What is Transferrin + High & Low Levels

Biochemistry, Transferrin

What is Transferrin + High & Low Levels

Iron is a vital element for several metabolic pathways and physiological processes[1]. The maintenance of iron homeostasis is essential as a change either decrease or excess pose harmful to 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, which 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.

Transferrin divides into subgroups; these are serum transferrin, lactotransferrin, and melanotransferrin[2]. Hepatocytes produce serum transferrin found in the serum, CSF, and semen.   Mucosal epithelial cells produce lactotransferrin seen in bodily secretions such as milk.

Lactotransferrin has antioxidants, 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, which is 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 production of hemoglobin and portions of erythrocytes.

The human body loses iron through perspiration, epithelial cell desquamation, and menstruation. Iron loss is obligatory, and there are no specific means to regulate it.

Therefore, iron homeostasis is hugely dependent on the tight regulation of absorption, which occurs mostly in the proximal intestine[5]. The iron-bound transferrin is vital to distribute iron to the different cells of the body.    

Transferrin is a free peptide (apotransferin) 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 (CO) 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 binding site of transferrin. Clathrin/receptor-mediated endocytosis mediates the uptake of iron by transferrin receptors[6].  An acidic environment of Ph5.

6 reduces iron-transferrin affinity, which encourages the release of iron from its binding site and endocytosed into a cell[1].    

Transferrin is a monomeric 80kDA glycoprotein, which consists 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 further 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 are made up of one aspartic acid, two tyrosine, a histidine, and an arginine[8]. Between each lobe forms a cleft, which allows iron binding. The transferrin molecule shaped to permit iron binding.

The sub-domains open to release iron and close when bound.

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 act as a protective scavenger.
  • Deliver WBC macrophages to all tissues[10]
  • Transferrin is a part of the innate immune system, the binding of transferrin to iron impedes bacterial survival.
  • Transferrin acts as a marker for inflammation; the level of transferrin decreases during inflammation.

The process of offloading iron-bound transferrin begins with transferrin binding to its cell surface transferrin receptor. It starts with the formation of clathrin-coated pits and 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, the binding of transferrin 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 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. 

In the laboratory, the reference range for transferrin is 204-360 mg/dL. Transferrin can be used to assess the iron level in the body along with other markers in the body. 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 solely read in isolation but in conjunction with other laboratory tests such as serum ferritin and TIBC. Ferritin is the first marker to become low, therefore more sensitive than transferrin in diagnosing Iron deficiency anemia[12].

  Total or Transferrin iron binding capacity (TIBC) is a test which measures the blood capacity to bind iron with transferrin.

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 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 leading 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 will lead to deposition of iron on tissues.

Other associations with transferrin and its receptors include,

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

To access free multiple choice questions on this topic, click here.

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Source: https://www.ncbi.nlm.nih.gov/books/NBK532928/

A guide to diagnosis of iron deficiency and iron deficiency anemia in digestive diseases

What is Transferrin + High & Low Levels

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Increased Serum Transferrin Saturation Is Associated with Lower Serum Transferrin Receptor Concentration

What is Transferrin + High & Low Levels

Background: Serum transferrin receptor (sTfR) concentrations are increased in iron deficiency. We wished to examine whether they are decreased in the presence of potential iron-loading conditions, as reflected by increased transferrin saturation (TS) on a single occasion.

Methods: We compared sTfR concentrations between 570 controls with normal iron status and 189 cases with increased serum TS on a single occasion; these latter individuals may be potential cases of iron overload.

Cases and controls were selected from adults who had been examined in the third National Health and Nutrition Examination Survey (1988–1994) and for whom excess sera were available to perform sTfR measurements after the survey’s completion.

Increased TS was defined as >60% for men and >55% for women; normal iron status was defined as having no evidence of iron deficiency, iron overload, or inflammation indicated by serum ferritin, TS, erythrocyte protoporphyrin, and C-reactive protein.

Results: Mean sTfR and mean log sTfR:ferritin were ∼10% and 24% lower, respectively, in cases than in controls (P 55% for women. These particular cutoffs were chosen because they had been used in a previous study of high TS values conducted by the CDC (15).

Because serum ferritin (SF) values can be increased in inflammatory conditions (16) as well as in individuals with high body iron stores, we did not use SF as a criterion to select cases.

In addition, a SF concentration within the reference interval does not necessarily preclude the possibility of hereditary hemochromatosis; it is also possible that affected individuals will not have increased SF concentrations because they have not yet developed substantial hepatic iron overload (17).

