Are You in Iron Overload?

BRMI Staff

Iron is vital for overall health, especially in children and young adults, as it supports red blood cell formation and energy-producing mitochondrial proteins. Yet understanding iron, and its complex role is more complicated. Furthermore, while enough iron is crucial, too much can lead to significant tissue damage and disease.

Health Risks of Iron Overload

Excessive iron accumulation presents significant health risks. Importantly, iron overload has been implicated in the pathogenesis of a wide spectrum of disorders, with clinical manifestations that overlap those of many major diseases, including neurodegenerative conditions such as Alzheimer’s disease, cardiovascular events such as myocardial infarction, hepatic pathologies such as cirrhosis, and impaired immune function, among others.

Liver

• Findings: Hyperpigmentation (“bronzing”) of sun-exposed or scarred areas.

• Mechanisms: Increased melanin synthesis with variable iron deposition.

Heart

• Findings: Dilated or restrictive cardiomyopathy, arrhythmias, and heart failure; outcomes improve with early iron unloading.

• Mechanisms: Entry of Fe²⁺ into cardiomyocytes via calcium channels, mitochondrial oxidative stress, disrupted calcium handling, apoptosis, and ferroptosis.

Pancreas (β-cells)

• Findings: “Bronze diabetes” and impaired insulin secretion.

• Mechanisms: β-cells, with low antioxidant defenses, are vulnerable to iron-driven oxidative stress and NTBI uptake, leading to dysfunction.

Endocrine Axis

• Findings: Hypogonadotropic hypogonadism is most common; less frequent are hypothyroidism and adrenal insufficiency.

• Mechanisms: Preferential pituitary iron deposition reduces LH/FSH production, impairing gonadal function. Broader endocrine dysfunction may follow.

Joints

• Findings: Early arthropathy, especially in the hands, with frequent pseudogout (CPPD); limited benefit from phlebotomy.

• Mechanisms: Iron disrupts cartilage and bone remodeling and promotes crystal formation.

Skin

• Findings: Hyperpigmentation (“bronzing”) of sun-exposed or scarred areas.

• Mechanisms: Increased melanin synthesis with variable iron deposition.

Immune System

• Findings: People with too much iron are more likely to get infections from “siderophilic” (iron-loving) bacteria such as Vibrio vulnificus and Yersinia.

• Mechanisms: Extra iron in the blood (non–transferrin-bound iron, or NTBI) gives bacteria fuel to grow. At the same time, excess iron weakens macrophages (immune cells that normally eat and destroy germs).

  • Normally, the liver makes a hormone called hepcidin that lowers iron in the blood (hypoferremia) as a defense against infection.

  • In hemochromatosis (a genetic iron overload condition), this protective system doesn’t work well, so bacteria can thrive more easily.

Brain & Nervous System

• Findings: Iron accumulation in the pituitary and other brain regions, with uncertain impact in classic hemochromatosis.

• Mechanisms: Deposition in select CNS structures; with brain iron accumulation (NBIA), where the connection between iron and brain damage is much stronger.

  
  

Spleen & Portal System

• Findings: Splenomegaly and hypersplenism usually reflect portal hypertension secondary to cirrhosis, rather than direct splenic iron toxicity.

• Mechanisms: The spleen filters blood by removing old red cells, recycling iron, storing blood elements, and activating immune defenses. Its venous outflow joins the hepatic portal system, which delivers nutrient- and iron-rich blood from the spleen and digestive organs to the liver for processing, detoxification, and storage.

Understanding Iron

According to Morley Robbins—an expert on iron metabolism and its relationship to copper—he explains that there are three main forms of iron. 

1.) The Working Forms of Iron ~79%

The most abundant form of iron in the human body is hemoglobin, which accounts for roughly 70% of total iron stores. Hemoglobin is a key protein in red blood cells, where it binds to oxygen in the lungs and transports it throughout the body to support cellular activity and energy production. Another significant portion—about 10%—is found in myoglobin, a protein located primarily in muscle tissue. Unlike hemoglobin, which distributes oxygen via the bloodstream, myoglobin serves as an oxygen reservoir within the muscles themselves, ensuring a steady supply during periods of high demand, such as exercise or strenuous activity.

