Acute liver injury following re-exposure to sevoflurane after a 12-year interval

1. Introduction

Sevoflurane is a widely used halogenated inhalational anesthetic with a favorable safety profile, particularly in terms of hepatic toxicity, when compared to other halogenated agents such as halothane, enflurane, isoflurane and desflurane [1]. Unlike these agents, sevoflurane undergoes minimal metabolism into reactive intermediates capable of forming hepatotoxic proteins, contributing to its reputation as the halogenated anesthetic with the lowest risk of liver injury [2, 3, 4, 5, 6, 7, 8, 9]. However, since its introduction into clinical practice, rare cases of sevoflurane-associated hepatotoxicity have been reported, some of which have resulted in fatal outcomes (a summary of related reported cases is presented in Table 1 (Ref. [10, 11, 12, 13, 14, 15, 16]). Due to the rare occurrence and often insidious onset of symptoms, the pathophysiological mechanisms underlying sevoflurane-induced liver injury remain unclear. Furthermore, no prior reports have described acute hepatic dysfunction manifesting within hours of exposure in the immediate postoperative period. This present case report presents the case of a middle-aged woman who developed acute liver injury within hours of undergoing middle cerebral artery aneurysm clipping surgery under sevoflurane anesthesia, 12 years after her last exposure to the drug. Additionally, a summary of related cases is provided to enhance the understanding of this rare but potentially serious adverse event.

2. Case report

A 70-year-old woman underwent elective clipping of a left middle cerebral artery aneurysm, which was incidentally detected during a Magnetic Resonance Imaging (MRI) performed for dizziness. Her medical history included hypertension, which was well controlled with amlodipine, and a documented penicillin allergy characterized by a rash. She had previously undergone three surgical procedures, with only the first involving the use of sevoflurane. Twelve years earlier, she had undergone radical rectal cancer resection under general anesthesia with sevoflurane inhalation in combination with intravenous propofol and sufentanil. The perioperative course was uneventful, and liver function tests (LFTs) were within normal limits preoperatively and on the first postoperative day, with no abnormalities detected during subsequent routine follow-up (Table 2). Her later surgical interventions were minor ophthalmic procedures performed under local anesthesia, without exposure to sevoflurane.

For the current procedure, the patient, weighing 61 kg, underwent anesthesia induction with 15 mg of propofol, 17.5 µg of sufentanil citrate, and 6 mg of vecuronium bromide, achieving successful tracheal intubation. Anesthesia was maintained with 0.5% sevoflurane inhalation, continuous infusion of propofol at 5 mg/kg/h for sedation, remifentanil hydrochloride at 0.05–0.11 µg/kg/min, and sufentanil citrate at 0.1 µg/kg/h, with additional 5 µg doses administered as needed for analgesia. The intraoperative course was uneventful, with the patient remaining deeply sedated and hemodynamically stable throughout. The procedure lasted 2 hours and 43 minutes, with an estimated blood loss of 100 mL and a urine output of 650 mL. Her mean arterial pressure (MAP) remained approximately 100 mmHg (systolic 130–140 mmHg, diastolic 70–80 mmHg), and oxygen saturation was consistently maintained between 99% and 100%. After the surgery, she was transferred to the intensive care unit (ICU), where she remained intubated and sedated.

Two hours after surgery, liver function tests (LFTs) revealed a significant increase in liver enzymes, with aspartate aminotransferase (AST) at 1641 U/L, alanine aminotransferase (ALT) at 477 U/L, total bilirubin at 25.9 µmol/L, bile acids at 91.4 µmol/L, gamma-glutamyl transferase (GGT) at 146 U/L and alkaline phosphatase (ALP) at 132 U/L. By six hours postoperatively, these values had further increased, peaking at AST 2911 U/L, ALT 868 U/L, total bilirubin 25.5 µmol/L, lactate dehydrogenase (LDH) 1588 U/L, GGT 185 U/L and ALP 145 U/L (Table 1). Given the rapid and clinically atypical progression of enzyme elevation, an urgent workup was initiated to identify potential hepatotoxic factors.

Comprehensive blood tests were performed, including hepatitis B virus DNA (HBV-DNA), hepatitis A virus (HAV), hepatitis E virus (HEV), the Toxoplasmosis, Other (Syphilis, HIV, etc.), Rubella, Cytomegalovirus, Herpes simplex virus (TORCH) panel, Epstein-Barr virus DNA (EBV-DNA), cytomegalovirus DNA (CMV-DNA), autoimmune antibodies, antinuclear antibody (ANA), immunoglobulin G4 (IgG4), immunoglobulin levels, ceruloplasmin and thyroid function, all of which returned negative results. Then, a thorough review of all administered medications was conducted to rule out drug-induced liver injury. Furthermore, bedside ultrasound showed no abnormalities in hepatic vasculature or the biliary system and no signs of inferior vena cava congestion (IVC diameter: 1.6 cm, distance maximum (dmax) 1.838 cm, distance minimum (dmin) 1.649 cm) or right ventricular dysfunction (Tricuspid Annular Plane Systolic Excursion TAPSE: 2.0 cm). The patient’s cardiovascular status remained stable, with no evidence of venous stasis or impaired hepatic perfusion.

An urgent multidisciplinary team (MDT) consultation, with specialists from anesthesiology, pharmacy and gastroenterology, was conducted. After systematically excluding other potential causes, a diagnosis of sevoflurane-induced liver injury was established. Given the severity of liver enzyme elevation, preparations were made for a liver biopsy in case of further deterioration.

