| Copper deficiency | |
|---|---|
| Other names | Hypocupremia |
 | |
| Ring Sideroblast smear, a sign of copper deficiency in the blood. | |
| Specialty | Endocrinology  |
| Risk factors | Alcoholism,gastric bypass surgery |
Copper deficiency, orhypocupremia, is defined as insufficientcopper to meet the body's needs, or as a serum copper level below the normal range.[1] Symptoms may includefatigue,decreased red blood cells, early greying of the hair, and neurological problems presenting asnumbness, tingling, muscle weakness, andataxia.[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 withvitamin B12 and other nutritional deficiencies.[2]
The most common cause of copper deficiency is a remote gastrointestinal surgery, such asgastric bypass surgery, due tomalabsorption of copper, orzinc 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 ascytochrome c oxidase, which is complex IV in the mitochondrialelectron transport chain,ceruloplasmin, Cu/Znsuperoxide dismutase, and inamine oxidases.[3] These enzymes catalyze reactions foroxidative phosphorylation, iron transportation, antioxidant and free radical scavenging and neutralization, andneurotransmitter synthesis, respectively.[3] Diets vary in the amount of copper they contain, but may provide about 5 mg/day, of which only 20-50% is absorbed.[2] The diet of the elderly may have a lower copper content than the recommended daily intake.[2] Dietary copper can be found inwhole graincereals,legumes,oysters, organ meats (particularlyliver),cherries,dark chocolate,fruits, leafy green vegetables,nuts,poultry,prunes, andsoybean products liketofu.[5]
Copper deficiency can have many hematological consequences, such asmyelodysplasia,anemia,low white blood cell count, andlow count of neutrophils (a type of white blood cell that is often called "the first line of defense" of the immune system).[2]
The characteristic hematological (blood) effects of copper deficiency areanemia (which may bemicrocytic, normocytic ormacrocytic) andneutropenia.[6]Thrombocytopenia (low bloodplatelets) is unusual.[2][7]
The peripheral blood andbone marrow aspirate findings in copper deficiency can mimicmyelodysplastic syndrome.[8]Bone marrow aspirate in both conditions may showdysplasia 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 cytoplasmicvacuoles within red and white cell precursors, andkaryotyping 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]
Copper deficiency can cause a wide variety of neurological problems includingmyelopathy, peripheralneuropathy, andoptic neuropathy.[3][7]
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, awareness of copper-deficiency myelopathy and its treatment has increased. Patients typically present difficulty walking (gait difficulty) caused bysensory ataxia (irregular muscle coordination) due todorsal 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 increasedT2 signalling at the posterior columns of the spinal cord in patients with myelopathy caused by copper deficiency.[3][7][12] T2 signalling is often an indicator of neurodegeneration. There are some changes in the spinal cord MRI involving the thoracic cord, the cervical cord, or sometimes both.[3][7] Copper deficiency myelopathy is often compared tosubacute combined degeneration (SCD).[10] Subacute combined degeneration is also a degeneration of the spinal cord, but insteadvitamin 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]
Another common symptom of copper deficiency isperipheral neuropathy, which is numbness or tingling that can start in the extremities and can sometimes progress radially inward towards the torso.[7][13] In anAdvances in Clinical Neuroscience & Rehabilitation published case report, a 69-year-old patient had progressively worsened neurological symptoms.[14] 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 reducedproprioception or sensation about the self's orientation.[14] Many people with the neurological effects of copper deficiency complain about very similar or identical symptoms as the patient.[3][13] This numbness and tingling pose a danger for the elderly because it increases their risk of falling and injuring themselves. Peripheralneuropathy 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 must be present for an extensive amount of time until such disabling conditions manifest.
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] Anoptical coherence tomography (OCT) shows some nerve fiber layer loss in most patients, suggesting the vision loss and color vision loss was secondary tooptic neuropathy or neurodegeneration.[13]
Bariatric surgery is a common cause of copper deficiency.[3][6] Bariatric surgery, such asgastric 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 andvitamin B12 and many other nutrients.[3] The symptoms of copper deficiencymyelopathy may take up to decades to develop.
