Alpha-1 Antitrypsin Deficiency

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at NOVA

α1-Antitrypsin (A1AT) is synthesized in the liver and protects lung alveolar tissues from destruction by neutrophil elastase.


α1-Antitrypsin (A1AT). Image source: Wikipedia, GNU Free Documentation License.

Alpha1 (α1) antitrypsin deficiency is an autosomal recessive condition (same as CF) that affects 1:1,700 persons (40,000 patients in the U.S.)

α1-antitrypsin deficiency in children leads to hemorrhagic disease, cholestasis and chronic liver disease. Liver disease results from retention of abnormal α1-antitrypsin in the endoplasmic reticulum of hepatocytes.

α1-antitrypsin deficiency in adults leads to emphysema; 2% of all adults with emphysema have α1-antitrypsin deficiency. Emphysema is closely linked to smoking.


Mind map of A1AT deficiency

Genetics and Physiology

α1-antitrypsin inactivates neutrophil elastase, thus preventing tissue destruction in the lungs.

The α1-antitrypsin (A1AT) gene is located on chromosome 14q near the immunoglobulin heavy chain genes. α1-antitrypsin is a member of the serine protease inhibitor family, which also includes C1 esterase inhibitor and antithrombin 3.

Every person has 2 copies of the A1AT gene. The electrofocusing results are notated as in PiMM, where Pi stands for protease inhibitor and "MM" is the banding pattern of that patient.

Alpha 1-antitrypsin levels in the blood depend on the genotype. Some mutant forms fail to fold properly, polymerise, and are retained in the endoplasmic reticulum. The serum levels of some of the common genotypes are:

PiMM: 100% (normal)
PiMS: 80% of normal serum level of A1AT
PiSS: 60% of normal serum level of A1AT
PiMZ: 60% of normal serum level of A1AT, mild deficiency
PiSZ: 40% of normal serum level of A1AT, moderate deficiency
PiZZ: 10-15% (severe alpha 1-antitrypsin deficiency)

Z means
Zig-zagged A1AT in the endoplasmic reticulum

Most normal persons have a Pi-MM phenotype. Over 95% of cases of pulmonary and hepatic disease are due to to the Pi-ZZ phenotype.

The mutant peptide results from a single-base mutation which changes an amino acid from glutamate to lysine. This amino acid change impairs the folding of the peptide within the endoplasmic reticulum. The defective peptide is retained within the endoplasmic reticulum and is secreted at a rate only 15% of normal rate. Therefore, only 15% of A1AT reaches the lungs.

Diagnosis

Diagnosis is made by measurement of serum α1-antitrypsin concentration combined with phenotyping by isoelectric focusing.

Serum α1-antitrypsin concentrations less than 80 mg/dL are diagnostic. Patients with serum concentrations less than 60 mg/dL are at high risk for disease. A1AT is an acute-phase protein

Who should be tested how for alpha-1-antitrypsin deficiency?

- all newborns with a bleeding disorder or prolonged neonatal jaundice should be tested
- all individuals with a history of asthma or chronic obstructive lung disease, particularly below the age of 40
- all siblings of index cases
- all individuals with unexpected liver cirrhosis

Symptomatic children with A1AT deficiency usually develop liver disease.

Adults with α1-antitrypsin deficiency present with emphysema in the third or fourth decade of life.

PFTs show obstruction, reduced diffusion capacity, and increased total lung capacity. After the age of 30 to 35 years FEV1 declines at an accelerated rate, which is worsened by cigarette smoking.

Smokers with α1-antitrypsin deficiency develop symptoms by 30 to 40 years, whereas nonsmokers do not become symptomatic until 50 years of age. Mean life expectancy for smokers is 50 years and 66 years for nonsmokers.

Emphysema caused by α1-antitrypsin deficiency is panacinar and affects the lower lungs. Emphysema caused by smoking is centrilobular and affects apical lungs.

CXR in A1AT show bibasilar bullae, in contrast to smokers in which bullae are located in the upper lobes.

Treatment

The most important treatment step is avoidance of cigarette smoking.

Replacement therapy with human plasma-derived A1AT can reverse the biochemical abnormalities in the lungs but not the liver disease. Intraveneous treatment with alpha1-protease inhibitor slows the decline in FEV1 and improves survival.