Normal iron status

Normal iron status was defined as having no evidence of iron deficiency, iron overload, or inflammation. To exclude those with iron deficiency, we excluded individuals with abnormal values for two or more of the following: SF, TS, or free erythrocyte protoporphyrin (FEP).

Cutoff values indicative of iron deficiency for these variables have been published previously (18).

We used a multivariable approach to define iron deficiency rather than excluding individuals with a single abnormal value because of the well-known overlap between normal and abnormal values in iron status indicators when assessing iron deficiency (19).

We also excluded individuals with high values for either TS (as defined previously) or SF (>400 μg/L for men, >200 μg/L for women 20–49 years of age, and >300 μg/L for women ≥50 years of age) (16). Finally, individuals with C-reactive protein values >10 mg/L were deleted to remove individuals with possible inflammation (19).

We selected all individuals in the excess sera pool who had increased TS on a single occasion to serve as cases. Three controls were selected at random from among those individuals in the excess sera pool who had normal iron status and who matched cases on single year of age, sex, and race or ethnicity.

There were 26 adults in NHANES III who had high TS values on a single occasion but did not have excess sera.

When compared with the actual high TS cases in our study, these 26 potential cases differed significantly only on 4 of the 14 selected demographic and biochemical characteristics considered in the present study: age, hematocrit, alanine aminotransferase (ALT), and aspartate aminotransferase (AST).

Potential cases without excess sera were older and had higher values of the three serum analytes than did cases with excess sera. Further analyses of the 26 potential cases without excess sera revealed that the significant difference in ALT and AST was attributable entirely to one individual with AST and ALT values that far exceeded those of the other potential cases (e.g.

, were outliers); when this potential case was deleted, ALT and AST values no longer differed between cases with and without excess sera. There were 793 potential normal iron status controls who matched cases on age, sex, and race or ethnicity but did not have excess sera.

These potential controls differed from the potential controls who did have excess sera for only 2 of the 11 biochemical variables included in this study: hematocrit (higher in potential controls without excess sera) and lactate dehydrogenase (lower in potential controls without excess sera). Furthermore, for each high TS case, there was an mean of 24 potential controls with excess sera (range, 2–55) available to be randomly selected as one of the three matched controls; thus it is unly that lack of excess sera introduced serious bias into our random selection of matched controls.

laboratory analyses

In the present study, we kept the excess sera samples frozen at −70 °C after their receipt from the storage bank until assayed for sTfR. We did not perform sTfR assays on hemolyzed samples. We measured sTfR using the Ramco TfR test kit (Ramco Laboratories). This assay is an enzyme immunoassay the double antibody sandwich method.

We diluted plasma or serum samples in buffer and pipetted them into microwells precoated with polyclonal antibody to TfR. We added horseradish peroxidase-conjugated murine monoclonal antibody specific for TfR to the wells and incubated for 2 h at room temperature.

We removed any unbound TfR and excess horseradish peroxidase conjugate from the wells by washing. We then added enzyme substrate to the wells. After the addition of an acid “stop” solution, we measured the product of the enzymatic reaction in a microplate reader (Multiskan MS) at 450 nm.

The absorbance of the resulting solution is directly proportional to the concentration of the TfR in the unknown samples and in the calibrators. We generated a calibration curve by plotting the absorbance values vs the concentration of the TfR calibrators provided in the kit.

We determined the concentration of the TfR in the sample by comparing the sample’s absorbance reading with the calibration curve graph with the aid of Genesis Lite software (Life Sciences International).

The other biochemical measures used in the present study were assayed as part of the main survey. Because details of the assay methods for these measures have been published elsewhere (20), they will only be summarized briefly here.

Hemoglobin, hematocrit, and red cell distribution width were measured in the mobile examination centers, using a Coulter S-Plus Jr electronic counter (Coulter Electronics) (14)(20).

Assays for the remaining iron status indicators used in the present study were performed by the Division of Environmental Health Laboratory Sciences, National Center for Environmental Health, CDC, Atlanta GA. TS was calculated by dividing serum iron by total iron binding capacity.

Serum iron and total iron binding capacity were measured colorimetrically with an ALPKEM RFA analyzer (Alpkem), and 10 g/L thiourea was added to complex Cu2+ to prevent copper interference (20). Serum iron and total iron binding capacity were not measured on hemolyzed samples. FEP was measured via fluorescence extraction, and SF was measured with the Bio-Rad Quantimmume IRMA kit (Bio-Rad Laboratories).

Because both SF and sTfR data were available in the present study, it was also possible to examine the ratio of these two variables.

In specific, we calculated the log of the sTfR:ferritin ratio by first converting sTfR from mg/L to μg/L and then calculating the log of the ratio of sTfR (μg/L):SF (μg/L) for each individual. Cook et al.

