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Changes in Early Serum Metal Ion Levels and Impact on Liver, Kidney, and Immune Markers Following Metal-on-Metal Total Hip Arthroplasty
The Journal of Arthroplasty 29 (2014) 612–616
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Changes in Early Serum Metal Ion Levels and Impact on Liver, Kidney, and Immune Markers Following Metal-on-Metal Total Hip Arthroplasty Zhefeng Chen, MD, Zhen Wang, Qing Wang, Weiding Cui, Feng Liu, PhD 1, Weimin Fan, PhD 1 Department of Orthopedics, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
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Article history: Received 7 June 2013 Accepted 24 July 2013 Keywords: metal-on-metal metal-on-polyethylene metal ion immunity hip arthroplasty
a b s t r a c t We retrospectively studied 32 consecutive patients (32 hips) who underwent THA with a Durom large-head, MOM articulation between January 2008 and December 2010. Of the patients who underwent THA using a Trilogy metal on polyethylene prosthesis during the same period, 32 were chosen to form the Trilogy group. 32 volunteers were chosen to form the control group. At the last follow-up, serum metal ion levels, liver and kidney function and host immunologic immune responses were evaluated. The mean Co and Cr levels in the Durom group were 4.33- and 1.95-fold higher than those in the Trilogy group. CD3 +, CD4 + and CD8 + cell levels in the Durom group were significantly decreased. The INF-γ level in the Durom group was significantly higher than that in the Trilogy and control groups. © 2014 Elsevier Inc. All rights reserved.
Polyethylene particle-induced osteolysis has been confirmed as the most important factor in the reduced survivorship of patients following metal-on-polyethylene total hip arthroplasty (THA) [1,2]. To reduce wear-related osteolysis and improve long-term survivorship of prosthesis recipients, highly cross-linked polyethylene, metalon-metal (MOM) articulation and ceramic-on-ceramic articulation have been introduced. With the improvement in metallurgy and manufacture design, MOM prostheses have been widely adopted because of superior wear performance, theoretically increased range of motion, and stability due to the large diameter femoral component [3–5]. Recent reports have shown good results of MOM THA [6,7]. However, because of the local and whole-body reaction due to metal ion release from MOM wear particles and the high revision rate of the acetabular component, the adverse effects and long-term results of MOM THA have recently become a concern [8]. Many studies have reported an elevated serum level of cobalt (Co) and chromium (Cr) ions in patients who received second generation MOM THA devices [9,10]. For example, Chandran et al [11] reported that the 9-year risk of developing chronic renal disease after primary MOM THA was 14% and severe or end-stage renal disease was 6%. Therefore, MOM articulation is not recommended for patients with inadequate renal function. On the contrary, Grübl et al [7] found no renal insufficiency after 10-year follow-up of MOM THA. However, there are no reports in the current literature that have evaluated liver function in patients following MOM THA.
Diffuse and perivascular infiltration of T and B lymphocytes, and plasma cells in tissues surrounding prostheses in patients following MOM THA have been reported [12–14]. The immunological response pattern and cell composition in MOM patients were different from those in metal-on-polyethylene patients. A lymphocyte-dominated immunological response in correlation to metal wear product was suggested [12,14]. In vitro analyses have shown that metal ions may be toxic to lymphocytes and lead to cell necrosis or apoptosis [15,16]. Some hematological alterations, such as a reduction in the number of leukocytes and some subpopulations of lymphocytes, have been observed in patients with aseptic loosening of a MOM THA in which the metal component is worn [17]. However, the type and degree of immunological responses to well-fixed MOM prostheses remain unclear. The present retrospective, case-controlled study was performed to compare the clinical outcomes, serum metal ion levels, host immunologic responses, and renal, liver, and immune function in patients following different types of hip implants. Patients who received nonmodular, large-head MOM acetabular component hip implants were compared with patients who received modern, modular titanium acetabular component hip implants using conventional head sizes and metal-on-highly cross-linked polyethylene articulations and healthy volunteers (controls) at a mean follow-up of 2 years. Material and Methods Implants
The Conflict of Interest statement associated with this article can be found at http:// dx.doi.org/10.1016/j.arth.2013.07.031. Reprint requests: Weimin Fan, PhD, Department of Orthopedics, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China. 1 Contributed equally to this study. 0883-5403/2903-0033$36.00/0 – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.arth.2013.07.031
The Durom cup non-modular acetabular component hip implant (Zimmer Holdings Inc., Warsaw, IN, USA) is composed of a highcarbon, forged Cr–Co bearing surface with a cup diameter range of 44–66 mm and a corresponding head range of 38–60 mm. The Trilogy modular titanium acetabular component hip implant (Zimmer
Z. Chen et al. / The Journal of Arthroplasty 29 (2014) 612–616
Holdings Inc., Warsaw, IN, USA) uses a 28-mm Cr–Co head on highly cross-linked polyethylene for articulation (Fig. 1). Patients The present study was approved by the ethical committee of the First Affiliated Hospital, Nanjing Medical University (Jiangsu, China) and informed consent was obtained from all patients prior to participation. We retrospectively analyzed 32 consecutive patients (32 hips; 18 women and 14 men; mean age, 57.4 years; age range, 37– 75 years; mean body mass index (BMI), 24.7 ± 3.17) who underwent THA and received a Durom large-head MOM non-modular acetabular component hip implant (Durom group) between January 2008 and December 2010. The indications for the implantation of the Durom prosthesis were osteoarthritis in four patients (four hips), osteonecrosis in 16 (16 hips), and femoral neck fracture in 12 (12 hips). A total of 32 patients who underwent THA and received a Trilogy metal on polyethylene prosthesis implant during the same period were chosen to form the Trilogy group. From 100 healthy volunteers without history of metal implantation, 32 were chosen to form the control group. The three groups were matched on age, gender, and BMI and compared using analysis of variance (ANOVA) and the chisquared test to ensure sample homogeneity. Operative Technique All THA procedures were performed using a modified Hardinge approach. The desired acetabular position was abduction of 45° and anteversion of 15°. All patients in the Durom group were implanted with large-diameter acetabulum (46–54 mm) and head (40–48 mm) components, whereas all patients in the Trilogy group were implanted with a conventional 28-mm metal head and highly cross-linked polyethylene liners. All procedures were performed by the two senior authors (Fan and Liu). Assessment Methods All patients underwent clinical examinations and the Harris Hip score was used to evaluate the physical function in hip and the Medical Outcome Study Short Form-36 (SF-36) score was used to measure physical health. Anteroposterior supine radiographs of the pelvis and anteroposterior radiographs of the hip and femur were made preoperatively, immediately postoperatively, and at the last follow-up, and then evaluated by two observers. The osteolysis and radiolucent lines on the acetabular side were determined according to the method of Delee and Charnley [18], whereas component migration or radiolucent lines on the femoral side were determined using the method of Gruen et al [19]. Inductively coupled plasma mass spectrometry was chosen to measure serum ion levels. The detection limits were 0.1 μg/L for Cr and 0.01 μg/L for Co. Blood samples from all patients were collected by
Fig. 1. The Durom cup (A) and Trilogy cup (B).
