Systemic Cobalt Toxicity from Total Hip Arthroplasties REVIEW of a RARE CONDITION PART 1 - HISTORY, MECHANISM, MEASUREMENTS, and PATHOPHYSIOLOGY

 SPECIALTY UPDATE Systemic cobalt toxicity from total hip arthroplasties REVIEW OF A RARE CONDITION PART 1 - HISTORY, MECHANISM, MEASUREMENTS, AND PATHOPHYSIOLOGY

A. C. Cheung, Recently, the use of metal-on-metal articulations in total hip arthroplasty (THA) has led to S. Banerjee, an increase in adverse events owing to local soft-tissue reactions from metal ions and wear J. J. Cherian, debris. While the majority of these implants perform well, it has been increasingly F. Wong, recognised that a small proportion of patients may develop complications secondary to J. Butany, systemic cobalt toxicity when these implants fail. However, distinguishing true toxicity from C. Gilbert, benign elevations in cobalt ion levels can be challenging. C. Overgaard, The purpose of this two part series is to review the use of cobalt alloys in THA and to K. Syed, highlight the following related topics of interest: mechanisms of cobalt ion release and their M. G. Zywiel, measurement, definitions of pathological cobalt ion levels, and the pathophysiology, risk J. J. Jacobs, factors and treatment of cobalt toxicity. Historically, these metal-on-metal arthroplasties are M. A. Mont composed of a chromium-cobalt articulation. The release of cobalt is due to the mechanical and oxidative stresses placed on the From Rubin Institute prosthetic joint. It exerts its pathological effects through direct cellular toxicity. for Advanced This manuscript will highlight the pathophysiology of cobalt toxicity in patients with Orthopedics, Sinai metal-on-metal hip arthroplasties. Hospital of Baltimore, Maryland, Take home message: Patients with new or evolving hip symptoms with a prior history of United States THA warrant orthopaedic surgical evaluation. Increased awareness of the range of systemic symptoms associated with cobalt toxicity, coupled with prompt orthopaedic intervention,

 A. C. Cheung, MD FRCP(C), may forestall the development of further complications. Gastroenterologist, Division of Gastroenterology  F. Wong, MD, Gastroenterologist, Cite this article: Bone Joint J 2016;98-B:6–13. Division of Gastroenterology  J. Butany, MD, Pathologist, Division of Pathology  C. Gilbert, MD, Cardiologist, Cobalt is a trace metal element which is essen- Agency (MHRA) published a report which rec- Division of Cardiology  C. Overgaard, MD, Cardiologist, tial for normal cellular metabolism, but at high ommended annual lifetime orthopaedic fol- Division of Cardiology, 1,2 Toronto General Hospital levels may lead to cellular apoptosis, necro- low-up and measurement serum cobalt and University of Toronto, 200 Elizabeth 3-5 5,6 Street, Toronto, Ontario, M5G 2C4, sis, and oxidative DNA damage. Histori- chromium ions, for all patients with MoM Canada. 21  J. J. Jacobs, MD, Orthopaedic cally, cobalt toxicity became a recognised arthroplasties, This was further supported by Surgeon Department of Orthopaedic Surgery clinical problem following industrial exposure, the Scientific Committee on Emerging and Rush University, 1611 W. Harrison St., Suite 400, Chicago, IL60612, as well as iatrogenic toxicity following treatment Newly Identified Heath Risks in September USA. 7-13 22  S. Banerjee, M.S (Orth), MRCS of anaemia with cobalt-chloride tablets. It 2014. The United States Food and Drug (Glasg), Resident Orthopaedic Surgeon has been used in a foam-stabilising agent in the Administration (FDA) also acknowledged the  J. J. Cherian, DO, Resident 14-16 Orthopaedic Surgeon beer industry, which led to an increase in risk of cobalt toxicity and its associated signs  M. A. Mont, MD, Orthopaedic 23 Surgeon, Rubin Institute for low-output cardiomyopathy that resolved and symptoms, in these arthroplasties. How- Advanced Orthopedics, Center for Joint Preservation and when cobalt was removed from the manufac- ever, the FDA has cautioned that currently no Replacement Sinai Hospital of Baltimore, 2401 turing process. standard exists for accurate and reproducible West Belvedere Avenue, Baltimore, Maryland, USA. Recently, there has been increased recogni- measurement of cobalt and suggests further  K. Syed, MD, Orthopaedic Surgeon tion of local and systemic adverse events asso- research. Similarly, the American Association  M. G. Zywiel, MD, Orthopaedic Surgeon, Division of Orthopaedic Surgery ciated with the release of cobalt ions and of Hip and Knee Surgeons and the American University of Toronto, 100 College Street Room 302, Toronto, Ontario, nanoparticles from total hip arthroplasties Association of Orthopaedic Surgeons (AAOS) M5G 1L5, Canada. Correspondence should be sent to (THA). In the last 15 years, the introduction have issued similar advisory statements on Dr M. A. Mont; e-mail: 24,25 [email protected]; and use of large-diameter metal-on-metal metal-related adverse reactions, although [email protected] (MoM) THAs and hip resurfacing arthro- they note that most patients have well-

