Copper deficiency

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Copper deficiency
Other namesHypocupremia
Ring Sideroblast smear, a sign of copper deficiency in the blood.
SpecialtyEndocrinology Edit this on Wikidata
Risk factorsAlcoholism, gastric bypass surgery

Copper deficiency, or hypocupremia, is defined either as insufficient copper to meet the needs of the body, or as a serum copper level below the normal range.[1] Symptoms may include fatigue, decreased red blood cells, early greying of the hair, and neurological problems presenting as numbness, tingling, muscle weakness, and ataxia.[2] The neurodegenerative syndrome of copper deficiency has been recognized for some time in ruminant animals, in which it is commonly known as "swayback".[3] Copper deficiency can manifest in parallel with vitamin B12 and other nutritional deficiencies.[2]

Overview

The most common cause of copper deficiency is a remote gastrointestinal surgery, such as gastric bypass surgery, due to malabsorption of copper, or zinc toxicity. On the other hand, Menkes disease is a genetic disorder of copper deficiency involving a wide variety of symptoms that is often fatal.[4]

Copper is required for the functioning of many enzymes, such as

cherries, dark chocolate, fruits, leafy green vegetables, nuts, poultry, prunes, and soybean products like tofu.[5]

Copper deficiency can have many hematological consequences, such as

myelodysplasia, anemia, 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).[2] Copper deficiency has long been known as a cause of myelodysplasia (when a blood profile has indicators of possible future leukemia development), but it was not until 2001 that copper deficiency was associated with neurological manifestations like sensory ataxia (irregular coordination due to proprioceptive loss), spasticity, muscle weakness, and more rarely visual loss due to damage in the peripheral nerves, myelopathy (disease of the spinal cord), and rarely optic neuropathy.[medical citation needed
]

Signs and symptoms

Blood symptoms

The characteristic hematological (blood) effects of copper deficiency are

platelets) is unusual.[2][7]

The peripheral blood and

karyotyping in cases of copper deficiency does not reveal cytogenetic features characteristic of myelodysplastic syndrome.[6][7]

Anemia and neutropenia typically resolve within six weeks of copper replacement.[8]

Neurological symptoms

Copper deficiency can cause a wide variety of neurological problems including

neuropathy, and optic neuropathy.[3][7]

Myelopathy

Copper deficiency myelopathy in humans was discovered and first described by Schleper and Stuerenburg in 2001.[9] 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 (

dorsal column dysfunction[7] or degeneration of the spinal cord (myelopathy).[3][10] 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.[11]

In brain MRI, there is often an increased

subacute combined degeneration (SCD).[10] Subacute combined degeneration is also a degeneration of the spinal cord, but instead vitamin B12 deficiency is the cause of the spinal degeneration.[3] SCD also has the same high T2 signalling intensities in the posterior column as copper deficient patient in MRI imaging.[12]

Peripheral neuropathy

Another common symptom of copper deficiency is

neuropathy
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.[13] The vision is usually lost in the peripheral views of the eye.[13] The bilateral vision loss is usually very gradual.[13][15] An optical coherence tomography (OCT) shows some nerve fiber layer loss in most patients, suggesting the vision loss and color vision loss was secondary to optic neuropathy or neurodegeneration.[13]

Causes

Surgery

Bariatric surgery is a common cause of copper deficiency.[3][6] 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 vitamin B12 and many other nutrients.[3] The symptoms of copper deficiency myelopathy may take up to decades to develop.

Zinc toxicity

Increased consumption of

celiac disease, memory impairment, and acne.[7] Zinc is found in many common vitamin supplements and is also found in denture creams.[7][15][16] Recently, several cases of copper deficiency myeloneuropathy were found to be caused by prolonged use of denture creams containing high quantities of zinc.[15][16]

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. The woman consumed over 600 coins, and started to show neurological symptoms such as unsteady gait and mild ataxia.[17]

Hereditary disorders

Menkes disease showing symptoms of the sparse, steel colored "kinky hair" and paleness

seizures, abnormally low temperatures, and a peculiar steel color hair that feels very rough.[4][18] Menkes disease is usually a fatal disease with most children dying within the first ten years of life.[4][18]

Other

It is rarely suggested that excess iron supplementation causes copper deficiency myelopathy.[3] Another rarer cause of copper deficiency is

celiac disease, probably due to malabsorption in the intestines.[3]
Still, a large percentage, around 20%, of cases have unknown causes.[3]

