Journal of the Neurological Sciences 349 (2015) 258–259
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor PPIs as possible risk factor for copper deficiency myelopathy Keywords: Copper deficiency myelopathy Proton pump inhibitors Spinal cord
Dear Sirs, Verma and colleagues recently described twenty-three patients with posterolateral myelopathy who were investigated for levels of vitamin B12, copper and zinc and followed up for six months [1]. They found that in six patients ceruloplasmin and 24 h urinary copper levels were low suggesting dietary copper deficiency. They argued that a normal western diet contains sufficient copper to meet daily requirements and hypothesized that the situation may be different in developing countries. Dietary copper intake may be low in some vegetarian diets involving infrequent consumption of foods rich in micronutrients. Copper bioavailability may be affected by dietary cysteine, molybdenum and zinc; the latter may be taken in excess through indiscriminate use of multivitamins which often contain zinc. It is known that copper and vitamin B12 deficiencies can potentially coexist [2] and indeed Verma et al. found three of their patients with posterolateral myelopathy to have such a dual deficiency state. Previous upper gastrointestinal surgery (both bariatric and nonbariatric) is the most common cause of copper deficiency, probably due to the reduction of the effective absorption area for particular micronutrients. Zinc overload and malabsorption represent less common etiologies, along with nephrotic syndromes, penicillamine and alkali therapy, and prolonged parenteral nutrition without copper supplementation [3,4]. In a significant percentage of patients (about 20%) the etiology of copper deficiency remains idiopathic [4], even after a careful history taking and extensive laboratory tests. We described two patients affected by copper deficiency myelopathy (CDM) that showed a significant clinical, neuroradiological, and neurophysiological improvement after proper supplementation therapy [5] and we recently diagnosed three further cases of CDM (unpublished data). Therefore, based on our data, we would like to discuss one important issue in relation to the etiology of CDM. In all the five patients we diagnosed with CDM, serum zinc was within the normal range and their past medical and surgical history was essentially unremarkable. Therefore, we concluded that all our patients were affected by idiopathic forms of CDM. Four of the five patients we diagnosed with CDM had been taking proton pump inhibitors (PPIs) for more than six years for different indications, including mild gastritis and gastroesophageal reflux disease. The absorption of copper in humans takes place in the stomach and proximal duodenum [3]. The uptake of copper is mediated by the membrane transporter Ctr1,
http://dx.doi.org/10.1016/j.jns.2015.01.009 0022-510X/© 2015 Elsevier B.V. All rights reserved.
whose expression is regulated by copper status, and then a P-type ATPase (ATP7A) transfers the copper across the basolateral membrane [4]. Ctr1-mediated copper absorption is an energy-independent process and it is stimulated by extracellular acidic pH and high potassium concentrations [6]. PPIs are potent inhibitors of H +/K + ATPase, located in the apical secretory membrane of the gastric parietal cells and are generally considered the most effective acid suppressive treatment [7]. The use of PPIs in the general population is increasing and this increase may continue over the coming years for different reasons, including further rise in the prevalence of gastroesophageal reflux disease and the availability of over the counter and generic PPIs [8]. Moreover, it has been reported that a substantial proportion of patients with indications not requiring long-term treatment actually use PPIs for an unnecessary extended period [9]. We hypothesize that a chronic and prolonged reduction of gastric acidity may impair copper absorption, thus prompting copper deficiency after several years of treatment with PPIs. Interestingly, PPI and histamine 2 receptor antagonist use has already been significantly associated with the presence of vitamin B12 deficiency [10]. This may explain the coexistence of combined copper and vitamin B12 deficiencies in some patients with myelopathy. It would be interesting to know whether the three patients with combined copper and vitamin B12 deficiencies described by Verma and colleagues [1] received PPIs or histamine 2 receptor antagonists. Our observations imply that PPIs may contribute to copper deficiency. We suggest that the discontinuation of PPIs should be strongly considered in patients with a definitive diagnosis of CDM, weighting up the risks and benefits of their continued use. Given the high prevalence of PPI use, further studies are needed to confirm our suggestion that PPIs constitute a risk factor for copper and vitamin B12 deficiency myelopathies and to elucidate the underlying pathophysiology. Conflict of interest No conflict of interest or financial interest is reported. T. Koudriavtseva reports consulting fees from Bayer Schering, and Institutional grant from Merck Serono, Biogen Idec, Novartis and Bayer Schering outside the submitted work. Other authors have nothing to declare. References [1] Verma R, Praharaj HN, Khanna VK, Garg RK, Singh MK, Malhotra HS. Study of micronutrients (copper, zinc and vitamin B12) in posterolateral myelopathies. J Neurol Sci 2013;329:11–6. http://dx.doi.org/10.1016/j.jns.2013.03.004. [2] Kumar N. Copper deficiency myelopathy (human swayback). Mayo Clin Proc Oct. 2006;81(10):1371–84. [3] Kumar N, Crum B, Petersen RC, Vernino SA, Ahlskog JE. Copper deficiency myelopathy. Arch Neurol 2004;61:762–6. [4] Jaiser SR, Winston GP. Copper deficiency myelopathy. J Neurol 2010;257:869–81. [5] Plantone D, Primiano G, Renna R, Restuccia D, Iorio R, Patanella KA, et al. Copper deficiency myelopathy: a report of two cases. J Spinal Cord Med Oct. 24 2014 http://dx.doi.org/10.1179/2045772314Y.0000000268 [Epub ahead of print]. [6] Lee J, Peña MM, Nose Y, Thiele DJ. Biochemical characterization of the human copper transporter Ctr1. J Biol Chem 2002;277:4380–7. [7] Horn J. The proton-pump inhibitors: similarities and differences. Clin Ther 2000;22: 266–80 [discussion 265].
