Clinical Orthopaedics and Related Research®

, Volume 472, Issue 3, pp 953–961 | Cite as

High Metal Ion Levels After Use of the ASR™ Device Correlate With Development of Pseudotumors and T Cell Activation

  • Nils P. Hailer
  • Mats Bengtsson
  • Christina Lundberg
  • Jan Milbrink
Clinical Research



Pseudotumors and immunologic alterations are reported in patients with elevated metal ion levels after resurfacing arthroplasty of the hip. A direct association of increased cobalt and chromium concentrations with the development of pseudotumors has not been established.


We hypothesized that (1) patients with higher blood cobalt and chromium concentrations are more likely to have pseudotumors develop, (2) elevated cobalt and chromium concentrations correlate with increased activation of defined T cell populations, and (3) elevated metal ion levels, small implant size, cup inclination angle, and patient age are risk factors for the development of pseudotumors.


A single-surgeon cohort of 78 patients with 84 Articular Surface Replacement® implants was retrospectively investigated. Between 2006 and 2010, we performed 84 THAs using the Articular Surface Replacement® implant; this represented 2% (84/4950) of all primary hip replacements performed during that period. Of the procedures performed using this implant, we screened 77 patients (99%) at a mean of 43 months after surgery (range, 24–60 months). Seventy-one patients were investigated using ultrasound scanning, and cobalt and chromium concentrations in whole blood were determined by high-resolution inductively coupled plasma mass spectrometry. Differential analysis of lymphocyte subsets was performed by flow cytometry in 53 patients. Results of immunologic analyses were investigated separately for patients with and without pseudotumors. Pseudotumors were found in 25 hips (35%) and were more common in women than in men (p = 0.02). Multivariable regression analysis was performed to identify risk factors for the development of pseudotumors.


Cobalt and chromium concentrations were greater in patients with pseudotumors than in those without (cobalt, median 8.3 versus median 1.0 μg/L, p < 0.001; chromium, median 5.9 versus median 1.3 μg/L, p < 0.001). The percentage of HLA-DR+CD4+ T cells was greater in patients with pseudotumors than in those without (p = 0.03), and the proportion of this lymphocyte subtype was positively correlated with cobalt concentrations (r = 0.3, p = 0.02). Multivariable regression analysis indicated that increasing cobalt levels were associated with the development of pseudotumors (p < 0.001), and that patients with larger implants were less likely to have them develop (p = 0.04); age and cup inclination were not risk factors.


We found a distinct association of elevated metal ion concentrations with the presence of pseudotumors and a correlation of increased cobalt concentrations with the proportion of activated T helper/regulator cells. Thus, the development of soft tissue masses after metal-on-metal arthroplasty could be accompanied by activation of T cells, indicating that this complication may be partly immunologically mediated. Further investigations of immunologic parameters in larger cohorts of patients with metal-on-metal arthroplasties are warranted.

Level of Evidence

Level III, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence.


