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74 (); 113-123
doi:
10.1016/j.jor.2025.12.064

A systematic review and meta-analysis of cases of prosthetic hip-associated cobalt toxicity in patients with prosthetic hip ceramic bearing fractures subsequently revised to metal-on-polyethylene implants

,
a National Orthopaedic Hospital Cappagh, Cappagh Rd, Finglas, Dublin 11, D11 EV29, Republic of Ireland
b St. Vincent's University Hospital, Elm Park, Dublin 4, D04 T6F4, Republic of Ireland

⁎Corresponding author: Patrick Sweeney. patricksweeney24@rcsi.ie

Received: , Accepted: ,
Professor P K Surendran Memorial Education Foundation
Disclaimer:
This article was originally published by Reed Elsevier India Pvt. Ltd. and was migrated to Scientific Scholar after the change of Publisher.

Abstract

Abstract

Prosthetic hip-associated cobalt toxicity (PHACT) remains a rare but serious complication, potentially leading to missed diagnoses and delayed treatment. This systematic review explores cases of PHACT associated with fractured ceramic bearing followed by revision surgery with metal-on-polyethylene implants. Notably, patients in this subgroup often exhibited earlier symptom onset and elevated cobalt ion levels. Through a systematic review, we aim to explore and summarise the most common symptoms and clinical outcomes associated with PHACT among this specific patient subgroup. Our focus is on identifying patterns of systemic symptoms and associated clinical outcomes.

Adhering to PRISMA guidelines, we conducted a structured search across PubMed, Medline, and Scopus databases. Inclusion criteria comprised published case reports or case series detailing PHACT cases after ceramic bearing fractures revised to metal-on-polyethylene bearings. Over 30 cases were identified, and their clinical presentations and outcomes were analysed.

The majority of PHACT cases in this cohort presented with cardiovascular manifestations (cardiomyopathy, cardiogenic shock, and heart failure), neurological symptoms (visual impairment, sensorineural hearing loss, and cognitive impairment), and endocrine dysfunction (thyroid dysfunction). Various atypical symptoms were also observed.

PHACT within this patient group presents insidiously with diverse, sometimes overlapping, systemic symptoms. The study highlights the potential for missed diagnoses due to the lack of apparent risk factors or related medical history. This review strongly advocates for proactive, registry data-driven identification of at-risk patients, as well as the opportunity for follow-up assessment and cobalt level monitoring. This study also highlights the importance of ceramic-on-polyethylene based revision in cases of ceramic bearing fractures.

Keywords

Systemic metallosis
Cobalt toxicity
Ceramic
Fracture
Total hip arthroplasty
Metal-on-polyethylene
1

1 Introduction

Total hip arthroplasty (THA) has emerged as a highly successful surgical procedure over the past few decades, with the capacity to restore physical function and positively impact patients' lives.1 Longevity analyses have shown that up to 58 % of primary THA's remain in situ 25 years post-op.1 Generations of prosthetic hip implant systems have evolved with variations in modular component parts, as well as the materials used, including metal (titanium or cobalt-chromium alloy), ceramic, and highly cross-linked polyethylene (HXLPE).2 Various combinations of bearing surface materials have emerged over the years including; metal-on-metal (MoM), metal-on-polyethylene (MoP), ceramic-on-ceramic (CoC), and ceramic-on-polyethylene (CoP). One of the challenges in developing the optimum component material has centred around identifying a material robust enough to resist wear or fracture, while remaining stable, and non-toxic.3

Metal ion toxicity (particularly cobalt toxicity) can arise as a result of metal-containing hip implants. Highly reactive metal ions can be generated by either corrosion of the metal component, or by a variety of wear mechanisms when the metal component articulates against surrounding surfaces under load.4 Two-body abrasive or adhesive wear occurs over time, e.g. as a result of the head articulating directly with the liner. Third-body wear occurs as a result of exogenous hard particles (e.g. ceramic particles, bone cement etc). These exogenous particles can become trapped between articulating surfaces; effectively acting as an abrasive “third-body”, substantially accelerating surface damage.2,5 Laboratory simulation studies have demonstrated that ceramic particles can be particularly abrasive third-bodies due to their distinct hardness and angularity.2,5 The local effects of metal ion toxicity in surrounding tissues are relatively well recognised in the literature. These local “adverse reactions to metal debris” (ARMD), range from local muscle necrosis, to pseudo-tumours, and osteolysis.6,7 By contrast, prosthetic hip-associated cobalt toxicity (PHACT) refers to a systemic toxicity, which is far more rare. This arises from cobalt ions entering the circulation; giving rise to a wide range of systemic pathologies.8,9

