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Home , Copper deficiency, Copper gluconate, Folate deficiency, Vitamin B12 deficiency

J Am Board Fam Med: first published as 10.3122/jabfm.19.2.191 on 2 March 2006. Downloaded from

BRIEF REPORTS Deficiency as Cause of Unexplained Hematologic and Neurologic Deficits in Patient with Prior Gastrointestinal Surgery

Joanne Wu, MD, MPH, Mari Ricker, MD, and John Muench, MD, MPH

Copper is a trace essential to hematopoiesis and to the structure and function of the nervous system. Copper deficiency is a rare cause of , , and myeloneuropathy, but should be considered in the differential diagnosis in a patient with prior gastrointestinal surgery. We report the case of a 51-year-old woman admitted for nonspecific neurologic symptoms ultimately found to be due to copper . (J Am Board Fam Med 2006;19:191–4.)

Case Reports Her Babinski’s reflex was positive bilaterally, and A 51-year-old female presented to the emergency her Romberg was strongly positive. Her patellar department complaining of numbness and tingling and brachioradialis deep tendon reflexes were hy- in her distal lower extremities that had progres- perreflexic bilaterally, but Achilles tendon reflexes sively worsened over the previous 4 weeks and had were normal. Her cranial nerves were intact, and begun to affect her fingers 2 days before presenta- her sensation of pain and temperature were normal. tion. In addition, the patient stated that over the Her motor strength was normal, but she had sig- past 2 weeks she had experienced a progressively nificant difficulty walking because of her sensory worsening shortness of breath, generalized weak- deficits. The physical examination was otherwise ness, fast heartbeat, and light-headedness. unremarkable. She had undergone a 16 years ago Laboratory tests in the emergency department with Roux-en-Y and partial small bowel resection included a hematocrit of 17% (normal range, 33% http://www.jabfm.org/ for treatment of Zollinger-Ellison syndrome as to 44.6%) with a mean corpuscular volume (MCV) well as a Whipple procedure for chronic pancreati- of 105.9 fL (normal range, 80 to 96 fL). At this tis. Since her surgeries, she received B12 point, the patient was admitted for management of supplementation intramuscularly and was con- anemia and further evaluation of neurologic symp- verted to oral supplementation several months be- toms. She received a transfusion of 2 units of fore her presentation in the emergency depart- packed red blood cells, which brought her hemat- ment. ocrit up to 27%. She was also started on 100 mcg of on 30 September 2021 by guest. Protected copyright. On presentation, the patient’s vital signs in- intramuscularly daily and 1 mg of cluded a temperature of 36.7°C, blood pressure of orally daily. 121/84, pulse of 80, respiratory rate of 18, oxygen The patient’s neurological and laboratory find- saturation of 100% on room air, and weight of 43.2 ings were initially attributed to vitamin B12 or kg. Initial neurological evaluation revealed dimin- folate deficiency, given her history of gastrointes- ished sensitivity to light touch and vibration and tinal surgery and recent conversion to oral vitamin decreased in her toes and ankles. B12 supplementation. However, her vitamin B12 and folate levels were available by the third day of Submitted 24 March 2005; revised 2 August 2005; ac- hospitalization, with a vitamin B12 level of 738 cepted 3 August 2005. pg/mL (normal range, 200 to 950 pg/mL) and From the Oregon Health and Science University, Port- land, OR. folate level greater than 24 ng/mL (normal level, Conflict of interest: none declared. Ͼ0.9 ng/mL). Methylmalonic acid was 0.77 Corresponding author: Mari Ricker, MD, Oregon Health ␮ Ͻ ␮ and Science University, 3181 SW Sam Jackson Park Road, mol/L (normal level, 0.4 mol/L) and homo- Portland, OR 97239. cysteine was 4.7 ␮mol/L (normal range, 4 to 12 http://www.jabfm.org Copper Deficiency in Gastrointestinal Surgery 191 J Am Board Fam Med: first published as 10.3122/jabfm.19.2.191 on 2 March 2006. Downloaded from

