eMedicine Specialties > Critical Care > Medical Topics

Halothane Hepatotoxicity

Ruben Peralta, MD, FACS, Professor of Surgery, Anesthesia and Emergency Medicine, Senior Medical Advisor, Board of Directors, Program Chief of Trauma, Emergency and Critical Care, Consulting Staff, Professor Juan Bosch Trauma Hospital, Dominican Republic
Karl A Poterack, MD, Consulting Staff, Department of Anesthesiology, Mayo Clinic Scottsdale; Sarah Guzofski, MD, Staff Physician, Department of Psychiatry, University of Massachusetts Medical School

Updated: Jun 17, 2008

Introduction

Background

Halothane and other halogenated inhalational anesthetic agents, such as enflurane, isoflurane, sevoflurane, and desflurane, are known to cause severe liver dysfunction. The National Halothane Study, a retrospective analysis, reviewed the incidence and mortality rates of postoperative hepatic necrosis from 1959-1962.¹ This study found that, of 82 cases of fatal hepatic necrosis, 9 cases were deemed likely to be drug induced. Seven of the 9 patients had received halothane. Based on this study, the risk of fatal halothane hepatotoxicity was estimated to be 1 in 35,000. When the World Health Organization (WHO) drug monitoring database was reviewed for the medications that most commonly cause fatal hepatotoxicity; halothane was one of the 10 most common causes. Given this risk, halothane is not recommended for use in adults.

Pathophysiology

Two major types of hepatotoxicity are associated with halothane administration. The two forms appear to be unrelated and are termed type I (mild) and type II (fulminant).

Type I hepatotoxicity is benign, self-limiting, and relatively common (up to 25-30% of those that receive halothane). This type is marked by mild transient increases in serum transaminase and glutathione S-transferase concentrations and by altered postoperative drug metabolism. Type I hepatotoxicity is not characterized by jaundice or clinically evident hepatocellular disease. Type I probably results from reductive (anaerobic) biotransformation of halothane rather than the normal oxidative pathway. It does not occur following administration of other volatile anesthetics because they are metabolized to a lesser degree and by different pathways than halothane.

Type II hepatotoxicity (also called halothane hepatitis) is associated with massive centrilobular liver necrosis that leads to fulminant liver failure; the fatality rate is 50%. Clinically, it is characterized clinically by fever, jaundice, and grossly elevated serum transaminase levels. Type II hepatotoxicity appears to be immune mediated. Halothane is oxidatively metabolized, producing trifluroacetyl metabolites to an intermediate compound. These metabolites bind liver proteins and, in genetically predisposed individuals, antibodies are formed to this metabolite-protein complex. The antibodies in turn mediate subsequent type II toxicity. Other hypothesized mechanisms of injury, including P450 inactivation and neutrophil involvement are under investigation.

Volatile anesthetics other than halothane also have the potential to cause type II hepatotoxicity. This risk is directly related to the relative degree of their oxidative metabolism to acetylated protein adducts. Approximately 20% of halothane is oxidatively metabolized compared to only 2% of enflurane and 0.2% of isoflurane; halothane carries a higher risk of hepatotoxicity. The occurrence of type II hepatotoxicity after enflurane or isoflurane administration is extremely rare with case reports and reviews have identified only a handful of instances involving these two agents.

Frequency

United States

Incidence of type I hepatotoxicity after halothane administration is 25-30%. Incidence of type II hepatotoxicity after halothane administration is 1 case per 6000-35,000 patients. The US National Halothane Study found otherwise unexplainable fatal hepatic necrosis after halothane administration in 1 per 35,000 cases.

The incidence after administration of other halogenated agents is much lower, including 2 cases per 1 million patients after enflurane administration, a few reports after isoflurane administration, and a single confirmed case after desflurane administration.

International

Review of the WHO database of medications that cause fatal hepatotoxicity revealed that halothane is one of the top 10 most likely medications to cause fatal hepatic necrosis worldwide.

