Alpha-1 antitrypsin deficiency (A1AD) is a clinically under-recognized hereditary genetic disorder that causes the defective production of alpha-1 antitrypsin protein and AAT protein protects the body from the neutrophil elastase enzyme, which is released from white blood cells to fight infection called alpha-1 antitrypsin (A1AT) which is found in the blood. This deficiency may predispose an individual to several illnesses and most commonly manifests as a chronic obstructive pulmonary disease (including bronchiectasis) and liver disease (especially cirrhosis and hepatoma), or more rarely, as a skin condition called panniculitis. A1AD is also more frequent among individuals with Wegener’s granulomatosis, now called polyangiitis with granulomatosis. A deficiency of A1AT allows substances that break down proteins (so-called proteolytic enzymes) to attack various tissues of the body. The attack results in destructive changes in the lungs (emphysema) and may also affect the liver and skin. Alpha-1 antitrypsin is ordinarily released by specialized, granules within a type of white blood cells (called neutrophils or polymorphonuclear leukocytes) in response to infection or inflammation. The deficiency of alpha-1 antitrypsin results in unbalanced (i.e., relatively unopposed) rapid breakdown of proteins (protease activity), especially in the supporting elastic structures of the lungs. Over years, this destruction can lead to progressive emphysema and is accelerated by smoking, some occupational exposures, and likely by other genetic modifiers of this risk which remain incompletely understood.
Causes
A1AT is caused by mutations in the SERPINA1 gene that is responsible for the production of the alpha-1 antitrypsin protein. Normally, this protein is produced in the liver and released in the blood and functions to protect the body from the neutrophil elastase enzyme. A1AT also appears to have anti-inflammatory effects independent of its anti-neutrophil elastase activity. Mutations in the SERPINA1 gene result in the production of an abnormal protein that gets trapped in the liver, resulting in low serum levels of A1AT that can predispose to lung breakdown by neutrophil elastase and other proteolytic enzymes (enzymes that break down proteins). In addition, abnormal A1AT protein can accumulate in the liver and cause scarring damage. Over 150 different mutations in the SERPINA1 gene have been identified to date, with the most common termed S and Z, whereas the normal version (allele) of the gene is termed M. The S allele causes serum levels of A1AT to be moderately low and the Z allele is associated with very low A1AT levels in the serum (~10-15% of normal). Other rare variants, called null, are associated with the complete absence of A1AT in the bloodstream because no protein is produced.
A1AT is inherited as an autosomal co-dominant genetic condition. Co-dominant genetic disorders occur when each inherited allele expresses some effect (like a lowered serum level of A1AT). In general, in a co-dominant condition, when the individual inherits two copies of an abnormal gene for the same trait, one from each parent, the risk of disease is higher than when only one abnormal allele is inherited. People who have two copies of the Z allele (ZZ) have severe deficiency of A1AT and are at high risk of developing emphysema. The risk for two carrier parents to both pass the altered gene and to have an affected (ZZ) child is 25% with each pregnancy, and in this circumstance, the risk to have a child who is a carrier like the parents is 50% with each pregnancy. Finally, the chance for a child to receive normal genes from both parents is 25%. In autosomal conditions, the inheritance risk is the same for males and females because the abnormal gene does not reside on the sex chromosomes (X or Y). In A1AT, the SERPIN1A gene resides on the long arm of the 14th chromosome.
If an individual receives one normal allele and one Z allele (MZ), the clinical risk of developing lung disease is considered to be small, though there may be a subset of these so-called heterozygous patients who are at higher risk, especially if they smoke. If an individual receives one S allele and one Z allele (SZ), they are also considered to be at increased risk to develop the chronic obstructive pulmonary disease if they smoke.
At least 150 alleles of AAT (SERPINA1) have been identified, and each has a letter code based upon electrophoretic mobility of the protein produced. The normal allele is referred to as “M,” and it is the most common version (allele) of the SERPINA1 gene. Most people in the general population have two copies of the M allele (MM) in each cell. Other versions of the SERPINA1 gene lead to reduced levels of alpha-1 antitrypsin. For instance, the S allele produces moderately low levels of this protein, and the Z allele produces very little AAT. Individuals with two copies of the Z allele (ZZ) in each cell are likely to have AAT deficiency. Those with the SZ combination have a higher risk of developing lung diseases (such as emphysema), particularly if they smoke.
Worldwide, it is estimated that 161 million people have one copy of the S or Z allele and one copy of the M allele in each cell (MS or MZ). Individuals with an MS (or SS) combination usually produce enough alpha-1 antitrypsin to protect their lungs. People with MZ alleles have a slightly increased risk of impaired lung or liver function.
