Azathioprine induced liver cirrhosis: An unusual side effect

doi:10.4236/ojgas.2013.36050

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Open Journal of Gastroenterology, 2013, 3, 295-297 OJGas

http://dx.doi.org/10.4236/ojgas.2013.36050 Published Online October 2013 (http://www.scirp.org/journal/ojgas/)

Azathioprine induced liver cirrhosis:

An unusual side effect

Aida Ben Slama Trabelsi1*, Eya Hamami1, Mehdi Ksiaa1, Ahlem Souguir1, Mohamed Ben Mabrouk2,

Ahlem Brahem1, Ali Jmaa1, Salem Ajmi1

1Department of Gastroenterology, Sahloul Hospital, Sousse, Tunisia

2Department of S u rgery, Sahloul Hospital, Sousse, Tunisia

Email: *[email protected]

Received 14 August 2013; revised 21 September 2013; accepted 6 October 2013

License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

In recent years, the hepatotoxic potential of thiopuri-

nes, in particular 6-thioguanine (6-TG), has been dis-

cussed in literature. However, cirrhosis was excep-

tionally reported. We report the case of a 56-year-old

woman with ileocaecal Crohn’s disease treated with

azathioprine. After taking azathioprine (2 mg/kg dai-

ly) for four years, she underwent surgical treatment

for acute intestinal obstruction. In peroperative, we

noticed a cirrhotic liver. A surgical biopsy was per-

formed and the diagnosis of cirrhosis was confirmed.

Autoimmune and viral liver diseases were ruled out

by laboratory parameters. Therefore, Azathioprine is

believed to be the causative factor for inducing liver

cirrhosis. Thus, treating inflammatory bowel disease

effectively while trying to limit iatrogenic disease is a

continuo us struggle.

Keywords: Azathioprine; Crohn’s Disease;

Hepatotoxicity; Liver Cirrhosis

1. INTRODUCTION

Nowadays, thiopurines (azathioprine (AZA) and mercap-

topurine (6 MP)) are the most commonly used immuno-

modulatory drugs for managing patients with inflam-

matory bowel disease (IBD) [1]. They are among the

pharmacological agents with the greatest potential to

cause adverse reactions. The side-effects of thiopurines

can be divided into dose independent or “allergic/idiosy-

ncratic” and dose-dependent events. Hepatic toxicity is

believed to be a dose independent side effect of AZA.

In recent years, the hepatotoxic profile of thiopurines

has been recognised. Most hepatic lesions described are

vascular, such as peliosis hepatis, veno-occlusive disease,

perisinusoidal fibrosis, hepatoportal sclerosis, and no-

dular regenerative hyperplasia.

Even after long term treatment, most series report a

rate of hepatic abnormalities of between 1% - 3%, which

are usually limited to abnormal liver function tests and

minor changes seen on liver biopsy specimens. The

occurrence of side-effects, however, is a major drawback

in the use of AZA or MP [2]. Cirrhosis is an excep tional

complication of thiopurine drugs; only one case was

reported in literature [3].

We report a rare case of liver cirrhosis in a Crohn’s

disease patient associated with AZA therapy and we try

to do a review of the literature regarding this complica-

tion.

2. CASE REPORT

A 56-year-old woman was followed, for 20 years, for

ileocaecal Crohn disease complicated with stenosis. A

corticosteroid pulse therapy was administered to induce

remission. In 2000, a surgical treatment consisting of an

ileocaecal resection was performed due to an acute in-

testinal obstruction caused by the terminal ileum stenosis

(Figure 1). During surgery, liver was macroscopically

normal. In the post-operative, Budesonide therapy was

immediately initiated. The disease remained quiescent

and regular laboratory controls including serum transa-

minases were normal.

In 2006, the patient was treated with AZA in doses of

2 mg/kg/j. She remained free of endoscopic and clinical

recurrence until 2010 when she underwent reoperation

for adhesions bowel obstruction. She had a new resection

of the ileum. At laparotomy, the liver was macroscopi-

cally fibrosed. A surgical hepatic biopsy specimen was

taken for histological examination and confirmed liver

cirrhosis.

