Clinical manifestations

Presentation and course

Neurologic manifestations. The most common neurologic manifestation of acquired copper deficiency is that of a myelopathy or myeloneuropathy that resembles the subacute combined degeneration seen with vitamin B12 deficiency (81; 30; 21; 54; 58; 48; 51; 55; 52; 45; 57; 79; 13; 45; 75; 83; 97; 82; 85; 40; 69; 18; 19; 31; 67; 84; 01; 35; 92; 33; 44; 16). Copper deficiency myeloneuropathy may have a subacute onset. It presents with a spastic gait and prominent sensory ataxia. The sensory ataxia is primarily due to dorsal column dysfunction. Clinical or electrophysiological evidence of an associated axonal peripheral neuropathy is common (45; 18). Mixed demyelination and axonal loss have been reported. EMG evidence of a polyradiculopathy has also been described. Myopathic potentials may be seen. A wrist drop or foot drop may be present (48; 51; 55; 24; 03). Peripheral neuropathy without myelopathy; CNS or PNS demyelination (including an acute inflammatory demyelinating polyneuropathy like presentation); myopathy with myelopathy; autonomic neuropathy (without associated symptoms) and myelopathy; optic neuropathy with or without myelopathy; optic neuritis with peripheral neuropathy; a non-length-dependent distribution of sensory manifestations with face and trunk involvement and electrodiagnostic or imaging studies suggestive of a sensory ganglionopathy (sensory neuronopathy); quadriparesis with MRI evidence of brainstem disease; cerebellar ataxia with a myeloneuropathy; and cognitive impairment with myelopathy have also been described in case reports in association with copper deficiency, but the significance of some of these reported associations need further study (76; 22; 77; 57; 94; 82; 85; 69; 99; 73; 44; 39; 78; 06; 86; 03). An optic neuropathy may coexist (98). Visual loss can be sudden in onset and rapidly progressive (67; 33; 44). The initial presentation of a peripheral neuropathy may be followed by a myeloneuropathy (13). In some reports, adequate details of the neurologic findings are not provided, making it difficult to ascertain if a myeloneuropathy or neuropathy was the predominant reason for the neurologic symptoms. Also reported is progressive, asymmetric weakness or electrodiagnostic evidence of denervation, suggestive of lower motor neuron disease (93; 69). In an additional patient, copper deficiency myelopathy had initially been misdiagnosed as postpolio syndrome (83). In some patients a pure or predominantly motor neuropathy is associated with the myelopathy (45). Of interest is a report that noted missense mutations in ATP7A (Menkes disease gene), which can cause an X-linked distal motor neuropathy (41). These patients don’t have overt signs of systemic copper deficiency. The ATP7A copper transporter may have an important role in motor neuron maintenance and function. One patient with a copper deficiency-related myelo-optico-neuropathy reported severe hyposmia and hypogeusia (85).

The myelopathy of copper deficiency closely mimics the subacute combined degeneration of vitamin B12 deficiency (55). Copper and vitamin B12 deficiency may coexist (48; 51; 55; 94; 13; 91). A prior history of vitamin B12 deficiency may be present, particularly in patients with a prior history of gastric surgery (48; 13; 45). Patients may be given vitamin B12 despite normal serum vitamin B12 levels (81). Coexisting iron deficiency may also be present (55; 13). Continued neurologic deterioration in patients with a history of vitamin B12 deficiency-related myelopathy who have a normal B12 level on B12 replacement should be evaluated for copper deficiency.

Clioquinol was initially developed as a tropical and intestinal antiseptic. It was commonly used as an over-the-counter antiparasitic agent. Its use resulted in over 10,000 cases of myelo-optico-neuropathy (SMON) in Japan in the 1960s to 1970s. Severely affected patients with SMON developed a green, hairy tongue due to green-black deposits of an iron chelate of clioquinol. Clioquinol was then withdrawn from the market. The precise mechanism of clioquinol-induced myelopathy has not been established. The myelo-optico-neuropathy seen with copper deficiency is similar to that seen due to the copper chelator clioquinol; it has been speculated that copper deficiency may have been the mechanism of clioquinol toxicity (56; 85; 80).