The patient was immediately treated with hepatoprotective agents, including magnesium isoglycyrrhizinate hydrate and polyene phosphatidylcholine. At 18 hours postoperatively, liver enzyme levels began to decline, with AST decreasing to 539 U/L, ALT to 598 U/L, total bilirubin to 16.3 µmol/L, and bile acids to 4.2 µmol/L. Given this improvement, and after discussion with the patient’s family, the planned liver biopsy was deferred, considering the risk-benefit balance. Over the following week, liver function normalized, the patient was successfully extubated, regained full consciousness, and was eventually discharged without further complications.

3. Discussion

Postoperative liver dysfunction associated with inhalational anesthetics is diagnosed after a systematic exclusion of other potential causes [17]. In the present case, intraoperative factors such as hypoxia, inadequate hepatic perfusion, ischemia-reperfusion injury or direct hepatic compression were ruled out, as the patient remained hemodynamically stable throughout surgery, and the procedure itself, a neurosurgical intervention with minimal blood loss, did not predispose her to hepatic injury.

Unlike other halogenated anesthetics, which undergo metabolism into trifluoroacetyl compounds capable of triggering immune-mediated liver injury, sevoflurane is primarily metabolized into hexafluoroisopropanol. This metabolite constitutes approximately 85% of its organic derivatives and is rapidly conjugated with glucuronic acid for urinary excretion, resulting in a relatively low hepatotoxic potential [18, 19]. However, despite this favorable profile, reports of severe hepatotoxicity following sevoflurane exposure have been documented, particularly in individuals with impaired renal function. One such case involved a child with mild renal insufficiency who developed significant liver injury after exposure to sevoflurane, suggesting that impaired renal clearance of its metabolites may contribute to hepatic dysfunction [20].

Despite concerns regarding potential hepatotoxicity, multicenter randomized controlled trials have demonstrated the safety of sevoflurane in liver transplantation, a procedure in which avoiding hepatotoxic agents is essential. These studies have found no significant differences in biochemical markers or clinical outcomes when comparing sevoflurane anesthesia with propofol [21]. However, in adults, cases of sevoflurane-induced liver injury remain limited to isolated reports, primarily following re-exposure (Table 1) [10, 11, 12, 13, 14, 15, 16]. These cases are often characterized by a rapid rise in liver enzymes, peaking within three days post-exposure, and are associated with symptoms of acute liver injury, including nausea, vomiting and fever [10, 11, 12, 13]. Even in patients without preexisting hepatic dysfunction, the progression of liver injury can be rapid, with some cases requiring liver transplantation or resulting in fatal outcomes [10, 11, 12, 13]. Histopathological findings in sevoflurane-induced liver injury typically reveal cholestatic damage, which is consistent with laboratory findings of elevated direct bilirubin, bile acids, alkaline phosphatase and gamma-glutamyl transferase. Liver biopsy specimens often show hepatocellular vacuolation, necrosis, and zone 3 cholestasis, further supporting the diagnosis [16, 22].

Animal studies suggest that sevoflurane-induced liver injury may result from disruptions in calcium homeostasis, leading to hepatocellular damage through mechanisms such as increased intracellular free calcium and membrane destabilization [12]. Further investigations have indicated that the sevoflurane metabolite, fluoromethyl-2, 2-difluoro-1-(trifluoromethyl) vinyl (Compound A), may contribute to cellular injury by activating free radical enzymes. Moreover, re-exposure has been associated with more severe hepatic reactions, with hepatocellular necrosis occurring due to excessive cytoplasmic free calcium accumulation [12]. In this present case, early recognition of hepatic injury in the ICU, along with timely supportive care, effectively mitigated the disease progression and prevented a more severe outcome. Thus, it could be recommended that clinicians remain vigilant for early signs of liver dysfunction in patients with prior exposure to halogenated anesthetics, particularly during re-exposure and consider early intervention, including liver biopsy or liver transplantation, in severe cases.

This case highlights the potential risk of acute liver injury following re-exposure to sevoflurane, even after an interval of 12 years. While sevoflurane is generally regarded as having minimal hepatotoxicity, the findings emphasize the need for careful liver function monitoring in patients with prior exposure to halogenated anesthetics, particularly when re-exposure occurs. Thus, recognizing the early signs of liver dysfunction and initiating timely intervention may be critical in preventing severe complications.

This case report has several limitations. First, although liver injury occurred following sevoflurane anesthesia, the possibility of other contributing factors, such as drug interactions, undiagnosed liver disease or unidentified variables, cannot be completely excluded. Second, the absence of a control group limits the ability to compare the risk of liver injury following repeated sevoflurane exposure with that associated with other anesthetics or the absence of exposure. Third, this report does not investigate the specific mechanisms underlying sevoflurane-induced liver injury, which limits its ability to provide a theoretical basis for targeted prevention or treatment strategies. Finally, the 12-year interval between the patient’s initial and subsequent sevoflurane exposure introduces uncertainty, as potential health changes or environmental exposures during this period cannot be fully accounted for.

In conclusion, while this case highlights the potential risk of liver injury following sevoflurane re-exposure, the findings cannot be generalized due to the inherent limitations of a single-case report. Larger prospective studies are necessary to validate this association, further elucidate the mechanisms underlying sevoflurane-induced hepatotoxicity, and identify patients who may be at increased risk.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Author contributions

ZPW—designed the present study; supervised the study; ensured correctness and revised the manuscript. SJM—wrote the manuscript and collected data. Manuscript revision and final approval of the version to be published.

Ethics approval and consent to participate

The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki, with approval granted by the Human Research Review Committee at West China Hospital, Sichuan University (Chengdu, China) (Number: 2024WCH-10277). The patient provided written informed consent. Consent was signed by the patient’s gave consent for her data, including images, to be published in the journal.

Acknowledgment

Not applicable.

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Conflict of interest

There were no interest conflict and legal liability in our report.

All the authors had completed disclosure of relationships and activities on the manuscript.