Alpha-1 Antitrypsin Deficiency: Gene Mutation, Symptoms, Treatment, and Life Expectancy

  • Medical Reviewer: Charles Patrick Davis, MD, PhD
    Charles Patrick Davis, MD, PhD

    Charles Patrick Davis, MD, PhD

    Dr. Charles "Pat" Davis, MD, PhD, is a board certified Emergency Medicine doctor who currently practices as a consultant and staff member for hospitals. He has a PhD in Microbiology (UT at Austin), and the MD (Univ. Texas Medical Branch, Galveston). He is a Clinical Professor (retired) in the Division of Emergency Medicine, UT Health Science Center at San Antonio, and has been the Chief of Emergency Medicine at UT Medical Branch and at UTHSCSA with over 250 publications.

Understanding COPD

Alpha-1 antitrypsin deficiency definition and facts*

*Facts medically reviewed by Charles P. Patrick, MD, PhD

  • Alpha1 antitrypsin deficiency (AATD, antitrypsin deficiency, or alpha 1 antitrypsin deficiency) is a disorder (disease) that causes the alpha-1 antitrypsin (AAT) protein to be reduced or missing from the blood. This protein is necessary for healthy lungs, and the body uses it to protect the lungs from damage. If a person has low or no levels of AAT their lungs may be damaged.
  • Statistically, the disorder affects about one in 1500 to 3500 individuals with European ancestry. It is uncommon in Asians.
  • The signs and symptoms most people experience with this deficiency are:
  • Mutations in the gene termed SERPNA1 cause alpha –1 antitrypsin deficiency.
  • A patient with lung or liver disease like COPD (chronic obstructive pulmonary disease) with no obvious cause maybe AATD deficient.
  • Doctors can confirm the diagnosis of this deficiency with blood tests or liver biopsy.
  • How doctors treat AATD depends on the patient’s signs and symptoms. Examples of treatments include:
  • Bronchodilators and inhaled steroids can help lung problems.
  • Intravenous use of purified human ATT (Prolastin) raise the level of ATT in the blood and lungs (augmentation therapy) - end stage lung and liver disease may need transplantation of these organs as a definitive treatment.
  • Management of AATD involves pulmonary function tests, liver function monitoring and yearly vaccinations against influenza. Moreover, doctors recommend that patient’s with the deficiency be vaccinated against hepatitis A and B, and pneumococcus.
  • The prognosis for someone with this problem is quite variable, and is related to the development and progression of severity of the symptoms. However, many people have a somewhat shortened lifespan. If the symptoms are severe, the prognosis can be very poor.
  • Medical professionals refer to alpha-1 antitrypsin deficiency.
    • AAT
    • AATD
    • Alpha-1 proteinase inhibitor
    • Alpha-1 related emphysema
    • Genetic emphysema
    • Hereditary pulmonary emphysema
    • Inherited emphysema

What is alpha-1 antitrypsin deficiency (AATD)?

Alpha-1 antitrypsin deficiency (AATD) is a disorder that causes a deficiency or absence of the alpha-1 antitrypsin (AAT) protein in the blood. AAT is made in the liver and sent through the bloodstream to the lungs, to protect the lungs from damage. Having low levels of ATT (or no ATT) can allow the lungs to become damaged, making breathing hard. Age of onset and severity of AATD can vary based on how much ATT an affected person is missing. In adults, symptoms may include shortness of breath; reduced ability to exercise; wheezing; respiratory infections; fatigue; vision problems; and weight loss. Some people have chronic obstructive pulmonary disease (COPD) or asthma. Liver disease (cirrhosis) may occur in affected children or adults. Rarely, AATD can cause a skin condition called panniculitis.[1] AATD is caused by mutations in the SERPINA1 gene and is inherited in a codominant manner.[2] Treatment is based on each person's symptoms and may include bronchodilators; antibiotics for upper respiratory tract infections; intravenous therapy of AAT; and/or lung transplantation in severe cases.[1][3]

Chart of signs and symptoms of lung and liver disease caused by AATD

The Human Phenotype Ontology (HPO) provides the following list of features that have been reported in people with this condition. Much of the information in the HPO comes from Orphanet, a European rare disease database. If available, the list includes a rough estimate of how common a feature is (its frequency). Frequencies are based on a specific study and may not be representative of all studies.

