Case Reports

Magnetic resonance image (MRI) contrast agents can induce profound complications, including gadolinium encephalopathy, kidney injury, gadolinium-associated plaques, and progressive systemic fibrosis, which can be fatal.^1-10 About 50% of MRIs use gadolinium-based contrast (Gd³⁺), a toxic rare earth metal ion that enhances imaging but requires binding with pharmaceutical ligands to reduce toxicity and promote renal elimination (Figure 1). Despite these measures, Gd³⁺ can persist in the body, including the brain.^11,12 Wastewater treatment fails to remove these agents, making Gd³⁺ a growing pollutant in water and the food chain.^13-15 Because Gd³⁺ is a rare earth metal ion in the milieu intérieur, there is an urgent need to study its biological and long-term effects (Appendix 1). 

Case Presentation

A 65-year-old Vietnam-era veteran presented to nephrology at the Raymond G. Murphy Veterans Affairs Medical Center (RGMVAMC) in Albuquerque, New Mexico, for evaluation of gadolinium-induced symptoms. His medical history included metabolic syndrome, hypertension, hyperlipidemia, hypogonadism, cervical spondylosis, and an elevated prostate-specific antigen, previously assessed with a contrast-enhanced MRI in 2019 (Gadobenic acid, 19 mL). Surgical history included cervical fusion and ankle hardware.

The patient had a scheduled MRI 25 days earlier, following an elevated prostate specific antigen test result, prompting urologic surveillance and concern for malignancy. In preparation for the contrast-enhanced MRI, his right arm was cannulated with a line primed with gadobenic acid contrast. Though the technician stated the infusion had not started, the patient’s symptoms began shortly after entry into the scanner, before any programmed pulse sequences. The patient experienced claustrophobia, diaphoresis, palpitations, xerostomia, dysgeusia, shortness of breath, and a sensation of heat in his groin, chest, “kidneys,” and lower back. The MRI was terminated prematurely in response to the patient’s acute symptomatology. The patient continued experiencing new symptoms intermittently during the following week, including lightheadedness, headaches, right clavicular pain, raspy voice, edema, and a sense of doom.

The patient presented to the RGMVAMC emergency department (ED) 8 days after the MRI with worsening symptoms and was hospitalized for 10 days. During this time, he was referred to nephrology for outpatient evaluation. While awaiting his nephrology appointment, the patient presented to the RGMVAMC ED 20 days after the initial episode with ongoing symptoms. “I thought I was dying,” he said. Laboratory results and a 12-lead electrocardiogram showed a finely static background, wide P waves (> 80 ms) with notching in lead II, sinusoidal P waves in V1, R transition in V2, RR’ in V2, ST flat in lead III, and sinus bradycardia (Table 1 and Appendix 2).

The patient’s medical and surgical histories were reviewed at the nephrology evaluation 25 days following the MRI. He reported that household water was sourced from a well and that he filtered his drinking water with a reverse osmosis system. He served in the US Army for 10 years as an engineer specializing in mechanical systems, power generation, and vehicles. Following Army retirement, the patient served in the US Air Force Reserves for 15 years, working as a crew chief in pneudraulics. The patient reported stopping tobacco use 1 year before and also reported regular use of a broad array of prescription medications and dietary supplements, including dexamethasone (4 mg twice daily), fluticasone nasal spray (50 mcg per nostril, twice daily), ibuprofen (400 mg twice daily, as needed), loratadine (10 mg daily), aspirin (81 mg daily), and metoprolol succinate (50 mg nightly). In addition, he reported consistent use of cholecalciferol (3000 IU daily), another supplemental vitamin D preparation, chelated magnesium glycinate (3 tablets daily for bone issues), turmeric (1 tablet daily), a multivitamin (Living Green Liquid Gel, daily), and a mega-B complex.

Physical examination revealed a well-nourished, tall man with hypertension (145/87 mmHg) and bilateral lower extremity edema. Oral examination showed poor dentition, including missing molars (#1-3, #14-16, #17-19, #30-31), with the anterior teeth replaced by bridges supported by dental implants. The review of systems was otherwise unremarkable, with nocturia noted before the consultation.

Serum and urine gadolinium testing, (Mayo Clinic Laboratories) revealed gadolinium levels of 0.3 mcg/24 h in the urine and 0.1 ng/mL in the serum. Nonzero values indicated detectable gadolinium, suggesting retention. The patient had a prior gadolinium exposure during a 2019 MRI (about 1340 days before) and suspected a repeat exposure on day 0, although the MRI technician stated that no contrast was administered. Given his elevated vitamin D levels, the patient was advised to minimize dietary supplements, particularly vitamin D, to avoid confounding symptoms. The plan included monitoring symptoms and a follow-up evaluation with repeat laboratory tests on day 116.

At the nephrology follow-up 4 months postexposure, the patient's symptoms had primarily abated, with a marked reduction in the previously noted metallic dysgeusia. Physical examination remained consistent with prior findings. He was afebrile (97.7 °F) with a blood pressure of 111/72 mmHg, a pulse of 63 beats per minute, and an oxygen saturation of 98% on ambient air. Laboratory analysis revealed serum and urine gadolinium levels below detectable thresholds (< 0.1 ng/mL and < 0.1 mcg/24 h). A 24-hour creatinine clearance, calculated from a urine volume of 1300 mL, measured at an optimal 106 mL/min, indicating preserved renal function (Tables 2 and 3). Of note, his 24-hour oxalate was above the reference range, with a urine pH below the reference range and a high supersaturation index for calcium oxalate.

Discussion

Use of enhanced MRI has increased in the Veterans Health Administration (Figure 2). A growing range of indications for enhanced procedures (eg, cardiac MRI) has contributed to this rise. The market has grown with new gadolinium-based contrast agents, such as gadopiclenol. However, reliance on untested assumptions about the safety of newer agents and need for robust clinical trials pose potential risks to patient safety.

Without prospective evidence, the American College of Radiology (ACR) classifies gadolinium-based contrast agents into 3 groups: Group 1, associated with the highest number of nephrogenic systemic fibrosis cases; Group 2, linked to few, if any, unconfounded cases; and Group 3, where data on nephrogenic systemic fibrosis risk have been limited. As of April 2024, the ACR reclassified Group 3 agents (Ablavar/Vasovist/Angiomark and Primovist/Eovist) into Group 2. Curiously, Vueway and Elucirem were approved in late 2022 and should clearly be categorized as Group 3 (Table 4).There were 19 cases of nephrogenic systemic fibrosis or similar manifestations, 8 of which were unconfounded by other factors. These patients had been exposed to gadobutrol, often combined with other agents. Gadobutrol—like other Group 2 agents—has been associated with nephrogenic systemic fibrosis.^16,17 Despite US Food and Drug Administration (FDA) documentation of rising reports, many clinicians remain unaware that nephrogenic systemic fibrosis is increasingly linked to Group 2 agents classified by the ACR.¹⁸ While declines in reported cases of nephrogenic systemic fibrosis may suggest reduced incidence, this trend may reflect diminished clinical vigilance and underreporting, particularly given emerging evidence implicating even Group 2 gadolinium-based contrast agents in delayed and underrecognized presentations. This information has yet to permeate the medical community, particularly among nephrologists. Considering these cases, revisiting the ACR guidelines may be prudent. 

To address this growing concern, clinicians must adopt stricter vigilance and actively pursue updated information to mitigate patient risks tied to these contrast agents. 

There exists an illusion of knowledge in disregarding the confounded exposures of MRI contrast agents. Ten distinct brands of contrast agents have been approved for clinical use. With repeated imaging, patients are often exposed to varying formulations of gadolinium-based agents. Yet investigators commonly discard these data points when assessing risk. By doing so, they assume—without evidence—that some formulations are inherently less likely to provoke adverse effects (AEs) than others. This untested presumption becomes perilous, especially given the limited understanding of the mechanisms underlying gadolinium-induced pathologies. As Aldous Huxley warned, “Facts do not cease to exist because they are ignored.”¹⁹

Gadolinium Persistence

Contrary to expectations, gadolinium persists in the body far longer than initially presumed. Symptoms associated with gadolinium exposure (SAGE) encapsulate the chronic, often enigmatic maladies tied to MRI contrast agents.²⁰ The prolonged retention of this rare earth metal offers a compelling hypothesis for the etiology of SAGE. It has been hypothesized that Lewis base-rich metabolites increase susceptibility to gadolinium-based contrast agent complications.²¹

The blood and urine concentration elimination curves of gadolinium are exponential and categorized as fast, intermediate, and long-term.¹ For urinary elimination, the function of the curves is exponential. The quantity of gadolinium in the urine at a time (t) after exposure (D_[Gd](t)) is equal to the product of the amount of gadolinium in the sample (urine or blood) at the end of the fast elimination period (D_[Gd](t₀)) and the exponential decay with k being a rate constant.

To the authors’ knowledge, we are the only research team currently investigating the rate constant for the intermediate- and long-term phase gadolinium elimination. The Retention and Toxicity of Gadolinium-based Contrast Agents study was approved by the University of New Mexico Health Sciences Center Institutional Review Board on May 27, 2020 (IRB ID 19-660). The data for the patient in this case were compared with preliminary results for patients with exposure-to-measurement intervals < 100 days. 

The patient in this case presented with detectable gadolinium levels in urine and serum shortly after an attempted contrast-enhanced MRI procedure (Figure 3). The presence of detectable gadolinium levels in the patient’s urine and serum suggests a likely exposure to a contrast agent about 27 days before his consultation. While the technician reported that no contrast was administered during the attempted MRI, it remains possible that a small amount was introduced during cannulation, potentially triggering the patient’s symptoms. Linear modeling of semilogarithmic plots for participants exposed to contrast agents within 100 days (urine: P = 1.8 × 10^ˉ8, adjusted r² = 0.62; blood: P = .005, adjusted r² = 0.21) provided clearance rates (k values) for urine and blood. Extrapolating from these models to the presumed exposure date, the intercepts estimate that the patient received between 0.5% and 8% of a standard contrast dose.

MRI contrast agents can cause skin disease. Systemic fibrosis is considered one of the most severe AEs. Skin pathophysiology involving myeloid cells is driven by elevated levels of monocyte chemoattractant protein-1, which recruits circulating fibroblasts via the C-C chemokine receptor 2.^22,23 This occurs alongside activation of NADPH oxidase Nox4.^4,24,25 Intracellular gadolinium-rich nanoparticles likely serve as catalysts for this reactive cascade.^{2,18,22,26,27} These particles assemble around intracellular lipid droplets and ferrule them in spiculated rare earth-rich shells that compromise cellular architecture.^{2,18,21,22,26,27} Frequently sequestered within endosomal compartments, they disrupt vesicular integrity and threaten cellular homeostasis. Interference with degradative systems such as the endolysosomal axis perturbs energy-recycling pathways—an insidious disturbance, particularly in cells with high metabolic demand. Skin-related symptoms are among the most frequently reported AEs, according to the FDA AE reporting system.¹⁸ 

Studies indicate repeated exposure to MRI contrast agents can lead to permanent gadolinium retention in the brain and other vital organs. Intravenous (IV) contrast agents cross the blood-brain barrier rapidly, while intrathecal administration has been linked to significant and lasting neurologic effects.¹⁸ 

Gadolinium is chemically bound to pharmaceutical ligands to enhance renal clearance and reduce toxicity. However, available data from human samples suggest potential ligand exchanges with undefined physiologic substances. This exchange may facilitate gadolinium precipitation and accumulation within cells into spiculated nanoparticles. Transmission electron microscopy reveals the formation of unilamellar bodies associated with mitochondriopathy and cellular damage, particularly in renal proximal tubules.^{2,18,22,26,27} It is proposed that intracellular nanoparticle formation represents a key mechanism driving the systemic symptoms observed in patients.^{1,2,18, 22,26,27} 

Any hypothesis based on free soluble gadolinium—or concept derived from it—should be discarded. The high affinity of pharmaceutical ligands for gadolinium suggests that the cationic rare earth metal remains predominantly in a ligand-bound, soluble form. It is hypothesized that gadolinium undergoes ligand exchange with physiologic substances, directly leading to nanoparticle formation. Current data demonstrate gadolinium precipitation according to the Le Chatelier’s principle. Since precipitated gadolinium does not readily re-equilibrate with pharmaceutical ligands, repeated administration of different contrast agent brands may contribute to nanoparticle growth.²⁶

Meanwhile, a growing number of patients are turning to chelation therapy, a largely untested treatment. The premise of chelation therapy is rooted in several unproven assumptions.^18,21 First, it assumes that clinically significant amounts of gadolinium persist in compartments such as the extracellular space, where they can be effectively chelated and cleared. Second, it presumes that free gadolinium is the primary driver of chronic symptoms, an assertion that remains scientifically unsubstantiated. Finally, chelation proponents overlook the potential harm caused by depleting essential physiological metals during the process, assuming without evidence that the scant removal of gadolinium outweighs the risk of physiological mineral depletion. 

These assumptions underpin an unproven remedy that demands critical scrutiny. Recent findings reveal that gadolinium deposits in the skin and kidney often take the form of intracellular nanoparticles, directly challenging the foundation of chelation therapy. Chelation advocates must demonstrate that these intracellular gadolinium deposits neither trigger cellular toxicity nor initiate a cytokine cascade. Chelation supporters must prove that the systemic response to these foreign particles is unrelated to the symptoms reported by patients. Until then, the validity of chelation therapy remains highly questionable.

The causality of the symptoms, mainly whether IV gadolinium was administered, was examined. The null hypothesis stated that the patient was not exposed to gadolinium. However, this hypothesis was contradicted by the detection of gadolinium in the serum and urine 27 days after the potential exposure. 

Two plausible explanations exist for the nonzero gadolinium levels detected in the serum and urine. The first possibility is that minute quantities of gadolinium were introduced during cannulation, with the amount being sufficient to persist in measurable concentrations 27 days postexposure. The second possibility is that the gadolinium originated from an MRI contrast agent administered 4 years earlier. In this scenario, gadolinium stored in organ reservoirs such as bone, liver, or kidneys may have been mobilized into the extracellular fluid compartment due to the administration of high-dose steroids 20 days after the recent contrast-enhanced MRI procedure attempt. Coyte et al reported elevated gadolinium levels in the serum, cord blood, breast milk, and placenta of pregnant women with prior exposure to MRI contrast agents.²⁸ These findings suggest that gadolinium, stored in organs such as bone may be remobilized by variables affecting bone remodeling (eg, high-dose steroids). 

Significantly, the patient exhibited elevated urinary oxalate levels. Previous research has found that oxalic acid reacts rapidly with MRI contrast agents, forming digadolinium trioxalate. While the gadolinium-rich nanoparticles identified in tissues such as the skin and kidney (including the human kidney) are amorphous, these in vitro findings establish a proof-of-concept: the intracellular environment facilitates gadolinium dissociation from pharmaceutical chelates. 

Furthermore, in vitro experiments show that proteins and lysosomal pH promote this dissociation, underscoring how human metabolic conditions—particularly oxalic acid concentration—may drive intracellular gadolinium deposition.

Patient Perspective

“They put something into my body that they cannot get out.” This stark realization underpins the patient’s profound concern about gadolinium-based contrast agents and their potential long-term effects. Reflecting on his experience, the patient expressed deep fears about the unknown future impacts: “I’m concerned about my kidneys, I’m concerned about my heart, and I’m concerned about my brain. I don’t know how this stuff is going to affect me in the future.”

He drew an unsettling parallel between gadolinium and heavy metals: “Heavy metal is poison. The body does not produce this kind of stuff on its own.” His reaction to the procedure left a lasting impression, prompting him to question the logic of using a substance that cannot be purged: “Why would you put something into someone’s body that you cannot extract? Nobody—nobody—should experience what I went through.”

The patient emphasized the lack of clear research on long-term outcomes, which compounds his anxiety: “If there was research that said, ‘Well, this is only going to affect these organs for this long,’ OK, I might be able to accept that. But there is no research like that. Nobody can tell me what’s going to happen in 5 years.”

Strengths and Limitations

A significant strength of this approach is the ability to track gadolinium elimination and symptom resolution over time, supported by unique access to intermediate and long-term clearance data from our ongoing research protocol. The investigators were equipped to back-extrapolate the exposure, which provided a rare opportunity to correlate gadolinium levels with clinical outcomes. The primary limitation is the lack of a defined clinical case definition for gadolinium toxicity and limited mechanistic understanding of SAGE, which hinders diagnosis and management.

Metabolites, proteins, and lipids rich in Lewis bases could initiate this process as substrates for intracellular gadolinium sedimentation. Future studies should investigate whether metabolic conditions such as oxalate burden or altered parathyroid hormone levels modulate gadolinium compartmentalization and tissue retention. If gadolinium-rich nanoparticle formation and accumulation disrupt cellular equilibrium, it underscores an urgent need to understand the implications of long-term gadolinium retention. The research team continues to gather evidence that the gadolinium cation remains chelated from the moment MRI contrast agents are administered through to the formation of intracellular nanoparticles. Retained gadolinium nanoparticles may act as a nidus, triggering cellular signaling cascades that lead to multisymptomatic illnesses. Intracellular and insoluble retained gadolinium challenges proponents of untested chelation therapies.

Conclusions

This case highlights emerging clinical and ethical concerns surrounding gadolinium-based contrast agent use. Clinicians may benefit from considering gadolinium retention as a contributor to persistent, unexplained symptoms—particularly in patients with recent imaging exposure. As contrast use continues to rise within federal health systems, regulatory and administrative stakeholders would do well to re-examine current safety frameworks. Informed consent should reflect what is known: gadolinium can remain in the body long after administration, potentially indefinitely. The long-term consequences of cumulative exposure remain poorly defined, but the presence of a lanthanide element in human tissue warrants greater attention from researchers and regulators alike. Interest in alternative imaging modalities and long-term safety monitoring would mark progress toward more transparent, accountable care.

Magnetic resonance image (MRI) contrast agents can induce profound complications, including gadolinium encephalopathy, kidney injury, gadolinium-associated plaques, and progressive systemic fibrosis, which can be fatal.^1-10 About 50% of MRIs use gadolinium-based contrast (Gd³⁺), a toxic rare earth metal ion that enhances imaging but requires binding with pharmaceutical ligands to reduce toxicity and promote renal elimination (Figure 1). Despite these measures, Gd³⁺ can persist in the body, including the brain.^11,12 Wastewater treatment fails to remove these agents, making Gd³⁺ a growing pollutant in water and the food chain.^13-15 Because Gd³⁺ is a rare earth metal ion in the milieu intérieur, there is an urgent need to study its biological and long-term effects (Appendix 1). 

Case Presentation

A 65-year-old Vietnam-era veteran presented to nephrology at the Raymond G. Murphy Veterans Affairs Medical Center (RGMVAMC) in Albuquerque, New Mexico, for evaluation of gadolinium-induced symptoms. His medical history included metabolic syndrome, hypertension, hyperlipidemia, hypogonadism, cervical spondylosis, and an elevated prostate-specific antigen, previously assessed with a contrast-enhanced MRI in 2019 (Gadobenic acid, 19 mL). Surgical history included cervical fusion and ankle hardware.

The patient had a scheduled MRI 25 days earlier, following an elevated prostate specific antigen test result, prompting urologic surveillance and concern for malignancy. In preparation for the contrast-enhanced MRI, his right arm was cannulated with a line primed with gadobenic acid contrast. Though the technician stated the infusion had not started, the patient’s symptoms began shortly after entry into the scanner, before any programmed pulse sequences. The patient experienced claustrophobia, diaphoresis, palpitations, xerostomia, dysgeusia, shortness of breath, and a sensation of heat in his groin, chest, “kidneys,” and lower back. The MRI was terminated prematurely in response to the patient’s acute symptomatology. The patient continued experiencing new symptoms intermittently during the following week, including lightheadedness, headaches, right clavicular pain, raspy voice, edema, and a sense of doom.

The patient presented to the RGMVAMC emergency department (ED) 8 days after the MRI with worsening symptoms and was hospitalized for 10 days. During this time, he was referred to nephrology for outpatient evaluation. While awaiting his nephrology appointment, the patient presented to the RGMVAMC ED 20 days after the initial episode with ongoing symptoms. “I thought I was dying,” he said. Laboratory results and a 12-lead electrocardiogram showed a finely static background, wide P waves (> 80 ms) with notching in lead II, sinusoidal P waves in V1, R transition in V2, RR’ in V2, ST flat in lead III, and sinus bradycardia (Table 1 and Appendix 2).

The patient’s medical and surgical histories were reviewed at the nephrology evaluation 25 days following the MRI. He reported that household water was sourced from a well and that he filtered his drinking water with a reverse osmosis system. He served in the US Army for 10 years as an engineer specializing in mechanical systems, power generation, and vehicles. Following Army retirement, the patient served in the US Air Force Reserves for 15 years, working as a crew chief in pneudraulics. The patient reported stopping tobacco use 1 year before and also reported regular use of a broad array of prescription medications and dietary supplements, including dexamethasone (4 mg twice daily), fluticasone nasal spray (50 mcg per nostril, twice daily), ibuprofen (400 mg twice daily, as needed), loratadine (10 mg daily), aspirin (81 mg daily), and metoprolol succinate (50 mg nightly). In addition, he reported consistent use of cholecalciferol (3000 IU daily), another supplemental vitamin D preparation, chelated magnesium glycinate (3 tablets daily for bone issues), turmeric (1 tablet daily), a multivitamin (Living Green Liquid Gel, daily), and a mega-B complex.

Physical examination revealed a well-nourished, tall man with hypertension (145/87 mmHg) and bilateral lower extremity edema. Oral examination showed poor dentition, including missing molars (#1-3, #14-16, #17-19, #30-31), with the anterior teeth replaced by bridges supported by dental implants. The review of systems was otherwise unremarkable, with nocturia noted before the consultation.

Serum and urine gadolinium testing, (Mayo Clinic Laboratories) revealed gadolinium levels of 0.3 mcg/24 h in the urine and 0.1 ng/mL in the serum. Nonzero values indicated detectable gadolinium, suggesting retention. The patient had a prior gadolinium exposure during a 2019 MRI (about 1340 days before) and suspected a repeat exposure on day 0, although the MRI technician stated that no contrast was administered. Given his elevated vitamin D levels, the patient was advised to minimize dietary supplements, particularly vitamin D, to avoid confounding symptoms. The plan included monitoring symptoms and a follow-up evaluation with repeat laboratory tests on day 116.

At the nephrology follow-up 4 months postexposure, the patient's symptoms had primarily abated, with a marked reduction in the previously noted metallic dysgeusia. Physical examination remained consistent with prior findings. He was afebrile (97.7 °F) with a blood pressure of 111/72 mmHg, a pulse of 63 beats per minute, and an oxygen saturation of 98% on ambient air. Laboratory analysis revealed serum and urine gadolinium levels below detectable thresholds (< 0.1 ng/mL and < 0.1 mcg/24 h). A 24-hour creatinine clearance, calculated from a urine volume of 1300 mL, measured at an optimal 106 mL/min, indicating preserved renal function (Tables 2 and 3). Of note, his 24-hour oxalate was above the reference range, with a urine pH below the reference range and a high supersaturation index for calcium oxalate.

Discussion

Use of enhanced MRI has increased in the Veterans Health Administration (Figure 2). A growing range of indications for enhanced procedures (eg, cardiac MRI) has contributed to this rise. The market has grown with new gadolinium-based contrast agents, such as gadopiclenol. However, reliance on untested assumptions about the safety of newer agents and need for robust clinical trials pose potential risks to patient safety.

Without prospective evidence, the American College of Radiology (ACR) classifies gadolinium-based contrast agents into 3 groups: Group 1, associated with the highest number of nephrogenic systemic fibrosis cases; Group 2, linked to few, if any, unconfounded cases; and Group 3, where data on nephrogenic systemic fibrosis risk have been limited. As of April 2024, the ACR reclassified Group 3 agents (Ablavar/Vasovist/Angiomark and Primovist/Eovist) into Group 2. Curiously, Vueway and Elucirem were approved in late 2022 and should clearly be categorized as Group 3 (Table 4).There were 19 cases of nephrogenic systemic fibrosis or similar manifestations, 8 of which were unconfounded by other factors. These patients had been exposed to gadobutrol, often combined with other agents. Gadobutrol—like other Group 2 agents—has been associated with nephrogenic systemic fibrosis.^16,17 Despite US Food and Drug Administration (FDA) documentation of rising reports, many clinicians remain unaware that nephrogenic systemic fibrosis is increasingly linked to Group 2 agents classified by the ACR.¹⁸ While declines in reported cases of nephrogenic systemic fibrosis may suggest reduced incidence, this trend may reflect diminished clinical vigilance and underreporting, particularly given emerging evidence implicating even Group 2 gadolinium-based contrast agents in delayed and underrecognized presentations. This information has yet to permeate the medical community, particularly among nephrologists. Considering these cases, revisiting the ACR guidelines may be prudent. 

To address this growing concern, clinicians must adopt stricter vigilance and actively pursue updated information to mitigate patient risks tied to these contrast agents. 

There exists an illusion of knowledge in disregarding the confounded exposures of MRI contrast agents. Ten distinct brands of contrast agents have been approved for clinical use. With repeated imaging, patients are often exposed to varying formulations of gadolinium-based agents. Yet investigators commonly discard these data points when assessing risk. By doing so, they assume—without evidence—that some formulations are inherently less likely to provoke adverse effects (AEs) than others. This untested presumption becomes perilous, especially given the limited understanding of the mechanisms underlying gadolinium-induced pathologies. As Aldous Huxley warned, “Facts do not cease to exist because they are ignored.”¹⁹

Gadolinium Persistence

Contrary to expectations, gadolinium persists in the body far longer than initially presumed. Symptoms associated with gadolinium exposure (SAGE) encapsulate the chronic, often enigmatic maladies tied to MRI contrast agents.²⁰ The prolonged retention of this rare earth metal offers a compelling hypothesis for the etiology of SAGE. It has been hypothesized that Lewis base-rich metabolites increase susceptibility to gadolinium-based contrast agent complications.²¹

The blood and urine concentration elimination curves of gadolinium are exponential and categorized as fast, intermediate, and long-term.¹ For urinary elimination, the function of the curves is exponential. The quantity of gadolinium in the urine at a time (t) after exposure (D_[Gd](t)) is equal to the product of the amount of gadolinium in the sample (urine or blood) at the end of the fast elimination period (D_[Gd](t₀)) and the exponential decay with k being a rate constant.

