 SPECIALTY UPDATE

Systemic cobalt toxicity from total hip

arthroplasties
REVIEW OF A RARE CONDITION PART 2. MEASUREMENT, RISK
FACTORS, AND STEP-WISE APPROACH TO TREATMENT

M. G. Zywiel, As adverse events related to metal on metal hip arthroplasty have been better understood,
J. J. Cherian, there has been increased interest in toxicity related to the high circulating levels of cobalt
S. Banerjee, ions. However, distinguishing true toxicity from benign elevations in cobalt levels can be
A. C. Cheung, challenging. The purpose of this review is to examine the use of cobalt alloys in total hip
F. Wong, arthroplasty, to review the methods of measuring circulating cobalt levels, to define a level
J. Butany, of cobalt which is considered pathological and to review the pathophysiology, risk factors
C. Gilbert, and treatment of cobalt toxicity. To the best of our knowledge, there are 18 published cases
C. Overgaard, where cobalt metal ion toxicity has been attributed to the use of cobalt-chromium alloys in
K. Syed, hip arthroplasty. Of these cases, the great majority reported systemic toxic reactions at
J. J. Jacobs, serum cobalt levels more than 100 μg/L. This review highlights some of the clinical features
M. A. Mont of cobalt toxicity, with the goal that early awareness may decrease the risk factors for the
development of cobalt toxicity and/or reduce its severity.
From Rubin Institute
for Advanced Take home message: Severe adverse events can arise from the release of cobalt from metal-
Orthopedics, on-metal arthroplasties, and as such, orthopaedic surgeons should not only be aware of the
Baltimore, United presenting problems, but also have the knowledge to treat appropriately.
States Cite this article: Bone Joint J 2016;98-B:14–20.
 M. G. Zywiel, MD, Orthopaedic
Surgeon
 K. Syed, MD, Orthopaedic
The recognition of adverse events associated cut-offs for the diagnosis of cobalt toxicity
Surgeon,
Division of Orthopaedic Surgery with the release of cobalt ions from metal- vary substantially between studies.21,22 Cobalt
University of Toronto, 100 College
Street Room 302, Toronto, Ontario, on-metal (MoM) hip arthroplasties has raised levels may be measured from whole blood,
M5G 1L5, Canada.
 J. J. Jacobs, MD, Orthopaedic concern about the systemic effects of cobalt. serum or erythrocytes, as metals ions are trans-
Surgeon, Orthopaedic Department
Rush University, 1611 W. Harrison St., Elevated cobalt ions arising from articulations ported both in plasma and red blood cells.23,24
can cause severe pathological effects.1-4 There
Suite 400, Chicago, IL, 60612, USA.
 J. J. Cherian, DO, Resident, There is no standard rate of conversion
Orthopaedic Surgeon, Department of
Orthopaedics appear to be a number of important risk fac- between these values, and they cannot be used
Philadelphia College of Osteopathic
Medicine, 4190 City Line Ave, tors, both in terms of the implant and the interchangeably as the extracellular and intra-
Philadelphia, PA 19131, USA.
 S. Banerjee, MD, M.S, MRCS, patient, associated with the risk of systemic cellular compartments appear to act indepen-
cobalt toxicity.5-8 There are isolated reports dently.23
Resident, Orthopaedic Surgeon
 M. A. Mont, MD, Orthopaedic
Surgeon,
Rubin Institute for Advanced relating to cobalt toxicity associated with One study of patients with well-functioning
Orthopedics
Sinai Hospital of Baltimore, 2401 West
Belvedere Avenue, Baltimore, MD
orthopaedic implants, however, there has not MoM THA showed a mean difference of only
21215, USA.
been a detailed and focused review of this -0.19 μg/L to 0.13 μg/L between levels of
 A. C. Cheung, MD FRCP,
Gastroenterologist, Division of
Gastroenterology, Toronto General
broad topic.2,5,9-20 cobalt measured in whole blood and serum
Hospital.
