Haptoglobin

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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 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 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 combines 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 hepatic cells 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

Measuring the level of haptoglobin in a patient's blood 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.

Further reading

• Graversen JH, Madsen M, Moestrup SK (2002). "CD163: a signal receptor scavenging haptoglobin-hemoglobin complexes from plasma". Int. J. Biochem. Cell Biol. 34 (4): 309–14. doi:10.1016/S1357-2725(01)00144-3. PMID 11854028.
• Madsen M, Graversen JH, Moestrup SK (2002). "Haptoglobin and CD163: captor and receptor gating hemoglobin to macrophage lysosomes". Redox Rep. 6 (6): 386–8. doi:10.1179/135100001101536490. PMID 11865982.
• Erickson LM, Kim HS, Maeda N (1993). "Junctions between genes in the haptoglobin gene cluster of primates". Genomics. 14 (4): 948–58. doi:10.1016/S0888-7543(05)80116-8. PMID 1478675.
• Maeda N (1985). "Nucleotide sequence of the haptoglobin and haptoglobin-related gene pair. The haptoglobin-related gene contains a retrovirus-like element". J. Biol. Chem. 260 (11): 6698–709. PMID 2987228.
• Simmers RN, Stupans I, Sutherland GR (1986). "Localization of the human haptoglobin genes distal to the fragile site at 16q22 using in situ hybridization". Cytogenet. Cell Genet. 41 (1): 38–41. doi:10.1159/000132193. PMID 3455911.
• van der Straten A, Falque JC, Loriau R, Bollen A, Cabezón T (1986). "Expression of cloned human haptoglobin and alpha 1-antitrypsin complementary DNAs in Saccharomyces cerevisiae". DNA. 5 (2): 129–36. doi:10.1089/dna.1986.5.129. PMID 3519135.
• Bensi G, Raugei G, Klefenz H, Cortese R (1985). "Structure and expression of the human haptoglobin locus". EMBO J. 4 (1): 119–26. PMC 554159. PMID 4018023.
• Malchy B, Dixon GH (1973). "Studies on the interchain disulfides of human haptoglobins". Can. J. Biochem. 51 (3): 249–64. doi:10.1139/o73-032. PMID 4573324.
• Raugei G, Bensi G, Colantuoni V, Romano V, Santoro C, Costanzo F, Cortese R (1983). "Sequence of human haptoglobin cDNA: evidence that the alpha and beta subunits are coded by the same mRNA". Nucleic Acids Res. 11 (17): 5811–9. doi:10.1093/nar/11.17.5811. PMC 326319. PMID 6310515.
• Yang F, Brune JL, Baldwin WD, Barnett DR, Bowman BH (1983). "Identification and characterization of human haptoglobin cDNA". Proc. Natl. Acad. Sci. U.S.A. 80 (19): 5875–9. doi:10.1073/pnas.80.19.5875. PMC 390178. PMID 6310599.
• Maeda N, Yang F, Barnett DR, Bowman BH, Smithies O (1984). "Duplication within the haptoglobin Hp2 gene". Nature. 309 (5964): 131–5. doi:10.1038/309131a0. PMID 6325933.
• Brune JL, Yang F, Barnett DR, Bowman BH (1984). "Evolution of haptoglobin: comparison of complementary DNA encoding Hp alpha 1S and Hp alpha 2FS". Nucleic Acids Res. 12 (11): 4531–8. doi:10.1093/nar/12.11.4531. PMC 318856. PMID 6330675.
• van der Straten A, Herzog A, Cabezón T, Bollen A (1984). "Characterization of human haptoglobin cDNAs coding for alpha 2FS beta and alpha 1S beta variants". FEBS Lett. 168 (1): 103–7. doi:10.1016/0014-5793(84)80215-X. PMID 6546723.
• vander Straten A, Herzog A, Jacobs P, Cabezón T, Bollen A (1984). "Molecular cloning of human haptoglobin cDNA: evidence for a single mRNA coding for alpha 2 and beta chains". EMBO J. 2 (6): 1003–7. PMC 555221. PMID 6688992.
• Kurosky A, Barnett DR, Lee TH, Touchstone B, Hay RE, Arnott MS, Bowman BH, Fitch WM (1980). "Covalent structure of human haptoglobin: a serine protease homolog". Proc. Natl. Acad. Sci. U.S.A. 77 (6): 3388–92. doi:10.1073/pnas.77.6.3388. PMC 349621. PMID 6997877.
• Eaton JW, Brandt P, Mahoney JR, Lee JT (1982). "Haptoglobin: a natural bacteriostat". Science. 215 (4533): 691–3. doi:10.1126/science.7036344. PMID 7036344.
• Kazim AL, Atassi MZ (1980). "Haemoglobin binding with haptoglobin. Unequivocal demonstration that the beta-chains of human haemoglobin bind to haptoglobin". Biochem. J. 185 (1): 285–7. PMC 1161299. PMID 7378053.
• Hillier LD, Lennon G, Becker M, Bonaldo MF, Chiapelli B, Chissoe S, Dietrich N, DuBuque T, Favello A, Gish W, Hawkins M, Hultman M, Kucaba T, Lacy M, Le M, Le N, Mardis E, Moore B, Morris M, Parsons J, Prange C, Rifkin L, Rohlfing T, Schellenberg K, Bento Soares M, Tan F, Thierry-Meg J, Trevaskis E, Underwood K, Wohldman P, Waterston R, Wilson R, Marra M (1997). "Generation and analysis of 280,000 human expressed sequence tags". Genome Res. 6 (9): 807–28. doi:10.1101/gr.6.9.807. PMID 8889549.
• Tabak S, Lev A, Valansi C, Aker O, Shalitin C (1997). "Transcriptionally active haptoglobin-related (Hpr) gene in hepatoma G2 and leukemia molt-4 cells". DNA Cell Biol. 15 (11): 1001–7. doi:10.1089/dna.1996.15.1001. PMID 8945641.
• Koda Y, Soejima M, Yoshioka N, Kimura H (1998). "The haptoglobin-gene deletion responsible for anhaptoglobinemia". American Journal of Human Genetics. 62 (2): 245–52. doi:10.1086/301701. PMC 1376878. PMID 9463309.

External links

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