Barry Sampson

The painful metal-on-metal hip resurfacing

We carried out metal artefact-reduction MRI, three-dimensional CT measurement of the position of the component and inductively-coupled plasma mass spectrometry analysis of cobalt and chromium levels in whole blood on 26 patients with unexplained pain following metal-on-metal resurfacing arthroplasty. MRI showed periprosthetic lesions around 16 hips, with 14 collections of fluid and two soft-tissue masses. The lesions were seen in both men and women and in symptomatic and asymptomatic hips. Using three-dimensional CT, the median inclination of the acetabular component was found to be 55 degrees and its positioning was outside the Lewinnek safe zone in 13 of 16 cases. Using inductively-coupled plasma mass spectrometry, the levels of blood metal ions tended to be higher in painful compared with well-functioning metal-on-metal hips. These three clinically useful investigations can help to determine the cause of failure of the implant, predict the need for future revision and aid the choice of revision prostheses.

Sequential changes in trace metal, metallothionein and calmodulin concentrations in healing skin wounds.

Metalloenzymes have an important role in repair and regenerative processes in skin wounds. Demands for different enzymes vary according to the phase in the healing cascade and constituent events. Sequential changes in the concentrations of calcium, copper, magnesium and zinc were studied in the incisional wound model in the rat over a 10 d period. Copper levels remained low (<10 μg/g dry weight) throughout, but calcium, magnesium and zinc increased from wounding and peaked at about 5 d at a time of high inflammation, granulation tissue formation and epidermal cell proliferation. Metal concentrations declined to normal by 7 d when inflammation had regressed, re‐epithelialisation of the wound site was complete and the ‘normalisation’ phase had commenced. Although the wound was overtly healed by 10 d, the epidermis was still moderately hyperplastic. In view of competitive binding of trace metals at membrane receptors and carrier proteins, the ratios or balance between these trace metals was examined and the significance is discussed. Using immunocytochemistry, we demonstrated increases in metallothionein immunoreactivity as an indication of zinc and copper activity in the papillary dermis and in basal epidermal cells near the wound margin 1–5 d after wounding. This is consistent with metalloenzyme requirements in inflammation and fibrogenesis. Calmodulin, a major cytosolic calcium binding protein was highest in maturing keratinocytes and in sebaceous gland cells of normal skin; it was notably more abundant in the epidermis near the wound margin and in re‐epithelialising areas at a time when local calcium levels were highest.

The chemical form of metallic debris in tissues surrounding metal-on-metal hips with unexplained failure

Implant-derived material from metal-on-metal (MOM) hip arthroplasties may be responsible for an unexplained tissue inflammatory response. The chemical form of the metal species in the tissues is predominantly chromium (Cr), but the currently used techniques have not been able to determine whether this is Cr(III) phosphate or Cr(III) oxide. The analytical challenge must overcome the fact that the metal in the tissues is at a relatively low concentration and tissue preparation or the microscopy beam used can affect the results. Microfocus X-ray spectroscopy using a synchrotron beam is useful in addressing both these issues. Using this technique we compared tissue from failed MOM hips with: (1) tissue from metal-on-polyethylene (MOP) hips; (2) chemical standards; (3) metal discs cut from MOM hips. The most abundant implant-related species in all MOM hip tissues contained Cr. Comparison with standards revealed the chemical form was Cr(III) phosphate, which did not vary with manufacturer type (four types analysed) or level of blood metal ions. Cobalt (Co) and molybdenum (Mo) were occasionally present in areas of high Cr. Co was normally found in a metallic state in the tissue, while Mo was found in an oxidized state. The variety of metallic species may have arisen from corrosion, wear or a combination of both. No evidence of Cr(VI) was seen in the tissues examined.

Surveillance of Patients with Metal-on-Metal Hip Resurfacing and Total Hip Prostheses: A Prospective Cohort Study to Investigate the Relationship Between Blood Metal Ion Levels and Implant Failure.

