Alpha 1-antitrypsin deficiency
Encyclopedia
Alpha 1-antitrypsin deficiency (α1-antitrypsin deficiency, A1AD or simply Alpha-1) is an autosomal recessive
genetic disorder
caused by defective production of alpha 1-antitrypsin
(A1AT), leading to decreased A1AT activity in the blood
and lungs, and deposition of excessive abnormal A1AT protein
in liver
cells. There are several forms and degrees of deficiency, principally depending on whether the sufferer has one or two copies of the affected gene. Severe A1AT deficiency causes panacinar emphysema
or COPD
in adult life in many people with the condition (especially if they are exposed to cigarette smoke), as well as various liver diseases in a minority of children and adults, and occasionally more unusual problems. It is treated by avoidance of damaging inhalants, by intravenous infusions of the A1AT protein, by transplantation
of the liver or lungs
, and by a variety of other measures, but it usually produces some degree of disability
and reduced life expectancy.
, wheezing
, rhonchi
, and rales
. The patient's symptoms may resemble recurrent respiratory infections or asthma
that does not respond to treatment. Individuals with A1AD may develop emphysema
during their thirties or forties even without a history of significant smoking
, though 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 a leading cause of liver transplantation
in newborns.
(A1AT) is produced in the liver
, and one of its functions is to protect the lungs from the neutrophil elastase
enzyme, which can disrupt connective tissue. Normal blood levels of alpha-1 antitrypsin are 1.5-3.5 g
/l
. In individuals with PiSS, PiMZ and PiSZ phenotype
s, 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 phenotype, A1AT levels are less than 15% of normal, and patients are likely to develop panacinar emphysema
at a young age; 50% 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
-resistant granules.
Cigarette
smoke is especially harmful to individuals with A1AD. In addition to increasing the inflammatory
reaction in the airway
s, cigarette
smoke directly inactivates alpha 1-antitrypsin
by oxidizing essential methionine
residues to sulfoxide
forms, decreasing the enzyme
activity by a factor of 2000.
As protein electrophoresis does not completely distinguish between A1AT and other minor proteins at the alpha-1 position (agarose gel), antitrypsin can be more directly and specifically measured using a nephelometric
or immunotubidimetric method. Thus, protein electrophoresis is useful for screening and identifying individuals likely to have a deficiency. A1AT is further analysed by isoelectric focusing
(IEF) in the pH range 4.5-5.5, where the protein migrates in a gel according to its isoelectric point
or charge in a pH gradient.
Normal A1AT is termed M, as it is migrates toward the center of such an IEF gel. Other variants are less functional, and are termed A-L and N-Z, dependent on whether they run proximal or distal to the M band. The presence of deviant bands on IEF can signify the presence of alpha 1-antitrypsin deficiency. Since the number of identified mutations has exceeded the number of letters in the alphabet, subscripts have been added to most recent discoveries in this area, as in the Pittsburgh mutation described above. As every person has two copies of the A1AT gene, a heterozygote with two different copies of the gene may have two different bands showing on electrofocusing, although a heterozygote with one null mutant that abolishes expression of the gene will only show one band. In blood test results, the IEF results are notated as, eg, PiMM, where Pi stands for protease inhibitor and "MM" is the banding pattern of that person.
Other detection methods include use of enzyme-linked-immuno-sorbent-assays in vitro and radial immunodiffusion
.
Alpha 1-antitrypsin levels in the blood depend on the genotype. Some mutant forms fail to fold properly and are, thus, targeted for destruction in the proteasome
, whereas others have a tendency to polymerise, thereafter being retained in the endoplasmic reticulum
. The serum levels of some of the common genotypes are:
PiZ is caused by a glutamate to lysine
mutation at position 342, while PiS is caused by a glutamate to valine mutation at position 264. Other rarer forms have been described; in all there are over 80 variants.
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 α1-antitrypsin is an acute phase reactant, its transcription
is markedly increased during inflammation
elsewhere in response to increased interleukin
-1 and 6 and TNFα production.