2.) The Storage Forms of Iron ~20%

Ferritin, Mitioferritin, and Hemosiderin serve as the storage forms of iron comprising ~20% of the iron in the body. 

Ferritin exists in three forms: the heavy chain (found primarily in the heart and kidney, and also present in the cell cytoplasm and nucleus), the light chain (found mainly in the liver and spleen), and secreted ferritin (measurable in blood tests and related to spleen function). 

Additionally, mitoferritin is stored inside the mitochondria (the energy centers of      cells). When extra storage of toxic iron is needed, (often due to low copper), hemosiderin serves to store this toxic overflow in tissues.

3.) Iron Transport and Recycling ~1%

The remaining fraction of iron in the body—known as serum iron—makes up only about 1% of total iron stores, yet it plays a disproportionately important role. Bound primarily to transferrin in the bloodstream, serum iron acts as the body’s delivery system, shuttling iron between its “working” forms, such as hemoglobin and myoglobin, and its storage depots, including ferritin, mitoferritin, and hemosiderin. A helpful way to picture this process is to imagine a fleet of delivery trucks: serum iron loads iron from storage, transports it through the circulation, and unloads it where it is required—whether for building new red blood cells in the bone marrow or supplying active tissues with oxygen-carrying capacity. In this way, serum iron ensures that the iron economy of the body runs smoothly and efficiently.

From the perspective of Robbins, ferritin and related stores should not be seen as a sign of strength or vitality. Instead, they reflect excess accumulation—a kind of waste storage that becomes necessary only when the recycling and transport system cannot keep pace with intake or turnover. Since the body is remarkably adept at recycling iron from old red blood cells, large reservoirs of storage iron are generally unnecessary; in fact, their buildup may be more indicative of imbalance than of health.

The Chemistry and Reactivity of Iron

Beyond the roles of iron in transport and storage, its chemical reactivity is just as important in understanding why balance matters. Iron atoms naturally contain unpaired electrons, which make them unstable and eager to react.

• One atom of iron = 4 unpaired electrons

• One ferritin molecule = ~10,000 unpaired electrons

• One hemosiderin molecule = ~100,000 unpaired electrons

In chemistry, nature resists the presence of unpaired electrons because they generate unstable interactions with surrounding molecules. 20 In the body, this instability translates into the generation of reactive oxygen species (ROS)—highly aggressive molecules that damage tissues. The most notorious example of this is the Fenton reaction, in which iron reacts with hydrogen peroxide (a byproduct of normal metabolism) to produce hydroxyl radicals, some of the most destructive free radicals known. These radicals can attack DNA, proteins, and lipids, setting off cascades of cellular injury that far exceed the initial stress.

Ferritin is relatively protective because it sequesters iron in a way that buffers this reactivity. However, when ferritin storage overflows, iron spills into hemosiderin, a less stable and poorly regulated storage form. Hemosiderin can leak reactive iron more easily, amplifying Fenton chemistry and tissue-specific ROS generation. This explains why iron overload states—such as hemochromatosis, repeated transfusions, or chronic inflammation—often lead to oxidative stress, fibrosis, and long-term organ injury.

In this sense, excess stored iron is not merely a passive reserve but a potential catalyst for cellular damage, highlighting the delicate balance between iron sufficiency and toxicity.

Nature does not like unpaired electrons. This buildup of reactive, unpaired electrons explains why excess stored iron can cause so much oxidative stress and tissue damage and why hemosiderin, which is highly reactive and can damage tissues. 

The Significance of Elevated Ferritin and Mortality

The Copenhagen City Heart Study: Ferritin & Mortality (CCHS) was a long-term population study that examined the link between baseline plasma ferritin levels and long-term mortality.