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the same nurse during the last follow-up examination. A 5-mL blood sample was collected from each patient in an individual syringe (Becton Dickinson & Company, Franklin Lake, NJ, USA) and centrifuged at 1000 g for 20 min to obtain serum, which was digested with nitric acid. The final serum sample was compared with aqueous standards and commercial blood controls to verify the results. The circulating alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and serum creatinine levels of the three groups were determined at the last followup evaluation. The circulating C3, C4, immunoglobulin (Ig)A, IgG, and IgM levels in all serum samples were determined at the last follow-up to evaluate the humoral immunity status of the patients. Thirty thousand cells were analyzed on a fluorescence-activated cell sorting (FACS) flow cytometer (FACSAria; BD Biosciences, San Jose, CA, USA) using FACSAria software (BD Biosciences). All plasma samples were thawed at room temperature and measured simultaneously on the FACSAria flow cytometer using Cytometric Bead Array Human Th1/Th 2 kits (BD Biosciences) for the concentrations of interferon (IFN)-γ and IL-4. Data were analyzed using BD CBA software (ver. 1.4.2; BD Biosciences) and are expressed as pg/mL. Statistical Analysis The mean Harris Hip Score and SF-36 Score were compared using two-sided Student’s t-test. The frequency distribution of lymphocyte subpopulations was calculated and the results were expressed as mean ± standard deviation ðx sÞ. Serum levels of Co and Cr ions in the three groups were evaluated by ANOVA. The level of significance was set at P = 0.05 for all statistical tests. All analyses were performed using SPSS software (ver. 16.0; SPSS Inc., Chicago, IL, USA). Results All patients in the Durom and Trilogy groups completed the follow-up examinations. The mean postoperative follow-up time was 24.9 months (range, 15–34 months) in the Durom group and 25.53 months (range, 15–35 months) in the Trilogy group. In the Durom group, the mean age at the time of surgery was 57.44 ± 12.25 years, 18 patients were female, and the mean patient BMI was 24.70 ± 3.17. In the Trilogy group, the mean age was 59.16 ± 13.97 years, 17 patients were female, and the mean BMI was 25.72 ± 3.27. The control group was comprised of 17 females and 15 males with a mean age of 58.46 ± 13.25 years old and a mean BMI of 24.84 ± 4.41. A comparison of the mean age and BMI among the three groups showed no significant differences by ANOVA (F = 0.138 and 0.733; P = 0.871 and 0.483). The Pearson test results showed no significant differences in gender ratio among the three groups (P = 0.404). The mean Harris Hip Score at the last follow-up examinations was 94.93 ± 5.24 in the Durom group and 89.07 ± 7.32 in the Trilogy group, which were not statistically different (t = 2.456, P = 0.084). The range of motion of the operated hips in abduction, adduction, internal rotation, and external rotation in the Durom group at the last follow-up was not different from that in the Trilogy group. However, the range of flexion in the Durom group was significantly higher compared to that in the Trilogy group (111.33° ± 9.35° vs. 94.23° ± 13.05°; t = 4.027, P = 0.000). The SF-36 satisfaction score in the Durom group at the last follow-up was significantly higher than that in Trilogy group (647.80 ± 87.19 vs. 600.70 ± 164.91; t = 0.963, P = 0.011). There was no detectable radiological migration of the acetabular components or radiolucent lines in both groups. At the last follow-up examination, the Co and Cr levels in the Durom group were 0.547 ± 0.512 μg/L and 0.135 ± 0.087 μg/L respectively. The Co and Cr levels in the Trilogy group were
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Fig. 2. The serum ion levels in the three groups [(A) serum Co levels, (B) serum Cr levels].