Letter to the Editor [8] Kuipers EJ. Proton pump inhibitors and gastric neoplasia. Gut 2006;55:1217–21. [9] Van Soest EM, Siersema PD, Dieleman JP, Sturkenboom MC, Kuipers EJ. Persistence and adherence to proton pump inhibitors in daily clinical practice. Aliment Pharmacol Ther 2006;24:377–85. [10] Lam JR, Schneider JL, Zhao W, Corley DA. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA 2013;310:2435–42. http://dx.doi.org/10.1001/jama.2013.280490.
Domenico Plantone* Rosaria Renna Multiple Sclerosis Center, Unit of Neurology, Regina Elena National Cancer Institute, IFO, Rome, Italy *Corresponding author at: Multiple Sclerosis Center, Unit of Neurology, Regina Elena National Cancer Institute, IFO, Rome, Italy. Tel.: +39 3205506307. E-mail address: [email protected].
259
Guido Primiano Institute of Neurology, Department of Geriatrics, Neurosciences and Orthopedics, Catholic University, Rome, Italy Arif Shukralla Department of Neurosciences, Royal Preston Hospital, Preston, UK Tatiana Koudriavtseva Multiple Sclerosis Center, Unit of Neurology, Regina Elena National Cancer Institute, IFO, Rome, Italy 23 November 2014
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor PPIs as possible risk factor for copper deficiency myelopathy Keywords: Copper deficiency myelopathy Proton pump inhibitors Spinal cord
Dear Sirs, Verma and colleagues recently described twenty-three patients with posterolateral myelopathy who were investigated for levels of vitamin B12, copper and zinc and followed up for six months [1]. They found that in six patients ceruloplasmin and 24 h urinary copper levels were low suggesting dietary copper deficiency. They argued that a normal western diet contains sufficient copper to meet daily requirements and hypothesized that the situation may be different in developing countries. Dietary copper intake may be low in some vegetarian diets involving infrequent consumption of foods rich in micronutrients. Copper bioavailability may be affected by dietary cysteine, molybdenum and zinc; the latter may be taken in excess through indiscriminate use of multivitamins which often contain zinc. It is known that copper and vitamin B12 deficiencies can potentially coexist [2] and indeed Verma et al. found three of their patients with posterolateral myelopathy to have such a dual deficiency state. Previous upper gastrointestinal surgery (both bariatric and nonbariatric) is the most common cause of copper deficiency, probably due to the reduction of the effective absorption area for particular micronutrients. Zinc overload and malabsorption represent less common etiologies, along with nephrotic syndromes, penicillamine and alkali therapy, and prolonged parenteral nutrition without copper supplementation [3,4]. In a significant percentage of patients (about 20%) the etiology of copper deficiency remains idiopathic [4], even after a careful history taking and extensive laboratory tests. We described two patients affected by copper deficiency myelopathy (CDM) that showed a significant clinical, neuroradiological, and neurophysiological improvement after proper supplementation therapy [5] and we recently diagnosed three further cases of CDM (unpublished data). Therefore, based on our data, we would like to discuss one important issue in relation to the etiology of CDM. In all the five patients we diagnosed with CDM, serum zinc was within the normal range and their past medical and surgical history was essentially unremarkable. Therefore, we concluded that all our patients were affected by idiopathic forms of CDM. Four of the five patients we diagnosed with CDM had been taking proton pump inhibitors (PPIs) for more than six years for different indications, including mild gastritis and gastroesophageal reflux disease. The absorption of copper in humans takes place in the stomach and proximal duodenum [3]. The uptake of copper is mediated by the membrane transporter Ctr1,
http://dx.doi.org/10.1016/j.jns.2015.01.009 0022-510X/© 2015 Elsevier B.V. All rights reserved.
