Alpha 1-Antitrypsin
Alpha 1-antitrypsin (aka A1AT) is a serine protease inhibitor (serpin). It protects tissue from enzymes from inflammatory cells, especially elastase. It is present in human blood at 1.5 - 3.5 gram/liter.
Alpha 1-Antitrypsin Function
A1AT is a 52 kDa serine protease inhibitor, and in medicine it is considered the most prominent one, given the fact that the words alpha1-antitrypsin and protease inhibitor (Pi) are often used interchangeably.
Most serpins inactivate enzymes by binding to them covalently, requiring very high levels to perform their function. In the acute phase reaction, a further elevation is required to "limit" the damage caused by activated neutrophil granulocytes and their enzyme elastase, which breaks down the connective tissue fiber elastin.
Like all serine protease inhibitors, A1AT has a characteristic area of secondary structure including beta sheets and alpha helices. It is in this area where mutations can lead to polymerisation and accumulation in the liver.
Alpha 1-Antitrypsin Role in Disease
Disorders of the enzyme include alpha 1-antitrypsin deficiency, a hereditary disorder in which lack of alpha 1-antitrypsin leads to uninhibited tissue breakdown during inflammation. This causes pulmonary emphysema and leads to liver cirrhosis in severe cases.
A remarkable form of Pi, termed PiPittsburgh, functions as an antithrombin (a related serpin), due to a mutation (Met358Arg). One patient with this abnormality has been described; he died of a lethal bleeding diathesis. This disorder proves the point that the serine protease inhibitors have a closely related structure.
Alpha 1-Antitrypsin Nomenclature
The enzyme is called "antitrypsin" because of its ability to covalently bind and irreversibly inactivate the enzyme trypsin. (Trypsin, a type of peptidase, is a digestive enzyme active in the duodenum and elsewhere.)
The term "alpha 1" refers to the enzyme's behaviour on protein electrophoresis. On electrophoresis, the protein component of the blood is separated by electric current. There are several "clusters", the first being albumin, the second being the alpha, the third beta and the fourth gamma (immunoglobulins). The non-albumin proteins are referred to as globulins.
The alpha region can be further divided into two sub-regions, termed "1" and "2". Alpha 1-antitrypsin is the main enzyme of the alpha-globulin 1 region.
Another name used is alpha-1 proteinase inhibitor (alpha1-PI).
Alpha 1-Antitrypsin Genetics
The gene is located on the long arm of the fourteenth chromosome (14q32.1).
Over 80 different versions of alpha1-antitrypsin have been described in various populations. North-West Europeans are most at risk for carrying a deviant form of A1AT.
Alpha 1-Antitrypsin Analysis
As protein electrophoresis is imprecise, A1AT is analysed by electrofocusing (isoelectric focusing analysis), where the protein is passed along a pH gradient.
Normal A1AT is termed "M", as it is neutral and does not run very far. Other variants are less functional, and are termed A-L and N-Z, dependent on whether they run more proximal or more distal to the M band. The presence of deviant bands on electrofocusing can signify the presence of alpha 1-antitrypsin deficiency.
As every person has two copies of the A1AT gene, a heterozygote (with two different copies of the gene), will have two different bands showing on electrofocusing.
In blood test results, the electrofocusing results are notated as in PiMM, where Pi stands for protease inhibitor and "MM" is the banding pattern of that patient.
Alpha 1-antitrypsin levels depend on the phenotype, as deviant forms are excreted inefficiently by the liver and polymerise in the endoplasmic reticulum:
- PiMM: 100% (normal)
- PiMS: 80%
- PiSS: 60%
- PiMZ: 60%
- PiSZ: 40%
- PiZZ: 10-15% (severe alpha 1-antitrypsin deficiency)
The non-M alleles are all the product of mutations in the "normal" (wild type) M variant.
- PiZ is caused by a glutamate to lysine mutation on position 342.
- PiS is caused by a glutamate to valine mutation on position 264.
- Other, rarer forms have been described; in all, there are over 80 variants.
Alpha 1-Antitrypsin Therapeutic Use
Recombinant alpha 1-antitrypsin is not yet commercially available, but is under investigation as a therapeutic modality in congenital deficiency. Therapeutic concentrates are prepared from the blood plasma of blood donors.