0.122 ± 0.221 μg/L and 4.724 ± 3.703 μg/L. The Co and Cr levels in the control group were 2.434 ± 1.192 μg/L and 2.326 ± 0.840 μg/L. Significant increases in Cr and Co levels were detected in the Durom group compared to the Trilogy and control groups (Co: Durom vs. Trilogy, P = 0.004; Durom vs. Control, P = 0.002; and Cr: Durom vs. Trilogy, P = 0.018; Durom vs. Control, P = 0.012). The Co and Cr levels in the Durom group were 4.05- and 1.94-fold higher compared to those in the Trilogy group. The differences in serum ion levels between the Trilogy and control groups were not statistically significant (Co: P = 0.934; Cr: P = 0.913) (Fig 2). The ALT, AST, BUN, and creatinine preoperative levels of patients in the Durom and Trilogy groups were not statistically different from those of the control group (P = 0.902, 0.074, 0.223, and 0.221, respectively). The differences in values among the three groups at the last follow-up examination were not statistically significant (P = 0.899, 0.248, 0.314, and 0.176, respectively). The C3, C4, IgA, IgG, and IgM serum levels in the Durom group at the last follow-up were 1.297 ± 0.225 g/L, 0.256 ± 0.071 g/L, 3.045 ± 1.121 g/L, 13.667 ± 3.255 g/L, and 1.300 ± 0.548 g/L, respectively. The C3, C4, IgA, IgG, and IgM serum levels in the Trilogy group were 1.457 ± 0.287 g/L, 0.309 ± 0.160 g/L, 3.131 ± 1.987 g/L, 12.484 ± 1.976 g/L, and 1.146 ± 0.411 g/L. There were no significant differences in humoral immunological data between the two groups (t = − 1.649, − 1.159, − 0.144, 1.138, and 0.829, respectively; P = 0.111, 0.257, 0.887, 0.265, and 0.414, respectively) (Fig. 3). The CD3 +, CD4+, and CD8 + subpopulations were 5824 ± 1407, 3214 ± 492, and 2611 ± 1348, respectively, in the Durom group, 9053 ± 1863, 5428 ± 1245, and 3625 ± 1047, respectively, in Trilogy group, and 9377 ± 1979, 5712 ± 1514, and 3665 ± 1181, respectively, in the control group. The one-way ANOVA results showed that the CD3 +, CD4+, and CD8+ cell levels in the Durom
Many clinical studies have reported evaluated serum Co and Cr levels after MOM THA and the disparity in these increased metal ion levels was obvious (Table). This disparity remained in other studies even though the implant and the follow-up interval were identical. After a 66-month follow-up of patients who received second generation MOM THA, Moroni et al [9] found that the serum Co and Cr levels were 5- and 8-fold higher compared to those of a healthy
Fig. 3. Serum C3, C4, IgA, IgG, and IgM levels in the Durom, Trilogy and control groups.
Fig. 4. The CD3+, CD4+ and CD8+ subpopulations among the three groups.
group were significantly lower compared to those in the Trilogy and control groups (P = 0.000 and 0.000; P = 0.000 and 0.000; and P = 0.032 and 0.024, respectively). There was no significant difference between the Trilogy and control groups in T-lymphocyte subpopulations (P = 0.634, 0.526, and 0.931, respectively) (Fig. 4). The mean serum INF-γ levels in the Durom, Trilogy, and control groups were 3.57 ± 0.76 pg/mL, 2.75 ± 0.47 pg/mL, and 2.79 ± 0.65 pg/mL, respectively, and the serum IL-4 levels were 1.85 ± 0.95 pg/mL, 2.42 ± 0.87 pg/mL, and 2.44 ± 0.77 pg/mL, respectively. The mean serum INF-γ level in the Durom group was significantly higher than that in the Trilogy and control groups (P = 0.002 and 0.002, respectively). There was no significant difference in the INF-γ levels among the Trilogy and control groups (P = 0.876) or in the serum IL-4 levels among the three groups (P = 0.091, 0.953, and 0.075, respectively). The ratio between INF-γ and IL-4 levels can be used as an index to evaluate the Th1/Th2 ratios, which were 2.09 ± 0.89, 1.26 ± 0.46, and 1.27 ± 0.54 in the Durom, Trilogy, and control groups, respectively. The Th1/Th2 ratio was significantly higher in the Durom group than in the Trilogy and control groups (P = 0.002 and 0.002, respectively), but there was no significant difference between the Trilogy and control groups (P = 0.953) (Fig. 5). Discussion
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Fig. 5. The serum INF-γ and IL-4 levels in the three groups.
control group. However, Garbuz et al [10] found that the serum Co and Cr levels at postoperative year 1 were 46- and 10.7-fold higher in patients following THA with second generation MOM devices. Moreover, a large number of studies regarding changes in metal ion levels after MOM THA focused on Caucasian patients and only the study by Hasegawa et al [21] evaluated changes in ion levels in Asian patients following THA with second generation MOM devices. In our study, Co and Cr ion levels were significantly increased at the last follow-up evaluations in the Durom group compared to the Trilogy and control groups. However, the Co and Cr levels in the Durom group were 4.33- and 1.95-fold higher than those in the Trilogy group, which were lower than reported elsewhere. The following reasons may account for this phenomenon: (1) Less wear of the artificial joint can be partly explained by lower body weight in Chinese patients as well as a more protective lifestyle during the postoperative period, and (2) according to the study by Brodner et al [30], the increased cup inclination in MOM THA could cause the remarkably elevated Co and Cr levels. We concentrated on cup position during Durom cup insertion and the average cup inclination was 42° as observed by postoperative radiological evaluations, which may have resulted in the avoidance of edge wear caused by increased cup inclination. The serum Cr levels in the three groups in the present study were obviously higher than those reported in most related studies. We speculated that the unusually elevated Cr level may have been caused by elevated serum Cr baseline levels, due to traditional Chinese diets and the subsequent environmental effects of Cr accumulation. Metals cannot be eliminated from tissues by metabolic degradation, but only by renal or gastrointestinal excretion [31]. Evidence from a recent animal study suggested that Cr ions can accumulate in the liver [32] and high levels in the body may cause hepatocellular necrosis. Chandran et al [11] reported that the 9-year risk of developing chronic renal disease after primary MOM THA was 14% and severe or end-stage renal disease was 6%. High doses of metal ions