BACKGROUND We designed a prospective, single-center study to assess whether blood metal ion levels could predict implant failure in patients managed with unilateral metal-on-metal hip resurfacing or total hip arthroplasty. METHODS Five hundred and ninety-seven patients who had received unilateral Articular Surface Replacement prostheses at least twelve months earlier were recruited. Blood metal ion levels were compared between the group of patients with failed implants and the group with non-failed implants. Implant failure was defined as prostheses associated with revision, an intention to revise, or poor patient-reported hip function (Oxford Hip Score, <31 of 48). Specificity, sensitivity, area under the curve, positive and negative predictive values, and odds ratios were calculated. Logistic regression analysis was used to identify other risk factors for implant failure. RESULTS Patients with failed arthroplasty had significantly higher blood cobalt and chromium ion levels than did patients with non-failed arthroplasty (p < 0.01). Blood cobalt ion levels were disproportionately raised in patients with failed total hip arthroplasty (8.2 μg/L) compared with patients with failed hip resurfacing (2.5 μg/L) (p = 0.018). Blood chromium ion levels were not significantly different in patients with failed total hip arthroplasty and failed hip resurfacing (p = 0.058). The maximum value of either metal ion had good discriminant ability to predict implant failure (area under the curve, 0.76). A 7-μg/L cutoff had a positive predictive value of 0.75 (95% confidence interval, 0.66 to 0.82) and a negative predictive value of 0.82 (95% confidence interval, 0.78 to 0.86). In patients managed with total hip arthroplasty, for each increase of 1 μg/L there was a 23% (p < 0.001) increase in the odds of them being in the failed group. For patients managed with hip resurfacing, the increase in odds was 5% (p < 0.001). CONCLUSIONS Raised levels of blood metal ions were associated with failed metal-on-metal hip resurfacings and total hip arthroplasties. A threshold level of 7 μg/L had inadequate sensitivity to be used in isolation as a screening test for implant failure, but it provided nearly optimal misclassification rates. No level had a perfect positive predictive value, and so we discourage surgeons from performing revision surgery based on blood metal ion levels alone. Levels of cobalt ions were raised out of proportion to levels of chromium ions in failed total hip arthroplasty and may reflect a different mechanism for metal ion generation. LEVEL OF EVIDENCE Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Clinical usefulness of blood metal measurements to assess the failure of metal-on-metal hip implants

In April 2010, a Medicines and Healthcare Products Regulatory Agency safety alert concerning all metal-on-metal (MOM) hip replacements recommended measuring chromium and cobalt concentrations when managing patients with painful prostheses. The need for this review is illustrated by the recent surge in requests for these blood tests from orthopaedic surgeons following this alert. The aim is to provide guidance to laboratories in assessing these requests and advising clinicians on interpretation. First, we summarize the basic terminology regarding the types of hip replacements, with emphasis on the MOM type. Second, we describe the clinical concerns over implant-derived wear debris in the local tissues and distant sites. Analytical aspects of the measurement of the relevant metal ions and what factors affect the levels measured are discussed. The application of inductively coupled plasma mass spectrometry techniques to the measurement of these metals is considered in detail. The biological effects of metal wear products are summarized with local toxicity and systemic biological effects considered, including carcinogenicity, genotoxicity and systemic toxicity. Clinical cases are used to illustrate pertinent points.

Metabolic syndrome and renal sodium handling in three ethnic groups living in England

Aim/hypothesisIncreased proximal renal sodium re-absorption is associated with central adiposity and insulin resistance in white men. Our study examined whether this association also exists in other ethnic groups with different prevalences of insulin resistance and associated metabolic abnormalities.MethodsWe studied the association between fractional renal excretion of endogenous lithium (FELi) and metabolic syndrome in a population study of 1190 randomly selected men and women who where 40 to 59 years of age (426 white, 397 of African and 367 of South Asian origin). Anthropometric values, blood pressure, biochemical values, questionnaire data and timed urine collections were obtained with standardised techniques. Endogenous lithium in serum and urine was measured by absorption spectrophotometry. Metabolic markers were the homeostasis model assessment (HOMA) index, waist circumference, serum triglycerides, serum HDL cholesterol and metabolic syndrome as defined by Adult Treatment Panel III criteria.ResultsIn white men and women a higher rate of proximal sodium re-absorption was inversely associated with higher waist circumference, serum triglycerides and HOMA index, and with lower serum HDL cholesterol (all p≤0.001). No associations were found in people of African or South Asian origin. The former had lower FELi than the other groups. White people with the metabolic syndrome had a lower FELi than those without (15.9% vs 19.0%; p=0.003). No difference was found in people of African or South Asian origin.Conclusions/interpretationIncreased proximal sodium re-absorption is associated with the metabolic syndrome in white men and women. This relationship is not seen in people of African or South Asian origin, despite a greater degree of insulin resistance.

