Alpha-1 antitrypsin deficiency
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Alpha-1 antitrypsin deficiency (Alpha-1) is an inherited, genetic condition or disorder (not a disease by itself, but with a risk of developing lung or liver disease), characterized by a reduced blood level of a protein (due to abnormal AAT gene) called alpha-1 antitrypsin (also referred as AAT or alpha-1 proteinase inhibitor or aPi).
This disorder was first described in 1963. It is more common in Caucasians (whites) and rare in other races. Individuals with Alpha-1 antitrypsin deficiency are frequently referred to as ‘Alphas’.
The manifestation of the disorder ranges from a symptom-free life to a late-stage, life threatening lung or liver disease, needing transplant. The alpha-1 antitrypsin is produced in the liver. The gene abnormality may cause a defective AAT manufacture or release from the liver or poor functioning of the enzyme. The function of AAT is to protect the body tissues from damage by proteolytic enzymes (those that break down proteins), especially from neutrophil elastase.
In normal persons there is a balance between AAT and neutrophil elastase. In Alphas, this protection is significantly reduced because of low AAT levels, which leads to increased susceptibility of damage to certain organs (lungs, liver, skin and blood vessels).
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Incidence
The exact incidence is not known, but it is estimated to be 1 in 3000-5000 persons. This is mainly due the presence of carriers (who carry the abnormal gene but there is no disease development). Further, persons with a mild to moderate disorder are not diagnosed early because of lack of characteristic presentation of symptoms, and due to the late occurrence of symptoms (beyond 40 years of life). Lastly awareness about Alpha-1 among the public as well as medical community is poor.
Since only severely affected individuals are identified, the true incidence may be more than 100 millions (including the carriers). Both sexes are affected equally.
Mortality and morbidity
The exact morbidity and mortality rates are unknown. Since the enzyme deficiency is present from birth, depending upon whether an individual is homozygous or carrier, the manifestations may vary. About ¾ of deaths are due to involvement of lungs (emphysema) and about 1/10th die due to liver involvement.
Pathophysiology
The protein AAT is encoded by a gene (PI) located on the distal long arm of chromosome 14. The altered configuration of AAT leads to deficiency of the enzyme in the lung and excess (due to retention) in the liver, leading to damage of both the organs. Injury to the lungs, skin, and blood vessels appears to be related to the destruction of a protein known as "elastin."
The protein elastin renders the tissues with elastic property —to stretch and then return to their normal state. Skin, blood
vessels, and lungs are rich in elastin. The normal functioning of the lungs appears to be particularly dependent on the presence
of elastin. In individuals with AAT deficiency neutrophil elastase activity is unchecked. This leads to destruction of alveoli
and leads to a condition called emphysema. The elastic fibers of bronchial tubes (airways) also may be damaged leading to airway
obstruction, a condition called as bronchiectasis.
The mechanism of liver injury is poorly understood but believed to be due to accumulation of the abnormal AAT protein in the
liver cells. Even though there is an excess of ATT in liver since it is a defective enzyme it cannot counteract the effects of
proteases that cross the intestinal barrier. This causes liver injury leading to cirrhosis in all age groups (newborns, children,
or adults). There is also an increased risk of cirrhosis and liver cancer in male homozygotes of ATT deficiency.
Clinical features
AAT deficiency is a classic monogenic disorder that display marked variability in disease susceptibility.
At birth AAT deficiency can cause neonatal jaundice, though it is rare. In children it can cause cirrhosis of the liver or hepatic failure. Symptoms depend upon the target organ (usually lungs), the duration and associated aggravating factors.
Usually the symptoms are mainly limited to the lungs and that too in adults. There may be initially productive cough (cough with sputum), followed by wheeze and eventually dyspnea (difficulty in breathing) as the condition progresses. In short the physical manifestations are akin to many diseases like asthma, emphysema, bronchiectasis, chronic obstructive pulmonary disease (COPD) etc. Depending upon the severity of emphysema there is enhanced work to breathe, obstruction to the respiratory tract and hyperinflation of the lungs (due to alveolar damage), significant weight loss (pulmonary cachexia).
Smoking, respiratory infections, exposure to smoke, fumes or dust; all accelerate alveolar destruction (because of recruitment of neutrophils which in turn release elastase). Hence smokers get dyspnea about 10 years sooner than non-smokers, suffering from alpha.
