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It is a protein that belongs to the serpin superfamily. It is encoded in humans by the SERPINA1 gene.
Alpha-1-antitrypsin is also known as α1-antitrypsin (A1AT, A1A, or AAT).
A protease inhibitor, it is also known as an alpha1-proteinase (A1PI) or alpha1-antiproteinase (A1AP) inhibitor because it inhibits several proteases (not just trypsin).
In older biomedical literature, it was sometimes referred to as a serum trypsin inhibitor (STI, old-fashioned terminology), as its ability as a trypsin inhibitor was a prominent feature of its initial study.
As a type of enzyme inhibitor, it protects tissues from inflammatory cell enzymes, especially neutrophil elastase, and has a blood reference range of 0.9-2.3 g / L.
In the US, the reference range is expressed in mg / dL or micromoles, but the concentration can rise many times with acute inflammation.
When the blood contains inadequate amounts of alpha-1-antitrypsin or functionally defective alpha-1-antitrypsin (as in alpha-1 antitrypsin deficiency), neutrophil elastase is excessively free to break down elastin.
Degrading the elasticity of the lungs, resulting in respiratory complications, such as chronic obstructive pulmonary disease , in adults.
Normally, alpha-1-antitrypsin leaves its site of origin, the liver, and joins the systemic circulation; defective alpha-1-antitrypsin may not be defective, accumulating in the liver, leading to cirrhosis in adults or children.
The alpha1-proteinase inhibitor is an endogenous and an exogenous protease inhibitor used as a medicine.
The dosage form is purified from human donor blood and is sold under the common name alpha1-proteinase inhibitor (human) and under various trade names (including Aralast NP, Glassia, Prolastin, Prolastin-C, and Zemaira).
Recombinant versions are also available, but are currently used in medical research rather than as medication.
History
Alpha-1 antitrypsin deficiency was discovered in 1963 by Carl-Bertil Laurell (1919-2001), at Lund University in Sweden.
Eriksson and Laurell first investigated the possibility of alpha-1-antitrypsin allelic variants leading to the disease in 1965.
Laurell , along with a medical resident, Sten Eriksson , made the discovery after observing the absence of the α1 band on protein electrophoresis in five of 1,500 samples; three of the five patient samples developed emphysema at a young age.
The link to liver disease was made six years later, when Harvey Sharp et al . described alpha-1 antitrypsin deficiency in the context of liver disease.
Function
Alpha-1-antitrypsin is a 52 kDa serpin and is considered the most prominent serpin in medicine; the terms α1-antitrypsin and protease inhibitor (Pi) are often used interchangeably.
Like all serine protease inhibitors, alpha-1-antitrypsin has a characteristic secondary structure of beta sheets and alpha helices. Mutations in these areas can lead to non-functional proteins that can polymerize and accumulate in the liver (childhood liver cirrhosis).
Nomenclature
The protein was initially named “antitrypsin” because of its ability to covalently bind and irreversibly inactivate the trypsin enzyme in vitro.
The term alpha-1 refers to the behavior of the protein in protein electrophoresis. In electrophoresis, the protein component of the blood is separated by electrical current.
There are several clusters, the first is albumin, the second is alpha, the third is beta, and the fourth is gamma (immunoglobulins). Proteins that are not albumins are called globulins.
The alpha region can be further divided into two subregions, named “1” and “2”. Alpha-1 antitrypsin is the major protein in the alpha-globulin 1 region. Another name used is alpha-1 proteinase inhibitor (α1-PI).
Genetics
The gene is located on the long arm of the chromosome (14q32.1). More than 100 dissimilar varieties of α1-antitrypsin have been detailed in various localities.
Northwest Europeans are most at risk of carrying one of the most common mutant forms of alpha-1-antitrypsin, the Z mutation (Glu342Lys in M1A, rs28929474).
Biochemical properties
Alpha-1-antitrypsin is a single chain glycoprotein consisting of 394 amino acids in the mature form and exhibits many glycoforms. The three N-linked glycosylation sites are primarily equipped with so-called diantennial N-glucans.
However, one particular site shows a considerable amount of heterogeneity as tri- and even tetraantennary N-glycans can bind to Asparagine 107 (UniProtKB amino acid nomenclature).
These glycans carry different amounts of negatively charged sialic acids; this causes the heterogeneity seen in normal alpha-1-antitrypsin when analyzed by isoelectric focusing.