Mortality/Morbidity

• Type I hepatotoxicity is transient, self-limited, and, usually, subclinical. Often, it is detected only if liver function tests are performed.
• Type II hepatotoxicity has a mortality rate of approximately 50%, which rises to 80% when hepatic encephalopathy is present. Type II has been successfully treated with orthotopic liver transplantation. Patients who survive the acute illness usually make a complete recovery.
• Risk factors include the following:
  • Multiple exposures (especially at intervals of <6 wk): This is the single greatest risk factor for halothane hepatitis.
  • Prior history of postanesthetic fever or jaundice
  • Obesity
  • Female sex
  • Middle age
  • Genetic predisposition
  • Enzyme induction (e.g., alcohol, barbiturate use)
  • Higher AST and bilirubin levels are associated with greater likelihood of fatal outcome or transplant.

Preexisting liver disease itself is not a risk factor for halothane hepatitis.

Sex

The male-to-female ratio is 1:2.

Age

• Halothane hepatotoxicity is more common in middle age.
• Although children were once thought to be unaffected, incidence has been demonstrated to be 1 case per 100,000-200,000 patients.

Clinical

History

• Type I (mild) halothane hepatotoxicity
  • Type I 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
  • Type II 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

• Physical findings in type II halothane hepatotoxicity
  • 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.

Causes

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

Differential Diagnoses

Workup

Laboratory Studies

• A CBC count with differential may show mild leukocytosis or eosinophilia.
• The bilirubin level may be more than 170 mcg/L.
• Serum transaminase levels are elevated.
• An enzyme-linked immunosorbent assay (ELISA) may reveal halothane-related antibodies.
• Eosinophilia occurs in 8-32% of patients with type II halothane hepatotoxicity.
• Serum autoantibodies may be present in 30-44% of patients with type II halothane hepatotoxicity

Procedures

Consider performing a liver biopsy. However, the findings in halothane hepatitis are indistinguishable from those of fulminant viral hepatitis.

Histologic Findings

Acute yellow atrophy and widespread centrilobular hepatocellular necrosis that is indistinguishable from fulminant viral hepatitis are observed.

Treatment

Medical Care

• No specific therapy is available for either fulminant hepatic necrosis or mild hepatotoxicity due to halothane. Only supportive therapy and orthotopic liver transplantation are available for hepatic necrosis.
• Because halothane hepatitis is a diagnosis of exclusion, ruling out other causes is essential.
• As in any form of fulminant hepatitis, take the following measures when instituting supportive therapy:
  • Maintain fluid and electrolyte balance.
  • Support hemodynamics as necessary.
  • Support ventilation as necessary.
  • Correct any alterations in coagulation.
  • Correct hypoglycemia.
  • Treat any other complications of the comatose state.
  • Restrict protein intake and administer oral lactulose or neomycin.
• High-dose corticosteroid therapy has been used in liver failure but has been shown ineffective in controlled trials.
• Molecular adsorbent recirculating system (MARS) is a safe temporary life support mechanism for patients awaiting liver transplantation or recovering from fulminant hepatic failure.

Surgical Care

• If fulminant liver failure occurs and liver function does not recover, orthotopic liver transplantation has been a successful option and may be considered.

Consultations

• Consult with a hepatologist for assistance in confirming the diagnosis.
• Consult with a critical care specialist for support of metabolic, respiratory, and cardiovascular issues.
• Consult with organ procurement team and transplant teams, including transplant surgeon, if liver failure is imminent.

Diet

Restrict protein intake and administer oral lactulose or neomycin.

Activity

Although bed rest is not essential for full recovery, many patients feel better with restricted physical activity.

Follow-up

Further Inpatient Care

Because clinical deterioration may be rapid and because of the high risk of mortality, patients may require monitoring in an intensive care unit.

Transfer

• Hospitalized patients may be discharged when the following criteria are met:
  • Significant improvement in symptoms
  • Normalization of prothrombin time
  • A substantial downward trend in the serum aminotransferase and bilirubin values occurs. Mildly elevated aminotransferase levels should not be considered contraindications to the gradual resumption of normal activity as tolerated.