Treatments currently being studied include recombinant and inhaled forms of A1AT. Other experimental therapies are aimed at the prevention of polymer
formation in the liver
.
, Iberian
and Saudi Arabia
n ancestry are at the highest risk for A1AD. Four percent carry the PiZ allele
; between 1 in 625 and 1 in 2000 are homozygous.
.
Laurell, along with a medical resident, Sten Eriksson, made the discovery after noting the absence of the α1 band on protein electrophoresis
in five of 1500 samples; three of the five patient samples were found to have developed emphysema at a young age.
The link with liver disease
was made six years later, when Dr. Harvey Sharp et al. described A1AD in the context of liver disease.
Recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...
genetic disorder
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
caused by defective production of alpha 1-antitrypsin
Alpha 1-antitrypsin
Alpha 1-Antitrypsin or α1-antitrypsin is a protease inhibitor belonging to the serpin superfamily. It is generally known as serum trypsin inhibitor. Alpha 1-antitrypsin is also referred to as alpha-1 proteinase inhibitor because it inhibits a wide variety of proteases...
(A1AT), leading to decreased A1AT activity in the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
and lungs, and deposition of excessive abnormal A1AT protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
in liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
cells. There are several forms and degrees of deficiency, principally depending on whether the sufferer has one or two copies of the affected gene. Severe A1AT deficiency causes panacinar emphysema
Emphysema
Emphysema is a long-term, progressive disease of the lungs that primarily causes shortness of breath. In people with emphysema, the tissues necessary to support the physical shape and function of the lungs are destroyed. It is included in a group of diseases called chronic obstructive pulmonary...
or COPD
Chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease , also known as chronic obstructive lung disease , chronic obstructive airway disease , chronic airflow limitation and chronic obstructive respiratory disease , is the co-occurrence of chronic bronchitis and emphysema, a pair of commonly co-existing diseases...
in adult life in many people with the condition (especially if they are exposed to cigarette smoke), as well as various liver diseases in a minority of children and adults, and occasionally more unusual problems. It is treated by avoidance of damaging inhalants, by intravenous infusions of the A1AT protein, by transplantation
Organ transplant
Organ transplantation is the moving of an organ from one body to another or from a donor site on the patient's own body, for the purpose of replacing the recipient's damaged or absent organ. The emerging field of regenerative medicine is allowing scientists and engineers to create organs to be...
of the liver or lungs
Lung transplantation
Lung transplantation, or pulmonary transplantation is a surgical procedure in which a patient's diseased lungs are partially or totally replaced by lungs which come from a donor...
, and by a variety of other measures, but it usually produces some degree of disability
Disability
A disability may be physical, cognitive, mental, sensory, emotional, developmental or some combination of these.Many people would rather be referred to as a person with a disability instead of handicapped...
and reduced life expectancy.
Signs and symptoms
Symptoms of alpha-1 antitrypsin deficiency include shortness of breathDyspnea
Dyspnea , shortness of breath , or air hunger, is the subjective symptom of breathlessness.It is a normal symptom of heavy exertion but becomes pathological if it occurs in unexpected situations...
, wheezing
Wheeze
A wheeze is a continuous, coarse, whistling sound produced in the respiratory airways during breathing. For wheezes to occur, some part of the respiratory tree must be narrowed or obstructed, or airflow velocity within the respiratory tree must be heightened...
, rhonchi
Rhonchi
Rhonchi is the coarse rattling sound somewhat like snoring, usually caused by secretion in bronchial airways. Rhonchi is the plural form of the singular word rhonchus.-Description:...
, and rales
Rales
Crackles, crepitations, or rales are the clicking, rattling, or crackling noises that may be made by one or both lungs of a human with a respiratory disease during inhalation. They are often heard only with a stethoscope...
