Clinical Biochemistry 48 (2015) 130–134
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Evidence against implant-derived cobalt toxicity: Case report and retrospective study of serum cobalt concentrations in an orthopedic implant population☆ Nicole V. Tolan a,⁎, Rafael J. Sierra b, Thomas P. Moyer a a b
Department of Laboratory Medicine & Pathology, Mayo Clinic, Rochester, MN, USA Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
a r t i c l e
i n f o
Article history: Received 2 June 2014 Received in revised form 30 September 2014 Accepted 30 October 2014 Available online 8 November 2014 Keywords: Cobalt toxicity Erythropoiesis Orthopedic implant Total hip arthroplasty
a b s t r a c t Objectives: Cobalt (Co) exposure has been documented to result in increased erythropoiesis. To evaluate the potential for implant-derived Co toxicity, we examined the relationship between serum Co (sCo) and erythrocyte counts (ERY) in a metal-containing total-hip arthroplasty implant population. Methods: Retrospective review of sCo concentrations identified 77 patients with concomitant ERY. Statistical analysis was performed to determine if there was a significant difference in ERY for patients divided into clinically relevant sCo ranges. A single detailed case review of a patient with a loose mal-positioned acetabular component and significantly elevated sCo was also performed for symptoms thought to arise from Co toxicity. Results: Statistical difference in ERY was not observed between patients with significantly elevated (N 10 ng/mL), elevated (4–10 ng/mL), modestly elevated (1.0–3.9 ng/mL), or normal (b 1.0 ng/mL) sCo. While the detailed case report was unremarkable for any of the clinical symptoms previously reported to be associated with Co toxicity and no increase in ERY was observed, this patient's sCo was 84 ng/mL. Conclusions: Increased erythropoiesis was not observed in patients with implant-derived increased sCo. Even with a sCo 100× the upper-limit of normal, the patient presented did not have increased ERY nor exhibit any symptoms ascribed with Co toxicity. © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Case report—initial presentation A 60 year old female patient was referred to the Orthopedics Department with a history of left hip pain that had become progressively worse over the previous four weeks. She described her pain as occurring throughout the left groin, buttock and anterior thigh. This pain had quickly progressed, preventing any weight bearing or motion of the hip joint without significant discomfort. Referral was for evaluation and surgical correction of a loose mal-positioned acetabular component of the cementless metal-on-metal (MoM) implant type. Seven years prior, she had the total hip arthroplasty (THA) performed outside the US with a MoM device. The index THA had failed to resolve the preoperative limp and pain that resulted from osteonecrosis of the left hip.
Abbreviations: ARMD, Adverse Reaction to Metal Debris; CBC, Complete Blood Count; EMR, Electronic Medical Record; ERY, Erythrocyte count; MoM, Metal-on-metal; MoP, Metal-on-Polyethylene; sCo, Serum Cobalt; sCr, Serum Chromium; THA, Total Hip Arthroplasty. ☆ Disclosure: The authors have no conflicts of interest to be disclosed. ⁎ Corresponding author at: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue Yamins 309, Boston, MA 02215, USA. Fax: +1 617 667 4533. E-mail address: [email protected] (N.V. Tolan).
Erythrocyte sedimentation rate and C-reactive protein were 4 mm/1 h and 3.6 mg/L respectively; within normal limits. A series of pelvic radiographic images clearly demonstrated a loose malpositioned acetabular component where articulation of the prosthetic femoral head had resulted in a notch-like erosion of the medial prosthetic femoral neck (Fig. 1) and accumulation of peri-prosthetic metallic debris around the defect. An MRI with metal-suppression showed no soft tissue mass to suggest pseudotumor. The patient's serum cobalt (Co) and chromium (Cr) concentrations were 84 ng/mL and 101 ng/mL, respectively. Background and introduction THA is a viable surgical option to relieve the pain and limited joint mobility associated with injury or advanced degenerative disease of the hip. The materials used in metal-containing THA devices are predominately comprised of Co and Cr along with various other metals to a lesser degree, such as nickel (Ni), molybdenum (Mo), manganese (Mn), iron (Fe), titanium (Ti) and tungsten (W) [1]. While the composition of the implant materials was selected for increased strength, durability, and resistance to corrosion, implant wear and misalignment can result in metal particles released into the fluid and tissues surrounding the hip joint. These particles are subject to active corrosion leading to increased circulating metal ions, most notably Co and Cr. Circulating
http://dx.doi.org/10.1016/j.clinbiochem.2014.10.012 0009-9120/© 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
N.V. Tolan et al. / Clinical Biochemistry 48 (2015) 130–134
Fig. 1. Pelvic radiograph of acetabular component rotation. Anterior left hip radiograph showing the pronounced rotation of the cementless acetabular component within the hip socket, resulting in a notch-like erosion of the neck of the prosthetic femoral head. Here it was noted that articulation of the hip resulted advanced wear, resulting in accumulation of periprosthetic metal debris which was visible on MRI with metal suppression.
