Halothane Hepatotoxicity Clinical Presentation

Updated: Oct 17, 2016
  • Author: Ruben Peralta, MD, FACS; Chief Editor: Michael R Pinsky, MD, CM, Dr(HC), FCCP, FAPS, MCCM  more...
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Type I (mild) halothane hepatotoxicity occurs within hours of halothane exposure. It does not occur after other agents. Type I is characterized by mild, transient elevations in serum transaminase and glutathione S- transferase concentrations. Jaundice is not observed, and no evidence of hepatocellular disease is present.

Type II (fulminant) halothane hepatotoxicity usually occurs 5-7 days following exposure, although it can be delayed by up to 4 weeks. Fever, leukocytosis, and eosinophilia are observed. Nonspecific gastrointestinal upset may be noted. Nausea and vomiting may occur. Patients may report arthralgias. Most prominently, the patient looks and feels unwell. Fulminant liver failure may ensue.

Hepatic dysfunction in the postoperative period has many possible causes. Halothane hepatotoxicity is a diagnosis of exclusion. Other potential causes of liver dysfunction should be considered, including other hepatotoxic medications, hypotension, hypoxia, and infection.


Physical Examination

Physical findings in type II halothane hepatotoxicity include delayed pyrexia (up to 75% of patients). Jaundice can be present 7-10 days after exposure, but it may occur earlier in previously exposed patients. Liver tenderness is common but hepatomegaly is usually mild. A nonspecific rash may be observed.



Type I halothane hepatotoxicity is attributed to reductive (anaerobic) halothane metabolism, with reactive metabolites causing lipid peroxidation and binding to cytochrome P-450.

With type II halothane hepatotoxicity, fulminant necrosis is now believed to be an immune phenomenon occurring in genetically susceptible individuals. Necrosis is initiated by oxidative halothane metabolism to an intermediate. This intermediate subsequently binds to liver proteins, inducing trifluoroacetylation and rendering them antigenic. This process stimulates the formation of antibodies, which, upon reexposure to halothane (or enflurane, isoflurane, or desflurane), initiates an immune-mediated necrosis.

The two forms are most likely unrelated, and patients who develop type I halothane hepatotoxicity are not at risk for type II.

Animal studies have found an increase in liver damage susceptibility in interleukin 10 (IL-10) knockout mice, and other similar study have found that halothane-induced liver injury is mediated by interleukin-17 in mice. [5, 6]



Fulminant liver failure is possible. In rare cases, cirrhosis may develop following halothane hepatitis. However, in most cases, liver function returns to normal. Halothane given with succinylcholine for induction anesthetic is associated with masseter spasm.