Halothane Hepatotoxicity 

Updated: Dec 17, 2019
Author: Ruben Peralta, MD, FACS; Chief Editor: Michael R Pinsky, MD, CM, Dr(HC), FCCP, FAPS, MCCM 



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.[2]


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).[3]

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 trifluoroacetyl 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.[4]

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.


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

With 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.[5, 6]



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 6,000-35,000 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.


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.[7]


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


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.


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%.

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[8] :

  • 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 (eg, 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.

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.




Type I (mild) halothane hepatotoxicity 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 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 Examination

Physical findings in type II halothane hepatotoxicity include 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.


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.





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


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.



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.

An animal study concluded that zinc has the potential to alleviate halothane-toxic effects in the liver of rats by demonstrating a reduction of hepatic enzyme levels and reduction in liver damage in the zinc-halothane group. Further translational studies are warranted.[9]

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

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.

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.


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.


Restrict protein intake and administer oral lactulose or neomycin.


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


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.

The anesthesia profession is becoming more aware of the occupational exposure and adverse environmental impact of inhalational anesthetics, which includes ozone damage and greenhouse gas effect. A call for the modification in anesthetics procedures and the role of total intravenous anesthesia in selected procedures is being advocated by some.[10]

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.