Contributed by Jessica Dwyer, MD and Octavia Peck Palmer, PhDFINAL DIAGNOSIS
ELEVATED BLOOD COBALT LEVELS IN A PATIENT WITH BILATERAL METAL-ON-METAL HIP PROSTHESES
DISCUSSION
The patient described in the preceding clinical vignette is an excellent example of a concerning medical topic emerging in the current news. Total hip replacement using implantable metal components is a common medical surgery that has been performed in North America for more than 50 years. The goal of total hip replacement is to maintain a functional joint while simultaneously delaying the need for surgical revision or replacement for as long as possible. Nearly 400,000 hip arthroplasty procedures are performed annually in the United States, and over the past decade, there has been an increasing trend of utilizing cobalt alloy-containing metal-on-metal prosthetic hip joints[1]. Conventional total hip prostheses are composed of a metal head that fits into a plastic, polyethylene cup. There have been concerns, especially among younger patients, that the plastic cup in conventional hip prostheses undergo more wear and tear with time, and are more likely to require revision. Therefore, metal-on-metal bearings have gained widespread popularity and have been used extensively, especially among younger, still active patients. The benefits touted by metal-on-metal prostheses is that there is less device wear since cobalt-alloy containing metal prostheses have a higher resistance to wear than polyethylene, a decreased risk of dislocation because of new designs and engineering modifications, and a decreased risk of device fracture[2-3]. However, there have been recent safety concerns regarding these prostheses, including excessive revision rates, local reactions to the prosthetic device, and high circulating metal ion levels in patients, which have led to product recalls, a medical device alert, and issuance of clinical guidelines by the United States' Food and Drug Administration (FDA). The biggest concern is that corrosion, wear, and other mechanical factors of the cobalt alloy-containing metal-on-metal prosthetic produce metal debris in the form of wear particles, which subsequently release soluble cobalt metal ions into the joint space and into the systemic circulation[4]. Over time, deposition of wear particles and metal ions in the joint space causes grey-black discoloration of the joint and elicits a localized chronic inflammatory response, findings referred to as metallosis. Metallosis is not a good thing, as it is often a cause of early prosthesis failure, and the tissue damage resulting from metallosis can compromise subsequent revision arthroplasties[5]. More importantly though, wear particles from the prosthesis also release soluble cobalt metal ions into the systemic circulation, creating incidentally elevated circulating concentrations of cobalt metal ions in these patients. Since cobalt has been shown to be carcinogenic and mutagenic in human and animal models, the potential for systemic toxicity and cancer risk are valid safety concerns for patients with these prostheses[4].
Cobalt Physiology
Cobalt is an essential, transition group metal present in trace amounts in the human diet, notably in fish, vegetables, and drinking water. It is an integral part of vitamin B12, and is required for oxygen transport in metabolism. When ingested, cobalt is rapidly absorbed from the small intestine, but the bioavailability is incomplete and variable[6]. When inhaled through the lungs, usually in the form of inorganic cobalt and cobalt oxide in dust and welding fumes, there is systemic dissemination of cobalt metal ions through the lymphatic and vascular system[6]. Following a single dose of cobalt, the concentration in the blood and serum is initially high, but rapidly decreases to a low level within 24 hours due to the combination of tissue uptake, primarily in the liver and kidney, and urinary excretion. Studies of whole-body retention of inorganic cobalt in physiologically normal adult human males after intravenous injection demonstrated that approximately 40% of the dose was eliminated within the first 24 hours, 70% by one week, after one month 20% was retained, and after one year 10% was retained[7-8]. With chronic systemic exposure, cobalt accumulates in tissue, again primarily the liver and kidney, and the cobalt level will be elevated in the serum, whole blood, and urine[9]. Following cessation of the chronic exposure, the concentration of cobalt decreases by 51±21% and 66±29% in the blood and urine, respectively[10].
Cobalt Toxicity
Cobalt deficiency has never been described in humans, but cobalt toxicity has been well-documented. Cobalt is acutely toxic in large doses, and in cumulative long-term, low level exposure, i.e occupational exposure from cobalt processing plants, hard metal industry, diamond polishing, and the ceramic industry. Most of what is known about cobalt toxicity comes from cases of ingestion or inhalation of excess cobalt. For example, a notable historical example of cobalt toxicity is the cohorts of patients given cobalt chloride nearly 40 years ago to treat refractory anemia. For some unclear reason, cobalt salts stimulate the production of erythropoietin, and before the availability of recombinant human erythropoietin, cobalt salts were regularly used in clinical practice for the treatment of anemia[6]. However, this practice was discontinued after some patients developed systemic symptoms of cobalt toxicity. The symptoms of cobalt toxicity documented in the literature are variable, but typically involve derangements of endocrine, cardiac, and neurological function[1]:
Endocrinopathy: The classic endocrinopathy associated with cobalt toxicity is hypothyroidism. According to some sources, hypothyroidism is also considered to be the most sensitive indicator of cobalt toxicity.
