Genetic counseling: Alpha 1 Antitrypsin Deficiency

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Alpha 1 Antitrypsin Deficiency

Introduction[]

Acknowledge any prior contact
Assess concerns and questions they have
Explain that their concerns will be addressed

Elicit Family History and Pedigree[]

Elicit Medical History[]

Include information about environmental/occupational hazards and smoking

What is Alpha 1 Antitrypsin Deficiency (ATT deficiency)?[]

Alpha-1 antitrypsin deficiency is an inherited disorder that causes low levels of, or no alpha-1 antitrypsin in the blood.
Alpha-1 antitrypsin is a protein that is made in the liver. The liver releases this protein into the bloodstream.
The deficiency of this protein may predispose an individual to several illnesses
- The most common illness in adults with alpha 1 antitrypsin deficiency is lung disease during the third and fourth decades of life. This is earlier than in those without the deficiency
  - Most commonly it is associated with chronic obstructive pulmonary disease (COPD).
  - COPD is characterized by coughing, shortness of breath, sputum production, rapid breathing, wheezing, and weight loss due to the energy required for labored breathing.
  - COPD includes chronic bronchitis and emphysema
    - chronic bronchitis - inflammation of the lining of the bronchial tubes
    - emphysema - permanent destruction of the alveoli
  - AAT Deficiency is the most common genetic cause of emphysema. It is also the most frequent cause of disability and early death among affected people.
  - Less commonly AAT deficiency may cause progressive liver damage (cirrhosis) or liver cancer.
  - 15-25% of affected patients develop cirrhosis and its complications, but 75% of individuals will not have any significant liver disease after the newborn period
  - Some patients with cirrhosis lead relatively normal lives for relatively long periods of time
  - Some patients have serious liver damage that requires a liver transplant.
  - Less than 3% may develop cancer of the liver.
Alpha-1 antitrypsin deficiency is the most common genetic cause of liver disease in children and is the most common genetic disease for which liver transplantation is undertaken in children.
- Some children show signs of liver failure at birth including jaundice, swelling of the abdomen, and poor feeding
- In some children, the signs of alpha-1 antitrypsin deficiency do not become apparent until early childhood or adolescence when they may develop hepatitis, enlarged spleen, ascites, pruritus and other signs of liver injury.
- Only 10-15% of children with alpha-1 antitrypsin deficiency develop liver disease. In some families one child may not show any signs of liver disease whereas a brother or sister may be seriously affected.
It is possible to have AAT deficiency without having developed symptoms yet or that has been misdiagnosed.
The reasons for the wide variability, from normal life span and normal activity through life, to severe liver or lung disease are largely unknown.

Who is at risk?[]

An estimated 1 in 1500 to 1 in 7000 people has alpha 1 antitrypsin deficiency world wide and it is found in nearly all populations.
It is very rare among people of Asian and African descent.
It is most prevalent among people of Northern European (Scandinavian and British) and Iberian (Spanish and Portugese) descent.
100,000 people are estimated to be affected in the U.S., and a similar number in Europe are thought to be affected
Of the estimated 100,000 in the U.S. only 10% have been diagnosed
Some researchers believe that it is more common than Cystic Fibrosis
It is thought that AAT deficiency is widely underdiagnosed or misdiagnosed as asthma or cigarette smoking induced COPD.
Estimated carrier frequencies in the above mentioned at risk populations have been quoted as high as 1:25
Research suggests that some carriers may be at increased risk for lung disease at a later age of onset.
Other more current research suggests that being a carrier is not a very important determining factor compared to other risks such as smoking.

How does a deficiency lead to lung disease?[]

Alpha-1 antitrypsin protects the lungs against another protein that can harm lung tissue. (It is called neutrophil elastase-- an enzyme released by white blood cells to help fight infections)
When the lungs do not have enough alpha-1 antitrypsin, these proteins are free to destroy lung tissue.
As a result, the lungs lose some of their ability to expand and contract (elasticity)
This leads to difficulty breathing.
Destruction of the alveoli can also occur and lead to emphysema
The speed at which lung tissue is destroyed varies with each person.
It is known that tobacco smoking worsens the lung damage.

How does a deficiency lead to liver disease?[]

Individuals with AAT deficiency often do not secrete AAT after it is made by the liver.
Some of the AAT is broken down but the portion that is not accumulates in the liver cells.
This accumulation can damage the liver and lead to cirrhosis.