Systemic PHACT emerged as a risk associated with MoM implants following a resurgence in their popularity in the early 2000's, ultimately leading to MoM prostheses largely falling out of favour.8 By contrast, the risk of PHACT remained relatively low among MoP implants. Fracture of a ceramic bearing component is a relatively rare, albeit possible complication of ceramic prostheses (CoC/CoP).3 In recent years, a growing number of case reports and series have appeared in the literature describing systemic PHACT in patients who had suffered a ceramic bearing fracture, which was subsequently revised to MoP bearings.10 The suggested hypothesis being that, in spite of debridement and irrigation during revision surgery, the vast microscopic ceramic particles which can be retained in the local tissues following ceramic bearing fracture, have the potential to cause catastrophic third-body abrasion and metal ion release.3,5 By contrast, the use of a CoP implant during revision of a fractured ceramic bearing could avoid this drastic metal ion release, and likely avoid this complication.

A pattern has emerged in the literature among reported cases of PHACT secondary to revision of fractured ceramic bearing to MoP implant, with many previously-well patients presenting with a similar array of systemic pathologies. Most commonly, these involve the neurological system; with sensorineural hearing loss, visual impairment and cognitive decline. The cardiovascular system; including cardiomyopathy and cardiogenic shock. As well as the endocrine and respiratory systems. Onset of symptoms is typically seen in the first two years after surgery, although many cases describe a more gradual onset.9

Given the insidious nature of this condition, and obvious potential for missed or delayed diagnoses, it is important to identify potentially at-risk patients, and to develop diagnostic criteria to recognise the condition before systemic damage becomes irreversible. We have carried out a systematic review of cases of PHACT among patients with fractured ceramic bearing subsequently revised with a MoP implant. Our aim was to further elucidate and summarise the common symptoms associated with this condition. We also aimed to investigate the patient outcomes associated with these symptoms. Our intention was that this will serve to inform recommendations for the management and recognition of PHACT in this patient cohort. We believe this will also highlight the opportunity and need for increased vigilance and monitoring of this patient cohort by way of follow-up through national registry databases.

2

2 Methods

2.1

2.1 Design and objectives

This systematic review was conducted in adherence with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Our aim was to explore and summarise the most common symptoms associated with systemic metallosis, and to analyse the reported clinical outcomes. The primary outcome measure was the full spectrum of presenting symptoms reported, and their associated physiological systems. Secondary outcome measures included peak blood cobalt concentrations, symptom onset time, survival, interventions required, and the extent of subsequent symptom resolution. As this was a systematic review of previously published studies, ethical approval was not required for this research.

2.2

2.2 Eligibility criteria

We included peer-reviewed case reports or series that; i). Described systemic metallosis; ii). Involved index ceramic hip bearing fracture; and iii). Were revised to MoP bearing prior to the onset of systemic manifestations.

Cases were excluded if they reported; revisions to non-MoP bearings after ceramic fracture, non-ceramic index implant fractures, instances of PHACT following primary THA only, or cases reporting local adverse tissue reactions (ARMD) only.

2.3

2.3 Search strategy

A structured literature search was carried out on October 10, 2024 using PubMed, Medline, Scopus, EMBASE, Cochrane Library (wiley), CINAHL (EBSCO), and Web of Science (Clarivate Analytics). Keywords included; “cobalt toxicity”, “ceramic”, “fracture”, “total hip arthroplasty”, and “metal-on-polyethylene”. The full search string is available as supplementary material. Duplicates were identified and removed using Endnote V20. Papers were screened for eligibility by title and abstract by two independent authors. Full text versions of appropriate studies were retrieved for further assessment. Disagreements regarding study selection where addressed during a consensus meeting. The process for case selection is illustrated in the PRISMA flowchart (Fig. 1.).

PRISMA 2020 Flow diagram of included cases.
Fig. 1 PRISMA 2020 Flow diagram of included cases.
2.4

2.4 Data collection

A data extraction proforma was developed to capture the relevant data using MS Excel. Variables gathered included; age, sex, indication for primary total hip arthroplasty, fractured component (head, liner, both), presenting symptoms, associated physiological systems, time to onset of symptoms (months), peak blood cobalt concentration (μg/L), definitive re-revision surgery, additional interventions required, symptom resolution (full, partial, none), and survival. Symptom onset time was standardised to months, regardless of whether the studies reported weeks or years. Blood cobalt concentrations were standardised to micrograms per litre (μg/L), and converted when reported in alternative units. Where symptom descriptions varied across studies, they were standardised to concise, clinically recognised descriptors (e.g., “hearing impairment” was recorded as “hearing loss”). Presenting symptoms were also mapped to physiological system categories. The included cases consistently reported blood cobalt levels and cobalt-related toxicity, whereas chromium levels were rarely documented. Consequently, chromium levels and chromium toxicity were not analysed in this review.

