Liver toxicity: the Achilles' heel of endothelin receptor antagonist therapy?

T he medical community has been alerted by case reports of serious liver injury associated with sitaxentan, an endothelin receptor antagonist (ERA) used for the treatment of pulmonary arterial hypertension (PAH). The first of these case reports was published in the June issue of the European Respiratory Journal and described a patient with PAH who was initially treated with bosentan, another ERA [1]. This treatment was stopped after 6 months because of an increase in liver aminotransferases. The liver enzymes quickly returned to normal upon withdrawal of bosentan and, a few months later, sitaxentan therapy was started. Four months after this, liver aminotransferases started to increase again and the drug was discontinued, but the liver enzymes continued to rise to almost 1,000 U?L and the patient developed mild hyperbilirubinemia. Under the assumption of a drug-related idiosyncratic reaction, corticosteroid therapy was initiated resulting in prompt and sustained normalisation of liver enzymes.