Hematological manifestations. The hematological hallmark of copper deficiency is anemia and neutropenia (22; 52; 28; 61; 66). Lymphopenia or thrombocytopenia with resulting pancytopenia is relatively rare. The anemia may be microcytic, macrocytic, or normocytic. Typical bone marrow findings include a left shift in granulocytic and erythroid maturation with cytoplasmic vacuolization in erythroid and myeloid precursors and the presence of ringed sideroblasts (76; 94; 28; 25; 64). Erythroid hyperplasia with decreased myeloid to erythroid ratio and dyserythropoiesis including megaloblastic changes may be seen. Hemosiderin-containing plasma cells may be present. Patients may be given a diagnosis of sideroblastic anemia or myelodysplastic syndrome or aplastic anemia. Patients with myelodysplastic syndrome typically do not have myeloid lineage vacuolization, abnormal nuclear lobulation of erythroid and myeloid precursors, or dysmegakaryopoiesis (61). The neurologic syndrome due to acquired copper deficiency may be present without the more commonly reported hematological manifestations.

Hepatic manifestations. The metabolic fates of copper and iron are closely linked through ceruloplasmin and hephaestin. Ceruloplasmin is the principal copper-carrying protein and decreases in acquired copper deficiency. Congenital absence of ceruloplasmin (aceruloplasminemia) results in tissue iron overload. Acquired copper deficiency may result in impaired iron utilization and abnormalities on blood iron studies (87). Hepatic iron overload or cirrhosis may occur and is likely mediated by hypoceruloplasminemia.

Prognosis and complications

Response of the hematological parameters (including bone marrow findings) is prompt and often complete (22; 21; 94; 45). Hematological recovery may be accompanied by reticulocytosis. Recovery of neurologic signs and symptoms is variable. Improvement in neurologic symptoms is generally absent though progression is typically halted (77; 21; 94; 45; 40). Improvement when present is often subjective and involves sensory symptoms (81; 77; 45). There are reports of definite improvement in the neurologic deficits, nerve conduction studies, evoked potential studies, autonomic function, and MRI signal change with normalization of serum copper (76; 30; 79; 45; 82; 97; 69). Also reported is stabilization or improvement in some patients who presented with clinical or electrodiagnostic evidence of lower motor neuron disease (93). A relapse in the copper-deficient state may not be necessarily accompanied by neurologic deterioration (77). Further, the initial response to copper replacement may not be sustained over time, and a relapse may occur during continued oral treatment (75).

Biological basis

Copper is a component of metalloenzymes that have a critical role in the structure and function of the nervous system. Copper functions as a prosthetic group in a number of enzymes that act as oxidases and permits electron transfer in key enzymatic pathways. These enzymes include cytochrome-c-oxidase for electron transport and oxidative phosphorylation in the mitochondrial respiratory chain, copper/zinc superoxide dismutase for antioxidant defense, tyrosinase for melanin synthesis, dopamine beta-hydroxylase for catecholamine biosynthesis, lysyl oxidase for crosslinking of collagen and elastin (in connective tissue, bones, and vasculature), peptidylglycine alpha-amidating monooxygenase for neuropeptide and peptide hormone processing, and ceruloplasmin (ferroxidase I) for brain iron homeostasis. Hephaestin is a multicopper ferroxidase necessary for iron egress from intestinal enterocytes into the circulation and is an important link between copper and iron metabolism in mammals. Reduction in cytochrome c oxidase activity may be the likely basis for neurologic dysfunction associated with the copper-deficient state. The similarities between copper deficiency myelopathy and subacute combined degeneration due to vitamin B12 deficiency have led to the speculation that dysfunction of the methylation cycle and associated failure of myelin maintenance may be the basis of neurologic derangement in copper deficiency (95).

Impaired erythroid and myeloid maturation and reduced erythrocyte and neutrophil life spans are the likely reasons for the anemia and neutropenia. Copper-containing enzymes likely play a role in cell differentiation and proliferation in the bone marrow. Decreased activity of copper/zinc superoxide dismutase may accelerate cell membrane defects and shorten the survival time of erythrocytes. Copper deficiency may also impair effective iron utilization and interfere with erythropoiesis.