  1. 1.
    Akbar M, Brewer JM, Grant MH. Effect of chromium and cobalt ions on primary human lymphocytes in vitro. J Immunotoxicol. 2011;8:140–149.PubMedCrossRefGoogle Scholar
  2. 2.
    Almousa SA, Greidanus NV, Masri BA, Duncan CP, Garbuz DS. The natural history of inflammatory pseudotumors in asymptomatic patients after metal-on-metal hip arthroplasty. Clin Orthop Relat Res. 2013 March 28 [Epub ahead of print].Google Scholar
  3. 3.
    al Saffar N, Revell PA. Interleukin-1 production by activated macrophages surrounding loosened orthopaedic implants: a potential role in osteolysis. Br J Rheumatol. 1994;33:309–316.Google Scholar
  4. 4.
    Anderson H, Toms AP, Cahir JG, Goodwin RW, Wimhurst J, Nolan JF. Grading the severity of soft tissue changes associated with metal-on-metal hip replacements: reliability of an MR grading system. Skeletal Radiol. 2011;40:303–307.PubMedCrossRefGoogle Scholar
  5. 5.
    Baecher-Allan C, Wolf E, Hafler DA. MHC class II expression identifies functionally distinct human regulatory T cells. J Immunol. 2006;176:4622–4631.PubMedGoogle Scholar
  6. 6.
    Bosker BH, Ettema HB, Boomsma MF, Kollen BJ, Maas M, Verheyen CC. High incidence of pseudotumour formation after large-diameter metal-on-metal total hip replacement: a prospective cohort study. J Bone Joint Surg Br. 2012;94:755–761.PubMedCrossRefGoogle Scholar
  7. 7.
    Chang EY, McAnally JL, Van Horne JR, Statum S, Wolfson T, Gamst A, Chung CB. Metal-on-metal total hip arthroplasty: do symptoms correlate with MR imaging findings? Radiology. 2012;265:848–857.PubMedCrossRefGoogle Scholar
  8. 8.
    Daniel J, Ziaee H, Pradhan C, McMinn DJ. Six-year results of a prospective study of metal ion levels in young patients with metal-on-metal hip resurfacings. J Bone Joint Surg Br. 2009;91:176–179.PubMedCrossRefGoogle Scholar
  9. 9.
    Davies AP, Willert HG, Campbell PA, Learmonth ID, Case CP. An unusual lymphocytic perivascular infiltration in tissues around contemporary metal-on-metal joint replacements. J Bone Joint Surg Am. 2005;87:18–27.PubMedCrossRefGoogle Scholar
  10. 10.
    de Steiger RN, Hang JR, Miller LN, Graves SE, Davidson DC. Five-year results of the ASR XL Acetabular System and the ASR Hip Resurfacing System: an analysis from the Australian Orthopaedic Association National Joint Replacement Registry. J Bone Joint Surg Am. 2011;93:2287–2293.PubMedCrossRefGoogle Scholar
  11. 11.
    Evans RL, Faldetta TJ, Humphreys RE, Pratt DM, Yunis EJ, Schlossman SF. Peripheral human T cells sensitized in mixed leukocyte culture synthesize and express Ia-like antigens. J Exp Med. 1978;148:1440–1445.PubMedCrossRefGoogle Scholar
  12. 12.
    Glyn-Jones S, Roques A, Taylor A, Kwon YM, McLardy-Smith P, Gill HS, Walter W, Tuke M, Murray D. The in vivo linear and volumetric wear of hip resurfacing implants revised for pseudotumor. J Bone Joint Surg Am. 2011;93:2180–2188.PubMedCrossRefGoogle Scholar
  13. 13.
    Hailer NP, Blaheta RA, Dahlstrand H, Stark A. Elevation of circulating HLA DR(+) CD8(+) T-cells and correlation with chromium and cobalt concentrations 6 years after metal-on-metal hip arthroplasty. Acta Orthop. 2011;82:6–12.PubMedCrossRefGoogle Scholar
  14. 14.
    Hallab NJ, Caicedo M, McAllister K, Skipor A, Amstutz H, Jacobs JJ. Asymptomatic prospective and retrospective cohorts with metal-on-metal hip arthroplasty indicate acquired lymphocyte reactivity varies with metal ion levels on a group basis. J Orthop Res. 2013;31:173–182.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Hart AJ, Hester T, Sinclair K, Powell JJ, Goodship AE, Pele L, Fersht NL, Skinner J. The association between metal ions from hip resurfacing and reduced T-cell counts. J Bone Joint Surg Br. 2006;88:449–454.PubMedCrossRefGoogle Scholar
  16. 16.
    Hart AJ, Satchithananda K, Liddle AD, Sabah SA, McRobbie D, Henckel J, Cobb JP, Skinner JA, Mitchell AW. Pseudotumors in association with well-functioning metal-on-metal hip prostheses: a case-control study using three-dimensional computed tomography and magnetic resonance imaging. J Bone Joint Surg Am. 2012;94:317–325.PubMedGoogle Scholar
  17. 17.
    Hart AJ, Skinner JA, Henckel J, Sampson B, Gordon F. Insufficient acetabular version increases blood metal ion levels after metal-on-metal hip resurfacing. Clin Orthop Relat Res. 2011;469:2590–2597.PubMedCrossRefGoogle Scholar
  18. 18.
    Kwon YM, Glyn-Jones S, Simpson DJ, Kamali A, McLardy-Smith P, Gill HS, Murray DW. Analysis of wear of retrieved metal-on-metal hip resurfacing implants revised due to pseudotumours. J Bone Joint Surg Br. 2010;92:356–361.PubMedCrossRefGoogle Scholar
  19. 19.
    Langton DJ, Joyce TJ, Jameson SS, Lord J, Van Orsouw M, Holland JP, Nargol AV, De Smet KA. Adverse reaction to metal debris following hip resurfacing: the influence of component type, orientation and volumetric wear. J Bone Joint Surg Br. 2011;93:164–171.PubMedCrossRefGoogle Scholar