. The patient's symptoms may resemble recurrent respiratory infections or asthma
Asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
that does not respond to treatment. Individuals with A1AD may develop emphysema
Emphysema
Emphysema is a long-term, progressive disease of the lungs that primarily causes shortness of breath. In people with emphysema, the tissues necessary to support the physical shape and function of the lungs are destroyed. It is included in a group of diseases called chronic obstructive pulmonary...
during their thirties or forties even without a history of significant smoking
Tobacco smoking
Tobacco smoking is the practice where tobacco is burned and the resulting smoke is inhaled. The practice may have begun as early as 5000–3000 BCE. Tobacco was introduced to Eurasia in the late 16th century where it followed common trade routes...
, though smoking greatly increases the risk for emphysema. A1AD also causes impaired liver function in some patients and may lead to cirrhosis
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
and liver failure
Liver failure
Acute liver failure is the appearance of severe complications rapidly after the first signs of liver disease , and indicates that the liver has sustained severe damage . The complications are hepatic encephalopathy and impaired protein synthesis...
(15%). It is a leading cause of liver transplantation
Liver transplantation
Liver transplantation or hepatic transplantation is the replacement of a diseased liver with a healthy liver allograft. The most commonly used technique is orthotopic transplantation, in which the native liver is removed and replaced by the donor organ in the same anatomic location as the original...
in newborns.
Associated conditions
α1-antitrypsin deficiency has been associated with a number of diseases:- CirrhosisCirrhosisCirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
- COPDChronic obstructive pulmonary diseaseChronic obstructive pulmonary disease , also known as chronic obstructive lung disease , chronic obstructive airway disease , chronic airflow limitation and chronic obstructive respiratory disease , is the co-occurrence of chronic bronchitis and emphysema, a pair of commonly co-existing diseases...
- PneumothoraxPneumothoraxPneumothorax is a collection of air or gas in the pleural cavity of the chest between the lung and the chest wall. It may occur spontaneously in people without chronic lung conditions as well as in those with lung disease , and many pneumothoraces occur after physical trauma to the chest, blast...
- AsthmaAsthmaAsthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
- Wegener's granulomatosisWegener's granulomatosisWegener's granulomatosis , more recently granulomatosis with polyangiitis , is an incurable form of vasculitis that affects the nose, lungs, kidneys and other organs. Due to its end-organ damage, it is life-threatening and requires long-term immunosuppression...
- PancreatitisPancreatitisPancreatitis is inflammation of the pancreas. It occurs when pancreatic enzymes that digest food are activated in the pancreas instead of the small intestine. It may be acute – beginning suddenly and lasting a few days, or chronic – occurring over many years...
- GallstoneGallstoneA gallstone is a crystalline concretion formed within the gallbladder by accretion of bile components. These calculi are formed in the gallbladder, but may pass distally into other parts of the biliary tract such as the cystic duct, common bile duct, pancreatic duct, or the ampulla of...
s - BronchiectasisBronchiectasisBronchiectasis is a disease state defined by localized, irreversible dilation of part of the bronchial tree caused by destruction of the muscle and elastic tissue. It is classified as an obstructive lung disease, along with emphysema, bronchitis, asthma, and cystic fibrosis...
- Pelvic organ prolapseProlapseProlapse literally means "to fall out of place", from the Latin prolabi meaning "to fall out". In medicine, prolapse is a condition where organs, such as the uterus, fall down or slip out of place. It is used for organs protruding through the vagina or the rectum or for the misalignment of the...
- Primary sclerosing cholangitisPrimary sclerosing cholangitisPrimary sclerosing cholangitis is a chronic liver disease caused by progressive inflammation and scarring of the bile ducts of the liver. The inflammation impedes the flow of bile to the gut, which can ultimately lead to liver cirrhosis, liver failure and liver cancer...
- Autoimmune hepatitisAutoimmune hepatitisAutoimmune Hepatitis is a disease of the liver that occurs when the body's immune system attacks cells of the liver. Anomalous presentation of human leukocyte antigen class II on the surface of hepatocytes, possibly due to genetic predisposition or acute liver infection, causes a cell-mediated...