Etiology and pathogenesis

Though rare, acquired copper deficiency has been well documented in humans (88; 04). The presence of multiple causes can increase the chances of development of a clinically significant deficiency state (85; 98). Coexistence of copper deficiency myelopathy with advanced degenerative cervical spondylosis can pose a management challenge (71). The commonest identified likely cause of copper deficiency in reported patients with a copper deficiency myelopathy has been a prior history of gastric surgery (for peptic ulcer disease, bariatric surgery, or intestinal resection) (81; 22; 58; 48; 51; 55; 13; 45; 75; 93; 38; 85; 28; 33; 07; 17; 98; 20; 42; 37; 65). A prior history of gastric surgery is present in nearly half the reported cases of copper deficiency myelopathy (95; 35). The duration between gastric surgery and onset of neurologic symptoms may range from less than a year to 46 years (45; 75; 35; 37). In a report, a posterolateral myelopathy related to copper or vitamin B12 deficiency was the commonest neurologic complication seen following bariatric surgery (38). One study noted copper deficiency in 15.4% of patients following Roux-en-Y gastric bypass surgery (12).

Excessive zinc ingestion is a well-recognized cause of copper deficiency (54; 79; 94; 83; 93; 85; 69; 31; 84; 01; 10; 100; 26). Zinc causes an upregulation of metallothionein production in the enterocytes. Metallothionein is an intracellular ligand, and copper has a higher affinity for metallothionein than zinc. Copper displaces zinc from metallothionein, binds preferentially to the metallothionein, remains in the enterocytes, and is lost in the stools as the intestinal cells are sloughed off. One report suggests that zinc toxicity may be causative (100). Zinc is believed to be essential for optimal functioning of the immune system and has been empirically used for this purpose, often in high doses, and at times with deleterious consequences; this has been a point of particular importance during the COVID-19 pandemic (15). In addition to the common use of zinc in the prevention or treatment of common colds and sinusitis, zinc therapy has been used for conditions like acrodermatitis enteropathica, hidradenitis suppurativa, treatment of decubitus ulcers, sickle cell disease, celiac disease, glucagonoma, hepatic encephalopathy, psychosis, memory impairment, diarrhea, myoclonic epilepsy, macular degeneration, and acne. Parenteral zinc overloading during chronic hemodialysis or oral zinc supplementation in patients on hemodialysis has also been associated with copper deficiency with or without a myelopathy (97; 70). Unusual, but not uncommon, sources of excess zinc have included patients who consumed excessive amounts of denture cream for long periods and very rarely patients swallowing zinc-containing coins (29; 94; 69; 31; 84; 10; 98; 36). One report suggests that some patients with copper deficiency of indeterminate cause may have had denture cream use as a possible source that was not specifically looked for (31). In this report, the use of denture fixatives in 11 patients with myeloneuropathy–hypocupremia–hyperzincemia was evaluated, and the study noted a history of poorly fitting dentures and application of excessive amounts of denture adhesives in all. Even in the absence of excess use or ingestion, denture cream use may be an unintentional zinc ingestion source that may compromise copper balance in patients with an additional cause for copper deficiency (85). Overtreatment of Wilson disease with zinc has rarely been reported to cause copper deficiency-related hematologic and neurologic manifestations (14; 11; 63; 96). Rarely, copper deficiency may be seen in Wilson disease in the absence of zinc toxicity; malabsorption or reduced oral intake due to dysphagia may be responsible (89). An elevated serum zinc level in the absence of obvious exogenous zinc ingestion has been reported, but these reports antedate the recognition of excess use of zinc-containing denture creams as a potential source of hypocupremia-related myelopathy (76; 77; 30; 21; 51; 94; 45). Urinary zinc excretion correlated poorly with serum zinc levels. A report describes the existence of myelopathy among zinc-smelter workers in upper Silesia during the late 19th century (60).