whose expression is regulated by copper status, and then a P-type ATPase (ATP7A) transfers the copper across the basolateral membrane [4]. Ctr1-mediated copper absorption is an energy-independent process and it is stimulated by extracellular acidic pH and high potassium concentrations [6]. PPIs are potent inhibitors of H +/K + ATPase, located in the apical secretory membrane of the gastric parietal cells and are generally considered the most effective acid suppressive treatment [7]. The use of PPIs in the general population is increasing and this increase may continue over the coming years for different reasons, including further rise in the prevalence of gastroesophageal reflux disease and the availability of over the counter and generic PPIs [8]. Moreover, it has been reported that a substantial proportion of patients with indications not requiring long-term treatment actually use PPIs for an unnecessary extended period [9]. We hypothesize that a chronic and prolonged reduction of gastric acidity may impair copper absorption, thus prompting copper deficiency after several years of treatment with PPIs. Interestingly, PPI and histamine 2 receptor antagonist use has already been significantly associated with the presence of vitamin B12 deficiency [10]. This may explain the coexistence of combined copper and vitamin B12 deficiencies in some patients with myelopathy. It would be interesting to know whether the three patients with combined copper and vitamin B12 deficiencies described by Verma and colleagues [1] received PPIs or histamine 2 receptor antagonists. Our observations imply that PPIs may contribute to copper deficiency. We suggest that the discontinuation of PPIs should be strongly considered in patients with a definitive diagnosis of CDM, weighting up the risks and benefits of their continued use. Given the high prevalence of PPI use, further studies are needed to confirm our suggestion that PPIs constitute a risk factor for copper and vitamin B12 deficiency myelopathies and to elucidate the underlying pathophysiology. Conflict of interest No conflict of interest or financial interest is reported. T. Koudriavtseva reports consulting fees from Bayer Schering, and Institutional grant from Merck Serono, Biogen Idec, Novartis and Bayer Schering outside the submitted work. Other authors have nothing to declare. References [1] Verma R, Praharaj HN, Khanna VK, Garg RK, Singh MK, Malhotra HS. Study of micronutrients (copper, zinc and vitamin B12) in posterolateral myelopathies. J Neurol Sci 2013;329:11–6. http://dx.doi.org/10.1016/j.jns.2013.03.004. [2] Kumar N. Copper deficiency myelopathy (human swayback). Mayo Clin Proc Oct. 2006;81(10):1371–84. [3] Kumar N, Crum B, Petersen RC, Vernino SA, Ahlskog JE. Copper deficiency myelopathy. Arch Neurol 2004;61:762–6. [4] Jaiser SR, Winston GP. Copper deficiency myelopathy. J Neurol 2010;257:869–81. [5] Plantone D, Primiano G, Renna R, Restuccia D, Iorio R, Patanella KA, et al. Copper deficiency myelopathy: a report of two cases. J Spinal Cord Med Oct. 24 2014 http://dx.doi.org/10.1179/2045772314Y.0000000268 [Epub ahead of print]. [6] Lee J, Peña MM, Nose Y, Thiele DJ. Biochemical characterization of the human copper transporter Ctr1. J Biol Chem 2002;277:4380–7. [7] Horn J. The proton-pump inhibitors: similarities and differences. Clin Ther 2000;22: 266–80 [discussion 265].
Letter to the Editor [8] Kuipers EJ. Proton pump inhibitors and gastric neoplasia. Gut 2006;55:1217–21. [9] Van Soest EM, Siersema PD, Dieleman JP, Sturkenboom MC, Kuipers EJ. Persistence and adherence to proton pump inhibitors in daily clinical practice. Aliment Pharmacol Ther 2006;24:377–85. [10] Lam JR, Schneider JL, Zhao W, Corley DA. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA 2013;310:2435–42. http://dx.doi.org/10.1001/jama.2013.280490.
Domenico Plantone* Rosaria Renna Multiple Sclerosis Center, Unit of Neurology, Regina Elena National Cancer Institute, IFO, Rome, Italy *Corresponding author at: Multiple Sclerosis Center, Unit of Neurology, Regina Elena National Cancer Institute, IFO, Rome, Italy. Tel.: +39 3205506307. E-mail address: [email protected].
259
Guido Primiano Institute of Neurology, Department of Geriatrics, Neurosciences and Orthopedics, Catholic University, Rome, Italy Arif Shukralla Department of Neurosciences, Royal Preston Hospital, Preston, UK Tatiana Koudriavtseva Multiple Sclerosis Center, Unit of Neurology, Regina Elena National Cancer Institute, IFO, Rome, Italy 23 November 2014
