Haptoglobin

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Haptoglobin
Identifiers
Symbols HP ; BP; HP2ALPHA2; HPA1S
External IDs OMIM140100 MGI96211 HomoloGene121756 GeneCards: HP Gene
RNA expression pattern
PBB GE HP 206697 s at tn.png
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:
72.09 – 72.09 Mb
Chr 8:
109.58 – 109.58 Mb
PubMed search [1] [2]
A model of α,β-hemoglobin/haptoglobin hexamer complex

Haptoglobin (abbreviated as Hp) is the 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 hemoglobin. This causes a decline in haptoglobin levels. Conversely, in extravascular hemolysis the reticuloendothelial system, especially splenic monocytes, phagocytose the erythrocytes and hemoglobin is not released into circulation; serum haptoglobin levels are therefore normal.

Function[edit]

Haptoglobin level is used to determine whether hematology needs to be consulted for hemolytic anemia. 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. [5]

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,[6] the incidence of coronary artery disease in type 1 diabetes,[7] Crohn's disease,[8] inflammatory disease behavior, primary sclerosing cholangitis, susceptibility to idiopathic Parkinson's disease,[9] and a reduced incidence of Plasmodium falciparum malaria.[10]

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.[11][12]

Some studies associate certain haptoglobin phenotypes with the risk of developing schizophrenia.[13]

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 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.[14]

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[edit]

References[edit]

  1. ^ Dobryszycka W (September 1997). "Biological functions of haptoglobin--new pieces to an old puzzle". Eur J Clin Chem Clin Biochem 35 (9): 647–54. PMID 9352226. 
  2. ^ Wassell J (2000). "Haptoglobin: function and polymorphism". Clin. Lab. 46 (11–12): 547–52. PMID 11109501. 
  3. ^ "Entrez Gene: HP". 
  4. ^ Trayhurn P, Wood IS (September 2004). "Adipokines: inflammation and the pleiotropic role of white adipose tissue". Br. J. Nutr. 92 (3): 347–55. doi:10.1079/BJN20041213. PMID 15469638. 
  5. ^ Saremi B, Al-Dawood A, Winand S, Müller U, Pappritz J, von Soosten D, Rehage J, Dänicke S, Häussler S, Mielenz M, Sauerwein H (May 2012). "Bovine haptoglobin as an adipokine: Serum concentrations and tissue expression in dairy cows receiving a conjugated linoleic acids supplement throughout lactation". Vet Immunol Immunopathol. 146 (3-4): 201–11. doi:10.1016/j.vetimm.2012.03.011. PMID 22498004. 
  6. ^ 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. 
  7. ^ Sadrzadeh SM, Bozorgmehr J (June 2004). "Haptoglobin phenotypes in health and disorders". Am. J. Clin. Pathol. 121 Suppl: S97–104. PMID 15298155. 
  8. ^ 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 (May 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. 
  9. ^ Costa-Mallen P, Checkoway H, Zabeti A, Edenfield MJ, Swanson PD, Longstreth WT, Franklin GM, Smith-Weller T, Sadrzadeh SM (March 2008). "The functional polymorphism of the hemoglobin-binding protein haptoglobin influences susceptibility to idiopathic Parkinson's disease". American Journal of Medical Genetics 147B (2): 216–22. doi:10.1002/ajmg.b.30593. PMID 17918239. 
  10. ^ Prentice AM, Ghattas H, Doherty C, Cox SE (December 2007). "Iron metabolism and malaria". Food Nutr Bull 28 (4 Suppl): S524–39. PMID 18297891. 
  11. ^ 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. 
  12. ^ Miederer SE, Hotz J (December 1969). "[Pathogenesis of kidney hemolysis]". Bruns Beitr Klin Chir (in German) 217 (7): 661–5. PMID 5404273. 
  13. ^ Gene Overview of All Published Schizophrenia-Association Studies for HP - SzGene database at Schizophrenia Research Forum.
  14. ^ Temple, Victor. "HEMOLYSIS AND JAUNDICE: An overview". Retrieved 9 July 2011. 

Further reading[edit]

External links[edit]