Halothane Hepatitis - Mechanism, Symptoms, Diagnosis, and Treatment

Introduction:

A drug called halothane was employed to induce and sustain general anesthesia. It significantly impacted medicine and anesthesia, but because of its adverse effect profile, it has subsequently lost acceptance. The development of less harmful gases that caused a reduced incidence of adverse effects followed shortly after halothane-induced hepatitis started to raise concerns. There are two distinct types of hepatotoxicity brought on by halothane: type 1, or mild hepatitis, characterized by high transaminase levels and self-limiting symptoms, and type 2, or severe hepatotoxicity, which is characterized by immediate catastrophic liver failure and usually life-threatening. Halothane metabolism in the liver generates free radicals that can impact cellular proteins and provide the immune system neo-antigens. Most cases of type 2 hepatitis develop after repeated encounters with these neo-antigens because sensitization causes a more severe reaction after several exposures.

What Is Halothane?

Halothane is a clear, thick, colorless liquid with a sweet, non-irritating smell. As an inhalational anesthetic, it is typically employed in healthcare situations. Halothane is the commonly used non-ether anesthetic in the operating room, despite being mostly superseded by isoflurane or sevoflurane. The fact that halothane is the most soluble anesthetic agent currently being used demonstrates that inspired or brain partial pressures have equilibrated. Although this property would seem to improve the safety profile of halothane, halothane is also the most potent inhalational anesthetic. Although halothane has several adverse effects, its lack of flammability and ease of administration generally led to its quick and widespread usage.

What Is Halothane-Induced Hepatotoxicity?

Halothane can cause two different types of hepatotoxicity: type 1, or mild hepatitis, which is characterized by high transaminase levels and symptoms that usually go away on their own, and type 2, or severe hepatotoxicity, which is characterized by sudden catastrophic liver failure and is typically life-threatening.

Free radicals produced by the liver's metabolism of halothane can damage cellular proteins and produce neo-antigens for the immune system. Since sensitization results in a more severe reaction after numerous exposures, the majority of cases of type 2 hepatitis manifest after repeated exposure to these neo-antigens.

Moreover, it is linked to higher circulating immune complexes, rash, and arthralgia levels. The hepatocyte-specific antibodies are seen in the serum of affected individuals. The intracellular metabolism of halothane and local changes in hepatic blood flow and oxygen demand, which lead to hepatic hypoxia, are thought to be responsible for mild forms of hepatic injury after exposure to halothane, even if more severe types are thought to be immune-mediated.

What Is the Mechanism of Halothane-Induced Hepatotoxicity?

Compared to other inhalational anesthetics, halothane undergoes more hepatic oxidative or reductive metabolism, which is predominantly driven by cytochrome P450 (CYP450). Under typical circumstances, cytochrome P450 2E1 and 2A6 catalyze up to one-third of the metabolism of halothane through the oxidative pathway, while less than one percent of it occurs through the reductive pathway.

The highly reactive compound trifluoroacetyl chloride (TFA), which is produced by the interaction of lysine with halothane metabolites, binds to the macromolecules of hepatocytes to produce neo-antigens. These neo-antigens are capable of inducing fulminant hepatitis and triggering immunological reactions against hepatocytes. Kupffer cells may also express neo-antigens, making them antigen-presenting cells. Free radicals created during nonoxidative halothane metabolization can cause lipid peroxidation, CYP450 inactivation, and lethal hepatocyte necrosis. They can also cause an increase in blood aminotransferase levels.

What Are the Symptoms of Halothane-Induced Hepatotoxicity?

Depending on the severity of the symptoms, there are two categories of hepatitis:

• Mild hepatitis with elevated aminotransferase levels and self-limiting symptoms.

• Severe hepatitis or acute liver failure.

The major causes of a mild form of hepatotoxicity are the metabolites of halothane breakdown and local hypoxia caused by insufficient blood flow and impaired oxygen intake. Following surgery, this disease typically manifests as high liver transaminase values. Some patients experience:

• Self-limited rash.

• Arthralgia.

• Lethargy.

• Nausea.

• Fever.

• Anorexia.

• Myalgia.

How to Diagnose Halothane-Induced Hepatotoxicity?

The diagnosis of halothane-induced hepatitis constitutes an exclusion. Most liver diseases are characterized by elevated serum aminotransferase levels, rash, arthralgia, jaundice, and hepatomegaly, which do not always indicate a specific diagnosis. However, other diagnoses, including surgical complications, preoperative hypotension, sepsis, infection, drug-induced hepatotoxicity, and viral hepatitis are considered diagnostic criteria.

What Are the Treatment Options for Halothane-Induced Hepatotoxicity?

Supportive therapy is typically used to treat halothane-induced hepatitis. Most mild cases resolve independently with little to no intervention and do not require intensive care. Most individuals respond well to various therapeutic approaches, including immediate liver transplantation. Patients are typically managed based on acute liver failure complications, such as hepatic encephalopathy, cerebral edema, renal failure, and metabolic disturbances. Some studies stated that jaundice has cleared up after methionine therapy. Although their efficacy has not been established, corticosteroids run the risk of hastening the progression of hepatitis.

The treatment option for both types of halothane hepatotoxicity is supportive therapy, which includes:

• Electrolyte and fluid balance.

• Therapeutic coagulation abnormalities.

• Hypoglycemic management.

• Ventilation.

• Supportive care with hemodynamics.

• Oral lactulose and limiting protein consumption.

• Type 2 halothane hepatitis is treated under intensive supportive care. Once acute liver failure is likely to occur, despite the best supportive measures, a liver transplant is typically required.

What Is the Prognosis of Halothane-Induced Hepatotoxicity?

Type 1 halothane hepatotoxicity often self-remits over several weeks, causing minimal long-term dysfunction in most cases, giving it a considerably better prognosis than type 2 hepatitis. If type 2 halothane hepatotoxicity has advanced to acute liver failure, the death rate is 50 percent, which might reach 80 percent, if hepatic encephalopathy has manifested. If acute liver failure worsens, immediate liver transplantation is necessary.

What Are the Complications of Halothane-Induced Hepatotoxicity?

• Halothane has been linked to both type 1 (benign) and type 2 hepatotoxicity (fulminant hepatitis).

• Increased serum aminotransferase levels and potential minor, self-limiting symptoms are linked to type 1.

• A higher mortality rate, severe hepatitis, and sudden liver failure are all symptoms of type 2 halothane hepatotoxicity.

• Halothane also has significant cardiac side effects, particularly among young children.

Conclusion:

Those who have general anesthesia are at risk for fatal hepatitis from halothane. Hence, preventing exposure is the best way to safeguard patients. Halothane exposure poses the highest risk, followed by previous exposure, obesity, and genetic predisposition. Before being exposed to halothane, patients should get instructions regarding weight management and personal or family history because it is sensible.