©2016 The British Editorial Society plasties, has been associated with a rise in functioning implants. In the United States, of Bone & Joint Surgery 17- doi:10.1302/0301-620X.98B1. reports of metal-related local adverse events. MoM articulations were used in approximately 36374 $2.00 20 In June 2012, the United Kingdom's Medi- 35% of hip arthroplasties in 2006, but usage Bone Joint J cines and Healthcare Products Regulatory has since declined rapidly worldwide.26,27 The 2016;98-B:6–13.

6 THE BONE & JOINT JOURNAL SYSTEMIC COBALT TOXICITY FROM TOTAL HIP ARTHROPLASTIES 7 increased level of clinical vigilance has shown that adverse Mechanisms of cobalt ion release events are more common than previously thought,18,19 and Cobalt does not occur in the elemental state in vivo, but, patients may develop, potentially, systemic symptoms.28 This exists as either a bi-valent (2+) or tri-valent (3+) cation that is not limited to only MoM articulations, but also other com- can complex with other extra- or intra-cellular molecules to ponent parts of modular THAs may be implicated.29 form cobalt oxides, organophosphates, and chlorides.4 The development of systemic cobalt toxicity from hip THA ion release ultimately occurs from oxidation- arthroplasty appears to be very rare. Only 18 cases have been reduction reactions with the surrounding environment that reported,28,30-37 ten involving MoM articulations. However, liberate cobalt ions from metal surfaces (i.e. corrosion). it is estimated that one million MoM hip arthroplasties had This can occur on any Co-Cr component surfaces, or been performed in the United States and 60 000 in the United through oxidative particle breakdown generated by Kingdom.38 The large numbers of potential patients at risk, mechanical wear. Metal wear particles are smaller than the coupled with the insidious and varied presentation of cobalt debris generated by other THA materials such as polyethyl- toxicity, suggests that all medical specialties should be aware ene, (measured in nanometres rather than micrometres).47 of the possibility of cobalt toxicity. Because they are similar in size to typical cellular compo- Although a variety of metal ions (e.g. cobalt, vanadium, nents and proteins, nanoparticles may enter the intra-cellu- and chromium) are released from prostheses and have been lar environment more efficiently when compared with implicated in the development of systemic symptoms, this larger debris particles and can directly affect gene transcrip- review will focus on cobalt toxicity.30,39-41 Specifically, in tion, or be involved in direct DNA damage.48,49 Nanopar- this article, we will review the use of cobalt alloys in THA, ticles are likely to have a different cytotoxicity profile than highlighting the following topics: historical context of larger-sized particles.47 cobalt in THA; mechanisms of ion release; and the path- Mechanical wear and the generation of metal particles, ophysiology of toxicity. can occur through contact between the intended bearing surfaces; surfaces contaminated with abrasive debris (third- Historical context of the use of cobalt alloys in hip body wear); two non-bearing surfaces; or one intended and arthroplasty one unintended bearing surface.50 The first three mecha- While modern THA has been used for approximately half a nisms are particularly relevant to understanding abnormal century, the earliest designs were developed in the late 19th cobalt ion release in hip arthroplasty, which is an inevitable century.42 Hip arthroplasties are subjected to considerable consequence in all arthroplasties. and dynamic mechanical loading in a saline environment. Corrosion is an electro-chemical process of oxidation- This requires mechanical and material stability, biocompat- reduction reactions resulting in the release of cobalt and