Introduction

Iron is vital for several metabolic pathways and physiological processes.[1] Maintaining iron homeostasis is essential, as both deficiency and excess can be harmful to the human body. Transferrin is a blood plasma glycoprotein that plays a central role in iron metabolism by delivering ferric ions to various tissues, such as the liver, spleen, and bone marrow. Transferrin has a high affinity for ferric iron; therefore, there is little free iron in the body as transferrin binds almost all plasma iron. Transferrin serves as the most critical ferric iron pool in the body and is an essential biochemical marker for determining body iron status.

Fundamentals

Transferrin is divided into 3 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, which is found in bodily secretions such as milk. Lactotransferrin possesses antioxidant, antimicrobial, and anti-inflammatory properties. All plasma iron is bound to transferrin.[3] The turnover rate of the transferrin-iron complex is approximately 10 times per day, which is crucial for meeting the daily demands of erythropoiesis.[4] Therefore, transferrin acts as a balance between iron release from the reticuloendothelial system and iron uptake by the bone marrow. 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 heavily depends on the tight regulation of absorption, which primarily occurs in the proximal part of the intestine.[5] Iron-bound transferrin is vital for distributing iron to cells throughout the body.

Cellular Level

Transferrin is a free peptide, known as 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 2 atoms of ferric iron (Fe³⁺) with high affinity. The carbonate also serves as a ligand to stabilize iron in the transferrin binding site. Clathrin/receptor-mediated endocytosis facilitates the uptake of iron by transferrin receptors.[6] An acidic environment with a pH of 5.6 reduces the affinity of iron-transferrin, encouraging iron release from its binding site and facilitating endocytosis into a cell.[1]

Molecular Level

Transferrin is a monomeric glycoprotein with a molecular weight of 80 kDa, consisting of 2 homologous lobes called N- and C-lobes.[7] A short peptide connects the 2 lobes. The carbohydrate moiety is attached to the C-lobe. Each lobe is subdivided into 2 subdomains—N1 and N2 in the N-lobe and C1 and C2 in the C-lobe. The sub-domains connect 2 antiparallel beta-sheets that act as flexible joints. The N- and C-lobes comprise 1 aspartic acid, 2 tyrosine residues, 1 histidine, and 1 arginine.[8] Between each lobe, a cleft is formed, which allows iron binding to occur. The transferrin molecule is shaped to permit iron binding. The subdomains open to release iron and close when bound.

Function

The functions of transferrin include:

• Free Fe³⁺ is insoluble at a neutral pH; when iron binds to transferrin, it becomes soluble. 
• Delivers and transfers iron to all the various biological tissues between sites of absorption, utilization, and storage.[9]
• Prevents the formation of reactive oxygen species.
• Chelates free toxic iron and acts as a protective scavenger.
• Delivers white blood cell macrophages to all tissues [10]
• Contributes to innate immunity by binding iron, thereby impeding bacterial survival.
• Serves as a marker for inflammation; the transferrin level decreases during periods of inflammation.

Mechanism

The offloading of iron-bound transferrin begins with transferrin binding to its cell surface transferrin receptor. The process 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 the iron-bound transferrin vesicle to release its iron ions. Additionally, transferrin binding to transferrin receptors reduces its affinity for iron. Once endocytosis occurs, two pathways can take place—degradation or recycling pathways.[11] 

• Degradation pathway: The degradation pathway is where the dissociation of ferric ions from transferrin occurs in the early and late endosomes. Iron can now be utilized for storage or incorporated into hemoglobin.
• Recycling pathway: The recycling pathway involves the recycling of transferrin. After the dissociation of iron, transferrin is referred to as apotransferrin. Apotransferrin remains bound to its receptor due to its high affinity for its receptors at a reduced pH.[11] The apotransferrin-receptor complex recycles back to the plasma membrane. At a neutral pH, apotransferrin dissociates from its receptor to enter the circulation, reload iron, and repeat the cycle.

Ultimately, 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 reference range for transferrin is between 204 and 360 mg/dL. Transferrin can assess the body's iron level and other markers. Testing transferrin levels can help 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 must be assessed alongside other tests, such as serum ferritin and total iron-binding capacity. Ferritin is the first marker to become low, and therefore, it is 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 typically associated with iron deficiency. 

Clinical Significance

Iron deficiency is the most common nutritional deficiency worldwide. Transferrin is a blood protein that binds to and transports iron. When iron levels are low, the body increases transferrin production to enhance iron capture, resulting in high transferrin levels but low transferrin saturation. This imbalance indicates that a significant portion of the transferrin is unbound, a key sign of iron deficiency anemia. The liver increases the production of transferrin as a form of homeostasis, enabling transferrin to bind to iron and transport it to cells. Upregulation of transferrin receptors occurs in iron deficiency anemia.[13]  Regarding the percentage of transferrin-iron complex, low iron-bound transferrin indicates low iron levels in the body, which in turn affects hemoglobin and erythropoiesis. Transferrin is therefore valuable not only in detecting iron deficiency but also in monitoring erythropoietic activity. In anemia of chronic disease, there is a decreased level of transferrin. The common causes of low transferrin are as follows:

• Liver damage leads to reduced production of transferrin
• Kidney injury leads to loss of transferrin in urine
• Infection
• Malignancy
• Atransferrinemia: A rare genetic disorder caused by mutations leading to the absence of transferrin. This condition results in hemosiderosis in the heart and liver, potentially leading to heart and liver failure. Treatment typically involves plasma infusion.

Low levels of transferrin in plasma indicate iron overload, which means the binding site of transferrin is highly saturated with iron. Iron overload suggests hemochromatosis, a condition that leads to the deposition of iron in 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 low-density lipoprotein levels [14]

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

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