Iron is an essential mineral that plays many important roles in the body. One of its main roles is to transport oxygen in the hemoglobin of red blood cells to tissues for energy production. While low amounts of iron can lead to poor health, too much can cause severe health problems.

This post covers:

  • Iron Metabolism and Homeostasis
  • Iron Lab Tests
  • Iron Deficiency Anemia – Stages, Different Types, and Genetic Causes
  • Iron Overload

Download SelfHacked lab test guide with optimal ranges here.

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4-Part Series

Part 1: Iron Metabolism, Lab Tests, Iron Deficiency Anemia and Overload

Part 2: Diseases Associated with Low Iron, and Ways to Increase or Decrease Iron

Part 3: Iron Intake, Supplementation, and Ways to Increase or Decrease It

Part 4: Negative Health Effects of High Iron

Introduction:

Iron (Fe) is an essential element critical for the growth and survival of nearly all organisms (R).

Key Roles of Iron in the Body

Iron is present in all cells and has several vital functions including:

  • Red blood cell production (erythropoiesis) (R, R2)
  • Oxygen and carbon dioxide transport, as a part of hemoglobin (R)
  • Oxygen transport and storage in muscles, as a part of myoglobin (R)
  • Energy production in the heart and muscles, as cytochromes and iron-dependent enzymes (R)
  • Protecting cells against the accumulation of reactive oxygen species, as a part (cofactor) of enzymes that break down the reactive oxygen species, including oxidases, peroxidases, and catalases
  • Production and degradation of DNA, RNA, proteins, carbohydrates, and lipids
  • Production of cells with high energy demand (muscle and heart cells) (R, R2)
  • Production of rapidly growing cells (tumor and blood cells) (R, R2)
  • Synthesis of neurotransmitters and myelin in the brain (R, R2)

Because iron has many important functions in the body and in the cells, low levels of iron can interfere with these processes, causing detrimental effects and eventually, death (R).

Disorders of iron homeostasis are common in humans and implicated in a wide spectrum of diseases ranging from anemia to neurological dysfunction (R).

Also, excessive levels of iron can form reactive oxygen species which lead to tissue and DNA damage (R).

Iron levels can change as a result of (R):

  • gene mutations
  • insufficient dietary intake
  • red blood cell transfusions
  • iron injections
  • excessive blood loss
  • impaired iron absorption
  • red blood cell rupture

Normal Iron Balance:

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Most well-nourished adults have approximately 3–5 g of iron.

It is one of the most abundant metals in the human body (R).

Nearly 60% of iron inside the body is incorporated into hemoglobin, and 10% in muscle myoglobin.

Another 10% of body iron is present in myoglobin in muscles, and iron-containing enzymes.

In healthy individuals, the remaining 20-30% of iron is stored as ferritin and haemosiderin (R, R2, R3).

Because free iron in the blood can cause oxidative damage, excess iron is bound to the protein transferrin in the circulation and storage proteins known as ferritin and hemosiderin in the liver, bone marrow, and spleen (RR2R3R4R5). The liver has the largest capacity to store excess iron (R).

Hepcidin and iron balance, source: https://www.ncbi.nlm.nih.gov/pubmed/22306005

Hepcidin and iron balance, source: https://www.ncbi.nlm.nih.gov/pubmed/22306005

To maintain iron homeostasis, hepcidin, a protein hormone secreted by the liver, inhibits dietary iron absorption in the gut and reduces blood iron levels when iron stores are sufficient (RR2).

Iron Absorption in the Small Intestine

Since the body lacks a pathway for iron excretion, total iron absorption is kept low by cells that line the wall of the small intestine (duodenum and jejunum) (R,R2). If the iron demands increase, then these cells will absorb more iron from inside the gut.

Heme iron

Heme iron (iron bound to hemoglobin and myoglobin found in meat) can be directly absorbed by intestinal cells. This process is independent of acidity and is not affected by inhibitors of iron absorption (i.e., phytate and polyphenols) and thus, more efficient (R).

Non-heme iron

Non-heme iron is much harder to absorb than heme iron because the intestine can only absorb the ferrous form (Fe2+) and not the ferric form (Fe3+).

At physiological (non-acidic) pH, ferrous iron (Fe2+) is readily oxidized to insoluble ferric iron (Fe3+), which cannot be absorbed (R).

Stomach acid helps the enzyme ferric reductase reduce Fe3+ into Fe2+, which allows the iron to get absorbed (R). Therefore, when stomach acid production is impaired (e.g., by acid pump inhibitors), non-heme iron absorption is significantly reduced (R).

Iron Reabsorption through Red Blood Cell Recycling

Roughly 1–2 mg of dietary iron is absorbed daily, however, processes like hemoglobin synthesis require 20–25 mg of iron per day. Most of this iron is obtained through the recycling of old red blood cells by resident macrophages (R).

