Joumal o3' Hepatology 1995, 23 351 354 Copwlght©Jomnalof Hepatologv 1995 Printed m Denmark All rtghts reserved Journal of Hepatology ISSN 0168-8278 Case Report Azathioprine-induced myelosuppression due to thiopurine methyltransferase deficiency in a patient with autoimmune hepatitis Ziv Ben Ari, Atul Mehta l, Lynne Lennard 2 and Andrew K. Burroughs Ltvet Tl ansplantatton Untt and Hepato-bthary Medteme, 1Department of Haematology, The Royal Free Hospital, Hampstead, London and 2Untve~stty Department of Medtcme and Pharmacology, The Royal Hallamshwe Hospttal, Sheffield, UK Azathioprine can cause severe myelosuppression. The inherited activity of the enzyme thiopurine methyl- transferase has been recently recognised as a major factor in the susceptibility to myelosuppression. Thi- opurine methyltransferase deficiency occurs at a fre- quency of one in 300 and is associated with profound myelosuppression after a short course of azathioprine. Very low thiopurine methyltransferase activity repre- sents the TPMTL/TPMTL genotype, and can be de- tected before therapy with azathioprine is started. We describe the first documented case of azathio- prine-induced severe myelosuppression due to thiopur- ine methyltransferase deficiency in autoimmune liver disease. The azathioprine dose was low (1 mg/kg) and pancytopenia occurred after 56 days therapy. It would be advisable to measure thiopurine methyltransferase activity before patients with autoimmune hepatitis are exposed to azathioprine. Key words: Autoimmune hepatitis; Azathioprine; My- elosuppression; Thiopurine methyltransferase. © Journal of Hepatoiogy. A ZATHIOPRINE1S the mare cytotoxic agent used for ~mmunosuppression in autoimmune diseases and is widely used to control allograft rejectaon in trans- plant surgery (1 4). Azathloprme-lnduced haematol- ogical toxicity includes macrocytosis (5), anaemia (6), thrombocytopenia (7), leucopenia (8) and pancyto- penia. Leucopenia is the most common adverse haem- atological effect, with an incidence of 5% (9) to 25% (1). There are many pubhshed reports of marrow apla- sla or severe pancytopenla associated with azathio- prlne (10-14). The severity of myelosuppresslon is vari- able, and until recently it was not clear if this was an idiosyncratic or a dose-dependent effect of azathio- prme. Only in recent years has it become clear that the susceptibility to profound myelosuppresslon is par- tially genetically based due to thlopurine methyltrans- ferase (TPMT) deficiency (15,16). Inherited as a gen- etic trait, TPMT deficiency occurs in 1 in 300 individ- uals, 11% of the population inherit an intermediate Recetved 20 DecembeJ 1994, revised 8 Match, accepted 22 Match 1995 Correspondence. Dr. A. K. Burroughs, Hepato-biliary and Liver Transplantatmn Unit, University Department of Medicine, The Royal Free Hospital, Hampstead, Lon- don NW3 2QG UK. level of activity, whilst 89% of subjects have high activ- ity of this enzyme (16). We describe the first documented case of azathlo- wine-induced myelosuppression due to TPMT de- ficiency in autoimmune liver disease. The indication for azathioprine therapy was failure to maintain remission with prednisolone. Case Report In 1986, a 43-year-old Caucasian architect was noted to have a raised gamma glutamyltranspeptidase (GGT) level during a medical check up. This was recorded again in 1988 with slightly raised alkaline phosphatase (ALP) and aspartate transaminase (AST) levels. They were still abnormal in Aprd 1990, and he was referred to our unit for further investigation. The patient was asymptomatic. He had had an episode of hepatitis A in 1970. He drank occasionally and was overweight (103 kg). He also had a 2-cm hepatomegaly. No other stigmata of chronic liver disease were observed. Blood tests showed: AST 66 u/1 (5-40), bilirubin 7 ltmol/1 (7-17), ALP 307 u/1 (<130), GGT 468 u/1 (5- 48), albumin 40 g/1 (35-50), haemoglobin 14.0 g/dl (13.5-17.5), white blood cell count 6.6× 109/1 (4.5-11), platelets 233×109/1 (140-400), prothrombin time 13 s 351