AAT phenotypes are based on the electrophoretic mobility of the proteins produced by the various abnormal AAT alleles. Genotyping is performed by identifying specific alleles in DNA.
Based on this, variants of AAT can be categorized into four basic groups:
- Normal that is associated with normal levels of AAT and normal function. The family of normal alleles is referred to as M, and the normal genotype is MM.
- Deficient that is associated with plasma AAT levels less than 35% of the average normal level. The most common deficient allele associated with emphysema is the Z allele, which is carried by about two to three percent of the Caucasian population in the United States.
- Null alleles that lead to no detectable AAT protein in the plasma. Individuals with the null genotype are the least common and are at risk for the most severe form of associated lung disease but not liver disease.
- Dysfunctional alleles produce a normal quantity of AAT protein, but the protein does not function properly.
Environmental factors, such as exposure to tobacco smoke, chemicals, and dust, likely impact the severity of alpha-1 antitrypsin deficiency.
Severe deficiency of AAT has a strong risk factor for early-onset emphysema, but not every severely deficient individual would develop emphysema. Risk factors for emphysema include cigarette smoking, dusty occupational exposure, parental history of chronic obstructive pulmonary disease (COPD), and a personal history of asthma, chronic bronchitis, or pneumonia.
Diagnosis
The diagnosis of A1AD is based on a low concentration of A1AT blood plasma in combination with a high-risk phenotype (demonstrated by isoelectric focusing) or genotype (by specific allele analysis [usually for the Z and S alleles and sometimes for additional alleles like the F and I alleles and some others on commercial tests]). In some instances, further testing to sequence the A1AT gene is needed to establish a firm diagnosis (i.e., mapping all the chemical elements [called nucleotides] that make up the A1AT gene).
Because A1AD often goes unrecognized, official guideline documents recommend that all individuals with fixed airflow obstruction on spirometry testing should be tested for the disorder. Also, all first-degree relatives of individuals found to have severe A1AD (i.e., siblings, children, and parents), individuals with panniculitis, and individuals with unexplained liver disease or bronchiectasis should be tested.
This disorder may be suspected when emphysema occurs in a young person, a nonsmoker, or someone with a family history of emphysema. A1AD should also be suspected in individuals with jaundice, hepatitis, portal hypertension, hepatocellular carcinoma, or someone with a family history of liver disease. As noted above, however, under-recognition may result from testing only a minority of at-risk individuals; thus, as noted above, recommendations for testing suggest that all adults with symptomatic COPD, along with other groups cited above, should be tested for A1AD.
Imaging: A chest x-ray is used to determine the pattern and extent of emphysema and exclude other causes of dyspnea. The “classic” pattern of emphysema in AAT deficiency is basilar predominant emphysematous bullae, although a range of patterns from basilar predominant to apical predominant emphysema may be seen. Some clinicians perform chest computed tomography (CT) scans for an initial assessment.[rx][rx]
- Bronchodilator responsiveness (defined as a post-bronchodilator forced expiratory volume in one second [FEV1] rise of 200 mL and 12%) is common.
- Pulmonary function testing is used to assess the presence and severity of lung disease. Spirometry is typically obtained before and after bronchodilator, lung volumes, and diffusing capacity for carbon monoxide (DLCO). If DLCO is below normal or if the patient reports exertional dyspnea, a six-minute walk test should be obtained.
- All adults with persistent airflow obstruction on spirometry should be tested for AAT deficiency, mainly those from geographic areas with a high prevalence of AAT deficiency.
Additional features that should lead clinicians to test for AAT deficiency include:
- Emphysema in a young individual (e.g., age 45 years or younger).
- Emphysema in a person who does not smoke or smokes minimally
- Emphysema characterized by predominant basilar changes on the chest radiograph.
- A family history of emphysema or liver disease. Clinical findings or history of panniculitis
- Clinical findings or history of unexplained chronic liver disease.
The diagnosis of severe AAT deficiency is confirmed by demonstrating a serum level below 11 micromols/L (approximately 57 mg/dL by nephelometry) in combination with a severe deficient phenotype assessed by testing for the most common deficient alleles (i.e., S, Z, I, F).
If the AAT serum level is greater than 20 micromol/L, it is unlikely that the patient has a clinically significant AAT deficiency, but if we are evaluating for the presence of particular mutations, genotyping is necessary to identify heterozygotes and mutations that have incomplete penetrance.
