Copper deficiency, or hypocupremia, is defined either as insufficient

copper Copper is a chemical element with the symbol Cu (from la, cuprum) and atomic number 29. It is a soft, malleable, and ductile metal with very high thermal and electrical conductivity. A freshly exposed surface of pure copper has a pink ...

to meet the needs of the body, or as a serum copper level below the normal range. Symptoms may include

fatigue Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...

, decreased red blood cells, early greying of the hair, and neurological problems presenting as numbness, tingling, muscle weakness, and

ataxia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...

. The neurodegenerative syndrome of copper deficiency has been recognized for some time in ruminant animals, in which it is commonly known as " swayback". Copper deficiency can manifest in parallel with

vitamin B12 Vitamin B12, also known as cobalamin, is a water-soluble vitamin involved in metabolism. It is one of eight B vitamins. It is required by animals, which use it as a cofactor in DNA synthesis, in both fatty acid and amino acid metabolism. ...

and other nutritional deficiencies.

Overview

The most common cause of copper deficiency is a remote gastrointestinal surgery, such as gastric bypass surgery, due to

malabsorption Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal (GI) tract. Impairment can be of single or multiple nutrients depending on the abnormality. This may lead to malnutrition and a variety ...

of copper, or zinc toxicity. On the other hand,

Menkes disease Menkes disease (MNK), also known as Menkes syndrome, is an X-linked recessive disorder caused by mutations in genes coding for the copper-transport protein ATP7A, leading to copper deficiency. Characteristic findings include kinky hair, growth ...

is a genetic disorder of copper deficiency involving a wide variety of symptoms that is often fatal. Copper is required for the functioning of many enzymes, such as

cytochrome c oxidase The enzyme cytochrome c oxidase or Complex IV, (was , now reclassified as a translocasEC 7.1.1.9 is a large transmembrane protein complex found in bacteria, archaea, and mitochondria of eukaryotes. It is the last enzyme in the respiratory elect ...

, which is complex IV in the mitochondrial

electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples ...

ceruloplasmin Ceruloplasmin (or caeruloplasmin) is a ferroxidase enzyme that in humans is encoded by the ''CP'' gene. Ceruloplasmin is the major copper-carrying protein in the blood, and in addition plays a role in iron metabolism. It was first described in 1 ...

, Cu/Zn

superoxide dismutase Superoxide dismutase (SOD, ) is an enzyme that alternately catalyzes the dismutation (or partitioning) of the superoxide () radical into ordinary molecular oxygen (O2) and hydrogen peroxide (). Superoxide is produced as a by-product of oxygen ...

, and in amine oxidases. These enzyme catalyze reactions for

oxidative phosphorylation Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine t ...

, iron transportation, antioxidant and free radical scavenging and neutralization, and

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neu ...

synthesis, respectively. Diets vary in the amount of copper they contain, but may provide about 5 mg/day, of which only 20-50% is absorbed. The diet of the elderly may have a lower copper content than the recommended daily intake. Dietary copper can be found in

whole grain A whole grain is a grain of any cereal and pseudocereal that contains the endosperm, germ, and bran, in contrast to refined grains, which retain only the endosperm. As part of a general healthy diet, consumption of whole grains is associated ...

cereal A cereal is any grass cultivated for the edible components of its grain (botanically, a type of fruit called a caryopsis), composed of the endosperm, germ, and bran. Cereal grain crops are grown in greater quantities and provide more food ...

legume A legume () is a plant in the family Fabaceae (or Leguminosae), or the fruit or seed of such a plant. When used as a dry grain, the seed is also called a pulse. Legumes are grown agriculturally, primarily for human consumption, for livestock for ...

oyster Oyster is the common name for a number of different families of salt-water bivalve molluscs that live in marine or brackish habitats. In some species, the valves are highly calcified, and many are somewhat irregular in shape. Many, but not ...

s, organ meats (particularly

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...

cherries A cherry is the fruit of many plants of the genus '' Prunus'', and is a fleshy drupe (stone fruit). Commercial cherries are obtained from cultivars of several species, such as the sweet ''Prunus avium'' and the sour ''Prunus cerasus''. The ...

