# Handbook of Genetic Counseling/Alpha 1 Antitrypsin Deficiency

Alpha 1 Antitrypsin Deficiency

## Introduction

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

## Elicit Medical History

* Include information about environmental/occupational hazards and smoking

## What is Alpha 1 Antitrypsin Deficiency (AAT 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 (and beyond). This is (often) 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.
*** AAT deficiency may cause progressive liver damage (cirrhosis) or liver cancer, primarily in those that have a ZZ phenotype.
*** 40-60% of ZZ patients experience liver disease in their lifetime. In infants, it is one of the most common causes for neonatal cholestasis. In a prospective study by Sveger et al in which 200,000 newborns were screened in the 1970's, 127 ZZ newborns were identified that are still followed today. Their data showed that life-threatening liver disease (over all risk 5%) can occur in the first few months or years of life but that 80% of those individuals are healthy and free of chronic disease by 18 years.
*** 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.
* There is currently no treatment for alpha-1 related liver disease.
* It is possible to have AAT deficiency without having developed symptoms yet or that has been misdiagnosed. It is possible to have the deficiency and never develop symptoms. Those with environmental exposures (to lung and/or liver) are more likely to develop symptoms and there is a correlation between environmental exposures and other genetic factors with age of onset and severity.
* The reasons for the wide variability, from normal life span and normal activity through life, to severe liver or lung disease are largely unknown. There are currently studies underway to understand this. If you are interested in participating in research, I would encourage you to contact the alpha-1 research registry at 1-877-886-2383.

## 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. In the US about 1 in 4455 has alpha-1(Stoller and Aboussouan, 2012.)
* 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 Portuguese) descent.
* 70,000-100,000 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. less than 10% have been diagnosed
* 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, particularly if they smoke.
* 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 ZZ type 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 is believed to cause 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 (serpina1) located on the distal long arm of chromosome 14.
* There are at least 120 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 allele contains a mutation. As a result there is not as much alpha 1 antitrypsin into the blood (~15% of normal amount).
* The protein formed from the Z allele has a glu changed to a lys
* This causes misfolding of the polypeptide and polymerization of alpha-1 antitrypsin Z molecules
* Polymerization of the Z alpha-1 antitrypsin molecules leads to accumulation of abnormal protein in hepatocytes, some of which is subsequently degraded. How and how much gets degraded are largely controlled by epigenetic mechanisms not yet identified but currently being researched
* 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. However, it has been shown that smokers that are carriers are at a higher risk for lung disease than the general population, it is therefore recommended that MZ's avoid smoking and working environments that constantly expose the lungs to dust or chemicals.
* 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 Britons, 1 to 2% of southern Europeans, and 2-3% of the heterogeneous white population in the United States are MZ (carrier) heterozygotes.
* If both parents are carriers for the Z allele then each pregnancy results in a 25% chance of having a child that will be ZZ and therfore at risk for lung and liver disease
* The S variant of this gene makes functional alpha 1 antitrypsin, but it is recycled faster and results in about 60% normal amounts secreted into the blood stream.
* If a person inherits two copies of the S variant then their alpha 1 antitrypsin levels are reduced (slightly higher than the MZ carrier) and they typically 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 (ex)F, Mmalton, Mheerlen(null), I).
* In some rare cases, a person's body may not produce any alpha-1 antitrypsin. This condition results from inheriting two genes that produce any functional protein . 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/dl or g/L, with a normal range from approximately 100-300 mg/dl. Levels less than 58 mg/dL or 11μM suggest severe deficiency. Those that are slightly below normal suggest carrier status, however, often a carrier can have a normal level, so it is important to order a phenotype and/or genotype test in addition to the serum level.
** Reference laboratories usually report the serum levels in micromolar concentration, with a normal range of 20-60 μM and a threshold level for emphysema at 11 micromol/L.
* The same blood sample can also be used to determine which type of protein or Pi type (the phenotype) you have by separating the alpha-1 antitrypsin proteins on a gel
** 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. A phenotype should be confirmed with genotype.
** 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.
Lastly, a genotype test typically screens for the S and Z allele (more depending on the lab).
Ideally, to have the most accurate diagnosis, the Alpha-1 Antitrypsin Profile will do all 3 (level, phenotype and genotype)

## Where is testing available?

* Free (confidential) test kits are available through the Alpha-1 Foundation's Alpha-1 Coded Testing Trial conducted through the Medical University of South Carolina and they take 2-4 weeks for the order to be processed. They test for both levels of protein and genotype. To participate visit their site at www.alphaoneregistry.org or call their Genetic Counselor at 1-877-785-3177 to discuss testing and any questions that you may have.
* Free genetic screening kits are also available through the drug companies that produce the only treatment specific to alpha-1 antitrypsin deficiency. They are Grifols, CSL Behring and Baxter. Information may be found online. Each test is a little different and must be taken to a doctor's office to be completed.
* Many commercial companies such as LabCorp and Mayo Medical Laboratories also offer alpha-1 testing. I recommend at least a level + genotype or phenotype. Ideally, the Alpha-1 antitrypsin profile will do the level + phenotype and reflex to a genotype.

## Reasons for being tested

* There are ways to help prevent further 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 protein replacement therapy: intravenous infusion of the purified human alpha-1 antitrypsin protein (augmentation therapy) used to treat patients that are severely deficient.
* 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
* Preimplantation Genetic Diagnosis with IVF is available
* Gene therapy in the future? Research has been done in mice using gene therapy for AAT deficiency

## Possible reasons for not being tested

* 1)Genetic discrimination- fear of being fired or losing insurance benefits due to a positive genetic test.
* GINA (genetic information non-discrimination act) went into law in 2008 and protects asymptomatic individuals from discrimination by health insurers and employers. Health insurance is further protected by ACA (Affordable Care Act, 2011). This does not protect against discrimination for life, long-term care or disability insurance. I recommend that healthy, asymptomatic individuals consider purchasing before pursuing genetic testing. For symptomatic individuals it is some what of a moot point as insurance carriers will likely use health information to deny/raise premiums. Additionally, it does not protect those in the military or work for federal government, although the law is largely observed to this point.
* 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
* 2)Fear of knowing health risks

## Other psychosocial issues to consider

* Anxiety associated with waiting for test results
* Anxiety and difficult decisions associated with knowing you and/or 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 if, when and how severely one might be affected.
* May encourage individuals to make healthier life choices

## References

* Teckman (2013). Liver Dissease in Alpha-1 Antitrypsin Deficiency: Current Understanding and Future Therapy. COPD Vol 10 (S1): 35-43
* Stoller and Aboussouan. (2012). A Review of α1-antitrypsin deficiency. Concise Clinica Review. Am J Respir Crit Care Med. Vol 185 (3) pp 246-259
* Fleming et al. (2001). Pilot Deficiency Study of Alpha 1 Antitrypsin Deficiency in Targeted Population. American Journal of Medical Genetics. 103:69-74
* AlphaNet website (AlphaNet is a not-for-profit health management company founded by individuals with Alpha-1 Antitrypsin Deficiency "Alphas" to provide comprehensive services for Alphas.)
* 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
* 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 2014 by Sara Wienke, MS CGC (alpha-1 genetic counseling center 1-877-785-3177).