April 2017 Issue

Nutrition Support 360: Copper Deficiency
By Theresa A. Fessler, MS, RDN, CNSC
Today's Dietitian
Vol. 19, No. 4, P. 16

Make a difference in the prevention and treatment of this unusual yet critical complication for patients on nutrition support.

The American Society for Parenteral and Enteral Nutrition recently emphasized the importance of identifying and treating malnutrition in hospitalized patients. Dietitians often focus on calories and protein, but micronutrient status also is important.

This article discusses a particular micronutrient: copper, one of the essential trace elements, also known by its symbol, Cu.

Case Studies
Consider the following two scenarios. A young woman with a high-output ileal fistula and exacerbation of Crohn's disease was transferred from another hospital where she received parenteral nutrition (PN), which lacked a multiple trace element (MTE) additive. She had transverse myelitis with progressive loss of ability to walk and was wheelchair dependent.

A middle-aged man with a history of Roux-en-Y gastric bypass surgery for obesity was admitted with malnutrition, anemia unresponsive to iron therapy, and lower extremity weakness that progressed to the need for a wheelchair. He was started on enteral nutrition (EN).

These patients had normal blood levels of vitamin B12 and thiamine and had severely low serum copper levels, as they both had conditions that increased their risk of copper deficiency. These cases and others like them are uncommon, but they can be disastrous for patients and their health care teams. RDs can make a difference in the prevention and treatment of copper deficiency by monitoring for specific risk factors and symptoms, and providing comprehensive plans for effective nutrition therapy.

Background
Copper is a component of several metalloenzymes that catalyze many different oxidase reactions in the body, eg, the conversion of dopamine to norepinephrine, serotonin degradation, and oxidation of ferrous iron. Copper is required for the body to build connective tissues, blood cells, and melanin; produce energy; transport iron; maintain neurologic function; and prevent oxidative damage.1,2 The majority of copper in the body is located in bone, muscle, the liver, the kidneys, and the brain. About 5% of the body's copper is in the bloodstream, of which up to 95% is bound to a carrier protein, ceruloplasmin.1,2

Dietary copper, found in a wide variety of foods including organ meats, cocoa, whole grains, nuts and seeds, and seafood, is absorbed mainly in the upper small intestine and to a lesser degree in the stomach. The recommended dietary allowance (RDA) for copper is 900 mcg per day.1 Up to 75% of oral copper is absorbed with intake of very small amounts in the diet, and the percentage declines as copper intake increases.1 About 80% of copper is excreted in bile and gastrointestinal (GI) secretions, and 20% in urine; therefore, patients on long-term PN with liver dysfunction and cholestasis are at risk of copper toxicity. Some of the copper that's excreted in bile is normally reabsorbed in enterohepatic circulation, so patients who lose excessive GI fluid draining from fistulae, biliary leaks, or ostomies are at risk of copper deficiency.2

Copper in Nutrition Support
The recommended daily parenteral requirement for copper is 0.3 mg. However, it's higher (0.4 mg to 0.5 mg) for patients with high GI fluid losses and lower (0.15 mg) for patients with cholestasis.3 Current adult parenteral MTE products in the United States contain 1 mg copper per dose, and single-element parenteral copper supplements are available as well as tablets or capsules for oral (or enteral) use.3 Commonly used adult EN products contain 1.5 mg to 3 mg copper in a volume of enteral formula that provides 1,500 kcal.4,5

Symptoms and Complications of Deficiency
Common symptoms of copper deficiency are anemia that's unresponsive to iron supplementation, neutropenia, and in some cases, thrombocytopenia or pancytopenia.2,3 RDs can find this hematologic information in lab reports for complete blood count. Copper deficiency also can result in neurologic dysfunction such as myelopathy and peripheral neuropathy, sometimes presenting as disordered gait and ataxia. Even after treatment, irreversible neurologic damage can remain.2

Low blood concentrations of copper and ceruloplasmin are helpful in diagnosing severe deficiency; however, results in the normal or high range don't necessarily rule out deficiency because serum ceruloplasmin increases in response to inflammation, trauma, surgery, myocardial infarction, liver disease, malignancy, and pregnancy.2,3

Who's at Risk?
Case reports in the literature dating back to the 1970s describe hematologic symptoms associated with copper deficiency due to lack of sufficient copper in PN. Many years ago MTE additives weren't yet available or not routinely used in PN, and more recently, MTE additives were temporarily unavailable due to product shortages.3,6 In some cases, clinicians intentionally omitted copper from PN for patients with cholestasis to avoid toxicity, yet even for those patients, severe deficiencies occurred within two to 15 months.3

Patients who undergo gastric bypass surgery are at risk of copper deficiency not only because they eat less but also because the surgical procedure alters the anatomy to bypass the duodenum and proximal jejunum where copper is absorbed. In a systematic review published in the June 2016 issue of Obesity Surgery, Kumar and colleagues found 34 cases of symptomatic copper deficiency in post-Roux-en-Y gastric bypass patients reported in 17 studies. After treatment, hematologic symptoms resolved quickly; however, eight of the 19 patients with neurologic symptoms had residual neurologic problems. The authors recommended multivitamin mineral supplements that contain at least 2 mg copper per day for postgastric bypass patients. 

