Haptoglobin

Haptoglobin
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 4WJG, 4X0I, 4X0L
Identifiers
Symbols	HP ; BP; HP2ALPHA2; HPA1S
External IDs	OMIM: 140100 MGI: 96211 HomoloGene: 121756 GeneCards: HP Gene
Gene ontology Molecular function • protein binding • antioxidant activity • hemoglobin binding Cellular component • extracellular region • extracellular space • haptoglobin-hemoglobin complex • extracellular exosome • endocytic vesicle lumen • blood microparticle Biological process • immune system process • receptor-mediated endocytosis • defense response • acute-phase response • positive regulation of cell death • response to hydrogen peroxide • defense response to bacterium • negative regulation of oxidoreductase activity • negative regulation of hydrogen peroxide catabolic process Sources: Amigo / QuickGO
RNA expression pattern
File:PBB GE HP 206697 s at tn.png
File:PBB GE HPR 208470 s at tn.png
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3240	15439
Ensembl	ENSG00000257017	ENSMUSG00000031722
UniProt	P00738	Q61646
RefSeq (mRNA)	NM_001126102	NM_017370
RefSeq (protein)	NP_001119574	NP_059066
Location (UCSC)	Chr 16: 72.05 – 72.06 Mb	Chr 8: 109.58 – 109.58 Mb
PubMed search	[1]	[2]

File:Hem-hap 4f4o.jpg

A model of α,β-hemoglobin/haptoglobin hexamer complex. There are 2 α,β-hemoglobin dimers depicted: one space filling model (yellow/orange), and one ribbon model (purple/blue). Each is bound by a haptoglobin molecule (both haptoglobin molecules are shown in pink, with one as a space filling model and one as a ribbon model).

Haptoglobin (abbreviated as Hp) is the protein that in humans is encoded by the HP gene. In blood plasma, haptoglobin binds free hemoglobin (Hb) released from erythrocytes with low 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 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 extravascular hemolysis the reticuloendothelial system, especially splenic monocytes, phagocytose the erythrocytes and hemoglobin is relatively not released into circulation; however, excess hemolysis can release some hemoglobin causing haptoglobin levels to be decreased. Therefore haptoglobin is not a reliable way to differentiate between intravascular and extravascular hemolysis.

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 hemoglobin, 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 such as skin, 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.

Structure

Haptoglobin, in its simplest form, consists of two alpha and two beta 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 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 mammals studied so far, some birds, e.g., cormorant 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).

Clinical significance

Mutations in this gene or its regulatory regions cause ahaptoglobinemia or hypohaptoglobinemia. This gene has also been linked to diabetic nephropathy, 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 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 acute-phase protein. HP has a protective influence on the hemolytic kidney.

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

Test protocol

Haptoglobin is ordered whenever a patient exhibits symptoms of anemia, 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.

Interpretation

A decrease in haptoglobin can support a diagnosis of hemolytic anemia, especially when correlated with a decreased red blood cell 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.

See Also

• Hemopexin
• Haptoglobin-related protein

References

• This article incorporates text from the United States National Library of Medicine, which is in the public domain.

External links

• Haptoglobins at the US National Library of Medicine Medical Subject Headings (MeSH)