- EmphysemaEmphysemaEmphysema is a long-term, progressive disease of the lungs that primarily causes shortness of breath. In people with emphysema, the tissues necessary to support the physical shape and function of the lungs are destroyed. It is included in a group of diseases called chronic obstructive pulmonary...
, predominantly involving the lower lobes and causing bullaeBlisterA blister is a small pocket of fluid within the upper layers of the skin, typically caused by forceful rubbing , burning, freezing, chemical exposure or infection. Most blisters are filled with a clear fluid called serum or plasma... - CancerCancerCancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
- Hepatocellular carcinomaHepatocellular carcinomaHepatocellular carcinoma is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitide infection or cirrhosis .Compared to other cancers, HCC is quite a rare tumor in the United States...
(liver) - Bladder carcinoma
- Gallbladder cancerGallbladder cancerGallbladder cancer is a relatively uncommon cancer. It has peculiar geographical distribution being common in central and South America, central and eastern Europe, Japan and northern India; it is also common in certain ethnic groups e.g. Native American Indians and Hispanics. If it is diagnosed...
- LymphomaLymphomaLymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
- Lung cancerLung cancerLung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
- Hepatocellular carcinoma
Pathophysiology
Alpha 1-antitrypsinAlpha 1-antitrypsin
Alpha 1-Antitrypsin or α1-antitrypsin is a protease inhibitor belonging to the serpin superfamily. It is generally known as serum trypsin inhibitor. Alpha 1-antitrypsin is also referred to as alpha-1 proteinase inhibitor because it inhibits a wide variety of proteases...
(A1AT) is produced in the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, and one of its functions is to protect the lungs from the neutrophil elastase
Elastase
In molecular biology, elastase is an enzyme from the class of proteases that break down proteins.- Forms and classification:There exist eight human genes for elastase:Bacterial forms: Organisms such as P...
enzyme, which can disrupt connective tissue. Normal blood levels of alpha-1 antitrypsin are 1.5-3.5 g
Gram
The gram is a metric system unit of mass....
/l
Litre
pic|200px|right|thumb|One litre is equivalent to this cubeEach side is 10 cm1 litre water = 1 kilogram water The litre is a metric system unit of volume equal to 1 cubic decimetre , to 1,000 cubic centimetres , and to 1/1,000 cubic metre...
. In individuals with PiSS, PiMZ and PiSZ phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
s, 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
Elastase
In molecular biology, elastase is an enzyme from the class of proteases that break down proteins.- Forms and classification:There exist eight human genes for elastase:Bacterial forms: Organisms such as P...
in people who do not smoke
Tobacco smoking
Tobacco smoking is the practice where tobacco is burned and the resulting smoke is inhaled. The practice may have begun as early as 5000–3000 BCE. Tobacco was introduced to Eurasia in the late 16th century where it followed common trade routes...
. However, in individuals with the PiZZ phenotype, A1AT levels are less than 15% of normal, and patients are likely to develop panacinar emphysema
Emphysema
Emphysema is a long-term, progressive disease of the lungs that primarily causes shortness of breath. In people with emphysema, the tissues necessary to support the physical shape and function of the lungs are destroyed. It is included in a group of diseases called chronic obstructive pulmonary...
at a young age; 50% of these patients will develop liver cirrhosis
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
, because the A1AT is not secreted properly and instead accumulates in the liver. A liver biopsy
Liver biopsy
Liver biopsy is the biopsy from the liver. It is a medical test that is done to aid diagnosis of liver disease, to assess the severity of known liver disease, and to monitor the progress of treatment.-History:...
in such cases will reveal PAS-positive, diastase
Diastase
A diastase is any one of a group of enzymes which catalyses the breakdown of starch into maltose. Alpha amylase degrades starch to a mixture of the disaccharide maltose, the trisaccharide maltotriose, which contains three α -linked glucose residues, and oligosaccharides known as dextrins that...