The normal plasma concentration of AAT ranges from 80 mg/dL to 220 mg/dL (20 to 48 micromol/L using nephelometry or 150 mg/dL to 350 mg/dL by radial immunodiffusion). However, given the variability in reference ranges, patients with a serum AAT level below 100 mg/dL (18.4 micromols/L) should be evaluated further with isoelectric focusing or genotyping.
Isoelectric focusing is the gold standard blood test for identifying AAT variants and is considered a phenotype test.
Genotyping of the protease inhibitor (Pi) locus is performed on a blood sample using polymerase chain reaction (PCR) technology or restriction fragment length polymorphisms. These tests detect the most common known variants (F, I, S, Z). Gene sequencing of exonic DNA can be used if both tests fail to determine the genetic variant.
Once clinical suspicion of panniculitis is aroused by a suggestive history and physical examination, the diagnosis of panniculitis is made by biopsy specimens of the skin lesions and blood tests to determine the level of circulating A1AT and the genotype.
Treatment
Treatments for emphysema associated with A1AD include standard medications used in managing patients with emphysema of all causes (such as inhaled bronchodilators, inhaled steroids, anticholinergics, oxygen therapy, and the administration of antibiotics or phosphodiesterase 5 inhibitors for the frequent respiratory infections) as well as (in specific subgroups) specific A1AT treatment called augmentation therapy. Exercise programs (pulmonary rehabilitation) and good nutrition may help increase the overall quality of daily living. People with emphysema must avoid smoking, employment that exposes the patient to lung irritants, and the use of non-medical aerosol sprays. Preventing infection as possible with yearly influenza and periodic pneumococcal vaccinations is also recommended.
Specific treatment of A1AD (for individuals with established emphysema) may also involve the use of augmentation therapy, which is the regular (usually once weekly), long-term infusion into the veins of deficient individuals of purified, pooled human plasma-derived A1AT. Currently, six drugs for augmentation therapy have received approval by the U.S. Food and Drug Administration: Prolastin, Aralast, Aralast NP, Zemaira, Prolastin-C, and Glass, of which the latter four are currently available. The best available evidence suggests that augmentation therapy may help slow the progression of lung damage due to A1AD. Augmentation therapy does not treat A1AD-related liver disease.
Lung volume reduction surgery (LVRS) or the surgical removal of large confluent areas of emphysema (bullae) may be appropriate in highly selected patients, though LVRS may confer less benefit to individuals with emphysema due to A1AD than to individuals with emphysema, not due to recognized genetic causes. As such, LVRS is rarely recommended for patients with A1AD.
Lung transplantation, single and double, has been performed successfully on many A1AD patients. This treatment option is performed only on patients with end-stage severe lung disease who otherwise qualify as candidates for such surgery.
No specific therapy is available for the liver disease associated with A1AD, though animal studies have shown promise for several drugs that can increase the liver’s ability to break down unsecreted A1AT (e.g., rapamycin and carbamazepine) and have prompted research studies on A1AD individuals. Similarly, other approaches currently under investigation regard agents that will decrease the production of the abnormal Z protein by liver cells, which could conceivably lessen the liver risk, though of course much more study is needed before any conclusion can be offered regarding these currently research-based approaches. Currently, management of A1AD-associated liver disease is directed at controlling symptoms. Special procedures may become necessary for some people with liver disease associated with A1AD. For example, shunts may be inserted to lower the pressure within the blood vessels in the liver, and dilated veins in the food tube (esophagus) may be clipped or banded to lower the risk of bleeding. Liver transplantation may be recommended for individuals with end-stage liver disease. Transplantation of a normal liver into an individual with A1AD should correct the liver abnormalities and restore the blood levels of A1AT to normal. At the same time, transplantation carries some risks related to the procedure itself and to the suppressed immunity from drugs taken to prevent rejection of the transplanted organ.
Genetic counseling is recommended for patients and their families.
Investigational Therapies
Promising prospects include gene therapy (by intramuscular or intrapleural injection of a virus carrying the normal human A1AT gene), administration of augmentation therapy by inhalation, modified approaches to intravenous augmentation therapy with recombinant molecules that may require less frequent infusions, the administration of agents that turn off the production of mutant A1AT protein in the liver, and the synthesis of normal A1AT in human or yeast cells for subsequent use in augmentation therapy. Early studies of so-called “corrector molecules” which may favorably allow better secretion of A1AD from the liver and of small molecules that prevent the misfolding of A1AD within the liver cell are underway. Also, studies examining the effect of a seizure drug called carbamazepine on liver disease in A1AD individuals and studies assessing differing doses of intravenous augmentation therapy are currently underway.
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.[rx] Avoiding smoking and getting vaccinated for influenza, pneumococcus, and hepatitis is also recommended.
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