To the Editors:
We were interested to read the letter from Lavelle et al. 1, together with the accompanying editorial 2, regarding liver toxicity in patients receiving endothelin receptor antagonist therapy (ERA) for pulmonary arterial hypertension. Both of these articles highlight the potential for severe liver toxicity in patients receiving sitaxentan and stress the continued need for regular monitoring of liver function tests in all patients receiving ERAs. In fact, the details of the reported cases show that severe liver toxicity can occur within the time period of a month and one of us (P.A. Corris) has experience of a further case of fulminant hepatic failure occurring on treatment with sitaxentan when the liver function tests were normal less than one month beforehand. This suggests that all patients and the patients’ relatives should be advised to report any symptoms or signs of hepatic disease, such as anorexia, abdominal pain or jaundice as soon as they are noticed.
We disagree with the suggestion that, based on current data, sitaxentan may be afflicted with a higher potential to severe liver toxicity. Severe toxicity has also been reported with bosentan, with or without other potential medication interactions.
Nagai et al. 3 reported multi organ failure following severe hepatitis (AST and ALT levels >5000 IU) in a patient receiving bosentan. That patient died. Dwyer et al. 4 reported severe toxicity with the combination of bosentan and methotrexate, which did not recur on the presence of methotrexate alone. One of us (P.A. Corris) has recently diagnosed a case of severe liver toxicity due to hypersensitivity reaction to ambrisentan. Humbert et al. 5 reported on nine patients satisfying Hy's law for severe liver toxicity due to bosentan therapy on the TRAX safety database, though no clinical details were reported. About 20% of patients treated with bosentan in Europe were not entered into that database, so there may have been more cases. Under-reporting of all medication-related complications is a chronic health care issue.
In summary, physicians should be aware that severe hepatic toxicity may be seen in patients receiving any of the current ERA therapies, and that there may be interactions with other potentially hepatotoxic medications. Patients must be advised to consult their prescribing physician urgently on the first signs and symptoms of hepatic toxicity, irrespective of normal liver function tests within a month earlier. Every case of severe hepatotoxicity should be reported. Knowing the true degree of vulnerability of this particular “Achilles' heel” will allow for better scientific conclusions.
Statement of interest
Statements of interest for both authors of this manuscript can be found at www.erj.ersjournals.com/misc/statements.dtl
- © ERS Journals Ltd