 F. Wong, MD, Gastroenterologist,
The aim of this review, the second of two samples. However, ion levels in the study sub-
Division of Gastroenterology, Toronto
General Hospital parts, is to examine the use of cobalt alloys in jects were well below 5 μg/L,24 and it is unclear
 J. Butany, MD, Pathologist,
Division of Pathology, Toronto total hip arthroplasty (THA) and the potential whether it would be possible to apply these
General Hospital,
 C. Gilbert, MD, Cardiologist, for systemic effects from elevated cobalt ion results generally to patients with higher cobalt
Division of Cardiology, Toronto
General Hospital
 C. Overgaard, MD, Cardiologist,
levels. We will focus on four main areas: the values. In contrast, another study attempted to
Division of Cardiology, Toronto
General Hospital
measurement of cobalt levels, the ident- determine a reliable conversion factor, but
University of Toronto, 200 Elizabeth
Street, Toronto, Ontario, M5G 2C4, ification of thresholds for toxicity, factors for because of the marked variability between
Canada.
Correspondence should be sent to
systemic effects and the treatment of cobalt serum and whole blood levels, the limits of
Dr M. A. Mont; e-mail:
mmont@lifebridgehealth.org; toxicity. agreement exceeded a range of ± 65%.23
rhondamont@aol.com
The comparison of ion levels is complicated
©2016 The British Editorial Society of Measurement of cobalt ion levels further by the use of diverse analytical methods
Bone & Joint Surgery
doi:10.1302/0301-620X.98B1.36712 Cobalt toxicity is a clinical diagnosis, but it is to determine the level of cobalt in whole blood.
$2.00
contingent on the measurement of cobalt ions These include acid digestion (where acids are
Bone Joint J
2016;98-B:14–20. in the blood. Methods of measurement and used to dissolve the organic matrix of blood to

14 THE BONE & JOINT JOURNAL

 SYSTEMIC COBALT TOXICITY FROM TOTAL HIP ARTHROPLASTIES
allow the metals ions to be examined separately in liquid
form); inductively-coupled plasma mass spectrometry;
chelation; pre-concentration (a process by which impurities
are removed, and the trace element is enriched to detectable
levels) and colourimetric methods. Each of these methods
have specific detection limits.25 The presence of trace met-
als in standard collection tubes may lead to inconsistent
results.26 Despite the associated potential for considerable
variation in measured levels, there are no accepted conven-
tions surrounding the assessment and reporting of cobalt
concentrations in published studies or guidelines.27
Despite this variability, the United Kingdom has created
the Trace Elements External Quality Assessment Scheme in
an attempt to bring a standardised technique for the
measurement and surveillance of cobalt levels.28,29 Similar
methods have been used in other nations in Europe.30,31
However, improvement in the consistency and efficacy of
such measurement techniques remains an ongoing area of
investigation.
Definition of pathological cobalt ion level
A variety of different units are used in the assessment of
cobalt levels in tissue or fluid. The most commonly
reported units are parts per billion (ppb), micrograms per
litre (μg/L), nanograms per millilitre (ng/ml) and
nanomoles per litre (nmol/L). These units are easily con-
vertible: 1 ppb = 1 μg/L = 1 ng/ml; these are approximately
equivalent to 16.97 nmol/L.
Cobalt is a naturally occurring element that is found in
food, water, and the environment.25,32 The level of cobalt in
drinking water is approximately 2 μg/L, and an adult will
ingest between 5 μg and 40 μg of cobalt per day.25 A study
using high-resolution inductively coupled plasma - mass
spectrometry determined the normal level of cobalt in the
serum to be approximately 0.1 ppb.33 The American
Agency for Toxic Substances and Disease Registry has pub-
lished guidelines with respect to the risk of toxicity from
inhaled and ingested cobalt,34 however, no guidelines exist
with respect to implanted devices, nor as to what levels of
cobalt in the blood or serum would be considered toxic.
