Is It PiZZ or Just Emphysema? Alpha 1-Antitrypsin Deficiency Pulmonary Manifestations Internal Medicine Grand Rounds Ronald E. Breininger, Jr., MD
Loyola University Lung Transplant Survivorship Doud, J.; Mc Cabe, M; et al.
Loyola University Transplant CostsDoud, J; Mc Cabe, M; et al. • Figures for heart-lung transplants • Median cost for initial care totals $240,000 • Follow up care and medications cost approximately $47,000 / year in 1993
Mortality versus FEV1 in PiZZ (untreated)(Patients over 18 years old)Wu, M; Eriksson, S
Smoking and Alpha 1-Deficiency • Normal patients lose 20-25cc in FEV1 per year while smokers lose 40-45cc per year • PiZZ non-smokers lose 80cc per year while PiZZ smokers lose 150cc per year • The decline reverts to 80cc per year if the patient quits smoking • Relative risk of death in patients who had ever smoked was 2.96 compared to never smokers • Larsson reported a 5O yo Pi M- smoker who had emphysema, despite 1/2 normal serum alpha 1-AT levels
Loyola University Lung Transplant CriteriaDoud, J; McCabe, M; et al • Single Lung Recipients: • Age <65 years old • Life expectancy < 12-18 months • No systemic disease or end organ failure • Taking <10 mg/d Prednisone • Acceptable cardiac function • Non-smoker at least 6 months • Good rehabilitation potential • Good psychosocial support system
Case Presentation HPI MB is a 49 yo wf who presents to her primary care physician for evaluation of shortness of breath. She relates that she has been getting more dyspneic with activity over the last few years, and now she has episodes of “sickness” periodically with fevers, cough, sputum production, and dyspnea. She also thinks she has asthma, like her daughter, which is often triggered at her work (clerical job). Finally, she thinks she is working in a “sick building”, as others around her complain of similar symptoms at times.
Case continued PMH Graves disease, s/p radioiodine ablation, now permanently hypothyroid Meds Synthroid .1mg /day Soc Married, 15 py smoker, quit 7 ya, 3 beers / week All NKDA Fam HX Father 69 cardiac dz, Mother 67 s/p MI, high TG’s Brother 41 healthy, Daughter with childhood asthma Son with “Hay fever” PE VSSAF, exhibits pursed lip breathing Only other significant finding is wheezes bilat. Labs NL cbc, smac (sgot=65), PFT= Mod. obstruction
Pulmonary Pathology • Panacinar Emphysema • Acini are uniformly enlarged from the respiratory bronchiole to the terminal alveoli. This type of emphysema is most severe at the lung bases. • Bronchiectasis • Proximal and medium sized bronchi are dilated due to destruction of elastic and muscular wall components. This leads to hypersecretion of mucus and bronchial inflammation due to recurrent infections.
A1-AT Disease Demographics • PiMM is wild genotype (normal) • Z allele about 1-3% of Northern European descent population • PiZZ is one of the most common lethal mutations among Northern European caucasians, rare among Blacks and Asians • PiZZ genotype estimated at 20-40,000 people in USA • S allele about 2-4% of Northern European descent population
Alpha 1-Antitrypsin Replacement • Plasma half life of normal molecule is about 5 days • Loss of even one side chain reduces this greatly • Gadek, et al, showed that weekly infusions of 4g purified alpha 1-antitrypsin would maintain serum levels above 35% normal in Pi ZZ patients with baseline levels of 15% • Hubbard, et al, showed that 250 mg/kg/month also would maintain levels greater than 35% of normal
Serum a1-AT Levels Over Time After 4g/Week Infusion (% nl vs time)Adapted from Gadek, et al
Alpha 1-AntitrypsinJanoff, A • 52 kD glycoprotein antiprotease (Pi) • 394 AA peptide with 3 complex carbohydrate side chains • Inhibits neutrophil elastase (NE), a 29 kD extracellular serine protease which degrades elastin and connective tissue. Due to its delicate framework, lung tissue is very susceptible to NE degradation. • In 1963, Laurell and Eriksson noted a deficiency in the alpha 1 globulin band of some patients with emphysema, linking deficiency states with disease • Over 80 mutations discovered to date, 17 are associated with severe alpha 1 deficiency and pulmonary disease.
Alpha 1-AntitrypsinMolecular Biology Crystal, R • Major site of synthesis is liver, producing 2g/day • Synthesized as a 418 AA precursor, then a 24 AA terminal signal peptide is cleaved as the molecule enters the rough endoplasmic reticulum. The molecule is then given 3 carbohydrate sidechains and is then actively transported out of the cell. • The PiZ mutation is a single DNA base substitution resulting in a GLU342 to LYS. This causes intracellular accumulation of the mutant protein with resulting serum deficiency. • In 1977, Mornex found that PiZZ mononuclear cells make a normal amount of mRNA, but only 10-15% of the synthesized protein was secreted.