Deterrence/Prevention

• The most conservative approach is to avoid halothane when reasonable alternatives exist. For example, because of the medicolegal climate in the United States, halothane is infrequently used in adults since several alternatives exist and any postanesthetic liver dysfunction is likely to be ascribed to halothane. In many other countries with different medicolegal climates, halothane is still widely used because of economic reasons.
• Carefully consider halothane use in any adult patient with recent exposure in the past 6 weeks. Recent exposure is the most important risk factor for type II fulminant hepatotoxicity.
• In patients with a history of jaundice and fever following previous halothane exposure, all volatile anesthetics (ie, halothane, enflurane, isoflurane, sevoflurane, desflurane) should be used with caution and indications should be documented.
• Patients with unexplained elevations of liver functions should not undergo anesthesia and elective surgery until a diagnosis has been confirmed. Any type of surgery and anesthesia in the setting of acute hepatitis carries the potential for increased mortality and morbidity.

Complications

• 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.

Prognosis

• If fulminant liver failure does not occur, patients usually make a full recovery.
• If fulminant liver failure occurs, the mortality rate can be 50%.
• If hepatic encephalopathy is present, the mortality rate can be 80%.

Patient Education

• Full informed consent should always be obtained and should include the indications for use and the possible risk of hepatotoxicity.
• Patients with a history of fever and jaundice following halothane exposure should be sure to communicate this to anesthesiologists and surgeons.
• General anesthesia is not contraindicated for future surgery because it can be provided without the use of volatile agents.
• For excellent patient education resources, visit eMedicine's Hepatitis Center and Liver, Gallbladder, and Pancreas Center. Also, see eMedicine's patient education articles Hepatitis A, Hepatitis B, Hepatitis C, and Cirrhosis.

Miscellaneous

Medicolegal Pitfalls

• The routine use of halothane for general anesthesia in adults is difficult to justify.
  • Hepatic dysfunction following anesthesia and surgery is likely to be blamed on halothane, even though it is statistically unlikely that the specific significant liver insult was due to halothane.
  • In adults, only a few specific indications exist for using halothane over other volatile agents.
• The extremely low incidence of halothane hepatitis in children and the suitability of halothane for inhalation inductions commonly used in children give clearer indications for its use in the pediatric population.

References

1. Subcommitee on the National Halothane Study of the Committee on Anesthesia, N. Summary of the national Halothane Study. Possible association between halothane anesthesia and postoperative hepatic necrosis. JAMA. Sep 5 1966;197(10):775-88. [Medline].

2. Baden JM, Rice SA. Metabolism and Toxicity of Inhaled Anesthetics. In: Miller RD, ed. Anesthesia. Philadelphia, Pa: Churchill Livingstone;2000:147-173.

3. Björnsson E, Olsson R. Outcome and prognostic markers in severe drug-induced liver disease. Hepatology. Aug 2005;42(2):481-9. [Medline].

4. Björnsson E, Olsson R. Suspected drug-induced liver fatalities reported to the WHO database. Dig Liver Dis. Jan 2006;38(1):33-8. [Medline].

5. Doria C, Mandalá L, Scott VL, Gruttadauria S, Marino IR. Fulminant hepatic failure bridged to liver transplantation with a molecular adsorbent recirculating system: a single-center experience. Dig Dis Sci. Jan 2006;51(1):47-53. [Medline].

6. Du WB, Li LJ, Huang JR, Yang Q, Liu XL, Li J. Effects of artificial liver support system on patients with acute or chronic liver failure. Transplant Proc. Dec 2005;37(10):4359-64. [Medline].

7. Elliott RH, Strunin L. Hepatotoxicity of volatile anaesthetics. Br J Anaesth. Mar 1993;70(3):339-48. [Medline].

8. Gelman S. Anesthesia and the Liver. Barash, Cullen, Stoelting, eds. In: Clinical Anesthesia. Philadelphia, Pa: J.B. Lippencott;1992:1185-1214.

9. Golembiewski J. Considerations in selecting an inhaled anesthetic agent: case studies. Am J Health Syst Pharm. Oct 15 2004;61 Suppl 4:S10-7. [Medline].

10. Kharasch ED. Volatile Anesthetics: Organ Toxicity. In: Atlee, JL ed. Complications in Anesthesia. 1999;57-9.

11. Kharasch ED, Hankins DC, Fenstamaker K, Cox K. Human halothane metabolism, lipid peroxidation, and cytochromes P(450)2A6 and P(450)3A4. Eur J Clin Pharmacol. Feb-Mar 2000;55(11-12):853-9. [Medline].

