carbamazepine-induced hepatitis

Serious carbamazepine hepatotoxicity is being recognized more frequently and is usually manifest as an acute granulomatous hepatitis that is self-limiting if the drug is withdrawn.

Clinical synopsis

 hepatic drug reaction
 fever
 anorexia
 malaise
 swinging fever
 jaundice
 right upper quadrant abdominal pain tenderness
 cholestasis
 hepatocellular injury
 granulomatous hepatitis.

Withdrawal of carbamazepine led to complete resolution of both clinical and biochemical abnormalities within 3 weeks.

Clinicians should be alert to this rare complication because it can be confused clinically with biliary tract sepsis and viral hepatitis.

Physiopathology

Carbamazepine is a drug commonly used in the treatment of neuropathic pain. It is an iminostilbene derivative that is extensively metabolized by the liver.

The idiosyncratic hypersensitivity reaction to Tegretol appears to be mediated by formation of an adduct and subsequent T-cell hypersensitivity.

Carbamazepine treatment is associated with minor, asymptomatic elevations in liver enzymes, usually GGT or alkaline phosphatase, in approximately 6% of children.

These elevations in hepatic enzymes are associated with the induction of hepatic cytochromes, and carbamazepine treatment does not need to be discontinued.

Major increases (eg, > 4 X normal range) in ALT and AST, however, are rare and may be signs of an anticonvulsant hypersensitivity reaction.

One hypothesis for this phenomenon is that patients with hypersensitivity reactions do not have the normal enzyme function needed to detoxify reactive intermediates, such as the arene oxide of carbamazepine.

Partial evidence of this is that patients with carbamazepine hypersensitivity reactions demonstrate varied mutations in microsomal epoxide hydrolase genes when compared with control subjects.

Loss of normal hydrolysis or conjugative metabolism of carbamazepine may permit reactive intermediates to produce cytologic injury, with subsequent hapten formation and immunologic reactions.

Most patients with hypersensitivity reactions also have skin reactions (Stevens-Johnson or toxic epidermal necrolysis) in addition to hepatitis.

Furthermore, patients with hypersensitivity reaction to carbamazepine will often experience similar reactions to the other aromatic amines, phenytoin and phenobarbital, and it is safest to convert the patient to treatment with an antiepileptic drug that has a different route of metabolism, such as gabapentin.

See aalso

 carbamazepine

References

 Carbamazepine induced granulomatous hepatitis. Swinburn BA, Croxson MS, Miller MV, Crawford KB. N Z Med J. 1986 Mar 12;99(797):167. PMID: 3457299