Treatment of Alpha 1 Deficiency • Emphasize SMOKING CESSATION • Treat the same as other emphysemics • Assess with full PFT’s and ABG • Decide if there is a response to beta-adrenergic bronchodilator therapy, and treat accordingly • Ipratropium inhaled • Chan, et al showed overall no response of emphysemics to inhaled steroids, but 2/14 showed >30% increase in FEV1 with inhaled budesonide (small placebo-controlled crossover study) • Oxygen for hypoxemic patients to relieve symptoms and help reduce risk of pulmonary hypertension • Aggressive antibiotic use for bronchitis/ pneumonias • Pneumovax, Fluvax • Replace with pooled alpha 1-antitrypsin 250mg/kg/month
Costs of Alpha 1-AntitrypsinReplacement Hay, J; Robin, E • It was estimated that alpha 1-antitrypsin replacement therapy would cost $20-30,000 per patient annually (1990) • Using cost modelling analysis, it was estimated that, if replacement therapy was 70% efficacious at preventing progressive lung disease, the cost per life year saved would be $28-72,000. At 30% efficacy the cost would be $50-128,000. • A recent lot of Prolastin@ was contaminated with the Creutzfeldt-Jakob virus and administered to at least 17 different patients.
Liver Transplantation • In 1973, Putnam, et al, performed hepatic transplantation in a 16 year old female for Pi ZZ induced childhood cirrhosis. • Pre-transplant alpha 1-AT levels were 55mg/dl of the Pi ZZ phenotype (nl = 140-470) • Post-transplant alpha 1-AT levels were 264mg/dl of the MM phenotype • Second transplant after rejection gave alpha 1-AT levels of 270mg/dl of donor’s MZ phenotype
Pi ZZ Natural History Larsson, C • An epidemiologic study of 246 adult Swedish individuals with Pi ZZ phenotype was conducted in 1978 • 184 patients developed COPD (emphysema, bronchitis, asthma ) • 34 patients initially presented with recurrent pneumonias, 27 eventually developed COPD • 28 patients had bronchiectasis (all also with COPD) • 29 patients had diagnosis of cirrhosis (3 heavy ETOH) • One patient had neonatal jaundice but no cirrhosis • 27 patients were diagnosed with cirrhosis after 50 y.o. • 8 of the 29 cirrhotics had hepatomas at autopsy • 37 patients had evidence for glomerular disease
Natural History continued • In 1986, Eriksson and Velez conducted a case control autopsy series in Malmo, Sweden, and found the following: • Of 20 Pi ZZ patients identified, 17 underwent autopsy. • A 1 1/2 year old male died of full blown cirrhosis • 3 female and 5 male adults had cirrhosis (odds ratio of 7.8) • All of the adults had clinical or macroscopically evident (and microscopically verified) emphysema • 5 patients had hepatoma at autopsy (odds ratio =20)
What’s So Exciting? • Alpha 1-antitrypsin disease is not just another treatable but incurable disease! • This disease, along with cystic fibrosis, enjoys a prominent position in the current research literature because of the potential for gene therapy to cure the underlying defect. • Alpha 1-antitrypsin disease is amenable to gene therapy because there appears to be no serious side effects from high serum levels of the native protein, thus eliminating the need for tight regulation of the protein production. Current investigations are using constitutive transcription promoters. • Reconstitution of less than normal serum levels of the native protein are still felt to be protective.
What’s So Exciting?, continued • Theoretically, gene therapy could instill functional alpha 1-antitrypsin genes into bone marrow pleuripotent stem cells, from which would come alveolar macrophages with the capacity to produce the intact protein. • It is possible to infect alveolar epithelial cells using engineered vectors, and detect the intact protein in BAL fluid and serum. • It is theoretically possible to infect replication competent host T-lymphocytes with the alpha 1-antitrypsin gene and promoter. • Using specific viruses, it should be possible to infect host hepatocytes with functional copies of the alpha 1-AT gene. But, will a PiZZM phenotype protect from cirrhosis?
Gene Therapy Knoell, D. • Three current delivery systems, retroviral, adenoviral, and plasmids • Retroviral recombinant virions • Uses an engineered RNA virus rendered incapable of replication • Have specific promoters and enhancer sequences to control mRNA synthesis of the desired gene. • Daughter cells receive copies of the gene, integrated in their DNA • Virus particles are unstable, and are most effectively transmitted ex-vivo, and also incorporate into host genome most effectively if host cells are dividing.
Gene Therapy, continued Knoell, D • Adenovirus system • Uses an engineered DNA virus • Infects cells in all stages of life cycle • DNA exists as an episome, and so can be lost from the host cells, and is not passed to progeny cells • Would require repeat infections to work, and this may be a problem immunologically as the virus is a foreign protein • Particle is stable, so in-vivo infection is possible
Gene Therapy, continued Knoell, D • Plasmid based delivery systems • DNA is engineered into a plasmid • Plasmid is packaged into liposomes or protein coat / capsid which can target host cells and facilitate plasmid entry • DNA is maintained episomally • Prone to degradation, and loss from the cell. Not passed on to progeny cells • Plasmid vectors not as efficient as current viral vectors