Alpha 1-Antitrypsin History
The possibility of allelic variants of A1AD leading to disease was first investigated by Dr U. Axelsson and Dr C.B. Laurell in 1965.
Alpha 1-antitrypsin deficiency (A1AD or Alpha-1) is a genetic disorder caused by reduced levels of alpha 1-antitrypsin in the blood. It can lead to emphysema and, in some cases, to liver disease.
Alpha 1-Antitrypsin Deficiency Signs and symptoms
Symptoms of alpha 1-antitrypsin deficiency include shortness of breath, recurring respiratory infections, or obstructive asthma that does not respond to treatment. Individuals with alpha-1 may develop emphysema during their thirties or forties, without a history of significant smoking (although smoking greatly increases the risk for emphysema). A1AD also causes impaired liver function in some patients and may lead to cirrhosis and liver failure (15%). It is the leading cause of liver transplantation in newborns.
Alpha 1-Antitrypsin Deficiency Pathophysiology
Please see alpha 1-antitrypsin for a discussion of the various genotypes and phenotypes associated with A1AD.
Alpha 1-antitrypsin (AAT) is produced in the liver, and one of its functions is to protect the lungs from the neutrophil elastase enzyme. Normal blood levels of alpha-1 antitrypsin are 1.5-3.5 gm/l. In individuals with PiSS, PiMZ and PiSZ phenotypes, blood levels of AAT are reduced to between 40 and 60 percent of normal levels. This is sufficient to protect the lungs from the effects of elastase in people who do not smoke. However, in individuals with the PiZZ phenotype, AAT levels are less than 15 percent of normal, and patients are likely to develop emphysema at a young age; 50 percent of these patients will develop liver cirrhosis, because the A1AT is not secreted properly and instead accumulates in the liver. A liver biopsy in such cases will reveal PAS-positive, diastase-negative granules.
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 rate of 2000.
Alpha 1-Antitrypsin Deficiency Treatment
In the United States, Canada, and several European countries, lung-affected A1AD patients 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 AAT replacement therapy are not available. It is currently recommended that patients begin augmentation therapy only after the onset of emphysema symptoms.
Augmentation therapy is not appropriate for liver-affected patients; treatment of A1AD-related liver damage focuses on alleviating the symptoms of the disease. In severe cases, liver transplantation may be necessary.
As alpha1-antitrypsin is an acute phase reactant, its transcription is markedly increased during inflammation elsewhere in response to increased interleukin-1 and 6 and TNFalpha production. Any treatment that blunts this response, specifically paracetamol (acetaminophen), can delay the accumulation of A1AD polymers in the liver and (hence) cirrhosis. A1AD patients are therefore encouraged to use paracetamol when slightly to moderately ill, even if they would otherwise not have used antipyretics.
Treatments currently being studied include recombinant and inhaled forms of AAT. Other experimental therapies are aimed at the prevention of polymer formation in the liver.
Alpha 1-Antitrypsin Deficiency Epidemiology
People of northern European ancestry are at the highest risk for A1AD. Four percent carry the PiZ allele; between 1 in 625 and 1 in 2000 are homozygous.
Alpha 1-Antitrypsin Deficiency Associated diseases
alpha1-antitrypsin deficiency has been associated with a number of diseases:
- Asthma
- Wegener's granulomatosis
- Pancreatitis
- Gallstones
- Bronchiectasia (possibly)
- Prolapse
- Cancer
- Hepatocellular carcinoma (liver)
- Bladder carcinoma
- Gallbladder carcinoma
- Lymphoma
- Lung cancer
Alpha 1-Antitrypsin History
A1AD was discovered in 1963 when Dr Carl-Bertil Laurell (1919?2001), at the university of Lund, Sweden, discovered the absence of the alpha1 band in 5 gels in a large series (1500) offered to his laboratory of 6 months. Sten Eriksson, a medical resident, discovered that three of these patients had developed emphysema at a young age.
The link with liver disease was made six years later, when Sharp et al described A1AD in the context of liver disease.
Sources: DiaPharma, Wikipedia, PubMed