ibility, and long-term wear resistance. Cobalt–chromium other ions from surfaces of cobalt-alloy implants. Like (Co-Cr) alloys were found to have one of the best combina- wear, it is an inevitability in all arthroplasties. Corrosion tions of high material toughness and yield strength (resist- and wear occur simultaneously and may be synergistic giv- ant to breakage and deformation), ductility (deformation ing rise to the term ‘tribocorrosion’.51 Tribocorrosion rather than breakage), hardness, wear and corrosion resist- incorporates both electro-chemical (corrosion) and ance, within the human body, and are highly compatible mechanical (tribological) behaviour of metals used in many with other implant metals.43 engineering applications, including joint arthroplasty. Approximately 350 000 THAs are performed annually in Important tribocorrosion processes leading to significant the United States alone,38 and survivorship > 90% is consist- amounts of debris include fretting corrosion of metal/metal ently reported at 15 to 20 years with established designs.44-46 modular junctions and the degradation of bearing surfaces Owing to the advantageous mechanical and metallurgical in MoM THA and hip resurfacing devices. properties, most contemporary THAs include components Articulation between unintended bearing surfaces can be made of Co-Cr alloys. Stainless steel (another material used in a source of metal particle generation. Virtually all contem- femoral head and femoral component manufacture) continues porary hip arthroplasties are modular, which allows varia- to be used, particularly in Europe. Stainless steel components ble implant choices for patients.52 However, micro-motion contain very little cobalt in comparison, and are not to be con- can sometimes occur at the non-articular interface of the fused with Co-Cr bearings mentioned below. It is important to different components (most commonly the taper junction note that there are a large number of different implant designs of head and neck).53 Micro-motion can initiate events available from a variety of manufacturers. For a single bearing resulting in localised loss of protective surface oxide layers, couple, there can be considerable differences in clinical behav- at the points of contact and movement, with subsequent iour as a consequence of design differences. As a result, while corrosion and cobalt ion release.29,54,55 Recently, large- there may be a ‘class-effect’ defined by the presence of a given diameter femoral heads, as used in certain MoM arthro- material or articular couple (e.g. MoM), large variability plasty designs have shown increased risk of this type of exists in the risk and magnitude of metal ion release between wear.56 Additionally, some THAs, which include additional specific implant designs, the specifics of which will be dis- modular junctions at the neck-stem interfaces, have shown cussed in further detail below. similar increased wear. These non-articulating junctions are

VOL. 98-B, No. 1, JANUARY 2016 8 A. C. CHEUNG, S. BANERJEE, J. J. CHERIAN, F. WONG, J. BUTANY, C. GILBERT, C. OVERGAARD, K. SYED, M. G. ZYWIEL, J. J. JACOBS, M. A. MONT susceptible to micro-motion and associated cobalt ion anaemia or recreational consumption of beer produced using release. This has led to the recall of these designs by manu- a foam-stabilising agent containing cobalt sulphate or cobalt facturers.57 chloride.74,75 Both the atria and the ventricles may be While cobalt ion release occurs in all Co-Cr components, affected.76 Patients with cardiac cobalt toxicity typically pre- systemic ion accumulation is limited by renal excretion, sent with shortness of breath, palpitations, and exertional which regulates homeostasis between ion generation and chest tightness, often leading to low-output, dilated cardio- loss.58-60 myopathy. The cardiomyopathy may induce atrial fibrilla- Abnormal wear and/or corrosion of a Co-Cr component tion or be complicated by pericardial effusion. through any mechanism can result in ongoing metal wear The exact pathophysiological mechanism of cobalt car- particles and/or cobalt ion generation. Wear particles col- diotoxicity remains unknown. One theory proposes that lect peri-articularly, and can be disseminated widely in the cobalt interferes with cardiac myocyte uptake of oxygen body through the bloodstream and the lymphatic system.61 through inhibition of alpha-lipoic acid sulfhydryl groups