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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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Halothane

Last Update: January 1, 2018.

OVERVIEW

Introduction

Halothane is a potent volatile halogenated anesthetic gas that has been linked to many cases of idiosyncratic acute liver injury that are frequently severe. The potential of halothane to cause hepatotoxicity and the greater safety of newer anesthetics has led to a decrease in its use, currently limited to special situations, particularly in children. Because halothane is relatively inexpensive it continues to be used in developing countries.

Background

Halothane (hal' oh thane) is a volatile anesthetic that was used widely in major surgery between its introduction in 1956 and falling out of favor in the mid 1990s. It is nonflammable, potent and well tolerated. Halothane is administered to produce end tidal concentrations of 0.7% to 1%. It has a somewhat slow onset of action and, therefore, like other halogenated inhalational anesthetics, it is used to maintain anesthesia after induction with other agents. Halothane is no longer available in the United States, but is still used in developing countries, particularly in pediatric patients. Halothane must be administered in a controlled situation by a properly trained and credentialed anesthesiologist or nurse anesthetist and is typically given in concentrations up to 1% with oxygen.

Hepatotoxicity

Prospective, serial blood testing often demonstrates minor transient elevations in serum aminotransferase levels in the 1 to 2 weeks after major surgery and anesthesia with halothane and other halogenated anesthetics. Appearance of ALT levels above 10 times the upper limit of normal, however, is uncommon and points to significant hepatotoxicity. Clinically apparent, severe hepatic injury from halothane is rare, occurring in ~1/15,000 cases after initial exposure, but in ~1/1,000 cases after repeated exposures. The injury is marked by acute elevations in serum aminotransferase levels (5- to 50-fold) and appearance of jaundice within 2 to 14 days of surgery. There are usually minimal increases in alkaline phosphatase levels. Fever occurs before onset of jaundice in a high proportion of patients and eosinophilia in up to 30%. Rash and arthralgias can also accompany the onset of hepatic injury. The acute liver injury may be self-limited and resolve within 4 to 8 weeks, but can be severe and lead to 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. Other risk factors are hypotension, older age, obesity and concurrent use of CYP 2E1 inducers. The differential diagnosis of acute liver injury after surgery and anesthesia is sometimes difficult, and a clinical picture similar to halothane hepatitis can be caused by shock or ischemia, sepsis, other idiosyncratic forms of drug induced liver injury and acute viral or herpes hepatitis. Indeed, many cases of severe liver injury arising soon after surgery and attributed to halothane or other halogenated anesthetics in the literature probably represent liver injury from shock and ischemia. Factors favoring the diagnosis of ischemic hepatitis are rapid onset after surgery, extremely high values for ALT, AST and LDH, and subsequent rapid fall in serum enzymes.

Likelihood score: A (well known cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism of halothane hepatotoxicity is suspected to be immunoallergic, caused by creation of reactive intermediates of the anesthetic. Approximately 60% to 80% of halothane is eliminated unchanged by the lungs, but a proportion is biotransformed by hepatic microsomal enzyme CYP 2E1 to a trifluoroacetic acid which can be detected in the urine, but which also can trifluoroacetylate hepatic proteins, some of which may be immunogenic and induce cytotoxic reactions. The clinical pattern of injury is suggestive of an allergic hepatitis with rapid onset of injury, fever, eosinophilia and accelerated and more severe injury with reexposure. Patients with halothane hepatitis often have antibodies to trifluoroacetylated proteins. On the other hand, the clinical and histological pattern of halothane hepatic injury also resembles chloroform induced liver damage with centrolobular somewhat bland necrosis, suggesting that toxic intermediates of reductive halothane metabolism may cause the injury by direct injury.

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 repeated halothane exposure has been described in health care workers repeatedly exposed to the agent, but the injury does not appear to lead to a chronic hepatitis if the exposure is terminated. Patients with halothane induced hepatitis should be cautioned against future exposure to a fluorinated hydrocarbon anesthetic such as isoflurane, enflurane, desflurane or sevoflurane.

Drug Class: Halogenated Anesthetics

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

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Halothane – Generic, Fluothane®

DRUG CLASS

Anesthetics, Halogenated

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NOMOLECULAR FORMULASTRUCTURE
Halothane 151-67-7 C2-H-Br-Cl-F3
Halothane chemical structure

