American Journal of Emergency Medicine 34 (2016) 340.e5–340.e6
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Case Report
The perfect storm: copper deficiency presenting as progressive peripheral neuropathy☆ Abstract A number of patients present to the emergency department (ED) with complaints of peripheral neuropathy. This case report highlights on an underrecognized etiology of progressive neuropathy in a woman who presented to our ED. Clinical signs, symptoms, as well as a high index of suspicion suggested copper deficiency. Hypocupremia manifests itself as a debilitating peripheral sensory and motor neuropathy, anemia, leukopenia, and abnormal red blood cell morphologies on a peripheral blood smear. Significant risk factors for the development of this illness include Roux-en-Y gastric bypass; excess zinc supplementation; and, in some instances, postmenopausal females. The article reviews pertinent literature. The emergency department (ED) is the door to a variety of clinical conditions. Practitioners working in the ED must be able to interpret clinical data obtained by many kinds of monitoring devices, apply formulas, understand laboratory values, and then integrate this information with their knowledge of the pathophysiology of the disease. One condition that is commonly seen in the ED and that has many possible etiologies is the peripheral neuropathy syndrome. We report a patient who presented to the ED with progressive peripheral neuropathy and hematologic abnormalities found to be secondary to copper deficiency. A 67-year-old woman presented to our ED with a 6-week history of unsteady gait, ascending weakness, numbness, and tingling involving both lower extremities and hands in a stocking-glove pattern. Over this period, her ability to ambulate gradually deteriorated to the point that she required wheelchair for ambulation. Her medical history was significant for Roux-en-Y (RYGB) surgery for the treatment of morbid obesity 17 years before presentation and a recent diagnosis of peripheral neuropathy 5 months before presentation in our ED. She was taking vitamin D3 5000 U 2 times daily and vitamin B12, 1000 μg intramuscular once a month for many years but on no other vitamin or mineral supplementation. On initial physical examination, she was awake, alert, and oriented. Her vital signs were within normal limits. Cardiopulmonary examination revealed no pathology. Neurologic examination was remarkable for absent positional and vibratory sensation in the lower and upper extremities to the elbow and knee. Fine touch sensation was decreased in a stocking distribution to the level of her thighs, and she had 2 + knee and 1 + ankle reflexes bilaterally with an absent Babinski sign. Her gait was broad based and unsteady. Her mental status and cranial nerve examinations were intact. Motor strength was mildly decreased, more significant in distal muscles.
☆ Conflicts of interest: No conflicts of interest, meetings, or grants to acknowledge.
0735-6757/© 2015 Elsevier Inc. All rights reserved.
Initial laboratory data revealed anemia (hemoglobin level = 10.1 g/dL, mean corpuscular volume = 104.2 fL, white blood cell = 2.3 × 103/μL); neutrophils, 8.4%; lymphocytes, 60.8%; monocytes, 13.5%; eosinophils, 15.8%; and basophils, 1.5%. Iron studies, folate, vitamin B12, homocysteine, methylmalonic acid, zinc, selenium, α and γ tocopherol, and myelin-associated glycoprotein antibody immunoglobulin M titers were within normal limits. Pyridoxine levels were mildly low. Serology markers for human immunodeficiency virus and Lyme disease were negative. Cerebrospinal fluid analysis and computed tomography of the brain, thoracic, and cervical spine as a part of neuropathy workup were unremarkable. Peripheral smear was notable for leukopenia and dimorphic red blood cells (See Figure). Electrophysiology studies revealed sensory motor neuropathy. Further laboratory examination demonstrated that the patient was markedly copper deficient, with a serum copper concentration of less than 10 μg/dL (normal limit 80-155 μg/dL). With the diagnosis of copper deficiency, the patient was started on copper gluconate 2 mg daily. Her symptoms improved over a period of days. She was transferred to inpatient rehabilitation for continuation of care. Copper, a widely available trace mineral, is essential for hematopoiesis as well as the function of neural, vascular, and skeletal tissues through incorporation into enzymes such as mitochondrial cytochrome c oxidase, superoxide dismutase, and lysyl oxidase [1,2]. In cases of documented