Patients with A1AT levels of less than 80 mg/dL (35% of normal) and airway obstruction are considered to candidates for intravenous augmentation therapy. It is most clearly indicated for patients with moderate degrees of airflow obstruction (FEV1 35-65% of predicted). Three preparations are available and each is approved at the same dose and administration - 60 mg/kg/wk given IV.

Alpha1-protease inhibitors (purified human alpha1-antiprotease inhibitors prepared from pooled human plasma):

- Prolastin 60 mg/kg IV qwk
- Aralast 60 mg/kg IV qwk
- Zemaira 60 mg/kg IV qwk

Approximate monthly cost as of 2007:

- Prolastin: 500 mg = $175, Cost/month = $5,880, Annual cost = $76,440 (3/1/05)
- Aralast: 400 mg = $204, Cost/month = $8,568, Annual cost = $111,384 (3/1/05)
- Zemaira: 1000 mg = $430, Cost/month = $8,600, Annual cost = $111,800 (5/1/07)

Smoking Cessation

Smoking directly causes more than 430,000 deaths each year.
25% of American adults smoke (50 million people).
70% have made at least one attempt to quit, 46% make an annual attempt.

Smoking during adolescence causes genetic changes that lead to lung cancer later in life, even a person had stopped smoking.

Involuntary smoking is the third most common preventable cause of death.

Physicians fail to discuss smoking cessation during 50% of patient visits. Physician’s advice increases the rates of smoking cessation by about 30%, particularly if a 3-4-minute counseling session is provided.

Telling smokers their spirometry "lung age" improves quit rates at 12 months from 6.4% to 13.6% according to a study of 561 UK smokers. The "lung age" concept (the age of the average person who has an FEV1 equal to the patient) was developed in 1985 to help patients understand complex PFTs and to show how they are prematurely aged by smoking.

Unaware of the UK study, the 2007 U.S. Preventive Services Task Force guidelines recommend against screening for COPD using spirometry.

References

Alpha1-Antitrypsin Deficiency: Treatment & Medication. eMedicine Specialties, Pulmonology, Obstructive Airways Diseases.
Allergy and Immunology MKSAP, 3rd edition.
Effect on smoking quit rate of telling patients their lung age: the Step2quit randomised controlled trial. BMJ, doi:10.1136/bmj.39503.582396.25 (published 6 March 2008).
Screening for Chronic Obstructive Pulmonary Disease Using Spirometry: Summary of the Evidence for the U.S. Preventive Services Task Force. Annals of Int Med, 1 April 2008 | Volume 148 Issue 7.
Augmentation Therapy for Emphysema Due to Alpha-1-antitrypsin Deficiency. Therapeutic Advances in Respiratory Disease and Medscape, 05/2008.
Hereditary alpha-1-antitrypsin deficiency and its clinical consequences. Laura Fregonese and Jan Stolk. Orphanet Journal of Rare Diseases 2008, 3:16doi:10.1186/1750-1172-3-16.
Myths and Misconceptions About {alpha}1-Antitrypsin Deficiency. James K. Stoller, MD, MS; Loutfi S. Aboussouan, MD. Arch Intern Med. 2009;169(6):546-550.
Alpha1-Antitrypsin Deficiency. NEJM, Volume 360:2749-2757 June 25, 2009 Number 26.

Further reading

Patient view: A good life, one breath at a time. Dianne Williamson. Worcester Telegram & Gazette Corp, 02/2008.
Fear of Insurance Trouble Leads Many to Shun or Hide DNA Tests. NYTimes, 02/2008.
Pop superstar Michael Jackson may need a lung transplant because of alpha-1 antitrypsin deficiency. WebMD, 12/2008.

Therapy with alpha-1 antitrypsin cannot be recommended, in view of the lack of evidence of clinical benefit and the high cost of treatment. The Cochrane Collaboration, 2010.

Alpha1-Antitrypsin Deficiency and Autophagy - NEJM, 2010 http://goo.gl/QjUzI
A 2012 Review of Alpha 1-Antitrypsin Deficiency - from Cleveland Clinic http://goo.gl/nYX0v

Published: 02/08/2008
Updated: 01/20/2012