Alpha 1-antitrypsin Deficiency
Disease Details
Family Health Simplified
- Description
- Alpha-1 antitrypsin deficiency is a genetic disorder that leads to decreased levels of the alpha-1 antitrypsin protein, resulting in lung disease and liver disease due to unregulated enzyme activity.
- Type
- Alpha-1 antitrypsin deficiency is a genetic disorder inherited in an autosomal codominant manner.
- Signs And Symptoms
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Individuals with A1AD may develop emphysema, or chronic obstructive pulmonary disease during their thirties or forties even without a history of smoking, though smoking greatly increases the risk. Symptoms may include shortness of breath (on exertion and later at rest), wheezing, and sputum production. Symptoms may resemble recurrent respiratory infections or asthma.A1AD may cause several manifestations associated with liver disease, which include impaired liver function and cirrhosis. In newborns, alpha-1 antitrypsin deficiency can result in early onset jaundice followed by prolonged jaundice. Between 3% and 5% of children with ZZ mutations develop life-threatening liver disease, including liver failure. A1AD is a leading reason for liver transplantation in newborns. In newborns and children, A1AD may cause jaundice, poor feeding, poor weight gain, hepatomegaly and splenomegaly.
Apart from COPD and chronic liver disease, α1-antitrypsin deficiency has been associated with necrotizing panniculitis (a skin condition) and with granulomatosis with polyangiitis in which inflammation of the blood vessels may affect a number of organs but predominantly the lungs and the kidneys. - Prognosis
- Alpha-1 antitrypsin deficiency can lead to several health complications, primarily affecting the lungs and liver. The prognosis varies greatly depending on the severity of the deficiency, lifestyle factors (such as smoking), and the presence of any related diseases. Individuals with severe deficiency are at increased risk for developing chronic obstructive pulmonary disease (COPD), emphysema, liver disease, and cirrhosis. Lifespan may be shortened, particularly if lung or liver disease progresses significantly. Regular medical follow-up, avoiding smoking, and early interventions are crucial for better outcomes. Personalized treatment and management plans can improve the quality of life for those affected.
- Onset
- Alpha-1 antitrypsin deficiency can have onset in infancy, childhood, or adulthood. Symptoms may vary widely with some individuals showing signs early in life, such as liver disease in infants and children, while others may not experience symptoms until adulthood, typically presenting with lung disease, such as emphysema.
- Prevalence
- Alpha-1 antitrypsin deficiency is a genetic disorder that occurs in 1 in 2,500 to 1 in 5,000 individuals of European descent. It is less common in people of African or Asian ancestry.
- Epidemiology
- People of Northern European and Iberian ancestry are at the highest risk for A1AD. Four percent of them carry the PiZ allele; between 1 in 625 and 1 in 2000 are homozygous.Another study detected a frequency of 1 in 1550 individuals. The highest prevalence of the PiZZ variant was recorded in the northern and western European countries with mean gene frequency of 0.0140. Worldwide, an estimated 1.1 million people have A1AT deficiency and roughly 116 million are carriers of mutations.A1AD is one of the most common genetic diseases worldwide and the second most common metabolic disease affecting the liver.
- Intractability
- Alpha-1 antitrypsin deficiency is considered a chronic and often progressive condition, but it is not entirely intractable. Treatments such as augmentation therapy, which involves infusions of alpha-1 antitrypsin protein, can help manage the symptoms and slow the progression of lung disease. Additionally, lifestyle changes, including avoiding smoking and reducing exposure to lung irritants, can significantly improve the quality of life for affected individuals. However, there is currently no cure for the underlying genetic condition.
- Disease Severity
- Alpha-1 antitrypsin deficiency is a genetic disorder that can lead to severe liver and lung disease. Severity varies widely among individuals. In the lungs, it can cause chronic obstructive pulmonary disease (COPD) and emphysema, often manifesting in early adulthood. In the liver, it can lead to cirrhosis and liver failure. Severity is influenced by environmental factors, such as smoking, which can exacerbate lung damage.