copper deficiency, full resolution of hematologic abnormalities and partial resolution of neurologic deterioration have been achieved with copper replacement [3]. There are no consistent guidelines defining optimal formulation, dosage, or duration of treatment for hypocupremia. Copper salts used for supplementation include copper gluconate, copper sulfate, and copper chloride. A few studies have successfully used oral supplementation in gastric bypass patients (2-mg copper gluconate daily or every other day), suggesting that supersaturation of intestinal copper transport systems is a reliable option despite malabsorption being a likely mechanism [4,5]. Others have reported using parenteral formulations at a dose of 1.5 to 3 mg/d of elemental copper [6,7]. Griffith et al [3] combined intermittent intravenous copper with oral therapy for weeks until normalization of serum copper and ceruloplasmin levels. In the setting of hypocupremia from zinc overload, discontinuation of zinc therapy is necessary, along with copper supplementation as needed [8]. Considering the variability with patient response, close monitoring of copper levels is necessary to establish appropriate dosage and prevent toxicity. Risk factors for hypocupremia include zinc excess and malabsorption, with RYGB now as the most common cause. Roux-en-Y surgery for morbid obesity is becoming increasingly common in the United States; most procedures bypass the duodenum and proximal
340.e6
L. Coyle et al. / American Journal of Emergency Medicine 34 (2016) 340.e5–340.e6
Mahnaz Entezaralmahdi, MD Department of Medicine, Houston Methodist Hospital, Houston, TX Mobolaji Adeola, PharmD Department of Medicine, Houston Methodist Hospital, Houston, TX Patricio De Hoyos, MD Department of Medicine, Houston Methodist Hospital, Houston, TX Ali Mehed, MD Department of Medicine, Houston Methodist Hospital, Houston, TX
Figure. Blood smear reveals leukopenia and dimorphic red blood cells.
Joseph Varon, MD Department of Medicine, Houston Methodist Hospital, Houston, TX Department of Critical Care, University General Hospital, Houston, TX Corresponding author at: 2219 Dorrington St, Houston, TX, 77030 Tel.: +1 713 669 1670; fax: +1 713 669 1671 E-mail address: [email protected] http://dx.doi.org/10.1016/j.ajem.2015.06.024 References
jejunum—the segments critical for copper absorption in humans [2,6,9]. Roux-en-Y patients are routinely prescribed multivitamin-mineral preparations, iron, calcium, and vitamin B12; but copper is not routinely supplemented as a specific nutrient, and copper depletion after RYGB is not widely studied [6,10]. Some investigators have shown copper deficiency as high as 18.8% after RYGB [11]. Female sex may be additional risk factor that rendered our patient susceptible to peripheral neuropathy from copper deficiency. Higher cupremia in females has long been established and is potentially secondary to larger copper requirements in females [9]. This sex-specific difference is likely from altered copper trafficking rather than differences in dietary intake as evident by mice models of copper-restricted diets [12]. Copper levels are found to be highest in females who are pregnant or taking oral contraceptives, which further this relationship by associating copper levels with estrogen status [13]. Prior studies have also discussed the high incidence of post-RYGB copper deficiency in females [11]. There is a variety of case reports of copper deficiency in females of postmenopausal or perimenopausal age [3,7,14]. This may indicate a susceptibility to copper deficiency after transitioning from a high estrogen to low estrogen state. Patients presenting to the ED with progressive peripheral neuropathy and a history of RYGB should be assessed for copper deficiency. Because of the progressive and sometimes irreversible neurologic consequence from copper deficiency, early diagnosis is prudent to facilitate prompt initiation of corrective therapy. Laura Coyle, MS Weill Cornell Medical College, New York City, NY
