Copper deficiency

Copper deficiency
Classification and external resources
ICD-10	E61.0
ICD-9	275.1

Copper deficiency is a very rare hematological and neurological disorder.^[1][2][3] The neurodegenerative syndrome of copper deficiency has been recognized for some time in ruminant animals, in which it is commonly known as "swayback"^[3] The disease involves a nutritional deficiency in the trace element copper.^[3] Copper is ubiquitous and daily requirement is low making acquired copper deficiency very rare. Copper deficiency can manifest in parallel with vitamin B12 deficiency and zinc toxicity.^[2] The most common cause of copper deficiency is a remote gastrointestinal surgery, such as gastric bypass surgery, due to malabsorption of copper. 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 involved in normalized function of many enzymes, such as cytochrome c oxidase, which is complex IV in mitochondrial electron transport chain, ceruloplasmin, Cu/Zn superoxide dismutase, and in amine oxidases.^[3] These enzyme catalyze reactions for oxidative phosphorylation, iron transportation, antioxidant and free radical scavenging and neutralization, and neurotransmitter synthesis, respectively.^[3] A regular diet contains a variable amount of copper, but may provide 5 mg/day, of which only 20-50% is absorbed.^[2] The diet of the elderly may contain a lower copper content than the recommended daily intake.^[2] Dietary copper can be found in whole grain cereals, legumes, oysters, organ meats (particularly liver), cherries, dark chocolate, fruits, leafy green vegetables, nuts, poultry, prunes, and soybeans products like tofu.^[5] The deficiency in copper can cause many hematological manifestations, such as myelodysplasia, anemia, leukopenia (low white blood cell count) and neutropenia (low count of neutrophils, a type of white blood cell that is often called "the first line of defense" for the immune system).^[2] Copper deficiency has long been known for as a cause of myelodysplasia(when a blood profile has indicators of possible future leukemia development), but it was until recently in 2001 that copper deficiency was associated with neurological manifestations. Some neurological manifestations can be sensory ataxia (irregular muscle coordination), peripheral neuropathy (damage in the peripheral nerves) and myelopathy (disease of the spinal cord).^[3]

Symptoms

Hematological Presentation

Ring Sideroblast smear 2010-01-13

Most sufferers generally complain about tiredness, fatigue, and light headedness. These are all common symptoms of anemia. Around half of the patients displayed some kind of anemia with markedly reduced leukocytes also known as “leukopenia”.^[1][2][6] In addition to leukopenia, many patients are deficient in neutrophils (neutropenia).^[2][6] Neutropenia has become a hematological hallmark, enabling physicians to investigate copper deficiency as a diagnosis.^[6] All types of anemia including microcytic (small red blood cells), macrocytic (large red blood cells, leaving insufficient amounts of hemoglobin per unit volume of blood) and normocytic (a deficiency in normal sized red blood cells) manifest.^[1][6] It is very rarely that thrombocytopenia, which is a syndrome of low blood platelets leading to slowed clotting and abnormal bleeding, is observed in patients.^[2][6] Usually prolonged copper deficiency has to persist to manifest thrombocytopenia.^[6] Many times during a bone marrow biopsy, decreased granulocyte (which are granulated white blood cells including neutrophils, eosinophils, and basophils) maturation, vacuolization of red blood cell precursors, and ringed sideroblastic cells are present.^[1][2][6] Sideroblastic cells have unusual patterns of iron clumping in the mitochondria that is visible when the cell is stained, receiving its name “ringed” sideroblast.^[3][7] Subacute combined degeneration is also a degeneration of the spinal cord, but instead of copper deficiency as the cause of degeneration, vitamin B12 deficiency is the cause.^[2][3] These bone marrow findings can lead to a diagnosis of myelodysplasia.^[1][6] Myelodysplasia is sometimes referred to “preleukemia.”.^[8] This disease often later progresses into a form of leukemia.^[8] Most of the people who are diagnosed with myelodysplasia will have to undergo a stem cell transplantation.^[8] A diagnosis of copper deficiency at the state is crucial to prevent unnecessary painful surgery, such as the bone marrow biopsy.