Normal Iron Loss

Around 1–2 mg of iron is lost daily through sweat, blood loss, and sloughing of mucosal and skin cells, but there is no organized method of iron excretion in mammals. Therefore, iron levels are balanced by increased (when levels are low) or decreased (when levels are high) absorption of dietary iron in the small intestine (R).

Iron Blood Tests

Blood iron tests are typically ordered as follow-up tests when routine tests such as a complete blood count, hemoglobin, and hematocrit levels show abnormal results.

The most common lab test for iron levels is ferritin, but other lab tests may be ordered when an iron deficiency or iron overload is suspected because each of these tests provide a slightly different piece of information about iron levels in the body (R).

You can download the SelfHacked lab test guide with optimal range here.

1) Serum ferritin

It is the most specific biochemical test that is associated with relative total body iron stores (R).

Generally, blood ferritin levels correlate with total body iron stores and can be used as a diagnostic marker for anemia and some inflammatory diseases (R).

It is also an acute phase reactant protein, which means it is elevated in people with infection, inflammatory disease, liver and kidney disease, and malignancy, obesity, and age (R, R2).

Plasma ferritin concentration declines early in the development of iron deficiency. Low serum ferritin concentrations thus are sensitive indicators of iron deficiency.

Read this post to learn more about ferritin with reference ranges.

According to the World Health Organization, the generally accepted cut-off level for blood ferritin levels in which iron stores are depleted is 15 ng/mL for people aged 5 years and older and 12 ng/mL for people younger than 5 years of age (R).

2) Blood Iron

Blood iron measures the amount of circulating iron in the blood
Blood iron is a poor measure of iron status in the body because
it has daily fluctuations, and it increases after the ingestion of iron-containing foods (R, R2).
A blood iron test without a TIBC and transferrin determination has very limited value except in cases of iron poisoning.
Reference Values:
Men: 65–175 µg/dL or 11.6–31.3 µmol/L
Women: 50–170 µg/dL or 9.0–30.4 µmol/L
Children: 50–120 µg/dL or 9.0–21.5 µmol/L
Newborns: 100–250 µg/dL or 17.9–44.8 µmol/L (R)

3) Total Iron-Binding Capacity

Total iron-binding capacity (TIBC) – measures proteins in the blood, including transferrin, which are available to bind with iron.
This test measures indirectly the transferrin, iron carrier in the blood, level in the blood.
Raised TIBC is characteristic of iron deficiency anemia.
Reference values:
Men: 250–450 µg/dL or 44.8–76.1 µmol/L
Women: 250–450 µg/dL or 44.8–76.1 µmol/L (R)

4) Unsaturated Iron-Binding Capacity

UIBC (unsaturated iron-binding capacity) measures the reserve capacity of transferrin, the portion of transferrin that has not yet been saturated with iron. UIBC also reflects transferrin levels.

5) Transferrin Saturation

Transferrin (iron) saturation – is the percentage of transferrin that is saturated with iron.
Reference values:
Men: 10%–50%
Women: 15%–50% (R)
Transferrin saturation <16% indicates iron deficiency, delivery of iron to developing red cells is impaired.
Values greater than 60% indicates iron overload (hemochromatosis, transfusional iron overload) (R).
The combined results of transferrin, iron, and TIBC tests are helpful in the differential diagnosis of anemia, iron-deficiency anemia, thalassemia, sideroblastic anemia, and hemochromatosis.

6) Red Cell Zinc Protoporphyrin

When there is an inadequate supply of iron, zinc is incorporated into the protoporphyrin ring of the heme structure, creating zinc protoporphyrin. An elevated zinc protoporphyrin is characteristic of iron deficient red blood cell production (R).

7) Serum Transferrin Receptor

Serum transferrin receptor (sTfR) – an elevated serum transferrin receptor is a marker of tissue iron deficiency and increased bone marrow erythropoietic activity.

Since concentrations of transferrin receptor rise when iron stores are depleted to promote cellular iron uptake, they can be used to estimate the magnitude of functional iron deficit once iron stores are depleted (R).

Transferrin levels reflect the extent of red blood cell production and iron demand since transferrin receptor is mainly derived from developing red blood cells (R).

Advantages of Serum Transferrin Receptor Testing:

  • It is an early and sensitive indicator of iron deficiency (R).
  • It can distinguish anemia from chronic disease from iron deficiency anemia.
  • It is not significantly affected by infection or inflammatory processes, and it does not vary with age, gender, or pregnancy (R, R2)

Reference range
Adults 2.8-8.5 mg/L (R), with optimal range of 0.84 – 1.97 mg/L (R).

Causes of Iron Deficiency

Iron deficiency is the most common nutritional deficiency in the world, affecting 66– 80% of the world’s population (R, R2).