To the authors’ knowledge, we are the only research team currently investigating the rate constant for the intermediate- and long-term phase gadolinium elimination. The Retention and Toxicity of Gadolinium-based Contrast Agents study was approved by the University of New Mexico Health Sciences Center Institutional Review Board on May 27, 2020 (IRB ID 19-660). The data for the patient in this case were compared with preliminary results for patients with exposure-to-measurement intervals < 100 days. 

The patient in this case presented with detectable gadolinium levels in urine and serum shortly after an attempted contrast-enhanced MRI procedure (Figure 3). The presence of detectable gadolinium levels in the patient’s urine and serum suggests a likely exposure to a contrast agent about 27 days before his consultation. While the technician reported that no contrast was administered during the attempted MRI, it remains possible that a small amount was introduced during cannulation, potentially triggering the patient’s symptoms. Linear modeling of semilogarithmic plots for participants exposed to contrast agents within 100 days (urine: P = 1.8 × 10^ˉ8, adjusted r² = 0.62; blood: P = .005, adjusted r² = 0.21) provided clearance rates (k values) for urine and blood. Extrapolating from these models to the presumed exposure date, the intercepts estimate that the patient received between 0.5% and 8% of a standard contrast dose.

MRI contrast agents can cause skin disease. Systemic fibrosis is considered one of the most severe AEs. Skin pathophysiology involving myeloid cells is driven by elevated levels of monocyte chemoattractant protein-1, which recruits circulating fibroblasts via the C-C chemokine receptor 2.^22,23 This occurs alongside activation of NADPH oxidase Nox4.^4,24,25 Intracellular gadolinium-rich nanoparticles likely serve as catalysts for this reactive cascade.^{2,18,22,26,27} These particles assemble around intracellular lipid droplets and ferrule them in spiculated rare earth-rich shells that compromise cellular architecture.^{2,18,21,22,26,27} Frequently sequestered within endosomal compartments, they disrupt vesicular integrity and threaten cellular homeostasis. Interference with degradative systems such as the endolysosomal axis perturbs energy-recycling pathways—an insidious disturbance, particularly in cells with high metabolic demand. Skin-related symptoms are among the most frequently reported AEs, according to the FDA AE reporting system.¹⁸ 

Studies indicate repeated exposure to MRI contrast agents can lead to permanent gadolinium retention in the brain and other vital organs. Intravenous (IV) contrast agents cross the blood-brain barrier rapidly, while intrathecal administration has been linked to significant and lasting neurologic effects.¹⁸ 

Gadolinium is chemically bound to pharmaceutical ligands to enhance renal clearance and reduce toxicity. However, available data from human samples suggest potential ligand exchanges with undefined physiologic substances. This exchange may facilitate gadolinium precipitation and accumulation within cells into spiculated nanoparticles. Transmission electron microscopy reveals the formation of unilamellar bodies associated with mitochondriopathy and cellular damage, particularly in renal proximal tubules.^{2,18,22,26,27} It is proposed that intracellular nanoparticle formation represents a key mechanism driving the systemic symptoms observed in patients.^{1,2,18, 22,26,27} 

Any hypothesis based on free soluble gadolinium—or concept derived from it—should be discarded. The high affinity of pharmaceutical ligands for gadolinium suggests that the cationic rare earth metal remains predominantly in a ligand-bound, soluble form. It is hypothesized that gadolinium undergoes ligand exchange with physiologic substances, directly leading to nanoparticle formation. Current data demonstrate gadolinium precipitation according to the Le Chatelier’s principle. Since precipitated gadolinium does not readily re-equilibrate with pharmaceutical ligands, repeated administration of different contrast agent brands may contribute to nanoparticle growth.²⁶

Meanwhile, a growing number of patients are turning to chelation therapy, a largely untested treatment. The premise of chelation therapy is rooted in several unproven assumptions.^18,21 First, it assumes that clinically significant amounts of gadolinium persist in compartments such as the extracellular space, where they can be effectively chelated and cleared. Second, it presumes that free gadolinium is the primary driver of chronic symptoms, an assertion that remains scientifically unsubstantiated. Finally, chelation proponents overlook the potential harm caused by depleting essential physiological metals during the process, assuming without evidence that the scant removal of gadolinium outweighs the risk of physiological mineral depletion. 

These assumptions underpin an unproven remedy that demands critical scrutiny. Recent findings reveal that gadolinium deposits in the skin and kidney often take the form of intracellular nanoparticles, directly challenging the foundation of chelation therapy. Chelation advocates must demonstrate that these intracellular gadolinium deposits neither trigger cellular toxicity nor initiate a cytokine cascade. Chelation supporters must prove that the systemic response to these foreign particles is unrelated to the symptoms reported by patients. Until then, the validity of chelation therapy remains highly questionable.

The causality of the symptoms, mainly whether IV gadolinium was administered, was examined. The null hypothesis stated that the patient was not exposed to gadolinium. However, this hypothesis was contradicted by the detection of gadolinium in the serum and urine 27 days after the potential exposure. 

Two plausible explanations exist for the nonzero gadolinium levels detected in the serum and urine. The first possibility is that minute quantities of gadolinium were introduced during cannulation, with the amount being sufficient to persist in measurable concentrations 27 days postexposure. The second possibility is that the gadolinium originated from an MRI contrast agent administered 4 years earlier. In this scenario, gadolinium stored in organ reservoirs such as bone, liver, or kidneys may have been mobilized into the extracellular fluid compartment due to the administration of high-dose steroids 20 days after the recent contrast-enhanced MRI procedure attempt. Coyte et al reported elevated gadolinium levels in the serum, cord blood, breast milk, and placenta of pregnant women with prior exposure to MRI contrast agents.²⁸ These findings suggest that gadolinium, stored in organs such as bone may be remobilized by variables affecting bone remodeling (eg, high-dose steroids). 

Significantly, the patient exhibited elevated urinary oxalate levels. Previous research has found that oxalic acid reacts rapidly with MRI contrast agents, forming digadolinium trioxalate. While the gadolinium-rich nanoparticles identified in tissues such as the skin and kidney (including the human kidney) are amorphous, these in vitro findings establish a proof-of-concept: the intracellular environment facilitates gadolinium dissociation from pharmaceutical chelates. 

Furthermore, in vitro experiments show that proteins and lysosomal pH promote this dissociation, underscoring how human metabolic conditions—particularly oxalic acid concentration—may drive intracellular gadolinium deposition.

Patient Perspective

“They put something into my body that they cannot get out.” This stark realization underpins the patient’s profound concern about gadolinium-based contrast agents and their potential long-term effects. Reflecting on his experience, the patient expressed deep fears about the unknown future impacts: “I’m concerned about my kidneys, I’m concerned about my heart, and I’m concerned about my brain. I don’t know how this stuff is going to affect me in the future.”

He drew an unsettling parallel between gadolinium and heavy metals: “Heavy metal is poison. The body does not produce this kind of stuff on its own.” His reaction to the procedure left a lasting impression, prompting him to question the logic of using a substance that cannot be purged: “Why would you put something into someone’s body that you cannot extract? Nobody—nobody—should experience what I went through.”

The patient emphasized the lack of clear research on long-term outcomes, which compounds his anxiety: “If there was research that said, ‘Well, this is only going to affect these organs for this long,’ OK, I might be able to accept that. But there is no research like that. Nobody can tell me what’s going to happen in 5 years.”

Strengths and Limitations

A significant strength of this approach is the ability to track gadolinium elimination and symptom resolution over time, supported by unique access to intermediate and long-term clearance data from our ongoing research protocol. The investigators were equipped to back-extrapolate the exposure, which provided a rare opportunity to correlate gadolinium levels with clinical outcomes. The primary limitation is the lack of a defined clinical case definition for gadolinium toxicity and limited mechanistic understanding of SAGE, which hinders diagnosis and management.

Metabolites, proteins, and lipids rich in Lewis bases could initiate this process as substrates for intracellular gadolinium sedimentation. Future studies should investigate whether metabolic conditions such as oxalate burden or altered parathyroid hormone levels modulate gadolinium compartmentalization and tissue retention. If gadolinium-rich nanoparticle formation and accumulation disrupt cellular equilibrium, it underscores an urgent need to understand the implications of long-term gadolinium retention. The research team continues to gather evidence that the gadolinium cation remains chelated from the moment MRI contrast agents are administered through to the formation of intracellular nanoparticles. Retained gadolinium nanoparticles may act as a nidus, triggering cellular signaling cascades that lead to multisymptomatic illnesses. Intracellular and insoluble retained gadolinium challenges proponents of untested chelation therapies.

Conclusions

This case highlights emerging clinical and ethical concerns surrounding gadolinium-based contrast agent use. Clinicians may benefit from considering gadolinium retention as a contributor to persistent, unexplained symptoms—particularly in patients with recent imaging exposure. As contrast use continues to rise within federal health systems, regulatory and administrative stakeholders would do well to re-examine current safety frameworks. Informed consent should reflect what is known: gadolinium can remain in the body long after administration, potentially indefinitely. The long-term consequences of cumulative exposure remain poorly defined, but the presence of a lanthanide element in human tissue warrants greater attention from researchers and regulators alike. Interest in alternative imaging modalities and long-term safety monitoring would mark progress toward more transparent, accountable care.

Magnetic resonance image (MRI) contrast agents can induce profound complications, including gadolinium encephalopathy, kidney injury, gadolinium-associated plaques, and progressive systemic fibrosis, which can be fatal.^1-10 About 50% of MRIs use gadolinium-based contrast (Gd³⁺), a toxic rare earth metal ion that enhances imaging but requires binding with pharmaceutical ligands to reduce toxicity and promote renal elimination (Figure 1). Despite these measures, Gd³⁺ can persist in the body, including the brain.^11,12 Wastewater treatment fails to remove these agents, making Gd³⁺ a growing pollutant in water and the food chain.^13-15 Because Gd³⁺ is a rare earth metal ion in the milieu intérieur, there is an urgent need to study its biological and long-term effects (Appendix 1). 

Case Presentation

A 65-year-old Vietnam-era veteran presented to nephrology at the Raymond G. Murphy Veterans Affairs Medical Center (RGMVAMC) in Albuquerque, New Mexico, for evaluation of gadolinium-induced symptoms. His medical history included metabolic syndrome, hypertension, hyperlipidemia, hypogonadism, cervical spondylosis, and an elevated prostate-specific antigen, previously assessed with a contrast-enhanced MRI in 2019 (Gadobenic acid, 19 mL). Surgical history included cervical fusion and ankle hardware.

The patient had a scheduled MRI 25 days earlier, following an elevated prostate specific antigen test result, prompting urologic surveillance and concern for malignancy. In preparation for the contrast-enhanced MRI, his right arm was cannulated with a line primed with gadobenic acid contrast. Though the technician stated the infusion had not started, the patient’s symptoms began shortly after entry into the scanner, before any programmed pulse sequences. The patient experienced claustrophobia, diaphoresis, palpitations, xerostomia, dysgeusia, shortness of breath, and a sensation of heat in his groin, chest, “kidneys,” and lower back. The MRI was terminated prematurely in response to the patient’s acute symptomatology. The patient continued experiencing new symptoms intermittently during the following week, including lightheadedness, headaches, right clavicular pain, raspy voice, edema, and a sense of doom.

The patient presented to the RGMVAMC emergency department (ED) 8 days after the MRI with worsening symptoms and was hospitalized for 10 days. During this time, he was referred to nephrology for outpatient evaluation. While awaiting his nephrology appointment, the patient presented to the RGMVAMC ED 20 days after the initial episode with ongoing symptoms. “I thought I was dying,” he said. Laboratory results and a 12-lead electrocardiogram showed a finely static background, wide P waves (> 80 ms) with notching in lead II, sinusoidal P waves in V1, R transition in V2, RR’ in V2, ST flat in lead III, and sinus bradycardia (Table 1 and Appendix 2).

The patient’s medical and surgical histories were reviewed at the nephrology evaluation 25 days following the MRI. He reported that household water was sourced from a well and that he filtered his drinking water with a reverse osmosis system. He served in the US Army for 10 years as an engineer specializing in mechanical systems, power generation, and vehicles. Following Army retirement, the patient served in the US Air Force Reserves for 15 years, working as a crew chief in pneudraulics. The patient reported stopping tobacco use 1 year before and also reported regular use of a broad array of prescription medications and dietary supplements, including dexamethasone (4 mg twice daily), fluticasone nasal spray (50 mcg per nostril, twice daily), ibuprofen (400 mg twice daily, as needed), loratadine (10 mg daily), aspirin (81 mg daily), and metoprolol succinate (50 mg nightly). In addition, he reported consistent use of cholecalciferol (3000 IU daily), another supplemental vitamin D preparation, chelated magnesium glycinate (3 tablets daily for bone issues), turmeric (1 tablet daily), a multivitamin (Living Green Liquid Gel, daily), and a mega-B complex.

Physical examination revealed a well-nourished, tall man with hypertension (145/87 mmHg) and bilateral lower extremity edema. Oral examination showed poor dentition, including missing molars (#1-3, #14-16, #17-19, #30-31), with the anterior teeth replaced by bridges supported by dental implants. The review of systems was otherwise unremarkable, with nocturia noted before the consultation.

Serum and urine gadolinium testing, (Mayo Clinic Laboratories) revealed gadolinium levels of 0.3 mcg/24 h in the urine and 0.1 ng/mL in the serum. Nonzero values indicated detectable gadolinium, suggesting retention. The patient had a prior gadolinium exposure during a 2019 MRI (about 1340 days before) and suspected a repeat exposure on day 0, although the MRI technician stated that no contrast was administered. Given his elevated vitamin D levels, the patient was advised to minimize dietary supplements, particularly vitamin D, to avoid confounding symptoms. The plan included monitoring symptoms and a follow-up evaluation with repeat laboratory tests on day 116.

At the nephrology follow-up 4 months postexposure, the patient's symptoms had primarily abated, with a marked reduction in the previously noted metallic dysgeusia. Physical examination remained consistent with prior findings. He was afebrile (97.7 °F) with a blood pressure of 111/72 mmHg, a pulse of 63 beats per minute, and an oxygen saturation of 98% on ambient air. Laboratory analysis revealed serum and urine gadolinium levels below detectable thresholds (< 0.1 ng/mL and < 0.1 mcg/24 h). A 24-hour creatinine clearance, calculated from a urine volume of 1300 mL, measured at an optimal 106 mL/min, indicating preserved renal function (Tables 2 and 3). Of note, his 24-hour oxalate was above the reference range, with a urine pH below the reference range and a high supersaturation index for calcium oxalate.

Discussion

Use of enhanced MRI has increased in the Veterans Health Administration (Figure 2). A growing range of indications for enhanced procedures (eg, cardiac MRI) has contributed to this rise. The market has grown with new gadolinium-based contrast agents, such as gadopiclenol. However, reliance on untested assumptions about the safety of newer agents and need for robust clinical trials pose potential risks to patient safety.

Without prospective evidence, the American College of Radiology (ACR) classifies gadolinium-based contrast agents into 3 groups: Group 1, associated with the highest number of nephrogenic systemic fibrosis cases; Group 2, linked to few, if any, unconfounded cases; and Group 3, where data on nephrogenic systemic fibrosis risk have been limited. As of April 2024, the ACR reclassified Group 3 agents (Ablavar/Vasovist/Angiomark and Primovist/Eovist) into Group 2. Curiously, Vueway and Elucirem were approved in late 2022 and should clearly be categorized as Group 3 (Table 4).There were 19 cases of nephrogenic systemic fibrosis or similar manifestations, 8 of which were unconfounded by other factors. These patients had been exposed to gadobutrol, often combined with other agents. Gadobutrol—like other Group 2 agents—has been associated with nephrogenic systemic fibrosis.^16,17 Despite US Food and Drug Administration (FDA) documentation of rising reports, many clinicians remain unaware that nephrogenic systemic fibrosis is increasingly linked to Group 2 agents classified by the ACR.¹⁸ While declines in reported cases of nephrogenic systemic fibrosis may suggest reduced incidence, this trend may reflect diminished clinical vigilance and underreporting, particularly given emerging evidence implicating even Group 2 gadolinium-based contrast agents in delayed and underrecognized presentations. This information has yet to permeate the medical community, particularly among nephrologists. Considering these cases, revisiting the ACR guidelines may be prudent. 

To address this growing concern, clinicians must adopt stricter vigilance and actively pursue updated information to mitigate patient risks tied to these contrast agents. 

There exists an illusion of knowledge in disregarding the confounded exposures of MRI contrast agents. Ten distinct brands of contrast agents have been approved for clinical use. With repeated imaging, patients are often exposed to varying formulations of gadolinium-based agents. Yet investigators commonly discard these data points when assessing risk. By doing so, they assume—without evidence—that some formulations are inherently less likely to provoke adverse effects (AEs) than others. This untested presumption becomes perilous, especially given the limited understanding of the mechanisms underlying gadolinium-induced pathologies. As Aldous Huxley warned, “Facts do not cease to exist because they are ignored.”¹⁹

Gadolinium Persistence

Contrary to expectations, gadolinium persists in the body far longer than initially presumed. Symptoms associated with gadolinium exposure (SAGE) encapsulate the chronic, often enigmatic maladies tied to MRI contrast agents.²⁰ The prolonged retention of this rare earth metal offers a compelling hypothesis for the etiology of SAGE. It has been hypothesized that Lewis base-rich metabolites increase susceptibility to gadolinium-based contrast agent complications.²¹

The blood and urine concentration elimination curves of gadolinium are exponential and categorized as fast, intermediate, and long-term.¹ For urinary elimination, the function of the curves is exponential. The quantity of gadolinium in the urine at a time (t) after exposure (D_[Gd](t)) is equal to the product of the amount of gadolinium in the sample (urine or blood) at the end of the fast elimination period (D_[Gd](t₀)) and the exponential decay with k being a rate constant.

To the authors’ knowledge, we are the only research team currently investigating the rate constant for the intermediate- and long-term phase gadolinium elimination. The Retention and Toxicity of Gadolinium-based Contrast Agents study was approved by the University of New Mexico Health Sciences Center Institutional Review Board on May 27, 2020 (IRB ID 19-660). The data for the patient in this case were compared with preliminary results for patients with exposure-to-measurement intervals < 100 days. 

The patient in this case presented with detectable gadolinium levels in urine and serum shortly after an attempted contrast-enhanced MRI procedure (Figure 3). The presence of detectable gadolinium levels in the patient’s urine and serum suggests a likely exposure to a contrast agent about 27 days before his consultation. While the technician reported that no contrast was administered during the attempted MRI, it remains possible that a small amount was introduced during cannulation, potentially triggering the patient’s symptoms. Linear modeling of semilogarithmic plots for participants exposed to contrast agents within 100 days (urine: P = 1.8 × 10^ˉ8, adjusted r² = 0.62; blood: P = .005, adjusted r² = 0.21) provided clearance rates (k values) for urine and blood. Extrapolating from these models to the presumed exposure date, the intercepts estimate that the patient received between 0.5% and 8% of a standard contrast dose.

MRI contrast agents can cause skin disease. Systemic fibrosis is considered one of the most severe AEs. Skin pathophysiology involving myeloid cells is driven by elevated levels of monocyte chemoattractant protein-1, which recruits circulating fibroblasts via the C-C chemokine receptor 2.^22,23 This occurs alongside activation of NADPH oxidase Nox4.^4,24,25 Intracellular gadolinium-rich nanoparticles likely serve as catalysts for this reactive cascade.^{2,18,22,26,27} These particles assemble around intracellular lipid droplets and ferrule them in spiculated rare earth-rich shells that compromise cellular architecture.^{2,18,21,22,26,27} Frequently sequestered within endosomal compartments, they disrupt vesicular integrity and threaten cellular homeostasis. Interference with degradative systems such as the endolysosomal axis perturbs energy-recycling pathways—an insidious disturbance, particularly in cells with high metabolic demand. Skin-related symptoms are among the most frequently reported AEs, according to the FDA AE reporting system.¹⁸ 

Studies indicate repeated exposure to MRI contrast agents can lead to permanent gadolinium retention in the brain and other vital organs. Intravenous (IV) contrast agents cross the blood-brain barrier rapidly, while intrathecal administration has been linked to significant and lasting neurologic effects.¹⁸ 

Gadolinium is chemically bound to pharmaceutical ligands to enhance renal clearance and reduce toxicity. However, available data from human samples suggest potential ligand exchanges with undefined physiologic substances. This exchange may facilitate gadolinium precipitation and accumulation within cells into spiculated nanoparticles. Transmission electron microscopy reveals the formation of unilamellar bodies associated with mitochondriopathy and cellular damage, particularly in renal proximal tubules.^{2,18,22,26,27} It is proposed that intracellular nanoparticle formation represents a key mechanism driving the systemic symptoms observed in patients.^{1,2,18, 22,26,27} 

Any hypothesis based on free soluble gadolinium—or concept derived from it—should be discarded. The high affinity of pharmaceutical ligands for gadolinium suggests that the cationic rare earth metal remains predominantly in a ligand-bound, soluble form. It is hypothesized that gadolinium undergoes ligand exchange with physiologic substances, directly leading to nanoparticle formation. Current data demonstrate gadolinium precipitation according to the Le Chatelier’s principle. Since precipitated gadolinium does not readily re-equilibrate with pharmaceutical ligands, repeated administration of different contrast agent brands may contribute to nanoparticle growth.²⁶

Meanwhile, a growing number of patients are turning to chelation therapy, a largely untested treatment. The premise of chelation therapy is rooted in several unproven assumptions.^18,21 First, it assumes that clinically significant amounts of gadolinium persist in compartments such as the extracellular space, where they can be effectively chelated and cleared. Second, it presumes that free gadolinium is the primary driver of chronic symptoms, an assertion that remains scientifically unsubstantiated. Finally, chelation proponents overlook the potential harm caused by depleting essential physiological metals during the process, assuming without evidence that the scant removal of gadolinium outweighs the risk of physiological mineral depletion. 

These assumptions underpin an unproven remedy that demands critical scrutiny. Recent findings reveal that gadolinium deposits in the skin and kidney often take the form of intracellular nanoparticles, directly challenging the foundation of chelation therapy. Chelation advocates must demonstrate that these intracellular gadolinium deposits neither trigger cellular toxicity nor initiate a cytokine cascade. Chelation supporters must prove that the systemic response to these foreign particles is unrelated to the symptoms reported by patients. Until then, the validity of chelation therapy remains highly questionable.

The causality of the symptoms, mainly whether IV gadolinium was administered, was examined. The null hypothesis stated that the patient was not exposed to gadolinium. However, this hypothesis was contradicted by the detection of gadolinium in the serum and urine 27 days after the potential exposure. 

Two plausible explanations exist for the nonzero gadolinium levels detected in the serum and urine. The first possibility is that minute quantities of gadolinium were introduced during cannulation, with the amount being sufficient to persist in measurable concentrations 27 days postexposure. The second possibility is that the gadolinium originated from an MRI contrast agent administered 4 years earlier. In this scenario, gadolinium stored in organ reservoirs such as bone, liver, or kidneys may have been mobilized into the extracellular fluid compartment due to the administration of high-dose steroids 20 days after the recent contrast-enhanced MRI procedure attempt. Coyte et al reported elevated gadolinium levels in the serum, cord blood, breast milk, and placenta of pregnant women with prior exposure to MRI contrast agents.²⁸ These findings suggest that gadolinium, stored in organs such as bone may be remobilized by variables affecting bone remodeling (eg, high-dose steroids). 

Significantly, the patient exhibited elevated urinary oxalate levels. Previous research has found that oxalic acid reacts rapidly with MRI contrast agents, forming digadolinium trioxalate. While the gadolinium-rich nanoparticles identified in tissues such as the skin and kidney (including the human kidney) are amorphous, these in vitro findings establish a proof-of-concept: the intracellular environment facilitates gadolinium dissociation from pharmaceutical chelates. 

Furthermore, in vitro experiments show that proteins and lysosomal pH promote this dissociation, underscoring how human metabolic conditions—particularly oxalic acid concentration—may drive intracellular gadolinium deposition.

Patient Perspective

“They put something into my body that they cannot get out.” This stark realization underpins the patient’s profound concern about gadolinium-based contrast agents and their potential long-term effects. Reflecting on his experience, the patient expressed deep fears about the unknown future impacts: “I’m concerned about my kidneys, I’m concerned about my heart, and I’m concerned about my brain. I don’t know how this stuff is going to affect me in the future.”

He drew an unsettling parallel between gadolinium and heavy metals: “Heavy metal is poison. The body does not produce this kind of stuff on its own.” His reaction to the procedure left a lasting impression, prompting him to question the logic of using a substance that cannot be purged: “Why would you put something into someone’s body that you cannot extract? Nobody—nobody—should experience what I went through.”

The patient emphasized the lack of clear research on long-term outcomes, which compounds his anxiety: “If there was research that said, ‘Well, this is only going to affect these organs for this long,’ OK, I might be able to accept that. But there is no research like that. Nobody can tell me what’s going to happen in 5 years.”

Strengths and Limitations

A significant strength of this approach is the ability to track gadolinium elimination and symptom resolution over time, supported by unique access to intermediate and long-term clearance data from our ongoing research protocol. The investigators were equipped to back-extrapolate the exposure, which provided a rare opportunity to correlate gadolinium levels with clinical outcomes. The primary limitation is the lack of a defined clinical case definition for gadolinium toxicity and limited mechanistic understanding of SAGE, which hinders diagnosis and management.