Co and Cr concentrations in blood serum are proportional to the surface area of the device, duration of the implant, and extent of implant wear [2–7]. The other major factor contributing to serum metal ion concentration is the acetabular cup angle, where angles greater than 55° can result in edge loading as well as increased wear and release of metal debris into the pelvic space surrounding the implant [8]. When blood samples are collected using metal-free blood collection techniques, the unexposed human population displays serum Co concentrations (sCo) and serum Cr concentrations (sCr) of b 1.0 and b0.3 ng/mL, respectively [3]. Patients with metal-containing implants in good condition who report no implant-related pain typically have increased sCo and sCr, ranging from 4.0 to 10 and 0.3 to 0.6 ng/mL, respectively. The sCo may be up to ten times greater than the unexposed reference interval in most of these patients. These concentrations have been demonstrated to increase temporally after implant with initial wear-in of the device that eventually reaches steady state concentrations of 4–10 ng/mL approximately three years post-operative [3,5,6]. The sCo can increase further with significant wear of the acetabular cup and femoral head with articulation of the hip. While sCo N10.0 ng/mL and sCr N1.0 ng/mL are indications of implant wear and possible adverse reaction to metal debris (ARMD, also called metallosis), sCo and sCr concentrations cannot be used as an independent predictor of implant function or be used as a recommendation for THA revision alone. These laboratory findings must be interpreted in clinical context and along with imaging studies. Co is an essential element, as it is a co-factor of vitamin B12 (hydroxycobalamin), and it is widely distributed throughout the environment. Increased concentrations through occupational exposure (mainly through inhalation) are considered significant and likely toxic if sCo N 5 ng/mL. Efforts of the World Health Organization's International Agency for Research on Cancer have focused on the effects of Co exposure through inhalation [9], ingestion [10], and through surgical implants and other foreign bodies [1]. Interstitial lung disease has been attributed to chronic inhalation of Co metal dust mixed with tungsten carbide particles, but not Co alone. The toxicity of Co (cobaltism)
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has mainly been documented in patients with inhalation exposure in the hard-metal alloy smelting industry [11]. In the mid 1960s acute and sudden dilated cardiomyopathy was described in a population of Canadian beer drinkers exposed to a brand of beer containing excessive cobalt chloride added as a foam stabilizer. While the deaths of these individuals were multi-causal in origin, cardiomyopathy, distinct from alcoholic cardiomyopathy, was found to be a major factor in the cause of death [12–16]. Epidemiological studies showed that after banning the Co additive, this form of Beer Drinkers' Cardiomyopathy disappeared [17,18]. While it was possible to reproduce similar acute cardiomyopathy in animal studies with excessive amounts of Co compounds [19–21], a combination of excessive Co intake and low protein diet was required. A major limitation to these findings was that no blood or urine Co concentrations were assessed to directly link cardiomyopathy to the Co beer additives. However, there was documentation at autopsy that hearts of those identified as having this Co-mediated cardiomyopathy contained ten times the amount of Co found in non-affected individuals [15]. The majority of the affected subjects also had elevated hemoglobin, hematocrit, and ERY counts which were interpreted as a result of Costimulated erythropoiesis. Increased erythropoiesis is a well-known effect of Co exposure [11,22]. Stimulation of erythropoiesis by administration of Co salts has been reported as a successful treatment for anemia [23]. Cobalt chloride can induce erythropoiesis in pregnant women, infants, and those with chronic anemia resulting from long-standing hemodialysis [24,25]. While excessive wear of implants is known to significantly increase sCo, little is known as to the long-term implications and potential for Co toxicity. We performed a retrospective study of concurrent sCo and ERY to investigate the erythropoietic effects of elevated sCo concentrations resulting from metal-containing THA, in an effort to better understand the potential for implant-induced Co toxicity. Methods This study was approved by the Mayo Clinic Institutional Review Board in Rochester, Minnesota. Retrospective data analysis was performed to determine the potential correlation between sCo concentrations and concurrent ERY. The electronic medical record (EMR) was reviewed between November 2009 and 2011 for patients who had sCo and ERY clinically ordered and resulted. Using the ELAN Dynamic Reaction Cell (DRC) II Inductively Coupled Plasma Mass Spectrometer (ICP-MS) (Perkin-Elmer, Waltham, MA), sCo was quantified in the Metals Laboratory at Mayo Clinic, Rochester. Blood was collected using metal-free collection technique [26] into royal bluetop Monoject trace element blood collection tubes (Covidien, Mansfield, MA) [27,28]. Due to an unacceptable method imprecision observed in whole blood during method validation (data not shown), this test is only performed in serum samples. Serum was separated from blood by centrifugation after the specimen was allowed to clot for 30 min, then serum was poured into a metal free tube for storage. Serum, calibration standards, controls (Utak, Valencia, CA) and blanks were then diluted with aqueous acidic diluent containing internal standards comprised of 50 μg/mL rhodium and gallium in 2% HNO3 and trace HCl. Calibration standards and controls were prepared in charcoal-stripped plasma, incorporating matrix-matched standard and QC materials. These specimens are aerosolized by a pneumatic high-pressure nebulizer driven by argon gas and directed into a high temperature (6800 K) argon gas plasma and subsequently quantified using a quadrupole mass spectrometer. The parent ion is monitored at 58.9332 amu and a calcium oxide (43Ca16O) correction is performed as it is an isobaric interference in the concentration determination for 59Co. As described above, the normal range for patients without metal containing implants is b1.0 ng/mL when collected using metal-free phlebotomy products. Concurrent sCo and ERY testing was defined as occurring in the same patient within 14 days of each other. The medical record was examined
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for each patient included in the study, to determine if they had received a transfusion 14 days prior to the concurrent ERY and sCo measurement. This was thought to likely complicate the potential sCo-derived erythropoiesis and these patients were excluded from the study. Concurrent ERY were derived from clinically ordered complete blood count (CBC) with or without white blood cell differential. These analyses were performed either in the Hospital Laboratory (XT-2000i/XT-1800i) or Central Clinical Laboratory (XE5000) of Mayo Clinic, using the Sysmex Hematology Analyzers (Sysmex America Inc., Linconshire, IL). With this instrumentation, the ERY was measured using a DC detection method coupled with hydrodynamic focusing. The normal reference range for patients N16 years old is 4.32–5.72 and 3.90–5.03 × 1012/L for males and females, respectively. Statistical analysis was performed to determine the significance of difference between the means of ERY (×1012/L) measured in patients with clinically relevant concentration ranges of sCo concentrations (b1.0, 1.0–3.9, 4.0–10.0, and N10 ng/mL). Results of ERY were presented as means and ranges with the number of measurements (n) comprising each group of sCo concentrations. Student's t-test was used to determine the two-tailed p-value for each population of sCo concentrations where a p-value b0.05 would be considered significantly different.
Results All test orders for sCo (n = 132) obtained from patients who were undergoing care at Mayo Clinic during the period of November 2009 to November 2011 were identified as the subjects for this study. Of these, 110 unique clinic patients were identified, and within that group, 77 patients had clinically ordered concurrent ERY without record of preceding RBC transfusion within 14 days. The male to female ratio of this population was 1.03 with an average age of 59 years, ranging from 30 to 77 years. For the entire population reviewed, independent of the indication for testing, sCo concentrations ranged from 0.2 to 108 ng/mL with a mean of 7.4 ng/mL, and ERY ranged from 2.9 to 6.4 × 1012/L. All EMRs were systematically reviewed for patients with sCo concentrations N 4.0 ng/mL, and fifty eight (98%) of these patients presented to Mayo Clinic for THA revision. In this group, the average sCo concentration was 14.6 ng/mL and the median value was 8.0 ng/mL. For comparative purposes, ERY (×1012/L) were grouped by sCo into concentration ranges of b1.0, 1.0–3.9, 4.0–10.0, and N 10 ng/mL. The means, standard deviations (SD), and ranges of ERY are shown for each group of sCo concentrations (Table 1). The calculated p-values are shown for the ERY between each sCo group (A-D) where significant difference was not observed between any of the sCo groups (p N 0.05). These data are represented graphically in Fig. 2, where the pairs of ERY and sCo concentrations are plotted by groups of sCo ranges along with quartile box plots and select p-values obtained from the Student's t-tests.