Cardiovascular dysfunction: A notable toxic effect of cobalt exposure is a severe and often fatal cardiomyopathy. This finding was well-documented in the 1960s among heavy beer drinkers after local breweries added cobalt chloride or cobalt sulfate to their beer as a foam stabilizer, so called beer drinkers' cardiomyopathy6. Post-mortem studies of the heart in these patients confirmed accumulation of cobalt within the myocardium. Cobalt-induced myocardial injury was also implicated in a study of hard metal workers chronically exposed to cobalt, and another study of Finnish cobalt workers revealed that cumulative cobalt exposure was associated with subclinical echocardiographic changes[6].
Neurologic dysfunction: There are various neurotoxic symptoms described in patients with presumed cobalt toxicity, including hearing loss, tinnitus, optic nerve atrophy, visual impairment, convulsions, vertigo, headaches, tremors, polyneuropathy, incoordination, cognitive decline, and depression. Unfortunately, most neurologic symptoms are highly subjective, but some can be proven objectively, including optic nerve atrophy, audiometry-confirmed hearing loss, and abnormal neurologic function illustrated by electrodiagnostic studies such as an electroencephalograms (EEG) or electromyograms (EMG).
Skin Malady: Exposure to cobalt can occasionally produce dermatitis, but typically hypersensitivity reactions are less commonly associated with cobalt than other metals, such as nickel.
Mechanism of Cobalt Toxicity
A precise, unifying mechanism of cobalt toxicity remains unclear. It has been proposed that many of the adverse effects of cobalt are secondary to its high affinity for sulfhydryl groups. Some of the mechanisms proposed include inhibition of crucial enzymes in mitochondrial oxidative phosphorylation, inhibition of thyroid iodinase, inhibition and competition with calcium binding and signaling, generation of reactive oxygen species, and direct cytotoxicity[1, 6].
Diagnosis of Cobalt Toxicity
The diagnosis of cobalt toxicity is based on the combination of clinical history and laboratory confirmation. The preferred method of testing is inductively coupled mass spectrometry for metal ion value determination, and the typical patient specimens tested include serum, whole blood, or urine. Cobalt metal ion values are typically reported in units of micrograms/liter (µg/L). In the blood, cobalt metal ions bind to albumin with an estimated free fraction of approximately 5 to 12%[6]. The more commonly reported value for cobalt metal ion concentration is the serum value, which is considered to be reflective of the extracellular fluid levels. Others suggest that whole blood values provide a more accurate assessment of systemic exposure[1, 6]. According to one reference, a serum cobalt metal ion concentration greater than 1 µg/L is suggestive of excessive cobalt exposure, and a value greater than 5 µg/L is considered likely toxic[11]. However, caution must be applied when testing and interpreting cobalt levels in patients with cobalt alloy-containing metal-on-metal prostheses since these patients tend to have incidentally higher circulating cobalt metal ion concentrations, sometimes greater than 5 µg/L, but may not have symptoms of cobalt toxicity. To this day, it is unclear whether elevated cobalt metal ion levels should be considered toxic in patients with cobalt alloy-containing metal-on-metal prostheses, especially if they are asymptomatic, since no clear correlation has even been made between cobalt concentration and physiologic effects (to be discussed later)[12]. Contrastingly, if a patient has subjective and objective clinical evidence of systemic cobalt toxicity, has elevated cobalt metal ion concentrations, and no history of a cobalt alloy-containing metal-on-metal prostheses, a diagnosis of cobalt toxicity may be more straightforward.
Treatment of Cobalt Toxicity
There is no consensus regarding the treatment of patients with systemic symptoms of cobalt toxicity, and clinical response to these treatments is inconsistently documented in the current literature[1]. The main objective of treatment is to eliminate the exposure to cobalt and to treat the systemic symptoms supportively, such as thyroid replacement therapy, beta-blockers, angiotensin-converting enzyme inhibitors (ACE inhibitors), diuresis, corticosteroid therapy, etc[1]. There are no established indications for chelation therapy[1].