Enteral tube feeding into the jejunum bypasses areas of initial copper absorption. Nishiwaki and colleagues compared copper status in two groups of mostly elderly patients on EN, 36 of whom were fed by gastrostomy and 23 into the jejunum. The amount of copper provided from the EN formulas was above the RDA. Serum copper was significantly lower in the jejunal-fed group after six, 12, and 24 months of feeding. Five of the six severely copper-deficient patients in that study had anemia and neutropenia, and all recovered after four months of supplementation with cocoa powder as a source of copper.7

Several other less-commonly reported risk factors for copper deficiency include short bowel syndrome and excess zinc intake. In a study published in the April/June 2015 issue of Arquivos de Gastroenterologia by Braga and colleagues, serum copper was below normal eight out of 11 short bowel syndrome patients using PN that contained 0.8 mg copper per day and who were advised to take oral vitamin-mineral supplements containing copper. This finding may be related to GI fluid loss and diminished absorptive capacity with short bowel syndrome. Zinc inhibits GI absorption of dietary copper.2 Therefore, zinc supplements shouldn't be taken long term, and if a person is receiving additional oral or enteral zinc, copper status should be monitored.2

Treatment
For copper-deficient patients with functional upper GI tracts, RDs can recommend 2 mg oral copper per day. For patients on EN, crushed tablets or capsule contents can be mixed with water and administered in feeding tubes followed by water. For patients on PN, use of standard MTE products prevents copper deficiency. Case reports indicate that hematologic symptoms improve within one to three weeks with use of a parenteral MTE product that contains 1 mg to 1.3 mg copper per day.3 For severe deficiency, physicians can prescribe 2 mg to 4 mg parenteral copper per day administered separately in IV fluid.2

Other Considerations
While this article focuses on copper, multiple deficiencies often coexist in malnourished patients. Copper deficiency symptoms are similar to those of iron, vitamin B12, thiamine, and folic acid. It's important for RDs to ensure that all other potential nutrient deficiencies are addressed. Besides deficiency, copper toxicity also is a risk for patients on long-term PN, thus copper content of PN may need to be decreased. Blood tests are expensive and have limited reliability, so they should be used judiciously when clinical signs or risks of nutrient abnormalities are present. Furthermore, RDs need to be aware that some disorders that appear to be nutrient deficiencies or toxicities may be caused by other nonnutrition-related factors.

Valuable Team Members 
Equipped with knowledge and ongoing awareness of the risk factors for copper deficiency, as well as knowing how to prevent, identify, and treat the condition, RDs can be a valuable asset to their patients and the health care team with whom they work.

— Theresa A. Fessler, MS, RDN, CNSC, is a nutrition support specialist for Morrison Healthcare and the University of Virginia Health System, and a freelance writer. She has worked in nutrition support for more than 26 years.

References
1. Copper. In: Institute of Medicine Panel on Micronutrients. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academies Press; 2001.

2. Livingstone C. Review of copper provision in the parenteral nutrition of adults [published online October 19, 2016]. Nutr Clin Pract. doi: 10.1177/0884533616673190.

3. Fessler TA. Trace elements in parenteral nutrition: a practical guide for dosage and monitoring for adult patients. Nutr Clin Pract. 2013;28(6):722-729.

4. Product category: therapeutic. Abbott Nutrition website. https://static.abbottnutrition.com/cms-prod/abbottnutrition-2016.com/img/Therapeutic.pdf. Updated December 12, 2016. Accessed January 7, 2017.

5. Our brands. Nestlé Health Science website. https://www.nestlehealthscience.us/brands. Accessed January 7, 2017. 

6. Palm E, Dotson B. Copper and zinc deficiency in a patient receiving long-term parenteral nutrition during a shortage of parenteral trace element products. JPEN J Parenter Enteral Nutr. 2015;39(8):986-989.

7. Nishiwaki S, Iwashita M, Goto N, et al. Predominant copper deficiency during prolonged enteral nutrition through a jejunostomy tube compared to that through a gastrostomy tube. Clin Nutr. 2011;30(5):585-589.