[1] Nagano T, Toyoda T, Tanabe H, Nagato T, Tsuchida T, Kitamura A, et al. Clinical features of hematological disorders caused by copper deficiency during long-term enteral nutrition. Intern Med 2005;44(6):554–9. [2] Bertinato J, Abbe MRL. Maintaining copper homeostasis: regulation of coppertrafficking proteins in response to copper deficiency or overload. J Nutr Biochem 2004;15:316–22. [3] Griffith D, Liff D, Winston E. Acquired copper deficiency: a potentially serious and preventable complication following gastric bypass surgery. Obesity 2009;17(4): 827–31. [4] O'Donnell K, Simmons M. Early-onset copper deficiency following Roux-en-Y gastric bypass. Nutr Clin Pract 2011;26(1):66–9. [5] Koch TR, Finelli FC. Postoperative metabolic and nutritional complications of bariatric surgery. Gastroenterol Clin N Am 2010;39(1):109–24. [6] Kumar N, Ahlskog JE, Gross JB. Acquired hypocupremia after gastric surgery. Clin Gastroenterol Hepatol 2004;2:1074–9. [7] Schleper B, Stuerenburg HJ. Copper deficiency-associated myelopathy in a 46-yearold woman. J Neurol 2001;248:705–6. [8] Shahidzadeh R, Sridhar S. Profound copper deficiency in a patient with gastric bypass. Am J Gastroenterol 2008;103:2660–2. [9] Wapnir RA. Copper absorption and bioavailability. Am J Clin Nutr 1998;67: 1054S–60S. [10] Tan JC, Burns DL, Royden JH. Severe ataxia, myelopathy, and peripheral neuropathy due to acquired copper deficiency in a patient with history of gastrectomy. JPEN 2006;30:446–50. [11] Gletsu-Miller N, Broderius M, Frediani JK, Zhao VM, Griffith DP, Davis Jr SS, et al. Incidence and prevalence of copper deficiency following Roux-en-Y gastric bypass surgery. Int J Obes 2012;36(3):328–35. [12] Quinn J, Harris C, Kaye J, Lind B, Carter R, Anekonda T, et al. Gender effects on plasma and brain copper. Int J Alzheimers Dis 2011;2011:4 [150916]. [13] Lopes PA, Santos MC, Vicente L, Rodrigues MO, Pavao ML, Neve J, et al. Trace element status (Se, Cu, Zn) in healthy Portuguese subjects of Lisbon population: a reference study. Biol Trace Elem Res 2004;101(1):1–17. [14] Goodman BP, Chong BW, Patel AC, Fletcher GP, Smith BE. Copper deficiency myeloneuropathy resembling B12 deficiency: partial resolution of MR imaging findings with copper supplementation. AJNR 2006;27:2112–4.
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Case Report
The perfect storm: copper deficiency presenting as progressive peripheral neuropathy☆ Abstract A number of patients present to the emergency department (ED) with complaints of peripheral neuropathy. This case report highlights on an underrecognized etiology of progressive neuropathy in a woman who presented to our ED. Clinical signs, symptoms, as well as a high index of suspicion suggested copper deficiency. Hypocupremia manifests itself as a debilitating peripheral sensory and motor neuropathy, anemia, leukopenia, and abnormal red blood cell morphologies on a peripheral blood smear. Significant risk factors for the development of this illness include Roux-en-Y gastric bypass; excess zinc supplementation; and, in some instances, postmenopausal females. The article reviews pertinent literature. The emergency department (ED) is the door to a variety of clinical conditions. Practitioners working in the ED must be able to interpret clinical data obtained by many kinds of monitoring devices, apply formulas, understand laboratory values, and then integrate this information with their knowledge of the pathophysiology of the disease. One condition that is commonly seen in the ED and that has many possible etiologies is the peripheral neuropathy syndrome. We report a patient who presented to the ED with progressive peripheral neuropathy and hematologic abnormalities found to be secondary to copper deficiency. A 67-year-old woman presented to our ED with a 6-week history of unsteady gait, ascending weakness, numbness, and tingling involving both lower extremities and hands in a stocking-glove pattern. Over this period, her ability to ambulate gradually deteriorated to the point that she required wheelchair for ambulation. Her medical history was significant for Roux-en-Y (RYGB) surgery for the treatment of morbid obesity 17 years before presentation and a recent diagnosis of peripheral neuropathy 5 months before presentation in our ED. She was taking vitamin D3 5000 U 2 times daily and vitamin B12, 1000 μg intramuscular once a month for many years but on no other vitamin or mineral supplementation. On initial physical examination, she was awake, alert, and oriented. Her vital signs were within normal limits. Cardiopulmonary examination revealed no pathology. Neurologic examination was remarkable for absent positional and vibratory sensation in the lower and upper extremities to the elbow and knee. Fine touch sensation was decreased in a stocking distribution to the level of her thighs, and she had 2 + knee and 1 + ankle reflexes bilaterally with an absent Babinski sign. Her gait was broad based and unsteady. Her mental status and cranial nerve examinations were intact. Motor strength was mildly decreased, more significant in distal muscles.
