Haptoglobin
Encyclopedia
Haptoglobin is a protein
that in humans is encoded by the HP gene
. In blood plasma
, haptoglobin binds free hemoglobin
(Hb) released from erythrocytes with high affinity and thereby inhibits its oxidative activity. The haptoglobin-hemoglobin complex
will then be removed by the reticuloendothelial system
(mostly the spleen
). In clinical settings, the haptoglobulin assay is used to screen for and monitor intravascular . In intravascular hemolysis free hemoglobin will be released into circulation and hence haptoglobin will bind the Hb. This causes a decline in Hp levels. Conversely, in extravascular hemolysis the reticuloendothelial system
, especially -splenic monocytes, phagocytose the erythrocytes and hemoglobin is not released into circulation and hence haptoglobin levels are normal.
, which allows degradative enzymes to gain access to the hemoglobin while at the same time preventing loss of iron through the kidneys and protecting the kidneys from damage by hemoglobin. For this reason it is often referred to as the suicide protein.
, lung
, and kidney
. In addition, the haptoglobin gene is expressed in murine and human adipose tissue.
Haptoglobin had been shown to be expressed in adipose tissue of cattle as well (Saremi et al, 2010).
Hp exists in two allelic forms in the human population, so-called Hp1 and Hp2, the latter one having arisen due to the partial duplication of Hp1 gene. Three genotypes of Hp, therefore, are found in humans: Hp1-1, Hp2-1, and Hp2-2. Hp of different genotype
s have been shown to bind hemoglobin with different affinities, with Hp2-2 being the weakest binder.
and ostrich
but also, in its simpler form, in bony fish, e.g., zebrafish. It is interesting to note that Hp is absent in at least some amphibians (Xenopus
) and neognathous birds (chicken and goose).
, the incidence of coronary artery disease in type 1 diabetes, Crohn's disease
, inflammatory disease behavior, primary sclerosing cholangitis
, susceptibility to idiopathic Parkinson's disease
, and a reduced incidence of Plasmodium falciparum malaria.
Since the reticuloendothelial system will remove the haptoglobin-hemoglobin complex from the body, haptoglobin levels will be decreased in hemolytic anemia
s. In the process of binding hemoglobin, haptoglobin sequesters the iron within hemoglobin, preventing iron-utilizing bacteria from benefiting from hemolysis. It is theorized that, because of this, haptoglobin has evolved into an acute-phase protein. HP has a protective influence on the hemolytic kidney.
Some studies associate certain haptoglobin phenotypes with the risk of developing schizophrenia
.
, such as pallor
, fatigue, or shortness of breath, along with physical signs of hemolysis, such as jaundice
or dark-colored urine. The test is also commonly ordered as a hemolytic anemia battery, which also includes a reticulocyte
count and a peripheral blood smear. It can also be ordered along with a Direct Antiglobulin Test
when a patient is suspected of having a transfusion reaction or symptoms of autoimmune hemolytic anemia
. Also, it may be ordered in conjunction with a bilirubin
.
, especially when correlated with a decreased RBC
count, Hemoglobin
, and Hematocrit
, and also an increased reticulocyte count.
If the reticulocyte count is increased, but the haptoglobin level is normal, this may indicate that cellular destruction is occurring in the spleen
and liver
, which may indicate a drug-induced hemolysis, or a red cell dysplasia
. The spleen and liver recognize an error in the red cells (either Drug coating the red cell membrane or a dysfunctional red cell membrane), and destroy the cell. This type of destruction does not release hemoglobin into the peripheral blood, so the haptoglobin cannot bind to it. Thus, the haptoglobin will stay normal if the hemolysis is not severe. In severe extra-vascular hemolysis, haptoglobin levels can also be low, when large amount of hemoglobin in the reticuloendothelial system leads to transfer of free hemoglobin into plasma.
If there are symptoms of anemia but both the reticulocyte count and the haptoglobin level are normal, the anemia is most likely not due to hemolysis, but instead some other error in cellular production, such as aplastic anemia
Haptoglobin levels that are decreased but do not accompany signs of anemia may indicate liver damage, as the liver is not producing enough haptoglobin to begin with.
As haptoglobin is indeed an acute-phase protein, any inflammatory process (infection, extreme stress, burns, major crush injury, allergy, etc.) may increase the levels of plasma haptoglobin.
