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Year : 2020  |  Volume : 11  |  Issue : 1  |  Page : 17-20  

Analysis of hematological metal element levels in orthopedic patients with implants

Institute of Orthopaedics and Traumatology, Coimbatore Medical College and Hospital, Coimbatore, Tamil Nadu, India

Date of Submission20-Mar-2019
Date of Decision01-May-2019
Date of Acceptance02-May-2019
Date of Web Publication11-Mar-2020

Correspondence Address:
Prof. Vetrivel Chezian Sengodan
Director of Institute of Orthopaedics and Traumatology, Coimbatore Medical College and Hospital, Coimbatore - 641 018, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jnsbm.JNSBM_120_19

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Background: The progressive increase in concentration of circulating metal by-products derived from the metal-based orthopedic implants may have deleterious effects in the patients over the long term. Therefore, it is necessary to profile the metal levels in the body of the patients receiving metal implants using appropriate highly sensitive techniques and strategies. Hence, in this study, we estimated the levels of metal in serum of patients with metal implants. Materials and Methods: Blood samples of 25 patients with metallic implants were collected at 6 months postsurgery. The blood samples were subjected to triple acid digestion and then analyzed through inductively coupled plasma–mass spectroscopy, and the blood levels of various metals were quantified. Results: An increase in serum levels of titanium was observed in the patients with metal implants at 6 months postsurgical implant. However, the levels of titanium were within the normal range (normal level <7.2 μg/l), and we did not observe any signs of detectable systemic toxicity. In contrast, the mean serum levels of cobalt (0.19–2.6 μg/l) and nickel (0.05–1.08 μg/l) were above the normal range. Conclusion: Orthopedic patients with metal implants had the serum levels of titanium within the normal range but had serum levels of cobalt and nickel above the normal range. Despite increase in the serum levels of cobalt and nickel, the patients did not show any clinical signs of toxicity.

Keywords: Arthroplasty, cobalt, inductively coupled plasma–mass spectroscopy, nickel, serum, titanium

How to cite this article:
Sengodan VC, Doddihithlu S. Analysis of hematological metal element levels in orthopedic patients with implants. J Nat Sc Biol Med 2020;11:17-20

How to cite this URL:
Sengodan VC, Doddihithlu S. Analysis of hematological metal element levels in orthopedic patients with implants. J Nat Sc Biol Med [serial online] 2020 [cited 2021 Jan 19];11:17-20. Available from:

   Introduction Top

Orthopedic procedures receiving implant/s have become a routine surgical practice to effectively and efficiently restore mobility and quality of life in patients. Increasing number of younger patients receiving orthopedic metal alloys has caused concern about the potential long-term biological effects of the metals leaching into the systemic circulation from the metal implants. The biological effects of the metal implants may be potentiated in the patients exposed to variety of metals through other sources such as food, water, environment, and some of the occupational risks.

The level of the metals leaching into the blood may be one of the reasons for systemic toxicity in addition to local deposition and reaction to the metal debris. The use of metal implants in the human body dates back to 4000 BC. Introduction of cobalt in 1936 became one of the most popular metal implants in orthopedic surgery.[1] In later part of that century, the discovery of titanium, nickel, manganese, and vanadium has further revolutionized the orthopedic implant armamentarium. Cobalt, chromium, titanium, nickel, manganese, and their alloys are some of the common metals used for manufacturing orthopedic implants.[2] Titanium alloy Ti6Al4V is one of the important components of total hip replacement.

Toxicity and allergy to the increasing metal levels is one of the most likely complications, which may either warrant removal of the implant or find an alternative alloy to serve the same purpose. Periodic supervision of the patients to detect any increase in the levels of metals in systemic circulation may help to potentially identify metal toxicity and early recognition of excessive wear out of the implant. Some surgeons consider increased levels of metals in serum as one of the hints along with radiological and clinical signs for planning a revision surgery. The degradation products of the implants used in orthopedic implants can exist in soluble form (ionic form, often attached to serum proteins) and/or as particle debris. The implants or its degradation products can potentially initiate systemic or local reaction in some patients.

The concern about the release of soluble metal ions should always be considered during clinical monitoring of patients receiving metal-based implants. The maximum amount of these metal ions is often found in the pseudocapsules surrounding the implant and can potentially be slowly released into systemic circulation. Hence, in this study, we aimed to estimate the exposure and biological activity of various metals released from orthopedic implants.

   Materials and Methods Top

This prospective study was performed from June 2016 to March 2018. Patients who underwent total hip arthroplasty (age group: 45–70 years) and titanium elastic nail (age group: 4–12 years) were included in this study. A total of 18 patients of total hip replacement and 7 patients of titanium elastic nail were included in the study. Four milliliters of blood samples was collected under sterile conditions using stainless steel needles with sterile syringes from the patients at 6 months postsurgery. Patients already having a metallic implant in the body, patients with a recent history of any implant removal, and patients occupationally exposed to high metal levels (miners and metallurgy workers) were excluded from the study.