The United Kingdom’s Medicines and Healthcare prod-
ucts Regulatory Agency (MHRA) has recommended metal
ion testing and careful follow-up of MoM arthroplasties for
local hip symptoms, especially if initial blood cobalt levels
are > 7 μg/L.35 However, the evidence underlying these rec-
ommendations has not been based on rigorous, prospective
studies. The United States Food and Drug Administration
has also raised concerns about the choice of cut-off values
and currently does not support any specific level. Further-
more, owing to the lack of standardised laboratory analytic
techniques, there is no reproducible way to measure serum
metal ion levels that has been validated at a regional or a
national level.26
Several authors have reported that high circulating metal
ions are associated with greater component wear in MoM
implants, and with the degree of corrosion observed at non-
VOL. 98-B, No. 1, JANUARY 2016
15
articular junctions.36,37 Likewise, it has been reported that
a relationship exists between the level of circulating metal
ions and loosening of implants, which ultimalty lead to
pain.33,38 However, other authors were not able to identify
significant associations between serum metal ion levels and
wear of components or clinical findings.39
Subsequent investigation demonstrated only modest sen-
sitivity and specificity (57% and 65%, respectively) of the
7 μg /L threshold in identifying patients with local hip
symptoms and adverse local tissue reactions.40 Likewise,
this cut-off had a sensitivity and specificity of 52% and
89%, respectively, for predicting revision of a locally symp-
tomatic MoM hip arthroplasty for reasons other than infec-
tion, aseptic loosening, or identified technical problems.22
More recently, a study from our group has recommended a
lower threshold of 4 μg/L for further investigation of pain-
less MoM hip arthroplasties as part of an orthopaedic eval-
uation and management algorithm.41 This cut-off was
reported to have high specificity (95%), but low sensitivity
(25%) in predicting poor function in unilateral hip resur-
facing.42 However, the authors cautioned that the role of
metal ion level testing is limited to serving as an adjunct to
clinical evaluation and other diagnostic testing. Addition-
ally, the authors were not aware of any recommendations
concerning blood cobalt level interpretation in the context
of other bearing surfaces. In a recent study of 209 MoM
THAs, Malek et al40 found that a further reduction in the
cut-off to 3.5 μg/L improved the sensitivity and the negative
predictive value to 86% and 74%. However, they found
this was associated with a substantial reduction in
specificity (27%) and positive predictive value (44%).
Limited data are available concerning the relationship
between levels of metal ions and systemic symptoms fol-
lowing THA. While symptoms of systemic cobalt toxicity
have been reported in four patients with large head MoM
THAs, and serum cobalt levels ranged between 14 μg/L and
24 μg/L,14,19 Lhotka et al43 reported mean whole blood
cobalt levels ranging from 16 μg/L to 36 μg/L at follow-up
times between 35 and 48 months in 259 patients with well-
functioning small-head MoM THAs in the absence of any
local or systemic symptoms. Of the 18 cases of cobalt tox-
icity thought to be secondary to THA reported to date,
patients with cobalt ion release secondary to ceramic parti-
cle third body wear had markedly higher whole blood and/
or serum levels of cobalt (median 528 μg/L; range 398 to
6521) than patients with MoM arthroplasties (median 35
μg/L; range 14 to 288), which is likely to be because of the
different modes of cobalt ion generation.2,5,9-20 However,
the lack of standardisation surrounding the assessment of
cobalt levels complicates comparisons between studies.