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...
that in humans is encoded by the HP gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. In blood plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
, haptoglobin binds free hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
(Hb) released from erythrocytes with high affinity and thereby inhibits its oxidative activity. The haptoglobin-hemoglobin complex
Protein complex
A multiprotein complex is a group of two or more associated polypeptide chains. If the different polypeptide chains contain different protein domain, the resulting multiprotein complex can have multiple catalytic functions...
will then be removed by the reticuloendothelial system
Reticuloendothelial system
"Reticuloendothelial system" is an older term for the mononuclear phagocyte system. The mononuclear phagocyte system consists primarily of monocytes and macrophages. The spleen is the largest unit of the mononuclear phagocyte system. The monocyte is formed in the bone marrow and transported by the...
(mostly the spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
). In clinical settings, the haptoglobulin assay is used to screen for and monitor intravascular . In intravascular hemolysis free hemoglobin will be released into circulation and hence haptoglobin will bind the Hb. This causes a decline in Hp levels. Conversely, in extravascular hemolysis the reticuloendothelial system
Reticuloendothelial system
"Reticuloendothelial system" is an older term for the mononuclear phagocyte system. The mononuclear phagocyte system consists primarily of monocytes and macrophages. The spleen is the largest unit of the mononuclear phagocyte system. The monocyte is formed in the bone marrow and transported by the...
, especially -splenic monocytes, phagocytose the erythrocytes and hemoglobin is not released into circulation and hence haptoglobin levels are normal.
Function
This gene encodes a preproprotein that is processed to yield both alpha and beta chains, which subsequently combine as a tetramer to produce haptoglobin. Haptoglobin functions to bind free plasma hemoglobinHemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
, which allows degradative enzymes to gain access to the hemoglobin while at the same time preventing loss of iron through the kidneys and protecting the kidneys from damage by hemoglobin. For this reason it is often referred to as the suicide protein.
Synthesis
Haptoglobin is produced mostly by hepatocytes but also by other tissues: e.g., skinSkin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
, lung
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
, and kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
. In addition, the haptoglobin gene is expressed in murine and human adipose tissue.
Haptoglobin had been shown to be expressed in adipose tissue of cattle as well (Saremi et al, 2010).
Structure
Haptoglobin, in its simplest form, consists of two α- and two β-chains, connected by disulfide bridges. The chains originate from a common precursor protein, which is proteolytically cleaved during protein synthesis.Hp exists in two allelic forms in the human population, so-called Hp1 and Hp2, the latter one having arisen due to the partial duplication of Hp1 gene. Three genotypes of Hp, therefore, are found in humans: Hp1-1, Hp2-1, and Hp2-2. Hp of different genotype
Genotype
The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...
s have been shown to bind hemoglobin with different affinities, with Hp2-2 being the weakest binder.
In other species
Hp has been found in all mammals studied so far, some birds, e.g., cormorantCormorant
The bird family Phalacrocoracidae is represented by some 40 species of cormorants and shags. Several different classifications of the family have been proposed recently, and the number of genera is disputed.- Names :...
and ostrich
Ostrich
The Ostrich is one or two species of large flightless birds native to Africa, the only living member of the genus Struthio. Some analyses indicate that the Somali Ostrich may be better considered a full species apart from the Common Ostrich, but most taxonomists consider it to be a...
but also, in its simpler form, in bony fish, e.g., zebrafish. It is interesting to note that Hp is absent in at least some amphibians (Xenopus
Xenopus
Xenopus is a genus of highly aquatic frogs native to Sub-Saharan Africa. There are 19 species in the Xenopus genus...
) and neognathous birds (chicken and goose).
Clinical significance
Mutations in this gene and/or its regulatory regions cause or hypohaptoglobinemia. This gene has also been linked to diabetic nephropathyDiabetic nephropathy
Diabetic nephropathy , also known as Kimmelstiel-Wilson syndrome, or nodular diabetic glomerulosclerosis and intercapillary glomerulonephritis, is a progressive kidney disease caused by angiopathy of capillaries in the kidney glomeruli. It is characterized by nephrotic syndrome and diffuse...
, the incidence of coronary artery disease in type 1 diabetes, Crohn's disease
Crohn's disease
Crohn's disease, also known as regional enteritis, is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms...
, inflammatory disease behavior, primary sclerosing cholangitis
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, liver failure and liver cancer...
