What's zinc got to do with it?

This case study examines a 59-year-old woman with weakness and fatigue of three weeks' duration.


A 59-year-old Caucasian woman presented to the Mayo Clinic emergency department with weakness and fatigue of three weeks' duration. She had been hospitalized one month prior after she lost her balance and fell while brushing her hair. A CT scan during the previous hospitalization had demonstrated a left extra-axial hematoma. The hemorrhage did not progress, and the patient went home. On return to the ED, she reported having some difficulty eating because of increased shaking while trying to feed herself. She denied any other recent illness.

Her medical history was significant for coronary artery disease, hypertension, dyslipidemia, chronic pancytopenia, osteoarthritis, pulmonary restrictive disease, GERD, renal insufficiency and a history of a seizure disorder. In 2009, she had undergone a Roux-en-Y gastric bypass with cholecystectomy for morbid obesity. After her bypass she began taking several supplements, including calcium citrate 950 mg one time daily, multivitamin tablet one time daily, potassium chloride 20 mEq tablet one time daily, thiamine 100 mg one time daily, and zinc sulfate 220 mg (50 mg elemental) four doses per day.

Physical exam revealed diffuse bilateral upper and lower extremity weakness. She had significantly decreased sensation in the bilateral lower extremities and no reflexes present in the bilateral lower extremities. Positional and vibratory sensation was diminished. Gait was unable to be assessed due to the patient's weakness and inability to stand. She had severe pitting edema bilaterally in the upper and lower extremities. The rest of her physical exam was essentially benign.

Initial laboratory examination revealed anemia (hemoglobin, 6.6 g/dL; normal, 12-15.5 g/dL), leukopenia (leukocytes, 1.7 × 109/L; normal, 3.5-10.5 × 109/L), and thrombocytopenia (platelets, 19 × 109/L; normal, 150-450 × 109/L). Blood iron studies, folate, and vitamin B12 were normal. Her serum zinc was 0.89 mcg/mL (normal, 0.66-1.1 mcg/mL); magnesium was 1.9 mg/dL (normal, 1.7-2.3 mg/dL); and copper was <0.10 mcg/mL (normal, 0.75-1.45 mcg/mL). Bone marrow biopsy found a hypocellular bone marrow with no diagnostic morphologic features of involvement by a hematologic neoplasm. The bone marrow findings were compatible with copper deficiency.

Discussion

Approximately 60% of dietary copper comes from vegetable products and 20% from meat, fish, and poultry (11. Johnson MA, Kays SE. Copper: its role in human nutrition. Nutrition Today 1990;25:6.). Animal models suggest that copper is mainly absorbed in the duodenum but also in the stomach and ileum (22. Van Campen DR, Mitchell EA. Absorption of Cu64, Zn65, Mo99, and Fe59 from ligated segments of the rat gastrointestinal tract. J Nutr. 1965;86:120-124.). It is transported to the liver bound to albumin. Once in the liver it is incorporated into ceruloplasmin, which acts as a transporter of copper to the rest of the body. Copper plays an important biological role in a number of enzymes responsible for antioxidant defense, dopamine synthesis, collagen cross-linking, electron transport, thrombosis, and melatonin production (33. Danks DM. Copper deficiency in humans. Annu Rev Nutr. 1988;8:235.).

Copper deficiency presents with a wide spectrum of symptoms, including microcytic hypochromic anemia, neutropenia, bone lesions, vascular lesions, central nervous system disorders and convulsion, and hair texture abnormalities (44. Tsugutoshi AOKI. Copper deficiency and the clinical practice. JMAJ. 2004;47:365-370.). Neurological manifestations often mimic B12 deficiency and include ataxia, neuropathy and cognitive deficits (55. Tan JC, Burns DL, Jones HR. Severe ataxia, myelopathy, and peripheral neuropathy due to acquired copper deficiency in a patient with history of gastrectomy. J Parenter Enteral Nutr. 2006;30:446.). Lab findings include low serum copper, ceruloplasmin, erythrocyte copper-zinc superoxide, and a decreased 24-hour urine copper excretion (11. Johnson MA, Kays SE. Copper: its role in human nutrition. Nutrition Today 1990;25:6.).

There are a variety of causes of copper deficiency. In premature infants, copper deficiency can occur in infants who are on milk formula (66. Shaw JC. Copper deficiency in term and preterm infants. In: Fomon SJ, Zlotkin S, eds. Nutritional Anemias. New York: Vevey/Raven Pr; 1992:105.). Menkes disease is an x-linked genetic disorder which results in a mutated transport protein responsible for copper uptake (77. Harris ED. Cellular copper transport and metabolism. Annu Rev Nutr. 2000;20:291.). Copper deficiency from Menkes often results in hypotonia and seizures and can lead to death during early childhood (88. Kaler SG, Holmes CS, Goldstein DS, Tang J, Godwin SC, Donsante A, Liew CJ, Sato S, Patronas N. Neonatal diagnosis and treatment of Menkes disease. N Engl J Med. 2008;358:605-14.).

In adults, gastric surgery is one of the main risk factor for hypocupremia (99. Kumar N, Ahlskog JE, Gross JB Jr. Acquired hypocupremia after gastric surgery. Clin Gastroenterol Hepatol. 2004;2:1074.). Roux-en-Y gastric bypass (RYGB) surgery is a common operation for morbid obesity. The procedure bypasses the duodenum and between 100 to 200 cm of proximal jejunum, where most copper absorption takes place (1010. Griffith DP, Liff DA, Ziegler TR, Esper GJ, Winton EF. Acquired copper deficiency: a potentially serious and preventable complication following gastric bypass surgery. Obesity. 2009;17:827-31.). Despite this risk, it is relatively rare to develop hypocupremia following gastric bypass surgery unless it is accompanied by some other factor, such as zinc ingestion (1111. Choi EH, Strum W. Hypocupremia-related myeloneuropathy following gastrojejunal bypass surgery. Ann Nutr Metab. 2010;57:190-2.). Zinc actively competes with copper for absorption in the jejunum.

Treatment of hypocupremia consists of parenteral and oral copper replacement. Case reports have suggested that serum copper and ceruloplasmin levels should return to normal within weeks of therapy (1010. Griffith DP, Liff DA, Ziegler TR, Esper GJ, Winton EF. Acquired copper deficiency: a potentially serious and preventable complication following gastric bypass surgery. Obesity. 2009;17:827-31.).

In conclusion, this patient presented with severe copper deficiency after gastric bypass complicated with generous zinc supplementation. Her zinc supplementation was stopped. Upon replacement with intravenous copper (4 mg daily for 5 days), her hematologic indices remained stable with slow improvement. Her follow-up copper level improved to 0.38 and she was continued on vitamin and mineral supplementation with an appropriate amount of zinc included.