The collected blood was stored in vacuum tubes containing anticoagulant ethylenediaminetetraacetate and then stored in cold storage (−10°C). Prior to analysis, the blood was thawed and subjected to centrifugation at 3000 rpm for 20 min. The supernatant fluid of 2 ml was collected and subjected to triple acid digestion using nitric acid, sulfuric acid, and perchloric acid in the ratio of 9:2:1. The solution was then kept in a heating mantle with temperature adjusted to 80°C and kept in the heating chamber until the solution dried [Figure 1]. Following this, distilled water was added to the test tube to make the volume up to 10 ml using a disposable micropipette. Impurities were filtered off, and the sample was kept in cold storage in a sterile Borosil glass vial. The sample was then subjected to Inductively coupled plasma-mass spectrometry (ICP-MS), and the metal element levels present in the sample were analyzed [Figure 2]. The results obtained were calculated taking into account the dilution and other acid digestion procedures adopted.
Figure 1: Samples in heating chamber

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Figure 2: Inductively coupled plasma–mass spectrometer

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   Results Top

The metal levels in the patient serum samples were analyzed using the inductively coupled plasma–mass spectroscopy (ICP-MS). The number of patients in different age groups included in this study is represented in a [Graph 1]. This study included seven cemented and eleven uncemented total hip arthroplasty patients and seven titanium elastic nail patients. No difference was observed in the serum level of titanium in patients of cemented versus uncemented hemiarthroplasty.

One patient with bilateral total hip replacement who was a known case of systemic lupus erythematosus continued to have skin lesions and had increased levels of titanium compared to other patients. However, the levels of titanium were within the normal limit. Four patients (three females and one male) continued to have pain in the operated hip. All patients were ambulatory except two who had become bedridden due to other comorbid medical conditions. Four patients developed serum creatinine levels of above 1.6 mg/dl, of which three were hypertensive and one was diabetic.

The average serum titanium level in our study was 0.26 μg/l [Table 1] which was within the normal serum titanium level.[3] One case of bilateral total hip replacement had a serum titanium level of 1.02 μg/l. The average serum cobalt level in our study was 35.79 μg/l (normal value: 0.3–7.5 μg/l).[4] Maximum cobalt level observed in this study was 130.8 μg/l. The average nickel level in the serum was observed to be 36.81 μg/l (normal level: 0.05–1.05 μg/l).[5]
Table 1: Mean values of various metals

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   Discussion Top

In this study, we observed an increase in the serum levels of cobalt and nickel but not titanium at 6 months post patients receiving metallic orthopedic implants. The potential health impact of such increased metals in the systemic circulation is of long-term health concern, although we did not observe any obvious clinical signs or symptoms at 6-month follow-up.

Previous studies using the atomic absorption spectrometry to quantify metal ions have also reported no changes in the serum levels of titanium, vanadium, and aluminum in 42 patients receiving orthopedic implants.[3] In this study, the mean duration of follow-up was 30–40 months from the date of surgery. Our study is consistent with this previous report despite using a more sensitive inductively coupled plasma–mass spectrometry (detection level up to 0.002 μg/l) for analyzing the metal levels in the serum samples. The comparison between various studies reporting metal levels in serum following orthopedic metal implants is summarized in [Table 2]. In an another study involving 32 patients (22 men and 10 women) who underwent interlocking femoral nailing with titanium implant,[6] the blood samples were analyzed using inductively coupled plasma–mass spectroscopy similar to our study. In this study, the blood samples were analyzed at 12 months postsurgery, and the average titanium level was 50.63 μg/l. The difference observed in comparison to our study may be attributed to the different surgical procedure, suggesting that the metal-leaching ability of various types of implants is highly variable.
Table 2: Comparison between different studies

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Although in our study we did not observe any clinical consequence of increased cobalt and nickel levels in the serum at 6 months of postsurgical follow-up, other studies have reported “arthroprosthetic cobaltism” highlighting metal-related systemic toxicity in patients receiving total hip replacement.[7] The metal-related systemic toxicities (symptoms included headache, fatigue, tinnitus, hearing loss, anxiety, cognitive decline, and depression) were attributed to increased anteversion, leading to significant amount of mismatch between head and shell diameter or surgical inadequacy leading to abrasive wear and tear of the prosthesis, which resulted in significant elevation of serum cobalt levels (up to 122 μg/l).[5] Incidentally, the metal-related systemic toxicities were improved after a revision surgery. In contrast, there are also reports of ten patients who were asymptomatic despite significant high level of cobalt (18–153 μg/l) at a mean follow-up of 4.2 years after a large metal on metal total hip arthroplasty. Neurological, radiological, and laboratory investigations regarding renal and thyroid functions did not show any significant signs of dysfunction in this study group. Similarly, in yet another study, 134 cemented titanium stem patients, prospectively assessed for the serum levels of metals, showed serum titanium below the detection limit of 1.43 μg/l.[8] Such study differences may be potentially attributed to differences in analytical methodology, implant specifications, and/or surgical procedures.

