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Halothane hepatitis

Section Editor
Sanjiv Chopra, MD, MACP
Deputy Editor
Kristen M Robson, MD, MBA, FACG


Inhaled anesthetics were first used in the mid-1800s with the discovery of diethyl ether [1,2]. Prior to the 1950s, ether and chloroform were used exclusively. Halothane, a halogenated anesthetic, was first synthesized in 1951 [3]. It was reported in 1956 as an anesthetic based on animal studies [4]. It was first introduced into use on January 20, 1956, and rapidly replaced both ether and chloroform as the surgical anesthetic of choice [3,5-8].

Isolated case reports of severe hepatitis were soon reported [9-13]. The Committee on Anesthesia of the National Academy of Sciences-National Research Council formed a group in 1961 to investigate the association of halothane with hepatotoxicity [3,14]. In 1969, the report was published. A review of 250,000 cases of halothane use revealed an incidence of fatal hepatic necrosis of approximately 1 in 35,000 exposures [15]. This review, however, was unable to establish a direct correlation between halothane use and liver damage [14]. A similar large-scale review in the United Kingdom showed nearly identical results [16]. Halothane became the most common cause of idiosyncratic drug-induced liver failure by the 1970s [17]. Since then, less and less hepatotoxic alternatives have been serially introduced: enflurane (1972), isoflurane (1981), desflurane (1993) and sevoflurane (1995) [18,19]. However, reports of hepatotoxicity with these medications also exist [20-33].

Initially, toxicity to halothane was not reported in children. Subsequent reports, however, demonstrated that the incidence of halothane-associated hepatitis in children is between 1 in 82,000 and 1 in 200,000 [34-39]. Halothane use in children has been largely replaced by sevoflurane [40]. The reason for the lower incidence of halothane-associated hepatitis observed in children is unclear [41,42].

Concern about hepatotoxicity has virtually eliminated the use of halothane in adults in the United States and Europe. Worldwide, however, halothane is possibly the most commonly used inhalational anesthetic, particularly in the Middle East and Africa [3,43,44]. This is predominantly due to its low cost compared to other anesthetics. Reports of hepatotoxicity continue to be published [45-48].

Approximately 60 to 80 percent of the inhaled anesthetics are eliminated unchanged via the respiratory system [49]. However, their lipophilic nature allows some systemic absorption. This portion of anesthetic must then be detoxified, a process occurring predominantly within the liver. The nontoxic product is then excreted in the urine.

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Literature review current through: Oct 2017. | This topic last updated: Sep 27, 2017.
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