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excreted by the kidneys in conjunction with the additional cytotoxicity of Cr 6+, may damage renal function after MOM THA. Marker et al [33] investigated the potential influence of elevated serum Co and Cr levels on renal function at a minimum 10-year follow-up period in 98 patients after MOM THA, but found no influence of serum Co or Cr concentrations on renal function [33]. In our study, the serum BUN and creatinine levels were not significantly elevated at the last follow-up in the Durom group compared to Trilogy and control groups, suggesting that elevated Co and Cr levels did not impair renal function over a short postoperative period. However, there is no report of liver function evaluation in patients following MOM THA in the current literature. From our data, unimpaired liver and renal function was evident shortly after MOM THA. However, a longer follow-up period in a larger patient cohort is needed to determine the exact effect of increased metal ion concentrations on renal and liver function. All metals in contact with biological systems undergo corrosion, leading to the release of metal ions, which can act as haptens and activate immune responses by forming complexes with native proteins [34]. Metal-protein complexes are considered to be candidate antigens for eliciting hypersensitivity responses. Metals that are known sensitizers include beryllium, nickel, Co, and Cr. In vitro analyses have shown that metal ions may be toxic to lymphocytes and induce cell necrosis or apoptosis [15,16]. Some hematological alterations, such as a reduction in the number of leukocytes and some subpopulations of lymphocytes, have been observed in patients with aseptic loosening of a THA in which the metal component becomes worn [17]. However, most of these studies were carried out on patients with aseptic loosening of the prosthetic device, thus it remains uncertain whether immunological alterations were involved in the failure of the implant or related to the presence of the implant or the underlying pathology. In the present study, we evaluated the immunological status in patients with well-fixed prostheses and our data showed no changes in humoral immunity in patients following MOM THA, but a statistically significant reduction of circulating T-lymphocytes, particularly CD4+ and CD8+ cells was observed. In contrast, this phenomenon was not observed in the Trilogy group. The decreases in CD4+ and CD8 + cell content suggested a generalized lymphosuppressive effect on the host immune system. In these patients, the high levels of circulating Cr and Co may have played crucial roles in immunological changes. Th1 and Th2 cells represent two subpopulations of CD4+ T cells, which can be differentiated by their cytokine profiles. Th1 cells produce IFN-γ, which induces differentiation of CD4 + T cells to Th1 cells and inhibits the proliferation of Th2 cells. In contrast, Th2 cells secrete both interleukin IL-4 and IL-10, which induce differentiation of Th2 cells and inhibit Th1 cells. Th1 activation contributes to cellmediated immunity whereas Th2 activation favors the humoral immune response. It is now recognized that the Th1/Th2 balance is
Table Literature Comparison of Serum Cobalt and Chromium Levels in Patients Following MOM THA. Type of Operation THA
Authors
Year
Maurer et al [20] Hasegawa et al [21] Lardanchet et al [22] Moroni et al [9] Vendittoli et al [23] Beaulé et al [24] Garbuz et al [10] Lazennec et al [25] Engh et al [26] Moroni et al [27] Witzleb et al [28] Savarino et al [29] Present study
2012 2012 2012 2011 2011 2011 2010 2009 2009 2008 2006 2002 2013
Follow-Up (Months) 24 24 12 56 12 24 12 108 24 25 24 24 24
Implant
Cobalt Median (μg/L)
ASRTM Cormet Durom Metasul Durom Profemur Durom Metasul Pinnacle Metasul Metasul Metasul Durom
3.6 2.3 2.76 1.44 2.21 4.02 5.09 1.55 0.77 1.33 1.7 1.33 0.547
Chromium Median (μg/L) 4.58 1.6 1.6 1.96 1.34 2.83 2.14 1.49 1.29 1.3 1.22 1.72 4.724
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important for immunoregulation [35], for this reason, it is of great importance to investigate how metal ion level change can influence the Th1/Th2 homeostasis. In this study, although a decrease in the CD4 + cell subset was found in the Durom group, a significant elevation in content of the type-1 cytokine IFN-γ was observed in the Durom group, whereas levels of the type-2 cytokine IL-4 were static in the three groups, suggesting that Th1 cells may dominate lymphocyte reactivity responses to metals in patients following MOM THA. It has been suggested that a Th1/Th2 imbalance underlies various immune diseases [35]. Examples of Th1-dominant reactions include delayed type hypersensitivity, contact hypersensitivity, experimental autoimmune encephalomyelitis and rheumatoid arthritis. Our results showed that immunological changes may be related to the presence of the implant, but the question remains as to whether these abnormalities are able to compromise host defense mechanisms against foreign organisms or deviant native cells. A moderate defect in the immune profile is not necessarily responsible for immediate adverse effects, because the immune system is flexible and able to employ alternative factors and compensatory mechanisms. Nevertheless, the results of our study suggested some caution in considering the immune status of patients who have received Durom MOM THA, since the consequences of a chronic defect could become clinically evident in the long term. The Durom and Trilogy prostheses manufactured by Zimmer Holdings Inc. were used in this study and all of the components were identical except for the articulation bearings. Thus, the bias caused by different materials and manufacturers was effectively avoided. However, because of the limited amount of samples and short follow-up period, a long-term follow-up is needed to identify postoperative hip function, serum metal ion levels, liver and renal function, and immune reaction in patients following Durom MOM THA. References 1. Emms NW, Stockley I, Hamer AJ, et al. Long-term outcome of a cementless, hemispherical, press-fit acetabular component: survivorship analysis and dose– response relationship to linear polyethylene wear. J Bone Joint Surg 2010;92B:856. 2. Hallan G, Lie SA, Havelin LI. High wear rates and extensive osteolysis in 3types of uncemented total hip arthroplasty: a review of the PCA, the Harris Galante and the Profile/Tri-Lock Plus arthroplasties with a minimum of 12 years median follow-up in 96 hips. Acta Orthop 2006;77:575. 3. Schmalzried TP, Peters PC, Maurer BT, et al. Long-duration metal-on-metal total hip arthroplasties with low wear of the articulating surfaces. J Arthroplasty 1996; 11:322. 4. Sieber HP, Rieker CB, Kottig P. Analysis of 118 second generation metal-on-metal retrived hip implants. J Bone Joint Surg 1999;80B:46. 5. Burroughs BR, Hallstrom B, Golladay GJ, et al. Range of motion and stability in total hip arthroplasty with 28-,32–38-, and 44-mm femoral head sizes. J Arthroplasty 2005;20:11. 6. Saito S, Tyu J, Watanabe M, et al. Mid-term results of Metasul metal-on-metal total hip arthroplasty. J Arthroplasty 2006;21(8):1105. 7. Grübl A, Marker M, Brodner W, et al. Long-term follow-up of metal-on-metal total hip replacement. J Orthop Res 2007;25:841. 8. Langton DJ, Jameson SS, Joyce TJ, et al. Early failure of metal-on-metal bearings in hip resurfacing and large-diameter total hip replacement: a consequence of excess wear. J Bone Joint Surg 2010;92B(1):38. 9. Moroni A, Savarino L, Hoque M, et al. Do ion levels in hip resurfacing differ from metal-on-metal THA at midterm? Clin Orthop Relat Res 2011;469:180.
