Monday, March 4, 2013

Metal allergy in patients with total hip replacement: A review

    Published before Print feb 2013
    Journal of International Medicine Research
  1. Yirong Zeng
  2. Wenjun Feng
  3. Third Department of Orthopaedics, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong Province, China
  4. Dr Yirong Zeng, Third Department of Orthopaedics, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, 16 Airport Road, Baiyun District, Guangzhou City, Guangdong Province 510405, China. Email:


Metal-on-metal prostheses are increasingly and widely used in total hip arthroplasty, and offer particular benefit to patients with osteoarthritis. Adverse effects related to the release of metal ions (such as cytotoxicity, genotoxicity, carcinogenicity and metal allergy) are common, however. The aims of this review article were to explore the relationship between corrosion products and implant-related hypersensitivity, define normal and toxic metal ion concentrations, and differentiate between allergy and infection in painful total hip replacement. The simultaneous presence of corrosion products and hypersensitivity-related tissue reactions indicates a relationship between the development of corrosion and implant-related hypersensitivity. There are no clear boundaries between normal and toxic metal ion concentrations. Several methods exist for the differential diagnosis of metal allergy and infection, including ultrasound-guided aspiration, patch testing and arthroscopic biopsy. More research is required to elucidate fully the relationship between metal articulations and allergy, and to determine the concentrations of metal ions that lead to harmful effects.


Total hip arthroplasty (THA) is one of the most clinically successful and effective surgeries, with reports indicating improved function, reduced pain and high rates of implant survivorship.1,2 There are three types of prosthesis available: metal-on-polyethylene; metal-on-metal; ceramic-on-ceramic. In patients with osteoarthritis, metal-on-metal is the implant of choice because such implants are relatively cheap and have low wear rates.35 Although THA has a high success rate, implant loosening may occur, with early symptoms including persistent pain and aseptic failure.6 These symptoms may be attributed to metal allergy, as patients are directly exposed to various metals and salts during surgery. These may combine with host proteins to become antigens or allergens, activating the host immune system and causing mild to severe allergy.7

Reports regarding the incidence, clinical manifestation, pathogenesis, diagnosis, and management of metal allergy are uncommon. The aims of this review article were to explore the relationship between corrosion products and implant-related hypersensitivity, define normal and toxic metal ion concentrations, and differentiate between allergy and infection in painful total hip replacement.

Materials and methods

A search of PubMed®/MEDLINE® and Embase was performed between November 2011 and December 2011 using the keywords ‘metal allergy’, ‘total hip arthroplasty’, ‘corrosion products’, ‘Co–CR–Mo alloy’, ‘allergic contact dermatitis’, ‘metal ion concentration’, ‘painful hip’ and ‘infection’. The search was performed with no restrictions on publication date. Additional reports were obtained from the database of the library at Guangzhou University of Traditional Chinese Medicine. The majority of articles were review studies, with some clinical observations and case studies.
The current review focused on articles that: (i) clearly illustrated the relationship between prosthesis corrosion and metal allergy; (ii) included reference levels of metal ions in body fluids; or (iii) included methods for differential diagnosis of infection and metal allergy.


Composition of metal articulations

Stainless steel, cobalt–chromium–molybdenum (Co–Cr–Mo) alloy, titanium and titanium alloy are widely used in hip prostheses because of their high corrosion resistance and durability.8,9 Vitallium, tantalum, vanadium and zirconium are also used.10

Stainless steel commonly contains chromium, nickel, manganese, molybdenum and a low concentration of carbon. The higher the purity of the metal implant, the better is its corrosion resistance.10 The strength and fatigue resistance of stainless steel have resulted in its widespread use.11 Titanium alloy contains no chromium, cobalt or nickel, so it lacks strength10 but is effectively physiologically inert and highly adherent to newly formed bone.12,13

Metal corrosion and metal ion release

There are many types of metal corrosion including crevice, fatigue, stress, fretting, galvanic, intergranular and pitting.14 Chloride ions, amino acids and proteins in the body can accelerate corrosion.8,11 Stainless steel, Co–Cr–Mo alloy, titanium and titanium alloy possess a surface oxide film that can prevent corrosion. Metallic biomaterials in aqueous solutions comprise active and passive surfaces that are simultaneously in contact with electrolytes.15 In this environment, the surface oxide film repeats a process of partial dissolution and reprecipitation in aqueous solution. Metal ions are gradually released when dissolution is faster than reprecipitation, and these ions may lead to metal allergy.
Nickel, cobalt and chromium are known to be allergenic,10 with studies reporting the development of nickel-related recalcitrant hand eczema as a response to nickel-containing jewellery.16,17 Cobalt compounds can cause a wide range of immunological reactions including irritant-type skin toxicity, and chromium and its salts can induce irritant contact dermatitis.18