- Healthcare Professionals
- Disease Ontology ID - DOID:13372
- Pathophysiology
- A1AT is a glycoprotein mainly produced in the liver by hepatocytes, and, in some quantity, by enterocytes, monocytes, and macrophages. In a healthy lung, it functions as an inhibitor against neutrophil elastase, a neutral serine protease that controls lung elastolytic activity which stimulates mucus secretion and CXCL8 release from epithelial cells that perpetuate the inflammatory state. With A1AT deficiency, neutrophil elastase can disrupt elastin and components of the alveolar wall of the lung that may lead to emphysema, and hypersecretion of mucus that can develop into chronic bronchitis. Both conditions are the makeup of chronic obstructive pulmonary disease (COPD).Normal blood levels of alpha-1 antitrypsin may vary with analytical method but are typically around 1.0-2.7 g/L. In individuals with PiSS, PiMZ and PiSZ genotypes, blood levels of A1AT are reduced to between 40 and 60% of normal levels; this is usually sufficient to protect the lungs from the effects of elastase in people who do not smoke. However, in individuals with the PiZZ genotype, A1AT levels are less than 15% of normal, and they are likely to develop panlobular emphysema at a young age. Cigarette smoke is especially harmful to individuals with A1AD. In addition to increasing the inflammatory reaction in the airways, cigarette smoke directly inactivates alpha-1 antitrypsin by oxidizing essential methionine residues to sulfoxide forms, decreasing the enzyme activity by a factor of 2,000.With A1AT deficiency, the pathogenesis of the lung disease is different from that of the liver disease, which is caused by the accumulation of abnormal A1AT proteins in the liver, resulting in liver damage. As such, lung disease and liver disease of A1AT deficiency appear unrelated, and the presence of one does not appear to predict the presence of the other. Between 10 and 15% of people with the PiZZ genotype will develop liver fibrosis or liver cirrhosis, because the A1AT is not secreted properly and therefore accumulates in the liver. The mutant Z form of A1AT protein undergoes inefficient protein folding (a physical process where a protein chain achieves its final conformation). 85 percent of the mutant Z form are unable to be secreted and remain in the hepatocyte. Nearly all liver disease caused by A1AT is due to the PiZZ genotype, although other genotypes involving different combinations of mutated alleles (compound heterozygotes) may also result in liver disease. A liver biopsy in such cases will reveal PAS-positive, diastase-resistant inclusions within hepatocytes. Unlike glycogen and other mucins which are diastase sensitive (i.e., diastase treatment disables PAS staining), A1AT deficient hepatocytes will stain with PAS even after diastase treatment
- Carrier Status
- Carrier status for alpha-1 antitrypsin deficiency involves having one normal allele and one deficient allele of the SERPINA1 gene. Carriers typically do not show symptoms but can pass the deficient allele to their offspring, potentially causing the condition if the other parent is also a carrier or affected.
- Mechanism
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Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder resulting from mutations in the SERPINA1 gene, which encodes the alpha-1-antitrypsin (AAT) protein. The key mechanisms and molecular aspects include:
1. **Mechanism**:
- **Protease Inhibition**: AAT is a serine protease inhibitor (serpin) that primarily protects tissues, especially the lungs, from enzyme damage by inhibiting neutrophil elastase.
- **Imbalance**: Deficiency in functional AAT leads to uncontrolled activity of neutrophil elastase, resulting in tissue damage, particularly in the lungs and liver.
2. **Molecular Mechanisms**:
- **Gene Mutations**: The most common mutations are the Z (Glu342Lys) and S (Glu264Val) alleles. The Z allele results in misfolded AAT proteins, which aggregate within the endoplasmic reticulum of hepatocytes, leading to reduced secretion and AAT plasma levels.
- **Hepatocellular Damage**: Misfolded AAT aggregates can cause liver damage, leading to conditions such as neonatal hepatitis, cirrhosis, and hepatocellular carcinoma.
- **Loss of Function**: The deficiency of functional AAT in the lungs leads to increased vulnerability to environmental factors like cigarette smoke and infections, causing chronic obstructive pulmonary disease (COPD) and emphysema.
Understanding these mechanisms provides insight into the clinical manifestations and potential therapeutic approaches for managing AATD. - Treatment
- Treatment of lung disease may include bronchodilators, inhaled steroids, and, when infections occur, antibiotics. Intravenous infusions of the A1AT protein or in severe disease lung transplantation may also be recommended. In those with severe liver disease liver transplantation may be an option. Avoiding smoking and getting vaccinated for influenza, pneumococcus, and hepatitis is also recommended.People with lung disease due to A1AD may receive intravenous infusions of alpha-1 antitrypsin, derived from donated human plasma. This augmentation therapy is thought to arrest the course of the disease and halt any further damage to the lungs. Long-term studies of the effectiveness of A1AT replacement therapy are not available. It is currently recommended that patients begin augmentation therapy only after the onset of emphysema symptoms. As of 2015 there were four IV augmentation therapy manufacturers in the United States, Canada, and several European countries. IV therapies are the standard mode of augmentation therapy delivery.Liver disease due to A1AD does not include any specific treatment, beyond routine care for chronic liver disease. However, the presence of cirrhosis affects treatment is several ways. Individuals with cirrhosis and portal hypertension should avoid contact sports to minimize the risk of splenic injury. All people with A1AD and cirrhosis should be screened for esophageal varices, and should avoid all alcohol consumption. Nonsteroidal antiinflammatory drugs (NSAIDs) should also be avoided, as these medications may worsen liver disease in general, and may particularly accelerate the liver injury associated with A1AD. Augmentation therapy is not appropriate for people with liver disease. If progressive liver failure or decompensated cirrhosis develop, then liver transplantation may be necessary.
