Halothane Hepatotoxicity

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
Coauthor(s): 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

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 metaboliteprotein 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:

o Multiple exposures (especially at intervals of <6 wk): This is the single greatest
risk factor for halothane hepatitis.
o Prior history of postanesthetic fever or jaundice

o Obesity
o Female sex
o Middle age
o Genetic predisposition
o Enzyme induction (e.g., alcohol, barbiturate use)
o 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

o Type I occurs within hours of halothane exposure.
o It does not occur after other agents.
o Type I is characterized by mild, transient elevations in serum transaminase and
glutathione S- transferase concentrations.
o Jaundice is not observed, and no evidence of hepatocellular disease is present.

Type II (fulminant) halothane hepatotoxicity

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

o Delayed pyrexia (up to 75% of patients)
o Jaundice can be present 7-10 days after exposure, but it may occur earlier in
previously exposed patients.
o Liver tenderness is common but hepatomegaly is usually mild.
o 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

o Fulminant necrosis is now believed to be an immune phenomenon occurring in
genetically susceptible individuals.

o 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
Abdominal Trauma, Blunt
Acute Liver Failure
Alcoholic Fatty Liver
Alcoholic Hepatitis
Biliary Obstruction
Cirrhosis
Hepatitis A
Hepatitis B
Hepatitis C

Hepatitis D
Hepatitis E
Hepatitis, Viral
Hepatorenal Syndrome
Multisystem Organ Failure of Sepsis
Sepsis, Bacterial
Septic Shock
Shock, Distributive

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:
o Maintain fluid and electrolyte balance.
o Support hemodynamics as necessary.
o Support ventilation as necessary.
o Correct any alterations in coagulation.
o Correct hypoglycemia.
o Treat any other complications of the comatose state.
o 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:
o Significant improvement in symptoms
o Normalization of prothrombin time

o 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.
o 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.
o 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):77588. [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. Bjrnsson E, Olsson R. Outcome and prognostic markers in severe drug-induced liver

disease. Hepatology. Aug 2005;42(2):481-9. [Medline].
4. Bjrnsson 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, Mandal L, Scott VL, Gruttadauria S, Marino IR. Fulminant hepatic failure
bridged to liver transplantation with a molecular adsorbent recirculating system: a singlecenter 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):435964. [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. FebMar 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):389412. [Medline].
13. Mikatti NE, Healy TE. Hepatic injury associated with halogenated anaesthetics: crosssensitization and its clinical implications. Eur J Anaesthesiol. Jan 1997;14(1):714. [Medline].
14. Ray DC, Drummond GB. Halothane hepatitis. Br J Anaesth. Jul 1991;67(1):8499. [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;9031014.

17. Stachnik J. Inhaled anesthetic agents. Am J Health Syst Pharm. Apr 1 2006;63(7):62334. [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].