2.5

2.5 Quality and risk of bias assessment

Included reports underwent a methodological quality assessment, using two established appraisal tools best suited for case-based designs. The Joanna Briggs Institute (JBI) checklist for case reports and series is a tool designed to appraise the quality of case reports.11,12 We recorded the percentage of checklist items answered “Yes” for each case. In order to classify the outcome of the JBI assessment, we categorised the quality of cases as follows: High (≥75 % Yes), Moderate (50–74 % Yes), or Low (<50 % Yes).

We also used a modified version of a checklist developed by Murad et al. to assess quality and risk of bias in case reports, similar to a study by Crutsen et al.10,13 It is a modification of the Newcastle-Ottawa Scale (NOS), consisting of an eight-question tool. As questions five and six were designed for pharmacological interventions, they were excluded from the assessment.14 Each study was therefore scored on a maximum of six items and classified as high (≥5), moderate 3,4, or low quality (≤2).

2.6

2.6 Data analysis

Descriptive and comparative statistical analyses were performed using Jamovi (version 2.6.26.0). Continuous variables are expressed as mean ± standard deviation (SD), or median with interquartile range (IQR) depending on data distribution. Statistical analyses were performed to measure: i). Peak cobalt levels vs. survival, ii). Peak cobalt levels vs. symptom resolution, iii). Fractured component vs. outcomes, iv). Time to onset vs survival. Non-parametric statistical tests (Mann-Whitney U test, Kruskal-Wallis test, Fisher's Exact test, and Chi-square test) were deemed most appropriate where data was not normally distributed, and involved small subgroups. P-values of <0.05 were considered statistically significant.

2.7

2.7 Handling of outliers

One cobalt level was identified as an extreme outlier (397,800 μg/L); due to its disproportionate effect on data distribution, this was excluded from statistical analyses but retained in the dataset and reported descriptively.

3

3 Results

3.1

3.1 Study selection

Our search identified 304 publications. Following removal of 87 duplicates, 217 records were screened by title and abstract. A further 154 records were excluded due to non-case report study designs. A further 35 were excluded following abstract review. 28 papers underwent full-text assessment. Screening of references yielded 2 additional cases. This resulted in 30 included papers, encompassing 31 individual cases (one two-patient case series) (see Table 1).

3.2

3.2 Quality assessment

The quality assessment analysis is summarised in Table 2 The majority of studies were deemed to reach good quality. All but one case scored highly on the JBI criteria for quality case description. Frequently, cases lacked standardized longitudinal follow-up, and toxicity sampling protocols. All but one case was deemed to reach high quality according to the adapted Murad et al. tool.