Furthermore, fucosylated triantennial N-glycans were shown to have fucose as part of the so-called Sialyl Lewis x epitope, which could confer particular protein cell recognition properties to this protein.
The single cysteine residue of alpha-1-antitrypsin at position 256 (UniProtKB nomenclature) is found to bind covalently to a single free cysteine via a disulfide bridge.
Analysis
The serum alpha-1-antitrypsin level is most often determined by adding an antibody that binds to alpha-1-antitrypsin, then using turbidimetry to measure the amount of alpha-1-antitrypsin present.
Other detection methods include the use of enzyme-linked immunoadsorbents and radial immunodiffusion.
Different analytical methods are used to determine the alpha-1-antitrypsin phenotype.
As protein electrophoresis is imprecise, the alpha-1-antitrypsin phenotype is analyzed by isoelectric focusing (IEF) in the pH range 4.5-5.5, where the protein migrates on a gel according to its isoelectric point or charge in a gradient of pH.
The normal alpha-1-antitrypsin is called M, since it migrates towards the center of this isoelectric targeting gel. Other varieties are less functional and are called AL and NZ, depending on whether they run proximal or distal to the M band.
Since the number of identified mutations has exceeded the number of letters of the alphabet, the subscripts have been added to the more recent discoveries in this area, as in the Pittsburgh mutation described above.
As each person has two copies of the alpha-1-antitrypsin gene, a heterozygote with two different copies of the gene may have two different bands that show up on electro-focusing, although the heterozygote with a null mutant that nullifies the gene’s expression will only show one band.
Alpha-1 antitrypsin levels in the blood depend on the genotype. Some mutant forms do not fold properly and therefore lead to destruction in the proteasome, while others tend to polymerize, being retained in the endoplasmic reticulum.
The serum levels of some of the common genotypes are:
- PiMM: 100% (normal).
- PiMS : 80% of normal serum alpha-1-antitrypsin level.
- PiSS : 60% of normal serum alpha-1-antitrypsin level.
- PiMZ : 60% of normal serum alpha-1-antitrypsin level.
- PiSZ : 40% of normal serum alpha-1-antitrypsin level.
- PiZZ : 10-15% (severe alpha-1 antitrypsin deficiency).
PiZ is caused by a mutation from glutamate to lysine at position 342 (366 in pre-processed form). Instead, PiS is caused by a mutation from glutamate to valine at position 264 (288 in pre-processed form).
Other more anomalous forms have been defined; in total, there are more than 80 varieties.
Alpha 1-antitrypsin deficiency
Alpha-1 antitrypsin deficiency (A1AD or AATD) is a genetic disorder that can cause lung or liver disease. The onset of lung problems is usually between 20 and 50 years old.
This can cause shortness of breath, wheezing, or an increased risk of lung infections. Complications can include chronic obstructive pulmonary disease, cirrhosis, neonatal jaundice, or panniculitis.
Alpha-1 antitrypsin deficiency is due to a mutation in the SERPINA1 gene that produces insufficient alpha-1 antitrypsin. Risk factors for lung disease include smoking and airborne dust.
The underlying mechanism involves unblocked neutrophil elastase and the accumulation of abnormal alpha-1 antitrypsin in the liver. It is autosomal co-dominant, which means that one defective allele tends to produce milder disease than two defective alleles.
The diagnosis is suspected based on symptoms and confirmed by blood tests or genetic testing.
Treatment of lung disease may include bronchodilators, inhaled steroids, and when infections occur with antibiotics. Intravenous infusions of alpha-1 antitrypsin protein or in severe lung transplantation may also be recommended.
In those with severe liver disease, liver transplantation may be an option. It is recommended to avoid smoking. Vaccination against influenza, pneumococcus, and hepatitis is also recommended.
Life expectancy among those who smoke is 50 years, while among those who do not smoke it is almost normal. This condition is inherited in an autosomal codominant pattern. Codominance means that two different versions of the gene can be active (expressed), and both versions contribute to the genetic trait.
The condition affects approximately 1 in 2,500 people of European descent. Severe illness occurs in about 1 in 5,000. In Asians it is rare.
About 3% of people with chronic obstructive pulmonary disease are believed to have the condition. Alpha-1 antitrypsin deficiency was first described in the 1960s.
Etiology
Alpha-1-antitrypsin deficiency is inherited by autosomal co-dominant transmission, which means that affected individuals have inherited an abnormal alpha-1-antitrypsin gene from each parent.