, dark chocolate,

fruit In botany, a fruit is the seed-bearing structure in flowering plants that is formed from the ovary after flowering. Fruits are the means by which flowering plants (also known as angiosperms) disseminate their seeds. Edible fruits in partic ...

s, leafy green vegetables, nuts,

poultry Poultry () are domesticated birds kept by humans for their eggs, their meat or their feathers. These birds are most typically members of the superorder Galloanserae (fowl), especially the order Galliformes (which includes chickens, qu ...

prune A prune is a dried plum, most commonly from the European plum (''Prunus domestica''). Not all plum species or varieties can be dried into prunes. A prune is the firm-fleshed fruit (plum) of '' Prunus domestica'' varieties that have a high so ...

s, and

soybean The soybean, soy bean, or soya bean (''Glycine max'') is a species of legume native to East Asia, widely grown for its edible bean, which has numerous uses. Traditional unfermented food uses of soybeans include soy milk, from which tofu ...

products like

tofu Tofu (), also known as bean curd in English, is a food prepared by coagulating soy milk and then pressing the resulting curds into solid white blocks of varying softness; it can be ''silken'', ''soft'', ''firm'', ''extra firm'' or ''super f ...

. Copper deficiency can have many hematological consequences, such as

myelodysplasia A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms ma ...

anemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, t ...

, low white blood cell count, and low count of neutrophils (a type of white blood cell that is often called "the first line of defense" of the immune system). Copper deficiency has long been known as a cause of myelodysplasia (when a blood profile has indicators of possible future

leukemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ...

development), but it was not until 2001 that copper deficiency was associated with neurological manifestations like

sensory ataxia Sensory ataxia is both a symptom and a sign in neurology. It is a form of ataxia (loss of coordination) caused not by cerebellar dysfunction but by loss of sensory input into the control of movement. Sensory ataxia is distinguished from cerebellar ...

(irregular coordination due to proprioceptive loss), spasticity, muscle weakness, and more rarely visual loss due to damage in the peripheral nerves,

myelopathy Myelopathy describes any neurologic deficit related to the spinal cord. The most common form of myelopathy in humans, '' cervical spondylotic myelopathy (CSM)'', also called ''degenerative cervical myelopathy'', results from narrowing of the spin ...

(disease of the spinal cord), and rarely

optic neuropathy Optic neuropathy is damage to the optic nerve from any cause. The optic nerve is a bundle of millions of fibers in the retina that sends visual signals to the brain. Damage and death of these nerve cells, or neurons, leads to characteristic featu ...

Signs and symptoms

Blood symptoms

The characteristic hematological (blood) effects of copper deficiency are

(which may be microcytic, normocytic or macrocytic) and

neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteri ...

Thrombocytopenia Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients a ...

(low blood

platelets Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ...

) is unusual. The peripheral blood and

bone marrow aspirate Bone marrow examination refers to the pathologic analysis of samples of bone marrow obtained by bone marrow biopsy (often called trephine biopsy) and bone marrow aspiration. Bone marrow examination is used in the diagnosis of a number of conditio ...

findings in copper deficiency can mimic myelodysplastic syndrome.

Bone marrow aspirate Bone marrow examination refers to the pathologic analysis of samples of bone marrow obtained by bone marrow biopsy (often called trephine biopsy) and bone marrow aspiration. Bone marrow examination is used in the diagnosis of a number of conditio ...

in both conditions may show

dysplasia Dysplasia is any of various types of abnormal growth or development of cells (microscopic scale) or organs ( macroscopic scale), and the abnormal histology or anatomical structure(s) resulting from such growth. Dysplasias on a mainly microscopi ...

of blood cell precursors and the presence of ring sideroblasts ( erythroblasts containing multiple iron granules around the nucleus). Unlike most cases of myelodysplastic syndrome, the bone marrow aspirate in copper deficiency characteristically shows cytoplasmic vacuoles within red and white cell precursors, and karyotyping in cases of copper deficiency does not reveal cytogenetic features characteristic of myelodysplastic syndrome. Anemia and neutropenia typically resolve within six weeks of copper replacement.

