Delayed Metal Hypersensitivity from Surgical Clips Causing Progressive Neuropathy

Abstract

Introduction:

Systemic immune reactions to surgical clips or implants remain underrecognized and pose a diagnostic challenge after minimally invasive surgeries. Although the incidence of metal hypersensitivity is increasing, these reactions are often overlooked because postoperative imaging and routine evaluations are frequently unremarkable.

Case Presentation:

A 65-year-old male developed progressive abdominal pain, bilateral lower extremity neuropathy, postprandial nausea, and autonomic dysfunction following laparoscopic cholecystectomy and inguinal hernia repair. Over several years, extensive imaging and evaluations failed to identify a structural cause. MELISA® testing revealed strong reactivity to multiple metals, with nickel most prominent. Diagnostic laparoscopy identified 16 retained metallic clips and an intestinal kink. Over six months of follow-up, removal of all clips led to stabilization of neuropathic and autonomic manifestations. Correction of the kink resulted in mild to moderate resolution of abdominal symptoms.

Discussion/Conclusion:

This case highlights the importance of considering metal hypersensitivity in patients with unexplained postoperative symptoms. MELISA® may aid in evaluating implant-related metal hypersensitivity; however, because no single diagnostic test definitively excludes this condition, clinical judgment and temporal association remain important when evaluating carefully selected patients.

INTRODUCTION

Metal hypersensitivity affects 10%–20% of the population, with nickel being the most common allergen.¹ Although most reactions present as dermatologic manifestations, such as contact dermatitis, systemic effects are increasingly recognized, including neuropathy, gastrointestinal disturbances, and autonomic dysfunction.^1–3 Metallic clips, commonly used for ductal and vascular ligation during minimally invasive surgery, can trigger hypersensitivity in susceptible individuals.⁴

Despite their widespread use, hypersensitivity reactions to surgical clips remain underdiagnosed. The proposed mechanism involves a Type IV delayed T-cell response: metal ions form hapten–protein complexes that activate antigen-presenting cells and CD4+ T cells, resulting in systemic inflammation.^3,5–8 These reactions may occur without structural abnormalities detectable on imaging, often delaying recognition and treatment.

The Memory Lymphocyte Immunostimulation Assay (MELISA®) is a useful tool for confirming systemic metal hypersensitivity in the postoperative setting.⁶ In this report, we describe a patient who developed localized and systemic nickel hypersensitivity following laparoscopic cholecystectomy and inguinal hernia repair with sixteen nickel-based surgical clips. Delayed recognition prolonged symptoms over 14 years, but surgical removal of the clips resulted in resolution of abdominal symptoms and stabilization of neuropathic and autonomic manifestations. Importantly, clinical symptoms and temporal association may justify clip removal even when MELISA® results are inconclusive.

This case underscores the need for increased awareness of implant-related metal hypersensitivity, consideration of nickel-free alternatives in sensitized individuals, and early diagnostic evaluation in patients with unexplained postoperative symptoms following minimally invasive surgery.

CASE PRESENTATION

History of Presenting Illness

A 65-year-old male presented with a 14-year history of chronic right upper quadrant abdominal pain, progressive bilateral lower extremity neuropathy, morning nausea, dry heaves (retching), perineal hyperhidrosis, and urinary urgency. Physical examination revealed right upper abdominal tenderness without peritoneal signs. Ambulation, muscle tonicity, proprioception, and reflexes were all within normal limits.

The patient reported a right inguinal hernia repair with mesh implantation in 2005, which reherniated in Jun 2011 because of mesh detachment. Revised right inguinal hernia repair was performed one month after reherniation; however, nausea and vomiting persisted postoperatively. The original 2005 hernia repair and the 2011 revision were performed at outside institutions, and detailed operative reports describing the mesh type, fixation technique, or specific purpose of clips used in those procedures were not available for review at the time of this report. Given ongoing intestinal symptoms and suggestive investigative findings, his medical team attributed his symptoms to gallbladder dysfunction. He subsequently underwent laparoscopic cholecystectomy in Sep 2011, during which sixteen unidentified metal surgical clips were placed. Following this surgery, the patient developed new-onset right upper abdominal pain, peripheral neuropathy, and recurrent nausea and vomiting beginning approximately in Dec 2011. These symptoms persisted for 14 years, described as intermittent and progressively worsening, without an established diagnosis.