☆ Conflicts of interest: No conflicts of interest, meetings, or grants to acknowledge.
0735-6757/© 2015 Elsevier Inc. All rights reserved.
Initial laboratory data revealed anemia (hemoglobin level = 10.1 g/dL, mean corpuscular volume = 104.2 fL, white blood cell = 2.3 × 103/μL); neutrophils, 8.4%; lymphocytes, 60.8%; monocytes, 13.5%; eosinophils, 15.8%; and basophils, 1.5%. Iron studies, folate, vitamin B12, homocysteine, methylmalonic acid, zinc, selenium, α and γ tocopherol, and myelin-associated glycoprotein antibody immunoglobulin M titers were within normal limits. Pyridoxine levels were mildly low. Serology markers for human immunodeficiency virus and Lyme disease were negative. Cerebrospinal fluid analysis and computed tomography of the brain, thoracic, and cervical spine as a part of neuropathy workup were unremarkable. Peripheral smear was notable for leukopenia and dimorphic red blood cells (See Figure). Electrophysiology studies revealed sensory motor neuropathy. Further laboratory examination demonstrated that the patient was markedly copper deficient, with a serum copper concentration of less than 10 μg/dL (normal limit 80-155 μg/dL). With the diagnosis of copper deficiency, the patient was started on copper gluconate 2 mg daily. Her symptoms improved over a period of days. She was transferred to inpatient rehabilitation for continuation of care. Copper, a widely available trace mineral, is essential for hematopoiesis as well as the function of neural, vascular, and skeletal tissues through incorporation into enzymes such as mitochondrial cytochrome c oxidase, superoxide dismutase, and lysyl oxidase [1,2]. In cases of documented copper deficiency, full resolution of hematologic abnormalities and partial resolution of neurologic deterioration have been achieved with copper replacement [3]. There are no consistent guidelines defining optimal formulation, dosage, or duration of treatment for hypocupremia. Copper salts used for supplementation include copper gluconate, copper sulfate, and copper chloride. A few studies have successfully used oral supplementation in gastric bypass patients (2-mg copper gluconate daily or every other day), suggesting that supersaturation of intestinal copper transport systems is a reliable option despite malabsorption being a likely mechanism [4,5]. Others have reported using parenteral formulations at a dose of 1.5 to 3 mg/d of elemental copper [6,7]. Griffith et al [3] combined intermittent intravenous copper with oral therapy for weeks until normalization of serum copper and ceruloplasmin levels. In the setting of hypocupremia from zinc overload, discontinuation of zinc therapy is necessary, along with copper supplementation as needed [8]. Considering the variability with patient response, close monitoring of copper levels is necessary to establish appropriate dosage and prevent toxicity. Risk factors for hypocupremia include zinc excess and malabsorption, with RYGB now as the most common cause. Roux-en-Y surgery for morbid obesity is becoming increasingly common in the United States; most procedures bypass the duodenum and proximal
340.e6
L. Coyle et al. / American Journal of Emergency Medicine 34 (2016) 340.e5–340.e6
Mahnaz Entezaralmahdi, MD Department of Medicine, Houston Methodist Hospital, Houston, TX Mobolaji Adeola, PharmD Department of Medicine, Houston Methodist Hospital, Houston, TX Patricio De Hoyos, MD Department of Medicine, Houston Methodist Hospital, Houston, TX Ali Mehed, MD Department of Medicine, Houston Methodist Hospital, Houston, TX
Figure. Blood smear reveals leukopenia and dimorphic red blood cells.
