Documentation:Alpha-1 Antitrypsin Deficiency
Overview
Alpha-1 antitrypsin deficiency (AATD) is a condition which affects the liver and lungs. Some individuals with AATD will develop chronic obstructive pulmonary disease (COPD), including emphysema and chronic bronchitis. Individuals with AATD are also at an increased risk of developing scarring of the liver, also known as cirrhosis.
AATD is one of the most common severe inherited conditions worldwide, and it more commonly affects individuals from northern and western Europe. It is caused by a mutation in the SERPINA1 gene which encodes for the alpha-1 antitrypsin protein. AATD is inherited in a recessive pattern. Genetic counsellors are medical professionals who can discuss the implications of this inherited condition, as well as testing options, for yourself and your family.
Genes and Inheritance
AAT deficiency is an inherited condition. It is caused by a change (mutation) in a gene, SERPINA1, which provides the body with instructions to make alpha-1 antitrypsin (AAT) protein (Darlington, Astrin, Muirhead, Desnick, & Smith, 1982). This altered gene leads to decreased levels of functional AAT protein. AAT works to protect the liver and lungs from enzymes, which when uncontrolled, can cause organ damage.
AATD follows an autosomal recessive inheritance pattern, meaning that a person must have two copies of the altered gene for the disease to be present. Individuals with this condition received one altered copy of the gene from their father and the other copy from their mother. Carriers who have only one copy of the altered gene are generally in good health. About 2% of the North American population are carriers for this condition (de Serres, Blanco, & Fernández-Bustillo, 2003).
There are multiple possible altered versions (alleles) of the SERPINA1 gene, but only a few lead to a low production of AAT. The three most common alleles in the Caucasian population are M, S and Z:
- The M allele is the most common, and it leads to a normal amount of alpha-1 antitrypsin.
- The S disease allele gives the instructions for a moderate amount of alpha-1 antitrypsin.
- The Z disease allele gives the instructions for a low amount of alpha-1 antitrypsin.
Individuals with SS, SZ and ZZ do not make enough alpha-1 antitrypsin. About 95% of individuals with AATD are ZZ. Individuals with MS and MZ are carriers for the condition. SS and MS are not associated with disease (Ferrarotti et al., 2012). It is important to keep in mind that not all individuals with the same combination of alleles will have the same symptoms and outcomes.
Epidemiology
Worldwide, alpha-1 antitrypsin deficiency is one of the most common severe inherited disorders. It affects an average of 1 in 3 500 individuals (De Serres, 2002) (Sveger, 1976) (Silverman et al., 1989), but it has been observed in numbers as high as 1 in 1 500 in some populations (Luisetti & Seersholm, 2004). In Canada, 1 in 37 individuals are carriers for the Z allele, and 1 in 14 individuals are carriers for the S allele (de Serres et al., 2003).
AATD affects all nationalities, with the highest prevalence (occurrence) of the condition in northern and western Europe (Luisetti & Seersholm, 2004). In addition, AATD has been seen in African blacks, Arabs and Jews in the Middle East, whites in North America, Australia and New Zealand, as well as in central, far east and southeast Asians (De Serres, 2002).
Signs and Symptoms
Lungs
Individuals with AATD are at an increased risk of COPD in adulthood (McElvaney et al., 1997). COPD is a lung disease in which airflow is reduced and affected individuals have long-term breathing problems. Common symptoms of COPD include shortness of breath, wheezing, chest tightness and a chronic cough. Emphysema and chronic bronchitis are older terms for COPD (GOLD, 2017). AATD is also known as alpha-1 related emphysema or inherited emphysema because of its association with lung disease.
Several individuals with AATD go undiagnosed because their respiratory symptoms are mild, or it is misdiagnosed as asthma. Smoking and exposure to other sources of air pollution can increase the risk of developing COPD in individuals with this condition (Tanash, Nilsson, Nilsson, & Piitulainen, 2008). Childhood-onset of lung disease is rarely seen in AATD (Cox & Talamo, 1979).