Table 1 Concurrent erythrocyte counts for patients with serum Co testing performed. Serum Co concentrations (ng/mL) Erythrocyte Counts (×1012/L)
Group A b1.0
Group B 1.0–3.9
Group C 4.0–10.0
Group D N10.0
Mean (SD) Data range Interquartile range n A,B p = 0.3249 A,C p = 0.6125 A,D p = 0.4106
4.5 (0.7) 3.4–6.4 3.89–4.8 20 B,C p = 0.5752 B,D p = 1.0000 C,D p = 0.6340
4.3 (0.6) 2. 9–5.1 3.66–4.66 22
4.4 (0.6) 2.9–5.3 4.01–4.84 24
4.3 (0.5) 3.2–4.9 4.06–4.66 11
Case report—detailed findings Detailed review of the EMR for the patient presented in this case report revealed that her past medical history was remarkable for two conditions: 1) Right vertebral malformation was found ten years prior, requiring continued treatment of her hypertension with an ACE inhibitor. This was thought to be the cause of a vascular episode that included significant nystagmus, vertigo and dysesthesias; these symptoms had completely resolved prior to the current visit. At the time of her evaluation just prior to THA revision she denied angina, dyspnea, or other symptoms of congestive heart failure or cardiomyopathy. She had regular heart rate and rhythm without murmurs, rubs, or gallops. An ECG was performed and was unremarkable, aside from low anterior forces. 2) Fifteen years prior, the patient was diagnosed with estrogen and progesterone receptor positive breast cancer. Following total mastectomy and radiation therapy at that time, she has remained without evidence of recurrence with continued Tamoxifen therapy. Posterior, anterior and lateral chest radiography was subsequently negative. During her multisystem evaluation, there was no mention of neurological complications in her EMR. The patient denied tobacco use and significant consumption of alcohol. Colon cancer screening, including proctoscopic exam and colon radiography, was performed and was unremarkable. Aside from infrequent irregularity, she had no symptoms of gastrointestinal complications and her fecal hemoglobin was 0.4 mg Hb/g and within the reference interval (0–2 mg Hb/g). She had no sign of renal failure; her serum creatinine was 0.6 mg/dL, within the reference interval (0.6–1.1 mg/dL) and a normal eGFR N 60 mL/min/1.73 m2. She did not present with any signs of hypothyroidism, and while her total and free thyroxine were not measured, her sensitive thyroidstimulating hormone was 0.88 mIU/L, which was within the normal range (0.30–5.0 mIU/L). She had no indication of increased erythropoiesis as her hemoglobin was 14.5 g/dL (12.0–15.5 g/dL), ERY 4.2 × 1012/L (3.90–5.03 × 1012/L), and ferritin 53 μg/L (20–200 μg/L) were all within the reference intervals (parentheses). Despite her unremarkable clinical presentation, her sCo and sCr were 84 and 101 ng/mL, respectively. Conclusions and discussion Prevalence of implant failure and ARMD including pseudotumor formation in patients who had THA with a Depuy Articular Surface Replacement (ASR) MoM acetabular cup and femoral head implant, resulted in FDA recall of these devices in 2010. These events caused a surge of publicity that in time propagated misconceptions surrounding metallosis and ARMD. These misconceptions were based on limited knowledge regarding the possibility of particle dissolution-derived serum metal toxicity. On histological examination of tissues from patients with hypersensitivity reactions to MoM THA, diffuse and perivascular infiltrates composed of T and B lymphocytes and plasma cells are evident along with a large degree of fibrin exudation, accumulation of macrophages, eosinophilic granulocytes and overall periprosthetic necrosis in and around the prosthetic space [29]. Histological review of necrotic granulomatous pseudotumors has been suggestive of a delayed-type IV immune response to MoM implant alloy components [30]. Similar to the hypersensitivity reaction without metallosis, a diffuse lymphocyte and variable plasma cell infiltrate can be found within these pseudotumors comprised predominately of macrophages, granulomas containing macrophages, and giant cells with extensive coagulative necrosis. Lymphoproliferative responses to Ni (but not Co or Cr) have been documented, but without a significant difference in response between patients with and without pseudotumors no direct association was found between the etiology of this reaction and ARMD [31]. MoM wear debris is typically b 50 nm in size [32], smaller than the polyethylene particles released from MoP (metal-on-polyethylene)
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Fig. 2. Relationship between erythrocyte counts and serum cobalt concentrations. Concurrent erythrocyte counts (×1012/L) for patients with serum Co concentrations within groups b1.0, 1.0–3.9, 4.0–10.0, N10.0 ng/mL, where the population grand mean is 4.27 ng/mL. Here, erythrocyte counts are not statistically different between any of the serum concentration ranges, indicating the lack of increased erythropoiesis as a function of serum Co.
implants, typically 200–800 nm, that elicit macrophage activation [33, 34]. Studies have shown that these particles are similar in size to bacteria and result in a host-defense mechanism. The response of macrophages to eliminate wear debris and their release of inflammatory mediators propagate the inflammatory response, leading to ulceration and eventual localized tissue necrosis. This reaction, involving a series of complex biological interactions between macrophages, osteoclasts and osteoblast is thought to result in the osteolysis of bone surrounding the MoP implants [29]. Limited studies have also suggested the involvement of Cr and Co particles in bone resorption [35,36]. The differences in physical and chemical characteristics of THA implant wear debris and how they may contribute to solid-state carcinogenesis [1,34] is beyond the scope of this report. While excessive wear resulting in peri-prosthetic particle accumulation can result in ARMD and elevated sCo, other pathological consequences such as Comediated DNA damage must be investigated in large epidemiological studies. The absence of well-documented increased rates of malignancies in peri-prosthetic tissues, where there is the highest number of implant wear particles, suggests that the impact on carcinogenesis is likely insignificant [29]. Most patients with THA MoM orthopedic implants have elevated sCo and sCr compared to unexposed individuals. The extent to which sCo and sCr are elevated correlates with the degree of implant wear [3]. Investigations have shown that in the case of Cr, correlation cannot be made between clinical findings associated with occupational exposure and those of orthopedic implants because of the difference of the in vivo chemical speciation, Cr6+ versus Cr3+ respectively [29]. Inhaled Cr6+ resulting from Cr electrolysis causes oxidative damage to pulmonary epithelium; in this process, Cr6+ is rapidly converted to Cr3+, a non-toxic form of Cr. Since there is no electrolytic process occurring in orthopedic implants, no Cr6+ is formed, so no toxicity would be anticipated. While Co is not highly toxic, high concentrations resulting from inhalation or ingestion can induce negative clinical manifestations [11, 37,38]. In the setting of chronic inhalation exposure, the associated findings include interstitial lung disease, pulmonary syndrome, skin irritation, allergy, gastrointestinal irritations, nausea, cardiomyopathy, hematological disorders, and thyroid abnormalities. Acutely, these include pulmonary edema, allergy, nausea, vomiting, hemorrhage and renal failure.