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Changes in Early Serum Metal Ion Levels and Impact on Liver, Kidney, and Immune Markers Following Metal-on-Metal Total Hip Arthroplasty Zhefeng Chen, MD, Zhen Wang, Qing Wang, Weiding Cui, Feng Liu, PhD 1, Weimin Fan, PhD 1 Department of Orthopedics, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
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Article history: Received 7 June 2013 Accepted 24 July 2013 Keywords: metal-on-metal metal-on-polyethylene metal ion immunity hip arthroplasty
a b s t r a c t We retrospectively studied 32 consecutive patients (32 hips) who underwent THA with a Durom large-head, MOM articulation between January 2008 and December 2010. Of the patients who underwent THA using a Trilogy metal on polyethylene prosthesis during the same period, 32 were chosen to form the Trilogy group. 32 volunteers were chosen to form the control group. At the last follow-up, serum metal ion levels, liver and kidney function and host immunologic immune responses were evaluated. The mean Co and Cr levels in the Durom group were 4.33- and 1.95-fold higher than those in the Trilogy group. CD3 +, CD4 + and CD8 + cell levels in the Durom group were significantly decreased. The INF-γ level in the Durom group was significantly higher than that in the Trilogy and control groups. © 2014 Elsevier Inc. All rights reserved.
Polyethylene particle-induced osteolysis has been confirmed as the most important factor in the reduced survivorship of patients following metal-on-polyethylene total hip arthroplasty (THA) [1,2]. To reduce wear-related osteolysis and improve long-term survivorship of prosthesis recipients, highly cross-linked polyethylene, metalon-metal (MOM) articulation and ceramic-on-ceramic articulation have been introduced. With the improvement in metallurgy and manufacture design, MOM prostheses have been widely adopted because of superior wear performance, theoretically increased range of motion, and stability due to the large diameter femoral component [3–5]. Recent reports have shown good results of MOM THA [6,7]. However, because of the local and whole-body reaction due to metal ion release from MOM wear particles and the high revision rate of the acetabular component, the adverse effects and long-term results of MOM THA have recently become a concern [8]. Many studies have reported an elevated serum level of cobalt (Co) and chromium (Cr) ions in patients who received second generation MOM THA devices [9,10]. For example, Chandran et al [11] reported that the 9-year risk of developing chronic renal disease after primary MOM THA was 14% and severe or end-stage renal disease was 6%. Therefore, MOM articulation is not recommended for patients with inadequate renal function. On the contrary, Grübl et al [7] found no renal insufficiency after 10-year follow-up of MOM THA. However, there are no reports in the current literature that have evaluated liver function in patients following MOM THA.
Diffuse and perivascular infiltration of T and B lymphocytes, and plasma cells in tissues surrounding prostheses in patients following MOM THA have been reported [12–14]. The immunological response pattern and cell composition in MOM patients were different from those in metal-on-polyethylene patients. A lymphocyte-dominated immunological response in correlation to metal wear product was suggested [12,14]. In vitro analyses have shown that metal ions may be toxic to lymphocytes and lead to cell necrosis or apoptosis [15,16]. Some hematological alterations, such as a reduction in the number of leukocytes and some subpopulations of lymphocytes, have been observed in patients with aseptic loosening of a MOM THA in which the metal component is worn [17]. However, the type and degree of immunological responses to well-fixed MOM prostheses remain unclear. The present retrospective, case-controlled study was performed to compare the clinical outcomes, serum metal ion levels, host immunologic responses, and renal, liver, and immune function in patients following different types of hip implants. Patients who received nonmodular, large-head MOM acetabular component hip implants were compared with patients who received modern, modular titanium acetabular component hip implants using conventional head sizes and metal-on-highly cross-linked polyethylene articulations and healthy volunteers (controls) at a mean follow-up of 2 years. Material and Methods Implants
The Conflict of Interest statement associated with this article can be found at http:// dx.doi.org/10.1016/j.arth.2013.07.031. Reprint requests: Weimin Fan, PhD, Department of Orthopedics, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China. 1 Contributed equally to this study. 0883-5403/2903-0033$36.00/0 – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.arth.2013.07.031
The Durom cup non-modular acetabular component hip implant (Zimmer Holdings Inc., Warsaw, IN, USA) is composed of a highcarbon, forged Cr–Co bearing surface with a cup diameter range of 44–66 mm and a corresponding head range of 38–60 mm. The Trilogy modular titanium acetabular component hip implant (Zimmer
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Holdings Inc., Warsaw, IN, USA) uses a 28-mm Cr–Co head on highly cross-linked polyethylene for articulation (Fig. 1). Patients The present study was approved by the ethical committee of the First Affiliated Hospital, Nanjing Medical University (Jiangsu, China) and informed consent was obtained from all patients prior to participation. We retrospectively analyzed 32 consecutive patients (32 hips; 18 women and 14 men; mean age, 57.4 years; age range, 37– 75 years; mean body mass index (BMI), 24.7 ± 3.17) who underwent THA and received a Durom large-head MOM non-modular acetabular component hip implant (Durom group) between January 2008 and December 2010. The indications for the implantation of the Durom prosthesis were osteoarthritis in four patients (four hips), osteonecrosis in 16 (16 hips), and femoral neck fracture in 12 (12 hips). A total of 32 patients who underwent THA and received a Trilogy metal on polyethylene prosthesis implant during the same period were chosen to form the Trilogy group. From 100 healthy volunteers without history of metal implantation, 32 were chosen to form the control group. The three groups were matched on age, gender, and BMI and compared using analysis of variance (ANOVA) and the chisquared test to ensure sample homogeneity. Operative Technique All THA procedures were performed using a modified Hardinge approach. The desired acetabular position was abduction of 45° and anteversion of 15°. All patients in the Durom group were implanted with large-diameter acetabulum (46–54 mm) and head (40–48 mm) components, whereas all patients in the Trilogy group were implanted with a conventional 28-mm metal head and highly cross-linked polyethylene liners. All procedures were performed by the two senior authors (Fan and Liu). Assessment Methods All patients underwent clinical examinations and the Harris Hip score was used to evaluate the physical function in hip and the Medical Outcome Study Short Form-36 (SF-36) score was used to measure physical health. Anteroposterior supine radiographs of the pelvis and anteroposterior radiographs of the hip and femur were made preoperatively, immediately postoperatively, and at the last follow-up, and then evaluated by two observers. The osteolysis and radiolucent lines on the acetabular side were determined according to the method of Delee and Charnley [18], whereas component migration or radiolucent lines on the femoral side were determined using the method of Gruen et al [19]. Inductively coupled plasma mass spectrometry was chosen to measure serum ion levels. The detection limits were 0.1 μg/L for Cr and 0.01 μg/L for Co. Blood samples from all patients were collected by
Fig. 1. The Durom cup (A) and Trilogy cup (B).