Arthroprosthetic cobaltism
Since 2006, there have been increasing reports in the literature of patients with cobalt alloy-containing metal prostheses developing systemic symptoms of cobalt toxicity, termed athroprosthetic cobaltism[13]. These patients presented with combinations of deafness, blindness, cognitive decline, headaches, convulsions, fatigue, heart failure, and hypothyroidism, all had hip pain resulting from periprosthetic metallosis, and all had serum cobalt concentrations of more than 60 µg/L. In 2010, the first published report of arthroprosthetic cobaltism specifically attributed to cobalt alloy-containing metal-on-metal hip prostheses was described[13]. These patients also presented with severe neurologic and cardiac symptoms, hip pain resulting from periprosthetic metallosis, and elevated serum cobalt concentrations, up to 122 µg/L. Since these reports, DePuy Orthopaedics, Inc (Warsaw, IN) recalled their ASRTM metal-on-metal bearings because of a five year-prosthetic failure rate of more than 12% due to metallosis[3]. Yet, more importantly, these patients with cobalt alloy-containing metal-on-metal hip prostheses that require revision surgeries due to metallosis have elevated circulating cobalt levels and may be at risk for systemic cobalt toxicity. Multiple studies have confirmed that patients with cobalt alloy-containing metal-on-metal hip prostheses, especially bilateral and/or malfunctioning prostheses, have significantly higher concentrations of circulating cobalt metal ions, usually greater than 10 µg/L and even sometimes up to 100 times that of physiologic levels4, [14-16]. However, studies comparing the clinical and laboratory features of patients with cobalt alloy-containing metal-on-metal hip prostheses and suspected cobalt toxicity to asymptomatic patients with metal-on-metal hip prostheses have not been performed. Therefore, there are no current definitive conclusions regarding the association of suspected arthroprosthetic cobaltism with specific clinical, physical, imaging, or laboratory findings. Instead, government authorities in the United States and United Kingdom have released recommendations for management of both symptomatic and asymptomatic patients with cobalt alloy-containing metal-on-metal hip prostheses and elevated circulating cobalt metal ion concentrations. In the United States, the FDA defines "symptomatic patients" as patients experiencing localized symptoms, such as pain or swelling at the hip, change in walking ability, and noise from the joint, after more than 3 months following implantation of the cobalt alloy-containing metal-on-metal hip prosthesis[17]. In these patients, they advise to consider serial cobalt metal ion testing, but also strongly advise interpretation of these levels in the context of the patient's clinical symptoms, baseline renal function, and potential alternative sources of cobalt. The FDA does not provide specific metal ion values that should trigger medical action, mostly because there is insufficient evidence to demonstrate a correlation between a specific cobalt metal ion level and specific pathology[17]. Therefore, the cobalt metal ion concentration value of concern is unknown. Essentially, they suggest that these patients should be followed carefully and specifically questioned regarding alterations in neurological, cardiac, and endocrine function. Yet, even if a patient is symptomatic and highly suspicious for arthroprosthetic cobaltism, there is inadequate information provided by the FDA to guide clinical decision making because no consensus has been reached in regard to treatment of these patients. Instead, if there is a gradual increase in circulating cobalt metal ion concentrations or there are concerning systemic symptoms, the patient should be promptly evaluated by an orthopedic surgeon for appropriate further medical action. In the United Kingdom, the Medicines and Healthcare Products Regulatory Agency (MHRA) recommends following patients with cobalt alloy-containing metal-on-metal hip prostheses for cobalt toxicity symptoms at least annually for five years post-implantation[1]. It is also recommended to perform cobalt metal ion testing and imaging studies for any patients that report painful hip replacements. If the whole blood cobalt metal ion concentration in these patients is greater than 7 µg/L, a second metal ion test should be performed three months later and the patient should be assessed for cardiac and neurologic symptoms[1]. Interestingly, the impetus for the inquiry leading to these recommendations was an increase in metal-on-metal hip device failure, not to address patients with systemic cobalt toxicity. Therefore the 7 µg/L threshold was derived from a population reference range, and indicates a potential for periprosthetic soft tissue reaction/metallosis and a need for closer surveillance[1]. This value was not derived from a comparison of symptomatic to asymptomatic patients with cobalt alloy-containing metal-on-metal prostheses, and thus does not serve as a threshold value to evaluate for systemic cobalt toxicity.
