Copper is an indispensable trace element. A deficiency of this element can creep up on the clinician like a bad penny if not equipped to recognize the clinical signs, symptoms, and an understanding of which patient populations are at risk. Copper is involved in the proper function of numerous organs and metabolic processes such as iron metabolism, neurotransmission, connective tissue formation, and others. Although a once rare deficiency state seen most often in parenteral nutrition deficient solutions, Roux-en-Y gastric bypass surgeries have brought this deficiency state into awareness. The purpose of this article is to identify patients at risk for copper deficiency, review the signs and symptoms, as well as provide recommendations for treatment and monitoring.
A long time nutritionally stable 33 year-old male with a history of short bowel syndrome due to necrotizing enterocolitis (NEC) as an infant presented for follow up in GI clinic with persistent leukopenia and neutropenia in the setting of recently increased stool output. The patient’s anatomy included approximately 30cm of small bowel anastomosed directly to 50cm of colon. The nutrition and hydration regimen included: oral intake of a short bowel diet, nocturnal infusion of 6 cans of Peptamen 1.5 via PEG, and 3 liters IV fluid. Teduglutide had been used x 2 years.
The patient’s baseline stool output markedly increased from 2.2 L to ~ 5 L per day, just before a hospital admission for this same problem 5 months prior, in the setting of a central line infection. His white blood count (WBC) and absolute neutrophil count (ANC) at that time were 1.81 k/uL and 960/mL. The cause of his increased stool output was unclear. CT enterography and stool studies for infection were unrevealing. Efforts to reduce the volume of stool output after discharge were moderately successful with a regimen of codeine 30 mg tid, Imodium 4mg qid, and gentle soluble fiber supplementation (Benefiber). On follow up in GI clinic, he was found to be persistently leukopenic, with WBC 1.89 k/uL and ANC 840/ mL. A copper level was tested and found to be <0.10 mcg/mL (reference: 0.75 – 1.45 mcg/mL). Dietary copper intake had until then included 6mg/ day from tube feedings and 2 mg/day from oral multivitamin, which is significantly greater than the typical daily intake of 1.2-1.6 mg/day. The patient was started on 2 mg/day of IV copper gluconate supplementation added to his IV fluids for 6 weeks. On subsequent recheck 3 weeks later after therapy, the patient’s copper level had increased to 0.91 mcg/mL. At that same check, his WBC and ANC had both normalized to 6.09 k/uL and 4220/mL respectively (Table 1).
Significant clinical events, such as a change in approach to nutrition (e.g.: transition from parenteral to enteral nutrition), or significant change in ostomy output can lead to either, subtle or overt, vitamin and trace element deficiencies. In this case, early recognition of copper deficiency helped to avoid potential downstream complications of more significant deficiency.
When you think of copper, what comes to mind? Copper pipes, pennies, copper pots and pans? What about an essential trace element that when deficient may result in neurological deficits, anemia, and neutropenia?
Copper is primarily absorbed in the stomach and proximal duodenum. It is involved in hematopoiesis, hemoglobin synthesis, neurotransmission, superoxide synthesis, formation of connective tissue and plays a role in the structure and function of the nervous system.1
Patients at Risk for Copper Deficiency
Risk factors for deficiency include malabsorptive diseases such as celiac disease, Crohn’s disease, gastrointestinal surgery, jejunal feedings, which occur distal to the primary sites of absorption, and prolonged parenteral nutrition without adequate supplementation (for complete list see Table 2).2,3,4
Bariatric surgeries in which a large portion of the stomach and duodenum are bypassed can lead to copper deficiency. Low serum copper levels have been reported in 10% of patients 2 years after Rouxen-Y bypass surgery. 5,6 Although a recent systematic review corroborated that 10% of RYGB patients develop asymptomatic copper deficiency, only a total of 34 cases of symptomatic copper deficiency have been reported in the literature, occurring on average 8.6 years after surgery with 97% being female.6 Of the 34 cases with symptoms, only 1 patient consumed a multivitamin with minerals.