ANNOTATED BIBLIOGRAPHY

References updated: 01 January 2018

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    (Review of hepatotoxicity from halothane and other volatile anesthetic agents published in 1999; provides a history of the controversy surrounding halothane hepatotoxicity, along with its biochemical and clinical characteristics, risk factors, histology, and suspected mechanisms).
  • Liver disease due to anaesthetic agents. In, Farrell GC. Drug-induced liver disease. Edinburgh: Churchill Livingstone, 1994, pp. 389-412.
    (Review of the history of halothane hepatitis with overview of the clinical features and pathogenesis).
  • Kenna JG. Mechanism, pathology, and clinical presentation of hepatotoxicity of anesthetic agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 403-22.
    (Review of hepatotoxicity of halothane and other halogenated anesthetic agents focusing on pathogenesis).
  • Patel PM, Patel HH, Roth DM. General anesthetics and therapeutic gases. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 527-64.
    (Textbook of pharmacology and therapeutics).
  • Brody GL, Sweet RB. Halothane anesthesia as a possible cause of massive hepatic necrosis. Anesthesiology 1963; 24: 29-37. [PubMed: 14015698]
    (Early description of 4 cases of severe liver injury after halothane: 3 women and one man, ages 51-74 years, latency ~12 days to symptoms, 15 days to jaundice, death by 20 days, autopsy showing centrolobular massive necrosis).
  • Lindenbaum J, Leifer E. Hepatic necrosis associated with halothane anesthesia. N Engl J Med 1963; 268: 525-30. [PubMed: 13930795]
    (Early, classic clinical description of 8 cases of halothane and one of methoxyflurane hepatitis: fever and then jaundice, typical hepatocellular enzyme pattern, slow to resolve).
  • Slater EM, Gibson JM, Dykes MH, Walzer SG. Postoperative hepatic necrosis. Its incidence and diagnostic value in association with the administration of halothane. N Engl J Med 1964; 270: 983-7. [PubMed: 14122794]
    (Among 14,685 procedures done at one institution under halothane anesthesia over a 3 year period, authors found only one case of severe acute hepatic necrosis suggestive of halothane hepatitis).
  • Summary of the National Halothane Study. Possible association between halothane anesthesia and postoperative hepatic necrosis. JAMA 1966; 197: 775-88. [PubMed: 5953371]
    (Analysis of all necropsies showing massive hepatic necrosis after anesthesia from 34 institutions from 1959-62 found most cases were explained by ischemia, sepsis or other conditions; among 82 cases, only 9 were considered “unexplained”, 7 followed halothane; Committee recommended further study rather than limitation of halothane use).
  • Klein NC, Jeffries GH. Hepatotoxicity after methoxyflurane administration. JAMA 1966; 197: 1037-9. [PubMed: 5953207]
    (58 year old woman developed fever followed by jaundice on day 7 after methoxyflurane anesthesia [bilirubin 4.4 mg/dL, ALT 2000 U/L, Alk P 3.5 time ULN, 28% eosinophils], resolving within one month).
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    (Analysis of 42 cases of halothane jaundice: 67% fatal; 72% previously exposed; 88% had fever, 95% jaundiced: onset jaundice in 2-15 days, ALT usually >5 times and Alk P <4 times ULN. Histology showed acute hepatitis with focal or submassive necrosis, occasionally steatosis).
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    (Analysis of 33 fatal and 8 nonfatal cases of suspected halothane hepatitis referred to pathologists at USC, found obesity and previous exposure to halothane within previous month to be risk factors, clinical pattern of fever several days before jaundice; histology separated into three stages: early, intermediate and late: necrotic, resorptive, and regenerative).
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    (Six dramatic cases of halothane hepatitis in patients receiving multiple exposures in a protocol of repeated cervical radium implants [2-4] over a short period of time, often with an earlier episode of fever, fatal in 2 cases: no further cases occurred once halothane use was stopped).
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    (Review of differential diagnosis of liver disease after surgery and anesthesia concluded that “halothane hepatitis is a real but rare entity”).
  • Paull A, Grant AK. Halothane hepatitis--a report of five cases. Med J Aust 1974; 1: 954-7. [PubMed: 4852220]
    (Five cases of halothane hepatitis from Australia, latency of 5 to 12 days often preceded by fever occurring after 2 to 4 exposures; 1 fatal, 2 had eosinophilia, AST 100-2800 U/L, bilirubin 3.8-34 mg/L, biopsies showed hepatitis with variable amounts of necrosis, focal to submassive).
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    (Classic review of halothane hepatitis; 26 patients, 25 adults, 69% women, often obese, 92% previously exposed, symptom onset in 1-12 days, jaundice rapidly following, AST markedly elevated, Alk P minimally increased, bilirubin 3.2-41.2 mg/dL; 42% fatal, no chronicity; striking demonstration of fever with previous exposures and acceleration of latency).
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    (Prospective study randomizing to halothane anesthesia or not and following AST at regular intervals found elevations in 15 halothane exposed and 4 control patients; peak AST levels 40-440 U/L ~7 days, all self limiting and asymptomatic; one case had recurrence on reexposure).
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    (3 pairs of cases of halothane hepatitis in close relatives: mother-daughter, sisters, first cousins; all Mexican, onset 2-10 days after anesthesia with fever [5/6], eosinophilia [3/6], half of which were fatal [3/6], somewhat vague in details).
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    (Serum from halothane hepatitis cases was cytotoxic to hepatocytes from rabbits given halothane, but only if animals were exposed to high concentrations of oxygen suggesting that oxidative metabolic pathway was involved).
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    (ELISA assays for anti-TFA using rat serum albumin had a high false positive rate and poor sensitivity compared to ELISAs and immunoblotting using purified TFA microsomal proteins as test antigens).
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    (Patients with halothane hepatitis develop antibody to a 58 kDa endoplasmic reticulum [ER] protein that becomes trifluoroacetylated with halothane exposure).
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    (Anti-CYP 2E1 found in serum of 25 of 56 patients with halothane hepatitis; antibody inhibited the enzyme and was directed at conformational epitopes).
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    (Rats treated with halothane developed trifluoroacetylated CYP2E1 in liver; and same protein is recognized by antibody present in 14 of 20 patients with halothane hepatitis, rarely in controls; TFA protein possibly present on hepatocyte membranes).
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    (59 cases of halothane hepatitis seen at 7 hospitals in Iran between 1994 and 2006; mean age 44 years, mean time to onset 15 days, 81% women, 22% obese, 61% previous exposure, 6 deaths [12%]).
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