A limited number of case reports have suggested a correlation between elevated sCo concentrations in THA MoM patients and nonspecific neurological symptoms including fatigue, ataxia, and decline in cognitive dysfunction [39–43]. Unfortunately, many of these observations were subjective; these symptoms could be due to the pain associated with failed THA, and not due to elevated sCo concentrations alone. These studies detail the clinical manifestations of THA-induced Co toxicity where sCo were all N 400 ng/mL and could in fact indicate a threshold for implant-derived cobaltism. We realize that the sCo for the patient presented here was much less than the concentrations found in these few number of case reports. However, our clinical experience suggests that THA MoM patients with sCo this high are extremely rare. While Mayo Clinic is a major referral center for THA revision, in our years of experience, we have not seen sCo results N200 ng/mL. Studies suggest that Co-mediated oxidative stress may play a role in the pathological findings of patients exposed to or ingesting excessive amounts of Co [11,44,45]. While environmental or occupational exposure will result in sCo typically less than those found with implant wear, the degree of sCo elevation and route of exposure may be a discriminating factor in the evolution of toxicity. It may be possible that at the extreme, sCo N400 ng/mL could result in a number of pathologies distinctly different from those observed through inhalation or ingestion. In the endemic cardiomyopathy documented in the Canadian beer drinkers' episode, affected individuals presented with symptoms quite different from these implant-derived, suspected Co toxicity case reports [46]. Animal studies recreating this type of cardiomyopathy, distinctly different from alcoholic cardiomyopathy, required the administration of excessively large doses of cobalt salts [19,20]. Most of the subjects in the Canadian beer drinkers' event had increased erythropoiesis, documented through elevated hemoglobin, hematocrit, and ERY. While sCo concentrations were not documented along with the extensive pathological review, these measures of polycythemia were interpreted as a result of increased Co exposure. The ERY for all 77 paired sCo concentrations studied here span a large range (2.9–6.4 × 1012/L) and highlight the lack of significant difference between the patients with sCo concentrations within the normal range (b 1.0 ng/mL) and those that were elevated. Of the entire population studied, only two patients had slightly elevated ERY, both males, at 5.78 and 6.37 × 1012/L. Their sCo concentrations were well
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within the normal range at 0.2 and 0.3 ng/mL, respectively. These particular patients had not undergone THA and the ERY elevations were due to other unrelated causes. Further analysis of patients who received transfusion within 120 days of the ERY (based on the average lifespan of the RBC), identified an additional four patients not previously excluded. Exclusion of these additional data points did not alter the findings of our study, but more stringently controlled for the potential of artifactually influenced ERY or erythropoiesis as a result of transfusion. The results of this study indicate that patients with THA and sCo in the range 4–108 ng/mL do not have Co-associated erythropoiesis, a finding similar to that of a literature review of all modes of increased serum Co [22]. This suggests against Co-meditated toxicity; however, the question of how high is too high, remains for these THA patients. Although difficult, further studies are needed to determine if the metal ions released by metal particles from MoM implants, estimated to be on the order of more than 1.0 × 1010 particles per day [32], can elevate sCo to a level where Co toxicity could result. The currently limited number of case reports and overall lack of investigations showing consistent toxic presentations of patients with implant-derived elevated sCo suggest little to no toxic impact in the majority of THA MoM patients. References [1] International Agency for Research on Cancer. Surgical implants and other foreign bodies. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, 74; 1999. [2] Clarke MT, Lee PT, Arora A, Villar RN. Levels of metal ions after small- and largediameter metal-on-metal hip arthroplasty. J Bone Joint Surg Br 2003;85:913–7. [3] De Smet K, De Haan R, Calistri A, Campbell PA, Ebramzadeh E, Pattyn C, et al. Metal ion measurement as a diagnostic tool to identify problems with metal-on-metal hip resurfacing. J Bone Joint Surg Am 2008;90(Suppl. 4):202–8. http://dx.doi.org/10. 2106/jbjs.h.00672. [4] Jacobs JJ, Skipor AK, Patterson LM, Hallab NJ, Paprosky WG, Black J, et al. Metal release in patients who have had a primary total hip arthroplasty. A prospective, controlled, longitudinal study. J Bone Joint Surg Am 1998;80:1447–58. [5] Lhotka C, Szekeres T, Steffan I, Zhuber K, Zweymuller K. Four-year study of cobalt and chromium blood levels in patients managed with two different metal-on-metal total hip replacements. J Orthop Res 2003;21:189–95. http://dx.doi.org/10.1016/s07360266(02)00152-3. [6] Liu TK, Liu SH, Chang CH, Yang RS. Concentration of metal elements in the blood and urine in the patients with cementless total knee arthroplasty. Tohoku J Exp Med 1998;185:253–62. [7] Estey MP, Diamandis EP, Van Der Straeten C, Tower SS, Hart AJ, Moyer TP, et al. Cobalt and chromium measurement in patients with metal hip prostheses. Clin Chem 2013;59:880–6. http://dx.doi.org/10.1373/clinchem.2012.193037. [8] De Haan R, Pattyn C, Gill HS, Murray DW, Campbell PA, De Smet K, et al. Correlation between inclination of the acetabular component and metal ion levels in metal-onmetal hip resurfacing replacement. J Bone Joint Surg Br 2008;90:1291–7. http://dx. doi.org/10.1302/0301-620x.90b10.20533. [9] International Agency for Research on Cancer. Cobalt in hard metals and cobalt sulfate, gallium arsenide, indium phosphide and vanadium pentoxide. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, 86; 2006. [10] International Agency for Research on Cancer. Chlorinated drinking-water, chlorination by-products, some other halogenated compounds, cobalt and cobalt compounds. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, 52; 1991. [11] Lison D. Handbook on the toxicology of metals. 3 ed. Amsterdam: Elsevier; 2007 511–28. [12] Alexander CS. Cobalt and the heart. Ann Intern Med 1969;70:411–3. http://dx.doi. org/10.7326/0003-4819-70-2-411. [13] Auger C, Chenard J, Bonenfant JL, Miller G, Roy PE, Morin YL, et al. Quebec beerdrinkers' cardiomyopathy. Can Med Assoc J 1967;97. [14] Barborik M, Dusek J. Case report: cardiomyopathy accompanying industrial cobalt exposure. Br Heart J 1972;34:113–6. [15] Kesteloot H, Roelandt J, Williams J, Claes J, Joossens J. An enquiry into the role of cobalt in the heart disease of chronic beer drinkers. Circulation 1968;37:854–64. http://dx.doi.org/10.1161/01.cir.37.5.854. [16] McDermott PH, Delaney RL, Egan JD, Sullivan JF. Myocardosis and cardiac failure in men. JAMA 1966;198:253–6. http://dx.doi.org/10.1001/jama.1966.03110160081026. [17] Bonow RO, Mann DL, Zipes DP, Libby P. Braunwald's heart disease: a textbook of cardiovascular medicine. 9th ed. Elsevier; 2011. [18] Sullivan J, Parker M, Carson SB. Tissue Co content in beer drinker's myocardiopathy. J Lab Clin Med 1968;71:893–8. [19] Grice HC, Goodman T, Munro IC, Wiberg GS, Morrison AB. Myocardial toxicity of cobalt in the rat. Ann N Y Acad Sci 1969;156:189–94. http://dx.doi.org/10.1111/j. 1749-6632.1969.tb16727.x.