Metabolites, proteins, and lipids rich in Lewis bases could initiate this process as substrates for intracellular gadolinium sedimentation. Future studies should investigate whether metabolic conditions such as oxalate burden or altered parathyroid hormone levels modulate gadolinium compartmentalization and tissue retention. If gadolinium-rich nanoparticle formation and accumulation disrupt cellular equilibrium, it underscores an urgent need to understand the implications of long-term gadolinium retention. The research team continues to gather evidence that the gadolinium cation remains chelated from the moment MRI contrast agents are administered through to the formation of intracellular nanoparticles. Retained gadolinium nanoparticles may act as a nidus, triggering cellular signaling cascades that lead to multisymptomatic illnesses. Intracellular and insoluble retained gadolinium challenges proponents of untested chelation therapies.

Conclusions

This case highlights emerging clinical and ethical concerns surrounding gadolinium-based contrast agent use. Clinicians may benefit from considering gadolinium retention as a contributor to persistent, unexplained symptoms—particularly in patients with recent imaging exposure. As contrast use continues to rise within federal health systems, regulatory and administrative stakeholders would do well to re-examine current safety frameworks. Informed consent should reflect what is known: gadolinium can remain in the body long after administration, potentially indefinitely. The long-term consequences of cumulative exposure remain poorly defined, but the presence of a lanthanide element in human tissue warrants greater attention from researchers and regulators alike. Interest in alternative imaging modalities and long-term safety monitoring would mark progress toward more transparent, accountable care.

Discussion

A diagnosis of lichen sclerosus (LS) was made based on clinical and dermoscopic features, followed by confirmation with histology. The patient’s presentation included typical signs and symptoms of LS: itching, burning, intermittent bleeding, perianal hemorrhage, fusion of the clitoral head, and fissures. Other presentations can include dyspareunia, erosions, and excoriations; however, these symptoms and signs were not reported or seen in this patient.

LS typically affects the anogenital region and has 2 peak incidences: in preadolescent teens and during the fifth to sixth decade of life.¹ This patient presented with a case of extragenital LS, which is less common than the classic presentation of LS that affects the genitals. This variant’s epidemiology differs, as it is less common in children and more common in postmenopausal women.² Extragenital LS presents as white, atrophic plaques with a predilection for sites including the trunk, breasts, upper arms, and sites of physical trauma, with symptoms of dryness and pruritus. Over time, the papules can coalesce and form ivory, scar-like papules or plaques with a wrinkled surface. In advanced stages, telangiectasia or follicular plugging can be present, along with flattening of the dermal-epidermal junction. This flat interface is fragile and can result in bullae that may become hemorrhagic.

Cutaneous squamous cell carcinoma (SCC) may infrequently arise from LS, similar to other chronic inflammatory dermatoses.³ Lichen planus is typically not associated with an increased risk of SCC, except in the oral and hypertrophic variants. However, LS may be considered a premalignant process, and many vulvar SCC cases are noted to have adjacent LS lesions.³

Autoimmune and genetic factors contribute to the pathogenesis of LS. Extracellular matrix protein 1 (ECM1) binds molecules of the basement membrane zone and dermis, contributing to the structure and integrity of skin. Autoantibodies against ECM1 and other antigens of the basement membrane zone, including BP180 and BP320, were found in LS.² HLA-DQ7 major histocompatibility complex class II antigens have been associated with LS.¹

On histologic examination, the epidermis of LS is atrophic with hyperkeratosis. The dermis shows homogenization and sclerosis of superficial collagen with a band-like lymphocytic infiltrate below the sclerosis. The basal layer is thickened, showing basal cell vacuolization and hydropic degeneration.⁴

First-line treatment for genital and extragenital variants of LS is high-potency topical steroids for 3 months or until the skin texture and color resolve (ie, clobetasol 0.05% cream or ointment). The second-line treatment is a topical calcineurin inhibitor. These treatments are used for management. They are not cures for LS, as relapse is possible after the initial treatment course is completed. Adverse effects of high potency topical steroids are skin burning, skin atrophy, and fragility, telangiectasia. The adverse effects of topical calcineurin inhibitors are stinging and burning on application.

Other Diagnostic Considerations

Inverse psoriasis (IP) is a variant of psoriasis that presents as erythematous, well-demarcated plaques with minimal scale in intertriginous areas and flexural surfaces. Localized dermatophyte, candidal, or bacterial infections can trigger IP.⁵ It occurs in about 3% to 7% of patients with plaque psoriasis and is thought to form due to koebnerization via mechanical friction of flexural zones.⁶ The patient described in this case did not have IP because IP would be more likely to present as a well-demarcated erythematous plaque rather than a patch.

Histologically, IP shows regular psoriasiform acanthosis and hypogranulosis of the epidermis, Munro microabscess, spongiform pustules of Kogoj, dilated tortuous dermal vessels, and thinning of the suprapapillary plates.⁵

Lichen planus pigmentosus-inversus (LPPI) is also known as lichen planus pigmentosus—intertriginous variant. This variant of lichen planus pigmentosus presents as multiple gray to dark brown macules and patches with poorly defined borders in a linear distribution limited to intertriginous areas, flexural surfaces, or following the lines of Blaschko.⁷ About 20% of cases present with frontal fibrosing alopecia. It is most common in individuals with intermediate and darker skin pigmentation, has a higher prevalence in females, and typically occurs within the third and fifth decades of life. Friction is a common trigger of LPPI.⁷ A diagnosis of LPPI is incorrect because the lesions would present as gray to dark brown macules, as opposed to the shiny white atrophic thin papules with surrounding pink and purple patches seen in this case.

Histologically, while both LS and LPPI share band-like lymphocytic infiltrate and basal cell vacuolization, findings in the dermis differ. LPPI shows melanophages and prominent melanin incontinence, while LS shows homogenization and sclerosis of superficial collagen.^1,8 LPPI also shows absence of compensatory keratinocyte proliferation.

Morphea is an inflammatory disease that affects the dermis and subcutaneous fat, resulting in sclerosis that appears scarlike. Its prevalence increases with age and has a 4:1 prevalence in females, with the plaque type being the most common variant. ⁹ The typical presentation of plaque-type morphea is an insidious onset of asymptomatic, slightly elevated, erythematous or violaceous, slightly edematous plaques with centrifugal expansion. The center of the plaque may become sclerotic and indurated, acquiring a shiny white color with a peripheral “lilac” ring. Trunk and upper extremity involvement is common. Morphea is associated with increased antisingle-stranded DNA, antitopoisomerase IIa, antiphospholipid, antifibrillin-1, and antihistone antibodies. Triggers of morphea are believed to be localized insults to the skin, including mechanical trauma, injections, vaccinations, and irradiation.⁹ This answer is incorrect because the patient’s lesions were pruritic and had genital involvement, which are not typical of morphea. Morphea can be differentiated with based on symptoms (lack of pruritus, pain, burning), morphology of lesions (induration versus atrophy), dermoscopy (fibrotic beams with less scale and hemorrhage vs keratotic follicular plugs), and histopathology (depth of inflammation in superficial and deep dermis).

Histology of morphea can differ based on the stage, whether the lesion is sampled in the inflammatory margin or central sclerosis, and the depth of affected skin. At the inflammatory margin, vascular changes, including endothelial swelling and edema, are present, as well as CD4+ T cells, eosinophils, plasma cells, and mast cells surrounding smaller blood vessels. In late stages, the inflammatory infiltrate is no longer present, the epidermis appears regular, and there is a flattened dermal-epidermal junction. Distinct features include homogenous collagen bundles that replace many dermal structures, with atrophic eccrine glands that appear “trapped” in the thickened dermis, and homogenized and hyalinized subcutis.⁹

Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma and presents as annular, erythematous or hypopigmented patches and plaques with fine scale and tumors on the buttocks and sun-protected areas of the limbs and trunk. Lesions can appear with prominent poikiloderma or atrophic or lichenified skin.¹⁰ It is most common in males of African descent aged 50 to 55 years. The etiology is largely unknown but believed to be multifactorial. This answer is incorrect because the lesions in this patient appeared more atrophic, were less well demarcated, and lacked the scale that would be present in MF.

On histology, both LS and MF show band-like lymphocytic infiltrate, however MF lacks the homogenization and sclerosis of superficial collagen that is present in the dermis of LS. Also, MF demonstrates epidermotropism of atypical lymphocytes forming Pautrier microabscess.¹⁰

Primary Care Role

Primary care physicians can diagnose and treat LS. Referral to dermatology is not mandatory. Note that topical steroids can be used daily for up to 12 weeks. In LS, early treatment is associated with improved outcomes and minimizes the risk of irreversible skin changes.¹¹ Follow-up during the treatment period is recommended to monitor subjective and objective response to treatment. Follow-up after the initial treatment is recommended since LS is typically chronic, can relapse, and SCC can infrequently arise from LS lesions.¹¹

Discussion

A diagnosis of lichen sclerosus (LS) was made based on clinical and dermoscopic features, followed by confirmation with histology. The patient’s presentation included typical signs and symptoms of LS: itching, burning, intermittent bleeding, perianal hemorrhage, fusion of the clitoral head, and fissures. Other presentations can include dyspareunia, erosions, and excoriations; however, these symptoms and signs were not reported or seen in this patient.

LS typically affects the anogenital region and has 2 peak incidences: in preadolescent teens and during the fifth to sixth decade of life.¹ This patient presented with a case of extragenital LS, which is less common than the classic presentation of LS that affects the genitals. This variant’s epidemiology differs, as it is less common in children and more common in postmenopausal women.² Extragenital LS presents as white, atrophic plaques with a predilection for sites including the trunk, breasts, upper arms, and sites of physical trauma, with symptoms of dryness and pruritus. Over time, the papules can coalesce and form ivory, scar-like papules or plaques with a wrinkled surface. In advanced stages, telangiectasia or follicular plugging can be present, along with flattening of the dermal-epidermal junction. This flat interface is fragile and can result in bullae that may become hemorrhagic.

Cutaneous squamous cell carcinoma (SCC) may infrequently arise from LS, similar to other chronic inflammatory dermatoses.³ Lichen planus is typically not associated with an increased risk of SCC, except in the oral and hypertrophic variants. However, LS may be considered a premalignant process, and many vulvar SCC cases are noted to have adjacent LS lesions.³

Autoimmune and genetic factors contribute to the pathogenesis of LS. Extracellular matrix protein 1 (ECM1) binds molecules of the basement membrane zone and dermis, contributing to the structure and integrity of skin. Autoantibodies against ECM1 and other antigens of the basement membrane zone, including BP180 and BP320, were found in LS.² HLA-DQ7 major histocompatibility complex class II antigens have been associated with LS.¹

On histologic examination, the epidermis of LS is atrophic with hyperkeratosis. The dermis shows homogenization and sclerosis of superficial collagen with a band-like lymphocytic infiltrate below the sclerosis. The basal layer is thickened, showing basal cell vacuolization and hydropic degeneration.⁴

First-line treatment for genital and extragenital variants of LS is high-potency topical steroids for 3 months or until the skin texture and color resolve (ie, clobetasol 0.05% cream or ointment). The second-line treatment is a topical calcineurin inhibitor. These treatments are used for management. They are not cures for LS, as relapse is possible after the initial treatment course is completed. Adverse effects of high potency topical steroids are skin burning, skin atrophy, and fragility, telangiectasia. The adverse effects of topical calcineurin inhibitors are stinging and burning on application.

Other Diagnostic Considerations

Inverse psoriasis (IP) is a variant of psoriasis that presents as erythematous, well-demarcated plaques with minimal scale in intertriginous areas and flexural surfaces. Localized dermatophyte, candidal, or bacterial infections can trigger IP.⁵ It occurs in about 3% to 7% of patients with plaque psoriasis and is thought to form due to koebnerization via mechanical friction of flexural zones.⁶ The patient described in this case did not have IP because IP would be more likely to present as a well-demarcated erythematous plaque rather than a patch.

Histologically, IP shows regular psoriasiform acanthosis and hypogranulosis of the epidermis, Munro microabscess, spongiform pustules of Kogoj, dilated tortuous dermal vessels, and thinning of the suprapapillary plates.⁵

Lichen planus pigmentosus-inversus (LPPI) is also known as lichen planus pigmentosus—intertriginous variant. This variant of lichen planus pigmentosus presents as multiple gray to dark brown macules and patches with poorly defined borders in a linear distribution limited to intertriginous areas, flexural surfaces, or following the lines of Blaschko.⁷ About 20% of cases present with frontal fibrosing alopecia. It is most common in individuals with intermediate and darker skin pigmentation, has a higher prevalence in females, and typically occurs within the third and fifth decades of life. Friction is a common trigger of LPPI.⁷ A diagnosis of LPPI is incorrect because the lesions would present as gray to dark brown macules, as opposed to the shiny white atrophic thin papules with surrounding pink and purple patches seen in this case.

Histologically, while both LS and LPPI share band-like lymphocytic infiltrate and basal cell vacuolization, findings in the dermis differ. LPPI shows melanophages and prominent melanin incontinence, while LS shows homogenization and sclerosis of superficial collagen.^1,8 LPPI also shows absence of compensatory keratinocyte proliferation.

Morphea is an inflammatory disease that affects the dermis and subcutaneous fat, resulting in sclerosis that appears scarlike. Its prevalence increases with age and has a 4:1 prevalence in females, with the plaque type being the most common variant. ⁹ The typical presentation of plaque-type morphea is an insidious onset of asymptomatic, slightly elevated, erythematous or violaceous, slightly edematous plaques with centrifugal expansion. The center of the plaque may become sclerotic and indurated, acquiring a shiny white color with a peripheral “lilac” ring. Trunk and upper extremity involvement is common. Morphea is associated with increased antisingle-stranded DNA, antitopoisomerase IIa, antiphospholipid, antifibrillin-1, and antihistone antibodies. Triggers of morphea are believed to be localized insults to the skin, including mechanical trauma, injections, vaccinations, and irradiation.⁹ This answer is incorrect because the patient’s lesions were pruritic and had genital involvement, which are not typical of morphea. Morphea can be differentiated with based on symptoms (lack of pruritus, pain, burning), morphology of lesions (induration versus atrophy), dermoscopy (fibrotic beams with less scale and hemorrhage vs keratotic follicular plugs), and histopathology (depth of inflammation in superficial and deep dermis).

Histology of morphea can differ based on the stage, whether the lesion is sampled in the inflammatory margin or central sclerosis, and the depth of affected skin. At the inflammatory margin, vascular changes, including endothelial swelling and edema, are present, as well as CD4+ T cells, eosinophils, plasma cells, and mast cells surrounding smaller blood vessels. In late stages, the inflammatory infiltrate is no longer present, the epidermis appears regular, and there is a flattened dermal-epidermal junction. Distinct features include homogenous collagen bundles that replace many dermal structures, with atrophic eccrine glands that appear “trapped” in the thickened dermis, and homogenized and hyalinized subcutis.⁹

Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma and presents as annular, erythematous or hypopigmented patches and plaques with fine scale and tumors on the buttocks and sun-protected areas of the limbs and trunk. Lesions can appear with prominent poikiloderma or atrophic or lichenified skin.¹⁰ It is most common in males of African descent aged 50 to 55 years. The etiology is largely unknown but believed to be multifactorial. This answer is incorrect because the lesions in this patient appeared more atrophic, were less well demarcated, and lacked the scale that would be present in MF.

On histology, both LS and MF show band-like lymphocytic infiltrate, however MF lacks the homogenization and sclerosis of superficial collagen that is present in the dermis of LS. Also, MF demonstrates epidermotropism of atypical lymphocytes forming Pautrier microabscess.¹⁰

Primary Care Role

Primary care physicians can diagnose and treat LS. Referral to dermatology is not mandatory. Note that topical steroids can be used daily for up to 12 weeks. In LS, early treatment is associated with improved outcomes and minimizes the risk of irreversible skin changes.¹¹ Follow-up during the treatment period is recommended to monitor subjective and objective response to treatment. Follow-up after the initial treatment is recommended since LS is typically chronic, can relapse, and SCC can infrequently arise from LS lesions.¹¹

Discussion

A diagnosis of lichen sclerosus (LS) was made based on clinical and dermoscopic features, followed by confirmation with histology. The patient’s presentation included typical signs and symptoms of LS: itching, burning, intermittent bleeding, perianal hemorrhage, fusion of the clitoral head, and fissures. Other presentations can include dyspareunia, erosions, and excoriations; however, these symptoms and signs were not reported or seen in this patient.

LS typically affects the anogenital region and has 2 peak incidences: in preadolescent teens and during the fifth to sixth decade of life.¹ This patient presented with a case of extragenital LS, which is less common than the classic presentation of LS that affects the genitals. This variant’s epidemiology differs, as it is less common in children and more common in postmenopausal women.² Extragenital LS presents as white, atrophic plaques with a predilection for sites including the trunk, breasts, upper arms, and sites of physical trauma, with symptoms of dryness and pruritus. Over time, the papules can coalesce and form ivory, scar-like papules or plaques with a wrinkled surface. In advanced stages, telangiectasia or follicular plugging can be present, along with flattening of the dermal-epidermal junction. This flat interface is fragile and can result in bullae that may become hemorrhagic.

Cutaneous squamous cell carcinoma (SCC) may infrequently arise from LS, similar to other chronic inflammatory dermatoses.³ Lichen planus is typically not associated with an increased risk of SCC, except in the oral and hypertrophic variants. However, LS may be considered a premalignant process, and many vulvar SCC cases are noted to have adjacent LS lesions.³

Autoimmune and genetic factors contribute to the pathogenesis of LS. Extracellular matrix protein 1 (ECM1) binds molecules of the basement membrane zone and dermis, contributing to the structure and integrity of skin. Autoantibodies against ECM1 and other antigens of the basement membrane zone, including BP180 and BP320, were found in LS.² HLA-DQ7 major histocompatibility complex class II antigens have been associated with LS.¹

On histologic examination, the epidermis of LS is atrophic with hyperkeratosis. The dermis shows homogenization and sclerosis of superficial collagen with a band-like lymphocytic infiltrate below the sclerosis. The basal layer is thickened, showing basal cell vacuolization and hydropic degeneration.⁴

First-line treatment for genital and extragenital variants of LS is high-potency topical steroids for 3 months or until the skin texture and color resolve (ie, clobetasol 0.05% cream or ointment). The second-line treatment is a topical calcineurin inhibitor. These treatments are used for management. They are not cures for LS, as relapse is possible after the initial treatment course is completed. Adverse effects of high potency topical steroids are skin burning, skin atrophy, and fragility, telangiectasia. The adverse effects of topical calcineurin inhibitors are stinging and burning on application.

Other Diagnostic Considerations

Inverse psoriasis (IP) is a variant of psoriasis that presents as erythematous, well-demarcated plaques with minimal scale in intertriginous areas and flexural surfaces. Localized dermatophyte, candidal, or bacterial infections can trigger IP.⁵ It occurs in about 3% to 7% of patients with plaque psoriasis and is thought to form due to koebnerization via mechanical friction of flexural zones.⁶ The patient described in this case did not have IP because IP would be more likely to present as a well-demarcated erythematous plaque rather than a patch.

Histologically, IP shows regular psoriasiform acanthosis and hypogranulosis of the epidermis, Munro microabscess, spongiform pustules of Kogoj, dilated tortuous dermal vessels, and thinning of the suprapapillary plates.⁵

Lichen planus pigmentosus-inversus (LPPI) is also known as lichen planus pigmentosus—intertriginous variant. This variant of lichen planus pigmentosus presents as multiple gray to dark brown macules and patches with poorly defined borders in a linear distribution limited to intertriginous areas, flexural surfaces, or following the lines of Blaschko.⁷ About 20% of cases present with frontal fibrosing alopecia. It is most common in individuals with intermediate and darker skin pigmentation, has a higher prevalence in females, and typically occurs within the third and fifth decades of life. Friction is a common trigger of LPPI.⁷ A diagnosis of LPPI is incorrect because the lesions would present as gray to dark brown macules, as opposed to the shiny white atrophic thin papules with surrounding pink and purple patches seen in this case.

Histologically, while both LS and LPPI share band-like lymphocytic infiltrate and basal cell vacuolization, findings in the dermis differ. LPPI shows melanophages and prominent melanin incontinence, while LS shows homogenization and sclerosis of superficial collagen.^1,8 LPPI also shows absence of compensatory keratinocyte proliferation.

Morphea is an inflammatory disease that affects the dermis and subcutaneous fat, resulting in sclerosis that appears scarlike. Its prevalence increases with age and has a 4:1 prevalence in females, with the plaque type being the most common variant. ⁹ The typical presentation of plaque-type morphea is an insidious onset of asymptomatic, slightly elevated, erythematous or violaceous, slightly edematous plaques with centrifugal expansion. The center of the plaque may become sclerotic and indurated, acquiring a shiny white color with a peripheral “lilac” ring. Trunk and upper extremity involvement is common. Morphea is associated with increased antisingle-stranded DNA, antitopoisomerase IIa, antiphospholipid, antifibrillin-1, and antihistone antibodies. Triggers of morphea are believed to be localized insults to the skin, including mechanical trauma, injections, vaccinations, and irradiation.⁹ This answer is incorrect because the patient’s lesions were pruritic and had genital involvement, which are not typical of morphea. Morphea can be differentiated with based on symptoms (lack of pruritus, pain, burning), morphology of lesions (induration versus atrophy), dermoscopy (fibrotic beams with less scale and hemorrhage vs keratotic follicular plugs), and histopathology (depth of inflammation in superficial and deep dermis).

Histology of morphea can differ based on the stage, whether the lesion is sampled in the inflammatory margin or central sclerosis, and the depth of affected skin. At the inflammatory margin, vascular changes, including endothelial swelling and edema, are present, as well as CD4+ T cells, eosinophils, plasma cells, and mast cells surrounding smaller blood vessels. In late stages, the inflammatory infiltrate is no longer present, the epidermis appears regular, and there is a flattened dermal-epidermal junction. Distinct features include homogenous collagen bundles that replace many dermal structures, with atrophic eccrine glands that appear “trapped” in the thickened dermis, and homogenized and hyalinized subcutis.⁹

Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma and presents as annular, erythematous or hypopigmented patches and plaques with fine scale and tumors on the buttocks and sun-protected areas of the limbs and trunk. Lesions can appear with prominent poikiloderma or atrophic or lichenified skin.¹⁰ It is most common in males of African descent aged 50 to 55 years. The etiology is largely unknown but believed to be multifactorial. This answer is incorrect because the lesions in this patient appeared more atrophic, were less well demarcated, and lacked the scale that would be present in MF.

On histology, both LS and MF show band-like lymphocytic infiltrate, however MF lacks the homogenization and sclerosis of superficial collagen that is present in the dermis of LS. Also, MF demonstrates epidermotropism of atypical lymphocytes forming Pautrier microabscess.¹⁰

Primary Care Role

Primary care physicians can diagnose and treat LS. Referral to dermatology is not mandatory. Note that topical steroids can be used daily for up to 12 weeks. In LS, early treatment is associated with improved outcomes and minimizes the risk of irreversible skin changes.¹¹ Follow-up during the treatment period is recommended to monitor subjective and objective response to treatment. Follow-up after the initial treatment is recommended since LS is typically chronic, can relapse, and SCC can infrequently arise from LS lesions.¹¹

Tracheal deviation mostly occurs from mechanical compression of the trachea, and can be caused by a variety of clinical conditions, including trauma,¹ pharyngeal abscess,² neck hematoma,³ thyroid enlargement,⁴ and kyphoscoliosis.⁵ These conditions often result in lateral tracheal deviation, which can be associated with tracheal compression and reduction in tracheal caliber.

Anterior-posterior (A-P) tracheal deviation has rarely been reported. Kyphoscoliosis, scarring after a tracheostomy, or innominate vein compression are probable causes of A-P tracheal deviation and can be associated with tracheal narrowing and vascular fistula formation. This report describes a case of difficult endotracheal tube (ETT) advancement secondary to unexpected acute posterior tracheal deviation encountered during cardiopulmonary resuscitation (CPR). A waiver of patient consent was obtained from the Human Research Protection Program at the US Department of Veterans Affairs (VA) Puget Sound Health Care System.

Case Presentation

A 50-year-old male with a history of chronic cerebral venous sinus thrombosis and taking enoxaparin, presented to the emergency department for recurrent headaches. He experienced sudden cardiac arrest, and CPR in the form of chest compression and bag mask ventilation was immediately initiated. With the patient's head in an extended position and using a video laryngoscope, a Cormack–Lehane grade 1 view of the glottic opening was obtained and the trachea was intubated with an 8 mm (internal diameter) polyvinyl chloride ETT. Tracheal intubation was confirmed by utilizing continuous EtCO₂ monitoring. The ETT was secured at 22 cm measured at the teeth.

After about 40 minutes of CPR, spontaneous circulation restarted and a portable A-P chest X-ray with the head in a neutral position indicated the ETT tip was at the level of the first rib (Figure 1). This finding, along with a persistent air leak, prompted blind advancement of the ETT to 26 cm at the teeth, but resistance to advancement was noted. A subsequent chest computed tomography (CT) with the head in a neutral position revealed the ETT remained inappropriately positioned with the tip measured 8.2 cm above the carina (Figure 2A). Concurrently, a sagittal CT view demonstrated significant posterior deviation of the mid and lower trachea. This deviation was determined to be the most likely cause of the difficulty encountered in advancing the ETT. No masses or lesions contributing to the acute tracheal angulation could be identified. Comparing CT imaging from 2 months prior, the trachea was of normal caliber and ordinarily aligned with the vertebral column (Figure 2B).

With the patient in Fowler position with the head midline, a flexible fiber-optic bronchoscopy was performed. Acute, almost 90-degree tracheal angulation was encountered and navigated by retroflexion of the flexible bronchoscope. Once the posterior tracheal wall was encountered, retroflexion was relaxed and the carina was visualized. The bronchoscope tip was placed near the carina, and the ETT was advanced over the fiber-optic bronchoscope to terminate 3 cm above the carina. A subsequent chest X-ray confirmed appropriate ETT position (Figure 3).