in The highly acidic environment of intra-cellular phagosomes the citric acid cycle, and transmembrane transport system may actually promote intra-cellular corrosion of phagocy- disruption, leading to increased intracellular calcium and tosed particles, resulting in additional cobalt ion release.62 inhibition of sympathetic tone.77 Many factors can cause abnormal wear and/or corrosion Various histopathological changes have been described which generate high cobalt ion levels that overwhelm the for cobalt-related cardiac toxicity. Light microscopy reveals body’s ability to sequester effectively, transport, and excrete myofibrillar hypertrophy, interstitial fibrosis, and muscle them. While certain implant materials or designs are at fibre degeneration which may be vacuolar, granular, or higher risk for these mechanisms, there is a complex inter- present with myofibril dissolution.74 Loss of myofibrils, play of implant and patient factors, which modulates risks sarcoplasmic reticulum glycogen deposition, and intra- for cobalt ion generation and toxicity. myofibril deposits consistent with cobalt particles are found on electron microscopy.78 However, calcified fibrils Pathophysiology of cobalt toxicity or other deposits within myofibrils are often absent, dif- Early in vitro studies examining cytotoxicity of heavy- ferentiating cobalt-induced cardiomyopathy from other metal alloys used in arthroplasties demonstrated that toxic aetiologies. cobalt can induce gross tissue necrosis and macrophage Alexander74 reported on cobalt toxic effects on myocar- toxicity.63,64 Recent studies suggest that the cytotoxic dium in 28 beer drinkers who presented with acute-onset effects of cobalt impair function in macrophages, fibro- left ventricular failure, acidosis, and cardiogenic shock blasts, and osteoblasts through free radical formation and following ingestion up to 10 mg/day of cobalt in beer. Pre- aneuploidy.65-67 This effect depends on nanoparticles dose, disposing factors, such as inadequate protein and vitamin size, and shape as released by articular surface wear, rather intake, and micronutrient deficiency may have increased than direct metal ion release alone.68 Particles which infil- patient susceptibility for this condition. Barborik and trate mitochondria and macrophages may undergo rapid Dusek79 reported on a fatal case of dilated cardiomyopathy intracellular corrosion, producing soluble cobalt ions, following four years of industrial exposure to cobalt. At which activate extrinsic and intrinsic apoptotic pathways. autopsy, cobalt content of cardiac tissue was substantially Cobalt can cause apoptosis and necrosis through multi- above normal at 140 μg/100 g of the heart’s dry weight. ple mechanisms such as DNA fragmentation and reactive Recently, there have been ten reports of suspected oxygen species generation.69,70 At lower doses, it leads to cobalt-induced cardiac toxicity following THA.28,32,36,80-85 cellular apoptosis, while at higher doses, it leads to cellular Gilbert et al80 reported on a fatal case of cobalt-induced necrosis and initiation of inflammatory cascades. dilated cardiomyopathy 14 months following revision of It should be noted that hip arthroplasties may cause both a ceramic-on-ceramic THA to a Co-Cr metal-on- local and systemic effects. Systemic toxicity occurs through polyethylene articulation, owing to ceramic liner fracture. diffusion and transport of soluble cobalt ions generated in The high whole blood cobalt concentration of 6521 μg/L the peri-articular space, or the transport of metal wear par- found was reported to result from third-body abrasive wear ticles through the lymphatic and vascular system with sub- of the Co-Cr components by residual debris from the frac- sequent deposition at remote sites. Locally, solid or cystic tured ceramic liner. Tower,35 reporting on two patients, peri-articular reactions known as ‘pseudotumours’ may found echocardiographic evidence of diastolic dysfunction form secondary to local tissue reactions. The topic of and pericardial effusion associated with serum cobalt of adverse local reactions has been reviewed elsewhere,71-73 so 122 μg/L in a 49-year-old man who underwent MoM THA we will focus on systemic effects of implant-associated approximately three years previously. The second patient, cobalt toxicity, distant to the peri-articular milieu. who had a serum cobalt of 23 μg/L, did not present with cardiac symptoms. In a subsequent report of five patients Cardiac by the same author (including the previous two patients), Most of our understanding of cobalt-induced myocardial tox- three of the five patients with ‘arthro-prosthetic’ cobaltism icity is derived from occupational exposure, oral treatment of following MoM THA, had evidence of cardiomyopathy

