CASE REPORT

Azathioprine Induced Liver Injury: A Case Report

Narendra S. Choudhary • Sachin Gupta •

Yogesh K. Chawla • Ajay Duseja •

Radha K. Dhiman • Ashim Das

Received: 9 October 2011 / Accepted: 5 January 2012 / Published online: 22 April 2012

� Springer Science+Business Media, LLC 2012

Keywords Azathioprine � Liver injury � Cholestasis

Introduction

Azathioprine is used commonly in clinical practice for

various autoimmune diseases. It is known to cause multiple

adverse effects including hepatotoxicity. Azathioprine-

induced liver injury is rare in clinical practice but can

manifest in several ways.

Here, we report a case of azathioprine-induced hepato-

toxicity manifesting as cholestatic jaundice.

Case Report

A 61-year-old obese male (BMI 32 kg/m2) had vesicular

lesions over arms and abdomen and was diagnosed as

subacute spongiotic dermatitis. He was started on azathi-

oprine at a dose of 50 mg twice a day. He developed

jaundice after 16 days of starting azathioprine therapy.

Liver function test revealed cholestatic type of liver injury

(Table 1). His hemogram and renal function tests were

normal. Work-up for hepatotrophic viruses, i.e. serologies

for A, B, C and E as well as HBV DNA and HCV RNA,

were negative. Markers for autoimmune liver disease were

negative. Liver biopsy revealed moderate canalicular and

intrahepatocytic cholestasis with maintained lobular archi-

tecture, portal tracts and bile ducts (Fig. 1). According to

RUCAM criteria (scoring system used for the diagnosis of

drug-induced liver injury), the score in this patient was 9,

which indicates highly probable/definite drug-induced

liver injury. The patient was managed conservatively

with cessation of azathioprine and supplemented with

ursodeoxycolic acid in a dose of 600 mg per day. He

showed significant improvement clinically as well as

biochemically.

Discussion

Azathioprine is a commonly used immunosuppressive

drug, mainly for patients of inflammatory bowel disease.

Drug-induced liver injuries (DILI) are difficult to diagnose;

RUCAM criteria are widely used for this purpose [1].

Recently, DILI has been defined as ALT C 5 times ele-

vation above upper limit of normal (ULN) or ALP eleva-

tion C2 times ULN or ALT C 3 ULN with simultaneous

elevation of bilirubin to C2 ULN. Clinical types of liver

injury are defined using an R value (R = ALT upper limit

of normal/ALP upper limit of normal); R C 5 signifies

hepatocellular injury while R B 2 signifies cholestatic

injury; R values in between 2 and 5 are suggestive of a

mixed type of liver injury [2]. Multiple mechanisms may

be related to azathioprine-related hepatotoxicity; these

include genetic predisposition (HLA association), elevated

thiopurine methyl transferase activity or oxidation of

azathioprine by xanthine oxidase (generation of reac-

tive oxygen species) [3]. Hepatotoxic manifestations of

azathioprine include destructive cholangitis, cholestatic

N. S. Choudhary � S. Gupta � Y. K. Chawla (&) � A. Duseja �R. K. Dhiman

Department of Hepatology, Post Graduate Institute

of Medical Education and Research, Chandigarh, India

e-mail: chawlayogesh@yahoo.co.in

A. Das

Department of Histopathology, Post Graduate Institute

of Medical Education and Research, Chandigarh, India

123

Dig Dis Sci (2012) 57:1717–1718

DOI 10.1007/s10620-012-2056-0

hepatitis, peliosis hepatitis, veno-occlusive disease of the

liver, perisinusoidal fibrosis and nodular regenerative

hyperplasia of the liver [4, 5]. Hepatocellular carcinoma

also has been reported with the use of azathioprine [6, 7].

Azathioprine-induced hepatotoxicity can be grouped into

three types: hypersensitivity, idiosyncratic cholestatic

reaction and endothelial cell injury (leading to portal

hypertension, veno-occlusive disease or peliosis hepatitis).

Few patients present with slightly elevated liver enzymes

that return to normal on follow up; in patients with marked

elevation of liver AST and ALT, the dose of azathioprine

can be reduced by 50% and can be increased later after

normalization of the liver function test. Hypersensitivity-

related hepatotoxicity occurs generally after 2–3 weeks

while it takes 3 months to 3 years for vascular pathology to

develop [8].

In a review, Gisbert et al. found mean prevalence of

about 3% for azathioprine-related liver injury in inflam-

matory bowel disease patients [8]. Bastida et al. followed

161 patients prospectively for a median of 271 days and

found abnormal liver function (ALT or ALP levels

were [50% the upper normal limit) in 13% and hepato-

toxicity in 10% of patients. Hepatotoxicity was detected

after a median of 85 days; acute hepatocellular hepatitis

occurred in 14 cases and acute cholestatic hepatitis in two

cases [9].

Conclusion

Azathioprine can produce various types of liver injuries,

most common being hepatocellular, cholestatic or mixed

type of liver injury. High degree of suspicion and early

dose reduction or cessation of drug is the cornerstone of

management.

References

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Table 1 Serial liver function test of patient

Parameter Date

19.09.2010 26.09.2010 23.10.10 30.11.2010 04.01.2011

Bilirubin (mg/dL; total/conjugated) 9.18/6.54 21.6/12 21.3/16.7 4.88/3.86 1.43/.8

AST (IU/L) 215 60 97 49 51

ALT (IU/L) 138 210 83 26 24

ALP (IU/L) 9 upper limit of normal 3 3 1 1

AST aspartate transaminase, ALT alanine transaminase, ALP alkaline phosphatase

Fig. 1 Liver biopsy reveals moderate canalicular and intrahepatocy-

tic cholestasis (arrows) with maintained lobular architecture, portal

tracts and bile ducts

1718 Dig Dis Sci (2012) 57:1717–1718

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