When should IV be considered over oral copper and how often should serum copper levels be assessed?

Comment by InpharmD Researcher

The American Society of Metabolic and Bariatric Surgery (ASMBS) recommends treating mild to moderate copper deficiency with 3 to 8 mg/day of oral copper gluconate or sulfate until indices return to normal. In patients with severe deficiency, 2 to 4 mg/day of IV copper is recommended to be given for six days until serum levels return to normal and neurological symptoms resolve. Specific copper levels considered to be ‘mild to moderate’ or ‘severe’ deficiency are not well defined, but ‘mild to moderate’ deficiency has been proposed to be 8-12 μmol/L or 0.5-0.8 mcg/dL. Once copper levels are normal, it is suggested to monitor copper levels every 3 months. Otherwise, copper serum levels should only be assessed in the presence of symptoms compatible with copper deficiency. See Table 1 for a proposed algorithm for the diagnosis and treatment of copper deficiency.

Background

According to the American Society for Metabolic and Bariatric Surgery’s (ASMBS) 2016 guideline update on micronutrients, in post-weight loss surgery patients with a copper deficiency, the recommended regimen for repletion of copper varies with the severity of deficiency. For patients with mild to moderate deficiency (including low hematological indices), it is recommended to treat with 3 to 8 mg/day of oral copper gluconate or sulfate until indices return to normal. In patients with severe deficiency, 2 to 4 mg/day of intravenous (IV) copper is recommended to be initiated for six days until serum levels return to normal and neurological symptoms resolve. Once copper levels are normal, it is suggested to monitor copper levels every 3 months. While specific copper levels were not given to determine the severity of deficiency, the normal plasma copper level is suggested to be 11.8 to 22.8 mmol/L. Additionally, the normal ceruloplasmin level is suggested to be 75-145 mcg/dL. Patients are considered to be in the critical range if their plasma copper level or ceruloplasmin level is <10 mmol/L or <75 mcg/dL, respectively. Early signs/symptoms of copper deficiency may include hypochromic anemia; neutropenia; pancytopenia; hair, skin and nails hypopigmentation; hypercholesterolemia; or impaired biomarkers of bone metabolism. Advanced signs/symptoms can include gait abnormalities; hypopigmentation of skin, hair or nails; peripheral neuropathies; or myelopathies. Laboratory indices that may be useful to identify or monitor copper deficiency include decreased erythrocyte superoxide dismutase activity and 24-hour urine copper. [1]

A 2019 review discusses the management of copper deficiency in the setting of parenteral nutrition, major burn, and bariatric bypass surgery. In general, the severity and the mechanism of deficiency will determine the route of administration (i.e., oral or parenteral). There are limited data to guide optimal dosage and duration of copper administration; however, it is known that copper administration has potentially deleterious side effects, particularly when given by the IV route. For this reason, the proposed max dose for IV administration is 10 mg. A tentative algorithm for the diagnosis and treatment of copper deficiency is also provided (see Table 1). [2]

For adults, the American Society of Parenteral and Enteral Nutrition (ASPEN) lowered their recommendations for copper administration during parenteral nutrition to 0.3 to 0.5 mg/day and 20 mcg/kg/day for children. However, the European Society for Enteral and Parenteral Nutrition (ESPEN) and Australian Society (AuSPEN) advocate doses of 0.5 to 1.0 mg/day. Patients with persistent gastrointestinal losses may require higher doses (plus 0.4 to 0.5 mg/day). Regular monitoring of copper blood level is recommended in long-term parenteral nutrition and is suggested to be done twice yearly and interpreted carefully. [2], [3], [4], [5]

For major burn patients, early IV administration (first 2-3 weeks) of copper may be necessary to prevent deficiency. Simultaneous losses in the exudate of other trace elements, such as zinc and selenium, and the competition between zinc and copper for intestinal absorption require the IV route. Duration of repletion should depend on the burned surface: 7 to 8 days for burns 20% to 40% of body surface area (BSA), 14 days for 40% to 60% BSA, and 30 days if > 60% BSA. For patients with burns > 20% BSA, a supplementation of 3.5 mg IV copper/day and up to 4 mg/day is suggested. Recent data, however, suggest that higher doses of parenteral copper (4.8-5.0 mg/day) are required if wounds are open, with weekly monitoring. [2], [3], [4], [5], [6]