Discussion

Tracheal deviation in the A-P dimension resulting in difficult tracheal intubation has rarely been reported. Previous reports have described anatomical lesions contributing to similar tracheal deviation, such as retro-tracheal thyroid tissue, pronounced cervical lordosis, and severe kyphoscoliosis with destructive cervical fusion.^5-8 In a study of the anatomical correlation of double lumen tube placement while using positron emission tomography CT, Cameron et al evaluated the size and angulation of the glottis and proximal trachea using calibrated CT measurements and an online digital protractor and note nearly perfect alignment of the pharynx and glottis.⁹ However, the trachea turned posteriorly relative to the glottis, resulting in an overall posterior angle of the proximal trachea compared to the glottis of 30.4 to 50.1 degrees, with no sex differences. The need to maneuver similar proximal tracheal angulation during endotracheal intubation has been reported as a cause of difficult intubation.¹⁰

In this case, the posterior angulation was not encountered in the proximal trachea but rather in the more distal trachea. The extreme A-P tracheal deviation was not associated with any identifiable masses or lesions. A CT performed 2 months prior demonstrated normal tracheal anatomy, and there was no interval history of neck trauma or tracheal obstruction suggestive of a likely cause for this deviation. This change in the patient’s tracheal anatomy was only discovered after CPR had been performed and as part of the workup for cardiac arrest. Iatrogenic injuries are known to occur during CPR. Common CPR-related airway injuries include tracheal mucosal injury from traumatic intubation and bony injuries to the chest wall from compressions.¹¹ Laryngeal cartilage damage from intubation may also occur, but tracheal displacement following CPR has not been previously reported.¹¹

This case of tracheal deviation is unlikely to be related to patient positioning, as the A-P deviation persisted in 3 separate head and neck alignments. First, during indirect laryngoscopy, performed in a standard sniffing position. Second, during the CT, performed in the supine position, with no head support. The acute A-P deviation seen in Figure 2 was clearly noted in this position. Lastly, flexible fiber-optic bronchoscopy was performed in a semiupright position with the head supported on a pillow. A-P deviation was encountered and navigated in this position during flexible fiber-optic guided ETT repositioning. 

Using magnetic resonance imaging, alterations in the alignment of pharyngeal and tracheal axes have been described with changes in neck positioning; however, tracheal deviation has not been described with changes in head and neck alignment.¹² Although the clinical presentation in this case was consistent with prior reports, we were unable to identify any previously reported anatomic cause for the tracheal deviation.^5,6,8 Initial glottic visualization with a video laryngoscope was unremarkable, but resistance to sufficient ETT advancement past the vocal cords and a persistent air leak due to cuff herniation through the glottic opening was noticeable. The ETT was maneuvered to an appropriate position in the trachea using a flexible fiber-optic bronchoscope. The acute angulation of the trachea that was appreciated on bronchoscopy did not result in kinking of the ETT both initially and after in-situ thermosoftening of the polyvinyl chloride tube.¹³ Previously reported instances of A-P tracheal deviation have outlined the necessity of using alternative techniques to establish a patent airway, including the use of a laryngeal mask airway and a cuffless ETT with saline-soaked gauze packing.^5,8 In 1 reported case, awake fiber-optic intubation was performed when difficult tracheal intubation was anticipated due to known A-P tracheal deviation.⁶

Failure of ETT advancement can be due to obstruction from the arytenoids and at the level of the vocal cords.¹⁴ When the ETT has been visualized to have traversed the vocal cords, tracheal A-P deviation should be considered as a cause of difficult ETT advancement. If an adequate endotracheal airway cannot be established, prompt consideration should be given to placement of a supraglottic airway. Early fiber-optic bronchoscopy should be used to establish the diagnosis and assist with proper ETT positioning.

Conclusions

This case illustrates the rare occurrence of A-P tracheal deviation leading to difficult intubation during CPR. The findings underscore the importance of considering A-P deviation as a potential cause of airway complications in emergency settings, especially in patients with previously normal tracheal anatomy. The successful use of flexible fiber-optic bronchoscopy in this case provides a valuable technique for addressing acute tracheal angulation. This report contributes to the limited literature on A-P tracheal deviation and serves as a reminder for clinicians to maintain a high index of suspicion for unusual airway challenges during critical interventions.

Tracheal deviation mostly occurs from mechanical compression of the trachea, and can be caused by a variety of clinical conditions, including trauma,¹ pharyngeal abscess,² neck hematoma,³ thyroid enlargement,⁴ and kyphoscoliosis.⁵ These conditions often result in lateral tracheal deviation, which can be associated with tracheal compression and reduction in tracheal caliber.

Anterior-posterior (A-P) tracheal deviation has rarely been reported. Kyphoscoliosis, scarring after a tracheostomy, or innominate vein compression are probable causes of A-P tracheal deviation and can be associated with tracheal narrowing and vascular fistula formation. This report describes a case of difficult endotracheal tube (ETT) advancement secondary to unexpected acute posterior tracheal deviation encountered during cardiopulmonary resuscitation (CPR). A waiver of patient consent was obtained from the Human Research Protection Program at the US Department of Veterans Affairs (VA) Puget Sound Health Care System.

Case Presentation

A 50-year-old male with a history of chronic cerebral venous sinus thrombosis and taking enoxaparin, presented to the emergency department for recurrent headaches. He experienced sudden cardiac arrest, and CPR in the form of chest compression and bag mask ventilation was immediately initiated. With the patient's head in an extended position and using a video laryngoscope, a Cormack–Lehane grade 1 view of the glottic opening was obtained and the trachea was intubated with an 8 mm (internal diameter) polyvinyl chloride ETT. Tracheal intubation was confirmed by utilizing continuous EtCO₂ monitoring. The ETT was secured at 22 cm measured at the teeth.

After about 40 minutes of CPR, spontaneous circulation restarted and a portable A-P chest X-ray with the head in a neutral position indicated the ETT tip was at the level of the first rib (Figure 1). This finding, along with a persistent air leak, prompted blind advancement of the ETT to 26 cm at the teeth, but resistance to advancement was noted. A subsequent chest computed tomography (CT) with the head in a neutral position revealed the ETT remained inappropriately positioned with the tip measured 8.2 cm above the carina (Figure 2A). Concurrently, a sagittal CT view demonstrated significant posterior deviation of the mid and lower trachea. This deviation was determined to be the most likely cause of the difficulty encountered in advancing the ETT. No masses or lesions contributing to the acute tracheal angulation could be identified. Comparing CT imaging from 2 months prior, the trachea was of normal caliber and ordinarily aligned with the vertebral column (Figure 2B).

With the patient in Fowler position with the head midline, a flexible fiber-optic bronchoscopy was performed. Acute, almost 90-degree tracheal angulation was encountered and navigated by retroflexion of the flexible bronchoscope. Once the posterior tracheal wall was encountered, retroflexion was relaxed and the carina was visualized. The bronchoscope tip was placed near the carina, and the ETT was advanced over the fiber-optic bronchoscope to terminate 3 cm above the carina. A subsequent chest X-ray confirmed appropriate ETT position (Figure 3).

Discussion

Tracheal deviation in the A-P dimension resulting in difficult tracheal intubation has rarely been reported. Previous reports have described anatomical lesions contributing to similar tracheal deviation, such as retro-tracheal thyroid tissue, pronounced cervical lordosis, and severe kyphoscoliosis with destructive cervical fusion.^5-8 In a study of the anatomical correlation of double lumen tube placement while using positron emission tomography CT, Cameron et al evaluated the size and angulation of the glottis and proximal trachea using calibrated CT measurements and an online digital protractor and note nearly perfect alignment of the pharynx and glottis.⁹ However, the trachea turned posteriorly relative to the glottis, resulting in an overall posterior angle of the proximal trachea compared to the glottis of 30.4 to 50.1 degrees, with no sex differences. The need to maneuver similar proximal tracheal angulation during endotracheal intubation has been reported as a cause of difficult intubation.¹⁰

In this case, the posterior angulation was not encountered in the proximal trachea but rather in the more distal trachea. The extreme A-P tracheal deviation was not associated with any identifiable masses or lesions. A CT performed 2 months prior demonstrated normal tracheal anatomy, and there was no interval history of neck trauma or tracheal obstruction suggestive of a likely cause for this deviation. This change in the patient’s tracheal anatomy was only discovered after CPR had been performed and as part of the workup for cardiac arrest. Iatrogenic injuries are known to occur during CPR. Common CPR-related airway injuries include tracheal mucosal injury from traumatic intubation and bony injuries to the chest wall from compressions.¹¹ Laryngeal cartilage damage from intubation may also occur, but tracheal displacement following CPR has not been previously reported.¹¹

This case of tracheal deviation is unlikely to be related to patient positioning, as the A-P deviation persisted in 3 separate head and neck alignments. First, during indirect laryngoscopy, performed in a standard sniffing position. Second, during the CT, performed in the supine position, with no head support. The acute A-P deviation seen in Figure 2 was clearly noted in this position. Lastly, flexible fiber-optic bronchoscopy was performed in a semiupright position with the head supported on a pillow. A-P deviation was encountered and navigated in this position during flexible fiber-optic guided ETT repositioning. 

Using magnetic resonance imaging, alterations in the alignment of pharyngeal and tracheal axes have been described with changes in neck positioning; however, tracheal deviation has not been described with changes in head and neck alignment.¹² Although the clinical presentation in this case was consistent with prior reports, we were unable to identify any previously reported anatomic cause for the tracheal deviation.^5,6,8 Initial glottic visualization with a video laryngoscope was unremarkable, but resistance to sufficient ETT advancement past the vocal cords and a persistent air leak due to cuff herniation through the glottic opening was noticeable. The ETT was maneuvered to an appropriate position in the trachea using a flexible fiber-optic bronchoscope. The acute angulation of the trachea that was appreciated on bronchoscopy did not result in kinking of the ETT both initially and after in-situ thermosoftening of the polyvinyl chloride tube.¹³ Previously reported instances of A-P tracheal deviation have outlined the necessity of using alternative techniques to establish a patent airway, including the use of a laryngeal mask airway and a cuffless ETT with saline-soaked gauze packing.^5,8 In 1 reported case, awake fiber-optic intubation was performed when difficult tracheal intubation was anticipated due to known A-P tracheal deviation.⁶

Failure of ETT advancement can be due to obstruction from the arytenoids and at the level of the vocal cords.¹⁴ When the ETT has been visualized to have traversed the vocal cords, tracheal A-P deviation should be considered as a cause of difficult ETT advancement. If an adequate endotracheal airway cannot be established, prompt consideration should be given to placement of a supraglottic airway. Early fiber-optic bronchoscopy should be used to establish the diagnosis and assist with proper ETT positioning.

Conclusions

This case illustrates the rare occurrence of A-P tracheal deviation leading to difficult intubation during CPR. The findings underscore the importance of considering A-P deviation as a potential cause of airway complications in emergency settings, especially in patients with previously normal tracheal anatomy. The successful use of flexible fiber-optic bronchoscopy in this case provides a valuable technique for addressing acute tracheal angulation. This report contributes to the limited literature on A-P tracheal deviation and serves as a reminder for clinicians to maintain a high index of suspicion for unusual airway challenges during critical interventions.

Tracheal deviation mostly occurs from mechanical compression of the trachea, and can be caused by a variety of clinical conditions, including trauma,¹ pharyngeal abscess,² neck hematoma,³ thyroid enlargement,⁴ and kyphoscoliosis.⁵ These conditions often result in lateral tracheal deviation, which can be associated with tracheal compression and reduction in tracheal caliber.

Anterior-posterior (A-P) tracheal deviation has rarely been reported. Kyphoscoliosis, scarring after a tracheostomy, or innominate vein compression are probable causes of A-P tracheal deviation and can be associated with tracheal narrowing and vascular fistula formation. This report describes a case of difficult endotracheal tube (ETT) advancement secondary to unexpected acute posterior tracheal deviation encountered during cardiopulmonary resuscitation (CPR). A waiver of patient consent was obtained from the Human Research Protection Program at the US Department of Veterans Affairs (VA) Puget Sound Health Care System.

Case Presentation

A 50-year-old male with a history of chronic cerebral venous sinus thrombosis and taking enoxaparin, presented to the emergency department for recurrent headaches. He experienced sudden cardiac arrest, and CPR in the form of chest compression and bag mask ventilation was immediately initiated. With the patient's head in an extended position and using a video laryngoscope, a Cormack–Lehane grade 1 view of the glottic opening was obtained and the trachea was intubated with an 8 mm (internal diameter) polyvinyl chloride ETT. Tracheal intubation was confirmed by utilizing continuous EtCO₂ monitoring. The ETT was secured at 22 cm measured at the teeth.

After about 40 minutes of CPR, spontaneous circulation restarted and a portable A-P chest X-ray with the head in a neutral position indicated the ETT tip was at the level of the first rib (Figure 1). This finding, along with a persistent air leak, prompted blind advancement of the ETT to 26 cm at the teeth, but resistance to advancement was noted. A subsequent chest computed tomography (CT) with the head in a neutral position revealed the ETT remained inappropriately positioned with the tip measured 8.2 cm above the carina (Figure 2A). Concurrently, a sagittal CT view demonstrated significant posterior deviation of the mid and lower trachea. This deviation was determined to be the most likely cause of the difficulty encountered in advancing the ETT. No masses or lesions contributing to the acute tracheal angulation could be identified. Comparing CT imaging from 2 months prior, the trachea was of normal caliber and ordinarily aligned with the vertebral column (Figure 2B).

With the patient in Fowler position with the head midline, a flexible fiber-optic bronchoscopy was performed. Acute, almost 90-degree tracheal angulation was encountered and navigated by retroflexion of the flexible bronchoscope. Once the posterior tracheal wall was encountered, retroflexion was relaxed and the carina was visualized. The bronchoscope tip was placed near the carina, and the ETT was advanced over the fiber-optic bronchoscope to terminate 3 cm above the carina. A subsequent chest X-ray confirmed appropriate ETT position (Figure 3).

Discussion

Tracheal deviation in the A-P dimension resulting in difficult tracheal intubation has rarely been reported. Previous reports have described anatomical lesions contributing to similar tracheal deviation, such as retro-tracheal thyroid tissue, pronounced cervical lordosis, and severe kyphoscoliosis with destructive cervical fusion.^5-8 In a study of the anatomical correlation of double lumen tube placement while using positron emission tomography CT, Cameron et al evaluated the size and angulation of the glottis and proximal trachea using calibrated CT measurements and an online digital protractor and note nearly perfect alignment of the pharynx and glottis.⁹ However, the trachea turned posteriorly relative to the glottis, resulting in an overall posterior angle of the proximal trachea compared to the glottis of 30.4 to 50.1 degrees, with no sex differences. The need to maneuver similar proximal tracheal angulation during endotracheal intubation has been reported as a cause of difficult intubation.¹⁰

In this case, the posterior angulation was not encountered in the proximal trachea but rather in the more distal trachea. The extreme A-P tracheal deviation was not associated with any identifiable masses or lesions. A CT performed 2 months prior demonstrated normal tracheal anatomy, and there was no interval history of neck trauma or tracheal obstruction suggestive of a likely cause for this deviation. This change in the patient’s tracheal anatomy was only discovered after CPR had been performed and as part of the workup for cardiac arrest. Iatrogenic injuries are known to occur during CPR. Common CPR-related airway injuries include tracheal mucosal injury from traumatic intubation and bony injuries to the chest wall from compressions.¹¹ Laryngeal cartilage damage from intubation may also occur, but tracheal displacement following CPR has not been previously reported.¹¹

This case of tracheal deviation is unlikely to be related to patient positioning, as the A-P deviation persisted in 3 separate head and neck alignments. First, during indirect laryngoscopy, performed in a standard sniffing position. Second, during the CT, performed in the supine position, with no head support. The acute A-P deviation seen in Figure 2 was clearly noted in this position. Lastly, flexible fiber-optic bronchoscopy was performed in a semiupright position with the head supported on a pillow. A-P deviation was encountered and navigated in this position during flexible fiber-optic guided ETT repositioning. 

Using magnetic resonance imaging, alterations in the alignment of pharyngeal and tracheal axes have been described with changes in neck positioning; however, tracheal deviation has not been described with changes in head and neck alignment.¹² Although the clinical presentation in this case was consistent with prior reports, we were unable to identify any previously reported anatomic cause for the tracheal deviation.^5,6,8 Initial glottic visualization with a video laryngoscope was unremarkable, but resistance to sufficient ETT advancement past the vocal cords and a persistent air leak due to cuff herniation through the glottic opening was noticeable. The ETT was maneuvered to an appropriate position in the trachea using a flexible fiber-optic bronchoscope. The acute angulation of the trachea that was appreciated on bronchoscopy did not result in kinking of the ETT both initially and after in-situ thermosoftening of the polyvinyl chloride tube.¹³ Previously reported instances of A-P tracheal deviation have outlined the necessity of using alternative techniques to establish a patent airway, including the use of a laryngeal mask airway and a cuffless ETT with saline-soaked gauze packing.^5,8 In 1 reported case, awake fiber-optic intubation was performed when difficult tracheal intubation was anticipated due to known A-P tracheal deviation.⁶

Failure of ETT advancement can be due to obstruction from the arytenoids and at the level of the vocal cords.¹⁴ When the ETT has been visualized to have traversed the vocal cords, tracheal A-P deviation should be considered as a cause of difficult ETT advancement. If an adequate endotracheal airway cannot be established, prompt consideration should be given to placement of a supraglottic airway. Early fiber-optic bronchoscopy should be used to establish the diagnosis and assist with proper ETT positioning.

Conclusions

This case illustrates the rare occurrence of A-P tracheal deviation leading to difficult intubation during CPR. The findings underscore the importance of considering A-P deviation as a potential cause of airway complications in emergency settings, especially in patients with previously normal tracheal anatomy. The successful use of flexible fiber-optic bronchoscopy in this case provides a valuable technique for addressing acute tracheal angulation. This report contributes to the limited literature on A-P tracheal deviation and serves as a reminder for clinicians to maintain a high index of suspicion for unusual airway challenges during critical interventions.

Topical application or injection of cosmeceuticals in conjunction with procedures such as facial microneedling (MN) has been associated with local and systemic complications.¹  Microneedling is an increasingly popular minimally invasive therapeutic procedure that is used for a wide range of dermatologic purposes, including facial rejuvenation.² Other indications for MN include minimizing the appearance of acne scars, surgical scars, stretch marks, wrinkles, and other cosmetic skin concerns. This procedure can be performed both at home and in a clinical setting, but at-home devices differ from procedures performed in a dermatology office. Clinicians use medical-grade devices for deeper penetration of the skin, yielding more effective results. In contrast, at-home MN devices are designed to be safer and less powerful with milder outcomes.

Although at-home options may be more accessible and affordable for patients, they also increase the risk for improper use and subsequent infection. Additionally, the use of cosmeceuticals such as vitamin E oil in conjunction with MN to enhance the effects of the procedure can lead to further complications. We report the case of a 44-year-old woman who developed a necrotic ulcer on the chin following self-treatment with vitamin E oil and an at-home MN device. While MN has been reported to be relatively safe when performed by board-certified dermatologists, clinicians should be vigilant in correlating clinical history and recent cosmetic procedures with the histologic findings for timely diagnosis and treatment of unusual lesions on the face.

Case Report

A 44-year-old woman presented to the emergency department with a progressively enlarging, necrotic, ulcerative lesion on the midline chin of 4 months’ duration. The patient reported that the lesion started as redness that developed into a painful oozing ulcer following application of vitamin E oil in conjunction with an at-home MN device (Figure 1). She purchased the vitamin E oil and MN device online and performed the procedure herself, applying the vitamin E oil to her whole face before, during, and after using the MN device, which contained 0.25-mm titanium needles. She denied undergoing any other recent cosmetic procedures.

The lesion initially was treated by the patient’s primary care physician with oral doxycycline for 6 weeks, followed by oral cephalexin and clindamycin for 2 weeks. Although the redness stabilized, the lesion continued to enlarge, which prompted her initial visit to our hospital 1 month after seeing her primary care physician. During this visit, the patient was given penicillin, and the ulcer was debrided and biopsied; however, no clinical improvement was seen. 

A biopsy during her initial emergency department visit and a repeat biopsy after 1 month showed similar findings of diffuse lymphohistiocytic and eosinophilic inflammation in the dermis (Figure 2) with poorly defined granulomas and multinucleated giant cells containing nonpolarizable exogenous material (Figure 3). Similar detached exogenous materials also were identified adjacent to the tissue. Diffuse re-epithelialization was seen, featuring pseudoepitheliomatous hyperplasia in association with the inflammatory process and granulation tissue (Figures 3 and 4). A higher-power view of the dermis showed foci of sclerosing lipogranuloma (Figure 4). Periodic acid–Schiff, Grocott methenamine silver, acid-fast bacilli, Fite, and Wright-Giemsa stains all were negative for microorganisms, and pancytokeratin staining was negative for carcinoma. These findings supported the diagnosis of a foreign body granulomatous reaction to an exogenous material—in this case, the vitamin E oil. Subsequent treatment with intralesional triamcinolone 10 mg/mL injection over 18 months resulted in progressive and drastic improvement of the lesion (Figure 5). A scar excision was performed, which further improved the lesion’s cosmetic appearance.

Comment

Application of various topical cosmeceuticals before, during, or after MN to enhance the effects of the procedure can introduce particles into the dermis, resulting in local or systemic hypersensitivity reactions. The associated adverse events can be divided into 2 main categories: adverse reactions related to the topical product or to the materials of the MN device itself.

A study showed that topical application of vitamin E oil to wounds on the skin does not improve the cosmetic appearance of scars.³ Instead, it is associated with a high incidence of contact dermatitis. A similar case of vitamin E injection, although without the concurrent use of an MN device, complicated by a facial lipogranuloma has been described.⁴ Sclerodermoid reaction, subcutaneous nodules, persistent edema, and ulceration at the site of vitamin E injection also have been described following the injection.^5,6 Because vitamin E is a lipid-soluble vitamin, its absorption in the human body is dependent on the presence of lipid or oil-like substances. The reactions mentioned above are associated with the vitamin E oil, which acts as a helper vehicle for lipid-soluble vitamins to be absorbed.⁷ Other ingredients in topical vitamin E oil include a combination of D-alpha-tocopherol, D-alpha-tocopheryl acetate, D-alpha-tocopheryl succinate, or mixed tocopherols.⁸ These ester conjugate forms of vitamin E also may play a role in its immunogenic properties and possibly contribute to adverse effects such as dermatitis and erythema. Further research is needed to investigate the impact of ester conjugate forms on skin reactions and individual responses.⁷

Hyaluronic acid is a relatively safe and commonly used topical treatment that acts as a lubricant during MN procedures to help the needles glide across the skin and prevent dragging. It also can be applied after the procedure for hydration purposes. Other common alternatives include peptides, ceramides, and epidermal growth factors. Topical products to avoid before, during, and 48 hours after undergoing MN include retinoids, vitamin C, vitamin E, exfoliants, serums that contain acids (eg, alpha hydroxy acids, beta hydroxy acids, glycolic acid, and lactic acid), serums that contain fragrance, and oil-based serums because they are associated with similar adverse effects.^8-10 A granulomatous reaction after an MN procedure also has been reported with the use of vitamin C serum.¹¹

The US Food and Drug Administration has approved the use of MN devices, including for at-home use, to improve the appearance of facial acne scars and wrinkles as well as abdominal scars in patients aged 22 years or older; however, MN devices are not approved for delivery of cosmeceuticals or other topical products into the skin. Therefore, there is no universal list of approved topicals to be used in conjunction with MN.¹²

Most MN devices are made of nickel and various other metals. Cases of contact dermatitis and delayed-type hypersensitivity granulomatous reaction with systemic symptoms have been reported after MN procedures due to the material of the MN device.^1,13,14

Conclusion

Microneedling is a minimally invasive procedure that causes nominal damage to the epidermis and superficial papillary dermis, stimulating a wound-healing cascade for collagen production.^15,16 Although not approved by the US Food and Drug Administration, MN performed at dermatology offices sometimes can be used in conjunction with topical products to enhance their absorption; however, while vitamin E is known for its antioxidant properties and potential skin benefits, the lipid substance acting as the vehicle is not absorbable by the skin and may cause a granulomatous reaction as the body attempts to encapsulate and digest the foreign substance.^10,17 Although rarely reported, the use of topical vitamins with MN—through intradermal injection or combined with MN—can be associated with severe complications, including local, sometimes systemic, and life-threatening complications. Clinicians should be vigilant in order to correlate clinical background and history of recent cosmetic procedures with the histologic findings for prompt diagnosis and timely treatment.

Topical application or injection of cosmeceuticals in conjunction with procedures such as facial microneedling (MN) has been associated with local and systemic complications.¹  Microneedling is an increasingly popular minimally invasive therapeutic procedure that is used for a wide range of dermatologic purposes, including facial rejuvenation.² Other indications for MN include minimizing the appearance of acne scars, surgical scars, stretch marks, wrinkles, and other cosmetic skin concerns. This procedure can be performed both at home and in a clinical setting, but at-home devices differ from procedures performed in a dermatology office. Clinicians use medical-grade devices for deeper penetration of the skin, yielding more effective results. In contrast, at-home MN devices are designed to be safer and less powerful with milder outcomes.

Although at-home options may be more accessible and affordable for patients, they also increase the risk for improper use and subsequent infection. Additionally, the use of cosmeceuticals such as vitamin E oil in conjunction with MN to enhance the effects of the procedure can lead to further complications. We report the case of a 44-year-old woman who developed a necrotic ulcer on the chin following self-treatment with vitamin E oil and an at-home MN device. While MN has been reported to be relatively safe when performed by board-certified dermatologists, clinicians should be vigilant in correlating clinical history and recent cosmetic procedures with the histologic findings for timely diagnosis and treatment of unusual lesions on the face.