Joseph Varon, MD Department of Medicine, Houston Methodist Hospital, Houston, TX Department of Critical Care, University General Hospital, Houston, TX Corresponding author at: 2219 Dorrington St, Houston, TX, 77030 Tel.: +1 713 669 1670; fax: +1 713 669 1671 E-mail address: [email protected] http://dx.doi.org/10.1016/j.ajem.2015.06.024 References
jejunum—the segments critical for copper absorption in humans [2,6,9]. Roux-en-Y patients are routinely prescribed multivitamin-mineral preparations, iron, calcium, and vitamin B12; but copper is not routinely supplemented as a specific nutrient, and copper depletion after RYGB is not widely studied [6,10]. Some investigators have shown copper deficiency as high as 18.8% after RYGB [11]. Female sex may be additional risk factor that rendered our patient susceptible to peripheral neuropathy from copper deficiency. Higher cupremia in females has long been established and is potentially secondary to larger copper requirements in females [9]. This sex-specific difference is likely from altered copper trafficking rather than differences in dietary intake as evident by mice models of copper-restricted diets [12]. Copper levels are found to be highest in females who are pregnant or taking oral contraceptives, which further this relationship by associating copper levels with estrogen status [13]. Prior studies have also discussed the high incidence of post-RYGB copper deficiency in females [11]. There is a variety of case reports of copper deficiency in females of postmenopausal or perimenopausal age [3,7,14]. This may indicate a susceptibility to copper deficiency after transitioning from a high estrogen to low estrogen state. Patients presenting to the ED with progressive peripheral neuropathy and a history of RYGB should be assessed for copper deficiency. Because of the progressive and sometimes irreversible neurologic consequence from copper deficiency, early diagnosis is prudent to facilitate prompt initiation of corrective therapy. Laura Coyle, MS Weill Cornell Medical College, New York City, NY
[1] Nagano T, Toyoda T, Tanabe H, Nagato T, Tsuchida T, Kitamura A, et al. Clinical features of hematological disorders caused by copper deficiency during long-term enteral nutrition. Intern Med 2005;44(6):554–9. [2] Bertinato J, Abbe MRL. Maintaining copper homeostasis: regulation of coppertrafficking proteins in response to copper deficiency or overload. J Nutr Biochem 2004;15:316–22. [3] Griffith D, Liff D, Winston E. Acquired copper deficiency: a potentially serious and preventable complication following gastric bypass surgery. Obesity 2009;17(4): 827–31. [4] O'Donnell K, Simmons M. Early-onset copper deficiency following Roux-en-Y gastric bypass. Nutr Clin Pract 2011;26(1):66–9. [5] Koch TR, Finelli FC. Postoperative metabolic and nutritional complications of bariatric surgery. Gastroenterol Clin N Am 2010;39(1):109–24. [6] Kumar N, Ahlskog JE, Gross JB. Acquired hypocupremia after gastric surgery. Clin Gastroenterol Hepatol 2004;2:1074–9. [7] Schleper B, Stuerenburg HJ. Copper deficiency-associated myelopathy in a 46-yearold woman. J Neurol 2001;248:705–6. [8] Shahidzadeh R, Sridhar S. Profound copper deficiency in a patient with gastric bypass. Am J Gastroenterol 2008;103:2660–2. [9] Wapnir RA. Copper absorption and bioavailability. Am J Clin Nutr 1998;67: 1054S–60S. [10] Tan JC, Burns DL, Royden JH. Severe ataxia, myelopathy, and peripheral neuropathy due to acquired copper deficiency in a patient with history of gastrectomy. JPEN 2006;30:446–50. [11] Gletsu-Miller N, Broderius M, Frediani JK, Zhao VM, Griffith DP, Davis Jr SS, et al. Incidence and prevalence of copper deficiency following Roux-en-Y gastric bypass surgery. Int J Obes 2012;36(3):328–35. [12] Quinn J, Harris C, Kaye J, Lind B, Carter R, Anekonda T, et al. Gender effects on plasma and brain copper. Int J Alzheimers Dis 2011;2011:4 [150916]. [13] Lopes PA, Santos MC, Vicente L, Rodrigues MO, Pavao ML, Neve J, et al. Trace element status (Se, Cu, Zn) in healthy Portuguese subjects of Lisbon population: a reference study. Biol Trace Elem Res 2004;101(1):1–17. [14] Goodman BP, Chong BW, Patel AC, Fletcher GP, Smith BE. Copper deficiency myeloneuropathy resembling B12 deficiency: partial resolution of MR imaging findings with copper supplementation. AJNR 2006;27:2112–4.