THE BONE & JOINT JOURNAL SYSTEMIC COBALT TOXICITY FROM TOTAL HIP ARTHROPLASTIES 9 secondary to elevated blood cobalt levels.36 Unfortunately, In the past years, there have been nine reports concerning the author did not clearly describe the cobalt blood levels hypothyroidism that potentially developed as a result of associated with cardiac dysfunction. high serum/plasma levels of cobalt following THA, with Despite these reports of cobalt-induced cardiomyopathy, cobalt levels > 250 μg/L in all of these cases.32,37,80,81,84,85 in most cases, a direct cause-and-effect relationship with Apel et al81 found gradual development of a multisystem ill- the magnitude of blood cobalt levels cannot be clearly ness over five years involving hypothyroidism, motor established. It is worth noting that cardiac symptoms have weakness, paroxysmal atrial fibrillation, and declining almost exclusively been reported in patients with markedly vision in a 65-year-old man following revision of a ceramic- elevated cobalt levels, with only one report of an afflicted on-ceramic prosthesis with a Co-Cr head after ceramic patients with cobalt < 100 μg/L. In addition, some of the head fracture. The plasma cobalt level was 7567 nmol/L, patients appeared additionally to have poor nutritional sta- with a blood chromium level of 894 nmol/L. Following re- tus and/or other underlying disease states such as severe revision with a metal head arthroplasty, there was a marked alcoholism or renal compromise,86 which could have fur- decrease in serum cobalt level, as well as general health, ther increased cobalt ion levels and/or contributed to the cardiac, and thyroid functional improvement. cardiac dysfunction. Lack of clear evidence, or alternative Currently, no direct evidence exists which supports the possible explanations for symptoms in these patients, sug- cause-and-effect relationship of blood cobalt concentration gests that it is difficult to assert that high cobalt concentra- < 250 μg/L and thyroid dysfunction after Co-Cr THA. tions are the single factor responsible for symptoms. However, at very high serum cobalt levels (> 4000 μg/L; However, two of the reports of cardiac dysfunction were in n = 2 cases) a reversible hypothyroidism has been reported patients who had extremely high serum cobalt levels in patients with a malfunctioning THA. (> 5000 μg/L) as a result of unrecognised malfunctioning hip arthroplasties. The data strongly suggest that these Haematology cobalt levels were important contributing factors to these Historically, cobalt was used as a treatment for anaemia patients’ symptoms.37,81 beginning in 1952, particularly in patients requiring haemodialysis.4-7 Cobalt-induced polycythaemia can also Thyroid occur and is speculated to occur by two main mechanisms. Much of what is known about the thyrotoxic effects of Cobalt impairs oxidative phosphorylation.76 The resulting cobalt comes from its use in the treatment of anaemia and tissue hypoxaemia stimulates erythropoietin production by from industrial exposure to cobalt-containing dyes.87 upregulating the production of Hypoxia-Inducible Factor 1 Patients with cobalt toxicity may develop signs and symp- (HIF-1).89 HIF-1 is a nuclear factor that activates transcrip- toms such as goitre, lassitude, lethargy, weakness, poor tion of erythropoietin. Cobalt chloride can activate erythro- concentration, and diminished reflexes suggestive of hypo- poietin production directly through induction of HIF-1.89 thyroidism.1 Mutations in the HIF-1 binding site disrupt hypoxia-induc- Cobalt can inhibit both iodine uptake and thyroperoxi- ible transcription and explains why some patients do not dase (tyrosine iodinase) activity, thereby preventing oxida- develop secondary polycythaemia despite toxic cobalt lev- tion of iodide and subsequent incorporation of iodine into els. In addition, cobalt can affect cell-mediated immunity, thyroxine.5,79 lymphocyte reactivity, and chemokine secretion. Biopsy specimens show large, irregular follicles with a There is only one reported case of polycythaemia occurring