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the same nurse during the last follow-up examination. A 5-mL blood sample was collected from each patient in an individual syringe (Becton Dickinson & Company, Franklin Lake, NJ, USA) and centrifuged at 1000 g for 20 min to obtain serum, which was digested with nitric acid. The final serum sample was compared with aqueous standards and commercial blood controls to verify the results. The circulating alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and serum creatinine levels of the three groups were determined at the last followup evaluation. The circulating C3, C4, immunoglobulin (Ig)A, IgG, and IgM levels in all serum samples were determined at the last follow-up to evaluate the humoral immunity status of the patients. Thirty thousand cells were analyzed on a fluorescence-activated cell sorting (FACS) flow cytometer (FACSAria; BD Biosciences, San Jose, CA, USA) using FACSAria software (BD Biosciences). All plasma samples were thawed at room temperature and measured simultaneously on the FACSAria flow cytometer using Cytometric Bead Array Human Th1/Th 2 kits (BD Biosciences) for the concentrations of interferon (IFN)-γ and IL-4. Data were analyzed using BD CBA software (ver. 1.4.2; BD Biosciences) and are expressed as pg/mL. Statistical Analysis The mean Harris Hip Score and SF-36 Score were compared using two-sided Student’s t-test. The frequency distribution of lymphocyte subpopulations was calculated and the results were expressed as mean ± standard deviation ðx sÞ. Serum levels of Co and Cr ions in the three groups were evaluated by ANOVA. The level of significance was set at P = 0.05 for all statistical tests. All analyses were performed using SPSS software (ver. 16.0; SPSS Inc., Chicago, IL, USA). Results All patients in the Durom and Trilogy groups completed the follow-up examinations. The mean postoperative follow-up time was 24.9 months (range, 15–34 months) in the Durom group and 25.53 months (range, 15–35 months) in the Trilogy group. In the Durom group, the mean age at the time of surgery was 57.44 ± 12.25 years, 18 patients were female, and the mean patient BMI was 24.70 ± 3.17. In the Trilogy group, the mean age was 59.16 ± 13.97 years, 17 patients were female, and the mean BMI was 25.72 ± 3.27. The control group was comprised of 17 females and 15 males with a mean age of 58.46 ± 13.25 years old and a mean BMI of 24.84 ± 4.41. A comparison of the mean age and BMI among the three groups showed no significant differences by ANOVA (F = 0.138 and 0.733; P = 0.871 and 0.483). The Pearson test results showed no significant differences in gender ratio among the three groups (P = 0.404). The mean Harris Hip Score at the last follow-up examinations was 94.93 ± 5.24 in the Durom group and 89.07 ± 7.32 in the Trilogy group, which were not statistically different (t = 2.456, P = 0.084). The range of motion of the operated hips in abduction, adduction, internal rotation, and external rotation in the Durom group at the last follow-up was not different from that in the Trilogy group. However, the range of flexion in the Durom group was significantly higher compared to that in the Trilogy group (111.33° ± 9.35° vs. 94.23° ± 13.05°; t = 4.027, P = 0.000). The SF-36 satisfaction score in the Durom group at the last follow-up was significantly higher than that in Trilogy group (647.80 ± 87.19 vs. 600.70 ± 164.91; t = 0.963, P = 0.011). There was no detectable radiological migration of the acetabular components or radiolucent lines in both groups. At the last follow-up examination, the Co and Cr levels in the Durom group were 0.547 ± 0.512 μg/L and 0.135 ± 0.087 μg/L respectively. The Co and Cr levels in the Trilogy group were
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Fig. 2. The serum ion levels in the three groups [(A) serum Co levels, (B) serum Cr levels].
0.122 ± 0.221 μg/L and 4.724 ± 3.703 μg/L. The Co and Cr levels in the control group were 2.434 ± 1.192 μg/L and 2.326 ± 0.840 μg/L. Significant increases in Cr and Co levels were detected in the Durom group compared to the Trilogy and control groups (Co: Durom vs. Trilogy, P = 0.004; Durom vs. Control, P = 0.002; and Cr: Durom vs. Trilogy, P = 0.018; Durom vs. Control, P = 0.012). The Co and Cr levels in the Durom group were 4.05- and 1.94-fold higher compared to those in the Trilogy group. The differences in serum ion levels between the Trilogy and control groups were not statistically significant (Co: P = 0.934; Cr: P = 0.913) (Fig 2). The ALT, AST, BUN, and creatinine preoperative levels of patients in the Durom and Trilogy groups were not statistically different from those of the control group (P = 0.902, 0.074, 0.223, and 0.221, respectively). The differences in values among the three groups at the last follow-up examination were not statistically significant (P = 0.899, 0.248, 0.314, and 0.176, respectively). The C3, C4, IgA, IgG, and IgM serum levels in the Durom group at the last follow-up were 1.297 ± 0.225 g/L, 0.256 ± 0.071 g/L, 3.045 ± 1.121 g/L, 13.667 ± 3.255 g/L, and 1.300 ± 0.548 g/L, respectively. The C3, C4, IgA, IgG, and IgM serum levels in the Trilogy group were 1.457 ± 0.287 g/L, 0.309 ± 0.160 g/L, 3.131 ± 1.987 g/L, 12.484 ± 1.976 g/L, and 1.146 ± 0.411 g/L. There were no significant differences in humoral immunological data between the two groups (t = − 1.649, − 1.159, − 0.144, 1.138, and 0.829, respectively; P = 0.111, 0.257, 0.887, 0.265, and 0.414, respectively) (Fig. 3). The CD3 +, CD4+, and CD8 + subpopulations were 5824 ± 1407, 3214 ± 492, and 2611 ± 1348, respectively, in the Durom group, 9053 ± 1863, 5428 ± 1245, and 3625 ± 1047, respectively, in Trilogy group, and 9377 ± 1979, 5712 ± 1514, and 3665 ± 1181, respectively, in the control group. The one-way ANOVA results showed that the CD3 +, CD4+, and CD8+ cell levels in the Durom
Many clinical studies have reported evaluated serum Co and Cr levels after MOM THA and the disparity in these increased metal ion levels was obvious (Table). This disparity remained in other studies even though the implant and the follow-up interval were identical. After a 66-month follow-up of patients who received second generation MOM THA, Moroni et al [9] found that the serum Co and Cr levels were 5- and 8-fold higher compared to those of a healthy
Fig. 3. Serum C3, C4, IgA, IgG, and IgM levels in the Durom, Trilogy and control groups.
