Intended for healthcare professionals

Practice Easily missed?

Copper deficiency

BMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g3691 (Published 17 June 2014) Cite this as: BMJ 2014;348:g3691
  1. S K Chhetri, specialist registrar in neurology12,
  2. R J Mills, consultant neurologist1,
  3. S Shaunak, consultant neurologist1,
  4. H C A Emsley, consultant neurologist12
  1. 1Department of Neurology, Royal Preston Hospital, Preston PR2 9HT, UK
  2. 2University of Manchester, Manchester M13 9PL, UK
  1. Correspondence to: hedley.emsley{at}manchester.ac.uk
  • Accepted 9 May 2014

A 73 year old man with treated pernicious anaemia and partial gastrectomy 30 years earlier consulted his GP with a 12 month history of progressive numbness of his feet and hands. A haematology opinion for normocytic anaemia, neutropenia, and lymphopenia led to an unremarkable bone marrow biopsy. Increasing unsteadiness and falls prompted neurology referral. He was found to have sensory ataxia with clinical, radiological (figure), and neurophysiological evidence of myelopathy and peripheral neuropathy. Vitamin B12 level was high, consistent with ongoing replacement. Low serum copper confirmed hypocupraemic myeloneuropathy. Copper replacement achieved resolution of the cytopenia within four weeks, and slow but minimal neurological improvement was seen over more than nine months of follow-up.

Figure1

T2 weighted sagittal magnetic resonance image of cervical spine showing increased signal intensity (arrowed) involving dorsal columns of the cervical spinal cord

What is hypocupraemia?

Copper is an essential trace element that plays a crucial role in the normal functioning of the neurological, haematological, vascular, skeletal, and antioxidant systems.1 2 Copper is absorbed in the stomach and proximal duodenum, but absorption can be impaired after upper gastrointestinal surgery. Such surgery, although not the sole cause of copper deficiency (hypocupraemia), is increasingly recognised as an important risk factor.3 Copper deficiency leads to several clinical presentations including cytopenia and profound neurological deficits.1 2 3 4

How common is copper deficiency?

Evidence is limited but several reports describe symptomatic copper deficiency.1 2 3 4 5 In a case series of 136 patients with gastric bypass surgery, 9.6% had hypocupraemia.6 Two other case series of 64 and 141 bariatric surgery patients respectively reported substantial hypocupraemia in 23% at 6 months and 70% at 3 years, 7 and a progressive reduction in average serum copper concentrations over five years.8

Reliable data on the overall population at risk of hypocupraemia from all causes, including bariatric surgery, are not available, but longitudinal collection of data would be valuable.

Why is copper deficiency missed?

Copper deficiency is an under recognised cause of neurological dysfunction and a spectrum of cytopenias.1 A retrospective review of 40 patients with hypocupraemia found the median interval from initial presentation with neurological or haematological findings to diagnosis of copper deficiency to be 1.1 years (range 10 weeks to 23 years).2 Misdiagnosis as a myelodysplastic syndrome might occur, given the similar haematolopathological findings including anaemia, leucopenia, and less commonly, thrombocytopenia.1 2 This is suggested by a recent retrospective analysis of copper deficiency in Scotland, which found that four out of 16 cases eventually diagnosed with hypocupraemia were initially seen by a haematologist.1

The clinical presentation is often clinically and radiologically indistinguishable from subacute combined degeneration (SACD) seen in patients with vitamin B12 deficiency. Confirmation of B12 deficiency in a patient with a clinical presentation resembling SACD might understandably lead to testing for copper deficiency not being undertaken, even though hypocupraemia might be comorbid with B12 deficiency, particularly in patients who have undergone gastric surgery.4 9

Moreover, the interval between gastric surgery and the onset of clinical symptoms can be long.4 5 9 A retrospective review of 55 cases of hypocupraemia found that the interval between upper gastrointestinal surgery and symptom onset ranged from five to 26 years in the bariatric group and 10 to 46 years in the non-bariatric group.4 Such long intervals might lead to diagnostic delay because a causal association might not be so readily considered, but observations of gradually declining copper levels over years lend clear support to causation.8

Risk factors for copper deficiency4

  • Upper gastrointestinal tract surgery

  • Gastrectomy

  • Bariatric surgery

  • Small bowel resection or bypass

  • Zinc overload

  • Zinc supplementation

  • Ingestion of zinc containing dental fixatives

  • Malabsorption syndromes

Why does it matter?