Over this period, the patient underwent extensive evaluation by his primary care provider, multiple gastroenterologists, and neurologists. Diagnostic workup included CT scans, MRI, and laboratory testing, none of which identified structural abnormalities to explain his gastrointestinal or neuropathic symptoms. A colonoscopy performed during this workup identified polyps in the hepatic flexure and adjacent ascending colon, in proximity to the retained gallbladder clips. His management included omeprazole for reflux and gabapentin extended-release(Gralise) for neuropathic pain.

Around 2016, the patient first became concerned about potential metal hypersensitivity after his sibling experienced complications attributed to titanium fixation fittings following craniotomy in 2011. He did not connect his own neuropathic symptoms to the surgical clips until early 2024. He subsequently underwent MELISA® testing in Feb 2024. Results (Table 1) demonstrated strong reactivity to nickel and gallium, positive reactivity to methylmercury, inorganic mercury, and cadmium, and weak reactivity to manganese, whereas titanium compounds were negative.

Table 1.

Patient MELISA® Test Results Summary

Metal	MELISA Result	Highest SI
Nickel	Strongly Positive	8.0
Gallium	Strongly Positive	4.5
Methylmercury (MeHg)	Positive	4.1
Inorganic Mercury (Hg)	Positive	3.5
Cadmium	Positive	3.4
Manganese	Weakly Positive	2.8
Titanium Dioxide	Negative	1.1
Titanium Sulfate	Negative	0.9

Note: An SI below 0.3 is cytotoxic; above 2.0 is weakly positive; above 3.0 confirms allergy; and above 10.0 is strongly positive, indicating lymphocyte proliferation exceeding tenfold. A reading of 3.0, for example, means cells tripled, suggesting an allergic reaction.

Past Medical History

The patient’s medical history was significant for chronic peripheral neuropathy (since 2011), prediabetes (elevated HbA1c not yet meeting formal type 2 diabetes diagnostic threshold), hypertension, Factor V Leiden mutation, and insomnia. He reported prior localized skin irritation from metal-containing jewelry but no documented formal allergies.

Surgical history included inguinal hernia repair (2005), revision repair (2011), cholecystectomy (2011), placement of a temporary nickel-containing inferior vena cava filter (Nov 2024; removed Jan 2025), tonsillectomy, lumbar fusion, and knee surgeries. He denied tobacco and illicit drug use and reported occasional alcohol consumption. Family history was notable for his sibling’s adverse reaction to titanium fixation fittings from craniotomy in 2011, as well as diabetes, hypertension, and melanoma. Current medications are listed in Table 2.

Table 2.

Patient’s Medical Regimen

Medication Name	Dose	Route	Frequency/Instructions
Amlodipine	5 mg	PO	Once daily
Lisinopril	20 mg	PO	Once daily
Metoprolol Succinate ER	25 mg	PO	Once daily
Omeprazole	40 mg	PO	Daily before breakfast
Repatha	140 mg/mL	Subcutaneous	Every 2 weeks
Tizanidine	4 mg	PO	Twice daily
Xarelto (Rivaroxaban)	20 mg	PO	Once daily
Zaleplon	10 mg	PO	As needed for insomnia

Treatment

Given persistent symptoms, a negative diagnostic workup for alternative etiologies, and strong clinical correlation with metal hypersensitivity as evidenced by MELISA® results, the patient was referred to the surgical team. Preoperative abdominal radiography (kidney-ureter-bladder [KUB] imaging) is frequently used by the senior surgeon to estimate the number and general distribution of retained surgical clips prior to re-exploration; however, its use is individualized and is not considered mandatory in every case, as definitive clip localization is ultimately achieved intraoperatively with fluoroscopy. Following a detailed discussion of risks and benefits—including the possibility that clip removal might not fully resolve all symptoms—the patient elected to proceed with laparoscopic clip removal.

Operative Findings

Diagnostic laparoscopy (as shown in Figures 1–3) revealed multiple metallic clips in the gallbladder fossa and the inguinal canal. Because the original cholecystectomy and inguinal hernia repairs were performed at outside institutions and their operative reports were not available for review, the exact number of clips attributable to each individual procedure, and the original surgeon's rationale for the total number of clips placed could not be determined. Intraoperative fluoroscopy confirmed and localized 16 retained surgical clips from prior procedures. All 16 clips were removed without complication. Removal of the clips adjacent to the cystic duct did not require replacement with alternative ligation or closure, as the cystic duct stump had long since sealed by mature scar tissue approximately 14 years after the index cholecystectomy, and no bile leak was identified intraoperatively or postoperatively. Laparoscopic exploration also identified a kink in the lower abdominal intestinal segment, attributable to a postoperative adhesive band rather than a retained or dislodged clip, which was surgically released.

