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. No histopathologic findings are specific to this entity. Type II hepatotoxicity is characterized clinically by fever, jaundice, and grossly elevated serum transaminase levels. Type II hepatotoxicity appears to be immune mediated and is initiated by oxidative halothane metabolism to an intermediate compound. This compound then binds to trifluoroacetylate proteins in the hepatic endoplasmic reticulum. Type II halothane hepatotoxicity has a fatality rate of 50%.
Type II hepatotoxicity is thought to occur in genetically predisposed individuals. The potential for volatile anesthetics to cause type II hepatotoxicity 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. The occurrence of type II hepatotoxicity after enflurane or isoflurane administration is extremely rare. Indeed, case reports and reviews have identified only a handful of instances.
Frequency:
- In the US: 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.
- Internationally: 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
- Prior history of postanesthetic fever or jaundice
- Obesity
- Female sex
- Middle age
- Genetic predisposition
- Enzyme induction (e.g., alcohol, barbiturate use)
- Multiple exposures
- Higher AST and bilirubin levels are associated with greater likelihood of fatal outcome or transplant.
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 immune, incidence has been demonstrated to be 1 case per 100,000-200,000 patients.
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 a transplant surgeon if liver failure occurs.
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.
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