␮mol/L). Her reticulocyte count was elevated to The patient felt subjectively stronger by the 3.1% (normal range, 0.5% to 1.5%), with an abso- fourteenth day after initiation of treatment, en- lute count of 56,300/mm3 (normal range, 10,000 to abling her to ambulate more stably with a walker or 90,000/mm3). Serum , ferritin, and transferrin cane, although her neurologic examination was ob- levels were normal, at 122 ␮g/dL (normal range, 40 jectively unchanged. She was then discharged from to 150 ␮g/dL), 259 ng/mL (normal range, 10 to the hospital on continued daily intravenous infu- 291 ng/mL), and 220 mg/dL (normal range, 200 to sions of copper chloride. Four months after dis- 400 mg/dL), respectively. Other laboratory find- charge (at the time of this writing), she was still ings included a white blood cell count of 2,000/ being treated with parenteral copper. Her copper 3 3 ␮ mm (normal range, 4400 to 11,000/mm ), with level had normalized to 97 g/dL. Although her 40% . However, she had normal plate- symptoms had not improved since going home, let counts and prothrombin times. Peripheral blood neither had they worsened. smears showed nucleated red blood cells but no polymorphic nucleated neutrophils. A bone mar- row biopsy was considered but refused by the pa- Discussion tient. Serum lead level was normal. Serum and Copper deficiency is quite rare in humans because urine protein electrophoreses were normal. Cere- it is a nutrient that is readily consumed and has a 1,2 brospinal fluid studies showed no evidence of in- very low daily requirement. It is present in le- fection and no oligoclonal bands. An antinuclear gumes, meats, and nuts, and is absorbed through the mucosa of the and proximal duode- antibody test was negative. num. With the plentiful supply of dietary copper, Imaging included magnetic resonance imaging acquired copper deficiency is relatively uncommon (MRI) of the brain and cervical spine, which compared with other causes of neurologic and he- showed a possible abnormal signal in the posterior matologic deficits, so it can be easily missed when columns of the cervical spine. This was followed up formulating differential diagnoses. with a high-resolution 3-Tesla MRI study for my- Copper is an essential trace metal that plays an elopathy, which was normal. Magnetic resonance integral role in many of our physiologic processes, angiography of the brain was then done with an including acting as a ligand to many proteins and incidental finding of frontal lobe developmental enzymes. It is crucial in the structure of venous anomaly but was otherwise normal. A chest, ␤-hydroxylase, the enzyme responsible for conver- http://www.jabfm.org/ abdominal, and pelvic computed tomography scan sion of dopamine to , which medi- did not show any significant lymphadenopathy. Af- ates many neurologic functions. In addition, copper ter the third day of hospitalization, she developed helps form cytochrome oxidase, a component in additional neurologic symptoms including 4/5 oxidative phosphorylation, and superoxide dis- strength in her iliopsoas and hamstrings and 3/5 mutase, an . Copper also acts as a ligand dorsiflexion and plantar flexion of both ankles. to II, which oxidizes iron, allowing it to on 30 September 2021 by guest. Protected copyright. Further laboratory studies were done, and her be mobilized and transported from hepatic stores Ͻ level was found to be 10 mg/dL to the for use in erythropoiesis.2 (normal range, 20 to 60 mg/dL), suggesting copper Thus, copper deficiency results in excessive iron in deficiency. The patient was started on 5.35 mg of the but insufficient iron in the marrow for copper chloride intravenous supplementation daily effective erythropoiesis.3 (equivalent to 2 mg of elemental copper). Her se- Although rare, there are several potential causes rum copper level was not checked until the third of copper deficiency. In previous reports, copper day of supplementation and was found to be low at deficiency has developed after gastric and bariatric 38 ␮g/dL (normal range, 80 to 155 ␮g/dL). Her surgery, probably due to malabsorption.4–6 Copper copper level increased to 53 ␮g/dL by the sixth day deficiency can also develop in patients receiving and to 72 ␮g/dL by the fourteenth day of treat- intravenous hyperalimentation without copper sup- ment. Because high serum levels have been plementation.7 It has also been found to be associ- associated with copper deficiency, the patient’s se- ated with hyperzincemia,8–10 although the causal rum zinc level was checked and found to be normal relationship is still unclear.11 In addition, Menkes at 96 ␮g/dL (normal range, 65 to 256 ␮g/dL). disease is a heritable disorder in which there is a