Neurological Presentation

Copper deficiency can cause a wide variety of neurological problems including, myelopathy, peripheral neuropathy, and optic neuropathy.^[3][6]

Myelopathy

Sufferers typically present difficulty walking (gait difficulty) caused by sensory ataxia (irregular muscle coordination) due to dorsal column dysfunction ^[6] or degeneration of the spinal cord (myelopathy).^[3][9] Patients with ataxic gait have problems balancing and display an unstable wide walk. They often feel tremors in their torso, causing side way jerks and lunges.^[10] 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.^[3][6][11] 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.^[3][6] Copper deficiency myelopathy is often compared to subacute combined degeneration (SCD).^[9] 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.^[11]

Peripheral Neuropathy

Another common symptom of copper deficiency is peripheral neuropathy, which is numbness or tingling that can start in the extremities and can sometimes progress radially inward towards the torso.^[6][12] In an Advances in Clinical Neuroscience & Rehabilitation (ACNR) published case report, a 69 year old patient had progressively worsened neurological symptoms.^[13] 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 or sensation about the self’s orientation.^[13] Many people suffering from the neurological effects of copper deficiency complain about very similar or identical symptoms as the patient.^[3][12] This numbness and tingling poses danger for the elderly because it increases their risk of falling and injuring themselves. Peripheral neuropathy can become very disabling leaving some patients dependent on wheel chairs or walking canes for mobility if there is 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 suffering from copper deficiency have shown signs of vision and color loss.^[12] The vision is usually lost in the peripheral views of the eye.^[12] The bilateral vision loss is usually very gradual.^[12] 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.^[12]

Causes

Surgery

Bariatric surgery is a common cause of copper deficiency.^[1][3] 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 in copper, but also in iron and vitamin B12 and many other nutrients.^[3] The symptoms of copper deficiency myelopathy may take a long time to develop, sometimes decades before the myelopathy symptoms manifest.

Zinc Toxicity

Increased consumption of zinc is another cause of copper deficiency.^[6] Zinc 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.^[6] Zinc is found in many common vitamin supplements and is also found in denture creams.^[6][14] Denture cream was recently accused of causing neurological problems, such as numbness, tingling, muscle weakness, and anemia, in their consumers due to copper deficiency caused by zinc toxicity.^[14]

Metallic zinc is the core of all United States currency coins, including copper coated pennies. People who ingest massive amount of coins will have elevated zinc levels, leading to zinc toxicity induced copper deficiency and thus displaying neurological symptoms. This is the case for a 57 year old woman who was diagnosed with schizophrenia.^[15] This woman consumed over 600 coins, and started to show neurological symptoms such as unsteady gait and mild ataxia.^[15]

Hereditary Disorders

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

Menkes disease is a congenital disease that is a cause of copper deficiency.^[4][6][16] Menkes disease is a hereditary condition caused by a defective gene involved with the metabolism of copper in the body.^[6] Menkes disease involves a wide variety of symptoms including floppy muscle tone, seizures, abnormally low temperatures, and a peculiar steel color hair that feels very rough.^[4][16] Menkes disease is usually a fatal disease with most children dying within the first ten years of life.^[4][16]

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]

Biochemical Etiology

Copper functions as a prosthetic group, which permits election transfers in key enzymatic pathways like the electron transport chain.^[2][3] 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	Metabolism of amines- histamines, putrescine, cadaverine
	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 Fe 3+, 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 hormone maturation- 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 homocysteine to generate methionine for the methylation cycle and tetrahydrofolate for purine synthesis
	Adenosylhomocysteinase (S-Adenosyl-L-homocysteine)	Regeneration of homocysteine from adenosylhomocyesteine (S-Adenosyl-L-homocysteine) in the methylation cycle

Neurological Etiology

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][9]

Methylation Cycle

Myelinated neuron

Another hypothesis is that copper deficiency myelopathy is caused by disruptions in the methylation cycle.^[9] The methylation cycle causes a transfer of a methyl group (-CH3) from methyltetrahydrofolate to a range of macromolecules by the suspected copper dependent enzyme methionine synthase.^[9] This cycle is able to produce purines, which are a component of DNA nucleotide bases, and also myelin proteins.^[9] 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.^[9]

Hematological Etiology

Iron Transportation

The anemia 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 facilitate its transfer across the basolateral membrane into circulation.^[1] Another iron transporting enzyme is ceruloplasmin.^[1] This enzyme is required to mobilize iron from the reticuloendothelial cell to plasma.^[1] Ceruloplasmin also oxidizes iron from its ferrous state to the ferric form that is required for iron binding.^[4] Impairment in these copper dependent enzymes that transport iron may cause the secondary iron deficiency anemia.^[1] Another speculation for the cause of anemia is involving the mitochondrial enzyme cytochrome c oxidase (complex IV in the electron transport chain). Studies have shown that animal models with impaired cytochrome c oxidase failed to synthesize heme from ferric iron at the normal rate.^[1] The lower rate of the enzyme might also cause the excess iron to clump, giving the heme an unusual pattern.^[1] This unusual pattern is also knows as ringed sideroblastic anemia cells.