Table 1 Summary data of included cases.
Case Paper Reported Presenting Features Major Systems Associated Onset Time (months) Peak Blood Cobalt (μg/L) Additional Interventions Symptoms Resolution Survival
1 Gautam et al.15 Dyspnoea; Fatigue; Weakness; Cardiomyopathy Respiratory; Constitutional; Cardiovascular 36 373.0 Re-revision surgery None No
2 Zywiel et al.16 Fatigue; Anorexia; Weight loss; Hypothyroidism; Hip pain; Dyspnoea; Cardiomyopathy; Pericardial effusion Constitutional; Endocrine; Musculoskeletal; Cardiovascular; Respiratory 6 6521.0 Re-revision surgery; Chelation Therapy; Mechanical circulatory support None No
3 Balbouzis et al.17 Hip pain; Erythema nodosum; Chorioretinitis; Papilledema; Granulomatous lung disease; Cardiomyopathy Musculoskeletal; Dermatologic; Ophthalmic; Respiratory; Cardiovascular 6 22.2 Re-revision surgery Full Yes
4 Biglia et al.18 Fever; Fatigue; Arthralgia; Hip pain; Lymphadenopathy; Anaemia; Constitutional; Musculoskeletal; Cardiovascular; Haematologic 12 7.0 Re-revision surgery Full Yes
5 Castrillo et al.19 Hearing loss; Fatigue; Weight loss; Cardiomyopathy; Heart failure; Cardiogenic shock; Arrhythmia; Polycythaemia Auditory; Constitutional; Cardiovascular; Haematologic 48 595.0 Re-revision surgery; Mechanical circulatory support; Heart transplant Full Yes
6 Choi et al.20 Dyspnoea; Fatigue; Hip pain; Paraesthesia; Dysaesthesia; Weakness; Hearing loss; Cardiomyopathy; Pericardial effusion Respiratory; Constitutional; Neurological; Musculoskeletal; Auditory; Cardiovascular 12 489.5 Re-revision surgery; Chelation Therapy Full Yes
7 Choi et al.20 Dyspnoea; Cardiomyopathy; Pericardial effusion; Renal failure; Heart failure Respiratory; Cardiovascular; Renal; Constitutional 72 111.98 Re-revision surgery; Heart and kidney transplant Partial Yes
8 Citak et al.21 Fatigue; Hip pain; Vision loss; Hearing loss; Myocarditis Constitutional; Musculoskeletal; Ophthalmic; Auditory; Cardiovascular 84 1000.0 Re-revision surgery Full Yes
9 Dahms et al.22 Heart failure; Hearing loss; Vision loss; Fever; Hypothyroidism; Lymphadenopathy; Cardiomyopathy Cardiovascular; Auditory; Ophthalmic; Endocrine; Constitutional; Gastrointestinal; Haematologic 18 884.0 Re-revision surgery; Chelation Therapy Partial Yes
10 Dolliana et al.23 Vision loss; Hearing loss; Cognitive decline; Weight loss; Diarrhoea; Rash; Hip pain; Weakness; Hypothyroidism; Hypertension; Renal failure; Cardiomyopathy; Arrhythmia Ophthalmic; Auditory; Neurological; Constitutional; Dermatologic; Musculoskeletal; Endocrine; Cardiovascular; Gastrointestinal; Renal 96 818.0 None No
11 Fox et al.24 Hip pain; Dyspnoea; Pulmonary embolism; Cardiomyopathy; Hearing loss; Dysgeusia; Weight loss; Fatigue Musculoskeletal; Respiratory; Cardiovascular; Auditory; Constitutional; Gastrointestinal 10 641.6 None No
12 Garcia et al.25 Vision loss; Central scotomas; Optic neuropathy; Retinopathy; Hearing loss; Hypothyroidism; Arrhythmia; Cardiomyopathy; Headaches; Fatigue; Paraesthesia Ophthalmic; Auditory; Endocrine; Cardiovascular; Neurological; Constitutional 12 1100.0 Re-revision surgery Partial Yes
13 Gilbert et al.26 Hip pain; Dyspnoea; Fatigue; Weight loss; Hypothyroidism; Cardiomyopathy; Pericardial effusion; Liver failure; Polycythaemia Musculoskeletal; Respiratory; Constitutional; Endocrine; Cardiovascular; Gastrointestinal; Haematologic 96 1085.0 Re-revision surgery; Mechanical circulatory support; Chelation therapy None No
14 Grant et al.27 Insomnia; Weight loss; Tachycardia; Paraesthesia; Hearing loss; Vision loss; Nausea; Vomiting; Dysgeusia; Hypothyroidism Endocrine; Cardiovascular; Neurological; Auditory; Ophthalmic; Constitutional; Gastrointestinal 2 2148.0 Re-revision surgery; Therapeutic plasma exchange; Haemodialysis; Chelation therapy Partial Yes
15 Griffiths et al.28 Hip pain; Weakness; Paraesthesia; Dyspnoea; Nausea; Vomiting; Weight loss; Hearing loss; Vision loss; Hypothyroidism; Polyneuropathy; Heart failure Musculoskeletal; Neurological; Respiratory; Gastrointestinal; Constitutional; Auditory; Ophthalmic; Endocrine; Cardiovascular 72 2700.0 Re-revision surgery; Chelation therapy Partial Yes
16 Grillo et al.29 Vision loss; Hearing loss; Hypothyroidism; Cardiomyopathy; Hip pain; Rash; Diarrhoea; Cognitive decline Ophthalmic; Auditory; Endocrine; Cardiovascular; Musculoskeletal; Dermatologic; Gastrointestinal; Neurological; Constitutional 9 1078.0 Re-revision surgery Partial Yes
17 Harris et al.30 Hip pain; Fatigue; Memory loss; Paraesthesia; Arrhythmia; Hypothyroidism; Vision loss Musculoskeletal; Constitutional; Neurological; Cardiovascular; Endocrine; Ophthalmic 96 788.0 Re-revision surgery Partial Yes
18 Heuer et al.31 Vision loss; Hearing loss; Polyneuropathy; Hypothyroidism; Hypertension; Polycythaemia; Paraesthesia; Cognitive decline Ophthalmic; Auditory; Neurological; Endocrine; Cardiovascular; Haematologic 12 884.0 Re-revision surgery; Chelation Therapy Partial Yes