-resistant granules.
Cigarette
Cigarette
A cigarette is a small roll of finely cut tobacco leaves wrapped in a cylinder of thin paper for smoking. The cigarette is ignited at one end and allowed to smoulder; its smoke is inhaled from the other end, which is held in or to the mouth and in some cases a cigarette holder may be used as well...
smoke is especially harmful to individuals with A1AD. In addition to increasing the inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
reaction in the airway
Airway
The pulmonary airway comprises those parts of the respiratory system through which air flows, conceptually beginning at the nose and mouth, and terminating in the alveoli...
s, cigarette
Cigarette
A cigarette is a small roll of finely cut tobacco leaves wrapped in a cylinder of thin paper for smoking. The cigarette is ignited at one end and allowed to smoulder; its smoke is inhaled from the other end, which is held in or to the mouth and in some cases a cigarette holder may be used as well...
smoke directly inactivates alpha 1-antitrypsin
Alpha 1-antitrypsin
Alpha 1-Antitrypsin or α1-antitrypsin is a protease inhibitor belonging to the serpin superfamily. It is generally known as serum trypsin inhibitor. Alpha 1-antitrypsin is also referred to as alpha-1 proteinase inhibitor because it inhibits a wide variety of proteases...
by oxidizing essential methionine
Methionine
Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...
residues to sulfoxide
Sulfoxide
A sulfoxide is a chemical compound containing a sulfinyl functional group attached to two carbon atoms. Sulfoxides can be considered as oxidized sulfides...
forms, decreasing the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
activity by a factor of 2000.
Diagnosis
A1AT deficiency remains undiagnosed in many patients. Patients are usually labelled as having COPD without an underlying cause. It is estimated that about 1% of all COPD patients actually have A1AT deficiency. Thus, testing should be performed for all patients with COPD, asthma with irreversible air-flow obstruction, unexplained liver disease, or necrotizing panniculitis. The initial test performed is serum A1AT level. A low level of A1AT confirms the diagnosis and further assessment with A1AT protein phenotyping and A1AT genotyping should be carried out subsequently.As protein electrophoresis does not completely distinguish between A1AT and other minor proteins at the alpha-1 position (agarose gel), antitrypsin can be more directly and specifically measured using a nephelometric
Nephelometry
Nephelometry is a technique used in immunology to determine levels of IgM, IgG, and IgA.It is performed by measuring the turbidity in a water sample by passing light through the sample being measured...
or immunotubidimetric method. Thus, protein electrophoresis is useful for screening and identifying individuals likely to have a deficiency. A1AT is further analysed by isoelectric focusing
Isoelectric focusing
Isoelectric focusing , also known as electrofocusing, is a technique for separating different molecules by their electric charge differences...
(IEF) in the pH range 4.5-5.5, where the protein migrates in a gel according to its isoelectric point
Isoelectric point
The isoelectric point , sometimes abbreviated to IEP, is the pH at which a particular molecule or surface carries no net electrical charge....
or charge in a pH gradient.
Normal A1AT is termed M, as it is migrates toward the center of such an IEF gel. Other variants are less functional, and are termed A-L and N-Z, dependent on whether they run proximal or distal to the M band. The presence of deviant bands on IEF can signify the presence of alpha 1-antitrypsin deficiency. Since the number of identified mutations has exceeded the number of letters in the alphabet, subscripts have been added to most recent discoveries in this area, as in the Pittsburgh mutation described above. As every person has two copies of the A1AT gene, a heterozygote with two different copies of the gene may have two different bands showing on electrofocusing, although a heterozygote with one null mutant that abolishes expression of the gene will only show one band. In blood test results, the IEF results are notated as, eg, PiMM, where Pi stands for protease inhibitor and "MM" is the banding pattern of that person.