In patients undergoing bariatric bypass surgery, several micronutrient deficiencies may develop over time, including copper deficit. For moderate deficiency (i.e., copper values 8-12 μmol/L, 0.5-0.8 mg/dL), the ASMBS Clinical Practice guidelines and the British Obesity and Metabolic Surgery Society (BOMSS) recommend the administration of 3-8 mg/day of copper sulfate or gluconate until level normalization or symptom resolution. In cases of severe deficiency, 2-4 mg/day of IV copper for 6 days is recommended, followed by enteral administration. Hematologic manifestations are noted to normalize by 12 weeks with proper treatment; the evolution of neurologic symptoms is unclear. While BOMSS recommends annual serum copper screening, ASMBS proposes such testing only in the presence of symptoms compatible with copper deficiency. [2,7,8]

References:

[1] Parrott J, Frank L, Rabena R, Craggs-Dino L, Isom KA, Greiman L. American Society for Metabolic and Bariatric Surgery Integrated Health Nutritional Guidelines for the Surgical Weight Loss Patient 2016 Update: Micronutrients. Surg Obes Relat Dis. 2017;13(5):727-741. doi:10.1016/j.soard.2016.12.018
[2] Altarelli M, Ben-Hamouda N, Schneider A, Berger MM. Copper Deficiency: Causes, Manifestations, and Treatment. Nutr Clin Pract. 2019;34(4):504-513. doi:10.1002/ncp.10328
[3] Vanek VW, Borum P, Buchman A, et al. A.S.P.E.N. position paper: recommendations for changes in commercially available parenteral multivitamin and multi-trace element products [published correction appears in Nutr Clin Pract. 2014 Oct;29(5):701. Dosage error in article text]. Nutr Clin Pract. 2012;27(4):440-491. doi:10.1177/0884533612446706
[4] Singer P, Blaser AR, Berger MM, et al. ESPEN guideline on clinical nutrition in the intensive care unit. Clin Nutr. 2019;38(1):48-79. doi:10.1016/j.clnu.2018.08.037
[5] Osland EJ, Ali A, Isenring E, Ball P, Davis M, Gillanders L. Australasian Society for Parenteral and Enteral Nutrition guidelines for supplementation of trace elements during parenteral nutrition. Asia Pac J Clin Nutr. 2014;23(4):545-554. doi:10.6133/apjcn.2014.23.4.21
[6] Rousseau AF, Losser MR, Ichai C, Berger MM. ESPEN endorsed recommendations: nutritional therapy in major burns [published correction appears in Clin Nutr. 2013 Dec;32(6):1083]. Clin Nutr. 2013;32(4):497-502. doi:10.1016/j.clnu.2013.02.012
[7] O'Kane M, Parretti HM, Pinkney J, Welbourn R, Hughes CA, Mok J, Walker N, Thomas D, Devin J, Coulman KD, Pinnock G, Batterham RL, Mahawar KK, Sharma M, Blakemore AI, McMillan I, Barth JH. British Obesity and Metabolic Surgery Society Guidelines on perioperative and postoperative biochemical monitoring and micronutrient replacement for patients undergoing bariatric surgery-2020 update. Obes Rev. 2020 Nov;21(11):e13087. doi: 10.1111/obr.13087
[8] Mechanick JI, Youdim A, Jones DB, Garvey WT, Hurley DL, McMahon MM, Heinberg LJ, Kushner R, Adams TD, Shikora S, Dixon JB, Brethauer S; American Association of Clinical Endocrinologists; Obesity Society; American Society for Metabolic & Bariatric Surgery. Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient--2013 update: cosponsored by American Association of Clinical Endocrinologists, The Obesity Society, and American Society for Metabolic & Bariatric Surgery. Obesity (Silver Spring). 2013 Mar;21 Suppl 1(0 1):S1-27. doi: 10.1002/oby.20461
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

When should IV be considered over oral copper and how often should serum copper levels be assessed?

Level of evidence

A - Multiple high-quality studies with consistent results  Read more→


Please see Tables 1-2 for your response.