Neurological symptoms

Copper deficiency can cause a wide variety of neurological problems including

, peripheral

neuropathy Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or o ...

, and

Myelopathy

Copper deficiency myelopathy in humans was discovered and first described by Schleper and Stuerenburg in 2001. They described a patient with a history of gastrectomy and partial colonic resection who presented with severe tetraparesis and painful paraesthesias and who was found on imaging to have dorsomedial cervical cord T2 hyperintensity. Upon further analysis, it was found that the patient had decreased levels of serum coeruloplasmin, serum copper, and CSF copper. The patient was treated with parenteral copper and the patient's paraesthesias did resolve. Since this discovery, there has been heightened and increasing awareness of copper-deficiency myelopathy and its treatment, and this disorder has been reviewed by Kumar. Patients typically present difficulty walking (

gait Gait is the pattern of movement of the limbs of animals, including humans, during locomotion over a solid substrate. Most animals use a variety of gaits, selecting gait based on speed, terrain, the need to maneuver, and energetic efficiency. ...

difficulty) caused by

(irregular muscle coordination) due to dorsal column dysfunction or degeneration of the spinal cord (

). Patients with ataxic gait have problems balancing and display an unstable wide walk. They often feel tremors in their torso, causing sideways jerks and lunges. In brain MRI, there is often an increased T2 signalling at the posterior columns of the spinal cord in patients with myelopathy caused by copper deficiency. T2 signalling is often an indicator of some kind of neurodegeneration. There are some changes in the spinal cord MRI involving the thoracic cord, the cervical cord or sometimes both. Copper deficiency myelopathy is often compared to subacute combined degeneration (SCD). Subacute combined degeneration is also a degeneration of the spinal cord, but instead

deficiency is the cause of the spinal degeneration. SCD also has the same high T2 signalling intensities in the posterior column as copper deficient patient in MRI imaging.

Peripheral neuropathy

Another common symptom of copper deficiency is

peripheral neuropathy Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or or ...

, which is numbness or tingling that can start in the extremities and can sometimes progress radially inward towards the torso. In an Advances in Clinical Neuroscience & Rehabilitation (ACNR) published case report, a 69-year-old patient had progressively worsened neurological symptoms. These symptoms included diminished upper limb reflexes with abnormal lower limb reflexes, sensation to light touch and pin prick was diminished above the waist, vibration sensation was lost in the sternum, and markedly reduced

proprioception Proprioception ( ), also referred to as kinaesthesia (or kinesthesia), is the sense of self-movement, force, and body position. It is sometimes described as the "sixth sense". Proprioception is mediated by proprioceptors, mechanosensory neurons ...

or sensation about the self's orientation. Many people with the neurological effects of copper deficiency complain about very similar or identical symptoms as the patient. This numbness and tingling poses danger for the elderly because it increases their risk of falling and injuring themselves. Peripheral

can become very disabling leaving some patients reliant on wheelchairs or walking canes for mobility if there is a lack of correct diagnosis. Rarely can copper deficiency cause major disabling symptoms. The deficiency will have to be present for an extensive amount of time until such disabling conditions manifest.

Optic neuropathy

Some patients with copper deficiency have shown signs of vision and color loss. The vision is usually lost in the peripheral views of the eye. The bilateral vision loss is usually very gradual. An

optical coherence tomography Optical coherence tomography (OCT) is an imaging technique that uses low-coherence light to capture micrometer-resolution, two- and three-dimensional images from within optical scattering media (e.g., biological tissue). It is used for medica ...

(OCT) shows some nerve fiber layer loss in most patients, suggesting the vision loss and color vision loss was secondary to

or neurodegeneration.