How is it inherited?[]

Alpha 1 antitrypsin deficiency is an autosomal recessive genetic condition
Explain genes and chromosomes
Alpha 1 antitrypsin is encoded by a gene (PI) located on the distal long arm of chromosome 14.
There are at least 75 different variations, or alleles, of the gene that make alpha 1 antitrypsin.
We get one copy of this gene from each of our parents
The M allele is the most common form (actually there are a group of M alleles along with other very rare normal variants)
If a person inherits an M gene from both their parents they will have normal levels of alpha 1 antitrypsin (MM genotype)
The Z gene is altered. As a result there is not as much alpha 1 antitrypsin into the blood.
The protein formed from the Z allele has a glu changed to a lys
This causes misfolding of the polypeptide
Decreased ability for normal protein folding leads to accumulation of abnormal protein in hepatocytes some of which is subsequently degraded
When a person inherits the Z gene from both parents they will have very low alpha-1 antitrypsin levels that can lead to tissue damage of the lungs and/or liver disease (ZZ genotype)
If a person inherits one M gene and one Z gene they are called a carrier. Although they usually have less alpha 1 antitrypsin in their blood then those with two M genes, they do not usually develop any symptoms because they still have sufficient amounts to protect their lungs.
MZ phenotype was associated with an increased prevalence of byssinosis compared with the MM phenotype: 3/8 (38%) and 25/187 (13%). An association between the MZ phenotype and familial allergy was also found, although the association was somewhat weaker.
5% of Scandinavians, 4% of Britains, 1 to 2% of southern Europeans, and 2-3% of the heterogeneous white population in the United States are MZ (carriers) heterozygotes.
If both parents are carriers for the Z allele than their children each have a 25% chance of having a child at risk for lung and liver disease
The S variant of this gene makes functional alpha 1 antitrypsin, but it is broken down and made nonfunctional more easily before it is secreted.
If a person inherits two copies of the S variant than their alpha 1 antitrypsin levels are reduced but they don't show any symptoms
If a person inherits one S and one Z variant they have a mildly increased risk for lung disease.
There is a relatively high frequency of the S allele (0.04-0.08 in U.S. Caucasians). Therefore MS heterozygotes are relatively frequent.
1 in 10 persons of European origin will be heterozygous for either the S or Z variant (MZ or MS genotype)
About 5 % of people with alpha 1 antitrypsin deficiency will have other rare allele variants.
In some rare cases, a person's body may not produce any alpha-1 antitrypsin. This condition results from inheriting two genes that don't allow any functioning protein to be made. It is called "null-null type."
The null-null phenotype is accompanied by emphysema as are the ZZ and SZ phenotypes but an important difference is that cirrhosis and liver cancer do not occur with the null-null phenotype because there is no abnormal antitrypsin product accumulation

Who should be tested?[]

The World Health Organization (WHO) recommends that all individuals with COPD as well as adults and adolescents with asthma be tested.
Clinical features that suggest the possibility of AAT deficiency and the need for serum testing include emphysema at an early age, emphysema in a nonsmoker (or light smoker), a family history of emphysema, emphysema of the lower lungs (as determined by chest radiograph), adult-onset asthma, and recurrent bronchitis.
It is also suggested that testing be done on most patients with chronic or recurrent respiratory symptoms (dyspnea, cough, wheezing) at least once.
It has been suggested that carrier screening should be performed on people in high- risk populations.

What is the test?[]

It is a simple blood test that can be done on a finger stick or venous blood sample
It will determine the amount of AAT in your blood (blood enzyme levels)
- Serum testing is a screening procedure. Most hospital laboratories report serum AAT levels in mg/mL, with a normal range from approximately 100-300 mg/mL. Levels less than 80 mg/mL suggest a significant risk for lung disease.
- Reference laboratories usually report the serum levels in micromolar concentration, with a normal range of 20-60 micromol/L and a threshold level for emphysema at 11 micromol/L.
The same blood sample can also be used to determine which type of protein (the phenotype) you have
- Therefore the phenotype test can tell you if you are a carrier for one of the genes that causes alpha 1 deficiency
- The phenotype is usually determined if alpha 1 antitrypsin levels are below 30 micromoles/ liter or if there is a known family history
- Therefore, to detect all heterozygous carriers it is important to make sure the lab performs phenotype testing.
- Phenotyping is required to confirm the presence of AAT deficiency. Do not initiate AAT replacement therapy without testing.
- The phenotype, PiZZ, is responsible for nearly all cases of AAT emphysema and liver disease. PiZZ phenotype serum levels range from 3.4-7 micromol/L, about 10-20% of the normal levels.