Individuals with ferritin ≥ 200 µg/L had an 11–20% higher overall mortality compared to those with ferritin < 200 µg/L 

• Mortality risk rose progressively with higher ferritin:

  • Hazard ratio for all-cause death at ≥600 vs <200 µg/L: 1.5

  • Median survival: 55 years for ≥600 µg/L, 72 years for 400–599, 76 years for 200–399, and 79 years for <200 µg/L

  • Elevated ferritin is also linked to higher cancer, endocrine, and cardiovascular mortality

    
    

Understanding Hemochromatosis and Related Iron Disorders

There are several iron-related disorders including hereditary hemochromatosis (HH), and other gene related SNIPS that can predispose individuals to increased iron levels. Proper diagnosis depends on lab assessments since symptoms often appear only after disease progression.

In HH, inherited gene mutations reduce hepcidin—a liver protein controlling iron absorption—leading to excessive iron accumulation initially in the liver, then spreading to organs such as the heart, pancreas, brain, skin, and more.

Menstruation naturally lowers iron levels, so premenopausal women usually have a lower risk. However, HH genes can still cause high iron in females and children. Non-hereditary or secondary hemochromatosis may result from other causes, like thalassemia or excessive dietary iron combined with insufficient blood loss.

The Complex Relationship Between Copper and Iron

Copper deficiency can paradoxically cause both low and high iron states. Copper is vital for enzymes like hephaestin and ceruloplasmin, which facilitate iron absorption and transport.

Without enough copper, iron absorption decreases, leading to anemia. Simultaneously, iron can become trapped in tissues due to ceruloplasmin deficiency, causing iron overload despite low blood iron. Prolonged copper deficiency may result in overall low iron. Lab profiles for copper-deficient anemia resemble iron-deficiency anemia, often coupled with weakened immune function. An interesting thought to consider is that iron is the most prevalent element--much of our foods are fortified with it--while simultaneously the World Health Organization calls iron deficiency anemia the most prevalent nutrient deficiency. 

Diagnostic Testing

A full iron panel (ferritin, TIBC, UIBC, serum iron, and saturation), CBC, liver enzymes, and copper/ceruloplasmin levels are recommended. High ferritin with iron saturation >45% suggests HH and warrants genetic testing.

Lab Levels

Marker	Typical Adult Range	Optimal Range Taken from various sources	Role / Notes
Hemoglobin (Hb)	Men: 13.8–17.2 g/dL Women: 12.1–15.1 g/dL	14 g/dl 13 g/dl	Carries oxygen in red blood cells; indicates oxygen delivery capacity.
Ferritin	Men: 20–300 ng/mL Women: 20–150 ng/mL	20–30 ng/mL	Main iron storage protein; high levels indicate excess stored iron.
Serum Iron	Men: 65–175 µg/dL Women: 50–170 µg/dL	100 µg/dL in men 80 µg/dL in women (interpreted with TIBC/saturation)	Iron circulating in blood bound to transferrin; delivers iron to cells.
Transferrin Saturation	US Units: ~2.0 -3.8 g/L	US Units: ~3.0 g/L	This measures the key “transport” protein that “recycles” iron from tissue back into the bloodstream.
TIBC (Total Iron-Binding Capacity)	240–450 µg/dL	~ 320 ug/dL for women, ~ 333 ug/dL for men	Reflects the blood’s capacity to carry iron; high when iron is low.
Copper  Ceruloplasmin	70–140 µg/dL Ceruloplasmin: 20–50 mg/dL	100 µg/dL 30 mg/dL	Copper is essential for loading iron into ferritin, transporting iron via transferrin, and preventing iron-related oxidative stress.

Treatment and Reduction Strategies

• Phlebotomy: Blood donation is the most effective therapy, with adjusted volumes for men, postmenopausal women, and premenopausal women.

• Supplements: Curcumin, silymarin, and alpha-lipoic acid show potential in reducing iron burden while supporting organ protection.

  
  

Summary:

Iron is essential yet potentially harmful when unbalanced. Excess iron contributes to multi-organ damage, including liver disease, cardiomyopathy, diabetes, endocrine dysfunction, joint disease, skin bronzing, immune compromise, and neurological changes. Hereditary hemochromatosis is the most studied iron-overload condition, but copper deficiency and secondary causes also play roles. Effective management requires early diagnosis, regular monitoring, iron-reducing strategies like phlebotomy, and supportive supplementation. Maintaining ferritin under 100 ng/mL significantly lowers disease risk.

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