In 2002, a team published the case of a woman in Blood who changed the understanding of a clinical picture that had long remained unnamed.
She presented with anemia unresponsive to iron, a declining white blood cell count, and progressive neurological impairment.
She was diagnosed with myelodysplastic syndrome, a bone marrow disease.
Gregg and his colleagues observed something else: the copper in her blood was severely low.
When copper was restored, her bone marrow began to function again.
The initial diagnosis was incorrect.
This woman had a history of gastric surgery.
This case illustrates digestive surgery as a cause of copper deficiency.
Stomach surgery for weight loss, or to treat an ulcer or stomach cancer, reduces or bypasses absorption areas. These interventions alter the sites where copper is normally absorbed.
Prolonged excess zinc represents another cause, through a distinct mechanism. Zinc prompts intestinal wall cells to produce more of a protein (metallothionein) that binds copper.
This protein captures copper arriving in the intestine and keeps it trapped. When these cells die and renew, the copper exits with them in the stool instead of entering the bloodstream.
Copper is involved in blood formation, iron utilization, cellular energy production, antioxidant protection, the stability of tissues supporting the body, and the integrity of the sheath (myelin) that protects nerves.
When it is lacking, several systems become dysregulated simultaneously. Copper remains invisible in standard assessments, and the investigation often stops before it is sought.
Too Much Zinc, Too Long, Without Monitoring Copper
Zinc is involved in over 300 enzymes. It supports immunity, wound healing, and protein synthesis.
A zinc deficiency causes clear signs: non-healing skin, altered taste, frequent infections, hair loss. But when taken as a supplement, it is often forgotten that it does not work alone.
The mechanism linking zinc and copper involves a protein (metallothionein) in the intestine that binds copper.
When zinc intake increases for a prolonged period, intestinal cells produce more of this protein to regulate its absorption. And it prefers copper over zinc. It captures and retains it.
Copper then becomes trapped in the intestinal wall cells, then eliminated in the stool when these cells renew, instead of entering the bloodstream.
What happens in the intestine is reflected in the blood.
Less copper available for the enzymes that depend on it, less protein (ceruloplasmin) that transports copper in the body, and gradually, a terrain that becomes fragile. Fatigue sets in, infections recur more often, and the skin loses its elasticity.
The risk depends on the dose and duration of zinc supplementation.
Some cases have been documented in individuals using zinc-rich dental adhesives or taking multiple supplements without checking cumulative amounts. Tingling in the hands, less stable walking, and anemia unresponsive to iron are observed.
Duration counts as much as dose. A few weeks are not enough to deplete copper reserves, but several months or even years create a favorable terrain.
The risk also depends on the digestive terrain: an inflamed intestinal wall, an intestine that absorbs poorly, stomach surgery for weight loss, or celiac disease already reduce copper absorption.
On these terrains, even moderate zinc supplementation can accelerate the imbalance.
When Copper Deficiency is Responsible for Iron Deficiency
Anemia persists despite normal or even high iron intake. Iron is taken, the assessment should improve, yet nothing changes. The problem is not always the iron itself.
Sometimes, there simply is not enough copper to mobilize it.
The protein (ceruloplasmin) that transports copper in the blood also transforms iron so it can circulate.
Another copper-containing protein (hephaestin) intervenes when iron crosses the intestinal wall and allows it to enter circulation. Without copper, this step fails.
Iron remains trapped in the intestinal wall cells, then lost in the stool when these cells die and renew. Iron absorption then becomes ineffective, even if the diet provides enough.
This mechanism explains why some anemias resist iron supplementation. Iron tablets increase intake, but if copper is lacking, iron cannot be mobilized or used.
Blood tests sometimes show normal or even high ferritin (iron reserve) with low blood iron and persistent anemia. This paradox rarely points to copper unless someone thinks to measure it.
This demonstrates that iron deficiency is not always due to a lack of dietary iron.
Anemia Resistant to Iron and Declining White Blood Cells
Copper deficiency anemia can present with red blood cells that are too small, normal-sized, or too large.
Some individuals present with isolated anemia, others develop a decrease in white blood cells, specifically a reduction in a type of white blood cell (neutrophils) that fights infections.
The exact mechanism of this neutropenia remains imperfectly elucidated. A disruption in the differentiation and maturation of precursor cells in the bone marrow is one proposed mechanism.
This picture may go unnoticed initially, then manifest with repeated infections: lingering colds, frequent urinary infections, slow healing. A viral cause or drug toxicity is sought, but copper is not always on the list of tests.
In some cases, a simultaneous decrease in red blood cells, white blood cells, and platelets is observed. This picture is rarer but has been documented in individuals taking high-dose zinc for years.
Anemia with enlarged red blood cells and a decrease in white blood cells often points to a vitamin B12 or vitamin B9 deficiency.