Concentrations of metal ions

Despite the high strength and corrosion resistance of metal prostheses, corrosion and the consequent release of metal ions into periprosthetic tissue is inevitable. Metal ions are metabolically essential, but can be cytotoxic, genotoxic, carcinogenic or allergenic in high concentrations.19,20 Patients receiving metal-on-metal hip replacements have increased concentrations of metal ions in blood and urine,19 and it is therefore necessary to clearly define the boundary between normal and toxic concentrations.
Metal ions including nickel, cobalt, and chromium are most commonly known to result in metal allergy, and, of these, nickel is preferentially released from prostheses.21 High concentrations of nickel were shown to be present in blood, synovial fluid and the joint capsule, with molybdenum levels being significantly lower.20 In addition, titanium, chromium and cobalt concentrations were increased in urine, blood, synovial fluid and the joint capsule in patients with THA.20 Reference concentrations of metal ions in various body fluids are given in Table 1. Different metals are present in different organs, for example chromium, titanium and nickel are mainly found in the lung, whereas cobalt is often detected in the kidney, heart, pseudocapsule, liver and spleen.2226 Binding of metal ions to proteins allows them to be systemically transported and either stored or excreted.20,29 Accumulation of a high concentration of metal ions beyond the metabolic ability of the liver and kidneys resulted in a type IV T-cell mediated hypersensitivity.30 Studies have so far been unable to provide clear boundaries for concentrations of cobalt, chromium and molybdenum in patients with THA. Further research is needed to enable the early diagnosis of metal allergy in these patients

Symptoms of metal allergy

Metal allergy in patients with THA generally presents as skin changes such as allergic contact dermatitis and prototypic delayed-type hypersensitivity eczema in periprosthetic tissue.31,32 Other reported cutaneous reactions include urticaria,33 vasculitis,34 bullous eruption, erythema multiforme, and swelling or tenderness.3537

Cutaneous reactions have been shown to occur more frequently in patients with static implants (screws, plates and nails) than in those with dynamic implants (hip and acetabular replacements), with an inverse relationship between the concentration of metal ions and the formation of allergic cutaneous reactions.38 Patients with metal allergy frequently complain of hip pain, suggesting that implant loosening may be a component of metal allergy.31 The relationship between dermal and deep implant allergy, and the exact role of hypersensitivity in the pathogenesis of the painful joint, remain unclear.

Differential diagnosis of metal allergy and infection

Both metal allergy and postoperative infection can lead to hip pain and early implant loosening, but require different intervention. Metal allergy can often be treated with a single-stage revision procedure, whereas infected implants require a two-stage revision.39,40 It is therefore crucial that an accurate diagnosis is made in order to plan the correct treatment.
It is difficult to differentiate between metal allergy and infection from clinical presentation alone, and laboratory analyses are required for accurate diagnosis. These include white blood cell/colloid scintigraphy, which provides an image of the distribution of reticulo–endothelial elements in the bone marrow. If infection is present, the infiltrate cells are mainly polymorphonuclear cells, and in metal allergy they are mainly lymphocytes. This method has been shown to have a sensitivity of 70% and a specificity of 100% for diagnosing infection in patients with THA.41

Analysis of fluid aspirated from the joint via ultrasound-guided arthroscopy is also useful for differential diagnosis, with metal allergy being associated with milky-coloured fluid and an absence of bacterial growth.42 In addition, arthroscopic biopsy has found grey, rubbery, necrotic soft tissue around infected hips but not those affected by metal allergy. Infected hips are free from any evidence of visible metallic ions and head-component damage.43

The standard method for identifying allergy is the patch test.44,45 Around 10% of patients with metal-on-metal prostheses were shown to have elevated concentrations of one or more of cobalt, chromium or nickel ions.46 In addition, patients with a history of allergy were more likely to exhibit metal allergy.46 Determination of the mechanism of immune response via quantification of migration inhibition factor and leucocyte inhibition factor can also be useful in differential diagnosis.37


Adverse reactions caused by metallic implants are rare, but the implications of these are unclear. The concentrations of metal ions associated with DNA damage and mutation, carcinogenicity and metal sensitivity remain unknown. More research is required to elucidate fully the relationships between metal articulations and allergy, and the concentrations of metal ions that lead to harmful effects. In addition, new methods for the differential diagnosis of metal allergy and infection would be valuable.

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