Alpha 1-antitrypsin deficiency (
α1-antitrypsin deficiency,
A1AD or
Alpha-1) is a
genetic disorderA genetic disorder is an illness caused by abnormalities in genes or chromosomes. While some diseases, such as cancer, are due in part to a genetic disorders, they can also be caused by environmental factors. Most disorders are quite rare and affect one person in every several thousands or millions...
caused by defective production of
alpha 1-antitrypsinAlpha 1-Antitrypsin or α
1-antitrypsin is a glycoprotein and generally known as serum trypsin inhibitor. Alpha 1- antitrypsin is also referred to as alpha-1 proteinase inhibitor because it is a serine protease inhibitor , inhibiting a wide variety of proteases...
(A1AT), leading to decreased A1AT activity in the
bloodBlood is a specialized bodily fluid that delivers necessary substances to the body's cells — such as nutrients and oxygen — and transports waste products away from those same cells....
and lungs, and deposition of excessive abnormal A1AT
proteinProteins are organic compounds made of amino acids arranged in a linear chain and folded into a globular form. The amino acids in a polymer chain are joined together by the peptide bonds between the carboxyl and amino groups of adjacent amino acid residues...
in
liverThe 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. Severe A1A deficiency causes panacinar
emphysemaEmphysema is a lung disease, characterized by an abnormal, permanent enlargement of air spaces distal to the terminal bronchioles. The disease is coupled with the destruction of walls, but without obvious fibrosis...
and/or
COPDChronic obstructive pulmonary disease refers to chronic bronchitis and emphysema, a pair of two commonly co-existing diseases of the lungs in which the airways become narrowed. This leads to a limitation of the flow of air to and from the lungs causing shortness of breath...
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
transplantationOrgan transplant is the moving of an organ from one body to another , for the purpose of replacing the recipient's damaged or failing organ with a working one from the donor site. Organ donors can be living or deceased...
of the liver or
lungsLung 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
disabilityDisability is defined by the Americans with Disabilities Act of 1990 as "a physical or mental impairment that substantially limits one or more major life activities."...
and reduced life expectancy.
Signs and symptoms
Symptoms of alpha-1 antitrypsin deficiency include
shortness of breathDyspnea or dyspnoea , from Latin dyspnoea, from Greek dyspnoia from dyspnoos, shortness of breath) or shortness of breath is a debilitating symptom that is the experience of unpleasant or uncomfortable respiratory sensations...
,
wheezingA 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...
,
rhonchiRhonchi 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
ralesRales, crackles or crepitations, are the clicking, rattling, or crackling noises heard on auscultation of the lung with a stethoscope during inhalation...
. The patient's symptoms may resemble recurrent respiratory infections or
asthmaAsthma is a predisposition to chronic inflammation of the lungs in which the airways are reversibly narrowed. Asthma affects 7% of the population of the United States, and 300 million worldwide...
that does not respond to treatment. Individuals with A1AD may develop
emphysemaEmphysema is a lung disease, characterized by an abnormal, permanent enlargement of air spaces distal to the terminal bronchioles. The disease is coupled with the destruction of walls, but without obvious fibrosis...
during their thirties or forties even without a history of significant
smoking Tobacco smoking is the practice where tobacco is burned and the vapors either tasted or inhaled. The practice began as early as 5000–3000 BC. Many civilizations burnt incense during religious rituals, which was later adopted for pleasure or as a social tool. Tobacco was introduced to the old world...
, though smoking greatly increases the risk for emphysema. A1AD also causes impaired liver function in some patients and may lead to
cirrhosisCirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrous scar tissue as well as regenerative nodules , leading to progressive loss of liver function...
and
liver failureAcute 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 transplantationLiver 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 the donor organ is placed in the same anatomic location as the original...
in newborns.
Pathophysiology
Please see alpha 1-antitrypsinAlpha 1-Antitrypsin or α
1-antitrypsin is a glycoprotein and generally known as serum trypsin inhibitor. Alpha 1- antitrypsin is also referred to as alpha-1 proteinase inhibitor because it is a serine protease inhibitor , inhibiting a wide variety of proteases...
for a discussion of the various genotypeThe genotype is the genetic constitution of a cell, an organism, or an individual usually with reference to a specific character under consideration...
s and phenotypeA phenotype is any observable characteristic or trait of an organism: such as its morphology, development, biochemical or physiological properties, or behavior. Phenotypes result from the expression of an organism's genes as well as the influence of environmental factors and possible interactions...
s associated with A1AD.
Alpha 1-antitrypsinAlpha 1-Antitrypsin or α
1-antitrypsin is a glycoprotein and generally known as serum trypsin inhibitor. Alpha 1- antitrypsin is also referred to as alpha-1 proteinase inhibitor because it is a serine protease inhibitor , inhibiting a wide variety of proteases...