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Clinical Biochemistry journal homepage: www.elsevier.com/locate/clinbiochem
Evidence against implant-derived cobalt toxicity: Case report and retrospective study of serum cobalt concentrations in an orthopedic implant population☆ Nicole V. Tolan a,⁎, Rafael J. Sierra b, Thomas P. Moyer a a b
Department of Laboratory Medicine & Pathology, Mayo Clinic, Rochester, MN, USA Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
a r t i c l e
i n f o
Article history: Received 2 June 2014 Received in revised form 30 September 2014 Accepted 30 October 2014 Available online 8 November 2014 Keywords: Cobalt toxicity Erythropoiesis Orthopedic implant Total hip arthroplasty
a b s t r a c t Objectives: Cobalt (Co) exposure has been documented to result in increased erythropoiesis. To evaluate the potential for implant-derived Co toxicity, we examined the relationship between serum Co (sCo) and erythrocyte counts (ERY) in a metal-containing total-hip arthroplasty implant population. Methods: Retrospective review of sCo concentrations identified 77 patients with concomitant ERY. Statistical analysis was performed to determine if there was a significant difference in ERY for patients divided into clinically relevant sCo ranges. A single detailed case review of a patient with a loose mal-positioned acetabular component and significantly elevated sCo was also performed for symptoms thought to arise from Co toxicity. Results: Statistical difference in ERY was not observed between patients with significantly elevated (N 10 ng/mL), elevated (4–10 ng/mL), modestly elevated (1.0–3.9 ng/mL), or normal (b 1.0 ng/mL) sCo. While the detailed case report was unremarkable for any of the clinical symptoms previously reported to be associated with Co toxicity and no increase in ERY was observed, this patient's sCo was 84 ng/mL. Conclusions: Increased erythropoiesis was not observed in patients with implant-derived increased sCo. Even with a sCo 100× the upper-limit of normal, the patient presented did not have increased ERY nor exhibit any symptoms ascribed with Co toxicity. © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Case report—initial presentation A 60 year old female patient was referred to the Orthopedics Department with a history of left hip pain that had become progressively worse over the previous four weeks. She described her pain as occurring throughout the left groin, buttock and anterior thigh. This pain had quickly progressed, preventing any weight bearing or motion of the hip joint without significant discomfort. Referral was for evaluation and surgical correction of a loose mal-positioned acetabular component of the cementless metal-on-metal (MoM) implant type. Seven years prior, she had the total hip arthroplasty (THA) performed outside the US with a MoM device. The index THA had failed to resolve the preoperative limp and pain that resulted from osteonecrosis of the left hip.
Abbreviations: ARMD, Adverse Reaction to Metal Debris; CBC, Complete Blood Count; EMR, Electronic Medical Record; ERY, Erythrocyte count; MoM, Metal-on-metal; MoP, Metal-on-Polyethylene; sCo, Serum Cobalt; sCr, Serum Chromium; THA, Total Hip Arthroplasty. ☆ Disclosure: The authors have no conflicts of interest to be disclosed. ⁎ Corresponding author at: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue Yamins 309, Boston, MA 02215, USA. Fax: +1 617 667 4533. E-mail address: [email protected] (N.V. Tolan).
Erythrocyte sedimentation rate and C-reactive protein were 4 mm/1 h and 3.6 mg/L respectively; within normal limits. A series of pelvic radiographic images clearly demonstrated a loose malpositioned acetabular component where articulation of the prosthetic femoral head had resulted in a notch-like erosion of the medial prosthetic femoral neck (Fig. 1) and accumulation of peri-prosthetic metallic debris around the defect. An MRI with metal-suppression showed no soft tissue mass to suggest pseudotumor. The patient's serum cobalt (Co) and chromium (Cr) concentrations were 84 ng/mL and 101 ng/mL, respectively. Background and introduction THA is a viable surgical option to relieve the pain and limited joint mobility associated with injury or advanced degenerative disease of the hip. The materials used in metal-containing THA devices are predominately comprised of Co and Cr along with various other metals to a lesser degree, such as nickel (Ni), molybdenum (Mo), manganese (Mn), iron (Fe), titanium (Ti) and tungsten (W) [1]. While the composition of the implant materials was selected for increased strength, durability, and resistance to corrosion, implant wear and misalignment can result in metal particles released into the fluid and tissues surrounding the hip joint. These particles are subject to active corrosion leading to increased circulating metal ions, most notably Co and Cr. Circulating
http://dx.doi.org/10.1016/j.clinbiochem.2014.10.012 0009-9120/© 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
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Fig. 1. Pelvic radiograph of acetabular component rotation. Anterior left hip radiograph showing the pronounced rotation of the cementless acetabular component within the hip socket, resulting in a notch-like erosion of the neck of the prosthetic femoral head. Here it was noted that articulation of the hip resulted advanced wear, resulting in accumulation of periprosthetic metal debris which was visible on MRI with metal suppression.
