (Prolastin®, Alpha-1 Proteinase Inhibitor [human]) and untreated control patients matched by age, sex, and smoking status. Results: Mean baseline age for 21 patients receiving augmentation therapy and 42 matched controls was 49.6 ± 11.0 years. Men composed 67% of the study population and women 33%. The data included a total of 344 serial determinations of FEV1. The median observation period was 5.6 year (2.5 to 9.0 years). At baseline, % of predicted FEV1 was >50% in 37% of the patients, 30% - 49% in 38%, and

Canadian Registry

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P=0.019

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Meta Analysis - AATD

• 5 studies with a total of 1509 patients • 4 non-randomized trials • 1 randomized trial

• Results • FEV1 decline was slower by 23%

with augmentation therapy • Mainly with FEV1 30%-65% of predicted

benefited (those with fastest decline) • CT densitometry may be a more sensitive

measurement of emphysema and its progression.

Chapman et al, 2009

PresenterPresentation NotesFour nonrandomized studies and one randomized trial with a total of 1509 patients were included. The decline in FEV1 was slower by 23% (absolute difference, 13.1 mL/y; CI, 1.5 to 25.3 mL/y) among all patients receiving augmentation therapy. This effect predominantly reflected the results in the subset of patients with baseline FEV1 percent predicted 30-65%. Augmentation of Alpha-1 reduced FEV1 decline in that subset by 26% (17.9 mL/y; CI, 9.6 to 26.1 mL/y). A significant effect of therapy was not apparent in patients with baseline FEV1 percent predicted < 30% or > 65%. Current evidence indicates that augmentation therapy effectively slows the rate of FEV1 decline in patients with Alpha-1 deficiency. Patients with moderate obstruction are the most likely to benefit.1

Reference:1. Chapman KR, Stockley RA, Dawkins C, et al. Augmentation therapy for 1-antitrypsin deficiency: a meta-analysis of randomized and non-randomized clinical studies [abstract]. Presented at the European Respiratory Society 15th Annual Congress, Copenhagen, Denmark; September 2005

The RAPID Trial – Newly Reported Presented at the 2013 ATS International Conference

• Placebo controlled – 2 year CT densitometry follow-up • Zemaira (60 mg/Kg)

• Placebo group crossed over to Rx – followed + 2 years. • Prespecified (in 2003) primary end point of combined CT

densitometry score at TLC and FRC was not significantly different (p=0.027) between treated and placebo.

• CT densitometry at TLC was significantly different (p=0.007) • None of the other secondary endpoints were different between

groups (FEV1, exacerbations, quality of life) • Placebo patients crossed over to treatment and followed for an

additional 2 years showed slowing of decline in CT densitometry at TLC

• N.B.: significance is p of 0.025 or better because this was analyzed as a one-sided test

The RAPID Trial

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Presented at the 2013 ATS International Conference

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Summary

• Alpha-1 Antitrypsin Deficiency is more common than previously taught and still perceived.

• It causes more than just emphysema.

• Testing for Alpha-1 is quick and easy.

• Augmentation therapy is available and effective.

Sometimes “Generic” COPD is actually “Genetic” COPD

Nota Bene

Thank You

Alpha-1 Antitrypsin DeficiencySlide Number 2ObjectivesSlide Number 4History of AATNormal AAT ProteinAlpha-1-antitrypsin – Z ProteinOther Deficient VariantsInheritance – Diagnostic LevelsPopulation Screening StudiesPrevalence of Alpha-1Slide Number 12Clinical Presentation�of Alpha-1Clinical Pulmonary PresentationSlide Number 15Why do those with Alpha-1 get Lung Disease?Normal Balance of Neutrophil Elastase & AATBalance of Neutrophil Elastase & AAT in a Deficient PatientRadiologySlide Number 20Not just “young” with COPDAATD and SurvivalMissed Clinical RecognitionMissed Clinical RecognitionAlpha-1 Liver DiseaseSlide Number 26Slide Number 27Highly Variable Hepatic RiskLiver ManagementTreatmentLiver ManagementPearlsTime to TestWho Should Be Tested?Lab TestingTesting via Finger StickSo you found an Alpha.Treatment OptionsSlide Number 39Augmentation TherapyAugmentation TherapyAATD Imbalance of Neutrophil Elastase & AATRole of Augmentation TherapyWhy Augmentation Therapy? Importance of Weekly DosingDoes Augmentation Clinically Work?US NHLBI Registry ‘87-95Mean FEV1 DeclineNHLBI Registry - MortalitySeersholm, 1997Danish Study GroupSlide Number 52Canadian Registry 2005Canadian Registry Meta Analysis - AATDThe RAPID Trial – Newly Reported�Presented at the 2013 ATS International ConferenceSlide Number 57SummarySlide Number 59Slide Number 60