Recently in November 2013, Pizon et al. from the Division of Toxicology at the University of Pittsburgh School of Medicine (Pittsburgh, PA, USA) proposed diagnostic criteria for arthroprosthetic cobaltism secondary to cobalt alloy-containing metal hip prostheses[18]. These criteria were created as an objective approach to making the diagnosis of arthroprosthetic cobaltism since the evaluation of systemic cobalt toxicity in patients with metal hip prostheses is often complicated by limited published data, subjective patient symptoms, comorbid conditions, or secondary financial gain. Their criteria are defined as:
The authors explain that these criteria are not a means to evaluate for prosthetic hardware failure, but are a means to specifically identify systemic cobalt toxicity by eliminating potentially subjective clinical symptoms. When these criteria are applied to the currently published cases of arthroprosthetic cobaltism secondary to cobalt alloy-containing metal-on-metal hip prostheses, the circulating serum cobalt metal ion concentrations are typically very high, usually approaching 100 µg/L, before systemic cobalt toxicity is objectively identified. Therefore, elevated cobalt metal ion levels should always be interpreted within the context of the patient's clinical history. Further studies validating these new proposed criteria are not currently available.
Finally, there is no current consensus regarding the management of patients with cobalt alloy-containing metal-on-metal hip prostheses and elevated circulating cobalt metal ion levels, and there is little information available regarding the clinical course of arthroprosthetic cobaltism from cobalt alloy-containing metal-on-metal hip prostheses. The main objective in treating symptomatic patients with cobalt alloy-containing metal-on-metal hip prostheses is hardware revision or removal[1]. A few studies have been conducted regarding the role of chelation therapy in arthroprosthetic cobaltism, but there is no reliable data to suggest its efficacy[1]. Studies following patients with arthroprosthetic cobaltism have demonstrated symptom improvement and declining circulating cobalt metal ion levels after removal of the implanted hardware, especially in patients with endocrinopathies and cardiomyopathy. However, other studies have demonstrated persistence of neurologic symptoms even after the hardware is removed[1]. Studies comparing the symptoms of patients pre-exposure, during exposure, at the point of maximal symptoms, and following hardware removal would be the most helpful in defining the clinical course of arthroprosthetic cobaltism, but these have not been performed. In general, improved case definitions, controlled studies, and improved surveillance are needed to fully elucidate the course of this relatively new disease and direct further investigations.
So, does the patient described in the previous clinical vignette have arthroprosthetic cobaltism secondary to his bilateral cobalt alloy-containing metal-on-metal hip prostheses? When the patient was discharged from the hospital in February 2013, he was evaluated in an outpatient toxicology clinic. During this appointment, he reported symptoms of intermittent confusion, short-term memory loss, difficulty concentrating, poor attention, dysthymia, increased falling episodes, fatigue, and chronic headaches since his bilateral hip replacements in 2008. The toxicologist evaluating the patient mentioned that the patient exhibited tangential speech, and that it was extremely difficult to elucidate a clear clinical history and progression of symptoms from the patient. In his assessment, the toxicologist noted that in the documented cases of arthroprosthetic cobaltism secondary to cobalt alloy-containing metal-on-metal hip prostheses, the serum cobalt metal ion concentration is often close to, if not greater than, 100 µg/L. However, the patient's most recent serum cobalt metal ion concentration during his hospitalization was 3.1 µg/L, and even at its highest level was 11.4 µg/L. Based on the most recent level, which is really only about 2-3 times the normal limit, the toxicologist was not convinced that this was consistent with cobalt toxicity. Instead, he attributed the slightly elevated serum cobalt metal ion level to mild leeching of cobalt from the prosthetic hip, a common occurrence in patients with prosthetic hips. In addition, he noted that the patient lacked other symptoms of systemic cobalt toxicity including hypothyroidism and cardiomyopathy. The patient's neurologic complaints are certainly found in patients with cobalt toxicity, but they are mostly subjective, non-specific, and when put in the context of the relatively low serum cobalt metal ion level, are unlikely to be the result of cobalt toxicity. Instead, the toxicologist alluded to the fact that the patient was not taking his pain medication and was endorsing symptoms of worsening anxiety and depression, medical conditions he was diagnosed with prior to his bilateral hip replacements in 2008. Untreated chronic pain and depression are both known to contribute to cognitive changes and somatic symptoms. Therefore, the final recommendations for this patient were that he be re-evaluated by his pain specialist, undergo extensive psychiatric testing, and have his hips re-assessed by orthopedic surgery.
REFERENCES
Contributed by Jessica Dwyer, MD and Octavia Peck Palmer, PhD
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