The association between the level of cobalt and patho-
logical effects is complex and not well understood. The vast
majority of investigations concerning the diagnostic value
of elevated cobalt ion levels have been performed in the
context of MoM articulations, with levels correlated with
either local adverse tissue reactions, or revision of the
16 M. G. ZYWIEL, J. J. CHERIAN, S. BANERJEE, A. C. CHEUNG, F. WONG, J. BUTANY, C. GILBERT, C. OVERGAARD, K. SYED, J. J. JACOBS, M. A. MONT
arthroplasty components. Given the number of different
modes of generation of cobalt ions, and the inconsistency
between blood cobalt levels and local or systemic symp-
toms, a clear definition of pathological cobalt ion levels
remains elusive. It is highly likely that the systemic risk
from cobalt ion release is complicated by patient-specific
factors that increase or decrease susceptibility. For these
reasons, routine measurement of blood cobalt levels has not
been recommended for all THAs, although some agencies
and authors have recommended their use in specific situa-
tions such as implants known to be at a high risk for
adverse events, symptomatic patients, and those with ultra-
sonographic or radiographic abnormalities.35 In any case,
blood cobalt ion levels alone are insufficient to guide treat-
ment, and should be used as an adjunct to clinical assess-
ment and other diagnostic modalities.
Risk factors for cobalt toxicity
Given that there are only 18 described cases of systemic
cobalt toxicity following MoM THA, it is difficult to delin-
eate risk factors that lead to this condition accurately, how-
ever, we do believe there are certain risk factors for wear
which may be surrogates.
Implant-related factors
A number of implant-related factors can lead to excess
wear or increased corrosion, which may lead to higher lev-
els of circulating cobalt and, potentially, a higher risk of
cobalt toxicity. As previously described, these include a
complex interplay of factors inherent to these implants,
including: the choice of bearing couples, the specific sizes
and geometry of individual prosthetic components, the
positioning of components, and potential contamination of
the periarticular region with debris from previous proce-
dures.8,37,44-47
It is important to note that while these factors may
increase the risk for metal particle or cobalt ion release, a
large majority of patients who have one or more of these
risk factors appear to continue to have well-functioning
asymptomatic hips.
Patient-related factors
Patient age and gender. It has been shown in one study
involving 111 patients that those < 60 years old are more
active than older patients and male patients are more active
than females.7 In a study of 37 patients following THA,
Schmalzried et al6 found that increased activity in younger
age groups (p < 0.0001) and male patients (p < 0.001) were
significantly correlated with implant wear. In a study of
1434 THAs, Wroblewski et al8 similarly found a higher rate
of wear in men (p = 0.042). Conversely, female patients
have been found to have a significantly higher revision rate
for psuedotumour from MoM hip resurfacing arthroplasty
compared with males (p < 0.0001), and the likelihood is
increased for those under the age of 40 years (p < 0.003).
These authors hypothesise that failure in female patients
may be related to allergic predisposition, increased range of
movement, altered gait, and the possibility that female
patients receive smaller head sizes, which can negatively
affect load transmission. However, while these are certainly
risk factors for wear and/or revision, the small number of
cases of systemic toxicity related to hip arthroplasty means
that it cannot be inferred that these are risk factors for tox-
icity.
Malnutrition. This is likely to be a contributing factor to
cobalt toxicity, primarily as a result of associated hypoalbu-
minaemia.48,49 The systemic distribution of cobalt is influ-
enced by its ability to bind to plasma proteins, as well as its
rate of transportation across cellular membranes. It is well
known from previous studies that toxicity is primarily
dependent on the ionised, rather than protein-bound, forms
of heavy metals. Typically, the large majority of serum
cobalt (88% to 95%) is bound to albumin. However, mal-
nutrition decreases the total albumin available, potentially
increasing unbound cobalt.50 Unbound divalent metal ions
are transported across the cell membrane via divalent metal
transporter 1 (DMT1), a ubiquitous pH-dependent trans-
porter, potentially increasing intracellular concentrations.
Unbound divalent metal ions can cause rupture of the outer
cell membrane and uncoupling of mitochondrial respira-
tion, leading to the production of reactive oxygen spe-
cies.51-53 These mechanisms of cellular toxicity have been
proposed in a number of neurodegenerative disorders,54,55
albeit not necessarily in association with increased cobalt
levels.
