Introduction

Iron is vital for several metabolic pathways and physiological processes.[1] Maintaining iron homeostasis is essential as a change, either decrease or excess, harms the human body. Transferrin has a high affinity to ferric iron; therefore, there is little free iron in the body as transferrin binds, in essence, all plasma. Transferrin is a blood plasma glycoprotein that plays a central role in iron metabolism and is responsible for ferric-ion delivery. Transferrin functions as the most critical ferric pool in the body. It transports iron through the blood to various tissues, such as the liver, spleen, and bone marrow. It is an essential biochemical marker of body iron status.

Fundamentals

Transferrin is divided into subgroups: serum transferrin, lactotransferrin, and melanotransferrin.[2] Hepatocytes produce serum transferrin, which is found in the serum, cerebrospinal fluid, and semen. Mucosal epithelial cells produce lactotransferrin, seen in bodily secretions such as milk. Lactotransferrin has antioxidants and antimicrobial and anti-inflammatory properties. All plasma iron is bound to transferrin.[3] The transferrin-bound iron complex turnover rate is about ten times a day, essential to meet the daily demands of erythropoiesis.[4] Therefore, transferrin acts as a balance between reticuloendothelial iron release and bone marrow uptake. Once iron is bound to transferrin, it is transported by transferrin to the bone marrow for the production of hemoglobin and portions of erythrocytes. The body loses iron through perspiration, epithelial cell desquamation, and menstruation. Iron loss is obligatory, and no specific means exist to regulate it. Therefore, iron homeostasis hugely depends on the tight regulation of absorption, which occurs mostly in the proximal intestine.[5] Iron-bound transferrin is vital for the distribution of iron to the body's different cells. 

Cellular Level

Transferrin is a free peptide (apotransferrin) that undergoes a conformation change after binding with iron. Iron circulates in the plasma until it attaches to a transferrin receptor on a target cell. A carbonate has to be present to help attract iron to transferrin by creating opposing repulsive charges. Transferrin can bind to two atoms of ferric iron (Fe³⁺) with high affinity. The carbonate needed also serves as a ligand to stabilize iron in the transferrin binding site. Clathrin/receptor-mediated endocytosis mediates the uptake of iron by transferrin receptors.[6] An acidic environment of Ph5.6 reduces iron-transferrin affinity, encouraging iron release from its binding site and endocytoses into a cell.[1]

Molecular Level

Transferrin is a monomeric 80kDA glycoprotein consisting of two homologous lobes called N- and C- lobes.[7] A short peptide connects the two lobes. The carbohydrate moiety is attached to the C-lobe. Each lobe is subdivided into two sub-domains- N1 and N2 for the N-lobe and C1 and C2 for the C-lobe. The sub-domains connect two antiparallel beta-sheets that act as flexible joints. The N and C lobes comprise one aspartic acid, two tyrosine, a histidine, and an arginine.[8] Between each lobe forms a cleft, which allows iron binding. The transferrin molecule is shaped to permit iron binding. The sub-domains open to release iron and close when bound.

Function

Functions of transferrin include:

• Free Fe³⁺ is insoluble at a neutral pH; when iron binds to transferrin, it becomes soluble. 
• Deliver and transfer iron to all the various biological tissues between sites of absorption, utilization, and storage.[9]
• Prevent the formation of reactive oxygen species.
• Chelate-free toxic iron and acts as a protective scavenger.
• Deliver WBC macrophages to all tissues[10]
• Transferrin is a part of the innate immune system; transferrin binding to iron impedes bacterial survival.
• Transferrin acts as a marker for inflammation; the transferrin level decreases during inflammation.

Mechanism

The offloading iron-bound transferrin begins with transferrin binding to its cell surface transferrin receptor. It starts with the formation of clathrin-coated pits and the internalization of the vesicle into the cytoplasm. The coated vesicle loses its clathrin coat due to a reduction in pH. The reduction of pH by hydrogen ion proton pumps (H⁺ ATPase) to a pH of 5.5 causes the dissociation of iron-bound transferrin vesicle to release its iron ions. Also, transferrin binding to transferrin receptors reduces its affinity for iron. Two pathways can occur once endocytosed–degradation or recycling pathways.[11] The degradation pathway is where the dissociation of ferric ions from transferrin occurs from an early and late endosome. Iron can now be utilized for storage or incorporated into hemoglobin. The recycling pathway involves the recycling of transferrin. After the dissociation of iron, transferrin is called apotransferrin. Apotransferrin remains bound to its receptor because it has a high affinity for its receptors at a reduced pH.[11] It recycles back to the plasma membrane, still bound to its receptor. At a neutral pH, apotransferrin dissociates from its receptor to enter the circulation, reload iron, and repeat the cycle. All transferrin receptors eventually follow the degradation pathway for receptor turnover. An example of a cell is an erythroid precursor in the bone marrow. 

Testing

The laboratory's reference range for transferrin is 204-360 mg/dL. Transferrin can assess the body's iron level and other markers. Transferrin level testing is used to determine the cause of anemia, examine iron metabolism, and determine the iron-carrying capacity of the blood. Transferrin saturation levels cannot be interpreted alone. They are used with other laboratory tests, such as serum ferritin and total iron binding capacity. Ferritin is the first marker to become low and, therefore, more sensitive than transferrin in diagnosing iron deficiency anemia.[12] Total or transferrin iron-binding capacity is a test that measures the blood's capacity to bind iron with transferrin. Low transferrin saturation is seen in iron deficiency. 

