Alpha-1 antitrypsin deficiency is a genetic disorder characterized by the production of abnormal alpha-1 antitrypsin. Alpha-1 antitrypsin (AAT) is a protease inhibitor that is produced in the liver and travels to the lungs, where it protects the lung from damage caused by neutrophil elastase (a protease released by white blood cells in response to lung irritation). Alpha-1 antitrypsin deficiency occurs when there is a mutation in the SERPINA1 gene, leading to the production of abnormal AAT that does not conform (fold) normally and builds up in the liver. This results in low levels of AAT in serum and lungs, allowing the destructive effects of neutrophil elastase to go unchecked. The result is emphysema and, in some patients, bronchiectasis. The accumulation of AAT in the liver may also result in liver disease.

The most important genetic aspect of alpha-1 antitrypsin deficiency is that there are many alleles for alpha-1 antitrypsin, and that various combinations of these alleles lead to different clinical manifestations. Alpha-1 antitrypsin deficiency is inherited in an autosomal co-dominant manner (protein products from both genes are produced). The most common alleles include:

Allele

AAT Production

AAT Serum Concentrations

M

Normal

Normal

S

Abnormal

Low

Z

Abnormal

Very Low

Rare

Abnormal

Varies

Null

None

None

 

The following in a brief description of the genotypes most commonly found in the population.

Genotype

Disease

AAT Blood Levels

Risk for Symptoms

Description

MM

Normal

Normal

None

90% of the population

MS

Carrier

80% of normal

Low

8% of the population

Little risk for lung or liver disease

MZ

Carrier

60% of normal

Low

3% of the population

Non smokers have little risk for lung disease

Smokers, particularly those who smoke heavily, will experience more loss of lung elasticity, which may lead to clinically apparent lung damage

SS

Alpha-1

50% of normal

Low

Little risk for lung or liver disease

SZ

Alpha-1

40% of normal

Moderate

Slightly increased risk of lung and liver disease (particularly in smokers)

ZZ

Alpha-1

10% of normal

Severe

Approximately 1 in 5000 in the population

High risk for developing COPD, which can occur in early adulthood

More susceptible to liver disease

Null Null

Alpha-1

None

Severe

High risk for developing COPD, which can occur in early adulthood

Little to no risk of liver disease because AAT is not produced (therefore does not accumulate in liver)

 

When both parents are heterozygotes (MZ), each sibling of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. In the rare instance in which one parent is homozygous (ZZ) and one parent is heterozygous, the risk for each sibling to be affected is 50%. Unless an individual with alpha-1 has children with a reproductive partner who is affected or a carrier, his/her offspring will be obligate heterozygotes (carriers) for the disease-causing mutation.

(Contributed by Dr. Diane Cox, PhD, FCCMG)

Physicians should consider testing their patients for alpha-1 if the following lung-related symptoms occur, or are a chronic condition:

  • Bronchiectasis
  • Recurring respiratory infections
  • Non-responsive asthma (in which obstruction persists despite optimal therapy)

 

Testing is also recommended if these common findings associated with liver disease in alpha-1 are present:

  • Cirrhosis
  • Unexplained liver problems
  • Elevated liver enzymes
  • Childhood failure to thrive

Screening for alpha-1 antitrypsin deficiency is easily and simply accomplished by requesting serum levels for alpha-1 antitrypsin, an inexpensive biochemical assay covered by all provincial fee schedules and done by all outpatient and hospital labs. If low levels are found, confirmation of the diagnosis of alpha-1 antitrypsin deficiency requires more specialized and less readily available genotyping.

If a low serum level is found it does not establish a diagnosis of clinically important severe deficiency. In fact, the majority of abnormal results are mildly reduced values found in carriers at low risk of having clinical disease, and confirmatory genotyping is needed. Some labs routinely refer low plasma results directly to a DNA diagnostic laboratory for genotyping. The exception is Alberta where both procedures are done by DynaLIFE. Please see, ' What are the options for genetic testing for Alpha-1 in Canada?' for detailed information on how to obtain genetic testing.

Interpretation of AAT Serum Concentration results:

*Please note that the ranges overlap and that the use of this table is not a substitute for genotyping

Genotype

g/L

mg/dL

uM

MM

1.04 - 2.27

104 - 276

20 - 53

MS

0.82 - 1.77

82 - 177

16 - 34

MZ

0.57 - 1.66

57 - 166

11 - 32

SS

0.78 - 1.56

78 - 156

15 - 30

SZ

0.42 - 0.82

42 - 82

8 - 16

ZZ

0.13 - 0.47

13 - 47

2.6 - 9.1

Null Null

0

0

0

University of Florida Reference Ranges

 

Phenotype

Prevalence %

µM

mg/dL

Emphysema Risk

MM

91

20 - 53

150 - 350

Background

MS

6.1

18 - 52

110 - 340

Background

MZ

2.7

17 - 33

90 - 210

Background

SS

0.1

15 - 33

100 - 200

Background

SZ

0.1

8 - 16

75 - 120

20 - 50%

ZZ

0.02

2 - 7

20 - 45

80 - 100%

Null Null

<0.01

0

0

100%

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1. After diagnosis, direct patients to our website for more information on alpha-1 (and support resources) and advise your patient to sign up for the Alpha-1 Canadian Registry (see About page). Patients can sign up by downloading the forms found here (please advise when filling out medical information). The clinical course and complications of alpha-1 antitrypsin deficiency are somewhat different from non-alpha-1 COPD and the participation of a respirologist (for lung disease) or hepatologist (for liver disease) familiar with alpha-1 antitrypsin deficiency is recommended.

 

2. Monitoring patients will depend on their level of lung and liver function. Lung function should be evaluated using Pulmonary Function Tests (spirometry, lung volume measurements and diffusion capacity) and a chest X-ray or high resolution CT of the lungs. Liver function tests should be performed periodically in all individuals with severe alpha-1 antitrypsin deficiency, and include measurements of AST/ALT, GT and ALP. A liver ultrasound examination is recommended at baseline. The status of fibroscan examinations is unclear at this time.

 

3. There are two main treatment strategies for patients with alpha-1. To specifically target the genetic condition, intravenous augmentation therapy (regular infusion of purified human AAT to augment deficient ATT serum concentrations) is widely prescribed in the United States and other countries and has been recommended by the Canadian Thoracic Society for affected individuals whose FEV1 is 25% to 80% of predicted and have never smoked or have quit smoking. To target symptoms of COPD, usual treatment with bronchodilators, inhaled corticosteroids, or combination inhalers is generally recommended. An action plan to treat exacerbations promptly is highly recommended. Please see the Canadian Thoracic Society's COPD Flare Up Action Plan here.

 

Additional measures to ensure continued health in alpha-1 patients include:

  • Vaccinations for influenza/pneumonia
  • Vaccinations for hepatitis A and B (especially for those with established liver disease)
  • Aggressive treatment of lung infections with antibiotics (because the lung attracts more leukocytes when an infection is present, and leukocytes release neutrophil elastase)
  • Supplemental Oxygen if required
  • Surgery (lung volume reduction or lung transplantation)

 

4. Life style changes that are recommended to patients with Alpha-1 include:

  • Quitting smoking and keeping away from second hand smoke
  • Low, infrequent or no alcohol consumption (especially in those with the ZZ genotype), as it may cause additional damage to the liver
  • Avoiding exposure to dust or fumes
  • Exercising regularly
  • Eating a well balanced diet
  • Maintaining a desirable body weight
  • Increasing hand hygiene to reduce bacterial and viral