Figure 1.

Laparoscopic visualization and dissection of gallbladder clips.

Figure 3.

Sixteen nickel-based metallic clips were removed during laparoscopic re-exploration.

Figure 2.

Intraoperative frontal radiograph demonstrating retained clips in the upper abdomen and pelvis.

Postoperative Care/Outcome

At six-month follow-up, the patient reported complete resolution of right upper- and lower-quadrant abdominal pain and nausea, with mild residual postprandial irritation in the ascending colon—symptoms that had persisted undiagnosed for 14 years—representing a dramatic improvement in quality of life. Additionally, correction of the intestinal kink resolved lower right quadrant pain. There was no clinical evidence of bile leak or hernia recurrence at the six-month follow-up, supporting the conclusion that clip removal did not compromise the durability of the prior hernia repair or the integrity of the cystic duct closure. Neuropathic progression also halted, with cessation of worsening urinary urgency and perineal hyperhidrosis, though no reversal of pre-existing neurological deficits was observed. Full neurological recovery was not anticipated given the 14-year chronicity of exposure, but stabilization of symptoms that had been progressively worsening for over a decade was a significant clinical outcome. The arrest of neuropathic progression following clip removal—in the absence of any other change in management during the interval—supports a strong temporal association between retained nickel-based clips and the patient’s systemic symptoms.

DISCUSSION

Metal Hypersensitivity across Medical Specialties

Metal-containing devices are used across nearly every surgical and medical specialty, and hypersensitivity reactions to them have been described well beyond general and orthopedic surgery. In dentistry, nickel- and other metal-containing restorations, implants, and orthodontic appliances have been associated with oral lichenoid lesions, which characteristically present unilaterally and asymmetrically on the oral mucosa and have been reported to resolve after removal of the causative metal.⁹ In gynecology, copper-containing intrauterine devices have similarly been reported to cause hypersensitivity reactions; in one report, a patient developed bilateral upper-extremity dermatitis two weeks after IUD placement that resolved after device removal despite only low-level copper reactivity on testing, a pattern echoed in similar reported cases.¹⁰ These cross-specialty examples reinforce that implant-related metal hypersensitivity is a generalizable phenomenon rather than one confined to a single surgical field, and that clinical resolution following removal of the causative metal—even in the setting of modest or equivocal reactivity on testing—has been observed consistently across device types and specialties.¹¹

Clinical Importance in Neurologic Manifestations and Systemic Symptoms

Although nickel hypersensitivity affects approximately 20% of the population,¹ systemic reactions to internal metal implants remain underrecognized as a postsurgical complication.^3,5 With continuous internal exposure, hypersensitivity may present as a constellation of systemic symptoms—including neuropathy, dysautonomia, fatigue, and gastrointestinal pain—consistent with systemic nickel allergy syndrome (SNAS) or implant-related metal intolerance.^5,7,8

Metal hypersensitivity has been associated with neurologic manifestations, including neuropathic pain, paresthesia, and autonomic dysfunction; however, these presentations remain underreported in the literature.^7,8 This case highlights the importance of considering the removal of offending implants in patients with suspected hypersensitivity, as prolonged retention may contribute to persistent, progressive, or irreversible symptoms. In this patient, surgical removal of the clips was associated with stabilization of neuropathic symptoms and improvement in systemic manifestations, supporting a strong temporal association between chronic metal exposure and progressive neurologic dysfunction.

Distinction between Cutaneous and Implant-Related Hypersensitivity

Traditional metal allergy presents as localized dermatitis following direct skin contact and typically resolves with avoidance (see Table 3).¹

Table 3.

Comparison of Cutaneous Metal Allergy (Contact Dermatitis) and Surgical Metal hypersensitivity^1,5,7,8

Feature	Cutaneous Allergy	Surgical Metal Hypersensitivity
Exposure	Surface contact	Internal constant exposure
Symptoms	Rash, pruritus	Neuropathy (pain and numbness in a radiculopathy fashion), GI pain, nausea, dysautonomia
Timing	Hours to days	Months to years
Diagnostics	Patch test	MELISA/LTT preferred
Pathophysiology	Localized	Systemic reaction affecting multiple systems (because of diffuse T-cell activation upon release and spread of metal ions)

In contrast, implant-related hypersensitivity involves continuous internal exposure to metal, triggering T cell activation throughout the body and leading to systemic immune activation and delayed-onset symptoms that may develop months to years after implantation (see Table 3).^5,7,8 These systemic reactions can include gastrointestinal symptoms, fatigue, dysautonomia, and neuropathy.

