Marion J. Fedoruk MD, CIH, DABT, FACMT, FACOEM
University of California, Irvine CA
December 9, 2014
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82 year old male: history of unilateral Metal on
Metal (MoM)-not subject to recall
Referred by orthopedist for elevated cobalt and
chromium (Co 9-12 ug/L: blood serum)
Concerned about increased cobalt levels: long term
effects
No local symptoms – good hip functioning and
imaging
Cycles about 15 miles a day
General cognitive decline, ophthalmic migraines,
fatigue, poor sleep depressed
Mayo web site- concerned that above 5 ug/l is toxic
and heard that in UK over 7 ug/L
Should he remove hip?
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1950s 1st generation MoM-ball+socket metal
1960s and 1970 Early MoM hip implantsreplaced by metal on polyethylene (MoP)better performance and lower failure rates
late 1970s MoP devices-problems with
loosening, polyethylene wear debris and
osteolysis (e.g., bone destruction).
1980s MoM 2nd generation: advantages touted
such as low rates of wear and increased
stability; younger patients approved in US 1999
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Total hip arthroplasty
In 2010, there were approximately 456,000 hip
replacement procedures in the U.S
An estimated 27% of implanted devices were
composed of MoM load bearing surfaces
(USFDA).
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2010 DePuy issued a recall of its ASR hip
devices, after it was found that they were
failing in about 13% failed within 5 years UK
unpunished
Recall unrelated to cobalt chromium toxicitylocal failure issue
Pressures mounts on MoM implants
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Corrosion and wear-produce soluble metal ions
and metal debris- nanometric size with large
area/volume ratio (10 E+12 -10 E+14 particles
per year
Cobalt ions are released from the surface of the
particles to surrounding tissues
Metallosis
Necrotic and inflammatory changes probably
being caused by metal cytotoxicity and cellmediated hypersensitivity
Tissue necrosis, osteolysis
Solid or cystic pseudotumors
Implant loosening or pain- leads to revision
surgery
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Increased levels of cobalt and chromium found
in blood of persons with MoM
No consensus what are safe levels
Epidemiological studies lacking
Misinterpretation about some guidance levels
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The UK Medicines and Healthcare products
Regulatory Agency (MHRA) issued a blood
cobalt guidance value of 7 μ g/L: may
require closer surveillance due to an
association with excessive implant wear
Guidance makes no mention of potential
adverse systemic health effects occurring
at blood cobalt concentrations at or
greater than 7 μ g/L
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Rare persons have been identified in seven peer
reviewed scientific
Five of the seven reports involved an initial failed
ceramic prostheses that was replaced with metal
bearing but retaining polyethylene acetabulum
socket- retained ceramic fragments
Two cases had largely subjective nonspecific
symptoms with much lower Co and Cr levels
(Tower)
Two suspect poisoning (Mao)
Ikeda et. al, 2010; Oldenburg, Wagner, & Baur, 2009; Pazzaglia et. al, 2011; Rizzetti
et. al, 2009; Steens et. al, 2006; Tower, 2010; Mao2011
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September 2007 progressive visual and hearing loss
which had started 9 months earlier
2001 left hip arthroplasty revised October 2001
rupture ceramic head
Mild hypothyroidism
Neural exam impairment CN II-XII
Distal sensorimotor neuropathy: abnormal EMG:NCV
MRI hyperintensity of optic nerve tracks
Diagnosis of axonal multi-neuropathy- presumed
immune-mediated vasculitis- prednisone
Progessive completely blind deaf wheel chair bound
lower limb hyposthenia
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High doses used to induce erythrocyte synthesis –
treat anemia from 1940s -1970s
Reversible hypothyroidism coincident with cobalt
Nerve deafness (Gardener 1953 and Schrrmacher
1967)
Optic atrophy/visual impairment
(1972) Occupational exposure: 49 year male
bilateral deafness (sensorineural) and visual failure
(optic atrophy) blood cobalt 234 ug/l. Improved
with renal from exposure (Meechan and Humphrey
1991)
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1966, syndrome: pericardial effusion, elevated
hemoglobin levels, congestive heart failure- heavy beer
drinkers in Quebec City: abrupt onset of left ventricular
failure, pericardial effusion polycythemia thyroid lesions
following heavy alcohol consumption
1967 epidemics ‘‘beer drinker’s cardiomyopathy’’ in
Omaha and Minneapolis
Local breweries used cobalt in doses of 1–1.5 mg cobalt
chloride/L beer as a method to reduce the effect of soap
residues from electric dishwashers on the formation of
foam doses of cobalt much less than the dose previously
used for refractory anemia
Doses received much lower than therapeutic use
Other factors operative: nutritional deficiency alcohol –
unkown factor?