12. Masubuchi Y, Horie T. Toxicological significance of mechanism-based inactivation of cytochrome p450 enzymes by drugs. Crit Rev Toxicol. Jun 2007;37(5):389-412. [Medline].

13. Mikatti NE, Healy TE. Hepatic injury associated with halogenated anaesthetics: cross- sensitization and its clinical implications. Eur J Anaesthesiol. Jan 1997;14(1):7-14. [Medline].

14. Ray DC, Drummond GB. Halothane hepatitis. Br J Anaesth. Jul 1991;67(1):84-99. [Medline].

15. Reichle FM, Conzen PF. Halogenated inhalational anaesthetics. Best Pract Res Clin Anaesthesiol. Mar 2003;17(1):29-46. [Medline].

16. Roizen MF. Anesthetic Implications of Concurrent Diseases. In: Anesthesia. 1994;903-1014.

17. Stachnik J. Inhaled anesthetic agents. Am J Health Syst Pharm. Apr 1 2006;63(7):623-34. [Medline].

18. You Q, Cheng L, Reilly TP, Wegmann D, Ju C. Role of neutrophils in a mouse model of halothane-induced liver injury. Hepatology. Dec 2006;44(6):1421-31. [Medline].

Keywords

halothane hepatotoxicity, halothane hepatitis, post-halothane liver dysfunction, hepatic toxicity, halogenated inhalational anesthetic agents, enflurane, isoflurane, sevoflurane, desflurane, centrilobular liver cell necrosis, fulminant liver failure, hepatic encephalopathy, orthotopic liver transplantation

Contributor Information and Disclosures

Author

Ruben Peralta, MD, FACS, Professor of Surgery, Anesthesia and Emergency Medicine, Senior Medical Advisor, Board of Directors, Program Chief of Trauma, Emergency and Critical Care, Consulting Staff, Professor Juan Bosch Trauma Hospital, Dominican Republic
Ruben Peralta, MD, FACS is a member of the following medical societies: American College of Surgeons, American Medical Association, Association for Academic Surgery, Eastern Association for the Surgery of Trauma, Massachusetts Medical Society, Society of Critical Care Medicine, and Society of Laparoendoscopic Surgeons
Disclosure: Nothing to disclose.

Coauthor(s)

Karl A Poterack, MD, Consulting Staff, Department of Anesthesiology, Mayo Clinic Scottsdale
Karl A Poterack, MD is a member of the following medical societies: American Society of Anesthesiologists
Disclosure: Nothing to disclose.

Sarah Guzofski, MD, Staff Physician, Department of Psychiatry, University of Massachusetts Medical School
Sarah Guzofski, MD is a member of the following medical societies: American Medical Association, American Psychiatric Association, and Massachusetts Medical Society
Disclosure: Nothing to disclose.

Medical Editor

Laurie Robin Grier, MD, Medical Director of MICU, Associate Professor of Medicine, Section of Pulmonary and Critical Care Medicine, Louisiana State University Health Science Center at Shreveport
Laurie Robin Grier, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Society for Parenteral and Enteral Nutrition, and Society of Critical Care Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Harold L Manning, MD, Associate Professor, Departments of Medicine, Anesthesiology and Physiology, Section of Pulmonary and Critical Care Medicine, Dartmouth Medical School
Harold L Manning, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and American Thoracic Society
Disclosure: Nothing to disclose.

CME Editor

Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Saint Louis University School of Medicine
Timothy D Rice, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Physicians
Disclosure: Nothing to disclose.

Chief Editor

Michael R Pinsky, MD, CM, Professor of Critical Care Medicine, Bioengineering, Cardiovascular Diseases and Anesthesiology, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center
Michael R Pinsky, MD, CM is a member of the following medical societies: American College of Chest Physicians, American College of Critical Care Medicine, American Heart Association, American Thoracic Society, Association of University Anesthetists, Shock Society, and Society of Critical Care Medicine
Disclosure: LiDCO Ltd Honoraria Consulting; iNTELOMED Intellectual property rights Board membership; Edwards Lifesciences Honoraria Consulting; Applied Physiology, Ltd Honoraria Consulting

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)