Practice Essentials
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]
Currently, halothane is rarely used in economically developed nations due to the availability of newer and safer volatile anesthetics, such as enflurane and sevoflurane. Halothane hepatotoxicity is more likely to occur in lower resource settings where halothane continues to be used.
Presentation
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 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.
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.
Diagnostics
A CBC count with differential may show mild leukocytosis or eosinophilia.
The bilirubin level may be more than 170 μg/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.
On histology, acute yellow atrophy and widespread centrilobular hepatocellular necrosis that is indistinguishable from fulminant viral hepatitis are observed.
Treatment
Also see Treatment.
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:
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Maintain fluid and electrolyte balance.
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Support hemodynamics as necessary.
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Support ventilation as necessary.
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Correct any alterations in coagulation.
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Correct hypoglycemia.
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Treat any other complications of the comatose state.
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Restrict protein intake and administer oral lactulose or neomycin.
Pathophysiology
Two major types of hepatotoxicity are associated with halothane administration. The 2 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.
Etiology
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 2 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]
Epidemiology
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 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.
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. [7]
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.
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%.
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] :
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Multiple exposures (especially at intervals of < 6 wk): This is the single greatest risk factor for halothane hepatitis.
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Prior history of postanesthetic fever or jaundice
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Obesity
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Female sex
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Middle age
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Genetic predisposition
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Enzyme induction (eg, alcohol, barbiturate use)
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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.