Case Report

A 44-year-old woman presented to the emergency department with a progressively enlarging, necrotic, ulcerative lesion on the midline chin of 4 months’ duration. The patient reported that the lesion started as redness that developed into a painful oozing ulcer following application of vitamin E oil in conjunction with an at-home MN device (Figure 1). She purchased the vitamin E oil and MN device online and performed the procedure herself, applying the vitamin E oil to her whole face before, during, and after using the MN device, which contained 0.25-mm titanium needles. She denied undergoing any other recent cosmetic procedures.

The lesion initially was treated by the patient’s primary care physician with oral doxycycline for 6 weeks, followed by oral cephalexin and clindamycin for 2 weeks. Although the redness stabilized, the lesion continued to enlarge, which prompted her initial visit to our hospital 1 month after seeing her primary care physician. During this visit, the patient was given penicillin, and the ulcer was debrided and biopsied; however, no clinical improvement was seen. 

A biopsy during her initial emergency department visit and a repeat biopsy after 1 month showed similar findings of diffuse lymphohistiocytic and eosinophilic inflammation in the dermis (Figure 2) with poorly defined granulomas and multinucleated giant cells containing nonpolarizable exogenous material (Figure 3). Similar detached exogenous materials also were identified adjacent to the tissue. Diffuse re-epithelialization was seen, featuring pseudoepitheliomatous hyperplasia in association with the inflammatory process and granulation tissue (Figures 3 and 4). A higher-power view of the dermis showed foci of sclerosing lipogranuloma (Figure 4). Periodic acid–Schiff, Grocott methenamine silver, acid-fast bacilli, Fite, and Wright-Giemsa stains all were negative for microorganisms, and pancytokeratin staining was negative for carcinoma. These findings supported the diagnosis of a foreign body granulomatous reaction to an exogenous material—in this case, the vitamin E oil. Subsequent treatment with intralesional triamcinolone 10 mg/mL injection over 18 months resulted in progressive and drastic improvement of the lesion (Figure 5). A scar excision was performed, which further improved the lesion’s cosmetic appearance.

Comment

Application of various topical cosmeceuticals before, during, or after MN to enhance the effects of the procedure can introduce particles into the dermis, resulting in local or systemic hypersensitivity reactions. The associated adverse events can be divided into 2 main categories: adverse reactions related to the topical product or to the materials of the MN device itself.

A study showed that topical application of vitamin E oil to wounds on the skin does not improve the cosmetic appearance of scars.³ Instead, it is associated with a high incidence of contact dermatitis. A similar case of vitamin E injection, although without the concurrent use of an MN device, complicated by a facial lipogranuloma has been described.⁴ Sclerodermoid reaction, subcutaneous nodules, persistent edema, and ulceration at the site of vitamin E injection also have been described following the injection.^5,6 Because vitamin E is a lipid-soluble vitamin, its absorption in the human body is dependent on the presence of lipid or oil-like substances. The reactions mentioned above are associated with the vitamin E oil, which acts as a helper vehicle for lipid-soluble vitamins to be absorbed.⁷ Other ingredients in topical vitamin E oil include a combination of D-alpha-tocopherol, D-alpha-tocopheryl acetate, D-alpha-tocopheryl succinate, or mixed tocopherols.⁸ These ester conjugate forms of vitamin E also may play a role in its immunogenic properties and possibly contribute to adverse effects such as dermatitis and erythema. Further research is needed to investigate the impact of ester conjugate forms on skin reactions and individual responses.⁷

Hyaluronic acid is a relatively safe and commonly used topical treatment that acts as a lubricant during MN procedures to help the needles glide across the skin and prevent dragging. It also can be applied after the procedure for hydration purposes. Other common alternatives include peptides, ceramides, and epidermal growth factors. Topical products to avoid before, during, and 48 hours after undergoing MN include retinoids, vitamin C, vitamin E, exfoliants, serums that contain acids (eg, alpha hydroxy acids, beta hydroxy acids, glycolic acid, and lactic acid), serums that contain fragrance, and oil-based serums because they are associated with similar adverse effects.^8-10 A granulomatous reaction after an MN procedure also has been reported with the use of vitamin C serum.¹¹

The US Food and Drug Administration has approved the use of MN devices, including for at-home use, to improve the appearance of facial acne scars and wrinkles as well as abdominal scars in patients aged 22 years or older; however, MN devices are not approved for delivery of cosmeceuticals or other topical products into the skin. Therefore, there is no universal list of approved topicals to be used in conjunction with MN.¹²

Most MN devices are made of nickel and various other metals. Cases of contact dermatitis and delayed-type hypersensitivity granulomatous reaction with systemic symptoms have been reported after MN procedures due to the material of the MN device.^1,13,14

Conclusion

Microneedling is a minimally invasive procedure that causes nominal damage to the epidermis and superficial papillary dermis, stimulating a wound-healing cascade for collagen production.^15,16 Although not approved by the US Food and Drug Administration, MN performed at dermatology offices sometimes can be used in conjunction with topical products to enhance their absorption; however, while vitamin E is known for its antioxidant properties and potential skin benefits, the lipid substance acting as the vehicle is not absorbable by the skin and may cause a granulomatous reaction as the body attempts to encapsulate and digest the foreign substance.^10,17 Although rarely reported, the use of topical vitamins with MN—through intradermal injection or combined with MN—can be associated with severe complications, including local, sometimes systemic, and life-threatening complications. Clinicians should be vigilant in order to correlate clinical background and history of recent cosmetic procedures with the histologic findings for prompt diagnosis and timely treatment.

Topical application or injection of cosmeceuticals in conjunction with procedures such as facial microneedling (MN) has been associated with local and systemic complications.¹  Microneedling is an increasingly popular minimally invasive therapeutic procedure that is used for a wide range of dermatologic purposes, including facial rejuvenation.² Other indications for MN include minimizing the appearance of acne scars, surgical scars, stretch marks, wrinkles, and other cosmetic skin concerns. This procedure can be performed both at home and in a clinical setting, but at-home devices differ from procedures performed in a dermatology office. Clinicians use medical-grade devices for deeper penetration of the skin, yielding more effective results. In contrast, at-home MN devices are designed to be safer and less powerful with milder outcomes.

Although at-home options may be more accessible and affordable for patients, they also increase the risk for improper use and subsequent infection. Additionally, the use of cosmeceuticals such as vitamin E oil in conjunction with MN to enhance the effects of the procedure can lead to further complications. We report the case of a 44-year-old woman who developed a necrotic ulcer on the chin following self-treatment with vitamin E oil and an at-home MN device. While MN has been reported to be relatively safe when performed by board-certified dermatologists, clinicians should be vigilant in correlating clinical history and recent cosmetic procedures with the histologic findings for timely diagnosis and treatment of unusual lesions on the face.

Case Report

A 44-year-old woman presented to the emergency department with a progressively enlarging, necrotic, ulcerative lesion on the midline chin of 4 months’ duration. The patient reported that the lesion started as redness that developed into a painful oozing ulcer following application of vitamin E oil in conjunction with an at-home MN device (Figure 1). She purchased the vitamin E oil and MN device online and performed the procedure herself, applying the vitamin E oil to her whole face before, during, and after using the MN device, which contained 0.25-mm titanium needles. She denied undergoing any other recent cosmetic procedures.

The lesion initially was treated by the patient’s primary care physician with oral doxycycline for 6 weeks, followed by oral cephalexin and clindamycin for 2 weeks. Although the redness stabilized, the lesion continued to enlarge, which prompted her initial visit to our hospital 1 month after seeing her primary care physician. During this visit, the patient was given penicillin, and the ulcer was debrided and biopsied; however, no clinical improvement was seen. 

A biopsy during her initial emergency department visit and a repeat biopsy after 1 month showed similar findings of diffuse lymphohistiocytic and eosinophilic inflammation in the dermis (Figure 2) with poorly defined granulomas and multinucleated giant cells containing nonpolarizable exogenous material (Figure 3). Similar detached exogenous materials also were identified adjacent to the tissue. Diffuse re-epithelialization was seen, featuring pseudoepitheliomatous hyperplasia in association with the inflammatory process and granulation tissue (Figures 3 and 4). A higher-power view of the dermis showed foci of sclerosing lipogranuloma (Figure 4). Periodic acid–Schiff, Grocott methenamine silver, acid-fast bacilli, Fite, and Wright-Giemsa stains all were negative for microorganisms, and pancytokeratin staining was negative for carcinoma. These findings supported the diagnosis of a foreign body granulomatous reaction to an exogenous material—in this case, the vitamin E oil. Subsequent treatment with intralesional triamcinolone 10 mg/mL injection over 18 months resulted in progressive and drastic improvement of the lesion (Figure 5). A scar excision was performed, which further improved the lesion’s cosmetic appearance.

Comment

Application of various topical cosmeceuticals before, during, or after MN to enhance the effects of the procedure can introduce particles into the dermis, resulting in local or systemic hypersensitivity reactions. The associated adverse events can be divided into 2 main categories: adverse reactions related to the topical product or to the materials of the MN device itself.

A study showed that topical application of vitamin E oil to wounds on the skin does not improve the cosmetic appearance of scars.³ Instead, it is associated with a high incidence of contact dermatitis. A similar case of vitamin E injection, although without the concurrent use of an MN device, complicated by a facial lipogranuloma has been described.⁴ Sclerodermoid reaction, subcutaneous nodules, persistent edema, and ulceration at the site of vitamin E injection also have been described following the injection.^5,6 Because vitamin E is a lipid-soluble vitamin, its absorption in the human body is dependent on the presence of lipid or oil-like substances. The reactions mentioned above are associated with the vitamin E oil, which acts as a helper vehicle for lipid-soluble vitamins to be absorbed.⁷ Other ingredients in topical vitamin E oil include a combination of D-alpha-tocopherol, D-alpha-tocopheryl acetate, D-alpha-tocopheryl succinate, or mixed tocopherols.⁸ These ester conjugate forms of vitamin E also may play a role in its immunogenic properties and possibly contribute to adverse effects such as dermatitis and erythema. Further research is needed to investigate the impact of ester conjugate forms on skin reactions and individual responses.⁷

Hyaluronic acid is a relatively safe and commonly used topical treatment that acts as a lubricant during MN procedures to help the needles glide across the skin and prevent dragging. It also can be applied after the procedure for hydration purposes. Other common alternatives include peptides, ceramides, and epidermal growth factors. Topical products to avoid before, during, and 48 hours after undergoing MN include retinoids, vitamin C, vitamin E, exfoliants, serums that contain acids (eg, alpha hydroxy acids, beta hydroxy acids, glycolic acid, and lactic acid), serums that contain fragrance, and oil-based serums because they are associated with similar adverse effects.^8-10 A granulomatous reaction after an MN procedure also has been reported with the use of vitamin C serum.¹¹

The US Food and Drug Administration has approved the use of MN devices, including for at-home use, to improve the appearance of facial acne scars and wrinkles as well as abdominal scars in patients aged 22 years or older; however, MN devices are not approved for delivery of cosmeceuticals or other topical products into the skin. Therefore, there is no universal list of approved topicals to be used in conjunction with MN.¹²

Most MN devices are made of nickel and various other metals. Cases of contact dermatitis and delayed-type hypersensitivity granulomatous reaction with systemic symptoms have been reported after MN procedures due to the material of the MN device.^1,13,14

Conclusion

Microneedling is a minimally invasive procedure that causes nominal damage to the epidermis and superficial papillary dermis, stimulating a wound-healing cascade for collagen production.^15,16 Although not approved by the US Food and Drug Administration, MN performed at dermatology offices sometimes can be used in conjunction with topical products to enhance their absorption; however, while vitamin E is known for its antioxidant properties and potential skin benefits, the lipid substance acting as the vehicle is not absorbable by the skin and may cause a granulomatous reaction as the body attempts to encapsulate and digest the foreign substance.^10,17 Although rarely reported, the use of topical vitamins with MN—through intradermal injection or combined with MN—can be associated with severe complications, including local, sometimes systemic, and life-threatening complications. Clinicians should be vigilant in order to correlate clinical background and history of recent cosmetic procedures with the histologic findings for prompt diagnosis and timely treatment.

Background

Autologous stem cell transplant (ASCT) is an important part of the treatment paradigm for patients with multiple myeloma (MM) and remains the standard of care for newly diagnosed patients. Blood product transfusion support in the form of platelets and packed red blood cells (pRBCs) is part of the standard of practice as supportive measures during the severely pancytopenic period. Some MM patients, such as those of Jehovah’s Witness (JW) faith, may have religious beliefs or preferences that preclude acceptance of such blood products. Some transplant centers have developed protocols to allow safe “bloodless” ASCT that allows these patients to receive this important treatment while adhering to their beliefs or preferences.

Case Presentation

A 61-year-old veteran of JW faith with newly diagnosed IgG Kappa Multiple Myeloma was referred to the Tennessee Valley Healthcare System (TVHS) Stem Cell Transplant program for consideration of “bloodless” ASCT. With the assistance and expertise of the academic affiliate, Vanderbilt University Medical Center’s established bloodless ASCT protocol, this same protocol was established at TVHS to optimize the patient’s care pretransplant (use of erythropoiesis stimulating agents, intravenous iron, B12 supplementation) as well as post-transplant (use of antifibrinolytics, close inpatient monitoring). Both Ethics and Legal consultation was obtained, and guidance was provided to create a life sustaining treatment (LST) note in the veteran’s electronic health record that captured the veteran’s blood product preference. Once all protocols and guidance were in place, the TVHS SCT/CT program proceeded to treat the veteran with a myeloablative melphalan ASCT. The patient tolerated the procedure exceptionally well with minimal complications. He achieved full engraftment on day +14 after ASCT as expected and was discharged from the inpatient setting. He was monitored in the outpatient setting until day +30 without further complications.

Conclusions

The TVHS SCT/CT performed the first ever bloodless autologous stem cell transplant within the VA. This pioneering effort to establish such protocols to provide care to all veterans whatever their personal or religious preferences is a testament to commitment of VA to provide care for all veterans and the willingness to innovate to do so.

Background

Autologous stem cell transplant (ASCT) is an important part of the treatment paradigm for patients with multiple myeloma (MM) and remains the standard of care for newly diagnosed patients. Blood product transfusion support in the form of platelets and packed red blood cells (pRBCs) is part of the standard of practice as supportive measures during the severely pancytopenic period. Some MM patients, such as those of Jehovah’s Witness (JW) faith, may have religious beliefs or preferences that preclude acceptance of such blood products. Some transplant centers have developed protocols to allow safe “bloodless” ASCT that allows these patients to receive this important treatment while adhering to their beliefs or preferences.

Case Presentation

A 61-year-old veteran of JW faith with newly diagnosed IgG Kappa Multiple Myeloma was referred to the Tennessee Valley Healthcare System (TVHS) Stem Cell Transplant program for consideration of “bloodless” ASCT. With the assistance and expertise of the academic affiliate, Vanderbilt University Medical Center’s established bloodless ASCT protocol, this same protocol was established at TVHS to optimize the patient’s care pretransplant (use of erythropoiesis stimulating agents, intravenous iron, B12 supplementation) as well as post-transplant (use of antifibrinolytics, close inpatient monitoring). Both Ethics and Legal consultation was obtained, and guidance was provided to create a life sustaining treatment (LST) note in the veteran’s electronic health record that captured the veteran’s blood product preference. Once all protocols and guidance were in place, the TVHS SCT/CT program proceeded to treat the veteran with a myeloablative melphalan ASCT. The patient tolerated the procedure exceptionally well with minimal complications. He achieved full engraftment on day +14 after ASCT as expected and was discharged from the inpatient setting. He was monitored in the outpatient setting until day +30 without further complications.

Conclusions

The TVHS SCT/CT performed the first ever bloodless autologous stem cell transplant within the VA. This pioneering effort to establish such protocols to provide care to all veterans whatever their personal or religious preferences is a testament to commitment of VA to provide care for all veterans and the willingness to innovate to do so.

Background

Autologous stem cell transplant (ASCT) is an important part of the treatment paradigm for patients with multiple myeloma (MM) and remains the standard of care for newly diagnosed patients. Blood product transfusion support in the form of platelets and packed red blood cells (pRBCs) is part of the standard of practice as supportive measures during the severely pancytopenic period. Some MM patients, such as those of Jehovah’s Witness (JW) faith, may have religious beliefs or preferences that preclude acceptance of such blood products. Some transplant centers have developed protocols to allow safe “bloodless” ASCT that allows these patients to receive this important treatment while adhering to their beliefs or preferences.

Case Presentation

A 61-year-old veteran of JW faith with newly diagnosed IgG Kappa Multiple Myeloma was referred to the Tennessee Valley Healthcare System (TVHS) Stem Cell Transplant program for consideration of “bloodless” ASCT. With the assistance and expertise of the academic affiliate, Vanderbilt University Medical Center’s established bloodless ASCT protocol, this same protocol was established at TVHS to optimize the patient’s care pretransplant (use of erythropoiesis stimulating agents, intravenous iron, B12 supplementation) as well as post-transplant (use of antifibrinolytics, close inpatient monitoring). Both Ethics and Legal consultation was obtained, and guidance was provided to create a life sustaining treatment (LST) note in the veteran’s electronic health record that captured the veteran’s blood product preference. Once all protocols and guidance were in place, the TVHS SCT/CT program proceeded to treat the veteran with a myeloablative melphalan ASCT. The patient tolerated the procedure exceptionally well with minimal complications. He achieved full engraftment on day +14 after ASCT as expected and was discharged from the inpatient setting. He was monitored in the outpatient setting until day +30 without further complications.

Conclusions

The TVHS SCT/CT performed the first ever bloodless autologous stem cell transplant within the VA. This pioneering effort to establish such protocols to provide care to all veterans whatever their personal or religious preferences is a testament to commitment of VA to provide care for all veterans and the willingness to innovate to do so.

Acute pancreatitis can be associated with multiorgan system failure, including respiratory failure, which has a high mortality rate. Acute respiratory distress syndrome (ARDS) is a known complication of severe, acute pancreatitis, and is fatal in up to 40% of cases. Mortality rates exceed 80% in patients with PaO₂/FiO₂ < 100 mm Hg.² Although ARDS is typically associated with bilateral pulmonary infiltrates, severe hypoxemia in pancreatitis may not be visible in radiography in up to 50% of cases.¹

Hypertriglyceridemia is the third-most common cause of acute pancreatitis, with an incidence of 2% to 10% among patients diagnosed with acute pancreatitis.^3.4 Elevated serum triglycerides have been proposed to trigger acute pancreatitis by increasing plasma viscosity, which leads to ischemia and inflammation of the pancreas.⁴ In severe cases of hypertriglyceridemia-induced acute pancreatitis, plasmapheresis is used to rapidly reduce serum chylomicron and triglyceride levels.³    

This case report discusses a patient with acute pancreatitis whose hypoxemia coincided with the severity of hypertriglyceridemia, but without radiographic evidence of pulmonary infiltrates or other known pulmonary causes.

Case Presentation

A 60-year-old male presented to the emergency department with several hours of diffuse abdominal pain, nausea, and vomiting. The patient reported that his symptoms began after eating fried chicken. He reported no dyspnea, fever, chills, or other symptoms. His medical history included type 2 diabetes (hemoglobin A_1c, 11.1%), Hashimoto hypothyroidism, severe obstructive sleep apnea not on continuous positive airway pressure (apnea-hypoxia index, 59/h), and obesity (body mass index, 52). Initial vital signs were afebrile, heart rate of 90 beats/min, and oxygen saturation (SpO₂) of 85% on 6L oxygen via nasal cannula. He was admitted to the intensive care unit and quickly maximized on high flow nasal cannula, ultimately requiring endotracheal intubation and mechanical ventilation.

Initial laboratory studies were remarkable for serum sodium of 120 mmol/L (reference range, 136-146 mmol/L), creatinine of 1.65 mg/dL (reference range, 0.52-1.28 mg/dL), anion gap of 18 mEq/L (reference range, 3-11 mEq/L), lipase level of 1115 U/L (reference range, 11-82 U/L), glucose level of 334 mg/dL (reference range, 70-110 mg/dL), white blood count of 13.1 K/uL (reference range, 4.5-11.0 K/uL), lactate level of 3.8 mmol/L (reference range, 0.5-2.2 mmol/L), triglyceride level of 1605 mg/dL (reference range, 40-160 mg/dL), cholesterol level of 565 mg/dL (reference range, < 200 mg/dL), aminotransferase of 21 U/L (reference range, 13-36 U/L), alanine aminotransferase of < 3 U/L (reference range, 7-45 U/L), and total bilirubin level of 1.6 mg/dL (reference range, 0.2-1 mg/dL).     

The patient had an initial arterial blood gas pH of 7.26, partial pressure of CO₂ and O₂ of 64.1 mm Hg and 74.1 mm Hg, respectively, on volume control with a tidal volume of 500 mL, positive end-expiratory pressure of 10 cm H₂O, respiratory rate of 26 breaths/min, and FiO₂ was 100%, which yielded a PaO₂/FiO₂ of 74 mm Hg. The patient was maintained in steep reverse-Trendelenburg position with moderate improvement in his SpO₂.    

Chest X-ray and computed tomography angiogram did not reveal pleural effusions, pulmonary infiltrates, or pulmonary embolism (Figure 1). Computed tomography of the abdomen and pelvis demonstrated severe acute interstitial edematous pancreatitis with no evidence of pancreatic necrosis or evidence of gallstones (Figure 2). A transthoracic echocardiogram with bubble was negative for intracardiac right to left shunting.    

The leading diagnosis was ARDS secondary to acute pancreatitis with hypoxemia exacerbated by morbid obesity and untreated obstructive sleep apnea leading to hypoventilation.

Treatment

The patient was intubated and restricted to nothing by mouth and provided fluid resuscitation with crystalloids. On hospital day 1, he remained intubated and on mechanical ventilation, started on plasmapheresis and continued insulin infusion for severe hypertriglyceridemia. The patient’s PaO₂/FiO₂ ratio remained persistently < 100 mm Hg despite maximal ventilatory support. After 3 sessions of plasmapheresis, the serum triglyceride levels and oxygen requirements improved (Figure 3).

Due to prolonged intubation, the patient ultimately required a tracheostomy. By hospital day 48, the patient was successfully weaned off mechanical ventilation. His tracheostomy was decannulated uneventfully on hospital day 55 and the stoma was closed. The patient was discharged to a skilled nursing home for rehabilitation and received intensive physical therapy for deconditioning from prolonged hospitalization.

Discussion

Respiratory insufficiency is a common and potentially lethal complication observed in one-third of patients with acute pancreatitis.¹ Radiographic evidence of pleural effusions, atelectasis and pulmonary infiltrates are often present. Acute lung injury (ALI) and ARDS are the most severe pulmonary complications of acute pancreatitis.⁵ It has been proposed that ALI and ARDS are driven by a hyperinflammatory state, which has multiple downstream effects. Pulmonary parenchymal and vascular damage has been associated with activated proinflammatory cytokines, trypsin, phospholipase A, and free fatty acids (Figure 4).¹

Hypoxemia secondary to acute pancreatitis may occur without initial radiographic findings and has been observed in up to half of patients.¹ Hypoxemia in ARDS occurs due to ventilation-perfusion defects causing gas exchange impairments which may be worsened further by high distending volumes and pressures on mechanical ventilation, dyssynchronous breathing, and/or lung derecruitment.⁶ Patients who require intubation for pancreatitis-associated ALI or ARDS eventually exhibit imaging findings consistent with their disease.¹ The patient in this case exhibited severe hypoxemia for several days despite persistently negative radiographic studies. His history of obstructive sleep apnea and a body mass index of 52 may have contributed to respiratory failure; however, assessment of other contributors to the acute and profound hypoxemia yielded largely unremarkable results. The patient did not have a history or evidence of heart failure and his hypoxemia did not improve with diuresis. He tested positive for COVID-19 on admission and was briefly treated with remdesivir and dexamethasone, but it was determined that the test was likely a false positive due to negative subsequent tests and elevated cycle thresholds (> 40). A concomitant COVID-19 infection likely did not contribute to his symptoms.    

Ventilation-perfusion mismatch is a well-recognized complication of pancreatitis, which results in right-to-left shunting.⁵ While we considered whether an intracardiac shunt may have contributed to the patient’s hypoxemia, a transthoracic echocardiogram with bubble contrast was negative.    

The patient had a peak serum triglyceride of > 6000 mg/dl, which meets the criteria for very severe hypertriglyceridemia.⁷ As observed in prior reports, the extent of the hypertriglyceridemia in this patient resulted in pronounced lipemic blood, which was appreciable by the eye and necessitated several rounds of centrifugation to analyze the laboratory studies.⁸ In this case, plasmapheresis was used to rapidly treat the hypertriglyceridemia, thereby reducing inflammation and further damage to the pancreas.⁹    

It is possible the patient’s hypertriglyceridemia may have been associated with his hypoxemia. His hypoxemia was most pronounced approximately 24 hours postadmission, which coincided with the peak of the hypertriglyceridemia. It remains unclear whether the severity of triglyceride elevation could accurately predict the severity of respiratory insufficiency. Hypoxemia is thought to modulate triglyceride metabolism through stimulation of intracellular lipolysis, upregulation of very low-density lipoproteins production in the liver, and inhibition of triglyceride-rich lipoprotein metabolism.¹⁰ Evidence from rodent studies supports the idea that acute hypoxemia increases triglycerides, and the degree of hypoxemia correlates with the elevated triglyceride levels.¹¹ However, this has not been consistently observed in humans and may vary by prandial state.^12,13 Thus, dysfunction of lipid metabolism may be a relevant clinical indicator of hypoxemia; further work is needed to elucidate this association.

Patient Perspective

The patient continues to undergo extensive rehabilitation following his prolonged illness and hospitalization. He expressed gratitude for the care received. However, he has limited and distorted recollection of the events during his hospitalization and stated that it felt “like an extraterrestrial state.”