Excess oral zinc supplements, including zinccontaining denture creams, have also led to copper deficiency. Copper and zinc are competitively absorbed in the proximal small bowel, both of which become bound to metallothionein (MT) and are stored within enterocytes. MT has a higher binding affinity to copper than to zinc and the MTcopper (Cu) complex is preferentially retained in the intestinal cells. Synthesis of MT is regulated by the amount of zinc ingested and when excessive amounts are consumed, more MT proteins are produced, forming more MT-Cu complexes, which are then excreted. Massive zinc ingestion thereby decreases copper absorption, leading to an increase in copper excretion.7
Enteral Feeding and Copper Deficiency
Many cases of copper deficiency in enterally fed patients have been reported in the literature. The reasons for the copper deficiency were attributed to the following: inadequate copper in the commercial formula, fiber-containing formula, jejunal delivery of feeding (however one report included two patients with gastrostomy feeding that were found deficient) (Table 3). What is interesting is that in Japan, copper deficiency was treated in some with cocoa powder, a good source of copper.
Signs and Symptoms of Copper Deficiency
Symptoms of copper deficiency include anemia, neutropenia, and pancytopenia (Table 4). Anemia may be macrocytic, normocytic or microcytic. Patients may also present with neurologic deficits including peripheral neuropathy, ataxia and muscle weakness.4 Copper deficiency has also been associated with myelopathy or myeloneuropathy resembling B12 deficiency which includes a spastic ataxic gait and sensory ataxia caused by dorsal spinal column degeneration.4,12 In addition, cases of optic neuropathy leading to blindness have been reported.13,14
In Kumar’s review of 34 cases with copper deficiency, 56% had neurological deficits, four of whom also presented with optic neuropathy. Anemia occurred in 50% of the patients, 12% had pancytopenia and 23.5% leukopenia/neutropenia in addition to anemia.6 Neurologic deficits may be present without hematologic manifestations.
Diagnosing a Copper Deficiency
Serum copper levels are used to diagnose a deficiency. It is important to remember that during the inflammatory response, ceruloplasmin, an acutephase protein that increases during inflammation and transports 80-95% of copper, can lead to elevated blood copper levels. 4 Altarelli suggests using low serum ceruloplasmin (<20 mg/dL) in addition to low serum copper levels with an elevated C-reactive protein to diagnose deficiency.4 According to Rohm et al., serum ceruloplasmin level may be more reliable if the deficiency is mild. MRI of the spinal cord shows increased T2 signal in the posterior dorsal column of the spinal cord during deficiency.1
Little evidence other than case reports exists on the appropriate amount, route or duration of copper needed to correct a deficiency. Copper repletion may not completely resolve deficits, but it appears to halt further neurological deterioration.1 Resolution of hematologic manifestations should return to normal within 4 to 12 weeks.4,8
The American Society for Metabolic and Bariatric Surgery (ASMBS) issued repletion recommendations for copper based on the severity of the deficiency.15 For mild to moderate deficiency based on low hematologic indices, use 3–8 mg/d of oral copper sulfate or gluconate until levels normalize. In cases of severe deficiency, use 2–4 mg/d IV copper for 6 days or until levels normalize and neurologic symptoms resolve. Once serum copper levels are normal, they should be monitored every 3 months. Several authors recommend 2-4 mg per day of elemental oral copper or IV route for a brief period of 5 days.4,16 According to Kumar’s practice, the repletion regimen involves 8 mg oral elemental copper for 1 week, 6 mg for the second week, 4 mg for the third week and 2 mg thereafter.17 If symptoms do not resolve or there is rapid deterioration, the author recommends 2 mg IV copper over 2 hours for 5 days. It has been recommended to continue to check copper levels periodically since cases of symptomatic and biochemical relapse have been reported. ASMBS recommends using supplemental copper when patients are consuming zinc supplements (1 mg copper for 8-15 mg zinc) although these specific amounts have not been studied.18 See Table 5 for replacement options for copper
Copper deficiency, while once rare, has received increased attention in recent years due to an increase in case reports, particularly in the bariatric literature. A trace element, copper is involved in many physiologic functions. Early recognition is imperative to prevent deficiency, but once deficient, to reverse the consequences of deficiency and prevent permanent damage from neurological complications. After reading this article, the clinician should be well equipped to not only identify copper deficiency, but to treat and monitor response to treatment. Table 6 includes final thoughts on treatment, monitoring, or considerations for patient’s refractory to oral copper treatment.