columnar, rather than cuboidal appearance, consistent with as a result of cobalt toxicity following THA.80 Gilbert et al80 decreased activity.80 There is also epithelial hypertrophy, found that a 52-year-old patient developed fatal multisystemic sparse, highly vacuolated colloid (which normally contains illness including polycythaemia (haemoglobin 190 g/l) 14 highly iodinated thyroglobulin) and multiple papillary months following hip revision to a metal-on-polyethylene intra-follicular projections.80 articulation for ceramic liner fracture. Serum cobalt levels It is debatable whether low-level occupational exposure were found to be substantially higher than normal at leads to clinically obvious hypothyroidism. The risk of 6251 μg/L (N: 0.032 μg/L to 0.29 μg/L) following revision. hypothyroidism correlates directly with the level and dura- There is limited evidence available to suggest a direct tion of cobalt exposure, with high exposure levels (5 mg/ cause-and-effect relationship between elevated cobalt levels day to 10 mg/day) being implicated.8 However, previous following THA and development of haematological abnor- reports demonstrate that several weeks following the cessa- malities such as polycythaemia. In addition, little is known tion of cobalt therapy, both hypothyroidism and goitre about the reversibility of the potential haematological con- resolve.1 In contrast, Christensen and Poulsen,88 in their sequences of cobalt toxicity following THA revision. study on health effects of exposure to cobalt compounds in Danish pottery painters, found no inhibitory effects on thy- Neurological roid function. They found that the ratio of T4 to T3 Cobalt toxicity can involve a number of neurologically- increased, suggestive of some interference with thyroid related organ systems including the auditory, ocular, cen- metabolism with cobalt exposure. tral, and peripheral nervous systems causing progressive

VOL. 98-B, No. 1, JANUARY 2016 10 A. C. CHEUNG, S. BANERJEE, J. J. CHERIAN, F. WONG, J. BUTANY, C. GILBERT, C. OVERGAARD, K. SYED, M. G. ZYWIEL, J. J. JACOBS, M. A. MONT deafness, visual loss, short-term memory loss, cognitive Hepatic changes, fatigue, depression, loss-of-concentration, head- Hepatoxicity is an uncommon manifestation of cobalt tox- aches, impaired reflexes, and vibration/position sense, as icity because of a high toxicity threshold. The liver is the well as limb paraesthesias.90 first site of cobalt accumulation causing reduced glu- Animal studies have shown that the neurotoxic effects of tathione levels.41 In a population study of 582 patients, cobalt are mediated through depletion of neurotransmitters involving inhaled cobalt particles, 56% of hard metal such as dopamine, noradrenaline, and serotonin90 and pre- workers experienced mild-to-moderate liver enzyme eleva- synaptic blockage of calcium channels.86 In addition, tion, while others experienced hepatomegaly. One patient cobalt ions induce the formation of reactive oxygen species died of hepatic congestion, although the authors postulated such as hydroxyl radicals that increase oxidative stress and this as secondary to congestive heart failure rather than pri- decrease glutathione levels. This can result in demyelina- mary hepatic pathology.87 tion and axonal loss, and toxic damage to oligodendro- Gross pathology demonstrated significant hyperaemia cytes, which are particularly sensitive to oxidative stresses. and inflammation, while light microscopy demonstrated Case series of cobalt neurotoxicity were documented in central vein displacement, condensation of hepatocyte cyto- the mid-1900s, when cobalt was used as a treatment for plasm, steatosis, increased inflammatory infiltrate, and anaemia. Tinnitus was described after four to 16 weeks of destruction of mitochondrial cristae.87 In animal studies, a treatment in four patients, while one patient developed dose-response relationship has been reported between ele- sensorineural deafness after 12 weeks.82 Other patients vated liver enzymes and cobalt ingestion.87 To date, there has developed paraesthesia and ataxia, associated with hypo- been only one report of hepatotoxicity, as evidenced by ele- reflexia and impaired vibration sense.6 All symptoms vated liver enzymes or serum bilirubin levels, associated with resolved within three to four months of cessation of cobalt elevated serum cobalt levels following a Co-Cr containing therapy. Another case