Conclusions

This report describes a case of marked hypoxemia in the setting of acute pancreatitis. Pulmonary insufficiency in acute pancreatitis is commonly associated with imaging findings such as atelectasis, pleural effusions, and pulmonary infiltrates; however, up to half of cases initially lack any radiographic findings. Plasmapheresis is an effective treatment for hypertriglyceridemia-induced pancreatitis to both directly reduce circulating triglycerides and inflammation. Plasmapheresis also represents a promising therapy for the prevention of further episodes of pancreatitis in patients with recurrent pancreatitis. We propose a feedback mechanism through which pancreatitis induces severe hypoxemia, which may modulate lipid metabolism and severe hypertriglyceridemia correlates with respiratory failure.

Acute pancreatitis can be associated with multiorgan system failure, including respiratory failure, which has a high mortality rate. Acute respiratory distress syndrome (ARDS) is a known complication of severe, acute pancreatitis, and is fatal in up to 40% of cases. Mortality rates exceed 80% in patients with PaO₂/FiO₂ < 100 mm Hg.² Although ARDS is typically associated with bilateral pulmonary infiltrates, severe hypoxemia in pancreatitis may not be visible in radiography in up to 50% of cases.¹

Hypertriglyceridemia is the third-most common cause of acute pancreatitis, with an incidence of 2% to 10% among patients diagnosed with acute pancreatitis.^3.4 Elevated serum triglycerides have been proposed to trigger acute pancreatitis by increasing plasma viscosity, which leads to ischemia and inflammation of the pancreas.⁴ In severe cases of hypertriglyceridemia-induced acute pancreatitis, plasmapheresis is used to rapidly reduce serum chylomicron and triglyceride levels.³    

This case report discusses a patient with acute pancreatitis whose hypoxemia coincided with the severity of hypertriglyceridemia, but without radiographic evidence of pulmonary infiltrates or other known pulmonary causes.

Case Presentation

A 60-year-old male presented to the emergency department with several hours of diffuse abdominal pain, nausea, and vomiting. The patient reported that his symptoms began after eating fried chicken. He reported no dyspnea, fever, chills, or other symptoms. His medical history included type 2 diabetes (hemoglobin A_1c, 11.1%), Hashimoto hypothyroidism, severe obstructive sleep apnea not on continuous positive airway pressure (apnea-hypoxia index, 59/h), and obesity (body mass index, 52). Initial vital signs were afebrile, heart rate of 90 beats/min, and oxygen saturation (SpO₂) of 85% on 6L oxygen via nasal cannula. He was admitted to the intensive care unit and quickly maximized on high flow nasal cannula, ultimately requiring endotracheal intubation and mechanical ventilation.

Initial laboratory studies were remarkable for serum sodium of 120 mmol/L (reference range, 136-146 mmol/L), creatinine of 1.65 mg/dL (reference range, 0.52-1.28 mg/dL), anion gap of 18 mEq/L (reference range, 3-11 mEq/L), lipase level of 1115 U/L (reference range, 11-82 U/L), glucose level of 334 mg/dL (reference range, 70-110 mg/dL), white blood count of 13.1 K/uL (reference range, 4.5-11.0 K/uL), lactate level of 3.8 mmol/L (reference range, 0.5-2.2 mmol/L), triglyceride level of 1605 mg/dL (reference range, 40-160 mg/dL), cholesterol level of 565 mg/dL (reference range, < 200 mg/dL), aminotransferase of 21 U/L (reference range, 13-36 U/L), alanine aminotransferase of < 3 U/L (reference range, 7-45 U/L), and total bilirubin level of 1.6 mg/dL (reference range, 0.2-1 mg/dL).     

The patient had an initial arterial blood gas pH of 7.26, partial pressure of CO₂ and O₂ of 64.1 mm Hg and 74.1 mm Hg, respectively, on volume control with a tidal volume of 500 mL, positive end-expiratory pressure of 10 cm H₂O, respiratory rate of 26 breaths/min, and FiO₂ was 100%, which yielded a PaO₂/FiO₂ of 74 mm Hg. The patient was maintained in steep reverse-Trendelenburg position with moderate improvement in his SpO₂.    

Chest X-ray and computed tomography angiogram did not reveal pleural effusions, pulmonary infiltrates, or pulmonary embolism (Figure 1). Computed tomography of the abdomen and pelvis demonstrated severe acute interstitial edematous pancreatitis with no evidence of pancreatic necrosis or evidence of gallstones (Figure 2). A transthoracic echocardiogram with bubble was negative for intracardiac right to left shunting.    

The leading diagnosis was ARDS secondary to acute pancreatitis with hypoxemia exacerbated by morbid obesity and untreated obstructive sleep apnea leading to hypoventilation.

Treatment

The patient was intubated and restricted to nothing by mouth and provided fluid resuscitation with crystalloids. On hospital day 1, he remained intubated and on mechanical ventilation, started on plasmapheresis and continued insulin infusion for severe hypertriglyceridemia. The patient’s PaO₂/FiO₂ ratio remained persistently < 100 mm Hg despite maximal ventilatory support. After 3 sessions of plasmapheresis, the serum triglyceride levels and oxygen requirements improved (Figure 3).

Due to prolonged intubation, the patient ultimately required a tracheostomy. By hospital day 48, the patient was successfully weaned off mechanical ventilation. His tracheostomy was decannulated uneventfully on hospital day 55 and the stoma was closed. The patient was discharged to a skilled nursing home for rehabilitation and received intensive physical therapy for deconditioning from prolonged hospitalization.

Discussion

Respiratory insufficiency is a common and potentially lethal complication observed in one-third of patients with acute pancreatitis.¹ Radiographic evidence of pleural effusions, atelectasis and pulmonary infiltrates are often present. Acute lung injury (ALI) and ARDS are the most severe pulmonary complications of acute pancreatitis.⁵ It has been proposed that ALI and ARDS are driven by a hyperinflammatory state, which has multiple downstream effects. Pulmonary parenchymal and vascular damage has been associated with activated proinflammatory cytokines, trypsin, phospholipase A, and free fatty acids (Figure 4).¹

Hypoxemia secondary to acute pancreatitis may occur without initial radiographic findings and has been observed in up to half of patients.¹ Hypoxemia in ARDS occurs due to ventilation-perfusion defects causing gas exchange impairments which may be worsened further by high distending volumes and pressures on mechanical ventilation, dyssynchronous breathing, and/or lung derecruitment.⁶ Patients who require intubation for pancreatitis-associated ALI or ARDS eventually exhibit imaging findings consistent with their disease.¹ The patient in this case exhibited severe hypoxemia for several days despite persistently negative radiographic studies. His history of obstructive sleep apnea and a body mass index of 52 may have contributed to respiratory failure; however, assessment of other contributors to the acute and profound hypoxemia yielded largely unremarkable results. The patient did not have a history or evidence of heart failure and his hypoxemia did not improve with diuresis. He tested positive for COVID-19 on admission and was briefly treated with remdesivir and dexamethasone, but it was determined that the test was likely a false positive due to negative subsequent tests and elevated cycle thresholds (> 40). A concomitant COVID-19 infection likely did not contribute to his symptoms.    

Ventilation-perfusion mismatch is a well-recognized complication of pancreatitis, which results in right-to-left shunting.⁵ While we considered whether an intracardiac shunt may have contributed to the patient’s hypoxemia, a transthoracic echocardiogram with bubble contrast was negative.    

The patient had a peak serum triglyceride of > 6000 mg/dl, which meets the criteria for very severe hypertriglyceridemia.⁷ As observed in prior reports, the extent of the hypertriglyceridemia in this patient resulted in pronounced lipemic blood, which was appreciable by the eye and necessitated several rounds of centrifugation to analyze the laboratory studies.⁸ In this case, plasmapheresis was used to rapidly treat the hypertriglyceridemia, thereby reducing inflammation and further damage to the pancreas.⁹    

It is possible the patient’s hypertriglyceridemia may have been associated with his hypoxemia. His hypoxemia was most pronounced approximately 24 hours postadmission, which coincided with the peak of the hypertriglyceridemia. It remains unclear whether the severity of triglyceride elevation could accurately predict the severity of respiratory insufficiency. Hypoxemia is thought to modulate triglyceride metabolism through stimulation of intracellular lipolysis, upregulation of very low-density lipoproteins production in the liver, and inhibition of triglyceride-rich lipoprotein metabolism.¹⁰ Evidence from rodent studies supports the idea that acute hypoxemia increases triglycerides, and the degree of hypoxemia correlates with the elevated triglyceride levels.¹¹ However, this has not been consistently observed in humans and may vary by prandial state.^12,13 Thus, dysfunction of lipid metabolism may be a relevant clinical indicator of hypoxemia; further work is needed to elucidate this association.

Patient Perspective

The patient continues to undergo extensive rehabilitation following his prolonged illness and hospitalization. He expressed gratitude for the care received. However, he has limited and distorted recollection of the events during his hospitalization and stated that it felt “like an extraterrestrial state.”

Conclusions

This report describes a case of marked hypoxemia in the setting of acute pancreatitis. Pulmonary insufficiency in acute pancreatitis is commonly associated with imaging findings such as atelectasis, pleural effusions, and pulmonary infiltrates; however, up to half of cases initially lack any radiographic findings. Plasmapheresis is an effective treatment for hypertriglyceridemia-induced pancreatitis to both directly reduce circulating triglycerides and inflammation. Plasmapheresis also represents a promising therapy for the prevention of further episodes of pancreatitis in patients with recurrent pancreatitis. We propose a feedback mechanism through which pancreatitis induces severe hypoxemia, which may modulate lipid metabolism and severe hypertriglyceridemia correlates with respiratory failure.

Acute pancreatitis can be associated with multiorgan system failure, including respiratory failure, which has a high mortality rate. Acute respiratory distress syndrome (ARDS) is a known complication of severe, acute pancreatitis, and is fatal in up to 40% of cases. Mortality rates exceed 80% in patients with PaO₂/FiO₂ < 100 mm Hg.² Although ARDS is typically associated with bilateral pulmonary infiltrates, severe hypoxemia in pancreatitis may not be visible in radiography in up to 50% of cases.¹

Hypertriglyceridemia is the third-most common cause of acute pancreatitis, with an incidence of 2% to 10% among patients diagnosed with acute pancreatitis.^3.4 Elevated serum triglycerides have been proposed to trigger acute pancreatitis by increasing plasma viscosity, which leads to ischemia and inflammation of the pancreas.⁴ In severe cases of hypertriglyceridemia-induced acute pancreatitis, plasmapheresis is used to rapidly reduce serum chylomicron and triglyceride levels.³    

This case report discusses a patient with acute pancreatitis whose hypoxemia coincided with the severity of hypertriglyceridemia, but without radiographic evidence of pulmonary infiltrates or other known pulmonary causes.

Case Presentation

A 60-year-old male presented to the emergency department with several hours of diffuse abdominal pain, nausea, and vomiting. The patient reported that his symptoms began after eating fried chicken. He reported no dyspnea, fever, chills, or other symptoms. His medical history included type 2 diabetes (hemoglobin A_1c, 11.1%), Hashimoto hypothyroidism, severe obstructive sleep apnea not on continuous positive airway pressure (apnea-hypoxia index, 59/h), and obesity (body mass index, 52). Initial vital signs were afebrile, heart rate of 90 beats/min, and oxygen saturation (SpO₂) of 85% on 6L oxygen via nasal cannula. He was admitted to the intensive care unit and quickly maximized on high flow nasal cannula, ultimately requiring endotracheal intubation and mechanical ventilation.

Initial laboratory studies were remarkable for serum sodium of 120 mmol/L (reference range, 136-146 mmol/L), creatinine of 1.65 mg/dL (reference range, 0.52-1.28 mg/dL), anion gap of 18 mEq/L (reference range, 3-11 mEq/L), lipase level of 1115 U/L (reference range, 11-82 U/L), glucose level of 334 mg/dL (reference range, 70-110 mg/dL), white blood count of 13.1 K/uL (reference range, 4.5-11.0 K/uL), lactate level of 3.8 mmol/L (reference range, 0.5-2.2 mmol/L), triglyceride level of 1605 mg/dL (reference range, 40-160 mg/dL), cholesterol level of 565 mg/dL (reference range, < 200 mg/dL), aminotransferase of 21 U/L (reference range, 13-36 U/L), alanine aminotransferase of < 3 U/L (reference range, 7-45 U/L), and total bilirubin level of 1.6 mg/dL (reference range, 0.2-1 mg/dL).     

The patient had an initial arterial blood gas pH of 7.26, partial pressure of CO₂ and O₂ of 64.1 mm Hg and 74.1 mm Hg, respectively, on volume control with a tidal volume of 500 mL, positive end-expiratory pressure of 10 cm H₂O, respiratory rate of 26 breaths/min, and FiO₂ was 100%, which yielded a PaO₂/FiO₂ of 74 mm Hg. The patient was maintained in steep reverse-Trendelenburg position with moderate improvement in his SpO₂.    

Chest X-ray and computed tomography angiogram did not reveal pleural effusions, pulmonary infiltrates, or pulmonary embolism (Figure 1). Computed tomography of the abdomen and pelvis demonstrated severe acute interstitial edematous pancreatitis with no evidence of pancreatic necrosis or evidence of gallstones (Figure 2). A transthoracic echocardiogram with bubble was negative for intracardiac right to left shunting.    

The leading diagnosis was ARDS secondary to acute pancreatitis with hypoxemia exacerbated by morbid obesity and untreated obstructive sleep apnea leading to hypoventilation.

Treatment

The patient was intubated and restricted to nothing by mouth and provided fluid resuscitation with crystalloids. On hospital day 1, he remained intubated and on mechanical ventilation, started on plasmapheresis and continued insulin infusion for severe hypertriglyceridemia. The patient’s PaO₂/FiO₂ ratio remained persistently < 100 mm Hg despite maximal ventilatory support. After 3 sessions of plasmapheresis, the serum triglyceride levels and oxygen requirements improved (Figure 3).

Due to prolonged intubation, the patient ultimately required a tracheostomy. By hospital day 48, the patient was successfully weaned off mechanical ventilation. His tracheostomy was decannulated uneventfully on hospital day 55 and the stoma was closed. The patient was discharged to a skilled nursing home for rehabilitation and received intensive physical therapy for deconditioning from prolonged hospitalization.

Discussion

Respiratory insufficiency is a common and potentially lethal complication observed in one-third of patients with acute pancreatitis.¹ Radiographic evidence of pleural effusions, atelectasis and pulmonary infiltrates are often present. Acute lung injury (ALI) and ARDS are the most severe pulmonary complications of acute pancreatitis.⁵ It has been proposed that ALI and ARDS are driven by a hyperinflammatory state, which has multiple downstream effects. Pulmonary parenchymal and vascular damage has been associated with activated proinflammatory cytokines, trypsin, phospholipase A, and free fatty acids (Figure 4).¹

Hypoxemia secondary to acute pancreatitis may occur without initial radiographic findings and has been observed in up to half of patients.¹ Hypoxemia in ARDS occurs due to ventilation-perfusion defects causing gas exchange impairments which may be worsened further by high distending volumes and pressures on mechanical ventilation, dyssynchronous breathing, and/or lung derecruitment.⁶ Patients who require intubation for pancreatitis-associated ALI or ARDS eventually exhibit imaging findings consistent with their disease.¹ The patient in this case exhibited severe hypoxemia for several days despite persistently negative radiographic studies. His history of obstructive sleep apnea and a body mass index of 52 may have contributed to respiratory failure; however, assessment of other contributors to the acute and profound hypoxemia yielded largely unremarkable results. The patient did not have a history or evidence of heart failure and his hypoxemia did not improve with diuresis. He tested positive for COVID-19 on admission and was briefly treated with remdesivir and dexamethasone, but it was determined that the test was likely a false positive due to negative subsequent tests and elevated cycle thresholds (> 40). A concomitant COVID-19 infection likely did not contribute to his symptoms.    

Ventilation-perfusion mismatch is a well-recognized complication of pancreatitis, which results in right-to-left shunting.⁵ While we considered whether an intracardiac shunt may have contributed to the patient’s hypoxemia, a transthoracic echocardiogram with bubble contrast was negative.    

The patient had a peak serum triglyceride of > 6000 mg/dl, which meets the criteria for very severe hypertriglyceridemia.⁷ As observed in prior reports, the extent of the hypertriglyceridemia in this patient resulted in pronounced lipemic blood, which was appreciable by the eye and necessitated several rounds of centrifugation to analyze the laboratory studies.⁸ In this case, plasmapheresis was used to rapidly treat the hypertriglyceridemia, thereby reducing inflammation and further damage to the pancreas.⁹    

It is possible the patient’s hypertriglyceridemia may have been associated with his hypoxemia. His hypoxemia was most pronounced approximately 24 hours postadmission, which coincided with the peak of the hypertriglyceridemia. It remains unclear whether the severity of triglyceride elevation could accurately predict the severity of respiratory insufficiency. Hypoxemia is thought to modulate triglyceride metabolism through stimulation of intracellular lipolysis, upregulation of very low-density lipoproteins production in the liver, and inhibition of triglyceride-rich lipoprotein metabolism.¹⁰ Evidence from rodent studies supports the idea that acute hypoxemia increases triglycerides, and the degree of hypoxemia correlates with the elevated triglyceride levels.¹¹ However, this has not been consistently observed in humans and may vary by prandial state.^12,13 Thus, dysfunction of lipid metabolism may be a relevant clinical indicator of hypoxemia; further work is needed to elucidate this association.

Patient Perspective

The patient continues to undergo extensive rehabilitation following his prolonged illness and hospitalization. He expressed gratitude for the care received. However, he has limited and distorted recollection of the events during his hospitalization and stated that it felt “like an extraterrestrial state.”

Conclusions

This report describes a case of marked hypoxemia in the setting of acute pancreatitis. Pulmonary insufficiency in acute pancreatitis is commonly associated with imaging findings such as atelectasis, pleural effusions, and pulmonary infiltrates; however, up to half of cases initially lack any radiographic findings. Plasmapheresis is an effective treatment for hypertriglyceridemia-induced pancreatitis to both directly reduce circulating triglycerides and inflammation. Plasmapheresis also represents a promising therapy for the prevention of further episodes of pancreatitis in patients with recurrent pancreatitis. We propose a feedback mechanism through which pancreatitis induces severe hypoxemia, which may modulate lipid metabolism and severe hypertriglyceridemia correlates with respiratory failure.

Histology is the gold standard for cirrhosis diagnosis. However, a combination of clinical history, physical examination findings, and supportive laboratory and radiographic features is generally sufficient to make the diagnosis. Routine ultrasound and computed tomography (CT) imaging often identifies a nodular liver contour with sequelae of portal hypertension, including splenomegaly, varices, and ascites, which can suggest cirrhosis when supported by laboratory parameters and clinical features. As a result, the diagnosis is typically made clinically.¹ Many patients with compensated cirrhosis go undetected. The presence of a decompensation event (ascites, spontaneous bacterial peritonitis, variceal hemorrhage, or hepatic encephalopathy) often leads to index diagnosis when patients were previously compensated. When a patient presents with suspected decompensated cirrhosis, it is important to consider other diagnoses with similar presentations and ensure that multiple disease processes are not contributing to the symptoms.

CASE PRESENTATION

A 64-year-old male with a history of intravenous (IV) methamphetamine use and prior incarceration presented with a 3-week history of progressively worsening generalized swelling. Prior to the onset of his symptoms, the patient injured his right lower extremity (RLE) in a bicycle accident, resulting in edema that progressed to bilateral lower extremity (BLE) edema and worsening fatigue, despite resolution of the initial injury. The patient gained weight though he could not quantify the amount. He experienced progressive hunger, thirst, and fatigue as well as increased sleep. Additionally, the patient experienced worsening dyspnea on exertion and orthopnea. He started using 2 pillows instead of 1 pillow at night.

The patient reported no fevers, chills, sputum production, chest pain, or paroxysmal nocturnal dyspnea. He had no known history of sexually transmitted infections, no significant history of alcohol use, and occasional tobacco and marijuana use. He had been incarcerated > 10 years before and last used IV methamphetamine 3 years before. He did not regularly take any medications.

The patient’s vital signs included a temperature of 98.2 °F; 78/min heart rate; 15/min respiratory rate; 159/109 mm Hg blood pressure; and 98% oxygen saturation on room air. He had gained 20 lbs in the past 4 months. He had pitting edema in both legs and arms, as well as periorbital swelling, but no jugular venous distention, abnormal heart sounds, or murmurs. Breath sounds were distant but clear to auscultation. His abdomen was distended with normal bowel sounds and no fluid wave; mild epigastric tenderness was present, but no intra-abdominal masses were palpated. He had spider angiomata on the upper chest but no other stigmata of cirrhosis, such as caput medusae or jaundice. Tattoos were noted.

Laboratory test results showed a platelet count of 178 x 10³/μL (reference range, 140- 440 ~ 10³μL).Creatinine was 0.80 mg/dL (reference range, < 1.28 mg/dL), with an estimated glomerular filtration rate (eGFR) of 99 mL/min/1.73 m² using the Chronic Kidney Disease-Epidemiology equation (reference range, > 60 mL/min/1.73 m²), (reference range, > 60 mL/min/1.73 m²), and Cystatin C was 1.14 mg/L (reference range, < 1.15 mg/L). His electrolytes and complete blood count were within normal limits, including sodium, 134 mmol/L; potassium, 4.4 mmol/L; chloride, 108 mmol/L; and carbon dioxide, 22.5 mmol/L.

Additional test results included alkaline phosphatase, 126 U/L (reference range, < 94 U/L); alanine transaminase, 41 U/L (reference range, < 45 U/L); aspartate aminotransferase, 70 U/L (reference range, < 35 U/L); total bilirubin, 0.6 mg/dL (reference range, < 1 mg/dL); albumin, 1.8 g/dL (reference range, 3.2-4.8 g/dL); and total protein, 6.3 g/dL (reference range, 5.9-8.3 g/dL). The patient’s international normalized ratio was 0.96 (reference range, 0.8-1.1), and brain natriuretic peptide was normal at 56 pg/mL. No prior laboratory results were available for comparison.

Urine toxicology was positive for amphetamines. Urinalysis demonstrated large occult blood, with a red blood cell count of 26/ HPF (reference range, 0/HPF) and proteinuria (100 mg/dL; reference range, negative), without bacteria, nitrites, or leukocyte esterase. Urine white blood cell count was 10/ HPF (reference range, 0/HPF), and fine granular casts and hyaline casts were present.

A noncontrast CT of the abdomen and pelvis in the emergency department showed an irregular liver contour with diffuse nodularity, multiple portosystemic collaterals, moderate abdominal and pelvic ascites, small bilateral pleural effusions with associated atelectasis, and anasarca consistent with cirrhosis (Figure 1). The patient was admitted to the internal medicine service for workup and management of newly diagnosed cirrhosis.

Paracentesis revealed straw-colored fluid with an ascitic fluid neutrophil count of 17/μL, a protein level of < 3 g/dL and albumin level of < 1.5 g/dL. Gram stain of the ascitic fluid showed a moderate white blood cell count with no organisms. Fluid culture showed no microbial growth.

Initial workup for cirrhosis demonstrated a positive total hepatitis A antibody. The patient had a nonreactive hepatitis B surface antigen and surface antibody, but a reactive hepatitis B core antibody; a hepatitis B DNA level was not ordered. He had a reactive hepatitis C antibody with a viral load of 4,490,000 II/mL (genotype 1a). The patient’s iron level was 120 μg/dL, with a calculated total iron-binding capacity (TIBC) of 126.2 μg/dL. His transferrin saturation (TSAT) (serum iron divided by TIBC) was 95%. The patient had nonreactive antinuclear antibody and antimitochondrial antibody tests and a positive antismooth muscle antibody test with a titer of 1:40. His α-fetoprotein (AFP) level was 505 ng/mL (reference range, < 8 ng/mL).

Follow-up MRI of the abdomen and pelvis showed cirrhotic morphology with large volume ascites and portosystemic collaterals, consistent with portal hypertension. Additionally, it showed multiple scattered peripheral sub centimeter hyperenhancing foci, most likely representing benign lesions.

The patient's spot urine protein-creatinine ratio was 3.76. To better quantify proteinuria, a 24-hour urine collection was performed and revealed 12.8 g/d of urine protein (reference range, 0-0.17 g/d). His serum triglyceride level was 175 mg/dL (reference range, 40-60 mg/dL); total cholesterol was 177 mg/ dL (reference range, ≤ 200 mg/dL); low density lipoprotein cholesterol was 98 mg/ dL (reference range, ≤ 130 mg/dL); and highdensity lipoprotein cholesterol was 43.8 mg/ dL (reference range, ≥ 40 mg/dL); C3 complement level was 71 mg/dL (reference range, 82-185 mg/dL); and C4 complement level was 22 mg/dL (reference range, 15-53 mg/ dL). His rheumatoid factor was < 14 IU/mL. Tests for rapid plasma reagin and HIV antigen- antibody were nonreactive, and the phospholipase A2 receptor antibody test was negative. The patient tested positive for QuantiFERON-TB Gold and qualitative cryoglobulin, which indicated a cryocrit of 1%.

A renal biopsy was performed, revealing diffuse podocyte foot process effacement and glomerulonephritis with low-grade C3 and immunoglobulin (Ig) G deposits, consistent with early membranoproliferative glomerulonephritis (MPGN) (Figures 2 and 3).

The patient was initially diuresed with IV furosemide without significant urine output. He was then diuresed with IV 25% albumin (total, 25 g), followed by IV furosemide 40 mg twice daily, which led to significant urine output and resolution of his anasarca. Given the patient’s hypoalbuminemic state, IV albumin was necessary to deliver furosemide to the proximal tubule. He was started on lisinopril for renal protection and discharged with spironolactone and furosemide for fluid management in the context of cirrhosis.

The patient was evaluated by the Liver Nodule Clinic, which includes specialists from hepatology, medical oncology, radiation oncology, interventional radiology, and diagnostic radiology. The team considered the patient’s medical history and characteristics of the nodules on imaging. Notable aspects of the patient’s history included hepatitis C virus (HCV) infection and an elevated AFP level, although imaging showed no lesion concerning for malignancy. Given these findings, the patient was scheduled for a liver biopsy to establish a tissue diagnosis of cirrhosis. Hepatology, nephrology, and infectious disease specialists coordinated to plan the management and treatment of latent tuberculosis (TB), chronic HCV, MPGN, compensated cirrhosis, and suspicious liver lesions.