(A1AT) is produced in the
liverThe 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 elastaseIn molecular biology, elastase is an enzyme from the class of proteases , that break down proteins.- Forms and classification:There exist two human genes for elastase:* Pancreatic elastase * Neutrophil elastase...
enzyme, which can disrupt connective tissue. Normal blood levels of alpha-1 antitrypsin are 1.5-3.5
gThe gram , ; symbol g, is a unit of mass.Originally defined as "the absolute weight of a volume of pure water equal to the cube of the hundredth part of a metre, and at the temperature of melting ice" , a gram is now defined as one one-thousandth of the SI base unit, the kilogram, or...
/
lThe litre or liter is a unit of volume. There are two official symbols: the Latin letter L in lower and upper case . The lower case L is also often written as a cursive ℓ, though this symbol has no official approval by any international bureau...
. In individuals with PiSS, PiMZ and PiSZ
phenotypeA phenotype is any observable characteristic or trait of an organism: such as its morphology, development, biochemical or physiological properties, or behavior. Phenotypes result from the expression of an organism's genes as well as the influence of environmental factors and possible interactions...
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
elastaseIn molecular biology, elastase is an enzyme from the class of proteases , that break down proteins.- Forms and classification:There exist two human genes for elastase:* Pancreatic elastase * Neutrophil elastase...
in people who do not
smoke Tobacco smoking is the practice where tobacco is burned and the vapors either tasted or inhaled. The practice began as early as 5000–3000 BC. Many civilizations burnt incense during religious rituals, which was later adopted for pleasure or as a social tool. Tobacco was introduced to the old world...
. However, in individuals with the PiZZ phenotype, A1AT levels are less than 15% of normal, and patients are likely to develop panacinar
emphysemaEmphysema is a lung disease, characterized by an abnormal, permanent enlargement of air spaces distal to the terminal bronchioles. The disease is coupled with the destruction of walls, but without obvious fibrosis...
at a young age; 50% of these patients will develop
liver cirrhosisCirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrous scar tissue as well as regenerative nodules , leading to progressive loss of liver function...
, because the A1AT is not secreted properly and instead accumulates in the liver. A
liver biopsyLiver 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,
diastaseA 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...
-negative granules.
CigaretteA cigarette is a product consumed through smoking and manufactured out of cured and finely cut tobacco leaves and reconstituted tobacco, often combined with other additives, then rolled or stuffed into a paper-wrapped cylinder...
smoke is especially harmful to individuals with A1AD. In addition to increasing the
inflammatoryInflammation is 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 as well as initiate the healing process for the tissue. Inflammation is not a...
reaction in the
airwayFor the Australian television series Airways, see Airways .The airways are those parts of the respiratory system through which air flows, to get from the external environment to the alveoli....
s,
cigaretteA cigarette is a product consumed through smoking and manufactured out of cured and finely cut tobacco leaves and reconstituted tobacco, often combined with other additives, then rolled or stuffed into a paper-wrapped cylinder...
smoke directly inactivates
alpha 1-antitrypsinAlpha 1-Antitrypsin or α
1-antitrypsin is a glycoprotein and generally known as serum trypsin inhibitor. Alpha 1- antitrypsin is also referred to as alpha-1 proteinase inhibitor because it is a serine protease inhibitor , inhibiting a wide variety of proteases...
by oxidizing essential
methionineMethionine is an α-amino acid with the chemical formula HO
2CCHCH
2CH
2SCH
3. This essential amino acid is classified as nonpolar.-Function:...
residues to
sulfoxideA 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
enzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, called the products. Almost all processes in a biological cell need enzymes to occur at...
activity by a factor of 2000.
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 may be necessary.
As α
1-antitrypsin is an acute phase reactant, its
transcriptionTranscription, or RNA synthesis, is the process of creating an equivalent 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 in the presence of the correct enzymes...
is markedly increased during
inflammationInflammation is 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 as well as initiate the healing process for the tissue. Inflammation is not a...
elsewhere in response to increased
interleukinInterleukins are a group of cytokines that were first seen to be expressed by white blood cells , The term interleukine, as a means of communication, 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
polymerA polymer is a large molecule composed of repeating structural units typically connected by covalent chemical bonds. While polymer in popular usage suggests plastic, the term actually refers to a large class of natural and synthetic materials with a variety of properties.Due to the extraordinary...
formation in the
liverThe 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
EuropeanThe European peoples are the various nations and ethnic groups of Europe. European ethnology is the field of anthropology focusing on Europe....