19 Ikeda et al.32 Dysaesthesia; Paraesthesia; Gait disturbance; Weakness; Hearing loss; Hypothyroidism; Malaise; Fever; Hip pain; Arthralgia Neurological; Auditory; Endocrine; Constitutional; Musculoskeletal 24 400.0 Re-revision surgery; Haemodialysis Partial Yes
20 Kim et al.33 Dyspnoea; Heart failure; Pleural effusion; Pericardial effusion; Hip pain; Weakness; Paraesthesia Cardiovascular; Respiratory; Musculoskeletal; Neurological 6 397800.0 Re-revision surgery; Chelation Therapy Partial Yes
21 Lecoanet et al.34 Fever; Weakness; Arrhythmia; Weight loss; Cognitive decline; Memory loss; Hearing loss; Vision loss; Dysgeusia Constitutional; Cardiovascular; Musculoskeletal; Neurological; Auditory; Ophthalmic; Gastrointestinal 12 1461.0 Re-revision surgery; Chelation Therapy Full Yes
22 Oldenburg et al.35 Fatigue; Cognitive decline; Paraesthesia; Headaches; Seizures; Weight loss; Rash; Dysgeusia; Hearing loss; Arrhythmia; Hypothyroidism; Cardiomyopathy Constitutional; Neurological; Dermatologic; Gastrointestinal; Haematologic; Auditory; Cardiovascular; Endocrine 3 625.0 Re-revision surgery Partial Yes
23 Pelayo-de Tomás et al.36 Hip pain; Weakness; Weight loss; Jaundice; Urticaria; Dysaesthesia; Hypothyroidism; Hearing loss Musculoskeletal; Constitutional; Dermatologic; Gastrointestinal; Neurological; Endocrine; Auditory 12 651.0 Re-revision surgery Full Yes
24 Pelclova et al.37 Paraesthesia; Gait disturbance; Weight loss; Hearing loss; Cardiomyopathy; Polyneuropathy; Hypothyroidism Neurological; Auditory; Cardiovascular; Endocrine; Constitutional; Musculoskeletal 14 506.0 Re-revision surgery; Chelation Therapy Partial Yes
25 Peters et al.38 Hip pain; Cognitive decline; Memory loss; Hypothyroidism; Vision loss; Vertigo; Hearing loss; Weight loss; Fatigue; Diarrhoea; Vomiting; Arrhythmia; Cardiomyopathy Musculoskeletal; Neurological; Endocrine; Ophthalmic; Auditory; Gastrointestinal; Constitutional; Cardiovascular 12 596.5 None No
26 Rizzetti et al.39 Vision loss; Hearing loss; Polyneuropathy; Weakness; Hypothyroidism; Weight loss; Fatigue; Headaches; Paraesthesia; Seizures Ophthalmic; Auditory; Neurological; Endocrine; Constitutional 9 549.0 Re-revision surgery; Chelation Therapy Partial Yes
27 Samargandi et al.40 Hearing loss; Vision loss; Hypothyroidism; Polycythaemia; Fatigue; Weakness; Paraesthesia; Cardiomyopathy; Hip pain Auditory; Ophthalmic; Endocrine; Haematologic; Neurological; Cardiovascular; Constitutional; Musculoskeletal 12 86.3 Re-revision surgery Partial Yes
28 Sanz Pérez et al.41 Hip pain; Dyspnoea; Fatigue; Cardiogenic shock; Polycythaemia Musculoskeletal; Respiratory; Cardiovascular; Constitutional; Haematologic 24 652.0 Re-revision surgery; Chelation Therapy; Heart transplant Full Yes
29 Vasukutty et al.42 Dyspnoea; Chest pain; Cardiomyopathy; Cognitive decline; Memory loss; Hip pain Cardiovascular; Neurological; Musculoskeletal 84 44.8 Re-revision surgery Partial Yes
30 Weber et al.43 Vision loss; Optic neuropathy; Hearing loss; Paraesthesia; Gait disturbance; Polycythaemia; Fatigue; Weight loss; Cardiomyopathy Ophthalmic; Auditory; Neurological; Haematologic; Constitutional; Cardiovascular 18 411.0 Re-revision surgery Partial Yes
31 Apel et al.44 Vision loss; Optic neuropathy; Retinopathy; Weakness; Bulbar palsy; Cardiomyopathy; Arrhythmia; Hypothyroidism; Pulmonary embolism; Fatigue Ophthalmic; Neurological; Cardiovascular; Endocrine; Respiratory; Constitutional 60 446.0 Re-revision surgery Partial Yes
Table 2 Quality assessment appraisal summary.
Study (Author, Year) Design JBI Criteria (%) JBI Quality Murad (0–6) Murad Quality
Apel et al. (2013) Case report 88 High 5.5 High
Balbouzis et al. (2016) Case report 88 High 5.5 High
Biglia et al. (2020) Case report 88 High 5.5 High
Castrillo et al. (2021) Case report 100 High 6 High
Choi et al. (2019) Case series 56 Moderate 4.5 Low
Citak et al. (2018) Case report 88 High 5.5 High
Dolliana et al. (2016) Case report 88 High 5.5 High
Fox et al. (2016) Case report 100 High 5.5 High
García et al. (2020) Case report 88 High 5.5 High
García et al. (2020) Case report 88 High 5 High
Gautam et al. (2019) Case report 100 High 5.5 High
Gilbert et al. (2013) Case report 88 High 5.5 High
Grant et al. (2016) Case report 88 High 5.5 High
Griffiths et al. (2015) Case report 88 High 5.5 High
Grillo et al. (2016) Case report 88 High 5.5 High
Harris et al. (2015) Case report 88 High 5.5 High
Heuer et al. (2022) Case report 88 High 5.5 High
Ikeda et al. (2010) Case report 88 High 5.5 High
Kim et al. (2016) Case report 100 High 5.5 High
Lecoanet et al. (2019) Case report 88 High 6 High
Oldenburg et al. (2009) Case report 88 High 5.5 High
Pelayo-de Tomás et al. (2017) Case report 88 High 5.5 High
Pelclová et al. (2012) Case report 88 High 6 High
Peters et al. (2017) Case report 100 High 5.5 High
Rizzetti et al. (2009) Case report 88 High 5.5 High
Samargandi et al. (2024) Case report 88 High 5.5 High
Sanz Pérez et al. (2019) Case report 88 High 6 High
Vasukutty et al. (2016) Case report 88 High 5.5 High
Weber et al. (2015) Case report 88 High 6 High
Zywiel et al. (2013) Case report 100 High 5.5 High
3.3