  20. 20.
    Langton DJ, Sidaginamale RP, Joyce TJ, Natu S, Blain P, Jefferson RD, Rushton S, Nargol AV. The clinical implications of elevated blood metal ion concentrations in asymptomatic patients with MoM hip resurfacings: a cohort study. BMJ open. 2013;3.Google Scholar
  21. 21.
    Langton DJ, Sprowson AP, Joyce TJ, Reed M, Carluke I, Partington P, Nargol AV. Blood metal ion concentrations after hip resurfacing arthroplasty: a comparative study of articular surface replacement and Birmingham Hip Resurfacing arthroplasties. J Bone Joint Surg Br. 2009;91:1287–1295.PubMedCrossRefGoogle Scholar
  22. 22.
    Medicines and Healthcare Products Regulatory Agency (MHRA). Medical Device Alert: ASR™ hip replacement implants manufactured by DePuy International Ltd (MDA/2010/069). Available at: Accessed September 16, 2013.
  23. 23.
    Nawabi DH, Gold S, Lyman S, Fields K, Padgett DE, Potter HG. MRI predicts ALVAL and tissue damage in metal-on-metal hip arthroplasty. Clin Orthop Relat Res. 2013 January 26 [Epub ahead of print].Google Scholar
  24. 24.
    Pandit H, Glyn-Jones S, McLardy-Smith P, Gundle R, Whitwell D, Gibbons CL, Ostlere S, Athanasou N, Gill HS, Murray DW. Pseudotumours associated with metal-on-metal hip resurfacings. J Bone Joint Surg Br. 2008;90:847–851.PubMedCrossRefGoogle Scholar
  25. 25.
    Penny JO, Ding M, Varmarken JE, Ovesen O, Overgaard S. Early micromovement of the Articular Surface Replacement (ASR) femoral component: two-year radiostereometry results. J Bone Joint Surg Br. 2012;94:1344–1350.PubMedCrossRefGoogle Scholar
  26. 26.
    Penny JO, Varmarken JE, Ovesen O, Nielsen C, Overgaard S. Metal ion levels and lymphocyte counts: ASR hip resurfacing prosthesis vs. standard THA. Acta Orthop. 2013;84:130–137.PubMedCrossRefGoogle Scholar
  27. 27.
    R Core Team. R: A Language and Environment for Statistical Computing. Vienna, Austria; R Foundation for Statistical Computing; 2006. Available at: Accessed September 17, 2013 (ISBN 3-900051-07-0).
  28. 28.
    Seppanen M, Makela K, Virolainen P, Remes V, Pulkkinen P, Eskelinen A. Hip resurfacing arthroplasty: short-term survivorship of 4,401 hips from the Finnish Arthroplasty Register. Acta Orthop. 2012;83:207–213.PubMedCrossRefGoogle Scholar
  29. 29.
    Swedish Hip and Knee Society. [Monitoring of metal-on-metal prostheses in Sweden][in Swedish]. Available at: Accessed July 1, 2013.
  30. 30.
    Toms AP, Marshall TJ, Cahir J, Darrah C, Nolan J, Donell ST, Barker T, Tucker JK. MRI of early symptomatic metal-on-metal total hip arthroplasty: a retrospective review of radiological findings in 20 hips. Clin Radiol. 2008;63:49–58.PubMedCrossRefGoogle Scholar
  31. 31.
    Underwood R, Matthies A, Cann P, Skinner JA, Hart AJ. A comparison of explanted Articular Surface Replacement and Birmingham Hip Resurfacing components. J Bone Joint Surg Br. 2011;93:1169–1177.PubMedCrossRefGoogle Scholar
  32. 32.
    van der Weegen W, Smolders JM, Sijbesma T, Hoekstra HJ, Brakel K, van Susante JL. High incidence of pseudotumours after hip resurfacing even in low risk patients; results from an intensified MRI screening protocol. Hip Int. 2013; 23: 243–249.PubMedCrossRefGoogle Scholar
  33. 33.
    Willert HG, Buchhorn GH, Fayyazi A, Flury R, Windler M, Koster G, Lohmann CH. Metal-on-metal bearings and hypersensitivity in patients with artificial hip joints: a clinical and histomorphological study. J Bone Joint Surg Am. 2005;87:28–36.PubMedCrossRefGoogle Scholar
  34. 34.
    Williams DH, Greidanus NV, Masri BA, Duncan CP, Garbuz DS. Prevalence of pseudotumor in asymptomatic patients after metal-on-metal hip arthroplasty. J Bone Joint Surg Am. 2011;93:2164–2171.PubMedCrossRefGoogle Scholar
  35. 35.
    Witzleb WC, Hanisch U, Kolar N, Krummenauer F, Guenther KP. Neo-capsule tissue reactions in metal-on-metal hip arthroplasty. Acta Orthop. 2007;78:211–220.PubMedCrossRefGoogle Scholar
  36. 36.
    Yu P, Fu YX. Tumor-infiltrating T lymphocytes: friends or foes? Lab Invest. 2006;86:231–245.PubMedCrossRefGoogle Scholar
  37. 37.
    Zustin J, Amling M, Krause M, Breer S, Hahn M, Morlock MM, Ruther W, Sauter G. Intraosseous lymphocytic infiltrates after hip resurfacing arthroplasty: a histopathological study on 181 retrieved femoral remnants. Virchows Archiv. 2009;454:581–588.PubMedCrossRefGoogle Scholar

Copyright information

© The Association of Bone and Joint Surgeons® 2013

Authors and Affiliations

  • Nils P. Hailer
    • 1
  • Mats Bengtsson
    • 2
  • Christina Lundberg
    • 3
  • Jan Milbrink
    • 1
  1. 1.Department of Orthopaedics, Institute of Surgical SciencesUppsala University HospitalUppsalaSweden
  2. 2.Department of Immunology, Genetics and PathologyUppsala University HospitalUppsalaSweden
  3. 3.Department of Radiology, Institute of Radiology, Oncology and Radiation SciencesUppsala University HospitalUppsalaSweden

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