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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Last Update: January 1, 2018.



Sevofurane is one of the most commonly used volatile anesthetic agents, particularly for outpatient anesthesia and has an excellent safety record. Sevoflurane has been implicated in rare single case reports of severe acute liver injury similar to halothane hepatitis.


Sevoflurane (see' voe flur' ane) is a widely used major anesthetic agent with rapid onset of action and rapid dispersal. Because of its rapid onset of action and lack of irritability to the airways, sevoflurane can be used to both induce and maintain anesthesia. Sevoflurane became available for use in the United States in 1995. Sevoflurane must be administered in a controlled situation by a properly trained and credentialed anesthesiologist or nurse anesthetist and is typically given in concentrations of 2% to 4% with oxygen.


Prospective, serial blood testing often demonstrates minor transient elevations in serum aminotransferase levels in the 1 to 2 weeks after major surgery. Appearance of ALT levels above 10 times the upper limit of normal, however, is distinctly unusual and points to significant hepatotoxicity. Clinically apparent, severe hepatic injury from sevoflurane is very rare, only isolated case reports having been published. The injury is marked by acute elevations in serum aminotransferase levels (5- to 50-fold) and appearance of jaundice within 2 to 21 days of surgery. There are usually minimal increases in alkaline phosphatase and gammaglutamyl transpeptidase levels. Jaundice is usually preceded by a day or two of fever and may be accompanied by rash and eosinophilia. The acute liver injury may be self-limited and resolve within 4 to 8 weeks, but can be severe and associated with acute liver failure. A strong risk factor is previous exposure to any of the halogenated anesthetics and particularly a history of halothane hepatitis or unexplained fever and rash after anesthesia with one of these agents. The differential diagnosis of acute liver injury after surgery and anesthesia is sometimes difficult, and a clinical picture similar to sevoflurane induced hepatitis can be caused by shock or ischemia, sepsis, other idiosyncratic forms of drug induced liver injury and acute viral or herpes hepatitis.

Likelihood score: B (highly likely cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism of sevoflurane hepatotoxicity is suspected to be similar to that of halothane and associated with creation of reactive intermediates. Sevoflurane is metabolized to a small extent by the microsomal drug metabolizing enzyme CYP 2E1 to a trifluoroacetylated reactive intermediate (TFA) that is capable of binding to multiple intracytoplasmic proteins forming potentially immunogenic adducts. The TFA adducts induce antibodies that can be detected in patients with sevoflurane- as well as halothane hepatotoxicity and are also found in a proportion of health care workers exposed to the volatile anesthetics.

Outcome and Management

Severity ranges from mild and transient aminotransferase elevations without symptoms or other evidence of liver injury, to a self limited symptomatic acute hepatitis-like reaction to a severe, acute hepatic failure. The severity and prognosis may relate in part of patient age, being more severe in the elderly and both milder and less common in children. Obesity may also be both a predisposing factor and predictor of outcome. Chronic liver injury from sevoflurane exposure has not been described. Patients with sevoflurane induced hepatitis should be cautioned against future exposure to a fluorinated hydrocarbon anesthetic such as halothane, enflurane, isoflurane or desflurane.

Drug Class: Halogenated Anesthetics

Other Drugs in the Class: Desflurane, Enflurane, Halothane, Isoflurane


Case 1. Suspected sevoflurane induced acute liver injury.

[Modified from a case in the database of the Drug-Induced Liver Injury Network]

A 49 year woman underwent arthroscopic surgery on her knee using midazolam, fentanyl, propofol and sevoflurane. She received a single IV infusion of cefazolin at the time of surgery. Eighteen days after surgery, she developed nausea, heartburn, and pruritus followed by dark urine. She had undergone general anesthesia three times in the past, but not in the previous year and the anesthetics used were not known. On admission, she was afebrile and physical examination revealed jaundice and mild hepatic tenderness. Laboratory tests showed elevations in serum enzymes and a total bilirubin of 4.0 mg/dL. There was no eosinophilia. Tests for hepatitis A, B and C and autoantibodies were normal. A liver ultrasound showed a gall bladder polyp, but no evidence of biliary obstruction. A liver biopsy showed cholestatic hepatitis with mild bile duct injury. She recovered rapidly and was asymptomatic and had normal liver tests a few weeks later.