- Rohm CL, Acree S, Lovett L. Progressive myeloneuropathy with
symptomatic anemia. BMJ Case Rep. 2019;12(12):1-5.
- Echeverria P. Copper deficiency risk in Roux-En-Y gastric bypass
and chronic jejunal enteral feedings. Support Line. 2011; 13(5):11-13.
- King D, Siau K, Senthil L, et al. Copper deficiency myelopathy after
upper gastrointestinal surgery. Nutr Clin Pract. 2017;20(10);1-5.
- Altarelli M, Ben-Hamouda N, Schneider A, et al. Copper Deficiency:
Causes, Manifestations, and Treatment. Nutr Clin Pract.
- Gletsu-Miller N, Broderius M, Frediani JK, et al. Incidence and
prevalence of copper deficiency following roux-en-y gastric bypass
surgery. Int J Obes. 2012;36(3):328-335.
- Kumar P, Hamza N, Madhok B, et al. Copper deficiency after gastric bypass for morbid obesity: a systematic review. 2016;26:1335-1342
Dolcourt B, Paxton J, Bora K, et al. Pennies for your thoughts: A
- case series of pancytopenia due to zinc-induced copper deficiency in
- the same patient. Clin Pract Cases Emerg Med. 2019;3(4):341–344.
- Myint ZW, Oo TH, Thein KZ, et al. Copper deficiency anemia: review article. Ann Hematol. 2018 Sep;97(9):1527-1534.
- Vallurupalli M, Divakaran S, Parnes A, et al. The Element of Surprise.
- N Engl J Med. 2019;381(14):1365-1371.
- Brown EA, Muller BR, Sampson B, et al. Urinary Iron Loss in the
- Nephrotic Syndrome. Postgrad Med J. 1984;60(700):125-8.
- Joshi S, McLarney M, Abramoff B. Copper deficiency related
- myelopathy 40 years following a jejunoileal bypass. Spinal Cord Ser
- Cases. 2019 Dec 16;5:104.
- Kumar N, Gross J, Ahlskog J. Copper deficiency myelopathy
- produces a clinical picture like subacute combined degeneration.
- Neurology. 2004;63:33-39
- Pineles S, Wilson C, Balcer L, et al. Combined Optic Neuropathy
- and Myelopathy Secondary to Copper Deficiency. Surv Ophthalmol.
- Naismith R, Shepherd J, Weihl C, et al. Arch Neurol. 2009;66(8):1025-
- Parrott J, Frank L, Rabena R, et al. American Society for Metabolic
- and Bariatric Surgery Integrated Health Nutritional Guidelines for
- the Surgical Weight Loss Patient 2016 Update: Micronutrients. Surg
- Obes Related Dis. 2017;13(5):727-741
- Jaiser S, Winston G. Copper deficiency myelopathy. J Neurol.
- Kumar N. copper deficiency myeloneuropathy. www.uptodate.com.
- December 17, 2018. Accessed March 20, 2020.
- Mechanic J, Youdim A, Jones D, et al. Clinical practice guidelines
- for the perioperative nutritional, metabolic and nonsurgical support
- of the bariatric surgery patient—2013 update. Surg Obes Rela Dis.
- Sandstead HH. Copper bioavailability and requirements. Am J Clin
- Nutr. 1982;35(4):809-14.
- Wapnir RA. Copper absorption and bioavailability. Am J Clin Nutr
- Shike M, Roulet M, Kurian R, et al. Copper metabolism and requirements in total parenteral nutrition. Gastroenterology. 1981;81:290-97