Liver
AATD increases an individual’s risk of developing cirrhosis, scarring of the liver. Symptoms of cirrhosis include a swollen abdomen, swollen feet or legs and jaundice (yellowing of the skin and whites of the eye) (Fairbanks & Tavill, 2008).
AATD is the most common genetic cause of liver disease in infants and children; however, only about 2-3% of children require a liver transplant due to advanced liver disease (Fairbanks & Tavill, 2008).
About one third of adults with AAT deficiency will develop cirrhosis. It is unknown which environmental and genetic factors make some individuals more likely to develop liver disease and not others. Cirrhosis also puts individuals at an increased risk of developing hepatocellular carcinoma, a type of liver cancer (Fairbanks & Tavill, 2008).
Not much is known about the health risks of carriers for the Z allele. Some studies have shown a relationship between carriers and chronic liver disease, but others have not. There is no relationship between liver disease and MS or SS genotypes (Fairbanks & Tavill, 2008).
Diagnosis
A blood test for AAT can be ordered by a doctor if a person's symptoms and family history are suspicious for the condition. This test measures the amount of functional alpha-1 antitrypsin protein levels in the blood. The concentration of AAT in a healthy individual is usually between 1.15 and 4 g/L. Sometimes genetic testing or other molecular testing techniques will also be done to confirm the diagnosis or if the blood test results are not informative (Snyder et al., 2006).
Treatment and Management
Augmentation Therapy
Lung disease caused by AATD that cannot be managed with regular COPD therapy can be treated by giving a patient alpha-1 antitrypsin intravenously (into the vein with a syringe). This type of therapy has been shown to help AATD patients with moderate types of COPD the most (Marciniuk et al., 2012) (Fairbanks & Tavill, 2008).
Liver Transplantation
There is no approved treatment for liver disease associated with this condition. Liver transplantation is an option for patients who develop cirrhosis or early-stage liver cancer. Transplantation replaces the diseased liver with that of a donor. A liver transplant can also help restore alpha-1 antitrypsin levels to normal (Fairbanks & Tavill, 2008).
Genetic Counselling
Alpha-1 antitrypsin deficiency is an inherited condition. If you have received a diagnosis of AATD, it may have implications for the health of your family members and children. To discuss testing options, your family members can consult their family doctor. A referral can also be made by a doctor to your local genetic counsellor. A list of genetics clinics across Canada can be found at the Canadian Association of Genetic Counsellors' website.
Carrier Testing for Family Members
Carrier testing for at-risk family members may be available if a genetic diagnosis of AATD has been made in the family. The below example shows the possible combination of alleles in an individual who has an affected sibling (ZZ).
If both parents are carriers (MZ), each sibling of an affected individual has:
· 1/4 chance of being affected (ZZ)
· 1/2 chance of being carrier (MZ)
· 1/4 chance being unaffected (MM)
If one parent is affected (ZZ) and the other parent is a carrier (MZ), each sibling of an affected individual has:
· 1/2 chance being affected (ZZ)
· 1/2 chance being carrier (MZ)
Family Planning
Prenatal genetic testing may be available when parents of the baby have had genetic testing themselves and their SERPINA1 status is known. This type of testing uses techniques called chorionic villus sampling and amniocentesis to take a small sample of tissue during pregnancy. It is difficult to predict before birth how mild or severe AATD will be in the child based on the results of a genetic test. The benefits and risks of genetic testing during pregnancy can be discussed with a genetic counsellor.
Gene Therapy
Clinical trials are underway to study the treatment of AATD using gene therapy technology (Flotte et al., 2011). One of the ways gene therapy works is by introducing a functional copy of the disease gene into the body to restore the patient’s ability to make a normal amount of protein. In the future, gene therapy may be a treatment option available to individuals with this condition. A functional copy of the SERPINA1 gene would be introduced into the body, leading to an increase in the amount of alpha-1 antitrypsin protein made by the patient themselves.
Patient Resources
Canadian Association of Genetic Counsellors
References
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Tanash, H. A., Nilsson, P. M., Nilsson, J. Å., & Piitulainen, E. (2008). Clinical course and prognosis of never-smokers with severe alpha-1-antitrypsin deficiency (PiZZ). Thorax, 63(12), 1091–1095.