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
Received 14 August 2013; revised 21 September 2013; accepted 6 October 2013
Copyright © 2013 Aida Ben Slama Trabelsi et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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
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) . 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 . Cirrhosis is an excep tional
complication of thiopurine drugs; only one case was
reported in literature .
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-
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
Liver function tests were normal. Viral liver diseases
*Corresponding a uthor.
A. B. S. Trabelsi et al. / Open Journal of Gastroenterology 3 (2013) 295-297
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.
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% .
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-
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 . 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-
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
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 .
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.
 Podolsky, D.K. (2002) Inflammatory bowel disease. New
England Journal of Medicine, 347, 417-429.
 Markowitz, J., Grancher, K., Kohn, N. and Daum, F.
(2002) Immunomodulatory therapy for pediatric inflam-
matory bowel disease: Changing patterns of use, 1990-
2000. American Journal of Gastroenterology, 97, 928-
 Boer, N.K.H., Mulder, C.J.J. and van Bodegraven, A.A.
Copyright © 2013 SciRes. OPEN ACCESS
A. B. S. Trabelsi et al. / Open Journal of Gastroenterology 3 (2013) 295-297
Copyright © 2013 SciRes.
(2005) Myelotoxicity and hepatotoxicity during azathio-
prine therapy. Netherlands Journal of Medicine, 63, 444-
 Pearson, D.C., May, G.R., Fick, G.H. and Sutherland,
L.R. (1995) Azathioprine and 6- mercaptopurine in Croh n’s
disease. A meta-analysis. Annals of Internal Medicine,
 Fraser, A.G., Orchard, T.R. and Jewell, D.P. (2002) The
efficacy of aza thiopri ne for the trea tment of i nflamma tory
bowel disease: A 30 year review. Gut, 50, 485-489.
 Lowry, P.W., Franklin, C.L., Weaver, A.L., et al. (2001)
Measurement of thiopurine methyltransferase activity and
azathioprine metabolites in patients with inflammatory
bowel disease. Gut, 49, 665-670.
 Gisbert, J.P., González-Lama, Y. and Maté, J. (2007)
Thiopurine-induced liver injury in patients with inflame-
matory bowel disease: A systematic review. American
Journal of Gastroenterology, 102, 1518-1527.
 Macdonald, A. (2006) Omega-3 fatty acids as adjunctive
therapy in Crohns disease. Gastroenterology Nursing, 29,
 Cuffari, C., Dassopoulos, T., Turnbough, L., Thompson,
R.E. and Bayless, T.M. (2004) Thiopurine methyltrans-
ferase activity influences clinical response to azathioprine
in inflammatory bowel disease. Clinical Gastroenterol-
ogy and Hepatology, 2, 410-417.
 Kiefer, K. and El-Matary, W. (2009) 6 mercaptopurine as
an alternative to azathioprine in azathioprine-induced he-
patoxicity. Inflammatory Bowel Diseases, 15, 318-319.
 Boson, W.L., Romano-Silva, M.A., Correa, H., Falcao,
R.P., Teixeira-Vidigal, P.V. and De Marco, L. (2003)
Thiopurine methyltransferase polymorphisms in a Bra-
zilian population. Pharmacogenomics Journal, 3, 178-
 Dubinsky, M.C., Lamothe, S. and Yang, H.Y. (2000)
Pharmacogenomics and metabolite measurement for 6-
mercaptopurine therapy in inflammatory bowel disease.
Gastroenterology, 118, 705-713.
 Dubinsky, M.C., Yang, H. and Hassard, P.V. (2002)
6-MP metabolite profiles provide a biochemical explana-
tion for 6-MP resistance in patients with inflammatory
bowel disease. Gastroenterology, 122, 904-915.
 Hosni-Ahmed, A., Barnes, J.D., Wan, J. and Jones, T.S.
(2011) Thiopurine methyltransferase predicts the extent
of cytotoxicty and DNA damage in astroglial cells after
thioguanine exposure. PLoS One, 6, e29163.
 Coulthard, S. and Hogarth, L. (2005) The thiopurines: An
update. Investigational New Drugs, 23, 523-532.
 Gastal, G.R., Moreira, S., Noble, C.F., Ferreira, L.E.,
França, P.H. and Pinho, M. (2012) Toxicity of azathio-
prine: Why and when? Analysis of the prevalence of
polymorphism in Joinville, SC, Brazil. Arquivos de Gas-
troenterologia, 49, 130-134.
LIST OF ABBREVIATIONS
6 MP: mercaptopurine
IBD: inflammatory bowel disease
6-TGNs: 6-thioguanine nucleotides
TPMT: thiopurine methyl transferase
6-MMP: 6-methylmercapt opurine