3.3 Data analysis

3.3.1

3.3.1 Patient demographics

Across 31 patients, the mean age at presentation was 58 (SD 9.7); median 58 (IQR 52.5–66) years. Seventeen patients (54.8 %) were men and 14 (45.2 %) were women. A majority underwent primary THA due to osteoarthritis (67.7 %), followed by avascular necrosis (22.6 %) and hip fracture (9.7 %). Ceramic head was fractured in 19 (61.3 %), while 11 (35.5 %) fractured the liner, and 1 (3.2 %) fractured both (Table 3).

Table 3 Summary of descriptive statistics.
Descriptive data Value
AGE & ONSET Mean (SD) Median (IQR)
Age (Years) 58 (9.7) 58 (52.5–66)
Symptom Onset Time (months) 31.9 (32.3) 12 (11.0–54.0)
SEX Count (%)
Male 17 (54.8)
Female 14 (45.2)
INDICATION FOR PRIMARY THA
Osteoarthritis 21 (67.7)
Avascular Necrosis 7 (22.6)
Hip Fracture 3 (9.7)
FRACTURE COMPONENT
Head 19 (61.3)
Liner 11 (35.5)
Head & Liner 1 (3.2)
COBALT LEVELS
Cobalt – Mean (SD) 922.5 (1207.5)
Cobalt – Median (IQR) 633.3 (419.8–971.0)
Cobalt – Minimum 7
Cobalt – Maximum 6521
CLINICAL OUTCOMES Count (%)
Survival
Yes 25 (80.6)
No 6 (19.4)
SYMPTOMS RESOLUTION
Full 8 (25.8)
Partial 17 (54.8)
None 6 (19.4)
INTERVENTIONS
Re-Revision Surgery 28 (90.3)
Chelation Therapy 12 (38.7)
Mechanical Circulatory Support 3 (9.7)
Heart Transplant 3 (9.7)
Haemodialysis 2 (6.5)
Kidney Transplant 1 (3.2)
Therapeutic Plasma Exchange 1 (3.2)
3.3.2

3.3.2 Time to symptom onset and cobalt exposure

Onset of systemic symptoms following MoP revision was seen in a mean 31.9 (SD 32.3), and median 12 (IQR 11–54) months. Patients presented with a wide spread of blood cobalt concentrations, with a mean 922.5 (SD 1207.5), and median 633.3 (IQR 419.8–971) μg/L. One extreme outlier (397,800 μg/L) was excluded from analysis in order to provide a more accurate view of spread (Table 3).

3.3.3

3.3.3 Presenting symptoms and systems

A wide array of overlapping symptoms were observed. The most frequently implicated systems were; cardiovascular (28; 90.3 %), and constitutional (27; 87.1 %). Neurological, auditory, and musculoskeletal systems were involved in 20 (64.5 %) patients each. Endocrine involvement occurred in 18 (58.1 %), with ophthalmic findings in 16 (51.6 %). Less common systems included haematologic, respiratory, renal, dermatological, and gastrointestinal (Table 4).