An isolated decrease in this type of white blood cell may lead to searching for a viral infection, drug toxicity, or bone marrow disease.
Copper is not systematically tested in these contexts unless someone thinks to check it.
Nerves and the Vitamin B12 Trap
Copper deficiency can cause progressive neurological impairment, often confused with vitamin B12 deficiency. Both create lesions of the sheath (myelin) that protects nerve fibers, and both can lead to spinal cord and leg nerve involvement.
Neurological signs often appear gradually, quietly. A tingling sensation in the feet, walking becomes less stable, progressive loss of sensitivity, muscle weakness, sometimes overly stiff muscles.
Some patients describe difficulty coordinating movements that sets in without apparent reason.
In some cases, the involvement also affects the optic nerve, with vision loss that may be mistaken for an isolated eye problem.
This picture resembles vitamin B12 deficiency so much that doctors often measure B12 first. When it returns normal, they look elsewhere, sometimes towards multiple sclerosis or another nerve disease, as copper is not always on the list of tests, especially if anemia is not prominent.
Copper deficiency can exist without major anemia. Some patients develop neurological signs before blood tests show anything obvious.
Others present with mild anemia, easily attributed to another cause, and neurological signs are seen as a separate problem.
Correcting copper deficiency can improve symptoms, but neurological recovery is often partial.
The longer the condition has been present, the more established the damage to the protective nerve sheath becomes, and the more difficult recovery is.
Mitochondria, Antioxidant Shield, and Collagen
A key enzyme in cellular energy production (cytochrome c oxidase) depends on copper to function. Without it, cells can no longer produce the energy they need for their daily work.
When it malfunctions, cells that need a lot of energy (nerve cells, muscles, heart) tire and can no longer keep up.
Fatigue sets in, recovery becomes slower, and some tissues can no longer maintain their normal activity.
An antioxidant enzyme (superoxide dismutase) that depends on copper and zinc neutralizes an aggressive molecule produced continuously by cellular work. Without copper, this enzyme loses its effectiveness, and cellular damage increases.
Cells age faster, membranes become fragile, and some tissues, like the brain and blood vessels, become more vulnerable.
A copper enzyme (lysyl oxidase) makes collagen and elastic fibers stronger, giving skin, joints, and vessels their strength and flexibility.
When this enzyme is lacking, joints become more fragile, skin heals less well, and blood vessels lose their stability.
This role of copper in collagen explains why some deficiencies manifest as joint disorders, easy bruising, or slowed healing.
Who Runs Out of Copper
In a review of 55 published cases of copper deficiency myelopathy, Jaiser and Winston documented in 2010 the distribution of causes.
Previous digestive surgery accounts for about 47% of these cases.
Stomach surgery for weight loss reduces the absorptive surface area and alters the sites where copper is normally absorbed.
Surgery to treat an ulcer or stomach cancer creates the same terrain.
Individuals who have undergone removal or bypass of part of the stomach are at risk, especially if their nutritional follow-up does not include regular measurement of essential minerals.
Tingling in the legs, less stable walking, or fatigue that sets in can appear months after surgery.
These individuals are medically monitored for vitamin B12 and iron, but rarely for copper.
Excess zinc accounts for about 16% of these cases. Some individuals take zinc continuously to boost immunity.
Others accumulate multiple supplement complexes without checking total amounts.
Zinc-rich dental adhesives, used for years, have also been documented as a cause of copper deficiency.
The risk concerns anyone taking zinc for a prolonged period without copper to counterbalance it, for whatever reason.
Individuals with celiac disease or long-term inflamed intestines may have reduced absorption of several nutrients, including copper.
Even without zinc supplementation, their fragile digestive terrain can make them vulnerable.
Fatigue, repeated infections, or anemia unresponsive to iron may signal this deficiency. This malabsorption accounts for about 15% of these cases.
Iron supplementation in excess accounts for about 2% of these cases. The authors specify that the causal role of iron remains uncertain in this context.
Parenteral nutrition prolonged without adequate copper intake can cause deficiency. This context mainly concerns hospitalized individuals or those in long-term care.
A very limited diet, low in copper sources, can contribute to imbalance when added to one of the terrains described above.
Nuts, legumes, organ meats, seafood, and cocoa are natural sources of copper.
What Blood Copper Does Not Tell
Measuring blood copper and the protein (ceruloplasmin) that transports it seems logical for diagnosing deficiency. But these two markers should not be interpreted in isolation. This protein increases in cases of inflammation, pregnancy, or during estrogen therapy.
When anemia resists despite iron, or fatigue persists with tingling, these measurements can help understand if copper is truly lacking or if inflammation is masking the picture.
Inflammation can increase this same protein as well as blood copper, thus masking an already present deficiency. Their interpretation must therefore consider the inflammatory context, particularly blood inflammation markers, as well as the analysis of blood cells and risk factors.