Signs and Symptoms of Alpha-1 Antitrypsin Deficiency
Signs and Symptoms

Approximate number of patients (when available)

EmphysemaVery frequent (present in 80%-90% of cases)
Hepatic failure (liver failure)Very frequent (present in 80%-90% of cases)
Hepatitis (liver inflammation or infection)Frequent (present in 30%-79% of cases)
An abnormally enlarged liver (hepatomegaly)Frequent (present in 30%-79% of cases)
Jaundice (signs of a liver problem)Frequent (present in 30%-79% of cases)
Cirrhosis (a complication of liver disease)Occasional (present in 5%-29% of cases)
Autosomal recessive inheritance
COPD (chronic obstructive pulmonary disease)
Shortness of breath (Dyspnea)
Elevated hepatic transaminases
Liver cancer (hepatocellular carcinoma)

Quick GuideCOPD Lung Symptoms, Diagnosis, Treatment

COPD Lung Symptoms, Diagnosis, Treatment

Prognosis and Life Expectancy for Genetic Diseases

The prognosis and life expectancy (how long a person can live with the disease or condition) for a person with a genetic condition depend upon the management and stability of symptoms, quality of life, and any potential complications associated with his or her health.

REFERENCE: NIH; Genetics Home Reference. "What is the prognosis of a genetic condition."

How common is alpha-1 antitrypsin deficiency?

Alpha-1 antitrypsin deficiency occurs worldwide, but its prevalence varies by population. This disorder affects about 1 in 1,500 to 3,500 individuals with European ancestry. It is uncommon in people of Asian descent. Many individuals with alpha-1 antitrypsin deficiency are likely undiagnosed, particularly people with a lung condition called chronic obstructive pulmonary disease (COPD). COPD can be caused by alpha-1 antitrypsin deficiency; however, the alpha-1 antitrypsin deficiency is often never diagnosed. Some people with alpha-1 antitrypsin deficiency are misdiagnosed with asthma.

What gene mutations cause alpha-1 antitrypsin deficiency?

Mutations in the SERPINA1 gene cause alpha-1 antitrypsin deficiency.

The SERPINA1 gene provides instructions for making a protein called alpha-1 antitrypsin. This protein protects the body from being damaged by a powerful enzyme called neutrophil elastase. Neutrophil elastase is released from white blood cells to fight infection, but it can attack normal tissues (such as lung tissue) if not carefully controlled by alpha-1 antitrypsin. Mutations in the SERPINA1 gene can lead to a shortage (deficiency) of alpha-1 antitrypsin protein or an abnormal form of the protein that cannot control neutrophil elastase. Uncontrolled, neutrophil elastase destroys alveoli, which can lead to emphysema. The abnormal form of alpha-1 antitrypsin can also accumulate in the liver and may damage this organ.

What tests diagnose AATD?

AATD may first be suspected in people with evidence of liver disease at any age, or lung disease (such as emphysema), especially when there is no obvious cause or it is diagnosed at a younger age.

Confirming the diagnosis involves a blood test showing a low serum concentration of the alpha-1 antitrypsin (AAT) protein, and either:

  • detecting a functionally deficient AAT protein variant by isoelectric focusing (a method for detecting mutations); or
  • detecting SERPINA1 gene mutations on both copies of the gene with molecular genetic testing. (This confirms the diagnosis when the above-mentioned tests are not performed or their results are not in agreement.)[3]

Specialists involved in the diagnosis may include primary care doctors, pulmonologists (lung specialists), and/or hepatologists (liver specialists).[4]

Alpha-1 antitrypsin deficiency treatment and management guidelines

Treatment of alpha-1 antitrypsin deficiency (AATD) depends on the symptoms and severity in each person. COPD and other related lung diseases are typically treated with standard therapy.[3][4] Bronchodilators and inhaled steroids can help open the airways and make breathing easier.[4]

Intravenous augmentation therapy (regular infusion of purified, human AAT to increase AAT concentrations) has been recommended for people with established fixed airflow obstruction (determined by a specific lung function test).[3] This therapy raises the level of the AAT protein in the blood and lungs.[4]

Lung transplantation may be an appropriate option for people with end-stage lung disease. Liver transplantation is the definitive treatment for advanced liver disease.[3]