Table 4 Summary of presenting symptoms by physiological system.
Symptoms by System Cases (%)
CARDIOVASCULAR 28 (90.3)
Cardiomyopathy 19 (61.3)
Arrhythmia 8 (25.8)
Pericardial effusion 5 (16.1)
Heart failure 5 (16.1)
Cardiogenic shock 2 (6.5)
Hypertension 2 (6.5)
Myocarditis 1 (3.2)
Tachycardia 1 (3.2)
Chest pain 1 (3.2)
CONSTITUTIONAL 27 (87.1)
Fatigue 17 (54.8)
Weight loss 14 (45.2)
Fever 4 (12.9)
Anorexia 1 (3.2)
Insomnia 1 (3.2)
Malaise 1 (3.2)
MUSCULOSKELETAL 20 (64.5)
Hip pain 18 (58.1)
Arthralgia 2 (6.5)
AUDITORY 20 (64.5)
Hearing loss 20 (64.5)
NEUROLOGICAL 20 (64.5)
Paraesthesia 13 (41.9)
Weakness 11 (35.5)
Cognitive decline 7 (22.6)
Dysgeusia 4 (12.9)
Polyneuropathy 4 (12.9)
Memory loss 4 (12.9)
Dysaesthesia 3 (9.7)
Headaches 3 (9.7)
Gait disturbance 3 (9.7)
Seizures 2 (6.5)
Vertigo 1 (3.2)
Bulbar palsy 1 (3.2)
ENDOCRINE 18 (58.1)
Hypothyroidism 18 (58.1)
OPHTHALMIC 16 (51.6)
Vision loss 15 (48.4)
Optic neuropathy 3 (9.7)
Retinopathy 2 (6.5)
Chorioretinitis 1 (3.2)
Papilledema 1 (3.2)
Central scotomas 1 (3.2)
RESPIRATORY 11 (35.5)
Dyspnoea 10 (32.3)
Pulmonary embolism 2 (6.5)
Granulomatous lung disease 1 (3.2)
Pleural effusion 1 (3.2)
GASTROINTESTINAL 11 (35.5)
Diarrhoea 3 (9.7)
Vomiting 3 (9.7)
Nausea 2 (6.5)
Liver failure 1 (3.2)
Jaundice 1 (3.2)
HAEMATOLOGIC 9 (29)
Polycythaemia 6 (19.4)
Lymphadenopathy 2 (6.5)
Anaemia 1 (3.2)
RENAL 2 (6.5)
Renal failure 2 (6.5)

The most common presenting symptom was hearing loss (64.5 %). Other common presentations included cardiomyopathy (61.3 %), hip pain (58.1 %), hypothyroidism (58.1 %), fatigue (54.8 %), vision loss (48.4 %), and paraesthesia (41.9 %). Polycythaemia, pericardial effusion, seizures, renal failure, granulomatous lung disease, and liver failure were less frequent (Table 4).

3.3.4

3.3.4 Interventions and clinical course

Definitive re-revision surgery was performed in 28 (90.3 %) patients. Those who did not undergo re-revision surgery had died before surgery could be carried out. Additional treatments included chelation in 12 (38.7 %), and mechanical circulatory support in 3 (9.7 %). Haemodialysis was required in 2 (6.5 %), heart transplantation in 3 (9.7 %), with renal transplant and therapeutic plasma exchange in 1 (3.2 %) patient each. Blood cobalt levels decreased following intervention in the majority of patients. Full resolution of symptoms was seen in 8 (25.8 %), partial improvement in 17 (54.8 %), and 6 (19.4 %) patients saw no improvement of symptoms. Overall survival at last follow-up was 80.6 % (Table 3).20

3.4

3.4 Comparative analyses

3.4.1

3.4.1 Peak cobalt and survival

Allowing for exclusion of one extreme outlier, there was no significant difference in peak cobalt levels between survivors and non-survivors. Survivors had a median 610 (IQR 408–913) μg/L, while non-survivors had a median 730 (IQR 608–1018) μg/L, p = 0.364.

3.4.2

3.4.2 Peak cobalt and symptom resolution

Analysis of cobalt levels according to symptom resolution showed those experiencing full resolution had a median blood cobalt of 623 μg/L, partial resolution was associated with 587 μg/L, while patients whose symptoms remained unchanged had a blood cobalt of 730 μg/L. Although numerically higher medians appeared in the no-resolution group, this pattern was not significant (p = 0.61).

3.4.3

3.4.3 Fractured component and outcomes

When outcomes were stratified according to fractured ceramic component, there was no significant difference in symptom resolution (p = 0.213). There was a trend toward higher mortality among fractured liners, albeit this was not deemed significant (p = 0.062).

3.4.4

3.4.4 Time to onset and survival

Time to onset of systemic symptoms after MoP revision was not significantly different between survivors and non-survivors (p = 0.614). Survivors had a median onset time of 12 months, compared with non-survivors who had a median onset time of 24 months.

4

4 Discussion

4.1

4.1 Principle findings

This systematic review analysed 31 published cases of PHACT occurring after fracture of a ceramic bearing, with revision to MoP articulation. Three key messages can be derived from the results. Firstly, the clinical picture is multisystemic, with a consistent pattern; dominated by cardiovascular, neurosensory, and constitutional involvement. The typical patient developed symptoms within approximately 1 year of MoP revision. Secondly, cobalt exposure levels were profoundly elevated in the majority of cases (median 633 μg/L; IQR 420–971). Thirdly, while re-revision surgery with extensive debridement formed the cornerstone of management, comparative statistical analyses were unable to identify reliable predictors of survival or recovery. These findings likely reflect a biological heterogeneity among patients.