Co and Cr concentrations in blood serum are proportional to the surface area of the device, duration of the implant, and extent of implant wear [2–7]. The other major factor contributing to serum metal ion concentration is the acetabular cup angle, where angles greater than 55° can result in edge loading as well as increased wear and release of metal debris into the pelvic space surrounding the implant [8]. When blood samples are collected using metal-free blood collection techniques, the unexposed human population displays serum Co concentrations (sCo) and serum Cr concentrations (sCr) of b 1.0 and b0.3 ng/mL, respectively [3]. Patients with metal-containing implants in good condition who report no implant-related pain typically have increased sCo and sCr, ranging from 4.0 to 10 and 0.3 to 0.6 ng/mL, respectively. The sCo may be up to ten times greater than the unexposed reference interval in most of these patients. These concentrations have been demonstrated to increase temporally after implant with initial wear-in of the device that eventually reaches steady state concentrations of 4–10 ng/mL approximately three years post-operative [3,5,6]. The sCo can increase further with significant wear of the acetabular cup and femoral head with articulation of the hip. While sCo N10.0 ng/mL and sCr N1.0 ng/mL are indications of implant wear and possible adverse reaction to metal debris (ARMD, also called metallosis), sCo and sCr concentrations cannot be used as an independent predictor of implant function or be used as a recommendation for THA revision alone. These laboratory findings must be interpreted in clinical context and along with imaging studies. Co is an essential element, as it is a co-factor of vitamin B12 (hydroxycobalamin), and it is widely distributed throughout the environment. Increased concentrations through occupational exposure (mainly through inhalation) are considered significant and likely toxic if sCo N 5 ng/mL. Efforts of the World Health Organization's International Agency for Research on Cancer have focused on the effects of Co exposure through inhalation [9], ingestion [10], and through surgical implants and other foreign bodies [1]. Interstitial lung disease has been attributed to chronic inhalation of Co metal dust mixed with tungsten carbide particles, but not Co alone. The toxicity of Co (cobaltism)
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has mainly been documented in patients with inhalation exposure in the hard-metal alloy smelting industry [11]. In the mid 1960s acute and sudden dilated cardiomyopathy was described in a population of Canadian beer drinkers exposed to a brand of beer containing excessive cobalt chloride added as a foam stabilizer. While the deaths of these individuals were multi-causal in origin, cardiomyopathy, distinct from alcoholic cardiomyopathy, was found to be a major factor in the cause of death [12–16]. Epidemiological studies showed that after banning the Co additive, this form of Beer Drinkers' Cardiomyopathy disappeared [17,18]. While it was possible to reproduce similar acute cardiomyopathy in animal studies with excessive amounts of Co compounds [19–21], a combination of excessive Co intake and low protein diet was required. A major limitation to these findings was that no blood or urine Co concentrations were assessed to directly link cardiomyopathy to the Co beer additives. However, there was documentation at autopsy that hearts of those identified as having this Co-mediated cardiomyopathy contained ten times the amount of Co found in non-affected individuals [15]. The majority of the affected subjects also had elevated hemoglobin, hematocrit, and ERY counts which were interpreted as a result of Costimulated erythropoiesis. Increased erythropoiesis is a well-known effect of Co exposure [11,22]. Stimulation of erythropoiesis by administration of Co salts has been reported as a successful treatment for anemia [23]. Cobalt chloride can induce erythropoiesis in pregnant women, infants, and those with chronic anemia resulting from long-standing hemodialysis [24,25]. While excessive wear of implants is known to significantly increase sCo, little is known as to the long-term implications and potential for Co toxicity. We performed a retrospective study of concurrent sCo and ERY to investigate the erythropoietic effects of elevated sCo concentrations resulting from metal-containing THA, in an effort to better understand the potential for implant-induced Co toxicity. Methods This study was approved by the Mayo Clinic Institutional Review Board in Rochester, Minnesota. Retrospective data analysis was performed to determine the potential correlation between sCo concentrations and concurrent ERY. The electronic medical record (EMR) was reviewed between November 2009 and 2011 for patients who had sCo and ERY clinically ordered and resulted. Using the ELAN Dynamic Reaction Cell (DRC) II Inductively Coupled Plasma Mass Spectrometer (ICP-MS) (Perkin-Elmer, Waltham, MA), sCo was quantified in the Metals Laboratory at Mayo Clinic, Rochester. Blood was collected using metal-free collection technique [26] into royal bluetop Monoject trace element blood collection tubes (Covidien, Mansfield, MA) [27,28]. Due to an unacceptable method imprecision observed in whole blood during method validation (data not shown), this test is only performed in serum samples. Serum was separated from blood by centrifugation after the specimen was allowed to clot for 30 min, then serum was poured into a metal free tube for storage. Serum, calibration standards, controls (Utak, Valencia, CA) and blanks were then diluted with aqueous acidic diluent containing internal standards comprised of 50 μg/mL rhodium and gallium in 2% HNO3 and trace HCl. Calibration standards and controls were prepared in charcoal-stripped plasma, incorporating matrix-matched standard and QC materials. These specimens are aerosolized by a pneumatic high-pressure nebulizer driven by argon gas and directed into a high temperature (6800 K) argon gas plasma and subsequently quantified using a quadrupole mass spectrometer. The parent ion is monitored at 58.9332 amu and a calcium oxide (43Ca16O) correction is performed as it is an isobaric interference in the concentration determination for 59Co. As described above, the normal range for patients without metal containing implants is b1.0 ng/mL when collected using metal-free phlebotomy products. Concurrent sCo and ERY testing was defined as occurring in the same patient within 14 days of each other. The medical record was examined
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for each patient included in the study, to determine if they had received a transfusion 14 days prior to the concurrent ERY and sCo measurement. This was thought to likely complicate the potential sCo-derived erythropoiesis and these patients were excluded from the study. Concurrent ERY were derived from clinically ordered complete blood count (CBC) with or without white blood cell differential. These analyses were performed either in the Hospital Laboratory (XT-2000i/XT-1800i) or Central Clinical Laboratory (XE5000) of Mayo Clinic, using the Sysmex Hematology Analyzers (Sysmex America Inc., Linconshire, IL). With this instrumentation, the ERY was measured using a DC detection method coupled with hydrodynamic focusing. The normal reference range for patients N16 years old is 4.32–5.72 and 3.90–5.03 × 1012/L for males and females, respectively. Statistical analysis was performed to determine the significance of difference between the means of ERY (×1012/L) measured in patients with clinically relevant concentration ranges of sCo concentrations (b1.0, 1.0–3.9, 4.0–10.0, and N10 ng/mL). Results of ERY were presented as means and ranges with the number of measurements (n) comprising each group of sCo concentrations. Student's t-test was used to determine the two-tailed p-value for each population of sCo concentrations where a p-value b0.05 would be considered significantly different.
Results All test orders for sCo (n = 132) obtained from patients who were undergoing care at Mayo Clinic during the period of November 2009 to November 2011 were identified as the subjects for this study. Of these, 110 unique clinic patients were identified, and within that group, 77 patients had clinically ordered concurrent ERY without record of preceding RBC transfusion within 14 days. The male to female ratio of this population was 1.03 with an average age of 59 years, ranging from 30 to 77 years. For the entire population reviewed, independent of the indication for testing, sCo concentrations ranged from 0.2 to 108 ng/mL with a mean of 7.4 ng/mL, and ERY ranged from 2.9 to 6.4 × 1012/L. All EMRs were systematically reviewed for patients with sCo concentrations N 4.0 ng/mL, and fifty eight (98%) of these patients presented to Mayo Clinic for THA revision. In this group, the average sCo concentration was 14.6 ng/mL and the median value was 8.0 ng/mL. For comparative purposes, ERY (×1012/L) were grouped by sCo into concentration ranges of b1.0, 1.0–3.9, 4.0–10.0, and N 10 ng/mL. The means, standard deviations (SD), and ranges of ERY are shown for each group of sCo concentrations (Table 1). The calculated p-values are shown for the ERY between each sCo group (A-D) where significant difference was not observed between any of the sCo groups (p N 0.05). These data are represented graphically in Fig. 2, where the pairs of ERY and sCo concentrations are plotted by groups of sCo ranges along with quartile box plots and select p-values obtained from the Student's t-tests.