When present, panniculitis may resolve on its own or after dapsone or doxycycline therapy. When this therapy does not help, it has responded to intravenous augmentation therapy in higher than usual doses.[3]

All people with severe AATD should have pulmonary function tests every 6 to 12 months. Those with ATT serum concentrations 10% to 20% of normal should have periodic evaluation of liver function to detect liver disease. People with established liver disease should have periodic ultrasounds of the liver to monitor for fibrotic changes and liver cancer (hepatocellular carcinoma).[3]

Yearly vaccinations against influenza and pneumococcus are recommended to lessen the progression of lung disease. Vaccination against hepatitis A and B is recommended to lessen the risk of liver disease. People with AATD should avoid smoking and occupations with exposure to environmental pollutants.[3]

Parents, older and younger siblings, and children of a person with severe AATD should be evaluated to identify as early as possible those who would benefit from treatment and preventive measures.[3]

Management guidelines

  • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
  • Orphanet Emergency Guidelines is an article which is expert-authored and peer-reviewed that is intended to guide health care professionals in emergency situations involving this condition

FDA approved treatment medications for AATD

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

Alpha1-Proteinase Inhibitor (Human) (Brand name: Prolastin) - Manufactured by Grifols United States: FDA-approved indication: For chronic replacement therapy of individuals having congenital deficiency of alpha1- proteinase inhibitor with clinically demonstrable panacinar emphysema.

What's the prognosis and life expectancy for a person with AATD?

The prognosis of a genetic condition includes its likely course, duration, and outcome. When health professionals refer to the prognosis of a disease, they may also mean the chance of recovery; however, most genetic conditions are life-long and are managed rather than cured.

Disease prognosis has multiple aspects, including:

  • How long a person with the disorder is likely to live (life expectancy)
  • Whether the signs and symptoms worsen (and how quickly) or are stable over time
  • Quality of life, such as independence in daily activities
  • Potential for complications and associated health

The prognosis of a genetic condition depends on many factors, including the specific diagnosis and an individual's particular signs and symptoms. Sometimes the associated genetic change, if known, can also give clues to the prognosis. Additionally, the course and outcome of a condition depends on the availability and effectiveness of treatment and management approaches. The prognosis of very rare diseases can be difficult to predict because so few affected individuals have been identified. Prognosis may also be difficult or impossible to establish if a person's diagnosis is unknown.

The prognoses of genetic disorders vary widely, often even among people with the same condition. Some genetic disorders cause physical and developmental problems that are so severe they are incompatible with life. These conditions may cause a miscarriage of an affected embryo or fetus, or an affected infant may be stillborn or die shortly after birth. People with less severe genetic conditions may live into childhood or adulthood but have a shortened lifespan due to health problems related to their disorder. Genetic conditions with a milder course may be associated with a normal lifespan and few related health issues.

The prognosis of a disease is based on probability, which means that it is likely but not certain that the disorder will follow a particular course. Your healthcare provider is the best resource for information about the prognosis of your specific genetic condition. He or she can assess your medical history and signs and symptoms to give you the most accurate estimate of your prognosis.

Where can I find information about treatment for alpha-1 antitrypsin deficiency?

These resources address the management of alpha-1 antitrypsin deficiency and may include treatment providers.

  • Gene Review: Alpha-1-Antitrypsin Deficiency

SOURCES:

NIH; GARD. "Alpha-1 antitrypsin deficiency." Updated: Apr, 06, 2016.
<https://rarediseases.info.nih.gov/diseases/5784/alpha-1-antitrypsin-deficiency>

NIH; Genetics Home Reference. "alpha-1 antitrypsin deficiency." Updated: Jun 13, 2017.
<https://ghr.nlm.nih.gov/condition/alpha-1-antitrypsin-deficiency>

Last Editorial Review: 6/22/2017

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Reviewed on 6/22/2017
References
SOURCES:

NIH; GARD. "Alpha-1 antitrypsin deficiency." Updated: Apr, 06, 2016.
<https://rarediseases.info.nih.gov/diseases/5784/alpha-1-antitrypsin-deficiency>

NIH; Genetics Home Reference. "alpha-1 antitrypsin deficiency." Updated: Jun 13, 2017.
<https://ghr.nlm.nih.gov/condition/alpha-1-antitrypsin-deficiency>

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