Emphysematous changes involve primarily the lower lung fields
Diagnosis
There is no specific physical sign that is characteristic for diagnosis of alpha.
Tachypnea, retraction of respiratory muscles (due to difficult breathing), wheezing, barrel chest (due to hyperinflation), emphysematous percussion findings, muffled heart sounds are some of the signs that can be seen or elicited, that too in moderate to severe cases.
Chest X-ray, CT scanning of chest, spirometry (to estimate the FVC and FEV1), plethysmography (to estimate the lung volume) and lung biopsy may aid in the diagnosis.
The diagnosis can be confirmed by serum AAT estimation. The normal range for healthy individuals is 90-200 mg/dl, but it varies with labs. However, low levels of AAT (<80 mg/dl) have major clinical importance in association with emphysema and liver disease. Alpha 1 test kit can be used for case detection, but confirmation needs estimation of AAT level with phenotyping. The altered AAT protein is the product of a single gene, but the disease phenotype is probably a result of many genes. It is pertinent to note that phenotyping is necessary to initiate AAT enzyme replacement therapy.
In rare cases confirmation can be done by assessing the function of the patient’s enzyme (functional assay of AAT). Molecular diagnosis can be done by genotyping using mouth swab.
The usual liver function tests (LFT) should also be undertaken to evaluate the liver status.
Differential Diagnosis
Some of the important conditions that confound the diagnosis of alpha are
Emphysema (due to other causes, however, severe AAT deficiency is a proven genetic risk factor for emphysema)
COPD (however, severe AAT deficiency is a proven genetic risk factor for COPD)
Bronchitis (acute as well as chronic, especially the later)
Treatment
The main goal of therapy is to limit the progression of lung disease. Avoid or minimize proinflammatory stimuli- longevity of survival depends upon quitting smoking, prompt detection and treatment of respiratory infections and control of asthma.
Other aspects of treatment are aimed at symptomatic relief, bronchial antiinflammatory agents (similar to treating emphysema due to other causes). Drugs used for this purpose (these do not cure the condition) are inhaled bronchodilators (Beta 2 stimulants [albuterol], anticholinergics [ipratropium]; systemically, xanthines [theophylline] and antiinflammatory drugs (inhaled or systemic) like glucocorticoids (preferably for short term).
Oxygen may be needed in severe cases.
Specific treatment- Respiratory enzymes (like Prolastin, Aralast, Zemaira) obtained from pooled human plasma. These are alpha1-protease/proteinase inhibitors that can replace the deficient enzyme. This has to be given as intravenous infusion every week. This sort of therapy is called as ‘Augmentation therapy’. Though this mode of treatment improves the lung AAT level, it has not been conclusively shown to improve either the survival or the disease progression. However there is a report that the mortality rate is lower in those who receive replacement therapy. At this stage there are no clear guidelines regarding AAT replacement therapy.
Surgery
In selected cases of alpha, removal of the most severely affected lung (volume reduction) or lung transplantation, if feasible, may be undertaken.
General measures like protein rich food, antioxidants (vitamin A, E, C), specific exercises to improve exercise tolerance and involvement in rehabilitation programs including counseling.
Prognosis
The prognosis is poor in males, smokers and symptomatic cases.
Prevention
Population screening may identify cases early; genetic counseling may also minimize the incidence. Appropriate counseling of those diagnosed to avoid smoking, exposure to fumes, alcohol intake need not be emphasized.
Future
Production of human AAT by transgenic means in other animals (goats) or by recombinant DNA technology (yeast) is underway. Feasibility of administration of AAT by inhalation route is also under study. Gene therapy to switch off production of the abnormal gene, replacement of the specific missing molecules are also under way.
References
- Online Mendelian Inheritance in Man Accessed from http://www3.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=107400
- Alpha1-antitrypsin (AAT) deficiency
- Randox Laboratories
- DeMeo D L and Silverman E K. 1-Antitrypsin deficiency • 2: Genetic aspects of 1-antitrypsin deficiency: phenotypes and genetic modifiers of emphysema risk. Thorax 2004;59:259-264
Author
This is original article by Dr.Gurusamy Sivagnanam
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