Fig. 4. The CD3+, CD4+ and CD8+ subpopulations among the three groups.
group were significantly lower compared to those in the Trilogy and control groups (P = 0.000 and 0.000; P = 0.000 and 0.000; and P = 0.032 and 0.024, respectively). There was no significant difference between the Trilogy and control groups in T-lymphocyte subpopulations (P = 0.634, 0.526, and 0.931, respectively) (Fig. 4). The mean serum INF-γ levels in the Durom, Trilogy, and control groups were 3.57 ± 0.76 pg/mL, 2.75 ± 0.47 pg/mL, and 2.79 ± 0.65 pg/mL, respectively, and the serum IL-4 levels were 1.85 ± 0.95 pg/mL, 2.42 ± 0.87 pg/mL, and 2.44 ± 0.77 pg/mL, respectively. The mean serum INF-γ level in the Durom group was significantly higher than that in the Trilogy and control groups (P = 0.002 and 0.002, respectively). There was no significant difference in the INF-γ levels among the Trilogy and control groups (P = 0.876) or in the serum IL-4 levels among the three groups (P = 0.091, 0.953, and 0.075, respectively). The ratio between INF-γ and IL-4 levels can be used as an index to evaluate the Th1/Th2 ratios, which were 2.09 ± 0.89, 1.26 ± 0.46, and 1.27 ± 0.54 in the Durom, Trilogy, and control groups, respectively. The Th1/Th2 ratio was significantly higher in the Durom group than in the Trilogy and control groups (P = 0.002 and 0.002, respectively), but there was no significant difference between the Trilogy and control groups (P = 0.953) (Fig. 5). Discussion
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Fig. 5. The serum INF-γ and IL-4 levels in the three groups.
control group. However, Garbuz et al [10] found that the serum Co and Cr levels at postoperative year 1 were 46- and 10.7-fold higher in patients following THA with second generation MOM devices. Moreover, a large number of studies regarding changes in metal ion levels after MOM THA focused on Caucasian patients and only the study by Hasegawa et al [21] evaluated changes in ion levels in Asian patients following THA with second generation MOM devices. In our study, Co and Cr ion levels were significantly increased at the last follow-up evaluations in the Durom group compared to the Trilogy and control groups. However, the Co and Cr levels in the Durom group were 4.33- and 1.95-fold higher than those in the Trilogy group, which were lower than reported elsewhere. The following reasons may account for this phenomenon: (1) Less wear of the artificial joint can be partly explained by lower body weight in Chinese patients as well as a more protective lifestyle during the postoperative period, and (2) according to the study by Brodner et al [30], the increased cup inclination in MOM THA could cause the remarkably elevated Co and Cr levels. We concentrated on cup position during Durom cup insertion and the average cup inclination was 42° as observed by postoperative radiological evaluations, which may have resulted in the avoidance of edge wear caused by increased cup inclination. The serum Cr levels in the three groups in the present study were obviously higher than those reported in most related studies. We speculated that the unusually elevated Cr level may have been caused by elevated serum Cr baseline levels, due to traditional Chinese diets and the subsequent environmental effects of Cr accumulation. Metals cannot be eliminated from tissues by metabolic degradation, but only by renal or gastrointestinal excretion [31]. Evidence from a recent animal study suggested that Cr ions can accumulate in the liver [32] and high levels in the body may cause hepatocellular necrosis. Chandran et al [11] reported that the 9-year risk of developing chronic renal disease after primary MOM THA was 14% and severe or end-stage renal disease was 6%. High doses of metal ions
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excreted by the kidneys in conjunction with the additional cytotoxicity of Cr 6+, may damage renal function after MOM THA. Marker et al [33] investigated the potential influence of elevated serum Co and Cr levels on renal function at a minimum 10-year follow-up period in 98 patients after MOM THA, but found no influence of serum Co or Cr concentrations on renal function [33]. In our study, the serum BUN and creatinine levels were not significantly elevated at the last follow-up in the Durom group compared to Trilogy and control groups, suggesting that elevated Co and Cr levels did not impair renal function over a short postoperative period. However, there is no report of liver function evaluation in patients following MOM THA in the current literature. From our data, unimpaired liver and renal function was evident shortly after MOM THA. However, a longer follow-up period in a larger patient cohort is needed to determine the exact effect of increased metal ion concentrations on renal and liver function. All metals in contact with biological systems undergo corrosion, leading to the release of metal ions, which can act as haptens and activate immune responses by forming complexes with native proteins [34]. Metal-protein complexes are considered to be candidate antigens for eliciting hypersensitivity responses. Metals that are known sensitizers include beryllium, nickel, Co, and Cr. In vitro analyses have shown that metal ions may be toxic to lymphocytes and induce cell necrosis or apoptosis [15,16]. Some hematological alterations, such as a reduction in the number of leukocytes and some subpopulations of lymphocytes, have been observed in patients with aseptic loosening of a THA in which the metal component becomes worn [17]. However, most of these studies were carried out on patients with aseptic loosening of the prosthetic device, thus it remains uncertain whether immunological alterations were involved in the