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erythrocytosis
hypothyroidism
cardiomyopathy
optic atrophy
hearing loss sensori neural
peripheral neuropathy
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No generaly accepted consensus for assessing
potential systemic health risks to implant
patients as a function of blood Co concentration.
The Mayo Clinic has suggested that undefined
Co-related effects might occur at blood Co
concentrations of 5 mg/L; however, the basis for
that suggestion is unclear (Mayo Clinic 2013)
Chromium is not thought to be a problem.
Trivalent chromium and not hexavalent
chromium (carcinogenic form)
• reference values: Co-values without clinical concern are at the moment:
less than 2 ug/L. The threshold value for clinical concern is expected to be
within the range of 2ug/L to 7 ug/L (exact levels have still to be
determined within this range;
• in increased values above the threshold additional imaging even in
asymptomatic patients is recommended.
Note: recommendations are based on local effects; critical
values for systemic effects have not yet been established
for patients after MoM implantation.
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Human volunteer experimental studies : cobalt ingestion 90 day
study to look at ADME and toxicity issues effect levels
Measured Co blood and urine levels, excretion as well as Co
speciation in serum, and a number of biochemical and clinical
parameters (nerve conduction, retinal assessment etc.) .
It was found in these studies that peak Co whole blood
concentration as high as 117 ug/L were not associated with
overall changes in hematological parameters such as increased
red blood cell (RBC) count, hemoglobin (Hgb) or hematocrit (Hct)
levels, nor with changes in cardiac, neurological or, thyroid
function.
Effects unlikely at levels of up to 300 ug/L
Source: Tvermoes BE, Unice KM, Paustenbach DJ, Finley BL, Otani JM, Galbraith
DA Effects and blood concentrations of cobalt after ingestion of 1 mg/d by
human volunteers for 90 d. Am J Clin Nutr. 2014 Mar;99(3):632-46
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Affect cobalt binding capacity
Affected by disease: scleroderma, diabetes,
bacterial or viral infections, end-stage renal
disease, liver cirrhosis, cancer, and
peripheral arterial disease
Genetic mutation may also decrease
albumin’s binding affinity for Co as the first
four residues of the N-terminus of albumin
bind both Cu and Co (Mothes and Faller
2007)
Unknown whether the presence of specific
mutations in the N-terminus results in
biologically significant
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30-day mortality rate following hip
arthroplasty ranges from around 0.2% to 0.8%
Medical complications including myocardial
infarction, cardiac failure, pneumonitis and
atelectasis, acute renal failure
thrombophlebitis, hemorrhage, urinary-tract
infections and gastrointestinal disturbances
have been reported to occur in 25% of
recipients
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Symptoms associated with systemic toxicity are
expected in the general population especially older
age groups
Such populations are expected to have visual and
hearing loses as well as other chronic diseases such
as cardiovascular disease, diabetes mellitus that
share clinical features with those of cobalt toxicity.
Determination regarding the presence of a cobalt
toxidrome should be based upon aggregate of
clinical findings, presence of increased metal ion at
levels in the range of those associated with systemic
toxicity in clinical literature, and clinical improvement
with diminution of metal ion levels if hip revision
surgery is performed.
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DePuy ASR (Johnson and Johnson 2.5 billion
8000 cases (recision surgery before August
13, 2013) base 250 K expect $4.0 billion
De Puy Oregon Department of Justice 4
devices sold 10,000 per hip
LA trial 8 million verdict – one month later
manufacturer victory Texas, then later Illinois