Although copper deficiency is rare, its early identification is essential to minimise its neurological sequelae, which are severely disabling and often irreversible.1 2 3 4 Copper deficiency can be easily treated and copper supplementation largely prevents further neurological decline, but neurological improvement is variable.1 2 3 4 A retrospective cohort study in Scotland, which identified 16 patients manifesting clinical sequelae of hypocupraemia (12 with neurological features), found that only 25% of patients show some improvement while 33% might continue to deteriorate with treatment.1 The haematological effects are relatively easily reversible, with 93% of cytopenias responding to copper replacement and management of the underlying cause.1

How is copper deficiency diagnosed?

Clinical features

The diagnosis should be considered in anyone with characteristic neurological or haematological abnormalities (or both), particularly patients with risk factors (box 1). Copper and zinc are competitively absorbed from the gastrointestinal tract; hence zinc excess leads to copper deficiency.1 4

Neurological manifestations include myelopathy, myeloneuropathy, and peripheral neuropathy.1 4 Patients characteristically present with lower limb paraesthesias and gait disorder with sensory ataxia or spasticity or both.

Investigations

Initial investigations in primary care should include a full blood count and measurement of serum copper. Typical haematological abnormalities are anaemia and leucopenia. Anaemia which might be microcytic, macrocytic, or normocytic, is the commonest cytopenia, followed by leucopenia; thrombocytopenia is infrequent.1 2 Laboratory indicators of copper deficiency include low serum copper.1 2 4 Vitamin B12 level should also be tested as B12 deficiency is an important differential diagnosis and may sometimes co-exist with copper deficiency. Zinc levels should also be requested if zinc excess is suspected. American bariatric surgery clinical practice guidelines recommend testing for copper deficiency in post-bariatric surgery patients with anaemia, neutropenia, myeloneuropathy, and impaired wound healing.10 Specialist referral would generally be pursued for suspected symptomatic hypocupraemia.

Specialist neurological investigations typically include magnetic resonance imaging and neurophysiology. Spinal cord magnetic resonance imaging is abnormal in about 47% of patients with copper deficiency myelopathy and might show increased T2 signal, most commonly in the dorsal midline cervical and thoracic cord.4 Neurophysiological studies might show axonal sensorimotor polyneuropathy.4

How is copper deficiency managed?

Treatment includes management of the underlying cause and copper supplementation. No studies have investigated with the dose, route, duration, or formulation of copper for supplementation. The salts that are commonly used include copper gluconate, copper sulphate, and copper chloride.4 Copper can be given orally or intravenously. The American Society for Metabolic and Bariatric Surgery Clinical Practice guidelines recommend routine oral copper supplementation (2 mg/d).10 These guidelines advise intravenous copper (2-4 mg/d) for six days for severe deficiency and subsequent treatment, or treatment of mild to moderate deficiency, with oral copper (3-8 mg/d) until levels normalise.10 The haematological abnormalities reverse within four to 12 weeks of therapy.1 Periodic assessment of serum copper is essential to determine adequacy of replacement; however, there are no guidelines to recommend the frequency of monitoring. In patients in whom excess zinc ingestion is the likely cause, discontinuing zinc supplementation might suffice.

Key points

  • Copper deficiency is an under recognised cause of cytopenias and myeloneuropathy

  • Copper deficiency may masquerade as a myelodysplastic syndrome or vitamin B12 deficiency; it might also co-exist with B12 deficiency

  • The neurological sequelae of copper deficiency can be debilitating and irreversible, making prompt recognition and treatment essential for successful outcomes

  • Clinicians should have a low threshold for measuring serum copper in patients with unexplained and refractory cytopenias or myeloneuropathy, especially in the context of previous upper gastrointestinal tract surgical procedures, excess zinc exposure, or malabsorption

Notes

Cite this as: BMJ 2014;348:g3691

Footnotes

  • This is one of a series of occasional articles highlighting conditions that may be more common than many doctors realise or may be missed at first presentation. The series advisers are Anthony Harnden, university lecturer in general practice, Department of Primary Health Care, University of Oxford, and Richard Lehman, general practitioner, Banbury. To suggest a topic, please email us at practice{at}bmj.com

  • We thank Maria Liga (consultant haematologist) and Raza Ansari (general practitioner) for general advice from a haematology and general practice perspective respectively.

  • Contributors: All authors contributed substantially to the conception and design of this work, its drafting, and/or critical revision for important intellectual content; they all approved the final version and accept accountability for the work.

  • Having read and understood the BMJ Group policy on declaration of interests, the authors declare that they have no competing interests.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

  • Patient consent obtained.

References

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