Copper is widely distributed in foods. The bioavailability of copper from diet is approximately 70%. Copper is probably absorbed from the stomach and proximal intestines. Bile is the major pathway for copper excretion. Excretion of copper into the gastrointestinal tract is the major pathway that regulates copper homeostasis and prevents deficiency or toxicity. Because of copper’s ubiquitous distribution and low daily requirement, acquired dietary copper deficiency is rare. Overt copper deficiency is not a public health concern for most population groups. Under certain circumstances, clinical conditions may predispose individuals to the risk of copper deficiency. Copper deficiency may occur in premature infants or low-birthweight infants and in malnourished infants (46). Other causes of copper deficiency include nephrotic syndrome, glomerulonephritis, a ketogenic diet, alcoholism, and enteropathies associated with malabsorption like cystic fibrosis, sprue, systemic sclerosis, Crohn disease, and celiac disease (57; 32; 18; 27; 92; 09; 23; 34). Copper deficiency myelopathy has been reported in celiac disease without gastrointestinal manifestations (19; 27; 08). Bacterial overgrowth has also been implicated as a cause of copper deficiency in a patient with a prior history of gastric surgery (85). Copper deficiency in celiac disease or other causes of malabsorption may be accompanied by deficiency of zinc, vitamin B12, vitamin A, vitamin D, vitamin E, and iron (32; 02).

Copper deficiency may be a complication of prolonged total parenteral nutrition, particularly so when copper supplementation in TPN is withheld due of cholestasis. Enteral feeding with inadequate copper has also been known to result in copper deficiency. Treatment (self-treatment) with the copper-chelating agent tetrathiomolybdate (obtained by placing an order on the Internet) has been reported to cause copper deficiency (59). Tetrathiomolybdate has anti-angiogenic properties and has been proposed in the treatment of metastatic cancers. Therapy with proton pump inhibitors has been suspected as a possible cause for copper deficiency in some patients (74).

At times the cause of the copper deficiency is unclear. A review of 55 case reports of copper deficiency myelopathy noted no identified cause in 20% of cases (35). In two patients with idiopathic hypocupremia and myelopathy, the copper content in the colonic mucosa was increased (48). In one of these patients a search for mutations in the Menkes gene (ATP7A) was negative (45). Emerging knowledge about copper transport may help clarify the etiology of idiopathic hypocupremia (90; 05).

Information on the pathology of copper deficiency myelopathy comes from animal studies. The typical distribution of lesions in the spinal cord is greater involvement of the cervical cord with less severe changes in the thoracic and lumbar segments (72). Wallerian degeneration and demyelination with microcavitation of the white matter of the spinal cord may be seen. A postmortem report of copper deficiency myelopathy showed the expected degeneration involving the dorsal and lateral columns (01). In two additional reports, concomitant folate deficiency and selenium deficiency were present (68; 43). Small inflammatory infiltrates have been seen on nerve biopsy in patients with a sensory predominant peripheral neuropathy in copper deficiency, but these are of doubtful clinical significance (86).

Epidemiology

In the largest reported series of copper deficiency myelopathy (25 patients) the age range at the time of diagnosis was 36 to 78 years (mean age, 56 years), and of those 25 patients, 20 were women (45). In one study, the prevalence and incidence of copper deficiency following Roux-en-Y gastric bypass (RYGB) surgery was determined to be 9.6% and 18.8%, respectively (17).

Prevention

In patients with copper deficiency myelopathy who have a known cause for copper deficiency, the most commonly identified cause is a prior history of gastric surgery. No information is available on routine monitoring of copper status after gastric surgery.

Differential diagnosis

Copper deficiency produces a myeloneuropathy that is similar to the subacute combined degeneration seen with vitamin B12 deficiency (55; 46; 47). Nitrous oxide toxicity results in a myelopathy because nitrous oxide oxidizes the cobalt core of vitamin B12 and renders the vitamin B12 inactive. Vitamin E deficiency can also cause a myeloneuropathy, often with spinocerebellar involvement. Folate deficiency often coexists with other nutrient deficiencies. It is unclear if folate deficiency in isolation can cause a myeloneuropathy. Myelopathy seen in the setting of infection with the human immunodeficiency virus may not be because of infection; deranged vitamin B12 metabolic pathways may be involved.

