Understanding Alpha-1 Antitrypsin Deficiency: causes and impact on lung, liver, and skin

Alpha-1 Antitrypsin Deficiency (AATD), also known as Alpha-1, is a genetic condition that can lead to lung, liver, and skin diseases. It occurs when there is a lack of a protein called Alpha-1 Antitrypsin (AAT) in the bloodstream. AAT, primarily produced by the liver, protects the body’s tissues, especially the lungs, from inflammation caused by infections and inhaled irritants. Reduced levels of AAT in the bloodstream result from abnormal AAT accumulation in the liver, leading to both liver disease and lung disease. Skin disease, known as panniculitis, can also develop. Diagnosis involves blood tests for AAT levels and phenotyping to identify gene mutations.

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What is Alpha-1 Antitrypsin Deficiency?

Alpha-1 Antitrypsin Deficiency, also known as Alpha-1, is a genetic condition that may result in lung, liver, and/or skin disease. Alpha-1 is caused by a lack of a protein called Alpha-1 Antitrypsin (AAT) in the bloodstream. AAT is primarily produced by the liver and protects tissues in the body during infections, especially the lungs from inflammation originating from infection and inhaled irritants, such as tobacco smoke. Decreased AAT in the bloodstream results from abnormal AAT that cannot be expelled from the liver at a normal rate. A build-up of abnormal AAT then occurs in the liver, causing both liver disease and reduced AAT levels in the bloodstream, which can lead to lung disease. Levels of AAT can be measured through a blood test.  A definitive diagnosis of Alpha-1 can only be confirmed through phenotyping.  Phenotyping will identify the two inherited genes and will indicate the level of deficiency.  Skin disease related to Alpha-1, called panniculitis, can also develop when protein breakdowns within the skin, leading to the development of plaques and nodules; this can be diagnosed through a skin biopsy.

What are the symptoms of Alpha-1 Antitrypsin Deficiency?

Symptoms related to the lung

  • Shortness of breath
  • Wheezing
  • Chronic bronchitis, which is cough and sputum (phlegm) production that lasts for a long time
  • Recurring chest colds
  • Less exercise tolerance
  • Year-round allergies
  • Bronchiectasis

Symptoms related to the liver

  • Unexplained liver disease or elevated liver enzymes
  • Eyes and skin turning yellow (jaundice)
  • Swelling of the abdomen (ascites) or legs

Symptoms related to the skin

  • Erythematous plaques and nodules on the skin
  • Nodules may be on the skin of the legs, arms, trunk, or face
  • Nodules may ulcerate, bleed, and leak oily material
  • Fever

How do you get Alpha-1 Antitrypsin Deficiency?

Everyone inherits two SERPINA1 genes that control the way AAT is generated, one from each parent. Within the SERPINA1 gene, the allele responsible for producing AAT can exist in over 100 forms, however, the two most common deficient alleles are labeled “Z” and “S”. When the allele is acting in a normal way it is labeled “M”.

M + Z allele combination

Because everyone inherits two genes, there are generally three possible combinations of these genes: MM, MZ or ZZ. These combinations are called genotypes.

  • MM: Individuals with two M alleles have a normal level of AAT in their blood. It’s estimated that 90-95% of the population have the MM genotype.
  • MZ: Individuals with one M allele and one Z allele will have a lower-than-normal level of AAT in their blood. Usually, the level isn’t low enough to cause major problems, however, these individuals may be more susceptible to lung disease if they smoke. Individuals with MZ genotype are “carrier” of the AATD gene – this means you can pass the affected gene on to your children.
  • ZZ: Individuals with two Z alleles will most severely manifest AATD. These individuals have a very low level of AAT in their blood – only 10%-20% of what it should be.

S + Z allele combination

The S allele causes a low AAT level when combined with the Z allele (SZ genotype) and results in a milder form of AATD. For these individuals, there is a lower risk of lung disease compared to ZZ patients, and smoking is the major risk factor for developing lung problems.

How common is Alpha-1 Antitrypsin Deficiency?

Alpha-1 is one of the most common genetic disorders among those with European ancestry, but it’s uncommon in people of non-European descent. One in 25 people of European descent have at least one abnormal copy of the gene for Alpha-1.

Who should be tested for Alpha-1 Antitrypsin Deficiency?

  • Everyone with emphysema, chronic obstructive pulmonary disease (COPD), or chronic bronchitis
  • People with bronchiectasis
  • Newborns or children and adults with unexplained liver disease
  • Blood relatives of a person diagnosed with Alpha-1
  • Anyone with panniculitis

On average, it takes 7 years for an alpha to learn the true cause behind his symptoms. By then, he has usually seen 5 doctors for his related health problems.

Medical disclaimer

The information provided should not be used for diagnosing or treating a health problem or disease. Always seek the guidance of your doctor or other qualified health professional with any questions you may have regarding your health or a medical condition.

Sources and further reading

European Alpha-1 Research Collaboration (EARCO) and European Lung Foundation (ELF) Factsheet
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European Respiratory Society Statement on Diagnosis and Treatment of Pulmonary Disease in AATD
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Cleveland Clinic Alpha-1 antitrypsin deficiency: Causes, symptoms & treatment
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