The patient chose to handle management and treatment as an outpatient. He was discharged with furosemide and spironolactone for anasarca management, and amlodipine and lisinopril for his hypertension and MPGN. Follow-up appointments were scheduled with infectious disease for management of latent TB and HCV, nephrology for MPGN, gastroenterology for cirrhosis, and interventional radiology for liver biopsy. Unfortunately, the patient was unhoused with limited access to transportation, which prevented timely follow-up. Given these social factors, immunosuppression was not started. Additionally, he did not start on HCV therapy because the viral load was still pending at time of discharge.

DISCUSSION

The diagnosis of decompensated cirrhosis was prematurely established, resulting in a diagnostic delay, a form of diagnostic error. However, on hospital day 2, the initial hypothesis of decompensated cirrhosis as the sole driver of the patient’s presentation was reconsidered due to the disconnect between the severity of hypoalbuminemia and diffuse edema (anasarca), and the absence of laboratory evidence of hepatic decompensation (normal international normalized ratio, bilirubin, and low but normal platelet count). Although image findings supported cirrhosis, laboratory markers did not indicate hepatic decompensation. The severity of hypoalbuminemia and anasarca, along with an indeterminate Serum-Ascites Albumin Gradient, prompted the patient’s care team to consider other causes, specifically, nephrotic syndrome.

The patien’s spot protein-to-creatinine ratio was 3.76 (reference range < 0.2 mg/mg creatinine), but a 24-hour urine protein collection was 12.8 g/day (reference range < 150 mg/day). While most spot urine protein- to-creatinine ratios (UPCR) correlate with a 24-hour urine collection, discrepancies can occur, as in this case. It is important to recognize that the spot UPCR assumes that patients are excreting 1000 mg of creatinine daily in their urine, which is not always the case. In addition, changes in urine osmolality can lead to different values. The gold standard for proteinuria is a 24-hour urine collection for protein and creatinine.

The patient’s nephrotic-range proteinuria and severe hypoalbuminemia are not solely explained by cirrhosis. In addition, the patient’s lower extremity edema pointed to nephrotic syndrome. The differential diagnosis for nephrotic syndrome includes both primary and secondary forms of membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis, and MPGN, a histopathological diagnosis that requires distinguishing between immune complex-mediated and complement-mediated forms. Other causes of nephrotic syndrome that do not fit in any of these buckets include amyloidosis, IgA nephropathy, and diabetes mellitus (DM). Despite DM being a common cause of nephrotic range proteinuria, it rarely leads to full nephrotic syndrome.

When considering the diagnosis, we reframed the patient’s clinical syndrome as compensated cirrhosis plus nephrotic syndrome. This approach prioritized identifying a cause that could explain both cirrhosis (from any cause) leading to IgA nephropathy or injection drug use serving as a risk factor for cirrhosis and nephrotic syndrome through HCV or AA amyloidosis, respectively. This problem representation guided us to the correct diagnosis. There are multiple renal diseases associated with HCV infection, including MPGN, membranous nephropathy, focal segmental glomerulosclerosis, and IgA nephropathy.² MPGN and mixed cryoglobulinemia are the most common. In the past, MPGN was classified as type I, II, and III.

The patient’s urine toxicology revealed recent amphetamine use, which can also lead to acute kidney injury through rhabdomyolysis or acute interstitial nephritis (AIN).³ In the cases of rhabdomyolysis, urinalysis would show positive heme without any red blood cell on microscopic analysis, which was not present in this case. AIN commonly manifests as acute kidney injury, pyuria, and proteinuria but without a decrease in complement levels.⁴ While the patient’s urine sediment included white blood cell (10/high-power field), the presence of microscopic hematuria, decreased complement levels, and proteinuria in the context of HCV positivity makes MPGN more likely than AIN.

Recently, there has been greater emphasis on using immunofluorescence for kidney biopsies. MPGN is now classified into 2 main categories: MPGN with mesangial immunoglobulins and C3 deposits in the capillary walls, and MPGN with C3 deposits but without Ig.⁵ MPGN with Ig-complement deposits is seen in autoimmune diseases and infections and is associated with dysproteinemias.

The renal biopsy in this patient was consistent with MPGN with immunofluorescence, a common finding in patients with infection. By synthesizing these data, we concluded that the patient represented a case of chronic HCV infection that led to MPGN with cryoglobulinemia. The normal C4 and negative RF do not suggest cryoglobulinemic crisis. Compensated cirrhosis was seen on imaging, pending liver biopsy.

Treatment

The management of MPGN secondary to HCV infection relies on the treatment of the underlying infection and clearance of viral load. Direct-acting antivirals have been used successfully in the treatment of HCV-associated MPGN. When cryoglobulinemia is present, immunosuppressive therapy is recommended. These regimens commonly include rituximab and steroids.⁵ Rituximab is also used for nephrotic syndrome associated with MPGN, as recommended in the 2018 Kidney Disease: Improving Global Outcomes guidelines.⁶

When initiating rituximab therapy in a patient who tests positive for hepatitis B (HBcAb positive or HBsAb positive), it is recommended to follow the established guidelines, which include treating them with entecavir for prophylaxis to prevent reactivation or a flare of hepatitis B.⁷ The patient in this case needed close follow-up in the nephrology and hepatology clinic. Immunosuppressive therapy was not pursued while the patient was admitted to the hospital due to instability with housing, transportation, and difficulty in ensuring close follow-up.

CONCLUSIONS

Clinicians should maintain a broad differential even in the face of confirmatory imaging and other objective findings. In the case of anasarca, nephrotic syndrome should be considered. Key causes of nephrotic syndromes include MPGN, membranous nephropathy, minimal change disease, and focal segmental glomerulosclerosis. MPGN is a histopathological diagnosis, and it is essential to identify if it is secondary to immune complexes or only complement mediated because Ig-complement deposits are seen in autoimmune disease and infection. The management of MPGN due to HCV infection relies on antiviral therapy. In the presence of cryoglobulinemia, immunosuppressive therapy is recommended.

Histology is the gold standard for cirrhosis diagnosis. However, a combination of clinical history, physical examination findings, and supportive laboratory and radiographic features is generally sufficient to make the diagnosis. Routine ultrasound and computed tomography (CT) imaging often identifies a nodular liver contour with sequelae of portal hypertension, including splenomegaly, varices, and ascites, which can suggest cirrhosis when supported by laboratory parameters and clinical features. As a result, the diagnosis is typically made clinically.¹ Many patients with compensated cirrhosis go undetected. The presence of a decompensation event (ascites, spontaneous bacterial peritonitis, variceal hemorrhage, or hepatic encephalopathy) often leads to index diagnosis when patients were previously compensated. When a patient presents with suspected decompensated cirrhosis, it is important to consider other diagnoses with similar presentations and ensure that multiple disease processes are not contributing to the symptoms.

CASE PRESENTATION

A 64-year-old male with a history of intravenous (IV) methamphetamine use and prior incarceration presented with a 3-week history of progressively worsening generalized swelling. Prior to the onset of his symptoms, the patient injured his right lower extremity (RLE) in a bicycle accident, resulting in edema that progressed to bilateral lower extremity (BLE) edema and worsening fatigue, despite resolution of the initial injury. The patient gained weight though he could not quantify the amount. He experienced progressive hunger, thirst, and fatigue as well as increased sleep. Additionally, the patient experienced worsening dyspnea on exertion and orthopnea. He started using 2 pillows instead of 1 pillow at night.

The patient reported no fevers, chills, sputum production, chest pain, or paroxysmal nocturnal dyspnea. He had no known history of sexually transmitted infections, no significant history of alcohol use, and occasional tobacco and marijuana use. He had been incarcerated > 10 years before and last used IV methamphetamine 3 years before. He did not regularly take any medications.

The patient’s vital signs included a temperature of 98.2 °F; 78/min heart rate; 15/min respiratory rate; 159/109 mm Hg blood pressure; and 98% oxygen saturation on room air. He had gained 20 lbs in the past 4 months. He had pitting edema in both legs and arms, as well as periorbital swelling, but no jugular venous distention, abnormal heart sounds, or murmurs. Breath sounds were distant but clear to auscultation. His abdomen was distended with normal bowel sounds and no fluid wave; mild epigastric tenderness was present, but no intra-abdominal masses were palpated. He had spider angiomata on the upper chest but no other stigmata of cirrhosis, such as caput medusae or jaundice. Tattoos were noted.

Laboratory test results showed a platelet count of 178 x 10³/μL (reference range, 140- 440 ~ 10³μL).Creatinine was 0.80 mg/dL (reference range, < 1.28 mg/dL), with an estimated glomerular filtration rate (eGFR) of 99 mL/min/1.73 m² using the Chronic Kidney Disease-Epidemiology equation (reference range, > 60 mL/min/1.73 m²), (reference range, > 60 mL/min/1.73 m²), and Cystatin C was 1.14 mg/L (reference range, < 1.15 mg/L). His electrolytes and complete blood count were within normal limits, including sodium, 134 mmol/L; potassium, 4.4 mmol/L; chloride, 108 mmol/L; and carbon dioxide, 22.5 mmol/L.

Additional test results included alkaline phosphatase, 126 U/L (reference range, < 94 U/L); alanine transaminase, 41 U/L (reference range, < 45 U/L); aspartate aminotransferase, 70 U/L (reference range, < 35 U/L); total bilirubin, 0.6 mg/dL (reference range, < 1 mg/dL); albumin, 1.8 g/dL (reference range, 3.2-4.8 g/dL); and total protein, 6.3 g/dL (reference range, 5.9-8.3 g/dL). The patient’s international normalized ratio was 0.96 (reference range, 0.8-1.1), and brain natriuretic peptide was normal at 56 pg/mL. No prior laboratory results were available for comparison.

Urine toxicology was positive for amphetamines. Urinalysis demonstrated large occult blood, with a red blood cell count of 26/ HPF (reference range, 0/HPF) and proteinuria (100 mg/dL; reference range, negative), without bacteria, nitrites, or leukocyte esterase. Urine white blood cell count was 10/ HPF (reference range, 0/HPF), and fine granular casts and hyaline casts were present.

A noncontrast CT of the abdomen and pelvis in the emergency department showed an irregular liver contour with diffuse nodularity, multiple portosystemic collaterals, moderate abdominal and pelvic ascites, small bilateral pleural effusions with associated atelectasis, and anasarca consistent with cirrhosis (Figure 1). The patient was admitted to the internal medicine service for workup and management of newly diagnosed cirrhosis.

Paracentesis revealed straw-colored fluid with an ascitic fluid neutrophil count of 17/μL, a protein level of < 3 g/dL and albumin level of < 1.5 g/dL. Gram stain of the ascitic fluid showed a moderate white blood cell count with no organisms. Fluid culture showed no microbial growth.

Initial workup for cirrhosis demonstrated a positive total hepatitis A antibody. The patient had a nonreactive hepatitis B surface antigen and surface antibody, but a reactive hepatitis B core antibody; a hepatitis B DNA level was not ordered. He had a reactive hepatitis C antibody with a viral load of 4,490,000 II/mL (genotype 1a). The patient’s iron level was 120 μg/dL, with a calculated total iron-binding capacity (TIBC) of 126.2 μg/dL. His transferrin saturation (TSAT) (serum iron divided by TIBC) was 95%. The patient had nonreactive antinuclear antibody and antimitochondrial antibody tests and a positive antismooth muscle antibody test with a titer of 1:40. His α-fetoprotein (AFP) level was 505 ng/mL (reference range, < 8 ng/mL).

Follow-up MRI of the abdomen and pelvis showed cirrhotic morphology with large volume ascites and portosystemic collaterals, consistent with portal hypertension. Additionally, it showed multiple scattered peripheral sub centimeter hyperenhancing foci, most likely representing benign lesions.

The patient's spot urine protein-creatinine ratio was 3.76. To better quantify proteinuria, a 24-hour urine collection was performed and revealed 12.8 g/d of urine protein (reference range, 0-0.17 g/d). His serum triglyceride level was 175 mg/dL (reference range, 40-60 mg/dL); total cholesterol was 177 mg/ dL (reference range, ≤ 200 mg/dL); low density lipoprotein cholesterol was 98 mg/ dL (reference range, ≤ 130 mg/dL); and highdensity lipoprotein cholesterol was 43.8 mg/ dL (reference range, ≥ 40 mg/dL); C3 complement level was 71 mg/dL (reference range, 82-185 mg/dL); and C4 complement level was 22 mg/dL (reference range, 15-53 mg/ dL). His rheumatoid factor was < 14 IU/mL. Tests for rapid plasma reagin and HIV antigen- antibody were nonreactive, and the phospholipase A2 receptor antibody test was negative. The patient tested positive for QuantiFERON-TB Gold and qualitative cryoglobulin, which indicated a cryocrit of 1%.

A renal biopsy was performed, revealing diffuse podocyte foot process effacement and glomerulonephritis with low-grade C3 and immunoglobulin (Ig) G deposits, consistent with early membranoproliferative glomerulonephritis (MPGN) (Figures 2 and 3).

The patient was initially diuresed with IV furosemide without significant urine output. He was then diuresed with IV 25% albumin (total, 25 g), followed by IV furosemide 40 mg twice daily, which led to significant urine output and resolution of his anasarca. Given the patient’s hypoalbuminemic state, IV albumin was necessary to deliver furosemide to the proximal tubule. He was started on lisinopril for renal protection and discharged with spironolactone and furosemide for fluid management in the context of cirrhosis.

The patient was evaluated by the Liver Nodule Clinic, which includes specialists from hepatology, medical oncology, radiation oncology, interventional radiology, and diagnostic radiology. The team considered the patient’s medical history and characteristics of the nodules on imaging. Notable aspects of the patient’s history included hepatitis C virus (HCV) infection and an elevated AFP level, although imaging showed no lesion concerning for malignancy. Given these findings, the patient was scheduled for a liver biopsy to establish a tissue diagnosis of cirrhosis. Hepatology, nephrology, and infectious disease specialists coordinated to plan the management and treatment of latent tuberculosis (TB), chronic HCV, MPGN, compensated cirrhosis, and suspicious liver lesions.

The patient chose to handle management and treatment as an outpatient. He was discharged with furosemide and spironolactone for anasarca management, and amlodipine and lisinopril for his hypertension and MPGN. Follow-up appointments were scheduled with infectious disease for management of latent TB and HCV, nephrology for MPGN, gastroenterology for cirrhosis, and interventional radiology for liver biopsy. Unfortunately, the patient was unhoused with limited access to transportation, which prevented timely follow-up. Given these social factors, immunosuppression was not started. Additionally, he did not start on HCV therapy because the viral load was still pending at time of discharge.

DISCUSSION

The diagnosis of decompensated cirrhosis was prematurely established, resulting in a diagnostic delay, a form of diagnostic error. However, on hospital day 2, the initial hypothesis of decompensated cirrhosis as the sole driver of the patient’s presentation was reconsidered due to the disconnect between the severity of hypoalbuminemia and diffuse edema (anasarca), and the absence of laboratory evidence of hepatic decompensation (normal international normalized ratio, bilirubin, and low but normal platelet count). Although image findings supported cirrhosis, laboratory markers did not indicate hepatic decompensation. The severity of hypoalbuminemia and anasarca, along with an indeterminate Serum-Ascites Albumin Gradient, prompted the patient’s care team to consider other causes, specifically, nephrotic syndrome.

The patien’s spot protein-to-creatinine ratio was 3.76 (reference range < 0.2 mg/mg creatinine), but a 24-hour urine protein collection was 12.8 g/day (reference range < 150 mg/day). While most spot urine protein- to-creatinine ratios (UPCR) correlate with a 24-hour urine collection, discrepancies can occur, as in this case. It is important to recognize that the spot UPCR assumes that patients are excreting 1000 mg of creatinine daily in their urine, which is not always the case. In addition, changes in urine osmolality can lead to different values. The gold standard for proteinuria is a 24-hour urine collection for protein and creatinine.

The patient’s nephrotic-range proteinuria and severe hypoalbuminemia are not solely explained by cirrhosis. In addition, the patient’s lower extremity edema pointed to nephrotic syndrome. The differential diagnosis for nephrotic syndrome includes both primary and secondary forms of membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis, and MPGN, a histopathological diagnosis that requires distinguishing between immune complex-mediated and complement-mediated forms. Other causes of nephrotic syndrome that do not fit in any of these buckets include amyloidosis, IgA nephropathy, and diabetes mellitus (DM). Despite DM being a common cause of nephrotic range proteinuria, it rarely leads to full nephrotic syndrome.

When considering the diagnosis, we reframed the patient’s clinical syndrome as compensated cirrhosis plus nephrotic syndrome. This approach prioritized identifying a cause that could explain both cirrhosis (from any cause) leading to IgA nephropathy or injection drug use serving as a risk factor for cirrhosis and nephrotic syndrome through HCV or AA amyloidosis, respectively. This problem representation guided us to the correct diagnosis. There are multiple renal diseases associated with HCV infection, including MPGN, membranous nephropathy, focal segmental glomerulosclerosis, and IgA nephropathy.² MPGN and mixed cryoglobulinemia are the most common. In the past, MPGN was classified as type I, II, and III.

The patient’s urine toxicology revealed recent amphetamine use, which can also lead to acute kidney injury through rhabdomyolysis or acute interstitial nephritis (AIN).³ In the cases of rhabdomyolysis, urinalysis would show positive heme without any red blood cell on microscopic analysis, which was not present in this case. AIN commonly manifests as acute kidney injury, pyuria, and proteinuria but without a decrease in complement levels.⁴ While the patient’s urine sediment included white blood cell (10/high-power field), the presence of microscopic hematuria, decreased complement levels, and proteinuria in the context of HCV positivity makes MPGN more likely than AIN.

Recently, there has been greater emphasis on using immunofluorescence for kidney biopsies. MPGN is now classified into 2 main categories: MPGN with mesangial immunoglobulins and C3 deposits in the capillary walls, and MPGN with C3 deposits but without Ig.⁵ MPGN with Ig-complement deposits is seen in autoimmune diseases and infections and is associated with dysproteinemias.

The renal biopsy in this patient was consistent with MPGN with immunofluorescence, a common finding in patients with infection. By synthesizing these data, we concluded that the patient represented a case of chronic HCV infection that led to MPGN with cryoglobulinemia. The normal C4 and negative RF do not suggest cryoglobulinemic crisis. Compensated cirrhosis was seen on imaging, pending liver biopsy.

Treatment

The management of MPGN secondary to HCV infection relies on the treatment of the underlying infection and clearance of viral load. Direct-acting antivirals have been used successfully in the treatment of HCV-associated MPGN. When cryoglobulinemia is present, immunosuppressive therapy is recommended. These regimens commonly include rituximab and steroids.⁵ Rituximab is also used for nephrotic syndrome associated with MPGN, as recommended in the 2018 Kidney Disease: Improving Global Outcomes guidelines.⁶

When initiating rituximab therapy in a patient who tests positive for hepatitis B (HBcAb positive or HBsAb positive), it is recommended to follow the established guidelines, which include treating them with entecavir for prophylaxis to prevent reactivation or a flare of hepatitis B.⁷ The patient in this case needed close follow-up in the nephrology and hepatology clinic. Immunosuppressive therapy was not pursued while the patient was admitted to the hospital due to instability with housing, transportation, and difficulty in ensuring close follow-up.

CONCLUSIONS

Clinicians should maintain a broad differential even in the face of confirmatory imaging and other objective findings. In the case of anasarca, nephrotic syndrome should be considered. Key causes of nephrotic syndromes include MPGN, membranous nephropathy, minimal change disease, and focal segmental glomerulosclerosis. MPGN is a histopathological diagnosis, and it is essential to identify if it is secondary to immune complexes or only complement mediated because Ig-complement deposits are seen in autoimmune disease and infection. The management of MPGN due to HCV infection relies on antiviral therapy. In the presence of cryoglobulinemia, immunosuppressive therapy is recommended.

Histology is the gold standard for cirrhosis diagnosis. However, a combination of clinical history, physical examination findings, and supportive laboratory and radiographic features is generally sufficient to make the diagnosis. Routine ultrasound and computed tomography (CT) imaging often identifies a nodular liver contour with sequelae of portal hypertension, including splenomegaly, varices, and ascites, which can suggest cirrhosis when supported by laboratory parameters and clinical features. As a result, the diagnosis is typically made clinically.¹ Many patients with compensated cirrhosis go undetected. The presence of a decompensation event (ascites, spontaneous bacterial peritonitis, variceal hemorrhage, or hepatic encephalopathy) often leads to index diagnosis when patients were previously compensated. When a patient presents with suspected decompensated cirrhosis, it is important to consider other diagnoses with similar presentations and ensure that multiple disease processes are not contributing to the symptoms.

CASE PRESENTATION

A 64-year-old male with a history of intravenous (IV) methamphetamine use and prior incarceration presented with a 3-week history of progressively worsening generalized swelling. Prior to the onset of his symptoms, the patient injured his right lower extremity (RLE) in a bicycle accident, resulting in edema that progressed to bilateral lower extremity (BLE) edema and worsening fatigue, despite resolution of the initial injury. The patient gained weight though he could not quantify the amount. He experienced progressive hunger, thirst, and fatigue as well as increased sleep. Additionally, the patient experienced worsening dyspnea on exertion and orthopnea. He started using 2 pillows instead of 1 pillow at night.

The patient reported no fevers, chills, sputum production, chest pain, or paroxysmal nocturnal dyspnea. He had no known history of sexually transmitted infections, no significant history of alcohol use, and occasional tobacco and marijuana use. He had been incarcerated > 10 years before and last used IV methamphetamine 3 years before. He did not regularly take any medications.

The patient’s vital signs included a temperature of 98.2 °F; 78/min heart rate; 15/min respiratory rate; 159/109 mm Hg blood pressure; and 98% oxygen saturation on room air. He had gained 20 lbs in the past 4 months. He had pitting edema in both legs and arms, as well as periorbital swelling, but no jugular venous distention, abnormal heart sounds, or murmurs. Breath sounds were distant but clear to auscultation. His abdomen was distended with normal bowel sounds and no fluid wave; mild epigastric tenderness was present, but no intra-abdominal masses were palpated. He had spider angiomata on the upper chest but no other stigmata of cirrhosis, such as caput medusae or jaundice. Tattoos were noted.

Laboratory test results showed a platelet count of 178 x 10³/μL (reference range, 140- 440 ~ 10³μL).Creatinine was 0.80 mg/dL (reference range, < 1.28 mg/dL), with an estimated glomerular filtration rate (eGFR) of 99 mL/min/1.73 m² using the Chronic Kidney Disease-Epidemiology equation (reference range, > 60 mL/min/1.73 m²), (reference range, > 60 mL/min/1.73 m²), and Cystatin C was 1.14 mg/L (reference range, < 1.15 mg/L). His electrolytes and complete blood count were within normal limits, including sodium, 134 mmol/L; potassium, 4.4 mmol/L; chloride, 108 mmol/L; and carbon dioxide, 22.5 mmol/L.

Additional test results included alkaline phosphatase, 126 U/L (reference range, < 94 U/L); alanine transaminase, 41 U/L (reference range, < 45 U/L); aspartate aminotransferase, 70 U/L (reference range, < 35 U/L); total bilirubin, 0.6 mg/dL (reference range, < 1 mg/dL); albumin, 1.8 g/dL (reference range, 3.2-4.8 g/dL); and total protein, 6.3 g/dL (reference range, 5.9-8.3 g/dL). The patient’s international normalized ratio was 0.96 (reference range, 0.8-1.1), and brain natriuretic peptide was normal at 56 pg/mL. No prior laboratory results were available for comparison.

Urine toxicology was positive for amphetamines. Urinalysis demonstrated large occult blood, with a red blood cell count of 26/ HPF (reference range, 0/HPF) and proteinuria (100 mg/dL; reference range, negative), without bacteria, nitrites, or leukocyte esterase. Urine white blood cell count was 10/ HPF (reference range, 0/HPF), and fine granular casts and hyaline casts were present.

A noncontrast CT of the abdomen and pelvis in the emergency department showed an irregular liver contour with diffuse nodularity, multiple portosystemic collaterals, moderate abdominal and pelvic ascites, small bilateral pleural effusions with associated atelectasis, and anasarca consistent with cirrhosis (Figure 1). The patient was admitted to the internal medicine service for workup and management of newly diagnosed cirrhosis.

Paracentesis revealed straw-colored fluid with an ascitic fluid neutrophil count of 17/μL, a protein level of < 3 g/dL and albumin level of < 1.5 g/dL. Gram stain of the ascitic fluid showed a moderate white blood cell count with no organisms. Fluid culture showed no microbial growth.

Initial workup for cirrhosis demonstrated a positive total hepatitis A antibody. The patient had a nonreactive hepatitis B surface antigen and surface antibody, but a reactive hepatitis B core antibody; a hepatitis B DNA level was not ordered. He had a reactive hepatitis C antibody with a viral load of 4,490,000 II/mL (genotype 1a). The patient’s iron level was 120 μg/dL, with a calculated total iron-binding capacity (TIBC) of 126.2 μg/dL. His transferrin saturation (TSAT) (serum iron divided by TIBC) was 95%. The patient had nonreactive antinuclear antibody and antimitochondrial antibody tests and a positive antismooth muscle antibody test with a titer of 1:40. His α-fetoprotein (AFP) level was 505 ng/mL (reference range, < 8 ng/mL).

Follow-up MRI of the abdomen and pelvis showed cirrhotic morphology with large volume ascites and portosystemic collaterals, consistent with portal hypertension. Additionally, it showed multiple scattered peripheral sub centimeter hyperenhancing foci, most likely representing benign lesions.