At least 150 alleles of alpha-1-antitrypsin (SERPINA1) have been identified, and each has a letter code based on the electrophoretic mobility of the protein produced.
The normal allele is known as “M” and is the most common version (allele) of the SERPINA1 gene. Most people in the general population have two copies of the M (MM) allele in each cell.
Other versions of the SERPINA1 gene lead to reduced levels of alpha-1 antitrypsin. For example, the S allele produces moderately low levels of this protein, and the Z allele produces very little alpha-1-antitrypsin.
People with two copies of the Z (ZZ) allele in each cell are likely to have alpha-1-antitrypsin deficiency. People with the SZ combination have a higher risk of developing lung diseases (such as emphysema ), especially if they smoke.
Worldwide, an estimated 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).
People with a combination of MS (or SS) usually make enough alpha-1 antitrypsin to protect their lungs. People with MZ alleles have a slightly higher risk of impaired lung or liver function .
Alpha-1-antitrypsin phenotypes are based on the electrophoretic mobility of proteins produced by the various abnormal alpha-1-antitrypsin alleles. Genotyping is done by identifying specific alleles in DNA.
Based on this, alpha-1-antitrypsin variants can be classified into four basic groups:
Normal that is associated with normal alpha-1-antitrypsin levels and normal function. The family of normal alleles is known as M, and the normal genotype is MM.
Deficient that is associated with plasma levels of alpha-1-antitrypsin below 35% of the average normal level. The most common deficient allele associated with emphysema is the Z allele, which is carried by approximately two to three percent of the Caucasian population in the United States.
Null alleles leading to an undetectable alpha-1-antitrypsin protein in 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 amount of alpha-1-antitrypsin protein, but the protein does not work properly.
Environmental factors, such as exposure to tobacco smoke, chemicals, and dust, likely affect the severity of alpha-1 antitrypsin deficiency.
Severe alpha-1-antitrypsin deficiency has a strong risk factor for early-onset emphysema, but not all severely deficient individuals would develop emphysema.
Risk factors for emphysema include smoking, dusty occupational exposure, a parental history of chronic obstructive pulmonary disease, and a personal history of asthma, chronic bronchitis, or pneumonia .
Signs and symptoms
Symptoms of alpha-1 antitrypsin deficiency include shortness of breath, wheezing, rhonchi, and rales. The patient’s symptoms may resemble recurrent respiratory infections or asthma that does not respond to treatment.
People with alpha-1 antitrypsin deficiency can develop emphysema in their 30s or 40s, even without a history of significant smoking, although smoking greatly increases the risk of emphysema.
Alpha-1 antitrypsin deficiency causes impaired liver function in some patients and can lead to cirrhosis and liver failure (15%).
In newborns, alpha-1 antitrypsin deficiency has indicators that include early-onset jaundice followed by prolonged jaundice. It is a leading indication for liver transplantation in newborns.
Diagnosis
Alpha-1 antitrypsin deficiency remains undiagnosed in many patients. Patients are generally labeled as chronic obstructive pulmonary disease patients without an underlying cause.
It is estimated that approximately 1% of all patients with chronic obstructive pulmonary disease actually have an alpha-1 antitrypsin deficiency.
Therefore, testing should be performed for all patients with chronic obstructive pulmonary disease, asthma with irreversible airflow obstruction, unexplained liver disease, or necrotizing panniculitis.
The initial test performed is the serum alpha-1 antitrypsin level. A low alpha-1 antitrypsin level confirms the diagnosis and subsequent evaluation with alpha-1 antitrypsin protein phenotyping and alpha-1 antitrypsin genotyping should be carried out subsequently.
Since protein electrophoresis does not completely distinguish between alpha-1 antitrypsin and other minor proteins at the alpha-1 position (agarose gel), antitrypsin can be more directly and specifically measured using a nephelometric or immunoturbidimetric method.
Therefore, protein electrophoresis is useful in detecting and identifying individuals who are likely to have a deficiency.
Since the number of identified mutations has exceeded the number of letters of the alphabet, the subscripts have been added to the more recent discoveries in this area, as in the Pittsburgh mutation described above.
Since each person has two copies of the alpha-1 antitrypsin gene, a heterozygote with two different copies of the gene can show two different bands on the electrofocus, although a heterozygote with a null mutant that nullifies the gene’s expression will only show one band.