It is especially common during pregnancy, affecting 40%–50% of women and their infants (R, R2).

Iron deficiency is the leading nutritional cause of anemia (R, R2).

Iron deficiency is due to:

1) Insufficient Dietary Iron Intake

A low dietary iron intake can be caused by (R):

  • malnutrition
  • a vegetarian or vegan diet, which lacks heme iron

2) Inadequate Iron Absorption

Several diseases of the digestive system could cause inadequate iron absorption, including (R, R2):

  • celiac disease
  • irritable bowel diseases, i.e. Crohn’s and ulcerative colitis (R)
  • internal bleeding
  • gastritis
  • bariatric and other weight loss surgery (R)
  • H. pylori infection (R)
  • Small Intestinal Bacterial Overgrowth (R)
  • gallstones or gallbladder problems (R)

Other causes of inadequate iron absorption include hemochromatosis and a high intake of food substances that inhibit iron absorption, such (R):

  • high intake of phytates (whole grains, legumes)
  • high intake of polyphenols (tea, coffee, wine)

3) Increased Iron Demand

Fast growth increases iron demand, so children, pregnant and lactating women are more likely to be iron deficient (R, R2).

4) Increased iron losses

Chronic bleeding in the gut can increase iron losses, including (R):

  • cancer
  • ulcers of the stomach or small intestine
  • hemorrhoids

Bleeding due to gynecological causes (R)

  • menstruation
  • endometriosis
  • myoma
  • uterine cancer
  • ulcers of the stomach

5) Other causes

Other causes of iron deficiency include (R):

  • surgery
  • trauma
  • childbirth
  • blood donation
  • parasitic infection (hookworm, tapeworm
  • prolonged anti-inflammatory drug use (ibuprofen, naproxen, diclofenac)

High risk groups for iron deficiency and iron deficiency anemia

  • Infants and young children (R, R2)
  • Obese children (R, R2)
  • Women of childbearing age and pregnant women (R, R2)
  • Endurance athletes (R)
  • Frequent blood donors (R)
  • Patients with cancer (colon, rectum, stomach; chemotherapy) (R)
  • People who have gut disorder (celiac disease, inflammatory bowel disease, and gut infections) (R)
  • People who have had gut surgery (gastrectomy, gut resection, bariatric surgery) (R, R2, R3)
  • People with heart failure (R)
  • Patients with chronic kidney disease (R)

Signs and symptoms of iron deficiency include fatigue, irritability, pale skin, cravings for ice, dirt, clay (pica), deformed nails (koilonychia), swollen tongue, and mouth soreness (R).

Iron deficiency is associated with lower cognitive test scores, shortened attention span, and reduced physical and mental activity in children and adults (R).

Genetics of Iron Deficiency

Genetic Mutations or SNPs that Increase Risks of Anemia (SelfDecode)

Genes SNP Risk Alleles
HFE rs1800562 A, A
LOC100507006 , LOC105374768 rs2698530 C, C, C
TF rs3811647 A, A
IGLV4-60 , LOC102724653 rs987710 G, G

To find out if you are genetically predisposed for iron deficiency anemia, run a 23andme DNA test and upload your raw data on SelfDecode.

Anemias Associated with Low Iron Levels

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1) Iron Deficiency Anemia

Iron deficiency anemia (IDA) impacts approximately 1-2 billion people worldwide.

In developing countries, it occurs among 23%-50% of pregnant women and young children (R).

IDA is characterized by a defect in hemoglobin synthesis, resulting in the reduced capacity of the red blood cells to deliver oxygen to tissues (R).

IDA can become severe, and cause lethargy, pale skin, shortness of breath, irritability, decreased appetite, failure to thrive, and heart failure (R, R2).

Children and women are at higher risk. Iron deficiency can result in preterm birth, poor growth and cognitive skills, and neurological dysfunction (R).

Iron deficiency represents a spectrum ranging from iron depletion, which causes no biological impairments, to iron-deficiency anemia, which affects the functioning of several organ systems (R).

Stages of iron deficiency anemia and corresponding changes in lab test numbers, source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381289/

Stages of iron deficiency anemia and corresponding changes in lab test numbers, source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381289/

Iron deficiency can be divided into 3 stages, including (R):

Phase 1: Pre-latent Stage – Depleted Iron Stores

Iron stores are lowered or absent, serum iron concentration, hemoglobin, and hematocrit are normal. This stage of iron deficiency is manifested with reduction or absence of bone marrow iron stores and reduced serum ferritin level.

Phase 2: Latent Stage

Serum iron (SI) and transferrin saturation are reduced in addition to reduced iron stores. Hemoglobin and hemocrit are still within normal limits.

Phase 3: Iron Deficiency Anemia

During this phase, in addition to the depletion of iron stores, serum iron, and transferrin saturation, hemoglobulin and hematocrit levels are reduced.