In the setting of malnutrition and subsequent hypoalbu-
minaemia, an increase in available non-protein-bound
cobalt ions allows for increased intracellular cobalt trans-
port. This increase in the intracellular ionised form of
cobalt may, therefore, potentially play a role in neuro-
toxicity and other forms of cellular toxicity, such as
nephrotoxicity.50 A study examining the serum of a
patient who developed cobalt neurotoxicity demonstrated
a disproportionately high level of cobalt in whole blood
rather than in plasma, suggesting a high level of non-
protein-bound cobalt.5
In cases of cobalt related cardiomyopathy described fol-
lowing ingestion of cobalt-enriched beer, anorexia was a
predominant feature at the time of presentation for the
majority of the patients.56,57 Patients with cobalt-related
cardiomyopathy were compared with a cohort with similar
patterns of beer consumption, but who were free of any evi-
dence of cardiomyopathy. Patients who had consumed sim-
ilar quantities of beer, but did not develop cardiomyopathy,
had higher nonalcoholic calorie intakes of 2000 kcal/day
compared with the cardiomyopathy group. Daily cobalt
consumption was relatively low (10 g/d) in the patients who
developed cardiomyopathy, which suggests that malnutri-
tion may have served as a likely factor.58,59
Renal failure. Oral cobalt administration was previously
used as a treatment for refractory anaemia in patients with
chronic renal failure. However, when given to patients with
THE BONE & JOINT JOURNAL
 SYSTEMIC COBALT TOXICITY FROM TOTAL HIP ARTHROPLASTIES
haemodialysis, they developed protracted elevated cobalt
blood levels and some appeared to have developed a fatal
cardiomyopathy. These findings highlight the role of the kid-
ney in the maintenance of cobalt homeostasis, given that it is
primarily excreted in urine.60 Consistent with this, an inves-
tigation of two patients with MoM THA and chronic renal
failure demonstrated that their blood cobalt levels were 100
times the levels described in the literature in patients with the
same type of prosthesis and no renal failure.61
Two animal studies have demonstrated tubular necrosis
in rats treated with high dose cobalt.62,63 The DMT1 trans-
porter is abundantly expressed in the kidneys, and the
transport of heavy metal ions into renal cells has been
reported to not only cause toxicity, but also compete with
the absorption of essential trace elements.49 Cobalt appears
to be re-absorbed by the proximal tubules, the loop of
Henle and the distal tubules. Most heavy metals can cause
a Fanconi-like syndrome following chronic intoxication,
and one case report of transient glycosuria, albuminuria
and aminoaciduria in an individual treated with six months
of oral cobalt for anaemia has been reported.64 However,
no definitive evidence of renal failure secondary to blood
cobalt in general, or cobalt release from THA has been
reported to date. Thus, while it does appear that renal fail-
ure impairs cobalt excretion resulting in elevated blood lev-
els, there is no evidence for renal toxicity as a result of
elevated blood cobalt from THA.
Case reports of systemic cobalt toxicity
Since 2006, there has been an increase in the number of
reports on systemic toxic manifestations following elevated
blood cobalt levels following hip arthroplasty. We identi-
fied 18 cases in the literature.2,5,9-20 Eight of these cases
were in patients with fractured ceramic bearings, revised to
metal on polyethylene bearings (n = 8). In these cases, it is
likely that residual ceramic debris led to accelerated third-
body wear, catastrophic failure of the revised metal modu-
lar femoral head, and elevated cobalt ions in the body. In
the remaining cases, the elevated cobalt ions were the result
of potentially malfunctioning MoM THAs (n = 10). The
median serum cobalt level which led to features of systemic
toxicity in these ten reports was 35 μg/L (range 14 to 288).
In all cases where revision surgery was performed, a nota-
ble decrease in serum cobalt levels was observed. However,
serum cobalt levels did not return to normal levels in any
studies where specific follow-up values were reported.