Pathophysiology

In type IV hypersensitivity reactions, metals act as haptens that bind host proteins and activate T-cell–mediated immune responses.⁷ Nickel ions act as haptens by binding to host proteins, forming immunogenic complexes that stimulate cytokine production, including IL-1β and TNF-α.⁸ These cytokines activate antigen-presenting cells such as macrophages, B cells, and Langerhans cells. The modified protein complexes are then processed and presented on MHC class II molecules to CD4+ T cells, leading to sensitization and propagation of a Type IV delayed hypersensitivity response upon re-exposure.⁷ This immune cascade results in persistent, cytokine-mediated inflammation that may manifest systemically.

In this case, the patient’s bilateral foot numbness and perineal hyperhidrosis are consistent with small-fiber peripheral neuropathy, which predominantly affects sensory and autonomic function. Small-fiber neuropathy involves the thinly myelinated Aδ fibers and unmyelinated C fibers and typically spares motor function.^12,13 Furthermore, the autonomic features observed in this patient, including perineal hyperhidrosis and urinary urgency, share a mechanistic overlap with sympathetically mediated pain syndromes, in which dysregulated autonomic signaling drives both sensory and sudomotor dysfunction.¹⁴

Additionally, nickel has been shown to directly activate Toll-like receptor 4, triggering NF-κB signaling, reactive oxygen species production, and dendritic cell activation, thereby amplifying the adaptive T-cell response.^15–17 Peripheral nerves—particularly small fibers with minimal or absent myelin—are especially vulnerable to oxidative damage from this inflammatory cascade, providing a potential mechanism for the patient’s neurologic manifestations.^12,14

Beyond localized tissue effects, metal ions released from implants can enter the systemic circulation and contribute to multisystem processes, including neuroinflammation, and nickel exposure, in particular, has been associated with a broad-spectrum cytokine response extending beyond IL-1β and TNF-α alone.^18,19 This systemic, multicytokine pattern may help explain the combined gastrointestinal, neurologic, and autonomic presentation observed in this patient (see Figure 4).

Figure 4.

Proposed (hypothesized) pathophysiologic mechanism of implant-related nickel hypersensitivity and associated neuropathic manifestations;^{7,8,12,14–19} this diagram represents a proposed hypothesis rather than an established or directly demonstrated mechanism. This diagram is the author's own creation and was created by Satyamedha Bathula, MD.

Diagnostic Clues and Challenges

Symptoms of implant-related hypersensitivity often overlap with other postoperative and neurologic conditions, including postcholecystectomy syndrome, radiculopathy, autonomic dysfunction, and metabolic neuropathies. The absence of structural abnormalities on imaging and the lack of standardized diagnostic criteria further complicate diagnosis.

Patch testing remains the gold standard for detecting localized hypersensitivity, whereas MELISA® may provide insight into systemic reactivity.^4,5 MELISA® may serve as an adjunct for identifying systemic metal sensitivity; however, its clinical utility remains debated because of variability in reproducibility.^4,20,21 This inconsistency extends across testing modalities more broadly: a study of total knee arthroplasty patients found only weak-to-minimal agreement between skin patch testing, lymphocyte proliferation testing, and lymphocyte transformation testing within the same individuals, with too few patients tested by MELISA® in that cohort to permit a correlation analysis; the authors concluded that no single test currently serves as a gold standard for metal hypersensitivity and that results should be interpreted with caution.²² Comparative outcome data, specifically in orthopedic implant patients, likewise show mixed utility of patch testing and lymphocyte transformation-based approaches.^23,24 A formal, prospectively-derived false-negative rate for MELISA® has not been established in the literature. Published performance data are mixed and population-dependent: in the largest validation cohort, nickel reactivity demonstrated 100% sensitivity among patients with confirmed or suspected nickel allergy, but specificity was lower, with several nickel-naïve controls showing low-level positive reactivity²⁰; other groups have been more critical of the assay's specificity for gold, palladium, and nickel.²¹ Our group has previously reported cases of patients with clinical symptoms of surgical clip- and implant-related metal hypersensitivity and equivocal MELISA® results who nonetheless improved after clip removal.²⁵ Similar findings have been reported by others, including a case of mixed metal allergy ancillary to surgical staples.²⁶ Similar precedent exists outside the MELISA® literature: a suture-anchor hypersensitivity case with negative patch testing to the implanted metals that resolved immediately after removal,²⁷ and a systematic review of metal hypersensitivity in foot and ankle orthopedic implants in which 57.8% of patients tested negative to their implant metal, yet a substantial proportion of implant-allergic patients still improved with hardware removal, with the review explicitly concluding that a negative test does not exclude clinically relevant hypersensitivity.²⁸ A structured diagnostic approach should include a detailed exposure history, exclusion of common postoperative pathologies, and targeted testing when clinical suspicion remains high. For US-based patients, Orthopedic Analysis, LLC (Chicago, IL) is a CLIA-certified laboratory offering domestic lymphocyte transformation testing (LTT) for implant-related metal hypersensitivity, providing an accessible alternative to international testing services such as MELISA® Diagnostics. Despite these limitations, MELISA® and LTT may support clinical decision-making in select cases. Importantly, even with negative MELISA® or LTT results, a strong temporal correlation between implant placement and symptom onset may support consideration of implant removal in carefully selected patients.