Key Points

Medication:Sevoflurane, 60 minutes anesthesia time
Pattern:Hepatocellular (R=5.4)
Severity:3+ (hospitalization for jaundice)
Latency:18 days to symptoms
Recovery:3 weeks
Other medications:Anesthesia included fentanyl, propofol and versed. One dose of cefazolin given at the time of surgery. Postoperatively given ibuprofen, naproxen, hydrocodone, and occasional acetaminophen. Chronic therapy of allergies with Allegra and Nasonex.

Laboratory Values

Postoperative DaysALT
Alk P
Bilirubin (mg/dL)Other
0Arthroscopic surgery under sevoflurane anesthesia
256303735.1Liver biopsy
Normal Values <45 <130


This patient developed jaundice and hepatic injury within 3 weeks of surgery under sevoflurane anesthesia. While the liver injury was attributed to the anesthetic by the reviewing physicians, the pattern of onset (latency of 3 weeks), clinical features (absence of fever, early appearance of pruritus) and liver histology (cholestasis) were atypical of anesthetic induced hepatotoxicity and more characteristic of penicillin or cephalosporin induced liver disease. The liver biopsy suggested a cholestatic hepatitis, even though the initial liver enzyme elevations were “hepatocellular”. Indeed, this case was later re-adjudicated as being very likely due to cefazolin rather than sevoflurane.

Case 2. Sevoflurane induced acute liver injury.

[Modified from: Singhal S, Gray T, Guzman G, Verma A, Anand K. Sevoflurane hepatotoxicity: a case report of sevoflurane hepatic necrosis and review of the literature. Am J Ther 2010; 17: 219-22. PubMed Citation]

A 37 year man underwent resection of an abdominal wall mass under midazolam, nitrous oxide, propofol and sevoflurane anesthesia and was discharged the same day. Three days after surgery, he developed nausea, vomiting, abdominal pain and jaundice. He had no history of liver disease, drug reactions, alcohol abuse or risk factors for viral hepatitis. He had undergone an appendectomy under general anesthesia four years previously, but the anesthetics used were not known. Other medications included postoperative pain management with codeine and acetaminophen (<1 gram daily). On admission, laboratory tests showed mild jaundice (total bilirubin 4.2 mg/dL, direct 1.8 mg/dL), but marked elevations in serum aminotransferase levels (ALT 3364 U/L, AST 3013 U/L) and minimal increase in alkaline phosphatase (336 U/L) and mild eosinophilia. These values had been mildly elevated one week previously at the time of a preoperative evaluation (Table). Tests for hepatitis A and B and autoantibodies were normal. Tests for Ebstein Barr virus suggested recent infection. A liver ultrasound showed no gallstones or evidence of biliary obstruction. During the first few days after admission he worsened with deepening jaundice and coagulopathy, the INR rising to 4.8. A liver biopsy showed centrolobular necrosis and inflammation and cholestasis with minimal or no fibrosis, suggestive of acute drug induced liver injury. Liver transplantation was considered, but he then began to improve spontaneously and over the next 4 months his symptoms resolved and liver test results returned to normal.

Key Points

Medication:Sevoflurane anesthesia
Pattern:Hepatocellular (R=20)
Severity:4+ (hospitalization, jaundice and coagulopathy)
Latency:3 days to symptoms
Recovery:4 months
Other medications:Anesthesia included nitrous oxide, propofol and midazolam. Postoperatively given acetaminophen (<1 gram daily) and codeine for pain

Laboratory Values

Postoperative DaysALT (U/L)Alk P (U/L)Bilirubin (mg/dL)Other
1361920025.6Liver biopsy
Normal Values <60 <121 <1.2


This patient developed jaundice and severe hepatic injury within 3 days of surgery under sevoflurane anesthesia. The clinical course was typical of halogenated anesthetic liver injury with a rapid onset, mild eosinophilia, a hepatocellular pattern of injury and severe course. Risk factors included previous anesthesia (although the agent used was not known). Unexplained were the abnormal liver tests obtained before surgery and the equivocal serology of EBV infection. Results of tests for hepatitis C and E were not provided.



Sevoflurane – Generic, Sevorane®, Ultane®


Anesthetics, Halogenated


Product labeling at DailyMed, National Library of Medicine, NIH


Sevoflurane 28523-86-6 C4-H3-F7-O
Sevoflurane chemical structure


References updated: 01 January 2018

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