192 JABFM March–April 2006 Vol. 19 No. 2 http://www.jabfm.org J Am Board Fam Med: first published as 10.3122/jabfm.19.2.191 on 2 March 2006. Downloaded from failure to transport absorbed copper to the rest of ripheral neuropathy, , and gait atax- the body from mucosal cells, which results in cop- ia.17 per deficiency and its sequelae.12 The differential diagnosis of patients with pre- Deficiency in the enzymes that copper normally sentations such as ours should include not only B12 supports can lead to striking neurologic deficits, and folate deficiency, but also problems such as including , , , op- central nervous system infection, multiple sclerosis, tic neuritis, and demyelination. The first docu- lupus, multiple myeloma, , or other ma- mented case of copper deficiency-associated my- lignancies. To diagnose copper deficiency, serum elopathy was of a 46-year-old woman who copper level should be measured; ceruloplasmin developed tetraparesis and painful al- level is nonspecific and can be an acute phase re- most 20 years after gastrectomy.13 In another study actant. Serum copper levels can be followed for of 13 patients with acquired copper deficiency, all adequacy of copper replacement therapy. Patients had gait difficulty and lower limb paresthesias, with with copper deficiency have been successfully 5 impaired proprioception and vibration sense in the treated with oral copper in the past but not in the distal lower limbs.5 Nine of those patients also had form of copper gluconate because of its poor bio- 18 reduced perceptions of pinprick and touch in a availability. Given that the cause of our patient’s stocking distribution, and 10 had positive Babins- deficiency was her abnormal gastrointestinal anat- ki’s sign. Three of the 13 had increased T2 signal in omy, we opted to treat her with parenteral copper the paramedian dorsal cervical cord. chloride. In prior case studies, neurologic improvement Patients with copper deficiency can also develop has been quite variable, although most patients profound hematopoietic deficits resulting in ane- seem to retain some deficit even with treatment, mia and leukopenia, although not all patients with and relapses can occur.5,7,9,10,19,20 The hematologic copper deficiency develop these manifestations. deficits, however, generally correct within 2 Sideroblastic changes and nuclear maturation de- months of beginning treatment.10,21 fects causing anemia and have been observed in erythroid precursors of patients with copper deficiency.1,14 A peripheral smear often re- Conclusion veals with hypochromic mi- Our patient had a history of extensive gastrointes- crocytic red cells. Granulocyte levels can become tinal surgeries and recent development of waxing http://www.jabfm.org/ very low, whereas counts remain normal. In and waning hematologic and neurologic deficits. the study mentioned above in which 13 patients Her symptoms were ultimately attributed to copper with copper deficiency were followed, 10 of the 13 deficiency. Prompt diagnosis and treatment of cop- had anemia or leukopenia.5 The MCV in anemia of per deficiency may help prevent the development copper deficiency is usually normal or increased, of further neurologic deficits. Physicians should be which can complicate the diagnosis, since megalo- aware that copper deficiency is part of the differ- blastic anemia is also characteristic of vitamin B12 ential diagnosis in patients with unexplained neu- on 30 September 2021 by guest. Protected copyright. or folate deficiency. rologic symptoms, anemia, and leukopenia, espe- Thus, the myelopathy, polyneuropathy, and cially those who have had prior gastrointestinal anemia produced by copper deficiency can mimic surgery. the deficits seen with vitamin B12 or folate defi- ciency. Subacute combined degeneration from vi- References tamin B12 deficiency involves the posterior and 1. Williams DM. Copper deficiency in humans. Semin lateral columns of the spinal cord and sometimes Hematol 1983;20:118–28. the peripheral nerves. In previous reports of pa- 2. Turnlund J. Copper. In: Shils M, Olson J, Shike M, tients with B12 deficiency, symptoms at presenta- editors. Modern in health and disease. Philadelphia: Lippincott; 1998. p. 241. tion included progressive sensory deficits, postural 3. Fields M, Bureau I, Lewis CG. Ferritin is not an instability, paresthesias, and megaloblastic ane- indicator of available hepatic iron stores in anemia of 15,16 mia. Likewise, a case report of a 38-year-old copper deficiency in rats. Clin Chem 1997;43(8 Pt woman with folate deficiency describes a presenta- 1):1457–9. tion with characteristics similar to ours, with pe- 4. Kumar N, Ahlskog JE, Gross JB, Jr. Acquired hypo- http://www.jabfm.org Copper Deficiency in Gastrointestinal Surgery 193 J Am Board Fam Med: first published as 10.3122/jabfm.19.2.191 on 2 March 2006. Downloaded from

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