Liver function tests were normal. Viral liver diseases

*Corresponding a uthor.

OPEN ACCESS

A. B. S. Trabelsi et al. / Open Journal of Gastroenterology 3 (2013) 295-297

296

Figure 1. CT scan: stenosis of terminal ileum.

were ruled out by laboratory parameters. Autoimmune

diseases of the liver are also unlikely in the absence of

autoantibodies. Then, AZA therapy (4 years) was belie-

ved to be the causative factor of cirrhosis.

3. DISCUSSION

The thiopurine drugs such as AZA and 6-MP represent

an effective and widely used immunosuppressant in the

therapeutic armamentarium of IBD. They can induce and

maintain remission of Crohn’s disease and ulcerative

colitis, and have steroid-sparing effects in patients with

steroid-dependent IBD [4,5]. However, their therapeutic

role is disputable because of toxicity. Up to 25% of pa-

tients may be unable to continue the drug due to side

effects. The incidence of hepatotoxicity associated with

thiopurine use is reported between 0% and 32% [6].

Many of the symptoms of hepatotoxicity can be non-

specific and can be confused with a flare-up of inflam-

matory bowel disease. As well, the subtype resulting in

portal hypertension can occur without biochemical ab-

normalities.

Thiopurine-induced hepatotoxicity can be grouped in-

to three syndromes: hype rsensitivity, idiosyn cratic chole-

static reaction, and endothelial cell injury (with resultant

raised portal pressures, veno-occlusive disease, or pelio-

sis hepatis, perisinusoidal fibrosis and nodular regenera-

tive hyperplasia) [7 ].

AZA and 6-MP are metabolized into active and inac-

tive metabolites by the same enzymatic cascade. AZA is

a pro-drug that is converted to 6-MP via a nonenzymatic

metabolic pathway and its imid azole derivative by gluta-

thione in the liver. Th en, 6-MP enters cells and is subject

to 3 competing enzymatic pathways [8]. It may be ac-

tivated via a multi-step enzymatic pathway to produce

the active metabolites, the 6-thioguanine nucleotides (6-

TGNs). 6-MP is also metabolized by thiopurine methyl

transferase (TPMT) to 6-methylmercaptopurine (6-MMP)

or by xanthine oxidase to 6-t h i ou ri c acid.

Several metabolites have been h eld responsible for in-

duction of adverse events. Many studies have shown that

hepatotoxicity seems to be related to the accumulation of

methylated metabolites such as 6-MMP [3,9]. The enzy-

me TPMT is the key enzyme in the metabolic pathway:

patients with very high TPMT activity are resistant to

thiopurine drugs due to shunting of 6-MP away from 6

TGN towards over production of 6-MMP [9,10], and at

the risk of hepatotoxicity due to high 6-MMP concen-

trations [11-16].

In our case, high TPMT activity can not be the mecha-

nism of hepatotoxicity. Indeed, azathioprine was effec-

tive in maintaining remission in our patien t at a do se of 2

mg/kg/day.

The hypothesis that high 6-TGN levels are hepatotoxic

may provide an explanation why our patient developed

liver cirrhosis. The higher occurrence of histological

liver abnormalities during 6-thioguanine (6-TG) treat-

ment in comparison with AZA or 6-mercaptopurine (6-

MP) may be explained by the significantly higher levels

of 6-TGN reached by 6-TG [3].

This case illustrates the potential toxicity of AZA,

highlights the need to monitor liver function tests in pa-

tients treated with thiopurine, and identifies the need for

additional research focused on the mechanism of thio-

purine-induced hepatic injury in patients treated with

thiopurines for inflammatory bowel disease. Cirrhosis

may be an exceptional complication of thiopurine drugs.

Knowledge of such side effect could justify the routine

use of abdominal ultrasound in monitoring patients on

thiopurine as liver fu nction tests may be normal.

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LIST OF ABBREVIATIONS

AZA: azathioprine

6 MP: mercaptopurine

IBD: inflammatory bowel disease

6-TGNs: 6-thioguanine nucleotides

TPMT: thiopurine methyl transferase

6-MMP: 6-methylmercapt opurine

6TG: 6-thioguanine