Algorithm for Diagnosis and Treatment of Copper Deficiency
< 0.5 mcg/mL (severe deficit) 0.5 to < 0.8 mcg/mL (deficit) 0.8 mcg/mL to 1.0 mcg/mL (gray zone) 0.8 to 1.2 mcg/mL (normal range)

≤ 0.8 mcg/mL (≤ 12.6 μmol/L)

Check ceruloplasmin

≤ 20 mg/dL: IV repletion

> 20 mg/dL: Favor PO repletion

0.8 to 1.0 mcg/mL (12.6 to 15.7 μmol/L)

Check ceruloplasmin

≤ 20 mg/dL: Favor PO repletion

> 20 mg/dL: Close monitoring (≈ 2 weeks)

≥ 1.0 mcg/mL (≥ 15.7 μmol/L)

Inflammation?

C-reactive protein ≥ 11 mg/L: Close monitoring (≈ 2 weeks)

C-reactive protein < 11 mg/L: Standard screening
References:

Adapted from:
Altarelli M, Ben-Hamouda N, Schneider A, Berger MM. Copper Deficiency: Causes, Manifestations, and Treatment. Nutr Clin Pract. 2019;34(4):504-513. doi:10.1002/ncp.10328

Acquired copper deficiency: a potentially serious and preventable complication following gastric bypass surgery
Design

Case series 
Case 1

A 53-year-old woman was admitted due to abnormal gait and anemia. The patient also reported bilateral paresthesias in her feet that worsened over time. Her past medical history was significant for a roux-en-Y gastric bypass (RYGB) and morbid obesity for approximately 21 years. After a bone marrow biopsy was performed to rule out myelodysplastic syndrome, she was referred to a cancer center. They found an extremely low serum copper concentration of 4 mcg/dL (normal = 80–155 mcg/dL), and ceruloplasmin concentration of 3 mg/dL (normal = 21–53 mg/dL).

She received intravenous copper at 2.4 mg/day over six days and intravenous vitamin B6 (50 mg/day) over three days. She was then discharged home, and weekly intravenous copper infusions (copper 2.4 mg over 2–3 hours) were arranged based on serial blood copper levels.

In addition, the patient was prescribed a complete high-potency oral multivitamin-mineral preparation twice daily (Women's Ultra Mega), oral vitamin B6 (50 mg/day), and oral copper gluconate (two 2 mg tablets BID for a total of 8 mg oral copper per day). One month after intravenous copper replacement was initiated, her plasma hematologic indices and serum copper levels had returned to normal. Four months after discharge from the hospital, intravenous copper was discontinued, and blood copper levels were maintained within the normal range on oral copper supplementation of 8 mg/day.
Case 2

A 58-year-old woman presented with an unsteady gait, numbness, and paresthesias of the lower extremities. Her past medical history was significant for an unspecified gastric bypass surgery approximately ten years prior to presentation for severe recurrent peptic ulcer disease. Initial laboratory examination demonstrated anemia, leukopenia, and severe neutropenia. Further laboratory examination demonstrated that the patient was markedly copper deficient, with a serum copper concentration of 2 mcg/dL and a serum ceruloplasmin concentration of 2 mg/dL.

The patient was given replacement with intravenous copper as an inpatient (2.4 mg daily for 6 days), followed by weekly intravenous copper (2.4 mg) combined with oral supplementation of 8 mg copper/day. Seven months following copper repletion (21 weeks of combined intravenous and oral copper therapy followed by 7 weeks of oral copper therapy alone), the patient did not need any assistance in walking, and her lower extremity neuropathy continued to improve.
Discussion

Treatment of copper deficiency consists of parenteral and oral copper replacement until normal copper levels in blood are achieved. These two patients each received intermittent IV copper combined with daily oral therapy until copper levels in blood were consistently within the normal range. Within weeks of therapy, serum copper and ceruloplasmin levels returned to normal and have remained so with daily oral therapy following several weeks of IV repletion. By the time both of these patients were on PO copper replacement only, their serum levels returned to >100 mcg/dL. 

 

References:

Griffith DP, Liff DA, Ziegler TR, Esper GJ, Winton EF. Acquired copper deficiency: a potentially serious and preventable complication following gastric bypass surgery. Obesity (Silver Spring). 2009;17(4):827-31.