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Genetic counseling: Alpha 1 Antitrypsin Deficiency

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Alpha 1 Antitrypsin Deficiency


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

Elicit Family History and PedigreeEdit

Elicit Medical HistoryEdit

  • Include information about environmental/occupational hazards and smoking

What is Alpha 1 Antitrypsin Deficiency (ATT deficiency)?Edit

  • 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?Edit

  • 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?Edit

  • 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?Edit

  • 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?Edit

  • 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?Edit

  • 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?Edit

  • 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?Edit

  • 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 testedEdit

  • 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)Edit

  • 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 testedEdit

  • 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 considerEdit

  • 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.


  • 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


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%


The information in this outline was last updated in 2001.

Material obtained under GFDL Licence from

Heckert GNU white 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."

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