Although multisystem involvement was found in all 18
cases, neurological (n = 13), cardiac (n = 10), and thyroid (n
= 9) effects were most commonly seen. Only one fatal case
has been reported, which was secondary to dilated cardio-
myopathy and multi-organ failure that failed to improve
following removal of implant.12,20
A direct cause and effect relationship between elevated
cobalt levels and the described systemic effects could not be
confirmed, and in some cases, there could be alternative
explanations for the observed symptoms. Moreover, in
VOL. 98-B, No. 1, JANUARY 2016
17
some cases there was a lack of clear detail concerning the
specific blood cobalt levels, the sampling and analytic
methods used, the temporal relationships between the
reported data, and/or other potential causes of the observed
symptoms. Thus, the ability to make conclusions about the
relationship between elevated cobalt levels following THA
and potential systemic symptoms is limited. Nevertheless,
the presence of several non-specific systemic symptoms that
are associated with cobalt toxicity in general highlights the
fact that vigilance is necessary to diagnose early symptoms
of malfunctioning cobalt-chromium (Co-Cr) THAs so that
timely intervention can be instituted to prevent potential
systemic effects and long-term harm.
Assessment and treatment
Assessment of patients with suspected cobalt toxicity. Cur-
rently, regulators advise that patients who underwent
MoM THA should undergo regular routine follow-up with
their orthopaedic surgeon, irrespective of symptomatic sta-
tus.41,44,65,66 Expeditious orthopaedic evaluation should be
made when patients experience painful symptoms related
to the hip which may be suggestive of a reaction to metal
debris. Recently, the American Association of Hip and
Knee Surgeons, American Academy of Orthopaedic Sur-
geons, and American Hip Society have proposed an algo-
rithm for the follow-up of patients who have undergone
MoM hip arthroplasty.65 Patients with signs or symptoms
suggestive of systemic cobalt toxicity should be assessed to
ascertain whether the prosthesis may be the potential
source of elevated cobalt ions.
The following diagnostic approach may be used by treat-
ing clinicians to identify those patients who potentially
have arthroplasty-associated cobalt toxicity:
- General history and clinical examination: a general
review of systems should attempt to elicit symptoms of
heart failure or arrythmias, hypothyroidism, paresthaesias,
auditory and visual deficits, mood and cognitive changes as
well as gastrointestinal symptoms such as anorexia and
weight loss. Signs of hypothyroidism, right- or left-sided
heart failure, paresthaesias, and malnutrition should be
specifically assessed.
- Hip-specific history and clinical examination: patients
should be asked about any hip and/or groin pain at rest, or
on active or passive range of movement. Knowledge of the
timing of surgery, including the number and reasons for
revisions, recurrent dislocations, and type of prosthesis and
bearing surfaces used, is often necessary in the evaluation of
a patient with suspected cobalt toxicity related to prosthe-
sis. Implant factors known to increase the risk of high
cobalt levels, such as large-diameter MoM arthroplasty, hip
resurfacing arthroplasty, or revision of a previous fractured
ceramic implant, should also be noted. An assessment to
indicate the presence of any squeaking, creaking, grinding,
swelling, or fluid collection around the hip should be
undertaken during hip examination. In the presence of any
of the above findings from the history or physical examina-
18 M. G. ZYWIEL, J. J. CHERIAN, S. BANERJEE, A. C. CHEUNG, F. WONG, J. BUTANY, C. GILBERT, C. OVERGAARD, K. SYED, J. J. JACOBS, M. A. MONT
tion by a general practitioner, a prompt referral to the
orthopaedic surgeon should be made for further in-depth
evaluation.
- Laboratory investigations: these should include a full
blood count with differential, erythrocyte sedimentation
rate, C-reactive protein, creatinine, urea and electrolytes,
liver enzymes and liver function tests (total bilirubin, albu-
min, international normalised ratio (INR)) and thyroid-
stimulating hormone. In patients with a painful MoM pros-
thesis, blood cobalt and chromium levels should be drawn.
To increase comparability of results, clinicians ordering
cobalt levels should collect blood samples in metal-free col-
lection tubes, use a laboratory with experience in analysing
such samples, and perform serial analyses using the same
laboratory and collection method.
