azathioprine is a prodrug of the purine mimic antimetabolite , 6-mercaptopurine , widely used in various autoimmune diseases and organ transplantation .
little is known about the pathogenesis and epidemiology of azathioprine - induced cholestatic hepatitis , a rare but dramatic iatrogenic complication .
a 73-year - old man presented to the emergency department at a tertiary center in south india with fever , vomiting , pruritus , and dark urine for seven days . before six weeks
graft rejection was subsequently diagnosed and 15 days prior to the presentation , he was started on azathioprine 50 mg and prednisone 40 mg once daily .
past medical history revealed chronic bronchitis , essential hypertension , dyslipidemia , and left ventricular diastolic dysfunction for two years .
the patient was on aspirin , atorvastatin , losartan , hydrochlorothiazide , and inhaled salmeterol plus fluticasone , ipratropium and salbutamol medications for the past two years with no history of adverse drug events or allergies .
examination revealed temperature 100.4f , pulse rate 100/min , blood pressure 106/70 mm hg , and respiratory rate 20/min .
cholangitis , sepsis with cholestasis , acute hepatitis ( of viral , drug or autoimmune aetiology ) , and systemic febrile illnesses like malaria , leptospirosis , and scrub typhus were considered as differential diagnosis .
investigations revealed conjugated hyperbilirubinemia , elevated transaminases and alkaline phosphatase , prolonged prothrombin time , and bilirubinuria [ table 1 ] .
blood smears for plasmodium and complete blood counts were unremarkable except for mild eosinophilia ( 549 cell/l ) .
blood cultures , hepatitis b surface antigen ( hbsag ) and serology for hepatitis a , c and e , human immunodeficiency virus , scrub typhus , and leptospirosis were negative .
the patient was discharged after 72 hours of intravenous antibacterials . selected serial hematologic and biochemical parameters
thirty - five days later , he again presented with persisting low - grade fever , severe pruritus , and jaundice with pale stools . clinical examination and
worsening of hyperbilirubinemia , normalization of transaminases and prothrombin time , and improvement in alkaline phosphatase were observed [ table 1 ] .
anti - nuclear antibody ( ana ) and liver kidney microsomal ( lkm-1 ) antibody for autoimmune hepatitis and anti - mitochondrial antibody ( ama ) for primary biliary cirrhosis were negative .
percutaneous liver biopsy showed perivenular hepatocanalicular cholestasis with mild lobular inflammation [ figure 1 ] .
perivenular canalicular cholestasis : bile plugs within dilated canaliculi ( arrows ) 400- h&e symptomatic treatment for pruritus with ursodiol and hydroxyzine were started from day 35 .
an ophthalmology consultation was reassuring ; topical prednisone for the operated eye was started ( the patient had stopped prednisone after the first visit ) . by day 42 ,
follow - up at 4.5 and 7.5 months showed that the patient was asymptomatic with normal liver function tests ( lfts ) , except for alkaline phosphatase which showed a declining trend .
hepatotoxicity due to azathioprine encompasses a spectrum of syndromes including predominant cholestasis , hypersensitivity ( characterized by hepatocellular injury ) and peliosis hepatis ( reflecting endothelial cell injury ) .
hepatic idiosyncratic drug reactions are believed to be due to genetic polymorphisms in drug - metabolizing pathways , or due to immunologic mechanisms .
azathioprine - induced cholestatic hepatitis has been reported in various settings including renal and cardiac transplantation , wegener granulomatosis , systemic lupus erythematosus , and inflammatory bowel disease .
the latency from the initial exposure to azathioprine to the onset of jaundice ranges from two weeks to three months in previous reports .
one author reports shortening of the latent period on rechallenging with azathioprine , characteristic of hypersensitivity reactions .
although this was our patient 's first exposure to azathioprine , a short latency of seven days preceded jaundice and fever .
wide variation is also noted in the time for clinical and biochemical recovery following drug withdrawal .
our patient had peak bilirubin levels seven weeks after starting azathioprine ( five weeks after stopping it ) , and clinical resolution at four months , with gradual subsidence of alkaline phosphatase beyond seven months .
previous authors document shorter recovery periods ranging from two weeks to two months with one case that had abnormal alkaline phosphatase and gamma - glutamyl transpeptidase beyond four months after cessation of azathioprine .
our patient was not rechallenged because there are no guidelines on rechallenge in azathioprine - related cholestatic hepatitis ; the toxicity was severe , and alternative drugs were available .
the exclusion of other causes of hepatitis with cholestasis in our resource - limited setting was governed by clinical relevance .
epstein - barr virus has been reported to cause cholestatic hepatitis , but not prolonged cholestasis .
the temporal profile of fever concurrent with jaundice and the negative serology argue against viral hepatitis .
an elevated serum angiotensin - converting enzyme raised the possibility of sarcoidosis ; this enzyme is also elevated in cholestatic disorders .
the histological absence of granulomas and normal serum calcium levels and chest radiographs decreased the likelihood of sarcoidosis .
however , the patient had been taking this medication for two years and it was not stopped during the episode .
our report highlights a rare hepatic complication of azathioprine that has a wide range of latency , severity and duration , and is probably reversible .
recent guidelines on monitoring for azathioprine toxicity require weekly blood counts and lfts until a maintenance dose is achieved , thereafter reducing to a minimum of once every three months . we would also stress the need for patient education and regular clinical assessment .
rechallenge following an idiosyncratic hepatic reaction to azathioprine is usually unwarranted in the current era of multiple therapeutic alternatives for immunomodulation .
 we report a case of cholestatic hepatitis developed one week after exposure to azathioprine . 
 the subsequent prolonged cholestatic phase was followed by full clinical remission . 
 current knowledge on pathogenesis and epidemiology and the diagnostic challenges presented by this rare complication are discussed , followed by recommendations for monitoring and management . 
Introduction
Case Report
Discussion