Management and Prevention

Removal of the offending device may be considered when clinical suspicion is high, even if diagnostic testing is inconclusive. With the increasing use of implant-based procedures, preoperative assessment for metal intolerance should be considered. Most laparoscopic clips are composed of nickel-containing alloys^4,5; alternative materials may be appropriate for individuals with nickel sensitization. The use of nickel-free materials, such as titanium or polymer clips, may reduce the risk of hypersensitivity reactions.^4,5 However, sensitivity to titanium implants has also been documented, including granulomatous tissue reactions, underscoring the importance of individualized preoperative allergy assessment.^2,29 Notably, standard MELISA® titanium testing evaluates pure titanium dioxide, not surgical titanium alloys (e.g., Ti6Al4V), which may contain trace nickel—potentially underestimating allergy risk in sensitized individuals.

Limitations and Future Research

Limited understanding of implant-related hypersensitivity and variability in diagnostic testing contribute to ongoing challenges in diagnosis and management. The nonspecific nature of systemic symptoms further complicates identification. Future research should focus on improving diagnostic accuracy and establishing standardized clinical guidelines. Additionally, the presence of prediabetes in this patient represents a potential confounder in the evaluation of neuropathic symptoms, as impaired glucose tolerance has been associated with small-fiber neuropathy independent of frank diabetes. Objective confirmation of small-fiber neuropathy (via skin biopsy or autonomic testing) was not performed, which limits diagnostic certainty. Several additional limitations should be noted. Because the original cholecystectomy and inguinal hernia repairs were performed at outside institutions, the operative reports detailing the technical indications for clip placement (e.g., hemostasis, mesh fixation, or peritoneal closure) were not available, and the reason the original surgeon(s) used a total of 16 clips could not be determined. Intraoperative fluoroscopy time was not specifically recorded in the available operative documentation and therefore, cannot be reported. This case did not include quantitative measurement of circulating nickel or other metal levels (e.g., by inductively coupled plasma mass spectrometry or graphite furnace atomic absorption spectrometry) before and after clip removal. Such assays reflect systemic metal exposure rather than the T-cell-mediated sensitization underlying Type IV hypersensitivity and are not part of the standard diagnostic evaluation for this mechanism; nonetheless, paired pre- and postexplantation levels could provide useful correlative evidence, and their absence is a limitation of this report. We recommend that future case reports and prospective series incorporate paired quantitative metal levels alongside MELISA®/LTT testing and symptom tracking to strengthen causal inference. Finally, the broader metal hypersensitivity literature includes reports of patients with diagnosed or self-reported metal hypersensitivity experiencing worse subjective outcomes independent of the specific implant used, raising the possibility that psychological or expectation-related factors can influence patient-reported symptoms in this population.²² Although the objective stabilization of this patient's neurologic progression and the resolution of his gastrointestinal symptoms argue against a purely psychological explanation, we cannot fully exclude a contribution from expectation effects, and this possibility should be considered when interpreting outcomes in future reports of implant removal for suspected metal hypersensitivity.

CONCLUSION

Identifying and promptly removing the source of metal hypersensitivity can produce significant clinical improvement, even after more than a decade of undiagnosed suffering. A 65-year-old male with 14 years of progressive neuropathy, abdominal pain, and autonomic dysfunction achieved complete resolution of gastrointestinal symptoms and stabilization of neuropathic progression following removal of 16 retained nickel-based surgical clips. Surgeons should consider metal hypersensitivity as a potential cause of unexplained postoperative symptoms, and clip removal may be considered when clinical suspicion is high. A robust clinical history and a temporal relationship between implant placement and symptom onset may support consideration of surgical intervention in select cases, even if MELISA® or LTT testing is inconclusive.