Azathioprine induced hepatitis in patients with inflammatory bowel disease

Abstract

I welcome Salem and colleagues recent article on Azathioprine induced cholestatic hepatitis [1]. Azathioprine is an immunosuppressant used in the management of a number of clinical conditions. Concerns at time of commencing azathioprine are related to bone marrow suppression, consequently the TPMT levels are checked to ensure appropriate dosing regimen. However, azathioprine induced hepatitis is a rare but serious problem, which manifests either as a problem associated with chronic use and a gradual derangement of liver function tests or more concerning an acute severe hepatitis occurring within weeks of commencing treatment. This latter presentation is well reported in the literature and demonstrated to occur in patients on azathioprine for a number of different clinical conditions. In our institution over the last 4 years there have been two patients with inflammatory bowel disease that developed severe hepatitis following commencement of azathioprine. In both cases, patients developed upper abdominal pain, nausea and felt generally unwell. Both patients denied taking other medications or herbal remedies at this time. The bloods tests demonstrated a negative liver screen (including viral hepatitis screen, immunoglobulins, ferritin, urinary copper, caeuroplasmin, liver autoantibodies). Both patients’ had a normal amylase and deranged liver function tests; with marked rise in bilirubin of [100 lmol/l, and associated transaminitis. Both these patients had normal TPMT levels ([25 pmol/h/mg), hence neither were heterozygote or homozygote for TPMT deficiency. The Naranjo ADR probability scale was applied to these cases, which determined that hepatitis was probably due to the azathioprine in both cases (Naranjo probability score of 5 in each case). Following worsening of liver function tests, the azathioprine was stopped in both cases; this lead to a complete resolution of abnormal liver biochemistry over a period of 4 and 6 weeks, respectively. Upon reviewing the literature regarding azathioprine induced hepatitis, TPMT deficiency was not recognized in a number of cases [2–4]. To date fortunately there have not been any deaths related to azathioprine induced hepatitis. In all published cases, liver function tests improve upon cessation of azathioprine. Currently there is no test available to identify which patients will develop severe azathioprine associated hepatitis. Therefore, it is our practice to monitor all patients commencing on azathioprine and we have a shared care protocol with the general practitioners. This involves full blood counts, renal and liver function tests being checked at weeks 2, 4 and 6 weeks following commencement of azathioprine. We recommend a similar pathways exist for all other specialties commencing patients on azathioprine to enable early detection of this rare but serious adverse effect of azathioprine. With reference to the article by Salem et al. [1], it is important to note that acute azathioprine associated hepatitis occurs in patients with normal TPMT as well as those with TPMT deficiency. Secondly, frequent and regular blood tests at commencement of therapy currently are the only way to determine if a patient is developing an acute hepatitis. R. Srirajaskanthan (&) D. Valliani University Hospital Lewisham, London, UK e-mail: r.srirajaskanthan@nhs.net