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Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder where the body produces low levels or defective forms of alpha-1 antitrypsin (AAT), a protein that helps protect tissues from enzyme damage. AAT is primarily produced in the liver and plays a key role in protecting the lungs from damage caused by enzymes, particularly neutrophil elastase, which can break down lung tissue.
Without enough functional AAT, the lungs are left vulnerable to damage, leading to conditions like chronic obstructive pulmonary disease (COPD), emphysema, and bronchiectasis. Additionally, the abnormal protein can accumulate in the liver, causing liver disease, cirrhosis, or even liver cancer.Â
AATD is a rare condition but is one of the most common genetic causes of liver and lung disease. Symptoms may include shortness of breath, wheezing, chronic cough, and unexplained liver problems. While there is no cure, treatment focuses on managing symptoms and preventing further lung and liver damage.
AATD is a genetic condition that is inherited in an autosomal co-dominant pattern.Â
Co-dominant inheritance is when both versions (alleles) of a gene are equally present in a person. A common example is blood type, where individuals with both A and B alleles will have an AB blood type, expressing both A and B antigens on their red blood cells. And autosomal means that the inheritance is not sex-dependent.
In AATD a person must inherit two abnormal copies of the SERPINA1 gene. One from each parent, to develop the full disease. If only one abnormal gene version is inherited, the person is considered a carrier and may have lower levels of AAT but typically does not develop significant symptoms.Â
The SERPINA1 gene provides instructions for making Alpha-1-antitrypsin (AAT). AAT is a serine protease inhibitor and it helps protect the lungs from damage caused by certain enzymes (proteins that speed up biochemical reactions), especially the neutrophil elastase. Neutrophil elastase is an enzyme produced by neutrophils, a type of white blood cell that helps fight infections.
This enzyme helps clear infections and repair tissues by breaking down proteins in bacteria and damaged tissue during inflammation. However, if not properly regulated, neutrophil elastase can also damage healthy tissues, particularly in the lungs. AAT is primarily produced in the liver and then released into the bloodstream to prevent excessive damage by neutrophil elastase.Â
Variations in the SERPINA1 gene can lead to AATD. The main genetic mutations in the SERPINA1 gene that cause AATD are the so-called Z-allele (p.Glu342Lys) and the S-allele (p.Glu264Val).Â
The Z-allele is the most severe variant, leading to the accumulation of defective AAT in the liver. Defective AAT refers to an improperly folded AAT protein. Proteins need to be folded into their proper form in order for them to be functional. Instead of being properly folded and secreted into the bloodstream to protect the lungs, these defective AAT proteins form long chains or polymers.
These polymers accumulate in the liver, contributing to liver damage, and some can be released into the bloodstream. Once in circulation, they do not function correctly, reducing protection against enzymes like neutrophil elastase in the lungs.Â
The S-allele causes a milder deficiency, but when combined with the Z allele (SZ genotype), it can still lead to moderate risk for lung disease. There are also rare mutations, such as null alleles, which result in no AAT production, and other deficiency alleles that cause abnormal AAT proteins. Together, these genetic variations disrupt AAT’s ability to protect tissues from enzyme damage ,particularly in the lungs.Â
The M-allele is the normal version of the SERPINA1 gene, responsible for producing the proper amount of functional AAT. Individuals with two copies of the M-allele have normal levels of AAT in their bloodstream, which helps protect the lungs from damage caused by enzymes like the neutrophil elastase.
An early study analyzed 1399 individuals from the Swiss Cohort Study on Air Pollution and Lung Diseases (SAPALDIA), sequencing exons 2 to 5 of SERPINA1 in 423 samples. Results showed that 64% had the normal MM genotype, while 36% carried at least one deficiency variant. The study revealed varying prevalence of genotypes in different AAT concentration ranges, with MS and MZ genotypes being more common in lower AAT levels. This research provides valuable information for diagnosing intermediate AAT deficiency.
A study published in February this year (2024) aimed to quantify circulating polymers (CP) in individuals with different SERPINA1 genotypes. Results showed elevated CP levels in patients with SZ and ZZ genotypes, with variability among individuals. CP levels were also higher in carriers of other rare AAT variants. These findings suggest CP measurement could help assess the severity of lung and liver diseases and identify the polymer-forming potential of rare AAT variants.