A baseline echocardiogram should be obtained if the
patient shows symptoms suggestive, or demonstrating
signs, of heart failure.
- Imaging: orthogonal plain-film radiographs of the hip
should be obtained. These may be helpful in revealing any
implant-related problems and require specialist ortho-
paedic interpretation in the context of the clinical picture.
Serial radiographic comparison is very helpful to assess
implant loosening and/or periprosthetic osteolysis. Metal
artifact reduction sequence MRI or an ultrasound of the hip
is often necessary to assess soft-tissue involvement and/or
pseudotumour formation, and is considered next in the
evaluation of patients with suspected malfunctioning THA,
along with blood metal levels. Furthermore, the Scientific
Committee on Emerging and Newly Identified Heath Risks
states that CT scans are also a diagnostic method for detect-
ing and quantifying peri-prosthetic osteolytic lesion.44 This
is particularly helpful in the presence of acetabular lesion
not easily identified on plain radiographs. These may also
detect and delineate solid or cystic masses when performed
with metal artifact reduction.67 However, this examination
exposes the patient to unwanted radiation.
- Consultations: It is important to discuss with our med-
ical colleagues that if there is the suspicion or diagnosis of
elevated cobalt levels in patients with cobalt-containing
implants, orthopaedic consultation should always be
sought immediately for appropriate evaluation, as these are
often the physicians initially evaluating the patient. As in
the majority of reports on otherwise well-functioning
MoM hip prostheses, the mean blood cobalt levels are
known to vary between 0.2 μg/L and 4 μg/L.21,68-71 The
MHRA guidelines suggest that a blood level above 7 μg/L
may be indicative of excessive wear in MoM hip implants,
and patients with levels beyond these need closer surveil-
lance for development of local adverse tissue reactions.35
However, no definitive cobalt level threshold is available to
suggest increased systemic health risks in patients with Co-
Cr containing THAs. Current evidence suggests that sys-
temic toxicity is extremely unlikely in the context of low
cobalt levels, even in the presence of hip pain or radio-
graphic abnormalities. The large majority of cases of sys-
temic symptoms were associated with cobalt levels greater
than 100 μg/L. Given the difficulty in diagnosis, it is always
appropriate to rule out other causes for any systemic symp-
toms, including other sources of cobalt toxicity, if appropri-
ate.
Pharmacological and medical treatment. Multiple chelators
have been used in the setting of acute heavy metal intoxi-
cation, such as non-sulphured conjugates (ethylenediami-
netetraacetate (EDTA), triethylenetetramine, deferoxamine
and deferiprone) or sulphured conjugates (meso-2,3,
dimercaptosuccinic acid, 2,3 -dimercapto-one-propanesul-
fonic acid and diethyldithiocarbamate).72 Concomitant
provision of amino acids such as methionine can improve
cellular transport of chelators.72 However, there is little
recent evidence on the use of pharmacological therapies in
the setting of chronic cobalt toxicity. Animal studies have
demonstrated that EDTA and N-acetylcysteine are the best
chelators.72,73 Agents such as dimercaprol and penicil-
lamine have been studied, but have not been shown to be
effective.74 Haemodialysis is unlikely to provide much
direct benefit, as the primarily protein-bound cobalt is not
removed from circulation. The administration of zinc
(Zn2+) has been reported to modulate heavy metal toxicity,
preventing renal dysfunction and Fanconi-like syndrome in
the setting of cadmium toxicity.75 The associated mecha-
nism, however, is unclear, and this therapy has not been
investigated in the setting of cobalt toxicity.