,
IberianThe Iberian Peninsula, or Iberia, is located in the extreme southwest of Europe and includes modern-day Spain, Portugal, Andorra and Gibraltar and a very small area of France. It is the westernmost of the three major southern European peninsulas—the Iberian, Italian, and Balkan peninsulas...
and
Saudi ArabiaSaudi Arabia , is an Arab country and the largest country of the Arabian Peninsula. It is bordered by Jordan on the northwest, Iraq on the north and northeast, Kuwait, Qatar, Bahrain, and the United Arab Emirates on the east, Oman on the southeast, and Yemen on the south...
n ancestry are at the highest risk for A1AD. Four percent carry the PiZ
alleleAn allele is one of a series of different forms of a gene. The word is a short form of allelomorph , which was used in the early days of genetics to describe variant forms of a gene detected as different phenotypes...
; between 1 in 625 and 1 in 2000 are homozygous.
Associated diseases
α
1-antitrypsin deficiency has been associated with a number of diseases:
- Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrous scar tissue as well as regenerative nodules , leading to progressive loss of liver function...
- COPD
Chronic obstructive pulmonary disease refers to chronic bronchitis and emphysema, a pair of two commonly co-existing diseases of the lungs in which the airways become narrowed. This leads to a limitation of the flow of air to and from the lungs causing shortness of breath...
- Pneumothorax
In medicine , a pneumothorax is a potential medical emergency wherein air or gas is present in the pleural cavity. A pneumothorax can occur spontaneously. It can also occur as the result of disease or injury to the lung, or due to a puncture to the chest wall...
- Asthma
Asthma is a predisposition to chronic inflammation of the lungs in which the airways are reversibly narrowed. Asthma affects 7% of the population of the United States, and 300 million worldwide...
- Wegener's granulomatosis
Wegener's granulomatosis is a form of vasculitis that affects the lungs, kidneys and other organs. Due to its end-organ damage, it can be a serious disease that requires long-term immunosuppression. It is named after Dr...
- Pancreatitis
Pancreatitis is inflammation of the pancreas that can occur in two very different forms. Acute pancreatitis is sudden while chronic pancreatitis "is characterized by recurring or persistent abdominal pain with or without steatorrhea or diabetes mellitus."...
- Gallstone
In medicine, gallstones are crystalline bodies formed within the body by accretion or concretion of normal or abnormal bile components.Gallstones can occur anywhere within the biliary tree, including the gallbladder and the common bile duct...
s
- Bronchiectasis
Bronchiectasis is a disease state defined by localized, irreversible dilation of part of the bronchial tree. It is classified as an obstructive lung disease, along with bronchitis and cystic fibrosis. Involved bronchi are dilated, inflamed, and easily collapsible, resulting in airflow obstruction...
(possibly)
- Prolapse
Prolapse literally means "To fall out of place". 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 valves of the heart...
- Primary sclerosing cholangitis
Primary 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 and liver failure. The underlying cause of the...
- Autoimmune hepatitis
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 immune response against the body's own liver, resulting in autoimmune hepatitis.Autoimmune hepatitis has an incidence of...
- Emphysema
Emphysema is a lung disease, characterized by an abnormal, permanent enlargement of air spaces distal to the terminal bronchioles. The disease is coupled with the destruction of walls, but without obvious fibrosis...
, predominantly involving the lower lobes and causing bullae
- Cancer
Cancer is a class of diseases in which a group of cells display uncontrolled growth , invasion , and sometimes metastasis...
- Hepatocellular carcinoma
Hepatocellular carcinoma is a primary malignancy of the liver. Most cases of HCC are secondary to either a viral hepatitide infection or cirrhosis...
(liver)
- Bladder carcinoma
- Gallbladder cancer
Gallbladder 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...
- Lymphoma
Lymphoma is a cancer that begins in the lymphocytes of the immune system and presents as a solid tumor of lymphoid cells. They often originate like balls in lymph nodes, presenting as an enlargement of the node...
- Lung cancer
Lung cancer is a disease of uncontrolled cell growth in tissues of the lung. This growth may lead to metastasis, which is the invasion of adjacent tissue and infiltration beyond the lungs. The vast majority of primary lung cancers are carcinomas of the lung, derived from epithelial cells...
History
A1AD was discovered in 1963 by Carl-Bertil Laurell (1919–2001), at the University of Lund in
SwedenSweden , officially the Kingdom of Sweden , is a Nordic country on the Scandinavian Peninsula in Northern Europe...
.
Laurell, along with a medical resident, Sten Eriksson, made the discovery after noting the absence of the α
1 band on protein
electrophoresisElectrophoresis 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 field caused clay particles...
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 diseaseLiver disease is a broad term describing any single number of diseases affecting the liver. Many are accompanied by jaundice caused by increased levels of bilirubin in the system...
was made six years later, when Sharp
et al. described A1AD in the context of liver disease.
External links