described markedly decreased visual THA. This patient had extreme blood cobalt levels (6521 μg/L), acuity when cobalt was used in the treatment of pancytopae- and ultimately died secondary to multi-organ failure. nia and hypercellular bone marrow.91 Investigations revealed reduced visual acuity bilaterally, with findings of optic disc Carcinogenicity and genotoxicity pallor, suggestive of optic atrophy and possibly impaired The possible role of cobalt compounds in inducing carcino- choroidal perfusion. The total dose of cobalt-chloride genesis and genotoxicity was evaluated by the International received over three years amounted to 73 g, almost half of Agency for Research on Cancer in 2003.88 They concluded which was given four months before the patient’s visual that cobalt was possibly carcinogenic. There is in vitro evi- symptoms. While symptoms did not resolve following dis- dence that cobalt ions can interfere with DNA repair mech- continuation of cobalt treatment, they did not progress. anisms,89 and cobalt containing compounds have been Of the 18 cases of cobalt toxicity that have been shown to have the capacity to cause direct DNA damage.90 described, 13 had evidence of neurotoxic manifesta- Sufficient evidence has been reported to support carcino- tions.30-36,81,85,92 Of these cases, none developed symptoms genic effects of cobalt sulphate and cobalt metal powder in of neurological dysfunction with cobalt levels below 20 μg/L, animals. Human studies, however, are limited to hard metal and only three had reported peak cobalt concentrations of workers exposed to cobalt dust and evaluated the subse- < 100 μg/L.35,36,92 The most common neurological symp- quent development of lung cancer. This makes extrapola- toms were paraesthesia, tinnitus, and visual loss. Peripheral tion of data to metal ion exposure in THA difficult. Recent nerve conduction studies were reported in three cases, with evidence from the United Kingdom has shown the presence variable findings. One study identified sensorimotor abnor- of DNA damage (aneuploidy and chromosomal transloca- malities,32 one reported absent sensory, but near-normal tions) in patients having cobalt-containing implants.37 Nev- motor function,30 while the third described mild amplitude ertheless, convincing in vivo evidence in humans is lacking. reductions only.33 Audiometry testing demonstrating Tharani et al,93 studied 110 792 total hip and 29 800 total sensorineural hearing loss, has been reported in six knee arthroplasties, and found no causal link between patients.30,32,36 In all cases, neurological impairment arthroplasties and cancer development. They found that the appeared to improve over several months following revi- total number of observed cases of cancer was 12 052 in sion THA, although the magnitude of improvement was patients who had undergone THAs, compared with 12 435 variable. expected cases of cancer in the general population in the Although abnormally high concentrations of serum same time period (risk ratio (RR), 0.97, 95% confidence cobalt can potentially increase the risks of progressive ocu- interval (CI) 0.95 to 0.99). In a similar study, Visuri et al94 lar, audio-vestibular, and cognitive impairment, it is not evaluated the occurrence of cancer in patients who had known whether these toxic effects are completely reversi- undergone MoM THA compared with the general popula- ble. There have only been a limited number of cases of tion. They found no difference in the incidence of the cancer cobalt-induced neurotoxicity in patients with high cobalt in both groups (RR = 0.95, 95% CI 0.79 to 1.13). Similarly, levels following malfunctioning THAs, and symptoms have a recent study using data from the National Joint Registry been reported over a range of ion levels. for England, Wales and Northern Ireland evaluated the risk