Causes

Surgery

Bariatric surgery Bariatric surgery (or weight loss surgery) includes a variety of procedures performed on people who are obese. Long term weight loss through the standard of care procedures ( Roux en-Y bypass, sleeve gastrectomy, and biliopancreatic diversio ...

is a common cause of copper deficiency. Bariatric surgery, such as gastric bypass surgery, is often used for weight control of the morbidly obese. The disruption of the intestines and stomach from the surgery can cause absorption difficulties not only as regards copper but also for iron and

and many other nutrients. The symptoms of copper deficiency

may take up to decades to develop.

Zinc toxicity

Increased consumption of

zinc Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...

is another cause of copper deficiency.

Zinc Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...

is often used for the prevention or treatment of common colds and sinusitis (inflammation of sinuses due to an infection), ulcers, sickle cell disease, celiac disease, memory impairment, and acne. Zinc is found in many common vitamin supplements and is also found in denture creams. Recently, several cases of copper deficiency myeloneuropathy were found to be caused by prolonged use of denture creams containing high quantities of zinc. A literature review found two cases of copper deficiency myelopathy secondary to parenteral zinc supplementation during chronic dialysis. Metallic zinc is the core of all United States currency coins, including copper-coated pennies. People who ingest a large number of coins will have elevated zinc levels, leading to zinc-toxicity-induced copper deficiency and the associated neurological symptoms. This was the case for a 57-year-old woman diagnosed with

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social w ...

. The woman consumed over 600 coins, and started to show neurological symptoms such as unsteady

and mild

Hereditary disorders

is a congenital disease that is a cause of copper deficiency. Menkes disease is a hereditary condition caused by a defective gene involved with the metabolism of copper in the body. Menkes disease involves a wide variety of symptoms including floppy muscle tone,

seizures An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with lo ...

, abnormally low temperatures, and a peculiar steel color hair that feels very rough. Menkes disease is usually a fatal disease with most children dying within the first ten years of life.

Other

It is rarely suggested that excess iron supplementation causes copper deficiency

. Another rarer cause of copper deficiency is celiac disease, probably due to malabsorption in the intestines. Still, a large percentage, around 20%, of cases have unknown causes.

Pathophysiology

Copper functions as a prosthetic group, which permits electron transfers in key enzymatic pathways like the

. electronic-book electronic- Copper is integrated in the enzymes

, which is involved in

cellular respiration Cellular respiration is the process by which biological fuels are oxidised in the presence of an inorganic electron acceptor such as oxygen to produce large amounts of energy, to drive the bulk production of ATP. Cellular respiration may be des ...

and

, Cu/Zn dismutase, which is involved in

antioxidant Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubrica ...

defense, and many more listed in the table below.

Neurological

Cytochrome c oxidase

There have been several hypotheses about the role of copper and some of its neurological manifestations. Some suggest that disruptions in

, also known as Complex IV, of the electron transport chain is responsible for the spinal cord degeneration.

Methylation cycle

Another hypothesis is that copper deficiency myelopathy is caused by disruptions in the

methylation In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These ...

cycle. The methylation cycle causes a transfer of a methyl group (-CH₃) from methyltetrahydrofolate to a range of

macromolecules A macromolecule is a very large molecule important to biophysical processes, such as a protein or nucleic acid. It is composed of thousands of covalently bonded atoms. Many macromolecules are polymers of smaller molecules called monomers. The ...

by the suspected copper dependent enzyme methionine synthase. This cycle is able to produce purines, which are a component of DNA nucleotide bases, and also

myelin Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can ...

proteins. The spinal cord is surrounded by a layer of protective protein coating called myelin (see figure). When this methionine synthase enzyme is disrupted, the methylation decreases and myelination of the spinal cord is impaired. This cycle ultimately causes

Hematological cause

Iron transportation

The

caused by copper deficiency is thought to be caused by impaired iron transport. Hephaestin is a copper containing ferroxidase enzyme located in the duodenal muscosa that oxidizes iron and facilitates its transfer across the basolateral membrane into circulation. Another iron transporting enzyme is