, susceptibility to idiopathic Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
, and a reduced incidence of Plasmodium falciparum malaria.
Since the reticuloendothelial system will remove the haptoglobin-hemoglobin complex from the body, haptoglobin levels will be decreased in hemolytic anemia
Hemolytic anemia
Hemolytic anemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells , either in the blood vessels or elsewhere in the human body . It has numerous possible causes, ranging from relatively harmless to life-threatening...
s. In the process of binding hemoglobin, haptoglobin sequesters the iron within hemoglobin, preventing iron-utilizing bacteria from benefiting from hemolysis. It is theorized that, because of this, haptoglobin has evolved into an acute-phase protein. HP has a protective influence on the hemolytic kidney.
Some studies associate certain haptoglobin phenotypes with the risk of developing schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
.
Test protocol
Haptoglobin is ordered whenever a patient exhibits symptoms of anemiaAnemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
, such as pallor
Pallor
Pallor is a reduced amount of oxyhaemoglobin in skin or mucous membrane, a pale color which can be caused by illness, emotional shock or stress, stimulant use, lack of exposure to sunlight, anaemia or genetics....
, fatigue, or shortness of breath, along with physical signs of hemolysis, such as jaundice
Jaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
or dark-colored urine. The test is also commonly ordered as a hemolytic anemia battery, which also includes a reticulocyte
Reticulocyte
Reticulocytes are immature red blood cells, typically composing about 1% of the red cells in the human body.Reticulocytes develop and mature in the red bone marrow and then circulate for about a day in the blood stream before developing into mature red blood cells. Like mature red blood cells,...
count and a peripheral blood smear. It can also be ordered along with a Direct Antiglobulin Test
Coombs test
Coombs test refers to two clinical blood tests used in immunohematology and immunology...
when a patient is suspected of having a transfusion reaction or symptoms of autoimmune hemolytic anemia
Autoimmune hemolytic anemia
Autoimmune hemolytic anemia occurs when antibodies directed against the person's own red blood cells cause the RBCs to burst , leading to insufficient plasma concentration. The lifetime of the RBCs is reduced from the normal 100–120 days to just a few days in serious cases...
. Also, it may be ordered in conjunction with a bilirubin
Bilirubin
Bilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...
.
Interpretation
A decrease in haptoglobin can support a diagnosis of hemolytic anemiaHemolytic anemia
Hemolytic anemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells , either in the blood vessels or elsewhere in the human body . It has numerous possible causes, ranging from relatively harmless to life-threatening...
, especially when correlated with a decreased RBC
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
count, Hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
, and Hematocrit
Hematocrit
The hematocrit or packed cell volume or erythrocyte volume fraction is the percentage of the concentration of red blood cells in blood. It is normally about 45% for men and 40% for women...
, and also an increased reticulocyte count.
If the reticulocyte count is increased, but the haptoglobin level is normal, this may indicate that cellular destruction is occurring in the spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
and 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...
, which may indicate a drug-induced hemolysis, or a red cell dysplasia
Dysplasia
Dysplasia , is a term used in pathology to refer to an abnormality of development. This generally consists of an expansion of immature cells, with a corresponding decrease in the number and location of mature cells. Dysplasia is often indicative of an early neoplastic process...
. The spleen and liver recognize an error in the red cells (either Drug coating the red cell membrane or a dysfunctional red cell membrane), and destroy the cell. This type of destruction does not release hemoglobin into the peripheral blood, so the haptoglobin cannot bind to it. Thus, the haptoglobin will stay normal if the hemolysis is not severe. In severe extra-vascular hemolysis, haptoglobin levels can also be low, when large amount of hemoglobin in the reticuloendothelial system leads to transfer of free hemoglobin into plasma.
If there are symptoms of anemia but both the reticulocyte count and the haptoglobin level are normal, the anemia is most likely not due to hemolysis, but instead some other error in cellular production, such as aplastic anemia
Aplastic anemia
Aplastic anemia is a condition where bone marrow does not produce sufficient new cells to replenish blood cells. The condition, per its name, involves both aplasia and anemia...
Haptoglobin levels that are decreased but do not accompany signs of anemia may indicate liver damage, as the liver is not producing enough haptoglobin to begin with.
As haptoglobin is indeed an acute-phase protein, any inflammatory process (infection, extreme stress, burns, major crush injury, allergy, etc.) may increase the levels of plasma haptoglobin.