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