The interdependence of copper-iron interactions

The interdependence of copper-iron interactions, and their importance in health management, remains overlooked and under-researched. Deficiencies or excesses of either mineral alters the effect of the other, and may alter local and general physiological processes.

Intake sources

Three key sources of copper (Cu) and iron (Fe) availability include -

• Dietary intake - includes both volume of foodstuffs consumed and level of copper and/or iron content of the foodstuffs;
• pH levels - significantly alter Cu and Fe absorption capacity. Gastric pH range for optimal absorption –

                  - Copper – 2.0-5.5,

                  - Iron – 2.0-4.0.

• Environmental exposure or occupational exposure - also includes foodstuffs and uncoated copper cookware. Bone mineral content is a reliable indicator of timing of exposure to metals -

                 - cancellous bone indicates recent exposure,

                 - cortical bone indicates longer term exposure.

• Bone remodelling – means there is a continual supply of metals, including copper and iron, being released into and absorbed from the blood. Their continuous availability in the blood increases risk of alteration to various physiologic processes.

Excretion mechanisms

Copper - excess copper is complexed with bile salts for both safe excretion via the biliary system and inhibited reabsorption.

Iron - absorption is tightly regulated as there is no active, regulated excretory system. When body iron stores increase and/or during infection and inflammation, hepcidin degrades Ferroportin1 to reduce serum iron levels. The primary causes of iron loss include shedding dead skin cells, loss of surface cells of enterocytes, and blood loss.

Key known intermediaries

The body of evidence is steadily increasing.

DCYTB (duodenal cytochrome B) - converts iron Fe3+ to Fe2+ and Cu2+ to Cu1+;

DMT1 (divalent mineral transporter1) - transports iron, and may also transport copper during iron deficiency.

ATP7A (copper transporter) - is essential for optimal iron transport. Decreased ATP7A is associated with decreased -

   - copper and iron levels in cells;

   - iron cellular uptake and export;

   - expression of iron and copper transport-related genes and proteins.

That iron depletion upregulates ATP7A expression indicates either ATP7A or copper impacts iron metabolism in enterocytes.

CTR1 (copper transporter) – essential for both copper absorption and distribution.

FPN1 (ferroportin1) - is an iron exporter and may be impacted by copper status or presence.

HEPC (hepcidin) - regulates iron homeostasis by inhibiting intestinal iron absorption and iron release from stores. Hepcidin may be stabilized by copper.

HEPH (hephaestin) - is a copper-containing protein that operates in conjunction with ferroportin1. HEPH is essential for optimal iron absorption under physiological conditions, but not during iron-deficiency or haemolytic anaemia.

CP (ceruloplasmin) - is a copper-dependent protein that releases iron from stores, and enables iron to bind to transferrin and ferritin.

Interactions  

The evidence is limited but steadily increasing.

Copper can affect iron homeostasis and even induce ferroptosis.

Iron utilization by developing red blood cells is copper dependent, albeit the mechanism of action remains unclear.

1. Low iron status

Copper promotes iron absorption especially during low iron status.

Iron depletion increases uptake of both iron and copper.

Iron or copper chelation increases iron transport.

Low iron decreases haemoglobin production causing tissue hypoxia that stimulates hypoxia-responsive transcription factor, HIF2α which is stabilized by copper. HIF2α transactivates several genes related to iron absorption including DCYTB, DMT1, FPN1, and ATP7A as well as the CTR1 gene.

An inverse relationship exists between iron and copper status and liver accumulation of both metals. Iron-depletion causes hepatic copper loading. likely due to increased copper absorption and/or decreased biliary copper excretion. Copper depletion causes hepatic iron loading, likely due to decreased CP activity resulting in impaired iron release from cells.

2. Low copper status

Copper depletion increases intake of both iron and copper.

Copper chelation increases iron transport.

Decreased Cu status can cause anaemia due to decreased release of iron from tissues. Effective treatment of this form of anaemia is copper supplementation.

Ceruloplasmin enables transfer of iron into and out of cells. Iron accumulation occurs in the presence of copper deficiency and is likely due to impaired CP activity.

Hephaestin is a copper-dependent protein that functions in iron metabolism. Copper depletion impairs intestinal iron absorption with consequent inhibition of HEPH expression and activity.

3. Excess iron status

A high iron intake may block copper transport by DMT1 and/or CTR1, ultimately causing copper depletion.

High dietary iron increased the dietary copper requirement in test animals. The authors commented people with iron overload may benefit from copper supplementation if they typically consume a low copper diet.

A high dietary iron intake induces copper depletion. This depletion is of concern in children and pregnant women as copper deficiency has significant negative impacts during growth periods. Iron supplementation is also a common recommendation for pregnant women. Several authors support the concept that iron supplements should also contain extra adequate copper.

Iron accumulation in organs commonly occurs when there is inadequate CP.

4. Excess copper status

Excess copper induces oxidative stress, DNA damage, and reduced cell proliferation.

Cuproptosis is a recently discovered form of regulated cell death triggered by excess Cu2+.

Copper accumulation in the liver during iron deficiency may enhance CP biosynthesis.

Clinical considerations

Both inadequate and excessive intakes of copper and iron have significant negative physiological impacts. Seemingly evidence in relation to optimal copper-iron administration ratios is not readily accessible. Consequently, advice regarding iron supplements may need to be considered in relation to impact on copper availability.

Clinical questions

What actions will you initiate as you a review a person whose prescribed medications include, or who may require, iron supplements, will you -

• recommend regular monitoring of a range of iron and copper markers?
• if there is not a timely response to iron administration, and the person is not prescribed acid-inhibiting medications, would you then question copper status?
• consider the negative impacts of other prescribed medications on iron and copper levels?
• recommend copper supplements in conjunction with iron supplements?
• recommend the Medications Advisory Committee develop guidelines to include copper supplements when iron supplements are prescribed?

Conclusions

The profound importance of copper-iron interactions is in the early stages of recognition. Based on current evidence, ensuring both adequate intake of both metals and including copper in iron supplements seems essential.

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