. This enzyme is required to mobilize iron from the reticuloendothelial cell to plasma. Ceruloplasmin also oxidizes iron from its ferrous state to the ferric form that is required for iron binding. Impairment in these copper dependent enzymes that transport iron may cause the secondary iron deficiency anemia. Another speculation for the cause of anemia is involving the mitochondrial enzyme

(complex IV in the electron transport chain). Studies have shown that animal models with impaired cytochrome c oxidase failed to synthesize

heme Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver. In biochemical terms, heme is a coordination complex "consis ...

from ferric iron at the normal rate. The lower rate of the enzyme might also cause the excess iron to clump, giving the heme an unusual pattern. This unusual pattern is also known as ringed sideroblastic anemia cells.

Cell growth halt

The cause of

is still unclear; however, the arrest of maturing

myelocyte A myelocyte is a young cell of the granulocytic series, occurring normally in bone marrow (can be found in circulating blood when caused by certain diseases). Structure When stained with the usual dyes, the cytoplasm is distinctly basophil ...

s, or

neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...

precursors, may cause the

deficiency.

Zinc intoxication

Zinc intoxication may cause

by blocking the absorption of copper from the stomach and

duodenum The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear, and the terms anterior intestine or proximal intestine m ...

. Zinc also upregulates the expression of chelator

metallothionein Metallothionein (MT) is a family of cysteine-rich, low molecular weight (MW ranging from 500 to 14000 Da) proteins. They are localized to the membrane of the Golgi apparatus. MTs have the capacity to bind both physiological (such as zinc, cop ...

enterocytes Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells which line the inner surface of the small and large intestines. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase i ...

, which are the majority of cells in the intestinal epithelium. Since copper has a higher affinity for metallothionein than zinc, the copper will remain bound inside the enterocyte, which will be later eliminated through the lumen. This mechanism is exploited therapeutically to achieve negative balance in Wilson's disease, which involves an excess of copper.

Diagnosis

The diagnosis of copper deficiency may be supported by a person's report of compatible signs and symptoms, findings from a thorough physical examination, and supportive laboratory evidence. Low levels of copper and

in the serum are consistent with the diagnosis as is a low 24 hour urine copper level. Additional supportive bloodwork findings also include

and

. MRI imaging may demonstrate increased T2 signal of the

dorsal column–medial lemniscus pathway The dorsal column–medial lemniscus pathway (DCML) (also known as the posterior column-medial lemniscus pathway, PCML) is a sensory pathway of the central nervous system that conveys sensations of fine touch, vibration, two-point discrimination, ...

Treatment

Copper deficiency is a very rare disease and is often misdiagnosed several times by physicians before concluding the deficiency of copper through differential diagnosis (copper serum test and bone marrow biopsy are usually conclusive in diagnosing copper deficiency). On average, patients are diagnosed with copper deficiency around 1.1 years after their first symptoms are reported to a physician. Copper deficiency can be treated with either oral copper supplementation or

intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

copper. If zinc intoxication is present, discontinuation of zinc may be sufficient to restore copper levels back to normal, but this usually is a very slow process. People with zinc intoxication will usually have to take copper supplements in addition to ceasing zinc consumption. Hematological manifestations are often quickly restored back to normal. The progression of the neurological symptoms will be stopped and sometimes improved with appropriate treatment, but residual neurological disability is common.

References

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External links

{{Medical resources , DiseasesDB = 3094 , ICD10 = {{ICD10, E, 61, 0, e, 50 , ICD9 = {{ICD9, 275.1 , ICDO = , OMIM = 121270 , MedlinePlus = , eMedicineSubj = , eMedicineTopic = , MeshID = {{Nutritional pathology {{Elements in biology {{DEFAULTSORT:Copper Deficiency Mineral deficiencies Deficiency Animal diseases