The patient's spot urine protein-creatinine ratio was 3.76. To better quantify proteinuria, a 24-hour urine collection was performed and revealed 12.8 g/d of urine protein (reference range, 0-0.17 g/d). His serum triglyceride level was 175 mg/dL (reference range, 40-60 mg/dL); total cholesterol was 177 mg/ dL (reference range, ≤ 200 mg/dL); low density lipoprotein cholesterol was 98 mg/ dL (reference range, ≤ 130 mg/dL); and highdensity lipoprotein cholesterol was 43.8 mg/ dL (reference range, ≥ 40 mg/dL); C3 complement level was 71 mg/dL (reference range, 82-185 mg/dL); and C4 complement level was 22 mg/dL (reference range, 15-53 mg/ dL). His rheumatoid factor was < 14 IU/mL. Tests for rapid plasma reagin and HIV antigen- antibody were nonreactive, and the phospholipase A2 receptor antibody test was negative. The patient tested positive for QuantiFERON-TB Gold and qualitative cryoglobulin, which indicated a cryocrit of 1%.

A renal biopsy was performed, revealing diffuse podocyte foot process effacement and glomerulonephritis with low-grade C3 and immunoglobulin (Ig) G deposits, consistent with early membranoproliferative glomerulonephritis (MPGN) (Figures 2 and 3).

The patient was initially diuresed with IV furosemide without significant urine output. He was then diuresed with IV 25% albumin (total, 25 g), followed by IV furosemide 40 mg twice daily, which led to significant urine output and resolution of his anasarca. Given the patient’s hypoalbuminemic state, IV albumin was necessary to deliver furosemide to the proximal tubule. He was started on lisinopril for renal protection and discharged with spironolactone and furosemide for fluid management in the context of cirrhosis.

The patient was evaluated by the Liver Nodule Clinic, which includes specialists from hepatology, medical oncology, radiation oncology, interventional radiology, and diagnostic radiology. The team considered the patient’s medical history and characteristics of the nodules on imaging. Notable aspects of the patient’s history included hepatitis C virus (HCV) infection and an elevated AFP level, although imaging showed no lesion concerning for malignancy. Given these findings, the patient was scheduled for a liver biopsy to establish a tissue diagnosis of cirrhosis. Hepatology, nephrology, and infectious disease specialists coordinated to plan the management and treatment of latent tuberculosis (TB), chronic HCV, MPGN, compensated cirrhosis, and suspicious liver lesions.

The patient chose to handle management and treatment as an outpatient. He was discharged with furosemide and spironolactone for anasarca management, and amlodipine and lisinopril for his hypertension and MPGN. Follow-up appointments were scheduled with infectious disease for management of latent TB and HCV, nephrology for MPGN, gastroenterology for cirrhosis, and interventional radiology for liver biopsy. Unfortunately, the patient was unhoused with limited access to transportation, which prevented timely follow-up. Given these social factors, immunosuppression was not started. Additionally, he did not start on HCV therapy because the viral load was still pending at time of discharge.

DISCUSSION

The diagnosis of decompensated cirrhosis was prematurely established, resulting in a diagnostic delay, a form of diagnostic error. However, on hospital day 2, the initial hypothesis of decompensated cirrhosis as the sole driver of the patient’s presentation was reconsidered due to the disconnect between the severity of hypoalbuminemia and diffuse edema (anasarca), and the absence of laboratory evidence of hepatic decompensation (normal international normalized ratio, bilirubin, and low but normal platelet count). Although image findings supported cirrhosis, laboratory markers did not indicate hepatic decompensation. The severity of hypoalbuminemia and anasarca, along with an indeterminate Serum-Ascites Albumin Gradient, prompted the patient’s care team to consider other causes, specifically, nephrotic syndrome.

The patien’s spot protein-to-creatinine ratio was 3.76 (reference range < 0.2 mg/mg creatinine), but a 24-hour urine protein collection was 12.8 g/day (reference range < 150 mg/day). While most spot urine protein- to-creatinine ratios (UPCR) correlate with a 24-hour urine collection, discrepancies can occur, as in this case. It is important to recognize that the spot UPCR assumes that patients are excreting 1000 mg of creatinine daily in their urine, which is not always the case. In addition, changes in urine osmolality can lead to different values. The gold standard for proteinuria is a 24-hour urine collection for protein and creatinine.

The patient’s nephrotic-range proteinuria and severe hypoalbuminemia are not solely explained by cirrhosis. In addition, the patient’s lower extremity edema pointed to nephrotic syndrome. The differential diagnosis for nephrotic syndrome includes both primary and secondary forms of membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis, and MPGN, a histopathological diagnosis that requires distinguishing between immune complex-mediated and complement-mediated forms. Other causes of nephrotic syndrome that do not fit in any of these buckets include amyloidosis, IgA nephropathy, and diabetes mellitus (DM). Despite DM being a common cause of nephrotic range proteinuria, it rarely leads to full nephrotic syndrome.

When considering the diagnosis, we reframed the patient’s clinical syndrome as compensated cirrhosis plus nephrotic syndrome. This approach prioritized identifying a cause that could explain both cirrhosis (from any cause) leading to IgA nephropathy or injection drug use serving as a risk factor for cirrhosis and nephrotic syndrome through HCV or AA amyloidosis, respectively. This problem representation guided us to the correct diagnosis. There are multiple renal diseases associated with HCV infection, including MPGN, membranous nephropathy, focal segmental glomerulosclerosis, and IgA nephropathy.² MPGN and mixed cryoglobulinemia are the most common. In the past, MPGN was classified as type I, II, and III.

The patient’s urine toxicology revealed recent amphetamine use, which can also lead to acute kidney injury through rhabdomyolysis or acute interstitial nephritis (AIN).³ In the cases of rhabdomyolysis, urinalysis would show positive heme without any red blood cell on microscopic analysis, which was not present in this case. AIN commonly manifests as acute kidney injury, pyuria, and proteinuria but without a decrease in complement levels.⁴ While the patient’s urine sediment included white blood cell (10/high-power field), the presence of microscopic hematuria, decreased complement levels, and proteinuria in the context of HCV positivity makes MPGN more likely than AIN.

Recently, there has been greater emphasis on using immunofluorescence for kidney biopsies. MPGN is now classified into 2 main categories: MPGN with mesangial immunoglobulins and C3 deposits in the capillary walls, and MPGN with C3 deposits but without Ig.⁵ MPGN with Ig-complement deposits is seen in autoimmune diseases and infections and is associated with dysproteinemias.

The renal biopsy in this patient was consistent with MPGN with immunofluorescence, a common finding in patients with infection. By synthesizing these data, we concluded that the patient represented a case of chronic HCV infection that led to MPGN with cryoglobulinemia. The normal C4 and negative RF do not suggest cryoglobulinemic crisis. Compensated cirrhosis was seen on imaging, pending liver biopsy.

Treatment

The management of MPGN secondary to HCV infection relies on the treatment of the underlying infection and clearance of viral load. Direct-acting antivirals have been used successfully in the treatment of HCV-associated MPGN. When cryoglobulinemia is present, immunosuppressive therapy is recommended. These regimens commonly include rituximab and steroids.⁵ Rituximab is also used for nephrotic syndrome associated with MPGN, as recommended in the 2018 Kidney Disease: Improving Global Outcomes guidelines.⁶

When initiating rituximab therapy in a patient who tests positive for hepatitis B (HBcAb positive or HBsAb positive), it is recommended to follow the established guidelines, which include treating them with entecavir for prophylaxis to prevent reactivation or a flare of hepatitis B.⁷ The patient in this case needed close follow-up in the nephrology and hepatology clinic. Immunosuppressive therapy was not pursued while the patient was admitted to the hospital due to instability with housing, transportation, and difficulty in ensuring close follow-up.

CONCLUSIONS

Clinicians should maintain a broad differential even in the face of confirmatory imaging and other objective findings. In the case of anasarca, nephrotic syndrome should be considered. Key causes of nephrotic syndromes include MPGN, membranous nephropathy, minimal change disease, and focal segmental glomerulosclerosis. MPGN is a histopathological diagnosis, and it is essential to identify if it is secondary to immune complexes or only complement mediated because Ig-complement deposits are seen in autoimmune disease and infection. The management of MPGN due to HCV infection relies on antiviral therapy. In the presence of cryoglobulinemia, immunosuppressive therapy is recommended.

A 90-year-old man presented for evaluation of a large basal cell carcinoma (BCC) involving the nasal region. The lesion was a 7×4-cm pink, crusted, verrucous plaque covering the majority of the nose and extending onto the malar cheeks that originally had been biopsied 26 years prior, and repeat biopsy was performed 3 years prior. Results from both biopsies were consistent with BCC. The patient had avoided treatment for many years due to fear of losing his nose.

Given the size and location of the tumor, surgical intervention posed major challenges for both functional and cosmetic outcomes. After careful consideration and discussion of treatment options, which included Mohs micrographic surgery (MMS), wide local excision, radiation therapy, and systemic therapy, the decision was made to start the patient on vismodegib 150 mg once daily as well as L-carnitine 330 mg twice daily to help with muscle cramps. A baseline complete metabolic panel with an estimated glomerular filtration rate was unremarkable.

By the patient’s first follow-up visit after 2 months of therapy, he had experienced marked clinical improvement with notable regression of the tumor (Figure 1). He reported no adverse effects (eg, muscle cramps, dysgeusia, hair loss, nausea, vomiting, diarrhea). At subsequent follow-up visits, the patient continued to demonstrate clinical improvement. His only adverse effect was a 6-kg weight loss over the prior 6 months of initiating therapy despite no changes in taste or appetite. His dose of vismodegib was decreased to an alternative regimen of 150 mg daily for the first 2 weeks of each month with a drug holiday the rest of the month. Since that time, his weight has stabilized and he has continued with treatment.

Comment

Vismodegib was the first Hedgehog (Hh) inhibitor approved by the US Food and Drug Administration for management of selected locally advanced and metastatic BCC in adults.^1,2 Genetic alterations in the Hh signaling pathway resulting in proliferation of basal cells are present in nearly all BCCs.² In normal function, when the Hh ligand is absent at the patched (PTCH1) receptor, smoothened (SMO) is inhibited. When Hh ligand binds PTCH1, SMO is activated with downstream effects of triggering cell survival and proliferation in the nucleus via GLI. Loss of function mutations at the PTCH1 receptor or SMO-activating mutations lead to the same downstream effects, even when Hh ligand is absent.¹ This allows for unregulated tumor growth.

Vismodegib is a small-molecule SMO inhibitor that blocks aberrant activation of the Hh signaling pathway, thereby slowing the growth of BCCs (Figure 2).^3,4 Vismodegib and sonidegib have been used to treat patients with basal cell nevus syndrome as well as metastatic or locally advanced BCCs. At least 50% of advanced BCCs develop resistance to vismodegib, commonly via acquiring mutations in SMO.⁴

Basal cell carcinoma can be classified as low or high risk based on risk for recurrence. First-line treatments for low-risk BCC are surgical excision, electrodessication and curettage, and MMS.⁴ Second-line treatment includes radiation therapy. High-risk tumors include those involving anatomic locations of Area H near the eyelids, nose, ears, hands, feet, or genitals in addition to tumors with an aggressive histologic subtype.^4,5 First-line treatments for high-risk BCC are MMS or surgical excision. Second-line treatments are radiation therapy or systemic therapy, such as vismodegib.⁴

Although Hh inhibitors are not a first-line treatment, our case highlights vismodegib’s effectiveness in the management of a large unresectable BCC on the nose of an elderly patient. Our patient opted out of surgical first-line options due to functional and cosmetic concerns.⁴ He also declined radiation treatment due to financial cost and difficulty with transportation. The patient chose to pursue systemic vismodegib therapy through shared decision-making with dermatology. Vismodegib treatment alone granted our patient a highly remarkable result.

There are limited clinical data on the effectiveness and safety profile of vismodegib in elderly patients, even though this is a high-risk population for BCC.⁶ In a study that categorized responses to vismodegib in 13 patients with canthal BCC, 5 experienced a complete clinical response (defined as complete regression of the tumor), and 8 achieved partial clinical response (defined as regression but not to the extent of a complete response).⁷ Our patient’s successful response is notable, as it reinforces vismodegib’s effectiveness as a treatment option for BCC in a sensitive facial area. In addition, our patient’s minimal adverse effect profile is evidence in support of establishing visogemib’s role as a viable treatment option in advanced BCC in the elderly.

Alternative dosing regimens of vismodegib involve the use of drug holidays.⁸ Utilizing a regimen of 1 week with and 3 weeks without vismodegib for 5 to 14 cycles has led to the resolution of BCC with decreased adverse effects.⁸ Furthermore, the MIKIE study demonstrated the efficacy of 2 dosing regimens: 12 weeks of vismodegib 150 mg followed by 3 cycles of 8 placebo weeks and 12 weeks of vismodegib 150 mg and 24 weeks of vismodegib 150 mg followed by 3 cycles of 8 placebo weeks and 8 weeks of vismodegib 150 mg.⁹ Both regimens appeared viable to treat BCC in patients who were at risk for treatment discontinuation due to adverse effects.¹⁰

One adverse effect associated with vismodegib is muscle cramps, which are a potential cause of treatment discontinuation. The mechanism by which vismodegib causes cramps is not fully understood but is attributed to contractions from Ca²⁺ influx into muscle cells and a lack of adenosine triphosphate to allow muscle relaxation.¹¹ This is due to vismodegib’s inhibition of the SMO signaling pathway and activation of the SMO–Ca2+/ AMP-related kinase axis.¹² L-carnitine can be used as an adjuvant with vismodegib to address this adverse effect. L-carnitine is found in muscle cells, where its role is to produce energy by utilizing fatty acids.¹³ It is hypothesized that L-carnitine helps prevent cramps through production of adenosine triphosphate via fatty acid Β-oxidation that aids in stabilizing the sarcolemma and promoting muscle relaxation in skeletal muscle.^13,14 Evidence suggests that making L-carnitine a common adjuvant to vismodegib can aid in preventing this adverse effect.

Vismodegib can be an effective treatment option for large nasal BCCs that are difficult to resect. Our case demonstrates both clinical efficacy and a favorable safety profile in an elderly patient. Further studies and long-term follow-up are warranted to establish the role of vismodegib in the evolving landscape of BCC management.

A 90-year-old man presented for evaluation of a large basal cell carcinoma (BCC) involving the nasal region. The lesion was a 7×4-cm pink, crusted, verrucous plaque covering the majority of the nose and extending onto the malar cheeks that originally had been biopsied 26 years prior, and repeat biopsy was performed 3 years prior. Results from both biopsies were consistent with BCC. The patient had avoided treatment for many years due to fear of losing his nose.

Given the size and location of the tumor, surgical intervention posed major challenges for both functional and cosmetic outcomes. After careful consideration and discussion of treatment options, which included Mohs micrographic surgery (MMS), wide local excision, radiation therapy, and systemic therapy, the decision was made to start the patient on vismodegib 150 mg once daily as well as L-carnitine 330 mg twice daily to help with muscle cramps. A baseline complete metabolic panel with an estimated glomerular filtration rate was unremarkable.

By the patient’s first follow-up visit after 2 months of therapy, he had experienced marked clinical improvement with notable regression of the tumor (Figure 1). He reported no adverse effects (eg, muscle cramps, dysgeusia, hair loss, nausea, vomiting, diarrhea). At subsequent follow-up visits, the patient continued to demonstrate clinical improvement. His only adverse effect was a 6-kg weight loss over the prior 6 months of initiating therapy despite no changes in taste or appetite. His dose of vismodegib was decreased to an alternative regimen of 150 mg daily for the first 2 weeks of each month with a drug holiday the rest of the month. Since that time, his weight has stabilized and he has continued with treatment.

Comment

Vismodegib was the first Hedgehog (Hh) inhibitor approved by the US Food and Drug Administration for management of selected locally advanced and metastatic BCC in adults.^1,2 Genetic alterations in the Hh signaling pathway resulting in proliferation of basal cells are present in nearly all BCCs.² In normal function, when the Hh ligand is absent at the patched (PTCH1) receptor, smoothened (SMO) is inhibited. When Hh ligand binds PTCH1, SMO is activated with downstream effects of triggering cell survival and proliferation in the nucleus via GLI. Loss of function mutations at the PTCH1 receptor or SMO-activating mutations lead to the same downstream effects, even when Hh ligand is absent.¹ This allows for unregulated tumor growth.

Vismodegib is a small-molecule SMO inhibitor that blocks aberrant activation of the Hh signaling pathway, thereby slowing the growth of BCCs (Figure 2).^3,4 Vismodegib and sonidegib have been used to treat patients with basal cell nevus syndrome as well as metastatic or locally advanced BCCs. At least 50% of advanced BCCs develop resistance to vismodegib, commonly via acquiring mutations in SMO.⁴

Basal cell carcinoma can be classified as low or high risk based on risk for recurrence. First-line treatments for low-risk BCC are surgical excision, electrodessication and curettage, and MMS.⁴ Second-line treatment includes radiation therapy. High-risk tumors include those involving anatomic locations of Area H near the eyelids, nose, ears, hands, feet, or genitals in addition to tumors with an aggressive histologic subtype.^4,5 First-line treatments for high-risk BCC are MMS or surgical excision. Second-line treatments are radiation therapy or systemic therapy, such as vismodegib.⁴

Although Hh inhibitors are not a first-line treatment, our case highlights vismodegib’s effectiveness in the management of a large unresectable BCC on the nose of an elderly patient. Our patient opted out of surgical first-line options due to functional and cosmetic concerns.⁴ He also declined radiation treatment due to financial cost and difficulty with transportation. The patient chose to pursue systemic vismodegib therapy through shared decision-making with dermatology. Vismodegib treatment alone granted our patient a highly remarkable result.

There are limited clinical data on the effectiveness and safety profile of vismodegib in elderly patients, even though this is a high-risk population for BCC.⁶ In a study that categorized responses to vismodegib in 13 patients with canthal BCC, 5 experienced a complete clinical response (defined as complete regression of the tumor), and 8 achieved partial clinical response (defined as regression but not to the extent of a complete response).⁷ Our patient’s successful response is notable, as it reinforces vismodegib’s effectiveness as a treatment option for BCC in a sensitive facial area. In addition, our patient’s minimal adverse effect profile is evidence in support of establishing visogemib’s role as a viable treatment option in advanced BCC in the elderly.

Alternative dosing regimens of vismodegib involve the use of drug holidays.⁸ Utilizing a regimen of 1 week with and 3 weeks without vismodegib for 5 to 14 cycles has led to the resolution of BCC with decreased adverse effects.⁸ Furthermore, the MIKIE study demonstrated the efficacy of 2 dosing regimens: 12 weeks of vismodegib 150 mg followed by 3 cycles of 8 placebo weeks and 12 weeks of vismodegib 150 mg and 24 weeks of vismodegib 150 mg followed by 3 cycles of 8 placebo weeks and 8 weeks of vismodegib 150 mg.⁹ Both regimens appeared viable to treat BCC in patients who were at risk for treatment discontinuation due to adverse effects.¹⁰

One adverse effect associated with vismodegib is muscle cramps, which are a potential cause of treatment discontinuation. The mechanism by which vismodegib causes cramps is not fully understood but is attributed to contractions from Ca²⁺ influx into muscle cells and a lack of adenosine triphosphate to allow muscle relaxation.¹¹ This is due to vismodegib’s inhibition of the SMO signaling pathway and activation of the SMO–Ca2+/ AMP-related kinase axis.¹² L-carnitine can be used as an adjuvant with vismodegib to address this adverse effect. L-carnitine is found in muscle cells, where its role is to produce energy by utilizing fatty acids.¹³ It is hypothesized that L-carnitine helps prevent cramps through production of adenosine triphosphate via fatty acid Β-oxidation that aids in stabilizing the sarcolemma and promoting muscle relaxation in skeletal muscle.^13,14 Evidence suggests that making L-carnitine a common adjuvant to vismodegib can aid in preventing this adverse effect.

Vismodegib can be an effective treatment option for large nasal BCCs that are difficult to resect. Our case demonstrates both clinical efficacy and a favorable safety profile in an elderly patient. Further studies and long-term follow-up are warranted to establish the role of vismodegib in the evolving landscape of BCC management.

A 90-year-old man presented for evaluation of a large basal cell carcinoma (BCC) involving the nasal region. The lesion was a 7×4-cm pink, crusted, verrucous plaque covering the majority of the nose and extending onto the malar cheeks that originally had been biopsied 26 years prior, and repeat biopsy was performed 3 years prior. Results from both biopsies were consistent with BCC. The patient had avoided treatment for many years due to fear of losing his nose.

Given the size and location of the tumor, surgical intervention posed major challenges for both functional and cosmetic outcomes. After careful consideration and discussion of treatment options, which included Mohs micrographic surgery (MMS), wide local excision, radiation therapy, and systemic therapy, the decision was made to start the patient on vismodegib 150 mg once daily as well as L-carnitine 330 mg twice daily to help with muscle cramps. A baseline complete metabolic panel with an estimated glomerular filtration rate was unremarkable.

By the patient’s first follow-up visit after 2 months of therapy, he had experienced marked clinical improvement with notable regression of the tumor (Figure 1). He reported no adverse effects (eg, muscle cramps, dysgeusia, hair loss, nausea, vomiting, diarrhea). At subsequent follow-up visits, the patient continued to demonstrate clinical improvement. His only adverse effect was a 6-kg weight loss over the prior 6 months of initiating therapy despite no changes in taste or appetite. His dose of vismodegib was decreased to an alternative regimen of 150 mg daily for the first 2 weeks of each month with a drug holiday the rest of the month. Since that time, his weight has stabilized and he has continued with treatment.

Comment

Vismodegib was the first Hedgehog (Hh) inhibitor approved by the US Food and Drug Administration for management of selected locally advanced and metastatic BCC in adults.^1,2 Genetic alterations in the Hh signaling pathway resulting in proliferation of basal cells are present in nearly all BCCs.² In normal function, when the Hh ligand is absent at the patched (PTCH1) receptor, smoothened (SMO) is inhibited. When Hh ligand binds PTCH1, SMO is activated with downstream effects of triggering cell survival and proliferation in the nucleus via GLI. Loss of function mutations at the PTCH1 receptor or SMO-activating mutations lead to the same downstream effects, even when Hh ligand is absent.¹ This allows for unregulated tumor growth.

Vismodegib is a small-molecule SMO inhibitor that blocks aberrant activation of the Hh signaling pathway, thereby slowing the growth of BCCs (Figure 2).^3,4 Vismodegib and sonidegib have been used to treat patients with basal cell nevus syndrome as well as metastatic or locally advanced BCCs. At least 50% of advanced BCCs develop resistance to vismodegib, commonly via acquiring mutations in SMO.⁴

Basal cell carcinoma can be classified as low or high risk based on risk for recurrence. First-line treatments for low-risk BCC are surgical excision, electrodessication and curettage, and MMS.⁴ Second-line treatment includes radiation therapy. High-risk tumors include those involving anatomic locations of Area H near the eyelids, nose, ears, hands, feet, or genitals in addition to tumors with an aggressive histologic subtype.^4,5 First-line treatments for high-risk BCC are MMS or surgical excision. Second-line treatments are radiation therapy or systemic therapy, such as vismodegib.⁴

Although Hh inhibitors are not a first-line treatment, our case highlights vismodegib’s effectiveness in the management of a large unresectable BCC on the nose of an elderly patient. Our patient opted out of surgical first-line options due to functional and cosmetic concerns.⁴ He also declined radiation treatment due to financial cost and difficulty with transportation. The patient chose to pursue systemic vismodegib therapy through shared decision-making with dermatology. Vismodegib treatment alone granted our patient a highly remarkable result.

There are limited clinical data on the effectiveness and safety profile of vismodegib in elderly patients, even though this is a high-risk population for BCC.⁶ In a study that categorized responses to vismodegib in 13 patients with canthal BCC, 5 experienced a complete clinical response (defined as complete regression of the tumor), and 8 achieved partial clinical response (defined as regression but not to the extent of a complete response).⁷ Our patient’s successful response is notable, as it reinforces vismodegib’s effectiveness as a treatment option for BCC in a sensitive facial area. In addition, our patient’s minimal adverse effect profile is evidence in support of establishing visogemib’s role as a viable treatment option in advanced BCC in the elderly.

Alternative dosing regimens of vismodegib involve the use of drug holidays.⁸ Utilizing a regimen of 1 week with and 3 weeks without vismodegib for 5 to 14 cycles has led to the resolution of BCC with decreased adverse effects.⁸ Furthermore, the MIKIE study demonstrated the efficacy of 2 dosing regimens: 12 weeks of vismodegib 150 mg followed by 3 cycles of 8 placebo weeks and 12 weeks of vismodegib 150 mg and 24 weeks of vismodegib 150 mg followed by 3 cycles of 8 placebo weeks and 8 weeks of vismodegib 150 mg.⁹ Both regimens appeared viable to treat BCC in patients who were at risk for treatment discontinuation due to adverse effects.¹⁰

One adverse effect associated with vismodegib is muscle cramps, which are a potential cause of treatment discontinuation. The mechanism by which vismodegib causes cramps is not fully understood but is attributed to contractions from Ca²⁺ influx into muscle cells and a lack of adenosine triphosphate to allow muscle relaxation.¹¹ This is due to vismodegib’s inhibition of the SMO signaling pathway and activation of the SMO–Ca2+/ AMP-related kinase axis.¹² L-carnitine can be used as an adjuvant with vismodegib to address this adverse effect. L-carnitine is found in muscle cells, where its role is to produce energy by utilizing fatty acids.¹³ It is hypothesized that L-carnitine helps prevent cramps through production of adenosine triphosphate via fatty acid Β-oxidation that aids in stabilizing the sarcolemma and promoting muscle relaxation in skeletal muscle.^13,14 Evidence suggests that making L-carnitine a common adjuvant to vismodegib can aid in preventing this adverse effect.

Vismodegib can be an effective treatment option for large nasal BCCs that are difficult to resect. Our case demonstrates both clinical efficacy and a favorable safety profile in an elderly patient. Further studies and long-term follow-up are warranted to establish the role of vismodegib in the evolving landscape of BCC management.