The present findings also reinforce the mechanistic basis for avoiding metal femoral heads when revising fractured ceramic components. Even after meticulous debridement, microscopic ceramic particles typically remain embedded within soft tissues and the joint space. These fragments cause severe third-body abrasion of cobalt-chromium heads, producing rapid and substantial cobalt release into the systemic circulation. CoP bearings are far more resistant to this mode of accelerated wear, and the use of a CoP construct is therefore recognised as the safest option to mitigate the risk of post-revision cobalt toxicity.

4.2

4.2 Context within the wider literature

While similar reviews have examined systemic metallosis across multiple component bearings in primary and revision data, to the best of our knowledge this is the first review to specifically examine PHACT in ceramic fractures revised to MoP.10 Furthermore, this study adds a comparative statistical analysis, offering additional insight. Our results found cardiovascular symptoms to be the most common presentation in this cohort. By contrast, neurological symptoms were the most common presentation in a similar study of primary and revision patients with any bearings.10 The median blood cobalt level in our study (633 μg/L) was significantly higher than levels reported in ARMD.45,46 Retrieval analyses involving ARMD patients found cobalt levels typically in the range of 5–40 μg/L.47 Our results support the theory that hard, highly angular particles disproportionately accelerate surface wear.2,5,48 The extreme outlier (397,800 μg/L) reported by Kim et al. emphasises how extraordinary cobalt exposures can be generated by retained ceramic particles.33 Given these markedly elevated cobalt levels and the rapidity of symptom onset observed across reported cases, the preference for ceramic-on-polyethylene bearings during revision procedures is further supported by the present synthesis.

4.3

4.3 Comparative statistical analysis

Our analyses did not demonstrate a significant difference in outcomes and survival with regard to blood cobalt level, fractured component part, or onset time. This may suggest that outcomes and survival are independent from these factors. Non-parametric tests were the most appropriate given the distribution of data, sample sizes, and variation between survivors and non-survivors. These rank based tests provide for greater robustness in non-normally distributed data. While the available sample sizes limited the ability to draw definitive inferences, the trend towards worse survival in liner fractures may serve to generate hypotheses for further research, with regard to a potential difference in generation of metal ions.

4.4

4.4 Strengths and limitations

This study was strengthened by a well-defined homogenous patient cohort, standardised data collection, and transparent, appropriate statistical analyses. The application of robust quality assessment and risk of bias tools further strengthened the study.11–13 Case reports and series are inherently vulnerable to selection and reporting bias, which will have limited this study. The statistical power will have been limited due to the sample size, which is expected in rare conditions. Furthermore, we could not account for any heterogeneity between studies with regard to blood sampling (whole blood vs. serum cobalt); with different laboratories likely using different assays.

4.5

4.5 Clinical implications and future direction

This study emphasises the importance of early recognition of this pattern of overlapping, non-specific symptoms among revision hip patients. Such heterogeneity in clinical presentations significantly increases the risk of delayed or misdiagnosis. The results of this study highlight the serious consequences of MoP revision following fractured ceramic bearings – with a mortality of nearly 20 %. Any patient with a history of MoP revision subsequent to fractured ceramic component, presenting with unexplained constitutional, cardiovascular, or neurosensory symptoms requires prompt cobalt testing and orthopaedic review. Source control with definitive re-revision surgery is the mainstay of treatment. Surgeons undertaking revision of fractured ceramic components should preferentially use a CoP construct. This configuration minimises the generation of metal ions in the presence of residual ceramic particles and substantially reduces the risk of developing systemic cobalt toxicity. While registry databases are routinely used in surveillance follow-up of MoM hip patients, this is currently not the case for patients with fractured ceramic bearing revised to MoP. Given the findings of this study, the authors propose that registry databases should be exploited to prospectively identify at-risk patients for serial screening and follow-up in a similar manner, in order to enhance patient safety.

5

5 Conclusion

Following a revision to MoP due to ceramic bearing fracture, patients are susceptible to exceptional cobalt exposure and multisystem toxicity, consistent with accelerated third-body wear of the cobalt-chromium metal head. While most patients improve after definitive re-revision surgery and supportive treatment, some sustain irreversible injury or die. Our systematic review and meta-analysis supports early recognition, urgent cobalt testing, and ceramic-based re-revision surgery in contaminated hips. We also highlight the opportunity for registry database-driven identification and monitoring of this small yet clearly high-risk population.

Ethics statement

As this was a systematic review of previously published studies, ethical approval was not required for this research.

CRediT author contribution statement

Patrick Sweeney: methodology, investigation, data curation, formal analysis, validation, writing – original draft, visualization, project administration.

James Broderick: conceptualization, methodology, investigation, data curation, validation, writing - review & editing, supervision, project administration.

Funding statement

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.

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