Cobalt from metal-on-metal hip replacements may be the clinically relevant active agent responsible for periprosthetic tissue reactions

Some types of metal-on-metal (MOM) hip replacements have unacceptably high rates of failure, such as the Ultima TPS MOM hip, with 13.8% failure at 5 years. This has been attributed to an inflammatory reaction following the release of cobalt (Co) and chromium (Cr) from the bearing surfaces and modular junctions. There is in vitro evidence that Co is more important than Cr in the inflammatory process, but there are no reported human tissue studies of the analysis of implant-derived metals.

A new separation procedure for Cu prior to stable isotope analysis by MC-ICP-MS

A novel ion exchange chromatography was developed for the separation of Cu from biological samples prior to stable isotope analyses. In contrast to previous methods, the new technique makes use of the different distribution coefficients of Cu(I) and Cu(II) to anion exchange resin and this helps to significantly improve the purity of the Cu separates obtained from biological samples, whilst maintaining crucial quantitative yields. Careful method validation confirmed that the procedure yields sufficiently pure Cu fractions after a single pass through the anion exchange columns, with a recovery of 100 ± 2%. Subsequent isotopic analyses of the Cu by multi-collector inductively coupled plasma mass spectrometry, using admixed Ni for mass bias correction, produced accurate Cu stable isotope data with a reproducibility of ±0.04‰ for pure standard solutions and of ±0.15‰ for samples of biological origin.

Experimental observations in the rat on the influence of cadmium on skin wound repair

Wound healing in the skin depends upon the availability of appropriate trace metals as enzyme cofactors and structural components in tissue repair. The present study forms part of a series of experimental investigations to examine the influence of xenobiotic elements with no known nutritional function and which are known to compete with essential trace metals. It was designed to investigate further the importance of trace metals in wound healing as an aid to wound management and to identify mechanisms of nonhealing which constitute a major problem in human medicine.Surgically induced skin wounds in young adult male Wistar rats were exposed topically to 0.2 ml of 0.01, 0.10 or 1.0% cadmium chloride (aq.) daily for up to 10 days. Control wounds received de‐ionized water only. Wounds exposed to cadmium chloride at 0.01 or 0.10% healed in a similar fashion to controls and exhibited a comparable histological profile with metallothionein distribution. Wounds receiving 1.0% cadmium chloride failed to heal or fully re‐epithelialize within 7 days and animals were humanely killed. They showed a persistent mass of inflammatory cell infiltration, oedema, wound debris and aberrant epidermal cell growth. Metallothionein concentrations in the epidermis and fibroblasts of the papillary dermis increased greatly by 5 days postwounding and remained high through the observation period.Cadmium was identified in the liver, kidney and wound sites. In the wound, 1.0% cadmium chloride induced statistically significant (P > 0.001) changes in local concentrations of zinc and calcium at key stages in the healing process, and as a consequence disturbed the trace metal balance necessary for normal wound repair. Zinc levels were increased twofold after 7 days, but calcium was markedly reduced. Local changes in the distribution of metallothionein indicate interaction of cadmium and trace metal carrier proteins as a probable mechanism for impaired wound healing. The cytotoxicity of cadmium is considered to be largely responsible.

A case of hyperzincemia with functional zinc depletion:a new disorder?

We report the case of an 11-y-old boy with a plasma Zn concentration greater than 200 μmol/L, but with symptoms consistent with Zn deficiency. He has had hepatosplenomegaly, rashes, stunted growth (<3rd centile), anemia, and impaired immune function since infancy. He also has vasculitis and osteoporosis. A plasma Zn-binding protein has been separated and characterized by a combination of size exclusion and ion exchange chromatography and electrophoretic studies and by immunologic methods. Antibodies to the partially purified protein have been raised in rabbits. Size exclusion chromatography shows that Zn is bound to a protein with a mass 110 000-300 000 kD. Electrophoretic and mass spectrometry studies suggest that the protein may be composed of several subunits. One component of the isolated protein reacts with antiserum to α2-macroglobulin; immunoprecipitation studies confirm that the protein is not α2-macroglobulin or a histidine-rich glycoprotein. Kinetic studies of zinc metabolism in the patient and his mother with stable Zn isotopes show the presence of increased exchangeable Zn, with a rapid flux from plasma to a stable pool. Liver and muscle Zn and Cu concentrations are raised, but with no abnormal liver histology. Immunoreactive metallothionein in the liver is increased. We suggest that this boy may suffer from a previously unrecognized inborn error of Zn metabolism causing symptomatic zinc deficiency.