Other detection methods include the use of in vitro enzyme-linked immunosorbent assays and radial immunodiffusion. The levels of alpha 1-antitrypsin in the blood depend on the genotype.
Some mutant forms do not fold properly and therefore are directed to destruction in the proteasome, while others have a tendency to polymerize, and are then retained in the endoplasmic reticulum.
Treatment
Treatment of lung disease may include bronchodilators, inhaled steroids, and when infections occur with antibiotics. Intravenous infusions of alpha1-antitrypsin protein may also be recommended or in the case of severe lung transplantation.
In those with severe liver disease, liver transplantation may be an option. It is also recommended to avoid smoking and to get vaccinated against influenza, pneumococcus and hepatitis.
Therapeutic use
It is currently available for bank investigation. People with lung disease due to alpha-1 antitrypsin deficiency may receive intravenous infusions of alpha-1 antitrypsin.
Intravenous therapies are the standard mode of administration of augmentation therapy. Researchers are exploring inhaled therapies.
Intravenous augmentation therapies are manufactured by the following companies and have been shown to be clinically identical to each other in terms of dosage and efficacy.
This augmentation therapy is believed to stop the course of the disease and stop any further damage to the lungs. Long-term studies of the effectiveness of alpha1-antitrypsin replacement therapy are not available.
It is currently recommended that patients begin augmentation therapy only after the onset of emphysema symptoms.
These intravenous alpha-1-antitrypsin augmentation therapy products can cost up to $ 100,000 per year per patient. They are administered intravenously at a dose of 60 mg / kg once a week.
A recent study analyzed and compared the three products approved by the Food and Drug Administration with respect to their primary structure and glycosylation.
All three products showed minor differences compared to normal human plasma alpha-1-antitrypsin, and are introduced during specific purification procedures.
However, these detected differences are not believed to have negative implications for patients.
Aerosol augmented alpha-1-antitrypsin therapy is being studied. This involves inhaling purified human alpha-1-antitrypsin into the lungs and trapping the alpha-1-antitrypsin in the lower respiratory tract.
However, inhaled alpha-1-antitrypsin may not reach elastin fibers in the lung where elastase injury occurs. Additional studies are underway.
Since 1995, significant progress has been made in improving survival for people affected with Alpha-1 through AlphaNet’s Alpha-1 Disease Management Program, a unique and innovative disease treatment program.
The results of this program were first documented in the Effects of a disease control program in individuals with alpha-1 antitrypsin deficiency.
Augmentation therapy is not appropriate for people with liver disease; The treatment of liver damage related to alpha-1 antitrypsin deficiency focuses on alleviating the symptoms of the disease. In severe cases, liver transplantation may be necessary.
epidemiology
Alpha-1 antitrypsin deficiency occurs worldwide, but its prevalence varies by population. This disorder affects about 1 in 1,500 to 3,500 people.
It is not common in people of Asian descent. Many people with alpha-1 antitrypsin deficiency probably go undiagnosed, especially people with a lung condition called chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease can be caused by alpha-1 antitrypsin deficiency; however, alpha-1 antitrypsin deficiency is often never diagnosed. Some people with alpha-1 antitrypsin deficiency are misdiagnosed with asthma.
People of Iberian and Northern European descent are at the highest risk for alpha-1 antitrypsin deficiency. Four percent carry the PiZ allele; between 1 in 625 and 1 in 2000 are homozygous.
Another study detected a frequency of 1 in 1550 individuals and a gene frequency of 0.026. The highest prevalence of the PiZZ variant (severe alpha-1 antitrypsin deficiency) was recorded in northern and western European countries with a mean gene frequency of 0.0140.
Pathophysiology
Emphysema in alpha-1-antitrypsin deficiency is considered due to an imbalance between the neutrophil elastase in the lung, which destroys elastin, and the elastase inhibitor alpha-1-antitrypsin, which protects against proteolytic degradation of the elastin.
This mechanism is called “loss of toxic function.” Specifically, smoking and infection increase elastase production in the lung, which increases lung breakdown.
In addition, antitrypsin “Z” polymers are chemotactic for neutrophils, which can contribute to local inflammation and tissue destruction in the lung.
The pathogenesis of liver disease is quite different and is called “toxic gain of function.” Liver disease is the result of the accumulation within the hepatocyte of the non-secreted variant protein alpha-1-antitrypsin.
Only those genotypes associated with the pathological polymerization of alpha-1-antitrypsin within the endoplasmic reticulum of hepatocytes produce disease.