Table 1 Concurrent erythrocyte counts for patients with serum Co testing performed. Serum Co concentrations (ng/mL) Erythrocyte Counts (×1012/L)
Group A b1.0
Group B 1.0–3.9
Group C 4.0–10.0
Group D N10.0
Mean (SD) Data range Interquartile range n A,B p = 0.3249 A,C p = 0.6125 A,D p = 0.4106
4.5 (0.7) 3.4–6.4 3.89–4.8 20 B,C p = 0.5752 B,D p = 1.0000 C,D p = 0.6340
4.3 (0.6) 2. 9–5.1 3.66–4.66 22
4.4 (0.6) 2.9–5.3 4.01–4.84 24
4.3 (0.5) 3.2–4.9 4.06–4.66 11
Case report—detailed findings Detailed review of the EMR for the patient presented in this case report revealed that her past medical history was remarkable for two conditions: 1) Right vertebral malformation was found ten years prior, requiring continued treatment of her hypertension with an ACE inhibitor. This was thought to be the cause of a vascular episode that included significant nystagmus, vertigo and dysesthesias; these symptoms had completely resolved prior to the current visit. At the time of her evaluation just prior to THA revision she denied angina, dyspnea, or other symptoms of congestive heart failure or cardiomyopathy. She had regular heart rate and rhythm without murmurs, rubs, or gallops. An ECG was performed and was unremarkable, aside from low anterior forces. 2) Fifteen years prior, the patient was diagnosed with estrogen and progesterone receptor positive breast cancer. Following total mastectomy and radiation therapy at that time, she has remained without evidence of recurrence with continued Tamoxifen therapy. Posterior, anterior and lateral chest radiography was subsequently negative. During her multisystem evaluation, there was no mention of neurological complications in her EMR. The patient denied tobacco use and significant consumption of alcohol. Colon cancer screening, including proctoscopic exam and colon radiography, was performed and was unremarkable. Aside from infrequent irregularity, she had no symptoms of gastrointestinal complications and her fecal hemoglobin was 0.4 mg Hb/g and within the reference interval (0–2 mg Hb/g). She had no sign of renal failure; her serum creatinine was 0.6 mg/dL, within the reference interval (0.6–1.1 mg/dL) and a normal eGFR N 60 mL/min/1.73 m2. She did not present with any signs of hypothyroidism, and while her total and free thyroxine were not measured, her sensitive thyroidstimulating hormone was 0.88 mIU/L, which was within the normal range (0.30–5.0 mIU/L). She had no indication of increased erythropoiesis as her hemoglobin was 14.5 g/dL (12.0–15.5 g/dL), ERY 4.2 × 1012/L (3.90–5.03 × 1012/L), and ferritin 53 μg/L (20–200 μg/L) were all within the reference intervals (parentheses). Despite her unremarkable clinical presentation, her sCo and sCr were 84 and 101 ng/mL, respectively. Conclusions and discussion Prevalence of implant failure and ARMD including pseudotumor formation in patients who had THA with a Depuy Articular Surface Replacement (ASR) MoM acetabular cup and femoral head implant, resulted in FDA recall of these devices in 2010. These events caused a surge of publicity that in time propagated misconceptions surrounding metallosis and ARMD. These misconceptions were based on limited knowledge regarding the possibility of particle dissolution-derived serum metal toxicity. On histological examination of tissues from patients with hypersensitivity reactions to MoM THA, diffuse and perivascular infiltrates composed of T and B lymphocytes and plasma cells are evident along with a large degree of fibrin exudation, accumulation of macrophages, eosinophilic granulocytes and overall periprosthetic necrosis in and around the prosthetic space [29]. Histological review of necrotic granulomatous pseudotumors has been suggestive of a delayed-type IV immune response to MoM implant alloy components [30]. Similar to the hypersensitivity reaction without metallosis, a diffuse lymphocyte and variable plasma cell infiltrate can be found within these pseudotumors comprised predominately of macrophages, granulomas containing macrophages, and giant cells with extensive coagulative necrosis. Lymphoproliferative responses to Ni (but not Co or Cr) have been documented, but without a significant difference in response between patients with and without pseudotumors no direct association was found between the etiology of this reaction and ARMD [31]. MoM wear debris is typically b 50 nm in size [32], smaller than the polyethylene particles released from MoP (metal-on-polyethylene)
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Fig. 2. Relationship between erythrocyte counts and serum cobalt concentrations. Concurrent erythrocyte counts (×1012/L) for patients with serum Co concentrations within groups b1.0, 1.0–3.9, 4.0–10.0, N10.0 ng/mL, where the population grand mean is 4.27 ng/mL. Here, erythrocyte counts are not statistically different between any of the serum concentration ranges, indicating the lack of increased erythropoiesis as a function of serum Co.
implants, typically 200–800 nm, that elicit macrophage activation [33, 34]. Studies have shown that these particles are similar in size to bacteria and result in a host-defense mechanism. The response of macrophages to eliminate wear debris and their release of inflammatory mediators propagate the inflammatory response, leading to ulceration and eventual localized tissue necrosis. This reaction, involving a series of complex biological interactions between macrophages, osteoclasts and osteoblast is thought to result in the osteolysis of bone surrounding the MoP implants [29]. Limited studies have also suggested the involvement of Cr and Co particles in bone resorption [35,36]. The differences in physical and chemical characteristics of THA implant wear debris and how they may contribute to solid-state carcinogenesis [1,34] is beyond the scope of this report. While excessive wear resulting in peri-prosthetic particle accumulation can result in ARMD and elevated sCo, other pathological consequences such as Comediated DNA damage must be investigated in large epidemiological studies. The absence of well-documented increased rates of malignancies in peri-prosthetic tissues, where there is the highest number of implant wear particles, suggests that the impact on carcinogenesis is likely insignificant [29]. Most patients with THA MoM orthopedic implants have elevated sCo and sCr compared to unexposed individuals. The extent to which sCo and sCr are elevated correlates with the degree of implant wear [3]. Investigations have shown that in the case of Cr, correlation cannot be made between clinical findings associated with occupational exposure and those of orthopedic implants because of the difference of the in vivo chemical speciation, Cr6+ versus Cr3+ respectively [29]. Inhaled Cr6+ resulting from Cr electrolysis causes oxidative damage to pulmonary epithelium; in this process, Cr6+ is rapidly converted to Cr3+, a non-toxic form of Cr. Since there is no electrolytic process occurring in orthopedic implants, no Cr6+ is formed, so no toxicity would be anticipated. While Co is not highly toxic, high concentrations resulting from inhalation or ingestion can induce negative clinical manifestations [11, 37,38]. In the setting of chronic inhalation exposure, the associated findings include interstitial lung disease, pulmonary syndrome, skin irritation, allergy, gastrointestinal irritations, nausea, cardiomyopathy, hematological disorders, and thyroid abnormalities. Acutely, these include pulmonary edema, allergy, nausea, vomiting, hemorrhage and renal failure.