failure of the implant or related to the presence of the implant or the underlying pathology. In the present study, we evaluated the immunological status in patients with well-fixed prostheses and our data showed no changes in humoral immunity in patients following MOM THA, but a statistically significant reduction of circulating T-lymphocytes, particularly CD4+ and CD8+ cells was observed. In contrast, this phenomenon was not observed in the Trilogy group. The decreases in CD4+ and CD8 + cell content suggested a generalized lymphosuppressive effect on the host immune system. In these patients, the high levels of circulating Cr and Co may have played crucial roles in immunological changes. Th1 and Th2 cells represent two subpopulations of CD4+ T cells, which can be differentiated by their cytokine profiles. Th1 cells produce IFN-γ, which induces differentiation of CD4 + T cells to Th1 cells and inhibits the proliferation of Th2 cells. In contrast, Th2 cells secrete both interleukin IL-4 and IL-10, which induce differentiation of Th2 cells and inhibit Th1 cells. Th1 activation contributes to cellmediated immunity whereas Th2 activation favors the humoral immune response. It is now recognized that the Th1/Th2 balance is
Table Literature Comparison of Serum Cobalt and Chromium Levels in Patients Following MOM THA. Type of Operation THA
Authors
Year
Maurer et al [20] Hasegawa et al [21] Lardanchet et al [22] Moroni et al [9] Vendittoli et al [23] Beaulé et al [24] Garbuz et al [10] Lazennec et al [25] Engh et al [26] Moroni et al [27] Witzleb et al [28] Savarino et al [29] Present study
2012 2012 2012 2011 2011 2011 2010 2009 2009 2008 2006 2002 2013
Follow-Up (Months) 24 24 12 56 12 24 12 108 24 25 24 24 24
Implant
Cobalt Median (μg/L)
ASRTM Cormet Durom Metasul Durom Profemur Durom Metasul Pinnacle Metasul Metasul Metasul Durom
3.6 2.3 2.76 1.44 2.21 4.02 5.09 1.55 0.77 1.33 1.7 1.33 0.547
Chromium Median (μg/L) 4.58 1.6 1.6 1.96 1.34 2.83 2.14 1.49 1.29 1.3 1.22 1.72 4.724
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important for immunoregulation [35], for this reason, it is of great importance to investigate how metal ion level change can influence the Th1/Th2 homeostasis. In this study, although a decrease in the CD4 + cell subset was found in the Durom group, a significant elevation in content of the type-1 cytokine IFN-γ was observed in the Durom group, whereas levels of the type-2 cytokine IL-4 were static in the three groups, suggesting that Th1 cells may dominate lymphocyte reactivity responses to metals in patients following MOM THA. It has been suggested that a Th1/Th2 imbalance underlies various immune diseases [35]. Examples of Th1-dominant reactions include delayed type hypersensitivity, contact hypersensitivity, experimental autoimmune encephalomyelitis and rheumatoid arthritis. Our results showed that immunological changes may be related to the presence of the implant, but the question remains as to whether these abnormalities are able to compromise host defense mechanisms against foreign organisms or deviant native cells. A moderate defect in the immune profile is not necessarily responsible for immediate adverse effects, because the immune system is flexible and able to employ alternative factors and compensatory mechanisms. Nevertheless, the results of our study suggested some caution in considering the immune status of patients who have received Durom MOM THA, since the consequences of a chronic defect could become clinically evident in the long term. The Durom and Trilogy prostheses manufactured by Zimmer Holdings Inc. were used in this study and all of the components were identical except for the articulation bearings. Thus, the bias caused by different materials and manufacturers was effectively avoided. However, because of the limited amount of samples and short follow-up period, a long-term follow-up is needed to identify postoperative hip function, serum metal ion levels, liver and renal function, and immune reaction in patients following Durom MOM THA. References 1. Emms NW, Stockley I, Hamer AJ, et al. Long-term outcome of a cementless, hemispherical, press-fit acetabular component: survivorship analysis and dose– response relationship to linear polyethylene wear. J Bone Joint Surg 2010;92B:856. 2. Hallan G, Lie SA, Havelin LI. High wear rates and extensive osteolysis in 3types of uncemented total hip arthroplasty: a review of the PCA, the Harris Galante and the Profile/Tri-Lock Plus arthroplasties with a minimum of 12 years median follow-up in 96 hips. Acta Orthop 2006;77:575. 3. Schmalzried TP, Peters PC, Maurer BT, et al. Long-duration metal-on-metal total hip arthroplasties with low wear of the articulating surfaces. J Arthroplasty 1996; 11:322. 4. Sieber HP, Rieker CB, Kottig P. Analysis of 118 second generation metal-on-metal retrived hip implants. J Bone Joint Surg 1999;80B:46. 5. Burroughs BR, Hallstrom B, Golladay GJ, et al. Range of motion and stability in total hip arthroplasty with 28-,32–38-, and 44-mm femoral head sizes. J Arthroplasty 2005;20:11. 6. Saito S, Tyu J, Watanabe M, et al. Mid-term results of Metasul metal-on-metal total hip arthroplasty. J Arthroplasty 2006;21(8):1105. 7. Grübl A, Marker M, Brodner W, et al. Long-term follow-up of metal-on-metal total hip replacement. J Orthop Res 2007;25:841. 8. Langton DJ, Jameson SS, Joyce TJ, et al. Early failure of metal-on-metal bearings in hip resurfacing and large-diameter total hip replacement: a consequence of excess wear. J Bone Joint Surg 2010;92B(1):38. 9. Moroni A, Savarino L, Hoque M, et al. Do ion levels in hip resurfacing differ from metal-on-metal THA at midterm? Clin Orthop Relat Res 2011;469:180.
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