Haptoglobin (abbreviated as Hp) is a protein that in humans is encoded by the HP gene.[1][2] 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 hemolytic anemia. 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.
Function edit
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.[3] For this reason it is often referred to as the suicide protein.
Synthesis edit
Haptoglobin is produced mostly by hepatocytes but also by other tissues: e.g., skin, lung, and kidney. In addition, the haptoglobin gene is expressed in murine and human adipose tissue.[4]
Haptoglobin had been shown to be expressed in adipose tissue of cattle as well (Saremi et al, 2010).
Structure edit
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 genotypes have been shown to bind hemoglobin with different affinities, with Hp2-2 being the weakest binder.
In other species edit
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 edit
Mutations in this gene and/or its regulatory regions cause ahaptoglobinemia or hypohaptoglobinemia. This gene has also been linked to diabetic nephropathy,[5] the incidence of coronary artery disease in type 1 diabetes,[6] Crohn's disease,[7] inflammatory disease behavior, primary sclerosing cholangitis, susceptibility to idiopathic Parkinson's disease,[8] and a reduced incidence of Plasmodium falciparum malaria.[9]
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.[10][11]
Some studies associate certain haptoglobin phenotypes with the risk of developing schizophrenia.[12]
Test protocol edit
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 edit
A decrease in haptoglobin can support a diagnosis of hemolytic anemia, 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.[13]
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.
References edit
- ^ Dobryszycka W (1997). "Biological functions of haptoglobin--new pieces to an old puzzle". Eur J Clin Chem Clin Biochem. 35 (9): 647–54. PMID 9352226.
{{cite journal}}: Unknown parameter|month=ignored (help) - ^ Wassell J (2000). "Haptoglobin: function and polymorphism". Clin. Lab. 46 (11–12): 547–52. PMID 11109501.
- ^ "Entrez Gene: HP".
- ^ Trayhurn P, Wood IS (2004). "Adipokines: inflammation and the pleiotropic role of white adipose tissue". Br. J. Nutr. 92 (3): 347–55. doi:10.1079/BJN20041213. PMID 15469638.
{{cite journal}}: Unknown parameter|month=ignored (help) - ^ Asleh R, Levy AP (2005). "In vivo and in vitro studies establishing haptoglobin as a major susceptibility gene for diabetic vascular disease". Vasc Health Risk Manag. 1 (1): 19–28. doi:10.2147/vhrm.1.1.19.58930. PMC 1993923. PMID 17319095.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Sadrzadeh SM, Bozorgmehr J (2004). "Haptoglobin phenotypes in health and disorders". Am. J. Clin. Pathol. 121 Suppl: S97–104. PMID 15298155.
{{cite journal}}: Unknown parameter|month=ignored (help) - ^ Papp M, Lakatos PL, Palatka K, Foldi I, Udvardy M, Harsfalvi J, Tornai I, Vitalis Z, Dinya T, Kovacs A, Molnar T, Demeter P, Papp J, Lakatos L, Altorjay I (2007). "Haptoglobin polymorphisms are associated with Crohn's disease, disease behavior, and extraintestinal manifestations in Hungarian patients". Dig. Dis. Sci. 52 (5): 1279–84. doi:10.1007/s10620-006-9615-1. PMID 17357835.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Costa-Mallen P, Checkoway H, Zabeti A, Edenfield MJ, Swanson PD, Longstreth WT, Franklin GM, Smith-Weller T, Sadrzadeh SM (2008). "The functional polymorphism of the hemoglobin-binding protein haptoglobin influences susceptibility to idiopathic Parkinson's disease". Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B (2): 216–22. doi:10.1002/ajmg.b.30593. PMID 17918239.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Prentice AM, Ghattas H, Doherty C, Cox SE (2007). "Iron metabolism and malaria". Food Nutr Bull. 28 (4 Suppl): S524–39. PMID 18297891.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Pintera J (1968). "The protective influence of haptoglobin on hemoglobinuric kidney. I. Biochemical and macroscopic observations". Folia Haematol. Int. Mag. Klin. Morphol. Blutforsch. 90 (1): 82–91. PMID 4176393.
- ^ Miederer SE, Hotz J (1969). "[Pathogenesis of kidney hemolysis]". Bruns Beitr Klin Chir (in German). 217 (7): 661–5. PMID 5404273.
{{cite journal}}: Unknown parameter|month=ignored (help) - ^ Gene Overview of All Published Schizophrenia-Association Studies for HP - SzGene database at Schizophrenia Research Forum.
- ^ Temple, Victor. "HEMOLYSIS AND JAUNDICE: An overview" (PDF). Retrieved 9 July 2011.
13. Saremi, B., M. Mielenz, A. Hosseini, C. Behrendt, S. Vorspohl, H. Sauerwein. 2010. Haptoglobin expression in different adipose tissues and adipocytes (in vitro) of dairy cattle. 19th DVG conference proceeding, Germany.
Further reading edit
External links edit
- Haptoglobins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
This article incorporates text from the United States National Library of Medicine, which is in the public domain.