Diagnostic workup

Laboratory indicators of copper deficiency include reduced serum copper or ceruloplasmin and a reduction in urinary copper excretion. Urinary copper declines only when dietary copper is very low (88). These parameters may not be sensitive to marginal copper status. Serum copper may be inadequate for assessing total body copper stores, and activity of copper enzymes like erythrocyte superoxide dismutase and platelet or leukocyte cytochrome c oxidase may be a better indicator of metabolically active copper stores. Serum or urinary zinc elevation may be seen in the absence of exogenous zinc ingestion. Changes in serum copper usually parallel the ceruloplasmin concentration. Ceruloplasmin is an acute-phase reactant, and the rise in ceruloplasmin is probably responsible for the increase in serum copper seen in a variety of conditions like pregnancy, oral contraceptive use, liver disease, malignancy, hematologic disease, myocardial infections, smoking, diabetes, uremia, and various inflammatory and infectious diseases. Copper deficiency could be masked under these conditions. A low serum copper or ceruloplasmin can be seen in Wilson disease or the Wilson disease heterozygote state. In Wilson disease, there is tissue copper overload, and urinary copper excretion is increased. Serum ceruloplasmin is absent in aceruloplasminemia. Hence, the laboratory detection of a low serum copper does not imply copper deficiency (46). Laboratory evaluation may also show anemia or leukopenia or, rarely, thrombocytopenia or pancytopenia anemia.

MRI and somatosensory-evoked potential studies provide additional evidence of posterior column dysfunction. The commonest abnormality on the spine MRI is increased T2 signal involving the dorsal column; rarely, signal change involving the lateral column may be seen (55; 45; 45; 85; 18; 44). This pattern is similar to the spine MRI changes seen in patients with vitamin B12 deficiency. The cervical cord is most commonly involved, and contrast enhancement typically is not present. In a review of 55 case reports of copper deficiency myelopathy, spine MRI abnormality was seen in 47% of cases (35). Also reported was accompanying signal change involving the pyramidal tract in the brainstem (44). Dorsal column signal change may also reflect a sensory neuronopathy (06). Nonspecific or confluent areas of increased signal involving the subcortical or periventricular white matter have been reported but are of uncertain significance (76; 77; 55; 85; 69). Somatosensory-evoked potential and nerve conduction studies suggest impaired central conduction and varying degrees of peripheral neuropathy (54; 83; 85; 18). Other reported electrophysiological abnormalities noted in patients with copper deficiency and neurologic manifestations include prolonged visual-evoked potentials and impaired central conduction on transcranial magnetic stimulation (76; 81; 77; 85).

Management

Supportive measures are discussed in Peripheral neuropathies: supportive measures and rehabilitation.

There have been no studies that address the most appropriate dose, duration, and route of copper supplementation. In patients with hematological manifestations of copper deficiency in whom excess zinc ingestion is present, stopping zinc supplementation may suffice, and no additional copper supplementation may be required (94). Copper may be given in addition to stopping zinc supplementation (93). Commonly used copper salts include copper gluconate, copper sulphate, and copper chloride. In our practice, we give 8 mg of elemental copper orally for a week, 6 mg for the second week, 4 mg for the third week, and 2 mg thereafter. Periodic assessment of serum copper is essential to determine adequacy of replacement and to decide on the most appropriate long-term administration strategy. Because of the need for long-term replacement, parenteral therapy is not preferred and generally not required, even in cases with a suspected absorption defect. At times, prolonged oral therapy may not result in improvement and parenteral therapy may be required. Some copper supplements may not be adequately absorbed when administered through a jejunostomy tube, necessitating parenteral therapy. If required, 2 mg of elemental copper may be administered intravenously daily for 5 days and periodically thereafter. Initial parenteral administration followed by oral therapy has also been used (22; 79; 13).

In one report, overtreatment of copper deficiency resulted in hepatic copper overload with cirrhosis that required liver transplantation; genetic testing for ATP7B mutations was negative (62).