AATD is diagnosed through a combination of clinical evaluation, blood tests, and genetic testing. If a doctor suspects AATD based on symptoms like unexplained lung or liver disease, they will first order a blood test to measure the levels of AAT in the bloodstream.Â
Low AAT levels may indicate a deficiency. If the levels are abnormal, further testing is done to identify the specific mutations in the SERPINA1 gene that cause AATD. Genetic testing can confirm the diagnosis by detecting these mutations.Â
Additionally, liver function tests, chest X-rays, or CT scans may be used to assess the extent of lung or liver damage caused by the condition. In some cases, a liver biopsy may be performed to check for abnormal protein buildup in the liver. Early diagnosis is important to help manage the condition and prevent further organ damage.
There is currently no cure for AATD, but treatments are available to manage the symptoms and prevent further damage to the lungs and liver. One of the main treatments for AATD-related lung disease is augmentation therapy, where individuals receive intravenous infusions of alpha-1 antitrypsin to raise the protein levels in their blood and help protect the lungs from damage.Â
Other treatments focus on managing the symptoms of lung disease, such as bronchodilators, inhaled steroids, and supplemental oxygen. For individuals with advanced liver disease or cirrhosis due to AATD, a liver transplant may be considered as a treatment option.Â
Additionally, lifestyle changes, such as quitting smoking and avoiding environmental pollutants, are crucial for slowing the progression of lung damage. While AATD cannot be cured, early diagnosis and proper management can significantly improve the quality of life for affected individuals.
A 2018 research paper elucidated a potential new treatment approach for AATD involving mRNA therapy targeting both the liver and lungs. Researchers transfected AAT patient fibroblasts (cells found in connective tissue that produce collagen and other fibers) and derived liver cells with SERPINA1-encoding mRNA.
They observed increased SerpinA1 protein expression in those cells. In animal studies, mRNA biodistribution and SerpinA1 expression were detected in the liver and lungs, the two primary organs affected by AAT deficiency. These findings suggest that SerpinA1 mRNA therapy could offer a promising treatment for AAT deficiency.
AATD is not an autoimmune disease. In autoimmune conditions, the immune system mistakenly attacks the body’s own tissues. The inflammation and tissue damage caused by the AAT deficiency can lead to chronic lung diseases like emphysema and chronic obstructive pulmonary disease (COPD), as well as liver disease. In some cases, the immune system’s response to ongoing tissue damage can complicate the condition, but the root cause of AATD is genetic, not autoimmune.
AATD can contribute to liver issues, including fatty liver disease, which occurs when excess fat builds up in the liver. In AATD, abnormal AAT proteins can accumulate in the liver, causing inflammation and damage to liver cells. Over time, this can lead to various liver conditions, including fatty liver, fibrosis, cirrhosis, and in severe cases, liver failure. Fatty liver disease associated with AATD can be a cause of steatohepatitis, a condition where fat buildup in the liver is accompanied by inflammation.Â
Not all individuals with AATD will develop liver problems, but those with severe mutations in the SERPINA1 gene are at a higher risk. Managing AATD through regular monitoring and lifestyle changes, such as maintaining a healthy diet and avoiding alcohol, can help reduce the risk of fatty liver and other liver-related complications.
AATD is a genetic disorder caused by mutations in the SERPINA1 gene, leading to low or defective AAT protein levels. AAT protects the lungs from damage caused by enzymes like neutrophil elastase, but insufficient levels can result in lung diseases such as emphysema, COPD, and bronchiectasis.
Additionally, defective AAT proteins may accumulate in the liver, causing liver damage, cirrhosis, or even liver cancer. The Z and S alleles of SERPINA1 are the primary genetic variants linked to AATD, with Z being the most severe. Research indicates that the presence of CP of AAT may serve as a biomarker for disease severity, particularly in individuals with the SZ and ZZ genotypes.
AATD is inherited in an autosomal co-dominant pattern, and individuals must inherit two defective copies of SERPINA1 to develop the full disease. Diagnosis involves blood tests to measure AAT levels and genetic testing to identify specific mutations. While there is no cure, treatments like augmentation therapy can manage symptoms and prevent further lung damage.
Liver transplants may be necessary for severe liver disease, and mRNA therapy holds promise as a potential treatment. Although AATD is not an autoimmune disease, it can lead to inflammation of liver and lung tissues due to the buildup of abnormal AAT proteins.
