Haptoglobin

Haptoglobin (abbreviated as Hp) is the is_associated_with::protein that in humans is encoded by the HP is_associated_with::gene. In is_associated_with::blood plasma, haptoglobin binds free is_associated_with::hemoglobin (Hb) released from is_associated_with::erythrocytes with high affinity and thereby inhibits its is_associated_with::oxidative activity. The haptoglobin-hemoglobin complex will then be removed by the is_associated_with::reticuloendothelial system (mostly the is_associated_with::spleen). In clinical settings, the haptoglobulin assay is used to screen for and monitor intravascular is_associated_with::hemolytic anemia. In intravascular hemolysis, free hemoglobin will be released into circulation and hence haptoglobin will bind the hemoglobin. This causes a decline in haptoglobin levels. Conversely, in is_associated_with::extravascular hemolysis the is_associated_with::reticuloendothelial system, especially splenic monocytes, phagocytose the erythrocytes and hemoglobin is not released into circulation; serum haptoglobin levels are therefore 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 is_associated_with::hemoglobin, which allows is_associated_with::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 is_associated_with::hepatocytes but also by other tissues such as is_associated_with::skin, is_associated_with::lung and is_associated_with::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.

Structure
Haptoglobin, in its simplest form, consists of two alpha and two beta chains, connected by is_associated_with::disulfide bridges. The chains originate from a common precursor protein, which is proteolytically cleaved during protein synthesis.

Hp exists in two is_associated_with::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 is_associated_with::genotypes 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 is_associated_with::mammals studied so far, some birds, e.g., is_associated_with::cormorant and is_associated_with::ostrich but also, in its simpler form, in is_associated_with::bony fish, e.g., is_associated_with::zebrafish. It is interesting to note that Hp is absent in at least some is_associated_with::amphibians (is_associated_with::Xenopus) and neognathous birds (chicken and goose).

Clinical significance
Mutations in this gene or its regulatory regions cause mutation_results_in::ahaptoglobinemia or hypohaptoglobinemia. This gene has also been linked to is_associated_with::diabetic nephropathy, the incidence of coronary artery disease in type 1 diabetes, is_associated_with::Crohn's disease, inflammatory disease behavior, is_associated_with::primary sclerosing cholangitis, susceptibility to idiopathic is_associated_with::Parkinson's disease, and a reduced incidence of is_associated_with::Plasmodium falciparum is_associated_with::malaria.

Since the reticuloendothelial system will remove the haptoglobin-hemoglobin complex from the body, haptoglobin levels will be decreased in is_associated_with::hemolytic anemias. 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 is_associated_with::acute-phase protein. HP has a protective influence on the hemolytic kidney.

Some studies associate certain haptoglobin phenotypes with the risk of developing is_associated_with::schizophrenia.

Test protocol
Haptoglobin is ordered whenever a patient exhibits symptoms of is_associated_with::anemia, such as is_associated_with::pallor, fatigue, or shortness of breath, along with physical signs of hemolysis, such as is_associated_with::jaundice or dark-colored urine. The test is also commonly ordered as a hemolytic anemia battery, which also includes a is_associated_with::reticulocyte count and a is_associated_with::peripheral blood smear. It can also be ordered along with a direct antiglobulin test when a patient is suspected of having a is_associated_with::transfusion reaction or symptoms of is_associated_with::autoimmune hemolytic anemia. Also, it may be ordered in conjunction with a is_associated_with::bilirubin.

Interpretation
A decrease in haptoglobin can support a diagnosis of is_associated_with::hemolytic anemia, especially when correlated with a decreased is_associated_with::red blood cell count, is_associated_with::hemoglobin, and is_associated_with::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 is_associated_with::spleen and is_associated_with::liver, which may indicate a is_associated_with::drug-induced hemolysis, or a red cell is_associated_with::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 is_associated_with::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 is_associated_with::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 is_associated_with::acute-phase protein, any inflammatory process (infection, extreme stress, burns, major crush injury, allergy, etc.) may increase the levels of plasma haptoglobin.