Where is testing available?[]

Free test kits are available through the Alpha-1 Foundation and they take 2-4 weeks for the order to be processed. They test for both levels of protein and phenotype so carrier status can be determined *Information and an order form is attached
It will take about two weeks to get the results back
Free genetic screening kits are also available through Bayer Laboratories at 800-288-8371, and samples can be processed for free at the AAT Deficiency Detection Center, University of Utah, 801-328-4662
Confidential testing is also available *Information about this is also attached
I attempted to contact the Cleveland Clinic foundation for information on testing, but they didn't return my call. Their number is 1-800-223-2273, ext. 43702
Other labs which perform testing are also included, but I didn't contact them

Reasons for being tested[]

There are ways to help prevent tissue damage in the lung such as:
- receive immunizations for flu and pneumonia
- receive early treatment for lung infections by seeing your doctor at the first sign of a cold or other lung problem
- avoid tobacco smoke, noxious fumes, dust, and pollution
- stay fit by doing regular exercise
- increase your alpha-1 antitrypsin by enzyme replacement therapy (intravenous infusion of the purified human enzyme (Prolastin) used to treat patients with the PiZZ, Piz(null), or Pi(null)(null) phenotypes.) *Information about this is attached.
You can also reduce symptoms of shortness of breath by doing the following:
- using medications (for example, bronchodilators, or inhaled steroids) prescribed by your doctor to help open your airways
- using oxygen if your doctor prescribes it
- doing pulmonary rehabilitation (including breathing techniques)

Family planning (knowing risks to future children)[]

As of 1987 prenatal testing is available for fetuses known to be at risk
Gene therapy in the future? Research has been done in mice using gene therapy for AAT deficiency

Possible reasons for not being tested[]

There is a reported case where a person lost their job after receiving a bill for treatment procedures in a woman with a positive test for alpha 1 antitrypsin deficiency
She was supported by the AlphaNet, the Alpha 1 Association, the Genetic Alliance, the National Partnership for Women and Families and the Coalition for Genetic Fairness
She won the right in Nov 2000 to pursue a wrongful discharge law suit.
Concerns about this may be avoided by confidential testing

Other psychosocial issues to consider[]

Anxiety associated with waiting for test results
Anxiety and difficult decisions associated with knowing you and your partner are carriers and may pass alpha 1 antitrypsin deficiency on to offspring
Anxiety that may come if testing positive for AAT deficiency in the absence of present symptoms due to the uncertainty about how severely one will be affected.

References[]

Fleming et al. (2001). Pilot Deficiency Study of Alpha 1 Antitrypsin Deficiency in Targeted Population. American Journal of Medical Genetics. 103:69-74
Alpha one foundation website(testing information and patient resource)
patient resources (information and support group it is in Spanish also)
website (contains great patient information that is easy to understand on signs and symptoms of the disorder as well as risk factors and treatment)
child liver disease(good patient resource about liver disease in children)
website (all of the in depth scientific information about the various types of alleles and review of research done)
website
website(genetic discrimination case relating to alpha 1 antitrypsin deficiency)
website
website (information about lung disease and testing)
website (AlphaNet is a not-for-profit health management company founded by Alphas to provide comprehensive services for alphas.)
website
website

Tables[]

Genotype	Amount of AAT produced (percent of normal)	Possible Health Concerns	Population Incidence
MM	normal (100%)	none	86.5%
MZ (Carrier)	somewhat reduced (60%)	usually none	3.9%
ZZ	significantly reduced (7%)	significant risk for lung and/ or liver disease	0.05%
FM	slightly reduced (97%)	none	0.4%
FS	somewhat reduced (66%)		0.05%
SS	somewhat reduced (71%)	none	0.1%
SZ	reduced (39%)	slightly increased risk for lung disease	0.3%
MS	within the normal range (81%)	none	8.0%
Null/null	none (0%)	lung disease only	< 0.7%

Notes[]

The information in this outline was last updated in 2001.

Material obtained under GFDL Licence from http://en.wikibooks.org/wiki/Handbook_of_Genetic_Counseling

Permission is granted to copy, distribute and/or modify this document under the terms of the GNU Free Documentation License, Version 1.2 or any later version published by the Free Software Foundation; with no Invariant Sections, no Front-Cover Texts, and no Back-Cover Texts. A copy of the license is included in the section entitled "GNU Free Documentation License."