Halothane Hepatotoxicity Clinical Presentation

  • Author: Ruben Peralta, MD, FACS; Chief Editor: Michael R Pinsky, MD, CM, FCCP, FCCM   more...
 
Updated: Jul 20, 2010
 

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.
Next

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.
Previous
Next

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.
  • 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.[2, 3]
Previous
Proceed to Differential Diagnoses
 
 
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 Association of Blood Banks, American College of Healthcare Executives, 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.

Specialty Editor Board

Laurie Robin Grier, MD  Medical Director of MICU, Professor of Medicine, Emergency Medicine, Anesthesiology and OBGYN, 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.

Francisco Talavera, PharmD, PhD  Senior Pharmacy Editor, eMedicine

Disclosure: eMedicine Salary Employment

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.

Timothy D Rice, MD  Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, St 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, FCCP, FCCM  Professor of Critical Care Medicine, Bioengineering, Cardiovascular Disease and Anesthesiology, Vice-Chair, Academic Affairs, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center

Michael R Pinsky, MD, CM, FCCP, FCCM 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; Cheetah Medical Consulting fee Consulting

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. Feng D, Wang Y, Xu Y, Luo Q, Lan B, Xu L. Interleukin 10 deficiency exacerbates halothane induced liver injury by increasing interleukin 8 expression and neutrophil infiltration. Biochem Pharmacol. Jan 15 2009;77(2):277-84. [Medline].

  3. Kobayashi E, Kobayashi M, Tsuneyama K, Fukami T, Nakajima M, Yokoi T. Halothane-induced liver injury is mediated by interleukin-17 in mice. Toxicol Sci. Oct 2009;111(2):302-10. [Medline].

  4. Unsal C, Celik JB, Toy H, Esen H, Otelcioglu S. Protective role of zinc pretreatment in hepatotoxicity induced by halothane. Eur J Anaesthesiol. Oct 2008;25(10):810-5. [Medline].

  5. Irwin MG, Trinh T, Yao CL. Occupational exposure to anaesthetic gases: a role for TIVA. Expert Opin Drug Saf. Jul 2009;8(4):473-83. [Medline].

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

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

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

  9. 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].

  10. 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].

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

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

  13. 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].

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

  15. 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].

  16. 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].

  17. 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].

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

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

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

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

  22. 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].

 
Previous
Next
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2012 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.