Pathophysiology

Copper functions as a prosthetic group, which permits electron transfers in key enzymatic pathways like the electron transport chain.[3][2][19] Copper is integrated in the enzymes cytochrome c oxidase, which is involved in cellular respiration and oxidative phosphorylation, Cu/Zn dismutase, which is involved in antioxidant defense, and many more listed in the table below.[2]

Several Copper Dependent Enzymes and Their Function[3]
Group Enzyme Function
Oxidases Flavin-containing amine oxidase Metabolism of neurotransmitters:
noradrenaline, dopamine, serotonin
and some dietary amines
Protein-lysine-6-oxidase (lysyl oxidase) Connective tissue synthesis- cross-linking of collagen and elastin
Copper-containing amine oxidase (a family of enzymes which includes primary-amine oxidase and diamine oxidase) Oxidation of biogenic amines including
histamines, putrescine, cadaverine
, and xenobiotic amines
Cytochrome c oxidase Oxidative phosphorylation, electron transport in the
mitochondrial membrane
Superoxide dismutase (Cu/Zn dismutase) Antioxidant and free radical scavenger, oxidizes dangerous
superoxides
to safer hydrogen peroxide
Ferroxidase I (ceruloplasmin) Iron transport-oxidation of Fe2+ to Fe3+, copper storage and transport, antioxidant and free radical neutralizer
Hephaestin (ferroxidase) Iron transport and oxidation of Fe2+ to Fe3+ in intestinal cells to enable iron uptake
Monooxygenases
Dopamine beta-monooxygenase
 Conversion of dopamine to norepinephrine
Peptidylglycine monooxygenase Peptide
amidation of alpha-terminal carboxylic acid group of glycine
Monophenol monooxygenase (Tyrosinase) Melanin synthesis
Methylation Cycle Methionine synthase Transfer of methyl group from methyltetrahydrofolate to
tetrahydrofolate for purine
synthesis
Adenosylhomocysteinase (S-Adenosyl-L-homocysteine) Regeneration of homocysteine from adenosylhomocyesteine (S-Adenosyl-L-homocysteine) in the methylation cycle

Neurological

Cytochrome c Oxidase mechanism in mitochondrial membrane

Cytochrome c oxidase

There have been several hypotheses about the role of copper and some of its neurological manifestations. Some suggest that disruptions in cytochrome c oxidase, also known as Complex IV, of the electron transport chain is responsible for the spinal cord degeneration.[3][10]

Methylation cycle

Myelinated neuron

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

nucleotide bases, and also myelin proteins.[10] 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 myelopathy.[10]

Hematological cause

Iron transportation

The

sideroblastic
anemia cells.

Cell growth halt

The cause of neutropenia is still unclear; however, the arrest of maturing myelocytes, or neutrophil precursors, may cause the neutrophil deficiency.[2][6]

Zinc intoxication

Zinc intoxication may cause

enterocytes, which are the majority of cells in the intestinal epithelium.[3] 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.[3] This mechanism is exploited therapeutically to achieve negative balance in Wilson's disease, which involves an excess of copper.[3]
But in copper-deficient individuals, zinc excess may cause this mechanism to further deplete copper levels.

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 ceruloplasmin in the serum are consistent with the diagnosis as is a low 24 hour urine copper level.[20] Additional supportive bloodwork findings also include neutropenia and anemia.[20] MRI imaging may demonstrate increased T2 signal of the dorsal column–medial lemniscus pathways.[20]

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.[3]
Copper deficiency can be treated with either oral copper supplementation or
intravenous copper.[7] 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.[7] 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.[7] The progression of the neurological symptoms will be stopped and sometimes improved with appropriate treatment, but residual neurological disability is common.[20]

See also

  • Copper in health
  • Copper deficiency and excess health conditions (non-genetic)

References

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  5. ^ "Copper Information: Benefits, Deficiencies, Food Sources".
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  11. ^ Ataxic gait demonstration. Online Medical Video
  12. ^
    S2CID 21488713
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  13. ^
    PMID 20451943
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  14. ^ a b Jaiser, S.R.; Duddy, R. (2007). "Copper deficiency masquerading as subacute combined degeneration of the cord and myelodysplastic syndrome" (PDF). ACNR: Advances in Clinical Neuroscience and Rehabilitation. 7 (3): 20–21. Archived from the original (PDF) on 2020-08-01. Retrieved 2010-11-29.
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  19. ISSN 1868-0402
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External links

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