Patients undergoing metal on metal total hip arthroplasties are at an increased risk for higher metal ion levels in the blood.[4] Although this increased risk is not always clinically translated, it is nevertheless essential to profile this risk for optimal clinical management. While the factors responsible for higher metal ion levels postsurgical implants may be many, a large head metal on metal prosthesis is seen as a major reason for an increased level of metals leaching into systemic circulation.[4] This study is consistent with our observations of higher cobalt and nickel levels in the circulation. High levels of cobalt caused by the disseminated particles from the femoral head lead to problems such as peripheral neuropathy, cardiomyopathy, and hypothyroidism. In majority of the cases, the levels of the metal decreased after implant removal, further supporting the hypothesis that the implant was the primary cause of rise in metal levels in circulation. Loss of metal from the head of implant embedded in the polyethylene liner as a result of wear and tear leads to increased levels of cobalt levels up to 6521 μg/l.[9] Such high levels of metals in circulation may have potential teratogenic or carcinogenic effects in addition to the local biological tissue reactions. Although epidemiological studies associating the higher metal levels in circulation postsurgical implants with clinically relevant damage to cardiac, renal, or nervous system are lacking, nevertheless such potential adverse effects may be enhanced in the presence of other comorbidities. In our study too, the lack of any adverse effects attributable to the increase in the serum cobalt and nickel levels is consistent with this previous report.[5]

It is very likely that the timing of measuring metal levels in circulation is very critical in assessing the impact of metals leaching from the implants. For instance, in a study involving 13 patients who had stainless steel hip prosthesis, only one patient showed an increase in serum and whole blood concentration of nickel which was taken 9–15 years after the replacement surgery.08] Such selective increase in the metal levels in circulation may be compounded by underlying clinical conditions such as myocardial infarction, renal hemodialysis, disulfiram therapy, cerebral stroke, intravenous infusion of albumin concentrates, and/or any other occupational exposure to nickel compounds. It is also likely that the bilateral hip replacement would be a contributory cause of increase in nickel levels in blood of patients with impaired renal clearance.

   Conclusion Top

This study showed that the mean serum level of titanium was below the toxic levels, but the mean serum levels of cobalt and nickel were elevated without any obvious clinical signs/symptoms in patients who had total hip replacement. Our interpretations should be viewed considering the study limitations: (1) serial blood level follow-up which was not performed, (2) small sample size, and (3) neurological examination which was not performed to assess cognitive or other higher neurological functions.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Park JB, Lakes RS. Hard tissue replacement II: Joints and teeth. In: Biomaterials an Introduction. 2nd ed. New York: Plenum; 1992. p. 317-54.  Back to cited text no. 1
Langley A, Dameron CT. Modern metal implant toxicity and anesthesia. J Australas Anaesth 2015:57-65. ISSN: 1032-2515.  Back to cited text no. 2
Jacobs JJ, Skipor AK, Black J, Urban RM, Galante JO. Release and excretion of metal in patients who have a total hip-replacement component made of titanium-base alloy. J Bone Joint Surg Am 1991;73:1475-86.  Back to cited text no. 3
Hartmann A, Hannemann F, Lützner J, Seidler A, Drexler H, Günther KP, et al. Metal ion concentrations in body fluids after implantation of hip replacements with metal-on-metal bearing – Systematic review of clinical and epidemiological studies. PLoS One 2013;8:e70359.  Back to cited text no. 4
Linden JV, Hopfer SM, Gossling HR, Sunderman FW Jr. Blood nickel concentrations in patients with stainless-steel hip prostheses. Ann Clin Lab Sci 1985;15:459-64.  Back to cited text no. 5
McGarry S, Morgan SJ, Grosskreuz RM, Williams AE, Smith WR. Serum titanium levels in individuals undergoing intramedullary femoral nailing with a titanium implant. J Trauma 2008;64:430-3.  Back to cited text no. 6
Oldenburg M, Wegner R, Baur X. Severe cobalt intoxication due to prosthesis wear in repeated total hip arthroplasty. J Arthroplasty 2009;24:825.e15-20.  Back to cited text no. 7
Boyer P, Lazennec JY, Poupon J, Rousseau MA, Ravaud P, Catonné Y, et al. Clinical and biological assessment of cemented titanium femoral stems: An 11-year experience. Int Orthop 2009;33:1209-15.  Back to cited text no. 8
Zywiel MG, Brandt JM, Overgaard CB, Cheung AC, Turgeon TR, Syed KA, et al. Fatal cardiomyopathy after revision total hip replacement for fracture of a ceramic liner. Bone Joint J 2013;95-B:31-7.  Back to cited text no. 9


  [Figure 1], [Figure 2]

  [Table 1], [Table 2]


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