Other detection methods include use of enzyme-linked-immuno-sorbent-assays in vitro and radial immunodiffusion
Immunodiffusion
Immunodiffusion is a diagnostic test which involves diffusion through a substance such as agar.Two commonly known forms are Ouchterlony double immunodiffusion and radial immunodiffusion....
.
Alpha 1-antitrypsin levels in the blood depend on the genotype. Some mutant forms fail to fold properly and are, thus, targeted for destruction in the proteasome
Proteasome
Proteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
, whereas others have a tendency to polymerise, thereafter being retained in the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
. The serum levels of some of the common genotypes are:
- PiMM: 100% (normal)
- PiMS: 80% of normal serum level of A1AT
- PiSS: 60% of normal serum level of A1AT
- PiMZ: 60% of normal serum level of A1AT
- PiSZ: 40% of normal serum level of A1AT
- PiZZ: 10-15% (severe alpha 1-antitrypsin deficiency)
PiZ is caused by a glutamate to lysine
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
mutation at position 342, while PiS is caused by a glutamate to valine mutation at position 264. Other rarer forms have been described; in all there are over 80 variants.
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 A1AT 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
Liver transplantation
Liver transplantation or hepatic transplantation is the replacement of a diseased liver with a healthy liver allograft. The most commonly used technique is orthotopic transplantation, in which the native liver is removed and replaced by the donor organ in the same anatomic location as the original...
may be necessary.
As α1-antitrypsin is an acute phase reactant, its transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
is markedly increased during inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
elsewhere in response to increased interleukin
Interleukin
Interleukins are a group of cytokines that were first seen to be expressed by white blood cells . The term interleukin derives from "as a means of communication", and "deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes"...
-1 and 6 and TNFα production.
Treatments currently being studied include recombinant and inhaled forms of A1AT. Other experimental therapies are aimed at the prevention of polymer
Polymer
A polymer is a large molecule composed of repeating structural units. These subunits are typically connected by covalent chemical bonds...
formation in the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
.
Epidemiology
People of northern EuropeanEuropean ethnic groups
The ethnic groups in Europe are the various ethnic groups that reside in the nations of Europe. European ethnology is the field of anthropology focusing on Europe....
, Iberian
Iberian Peninsula
The Iberian Peninsula , sometimes called Iberia, is located in the extreme southwest of Europe and includes the modern-day sovereign states of Spain, Portugal and Andorra, as well as the British Overseas Territory of Gibraltar...
and Saudi Arabia
Saudi Arabia
The Kingdom of Saudi Arabia , commonly known in British English as Saudi Arabia and in Arabic as as-Sa‘ūdiyyah , is the largest state in Western Asia by land area, constituting the bulk of the Arabian Peninsula, and the second-largest in the Arab World...
n ancestry are at the highest risk for A1AD. Four percent carry the PiZ allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
; between 1 in 625 and 1 in 2000 are homozygous.
History
A1AD was discovered in 1963 by Carl-Bertil Laurell (1919–2001), at the University of Lund in SwedenSweden
Sweden , officially the Kingdom of Sweden , is a Nordic country on the Scandinavian Peninsula in Northern Europe. Sweden borders with Norway and Finland and is connected to Denmark by a bridge-tunnel across the Öresund....
.
Laurell, along with a medical resident, Sten Eriksson, made the discovery after noting the absence of the α1 band on protein electrophoresis
Electrophoresis
Electrophoresis, also called cataphoresis, is the motion of dispersed particles relative to a fluid under the influence of a spatially uniform electric field. This electrokinetic phenomenon was observed for the first time in 1807 by Reuss , who noticed that the application of a constant electric...
in five of 1500 samples; three of the five patient samples were found to have developed emphysema at a young age.
The link with liver disease
Liver disease
Liver disease is a broad term describing any single number of diseases affecting the liver.-Diseases:* Hepatitis, inflammation of the liver, caused mainly by various viruses but also by some poisons , autoimmunity or hereditary conditions...
was made six years later, when Dr. Harvey Sharp et al. described A1AD in the context of liver disease.