(3) found that this ratio had a precise, linear relationship with body iron stores, and thus it has been proposed as a useful index of body iron.

C-reactive protein was measured by latex-enhanced nephelometry at the Immunology Division, University of Washington, Seattle WA (20). Serum analytes related to liver function (ALT, AST, lactate dehydrogenase, and total bilirubin) were measured with a Hitachi Model 737 multichannel Analyzer (Boehringer Mannheim Diagnostics) at the White Sands Research Center, Alamagordo NM (20).


We performed all analyses using SAS (21). Because the sample was not a random or representative subset of the larger NHANES III sample, we did not use sampling weights in the analyses; therefore, results cannot be considered representative of the US population.

We used statistical methods to account for the use of individually matched cases and controls in all statistical comparisons. This is necessary to ensure that matching does not introduce bias into the exposure distribution of the controls (22).

Specifically, to assess whether sTfR values differed by iron status group, we (a) calculated the mean of the differences in sTfR and log sTfR:ferritin ratio for each matched case-control set and tested whether this mean was zero; (b) computed the odds ratio of having a sTfR value below the lower limit of the reference interval as stated by the assay kit manufacturer (e.g., 64.9%. We used the latter approach primarily to provide a second method to examine the relationship of log sTfR:ferritin ratio in the detailed iron status groups because values for log sTfR:ferritin ratio might be artificially reduced in the group that was formed on the basis of both high SF and high TS. The value of 64.9% was the median TS value in the increased TS group overall (range, 55–98.5%).


The distribution of the single high TS cases by age, sex, and race or ethnicity is shown in Table 1. Most of the male cases were either young Mexican-American men (29%) or non-Hispanic white men of either age group (22%

Source: https://academic.oup.com/clinchem/article/45/12/2191/5643292

What is Transferrin + High & Low Levels

What is Transferrin + High & Low Levels

Transferrin is a protein that binds iron and transports it to where it’s needed. When there is enough transferrin, your body can effectively use the iron you get from the diet.

Iron availability dictates transferrin production, but transferrin levels are also influenced by inflammation, liver, and kidney disease.

Keep reading to learn more about high and low transferrin levels and ways to improve them.

What is Transferrin?

Transferrin is a protein that binds iron and transports it throughout the body. It is the main iron carrier in the blood. When you have enough transferrin, your body can effectively use the iron you get from your diet [1, 2].

Transferrin levels increase with iron deficiency. When iron is low, your body will try to compensate by making more transferrin to increase the availability of iron [3].

On the other hand, transferrin will decrease with iron overload [4, 5].

This protein is produced in the liver, so its levels are also associated with your liver health and inflammation in general. Transferrin is a negative acute phase protein. This means that with inflammation, the liver increases the production of inflammation-associated proteins (e.g. CRP, ferritin) while it decreases the production of proteins such as transferrin [6, 7].

Transferrin levels can be measured directly with a blood test. Alternatively, they can also be measured indirectly using total iron binding capacity (TIBC).

Normal Range

In healthy people, transferrin levels will normally be between 200 – 370 mg/dL (milligrams per deciliter).

Levels may vary slightly between laboratories, due to differences in equipment, techniques, and chemicals used.

Causes of High Transferrin Levels

The most common cause of high transferrin levels is iron deficiency [8, 9, 10].

Work with your doctor or another health care professional to get an accurate diagnosis. Your doctor will interpret your result, taking into account your medical history, symptoms, and other test results.

Iron deficiency can have many causes, including dietary deficiency, bleeding (e.g. menstrual bleeding or ulcers), gut disorders that decrease iron absorption (e.g. celiac disease), or toxins (e.g. lead).

Ways to Decrease Transferrin Levels

The most important thing is to work with your doctor to find out what’s causing your high transferrin and to treat any underlying conditions. The additional lifestyle changes listed below are other things you may want to discuss with your doctor. None of these strategies should ever be done in place of what your doctor recommends or prescribes!

If you have iron deficiency anemia, your doctor may prescribe iron therapy [11]. Keep in mind that It may take several months of supplementation to correct iron deficiency.

Make sure your diet is healthy and well balanced. Increase your intake of foods that are rich in iron to replenish your iron stores. These include red meat, poultry, fish, beans, lentils, tofu, tempeh, nuts, and seeds.

An easy way to get more iron in your meals is to use cast iron utensils [12].

Refrain from drinking coffee, milk, cocoa, or green, black and herbal tea within an hour before or after a meal, as these decrease iron absorption from food. For example, a study suggests that compared to water, drinking cocoa can inhibit iron absorption by about 70%, while black tea can decrease iron absorption by as much as 80 to 90% [13, 14, 15, 16, 17, 18].