Blood copper mainly reflects copper bound to the protein that transports it (ceruloplasmin). When this protein decreases, blood copper also decreases. But ceruloplasmin can decrease for reasons other than deficiency: liver damage, genetic anomaly, or abnormal redistribution of copper in tissues.
Wilson’s disease illustrates an opposite picture: copper accumulates in the liver and brain, sometimes causing neurological and hepatic disorders, while the protein that transports copper remains low and blood copper can paradoxically be low. This is not a deficiency; it is a localized toxic excess, but blood test values can look similar.
“Free copper” calculated from total copper and ceruloplasmin presents significant variability and is not considered reliable.
Specialized laboratories can directly measure certain fractions of copper not bound to this protein, notably exchangeable copper.
These tests are mainly used in the evaluation of Wilson’s disease and are not widely available in routine practice.
Measuring whether this protein properly transforms iron for circulation can also provide useful information, but it is rarely done in routine practice.
Context remains essential. Low blood copper, low ceruloplasmin, with anemia resistant to iron, a decrease in white blood cells, or neurological signs, in someone who has taken zinc for months, or who has a fragile digestive terrain, strongly points to deficiency. But an isolated value, without context, is not enough.
Deficiency, Balance, Excess: Three Readings
Copper status cannot be assessed from a single reading. There are three distinct levels: deficiency, the right level, and excess.
Deficiency manifests as too low blood copper, a decrease in the protein that transports it, anemia unresponsive to iron, a possible decrease in white blood cells, and sometimes neurological involvement.
It mainly develops on terrains where the intestine absorbs poorly, after prolonged zinc supplementation, or with insufficient dietary intake.
When copper is at the right level, copper and ceruloplasmin levels remain within usual reference ranges, without body signs showing deficiency or overload.
Excess copper, or overload, is mainly seen in Wilson’s disease, a hereditary disease where copper accumulates in the liver, brain, and other organs.
The picture here is very different: the liver is affected, neurological involvement and a colored ring around the eye may be present but not in all patients, especially in some primarily hepatic forms, and ceruloplasmin is generally low.
Diagnosis relies on a set of elements: ceruloplasmin, copper eliminated in 24-hour urine, eye examination, genetic test of the gene that regulates copper in the body (ATP7B), and, depending on the case, copper measurement in the liver.
Brain MRI scans show associated lesions but do not measure the amount of accumulated copper.
Some acquired overloads also exist, related to environmental or occupational exposure, but they remain rare.
An isolated value is never enough. Copper must be interpreted in context: digestive terrain, dietary intake, supplementation, inflammation, liver, body signs.
FAQ
Why can copper deficiency be confused with myelodysplastic syndrome?
The bone marrow of a person deficient in copper can resemble that of myelodysplastic syndrome, a bone marrow disorder in which abnormal blood cells are produced.
Some anomalies under the microscope may resemble or overlap, without the two clinical pictures being identical, and some characteristics allow differentiation: red blood cell precursors with small empty pockets inside, cells accumulating iron in a ring around the nucleus (sideroblasts), and a general decrease in blood cell production.
Gregg and colleagues documented it in 2002 in Blood: a woman diagnosed with myelodysplastic syndrome actually had copper deficiency, linked to previous gastric surgery.
Once copper was restored, the marrow returned to normal production.
The problem is that the two conditions look so similar that the nutritional terrain can be overlooked and the condition treated as a blood or bone marrow disease when the body simply lacks an essential mineral.
Which foods are richest in copper and does diet suffice when zinc intake remains too high?
Beef or lamb liver, oysters and other seafood, and unsweetened cocoa are among the most copper-dense sources.
But when zinc remains too high for too long, it increases the production of a protein (metallothionein) in the intestine that retains copper in the wall cells.
This protein prevents it from entering the bloodstream.
Diet alone does not overcome this trap: copper arrives on the plate, but it remains blocked at the door.
You can eat liver every day, but if this protein retains copper, it will not get in.
This mechanism explains why some people remain deficient despite a copper-rich diet, and why zinc must first be rebalanced before copper can circulate again.
Can zinc and copper be taken simultaneously to avoid imbalance?
Taking zinc and copper at the same time does not guarantee their balance. Zinc increases the production of a protein (metallothionein) in the intestine that retains copper in the wall cells. This mechanism continues to act when zinc intake remains too high or continues for too long.
Balance depends on total amounts consumed, duration of supplementation, dietary intake, and digestive absorption capacity.
DISCLAIMER: This article is for informational purposes only and does not replace personalized medical advice. The information presented aims to clarify documented biological mechanisms; any decision about your health, especially with medical conditions, ongoing treatment, or scheduled surgery, should be discussed with a qualified healthcare professional.
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