A limited number of case reports have suggested a correlation between elevated sCo concentrations in THA MoM patients and nonspecific neurological symptoms including fatigue, ataxia, and decline in cognitive dysfunction [39–43]. Unfortunately, many of these observations were subjective; these symptoms could be due to the pain associated with failed THA, and not due to elevated sCo concentrations alone. These studies detail the clinical manifestations of THA-induced Co toxicity where sCo were all N 400 ng/mL and could in fact indicate a threshold for implant-derived cobaltism. We realize that the sCo for the patient presented here was much less than the concentrations found in these few number of case reports. However, our clinical experience suggests that THA MoM patients with sCo this high are extremely rare. While Mayo Clinic is a major referral center for THA revision, in our years of experience, we have not seen sCo results N200 ng/mL. Studies suggest that Co-mediated oxidative stress may play a role in the pathological findings of patients exposed to or ingesting excessive amounts of Co [11,44,45]. While environmental or occupational exposure will result in sCo typically less than those found with implant wear, the degree of sCo elevation and route of exposure may be a discriminating factor in the evolution of toxicity. It may be possible that at the extreme, sCo N400 ng/mL could result in a number of pathologies distinctly different from those observed through inhalation or ingestion. In the endemic cardiomyopathy documented in the Canadian beer drinkers' episode, affected individuals presented with symptoms quite different from these implant-derived, suspected Co toxicity case reports [46]. Animal studies recreating this type of cardiomyopathy, distinctly different from alcoholic cardiomyopathy, required the administration of excessively large doses of cobalt salts [19,20]. Most of the subjects in the Canadian beer drinkers' event had increased erythropoiesis, documented through elevated hemoglobin, hematocrit, and ERY. While sCo concentrations were not documented along with the extensive pathological review, these measures of polycythemia were interpreted as a result of increased Co exposure. The ERY for all 77 paired sCo concentrations studied here span a large range (2.9–6.4 × 1012/L) and highlight the lack of significant difference between the patients with sCo concentrations within the normal range (b 1.0 ng/mL) and those that were elevated. Of the entire population studied, only two patients had slightly elevated ERY, both males, at 5.78 and 6.37 × 1012/L. Their sCo concentrations were well
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within the normal range at 0.2 and 0.3 ng/mL, respectively. These particular patients had not undergone THA and the ERY elevations were due to other unrelated causes. Further analysis of patients who received transfusion within 120 days of the ERY (based on the average lifespan of the RBC), identified an additional four patients not previously excluded. Exclusion of these additional data points did not alter the findings of our study, but more stringently controlled for the potential of artifactually influenced ERY or erythropoiesis as a result of transfusion. The results of this study indicate that patients with THA and sCo in the range 4–108 ng/mL do not have Co-associated erythropoiesis, a finding similar to that of a literature review of all modes of increased serum Co [22]. This suggests against Co-meditated toxicity; however, the question of how high is too high, remains for these THA patients. Although difficult, further studies are needed to determine if the metal ions released by metal particles from MoM implants, estimated to be on the order of more than 1.0 × 1010 particles per day [32], can elevate sCo to a level where Co toxicity could result. The currently limited number of case reports and overall lack of investigations showing consistent toxic presentations of patients with implant-derived elevated sCo suggest little to no toxic impact in the majority of THA MoM patients. References [1] International Agency for Research on Cancer. Surgical implants and other foreign bodies. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, 74; 1999. [2] Clarke MT, Lee PT, Arora A, Villar RN. Levels of metal ions after small- and largediameter metal-on-metal hip arthroplasty. J Bone Joint Surg Br 2003;85:913–7. [3] De Smet K, De Haan R, Calistri A, Campbell PA, Ebramzadeh E, Pattyn C, et al. Metal ion measurement as a diagnostic tool to identify problems with metal-on-metal hip resurfacing. J Bone Joint Surg Am 2008;90(Suppl. 4):202–8. http://dx.doi.org/10. 2106/jbjs.h.00672. [4] Jacobs JJ, Skipor AK, Patterson LM, Hallab NJ, Paprosky WG, Black J, et al. Metal release in patients who have had a primary total hip arthroplasty. A prospective, controlled, longitudinal study. J Bone Joint Surg Am 1998;80:1447–58. [5] Lhotka C, Szekeres T, Steffan I, Zhuber K, Zweymuller K. Four-year study of cobalt and chromium blood levels in patients managed with two different metal-on-metal total hip replacements. J Orthop Res 2003;21:189–95. http://dx.doi.org/10.1016/s07360266(02)00152-3. [6] Liu TK, Liu SH, Chang CH, Yang RS. Concentration of metal elements in the blood and urine in the patients with cementless total knee arthroplasty. Tohoku J Exp Med 1998;185:253–62. [7] Estey MP, Diamandis EP, Van Der Straeten C, Tower SS, Hart AJ, Moyer TP, et al. Cobalt and chromium measurement in patients with metal hip prostheses. Clin Chem 2013;59:880–6. http://dx.doi.org/10.1373/clinchem.2012.193037. [8] De Haan R, Pattyn C, Gill HS, Murray DW, Campbell PA, De Smet K, et al. Correlation between inclination of the acetabular component and metal ion levels in metal-onmetal hip resurfacing replacement. J Bone Joint Surg Br 2008;90:1291–7. http://dx. doi.org/10.1302/0301-620x.90b10.20533. [9] International Agency for Research on Cancer. Cobalt in hard metals and cobalt sulfate, gallium arsenide, indium phosphide and vanadium pentoxide. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, 86; 2006. [10] International Agency for Research on Cancer. Chlorinated drinking-water, chlorination by-products, some other halogenated compounds, cobalt and cobalt compounds. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, 52; 1991. [11] Lison D. Handbook on the toxicology of metals. 3 ed. Amsterdam: Elsevier; 2007 511–28. [12] Alexander CS. Cobalt and the heart. Ann Intern Med 1969;70:411–3. http://dx.doi. org/10.7326/0003-4819-70-2-411. [13] Auger C, Chenard J, Bonenfant JL, Miller G, Roy PE, Morin YL, et al. Quebec beerdrinkers' cardiomyopathy. Can Med Assoc J 1967;97. [14] Barborik M, Dusek J. Case report: cardiomyopathy accompanying industrial cobalt exposure. Br Heart J 1972;34:113–6. [15] Kesteloot H, Roelandt J, Williams J, Claes J, Joossens J. An enquiry into the role of cobalt in the heart disease of chronic beer drinkers. Circulation 1968;37:854–64. http://dx.doi.org/10.1161/01.cir.37.5.854. [16] McDermott PH, Delaney RL, Egan JD, Sullivan JF. Myocardosis and cardiac failure in men. JAMA 1966;198:253–6. http://dx.doi.org/10.1001/jama.1966.03110160081026. [17] Bonow RO, Mann DL, Zipes DP, Libby P. Braunwald's heart disease: a textbook of cardiovascular medicine. 9th ed. Elsevier; 2011. [18] Sullivan J, Parker M, Carson SB. Tissue Co content in beer drinker's myocardiopathy. J Lab Clin Med 1968;71:893–8. [19] Grice HC, Goodman T, Munro IC, Wiberg GS, Morrison AB. Myocardial toxicity of cobalt in the rat. Ann N Y Acad Sci 1969;156:189–94. http://dx.doi.org/10.1111/j. 1749-6632.1969.tb16727.x.
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