Cell Growth Hault

The cause of neutropenia is still unclear; however, the arrest of maturing myelocytes, or neutrophil precursors, may cause the neutrophil deficiency.^[1][2]

Zinc Intoxication

Zinc intoxication may cause anemia by blocking the absorption of copper from the stomach and duodenum.^[3] Zinc also upregulates the expression of chelator metallothionein in 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]

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.^[6] 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.^[6] People who suffer from zinc intoxication will usually have to take copper supplements in addition to ceasing zinc consumption. Hematological manifestations are often quickly restored back to normal.^[6] The neurological symptoms will often, but not always, cease.^[6]

See also

• copper in health

References

1. ^ ^{a b c d e f g h i j k l m} Klevay, L. M. (2006). "Myelodysplasia," myeloneuropathy, and copper deficiency. Mayo Clinic Proceedings, 81(1), 132-132.
2. ^ ^{a b c d e f g h i j k l m} Halfdanarson, T. R., Kumar, N., Li, C. Y., Phyliky, R. L., & Hogan, W. J. (2008). Hematological manifestations of copper deficiency: a retrospective review. [Article]. European Journal of Haematology, 80(6), 523-531.
3. ^ ^{a b c d e f g h i j k l m n o p q r s t u v w x y z aa} Jaiser, S. R., & Winston, G. P. (2010). Copper deficiency myelopathy. [Review]. Journal of Neurology, 257(6), 869-881.
4. ^ ^{a b c d e} Kodama, H., & Fujisawa, C. (2009). Copper metabolism and inherited copper transport disorders: molecular mechanisms, screening, and treatment. Metallomics, 1(1), 42-52.
5. ^ Copper Information: Benefits, Deficiencies, Food Sources. http://www.healthvitaminsguide.com/minerals/copper.htm
6. ^ ^{a b c d e f g h i j k l m n o p q r s t u v} Kumar, N. (2006). Copper deficiency myelopathy (human swayback). Mayo Clinic Proceedings, 81(10), 1371-1384.
7. ^ Iolascon, A., De Falco, L., & Beaumont, C. (2009). Molecular basis of inherited microcytic anemia due to defects in iron acquisition or heme synthesis. Haematologica-the Hematology Journal, 94(3), 395-408.
8. ^ ^{a b c} Myelodysplastic Syndromes. The Leukemia and Lymphoma Society, http://www.leukemia-lymphoma.org/all_page?item_id=55442.
9. ^ ^{a b c d e f g} Jaiser, S. R., & Winston, G. P. (2008). Copper deficiency myelopathy and subacute combined degeneration of the cord: why is the phenotype so similar? Journal of Neurology, 255, P569.
10. ^ Ataxic Gait Demonstration. Online Medical Video. http://www.youtube.com/watch?v=FpiEprzObIU&feature=related
11. ^ ^{a b} Bolamperti, L., Leone, M. A., Stecco, A., Reggiani, M., Pirisi, M., Carriero, A., et al. (2009). Myeloneuropathy due to copper deficiency: clinical and MRI findings after copper supplementation. [Article]. Neurological Sciences, 30(6), 521-524.
12. ^ ^{a b c d e f} Pineles, S. L., Wilson, C. A., Balcer, L. J., Slater, R., & Galetta, S. L. (2010). Combined Optic Neuropathy and Myelopathy Secondary to Copper Deficiency. [Review]. Survey of Ophthalmology, 55(4), 386-392.
13. ^ ^{a b} Jaiser, Stephan R. and Duddy, R. Copper Deficiency Masquerading as Subacute Combined Degeneration of the Cord and Myelodysplastic Syndrome. Advances in clinical neuroscience and rehabilitation, http://www.acnr.co.uk/JA07/ACNR_JA07_abnwinner.pdf
14. ^ ^{a b} Hedera, P., Peltier, A., Fink, J. K., Wilcock, S., London, Z., & Brewer, G. J. (2009). Myelopolyneuropathy and pancytopenia due to copper deficiency and high zinc levels of unknown origin II. The denture cream is a primary source of excessive zinc. [Article]. Neurotoxicology (Amsterdam), 30(6), 996-999.
15. ^ ^{a b} Dhawan, S. S., Ryder, K. M., & Pritchard, E. (2008). Massive penny ingestion: The loot with local and systemic effects. [Article]. Journal of Emergency Medicine, 35(1), 33-37.
16. ^ ^{a b c} Kaler, S. G., Liew, C. J., Donsante, A., Hicks, J. D., Sato, S., & Greenfield, J. C. (2010). Molecular correlates of epilepsy in early diagnosed and treated Menkes disease. Journal of Inherited Metabolic Disease, 33(5), 583-589.