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Anticonvulsant hypersensitivity syndrome and drug-induced hepatic injury.

In this issue of the Journal, Ouellet et al 1 detail a case of fulminant hepatitis induced by lamotrigine, in which a 40year-old female patient presented with features characteristic of anticonvulsant hypersensitivity syndrome (AHS). Causality is appropriately linked to lamotrigine, given that the signs appeared shortly after a dosage escalation, and clinical improvement followed drug discontinuation. The case emphasizes the importance for prescribers to be aware of this serious, potentially life-threatening hypersensitivity syndrome when prescribing lamotrigine or other anticonvulsants linked to this problem. Specifically, the evidence of fever and rash without another identifiable cause in this patient was highly suspicious for AHS. The case also highlights the need for providers to consider druginduced injury in the presence of acute hepatotoxicity. Antiepileptics linked to AHS include carbamazepine, oxcarbamazepine, phenobarbital, phenytoin, and primidone. It appears that the responsible anticonvulsants all break down into intermediate metabolites, namely arene oxides. When the metabolites cannot be detoxified, the immune reaction described in the case report can lead to cellular destruction, and arene oxide metabolites can form covalent bonds with surrounding cells, making them cytotoxic to a variety of organs and tissues. Because cross-reactivity for these drugs can be up to 80%, patients who have experienced AHS should never receive anticonvulsants linked to the reaction. The emergence of hypersensitivity reactions with skin involvement is not limited to anticonvulsants. Corticosteroids, nonsteroidal anti-inflammatory drugs, and sulfonamides are among the drug classes known to produce hypersensitivity reactions with dermatologic features, as are some antihypertensives like atenolol, captopril, and diltiazem. A variety of other medications have been associated with hypersensitivity reactions. Interestingly, facial involvement with a rash is uncommon unless the offending agent is an anticonvulsant, although, in this case, rash was only noted on the torso. As the authors reported, liver injury is a common feature of AHS. Furthermore, drug-induced liver injury is a potential toxicity of many drugs, including analgesics, antimicrobials, cardiovascular drugs, and cancer chemotherapies. In fact, drugs are the primary cause of fulminant hepatic failure in the United States and Europe. Among potentially hepatotoxic drugs, anticonvulsants have been named among the drug classes most commonly associated with fatalities. This case also emphasizes the importance of screening patients for hepatic impairment; considering the impact of combining multiple drugs with potential hepatotoxic effects or drugdrug interactions; and utilizing drug monitoring plans which support early identification of drug-induced injury. Keys to successful management of AHS include early recognition, discontinuation of the offending agent, hospitalization, and interim therapy for epilepsy or any other serious condition being treated with the anticonvulsant. For epilepsy, short-term benzodiazepine therapy may be used. For epilepsy or bipolar disorder, consideration may be given to the nonaromatic anticonvulsant valproic acid after the acute or recovery phase has passed due to the drug’s potential liver effects. Additional management may include enteral nutrition and consultation with specialists, depending on organ involvement. Cutaneous eruptions have been treated with topical or systemic corticosteroids, antihistamines, and moistened skin wraps.