Phytates found in whole grains and legumes also decrease iron absorption. When you eat them, add foods rich in vitamin A and beta-carotene – research shows that they can increase iron absorption and can override the influence of phytates [19, 20, 21]. Foods rich in vitamin A and beta-carotene include carrots, sweet potatoes, fish, cantaloupe, bell peppers, squash, and grapefruit.

Increase the amount of vitamin C-rich foods in your diet. Sprinkle some lemon juice on your steak and salads. If you are taking iron supplements, you can take them with orange juice. Vitamin C increases the bioavailability of iron and its absorption in the gut [22].

Avoid aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen – they can cause gut injuries and increase the loss of blood and therefore iron [23, 24].

Try not to take your iron-rich meals or iron supplements within 2 hours of antacids and heartburn medication [25].

Causes of Low Transferrin Levels

Causes shown here are commonly associated with low transferrin levels. Work with your doctor or another health care professional to get an accurate diagnosis. Your doctor will interpret your result, taking into account your medical history, symptoms, and other test results.

1) Iron Overload

The most common cause of low transferrin levels is iron overload (excess iron) [26, 10].

Iron overload can be due to iron poisoning (acute), or due to chronic overload due to hereditary disorders such as hemochromatosis, thalassemia, or sickle cell anemia [27, 9].

2) Inflammation

As mentioned above, transferrin is a negative acute phase protein. When the liver increases the production of inflammation-associated proteins (e.g.

CRP, ferritin) it decreases the production of transferrin.

A number of conditions such as infection and cancer can decrease transferrin levels [6, 7, 28].

In an observational study of 297 people, people with active inflammatory bowel disease (IBD: both Crohn’s disease and ulcerative colitis) had significantly lower transferrin levels. Increased IBD activity and inflammation severity were associated with lower transferrin levels [29].

Similarly, a study compared 20 patients with chronic periodontitis (gum inflammation) and 20 healthy people. It found that those with chronic gum inflammation had lower transferrin levels. Three months after the inflammation was treated blood transferrin levels increased back to the levels seen in healthy subjects [30].

Preeclampsia, a condition that causes high blood pressure during pregnancy, is associated with inflammation. Women with preeclampsia can have decreased transferrin levels [31, 32].

3) Liver Disease

People with liver disease have significantly lower transferrin levels than healthy people [33, 27].

In liver disease, the liver can’t produce transferrin effectively [34].

This can be caused by impaired liver function, inflammation, or alcohol consumption [35].

4) Malnutrition

To produce protein, the liver needs resources. It needs amino acids that you obtain as dietary protein. When there’s a lack of protein in the diet, your liver can’t produce transferrin effectively [36].

In studies with over 80 children, the ones that were malnourished had significantly lower transferrin levels [37, 38].

5) Kidney Disorders

Nephrotic syndrome is a kidney disorder that causes the body to excrete too much protein in the urine. Transferrin is one of the proteins that gets excreted. That’s why people with nephrotic syndrome may have significant transferrin loss [39, 40].

6) Genetics

Transferrin can be low due to genetic causes [41, 42].

Ways to Increase Transferrin Levels

The most important thing is to work with your doctor to find out what’s causing your low transferrin and to treat any underlying conditions. The additional lifestyle changes listed below are other things you may want to discuss with your doctor. None of these strategies should ever be done in place of what your doctor recommends or prescribes!

If your transferrin is low due to iron overload:

  • Avoid foods that are high in iron, such as red meat, fish, and poultry [43].
  • Eat more foods that reduce iron absorption such as fiber and phytic acid (from whole grains) and chili [44, 45, 46].
  • Drink more coffee, cocoa, green tea and herbal teas, such as chamomile, lime flower, pennyflower, mint, and vervain with meals – all of these decrease iron absorption [15, 47, 14, 16, 48, 17].
  • Avoid using cast iron utensils. They increase the amount of iron in meals [12].
  • Get more exercise. Regularly exercising will help prevent your iron levels from becoming too high [49, 50].

In more severe cases of iron overload, your doctor may prescribe blood donation, blood removal (phlebotomy), or drugs that bind and remove iron (chelation) [51].

Discuss the following supplements with your doctor. Studies suggest they may help with iron overload:

  • Curcumin [52, 53]
  • Milk thistle [54, 55]

Remember, always speak to your doctor before taking any supplements, because they may interfere with your health condition or your treatment/medications!

Source: https://selfhacked.com/blog/transferrin/