- Compassionate Use Treatment
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For Alpha-1 Antitrypsin Deficiency (AATD), the following treatments may fall under compassionate use, off-label, or experimental categories:
1. **Compassionate Use Treatment**:
- **Alpha-1 Antitrypsin Augmentation Therapy**: This is often provided under compassionate use for patients with severe AATD who have not responded to standard treatment protocols. It involves intravenous infusion of alpha-1 antitrypsin protein derived from human plasma.
2. **Off-label Treatments**:
- **Inhaled Corticosteroids**: While primarily used for asthma or chronic obstructive pulmonary disease (COPD), they might be prescribed off-label to manage lung inflammation in AATD patients.
- **Macrolide Antibiotics (e.g., Azithromycin)**: Sometimes used off-label for their anti-inflammatory properties in patients with frequent exacerbations of lung disease.
3. **Experimental Treatments**:
- **Gene Therapy**: Researchers are exploring the potential of gene therapy to insert functional copies of the SERPINA1 gene (which encodes alpha-1 antitrypsin) into patients’ cells.
- **RNA Interference (RNAi)**: Investigational therapies aim to reduce the production of mutant alpha-1 antitrypsin protein that can accumulate and cause liver damage.
- **CRISPR/Cas9 Gene Editing**: Preclinical studies are investigating the use of CRISPR technology to correct the genetic mutation that causes AATD.
These treatments are typically part of clinical trials and may not be widely available outside of these controlled settings. - Lifestyle Recommendations
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For individuals with alpha-1 antitrypsin deficiency:
1. **Avoid Smoking**: Cigarette smoke can accelerate lung damage in individuals with this condition.
2. **Minimize Alcohol Consumption**: Alcohol can affect liver health, which is critical for those with alpha-1 antitrypsin deficiency.
3. **Maintain a Healthy Diet**: A balanced diet supports overall health and provides essential nutrients.
4. **Regular Exercise**: Exercise can improve lung function and overall health, but should be done under medical advice.
5. **Infection Prevention**: Practice good hygiene, get vaccinated for flu and pneumonia, and avoid people who are sick to reduce the risk of respiratory infections.
6. **Regular Medical Checkups**: Monitor lung and liver function regularly with a healthcare provider.
7. **Environmental Controls**: Avoid pollutants and occupational hazards such as dust and chemical fumes.
8. **Stress Management**: Techniques like yoga, meditation, or deep-breathing exercises can be beneficial.
It is crucial to follow these recommendations and work closely with healthcare providers to manage the condition effectively. - Medication
- Medications for Alpha-1 Antitrypsin Deficiency often involve augmentation therapy with alpha-1 proteinase inhibitor (A1PI) to raise the levels of the protein in the blood and lungs. Other treatments may include bronchodilators and corticosteroids to manage symptoms related to lung disease.
- Repurposable Drugs
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Alpha-1 antitrypsin deficiency is a genetic disorder that can lead to lung and liver disease. Some repurposed drugs that have shown potential in treating this condition include:
1. **Alpha-1 antitrypsin augmentation therapy**: Currently approved therapies that infuse purified human A1AT protein have been repurposed for those with lung disease.
2. **Pirfenidone**: An antifibrotic agent originally approved for idiopathic pulmonary fibrosis, showing potential in reducing lung fibrosis in A1AT deficiency.
3. **N-Acetylcysteine (NAC)**: An antioxidant that helps reduce oxidative stress and inflammation in the lungs.
4. **Liver Transplantation and Management Drugs**: For severe liver disease cases, general liver management medications might be required as part of the therapy.
These treatments aim to manage symptoms and slow the progression of the disease rather than cure it. - Metabolites
- For alpha-1 antitrypsin deficiency, the specific metabolite to be aware of is alpha-1 antitrypsin (A1AT) itself. This protein is produced in the liver and protects the lungs from neutrophil elastase, an enzyme that can damage lung tissue. Deficiency in A1AT can lead to uncontrolled enzyme activity, causing lung diseases like emphysema and liver diseases due to the accumulation of the misfolded protein in hepatocytes. There are no significant other metabolites directly linked to the pathogenesis of the deficiency.
- Nutraceuticals
- Nutraceuticals, which are food or dietary supplements with potential health benefits beyond basic nutrition, do not have established, clinically proven effects in the management of alpha-1 antitrypsin deficiency (AATD). Management of AATD typically involves lifestyle modifications, pulmonary rehabilitation, and medical treatments like augmentation therapy. It's always important to consult healthcare providers before taking any new supplements.
- Peptides
- Alpha-1-antitrypsin deficiency is a genetic disorder that results in reduced levels of alpha-1 antitrypsin (AAT), a protein that protects tissues from enzyme damage. Peptides related to this condition involve the AAT protein itself, which consists of 394 amino acids. Mutations in the SERPINA1 gene lead to dysfunctional AAT peptides, compromising their ability to inhibit neutrophil elastase and other proteolytic enzymes. This deficiency primarily affects the lungs and liver, potentially causing chronic obstructive pulmonary disease (COPD) and liver disease. Treatments can include AAT augmentation therapy, which introduces functional AAT protein into the bloodstream to mitigate the disease's effects.