Although therapy with chelating agents can potentially
reduce blood metal ion levels, current evidence is equivo-
cal with regards to improvement in systemic symptoms fol-
lowing implant related cobalt toxicity. In their report of a
56-year-old man with suspected cobalt intoxication (serum
Co levels 506 μg/L; serum Cr level 14 μg/L), Pelclova et al5
found substantial improvement of most neurological symp-
toms other than loss of hearing following treatment with a
total of 10 g of 2,3-dimercaptopropane-one-sulphonate
over one month. However, this treatment was started after
removal of the failed prosthesis, and thus the relative con-
tribution of the chelation therapy is unknown. Authors
have reported reduction in metal levels, but a lack of
marked improvement in clinical symptoms following med-
ical treatment with chelating agents.76-78 Gilbert et al12
reported on the development of a multisystem illness with
cobalt levels of 6521 μg/L, 14 months following revision
THA for a fracture of the ceramic liner in a 46-year-old
man. The authors found that the blood cobalt level
decreased to 2618 μg/L, following removal of the prosthe-
sis, and two weeks of therapy with dimercaprol. Neverthe-
less, deterioration of the clinical condition occurred during
the period of chelation therapy with development of multi-
organ failure. Rizzetti et al17 found no improvement in neu-
rological symptoms with treatment with EDTA (and
retention of the prosthesis) in their report of a 58-year-old
female patient who presented with complete visual and
hearing loss and elevated blood cobalt levels (549 μg/L) one
year following revision THA for fracture of the ceramic
THE BONE & JOINT JOURNAL
 SYSTEMIC COBALT TOXICITY FROM TOTAL HIP ARTHROPLASTIES
head. The authors, however, did report that the chelating
treatments substantially improved metal ion levels.
Surgical treatment. The definitive treatment for implant-
related cobalt toxicity is revision, thus eliminating the
source of excessive cobalt release.65,79-81 In our opinion, at
the time of revision, components which minimise the gen-
eration of cobalt debris (e.g., decreased modularity, avoid-
ance of MoM bearings, using titanium alloy components
and ceramic heads) should be considered. In cases where
there is concern that the patient will not be able to tolerate
a full revision surgery, an excision arthroplasty can be con-
templated, with implantation of a new prosthesis delayed
until the patient’s medical condition improves sufficiently
to tolerate the procedure.
The evidence available in the literature is based on a few
case reports. Despite its rarity, systemic cobalt toxicity may
cause marked morbidity, and even death. The pathogenesis
of cobalt toxicity is not well understood, however it
appears to be a consequence of a complex interplay of
patient, surgical and device factors.
It is important to realise that, although some regulatory
agencies have begun to assess the potential for cobalt tox-
icity associated with THA, there are no universally
accepted criteria for what constitutes a toxic cobalt level,
nor are there consistent guidelines surrounding the meas-
urement of cobalt in whole blood, serum, or erythrocytes.
Similarly, there has been considerable variation in the
symptoms, signs, and cobalt levels associated with implant-
related cobalt toxicity reported to date. An increased
awareness of the range of symptoms of cobalt toxicity, and
the role of early orthopaedic intervention when these symp-
toms do occur, may forestall the development of further
complications.
Supplementary material
A table showing case reports of systemic toxicity
after total hip arthroplasty is available alongside the
online version of this article at www.bjj.boneandjoint.org.u
Author contributions:
M. G. Zywiel: Writing, Literature Review, Critical Revision.
J. J. Cherian: Writing, Literature Review, Critical Revision.
S. Banerjee: Writing, Literature Review, Critical Revision.
A. C. Cheung: Writing, Literature Review, Critical Revision.
F. Wong: Writing, Literature Review, Critical Revision.
J. Butany: Writing, Literature Review, Critical Revision.
C. Gilbert: Writing, Literature Review, Critical Revision.
C. Overgaard: Writing, Literature Review, Critical Revision.
K. Syed: Writing, Literature Review, Critical Revision.
J. J. Jacobs: Writing, Literature Review, Critical Revision.
M. A. Mont: Writing, Literature Review, Critical Revision.
No benefits in any form have been received or will be received from a commer-
cial party related directly or indirectly to the subject of this article.
This article was primary edited by A. D. Liddle and first proof edited by G. Scott.
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