The red blood cells of individuals that have iron-deficiency anemia are smaller and paler than normal (R)

2) Anemia of Chronic Inflammation or Infection

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The pathogenesis of anemia of chronic disease, source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2492976/

Anemia of chronic disease involves the reduction of iron levels that is not caused by blood loss during (R, R2):

  • chronic infection
  • trauma
  • cancer
  • inflammatory disease
  • organ failure

Tissues injured by infections or inflammation release cytokines that reduce iron blood levels and red blood cell production, therefore leading to the development of anemia (R).

Because iron is important for the growth of pathogens and cancer cells, when there is an infection or inflammation, the body tries to inhibit the growth of the pathogens by reducing iron levels (R).

An inflammatory cytokine IL-6 stimulates the liver cells to produce more hepcidin, thereby reducing iron by inhibiting iron absorption and allowing macrophages to take up more iron (R, R2).

TNF-alpha and IFN-gamma increase production of nitric oxide (NO) by stimulating the enzyme inducible NO synthase (iNOS), and thus increasing iron storage in the cell (R).

NO along with inflammatory cytokines TNF-alpha, IL-1, and INF-gamma decrease red blood cell production (erythropoiesis) by direct inhibition of red blood cell precursors in the bone marrow (R, R2).

IL-1 and TNF-alpha also decrease production of erythropoietin in the kidney and the ability of the bone marrow to respond to this hormone (R, R2).

Inflammatory cytokines activate macrophages to destroy red blood cells prematurely (R).

However, other cytokines have different effects. In fact, TNF-alpha inhibit hepcidin production (R).

Anemia of chronic disease is considered to be a mild-to-moderate form of anemia and treatment is primarily centered on the underlying condition (R).

3) Iron Deficiency is Characteristic of Iron-Refractory Iron-Deficiency Anemia (IRIDA)

Iron-refractory iron deficiency anemia is caused by a rare mutation in a gene (encoding Matriptase-2, an iron regulatory enzyme) expressed in the liver, which leads to high hepcidin levels. As a result, iron absorption from the intestine and release from macrophages is inhibited, resulting in severe iron deficiency (R,R2).

Causes of Iron Overload

Iron toxicity (acute iron overload) occurs mainly in children.
Taking 20 mg of elemental iron per kg of body weight causes vomiting and diarrhea.
In severe cases, taking about 60 mg per kg body weight (11 of commonly sold 27 mg tablets of ferrous sulfate) causes blood loss, multiple organ dysfunction, and death (R).
Causes of chronic iron overload include:

  • Hereditary hemochromatosis (R, R2
  • Iron loading anemias (thalassemia major, sideroblastic anemia, aplastic anemia) (R, R2)
  • Repeated blood transfusions and intravenous iron overload (R)
  • Chronic liver disease (hepatitis, alcoholic liver disease) (R)

Technicals

Iron Transport from the Small Intestine

Once inside the intestinal membrane, iron (Fe2+) is either stored as ferritin or exported out of the cell into the bloodstream via the iron exporter, ferroportin (R).

Exported iron is scavenged by transferrin, which maintains iron in a soluble state and delivers it into tissues (R).

The body’s rate of iron absorption depends on the action of hepcidin, a circulating hormone secreted by the liver that decreases iron absorption (R).

It prevents systemic iron and transferrin overload by inhibiting iron release from intestinal cells, macrophages, and liver cells (by binding to iron exporter ferroportin, which prevents iron entry into the blood) (R,R2).

Current understanding of how Hepcidin level is regulated, including by the inflammatory cytokine IL-6 source: https://www.ncbi.nlm.nih.gov/pubmed/22306005

Current understanding of how Hepcidin level is regulated, including by the inflammatory cytokine IL-6 source: https://www.ncbi.nlm.nih.gov/pubmed/22306005

Blood hepcidin levels are elevated in response to inflammation and high blood iron concentrations and are lowered during hypoxia (low oxygen) (R).

When blood iron levels are low, hepcidin production in the liver is decreased to allow for increased iron absorption and mobilization from body stores (R).

Conversely, when iron stores are sufficient, hepcidin inhibits iron absorption, promotes cellular iron storage, and reduces blood iron levels (R).

Most hereditary iron disorders like anemia and hemochromatosis result from mutations in genes affecting hepcidin production (R).

4-Part Series (To Be Continued)

Part 1: Iron Metabolism, Lab Tests, Iron Deficiency Anemia and Overload

Part 2: Diseases Associated with Low Iron, and Ways to Increase or Decrease Iron

Part 3: Iron Intake, Supplementation, and Ways to Increase or Decrease It

Part 4: Negative Health Effects of High Iron


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2 COMMENTS

  • starr1975

    I disagree.

  • Steven Sevek

    How can you have all this information on iron metabolism without including ceruloplasmin and copper?

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