Clinical Significance

Iron deficiency is recognized as the most prevalent nutritional deficit in the world. The amount of transferrin in the blood indicates the amount of iron in the body. High transferrin signifies low iron, which means there is less iron bound to transferrin, allowing for a high circulation of non-bound iron transferrin in the body, revealing a possible iron deficiency anemia. The liver increases the production of transferrin as a form of homeostasis to enable transferrin to bind to iron and transport it to the cells. Upregulation of transferrin receptors occurs in iron deficiency anemia.[13]  Concerning the percentage of transferrin-iron complex, low iron-bound transferrin indicates low iron levels in the body, which affects hemoglobin and erythropoiesis. The significance of transferrin is that it can detect iron deficiency and can be used to monitor erythropoiesis. In anemia of chronic disease, there is a decreased transferrin level. Causes of low transferrin:

• Liver damage leads to reduced production of transferrin
• Kidney insult or injury leads to loss of transferrin in urine.
• Infection
• Malignancy
• Atransferrinemia: A genetic mutation resulting in the absence of transferrin, which leads to hemosiderosis in the heart and liver, which can lead to heart and liver failure. This condition is treated by plasma infusion.

Low transferrin in plasma indicates iron overload, which means the binding site of transferrin is highly saturated with iron. Iron overload suggests hemochromatosis, which leads to iron deposition on tissues. Other associations with transferrin and its receptors include,

• Diminishing tumor cells when the receptor is used to attract antibodies
• High transferrin saturation increases the risk of cardiovascular mortality if patients have high transferrin saturation (>55%) and LDL levels[14]

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Steere AN, Byrne SL, Chasteen ND, Mason AB. Kinetics of iron release from transferrin bound to the transferrin receptor at endosomal pH. Biochim Biophys Acta. 2012 Mar;1820(3):326-33. [PMC free article: PMC3253137] [PubMed: 21699959]

2.

Wally J, Buchanan SK. A structural comparison of human serum transferrin and human lactoferrin. Biometals. 2007 Jun;20(3-4):249-62. [PMC free article: PMC2547852] [PubMed: 17216400]

3.

Giansanti F, Panella G, Leboffe L, Antonini G. Lactoferrin from Milk: Nutraceutical and Pharmacological Properties. Pharmaceuticals (Basel). 2016 Sep 27;9(4) [PMC free article: PMC5198036] [PubMed: 27690059]

4.

Dautry-Varsat A. Receptor-mediated endocytosis: the intracellular journey of transferrin and its receptor. Biochimie. 1986 Mar;68(3):375-81. [PubMed: 2874839]

5.

Anderson ER, Shah YM. Iron homeostasis in the liver. Compr Physiol. 2013 Jan;3(1):315-30. [PMC free article: PMC3936199] [PubMed: 23720289]

6.

Luck AN, Mason AB. Transferrin-mediated cellular iron delivery. Curr Top Membr. 2012;69:3-35. [PMC free article: PMC4479283] [PubMed: 23046645]

7.

Wally J, Halbrooks PJ, Vonrhein C, Rould MA, Everse SJ, Mason AB, Buchanan SK. The crystal structure of iron-free human serum transferrin provides insight into inter-lobe communication and receptor binding. J Biol Chem. 2006 Aug 25;281(34):24934-44. [PMC free article: PMC1895924] [PubMed: 16793765]

8.

Hall DR, Hadden JM, Leonard GA, Bailey S, Neu M, Winn M, Lindley PF. The crystal and molecular structures of diferric porcine and rabbit serum transferrins at resolutions of 2.15 and 2.60 A, respectively. Acta Crystallogr D Biol Crystallogr. 2002 Jan;58(Pt 1):70-80. [PubMed: 11752780]

9.

Tandara L, Salamunic I. Iron metabolism: current facts and future directions. Biochem Med (Zagreb). 2012;22(3):311-28. [PMC free article: PMC3900049] [PubMed: 23092063]

10.

Gordon S, Plüddemann A. Tissue macrophages: heterogeneity and functions. BMC Biol. 2017 Jun 29;15(1):53. [PMC free article: PMC5492929] [PubMed: 28662662]

11.

Grant BD, Donaldson JG. Pathways and mechanisms of endocytic recycling. Nat Rev Mol Cell Biol. 2009 Sep;10(9):597-608. [PMC free article: PMC3038567] [PubMed: 19696797]

12.

Waldvogel-Abramowski S, Waeber G, Gassner C, Buser A, Frey BM, Favrat B, Tissot JD. Physiology of iron metabolism. Transfus Med Hemother. 2014 Jun;41(3):213-21. [PMC free article: PMC4086762] [PubMed: 25053935]

13.

Bermejo F, García-López S. A guide to diagnosis of iron deficiency and iron deficiency anemia in digestive diseases. World J Gastroenterol. 2009 Oct 07;15(37):4638-43. [PMC free article: PMC2754511] [PubMed: 19787826]

14.

Wells BJ, Mainous AG, King DE, Gill JM, Carek PJ, Geesey ME. The combined effect of transferrin saturation and low density lipoprotein on mortality. Fam Med. 2004 May;36(5):324-9. [PubMed: 15129378]

Disclosure: Aminat Ogun declares no relevant financial relationships with ineligible companies.

Disclosure: Adebayo Adeyinka declares no relevant financial relationships with ineligible companies.