Increasedzinc consumption is another cause of copper deficiency.[7]Zinc is often used for the prevention or treatment of common colds andsinusitis (inflammation of sinuses due to an infection), ulcers,sickle cell disease,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 many 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 withschizophrenia. The woman consumed over 600 coins and started to show neurological symptoms such as unsteadygait and mildataxia.[17]
Menkes disease is a congenital disease that is a cause of copper deficiency.[4][7][18] Menkes disease is a hereditary condition caused by a defective gene involved with the metabolism of copper in the body.[7] Menkes disease has a wide variety of symptoms including floppy muscle tone,seizures, abnormally low body temperature, and a peculiar steel color hair that feels very rough.[4][18] Menkes disease is usually fatal, with the majority of affected children dying within the first ten years of life.[4][18]
It is rarely suggested that excess iron supplementation causes copper deficiencymyelopathy.[3]Another rarer cause of copper deficiency isceliac disease, probably due to malabsorption in the intestines.[3]Still, a large percentage, around 20%, of cases have unknown causes.[3]
Copper functions as a prosthetic group, permitting electron transfers in key enzymatic pathways like theelectron transport chain.[3][2][19] Copper is integrated in the enzymescytochrome c oxidase, which is involved incellular respiration andoxidative phosphorylation, Cu/Zn dismutase, which is involved inantioxidant defense, and many more listed in the table below.[2]
| Group | Enzyme | Function |
|---|---|---|
| Oxidases | Flavin-containingamine oxidase | Metabolism of neurotransmitters:noradrenaline,dopamine,serotonin and some dietary amines |
| Protein-lysine-6-oxidase (lysyl oxidase) | Connective tissue synthesis- cross-linking ofcollagen andelastin | |
| Copper-containing amine oxidase (a family of enzymes which includesprimary-amine oxidase anddiamine oxidase) | Oxidation of biogenic amines includingneurotransmitters,histamines,putrescine,cadaverine, and xenobiotic amines | |
| Cytochrome c oxidase | Oxidative phosphorylation, electron transport in themitochondrial membrane | |
| Superoxide dismutase (Cu/Zn dismutase) | Antioxidant and free radical scavenger, oxidizes dangeroussuperoxides 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 ofdopamine tonorepinephrine |
| Peptidylglycine monooxygenase | Peptidehormone maturation-amidation of alpha-terminalcarboxylic acid group ofglycine | |
| Monophenol monooxygenase (Tyrosinase) | Melanin synthesis | |
| Methylation Cycle | Methionine synthase | Transfer of methyl group from methyltetrahydrofolate tohomocysteine to generatemethionine for the methylation cycle andtetrahydrofolate forpurine synthesis |
| Adenosylhomocysteinase (S-Adenosyl-L-homocysteine) | Regeneration ofhomocysteine from adenosylhomocyesteine (S-Adenosyl-L-homocysteine) in the methylation cycle |
There have been several hypotheses about the role of copper and some of its neurological manifestations. Some suggest that disruptions incytochrome c oxidase, also known as Complex IV, of the electron transport chain, is responsible for spinal cord degeneration.[3][10]
Another hypothesis is that copper deficiency myelopathy is caused by disruptions in themethylation cycle.[10] The methylation cycle causes a transfer of a methyl group (-CH3) frommethyltetrahydrofolate to a range ofmacromolecules by the suspected copper-dependent enzymemethionine synthase.[10] This cycle is able to producepurines, which are a component of DNAnucleotide bases, and alsomyelin 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 causesmyelopathy.[10]
Theanemia caused by copper deficiency is thought to be caused by impaired iron transport.Hephaestin is a copper-containingferroxidase enzyme located in the duodenal mucosa that oxidizes iron and facilitates its transfer across the basolateral membrane into circulation.[6] Another iron transporting enzyme isceruloplasmin.[6] This enzyme is required to mobilize iron from the reticuloendothelial cell to plasma.[6] Ceruloplasmin also oxidizes iron from its ferrous state to the ferric form required for iron binding.[4] Impairment in these copper-dependent enzymes that transport iron may cause secondary iron deficiency anemia.[6] Another speculation for the cause of anaemia involves the mitochondrial enzymecytochrome c oxidase (complex IV in the electron transport chain). Studies have shown that animal models with impaired cytochrome c oxidase failed to synthesizeheme fromferric iron at the normal rate.[6] The lower rate of the enzyme might also cause the excess iron to clump, giving the haeme an unusual pattern.[6] This unusual pattern is also known as ringedsideroblastic anemia cells.
The cause ofneutropenia is still unclear; however, the arrest of maturingmyelocytes, orneutrophil precursors, may cause theneutrophil deficiency.[2][6]
Zinc intoxication may causeanemia by blocking the absorption of copper from the stomach andduodenum.[3] Zinc also upregulates the expression ofchelatormetallothionein inenterocytes, 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 thelumen.[3] This mechanism is exploited therapeutically to achieve negative balance inWilson'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.
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 andceruloplasmin in the serum are consistent with the diagnosis as is a low 24-hour urine copper level.[20] Additional supportive bloodwork findings also includeneutropenia andanemia.[20] MRI imaging may demonstrate increased T2 signal of thedorsal column–medial lemniscus pathways.[20]
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 andbone 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 orintravenous copper.[7] If zinc intoxication is present, discontinuation of zinc may be sufficient to restore copper levels 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 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]