THE BONE & JOINT JOURNAL SYSTEMIC COBALT TOXICITY FROM TOTAL HIP ARTHROPLASTIES 11 of cancer in 11 540 patients who underwent THA between 3. Catelas I, Petit A, Vali H, et al. Quantitative analysis of macrophage apoptosis vs. 2003 and 2010. The authors stratified patients into three necrosis induced by cobalt and chromium ions in vitro. Biomaterials 2005;26:2441– 2453. cohorts: MoM THA, hip resurfacing arthroplasty, and THA 4. Simonsen LO, Harbak H, Bennekou P. Cobalt metabolism and toxicology--a brief with other bearing surfaces. The authors demonstrated a update. Sci Total Environ 2012;432:210–215. similar cancer risk in patients with resurfacing (RR = 0.69; 5. Alarifi S, Ali D, y AO, et al. Oxidative stress contributes to cobalt oxide nanoparti- 95% CI 0.39 to 1.22) and THA with other bearing surfaces cles-induced cytotoxicity and DNA damage in human hepatocarcinoma cells. Int J Nanomedicine 2013;8:189–199. (RR = 0.96; 95% CI 0.64 to 1.43) compared with individu- 95 6. Harris RM, Williams TD, Hodges NJ, Waring RH. Reactive oxygen species and als who received MoM THA. Multiple Scandinavian data- oxidative DNA damage mediate the cytotoxicity of tungsten-nickel-cobalt alloys in base studies demonstrated that the cancer risk in patients vitro. Toxicol Appl Pharmacol 2011;250:19–28. who had MoM hip arthroplasties was similar to the general 7. Gross RT, Kriss JP, Spaet TH. The hematopoletic and goltrogenic effects of cobaltous chloride in patients with sickle cell anemia. Pediatrics 1955;15:284–290. population.94,96-100 8. Holly RG. Studies on iron and cobalt metabolism. J Clin Endocrinol 1956;16:831–833. In summary, THA remains a successful procedure for the 9. Holly RG. Studies on iron and cobalt metabolism. J Am Med Assoc 1955;158:1349– treatment of end-stage degenerative hip disease. However, 1352. concerns have been raised about the impact of metal debris 10. Curtis JR, Goode GC, Herrington J, Urdaneta LE. Possible cobalt toxicity in main- and ion release on patient morbidity and decreasing implant tenance hemodialysis patients after treatment with cobaltous chloride: a study of blood and tissue cobalt concentrations in normal subjects and patients with terminal longevity in cobalt containing MoM articulations. Although and renal failure. Clin Nephrol 1976;5:61–65. patients who have prostheses with Co-Cr bearing surfaces, 11. Duckham JM, Lee HA. The treatment of refractory anaemia of chronic renal failure or who have implants revised to a Co-Cr component follow- with cobalt chloride. Q J Med 1976;45:277–294. ing fracture of a ceramic component, are theoretically at 12. Schirrmacher UO. Case of cobalt poisoning. Br Med J 1967;1:544–545. increased risk for systemic cobalt toxicity, this is a rare phe- 13. Taylor A, Marks V, Shabaan AA. Cobalt induced lipaemia and erythropoiesis. Dev Toxicol Environ Sci 1977;1:105–108. nomenon. 14. Kesteloot H, Roelandt J, Willems J, Claes JH, Joossens JV. An enquiry into the There is no one symptom that is pathognomonic of role of cobalt in the heart disease of chronic beer drinkers. Circulation 1968;37:854– cobalt toxicity, but rather it is a constellation of systemic 864. symptoms often associated with hip pain. Given the fre- 15. Morin Y, Daniel P. Quebec beer-drinkers’ cardiomyopathy: etiological considerations. Can Med Assoc J 1967;97:926–928. quently insidious nature of symptoms associated with this 16. Sullivan JF, Egan JD, George RP. A distinctive myocardiopathy occurring in phenomenon, and the non-specific nature of systemic Omaha, Nebraska: clinical aspects. Ann N Y Acad Sci 1969;156:526–543. symptoms, clinicians should be aware of this rare, but 17. Bozic KJ, Browne J, Dangles CJ, et al. Modern metal-on-metal hip implants. J potentially devastating condition, and be familiar with a Am Acad Orthop Surg 2012;20:402–406. systematic approach to its diagnosis. The presence of new 18. Glyn-Jones S, Pandit H, Kwon YM, et al. 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Increased awareness of the range of symp- Food and Drug Administration. http://www.fda.gov/MedicalDevices/Productsand- toms associated with cobalt toxicity, and early orthopaedic MedicalProcedures/ImplantsandProsthetics/MetalonMetalHipImplants/ intervention when these symptoms do occur, may forestall ucm241770.htm (date last accessed 16 September 2015). the development of further complications. 21. No authors listed. Medial device alert: All metal-on-metal (MoM) hip replacements (MDA/2012/036). Medicines and healthcare products regulatory agency. http:// Author contributions: www.mhra.gov.uk/home/groups/dts-bs/documents/medicaldevicealert/ A. C. Cheung: Writing, Literature Review, Critical Revision. con155767.pdf (date last accessed 16 September 2015). S. Banerjee: Writing, Literature Review, Critical Revision. 22. No authors listed. The safety of Metal-on-Metal joint replacements with a particu- J. J. Cherian: Writing, Literature Review, Critical Revision. lar focus on hip implants. 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