Alves, Atecla N. L.

Chocair, Pedro R.

Duley, John A.

Fortini, Alexandre S.

Mendes, Maria E.

Nahas, William C.

Pacheco-Neto, Maurílio

Sumita, Nairo M.

Torres, Larissa H. L.

University of Queensland eSpace

39
RELATO DE CASO
A case report of azathioprine-induced recurrent acute pancreatitis 
associated with high levels of 6-thioguanine nucleotides in a 
renal transplant recipient
MAURÍLIO PACHECO-NETO1, ATECLA N. L. ALVES1, ALEXANDRE S. FORTINI1, NAIRO M. SUMITA1, MARIA E. MENDES1, LARISSA H. L. TORRES2, 
JOHN A. DULEY3, WILLIAM C. NAHAS4, PEDRO R. CHOCAIR4
1Hospital das Clínicas, Medical School, Universidade de São Paulo (HC-FMUSP), Central Laboratory Division, Laboratory of Medical Investigation 03, Department of Clinical Pathology, 
FMUSP, SP, Brazil
2Department of Toxicology, Pharmaceutical Sciences School, Universidade de São Paulo (USP), SP, Brazil 
3School of Pharmacy, University of Queensland, and Mater Medical Research Institute, Brisbane, Australia
4Renal Transplantation Unit, HC-FMUSP, SP, Brazil
Correspondence to: 
Pedro R. Chocair
Hospital Alemão Oswaldo Cruz
Diretoria Clínica
Rua João Julião, 331 – Paraíso
CEP: 01323-903
São Paulo, SP, Brazil
Phone/Fax: +55 (11) 3549-0000 
3287-8177
diretoriaclinica@haoc.com.br
Conflict of interest: None.
SUMMARY
Background: Myelotoxicity is the most common side effect associated with the use of azathioprine (AZA) 
in transplant recipients, while other side effects – rash, nausea, flu-like symptoms, diarrhea, hepatitis, and 
pancreatitis – are relatively rare. This is the first report of the evolution in a kidney transplant recipient 
of recurrent acute pancreatitis related to the use of AZA and high levels of 6-thioguanine nucleotide 
(6-TGN). Case report: A 57-year-old Brazilian male renal transplant patient remained stable for 30 years 
on a maintenance immunosuppressive regimen of AZA and prednisone. The patient experienced three 
episodes of mild acute pancreatitis in 2004, 2007 and 2008, and despite intensive investigation, AZA 
was not suspected as the causal agent of pancreatitis. In October 2008 the patient was found to have 
raised levels of erythrocyte 6-TGN, which resolved rapidly when AZA was interrupted. His maintenance 
immunosuppression regimen was subsequently changed to mycophenolate mofetil/ tacrolimus/ pred-
nisone. Discussion: Despite the classic pharmacogenetic model for thiopurines afforded by thiopurine 
methyltransferase (TPMT) and highly variable pharmacokinetics, AZA continues to be used empirically, 
i.e. mg/kg. In transplant recipients, AZA is usually employed as part of polytherapy, which complicates 
the elucidation of the cause of drug-related side effects. We propose that therapeutic drug monitoring 
of AZA metabolites is useful for differential diagnosis of the causes of drug-related side effects, such as 
acute pancreatitis.
Keywords: Azathioprine; renal transplant; pancreatitis; 6-TGN; immunosuppression.
©2012 Elsevier Editora Ltda. All rights reserved.
RESUMO
Relato de caso de pancreatite aguda recorrente induzida por  
azatioprina associada a altos níveis de nucleotídeos de 6-tioguanina 
em receptor de transplante renal
Introdução: A mielotoxicidade é o efeito colateral mais comum associado ao uso de azatioprina (AZA) 
em transplante, enquanto outros efeitos colaterais – erupção cutânea, náusea, sintomas semelhantes à 
gripe, diarreia, hepatite e pancreatite – são relativamente raros. Apresentamos um primeiro relato sobre 
a evolução de um receptor de transplante renal com pancreatite aguda recorrente relacionada ao uso 
de AZA e altos níveis de nucleotídeos de 6-tioguanina (6-TGN). Relato de caso: Paciente brasileiro, 57 
anos, sexo masculino, transplantado renal em condição estável durante 30 anos com regime imunos-
supressor de manutenção constituído de AZA e prednisona. O paciente apresentou três episódios de 
pancreatite aguda leve em 2004, 2007 e 2008, e apesar de intensa investigação, não houve suspeita da AZA 
como agente causal da pancreatite. Em outubro de 2008 foram encontrados níveis elevados de 6-TGN 
eritrocitária no paciente, o que se resolveu rapidamente quando a AZA foi interrompida. Seu regime 
de imunossupressão de manutenção foi posteriormente alterado para micofenolato mofetil/ tacrolimus/ 
prednisona. Discussão: Apesar do modelo farmacogenético clássico para tiopurinas, proporcionado pela 
tiopurina metilltransfansferase (TPMT) e farmacocinética altamente variável, a AZA continua a ser usa-
da de forma empírica, ou seja, em mg/kg. Para transplantes, AZA é normalmente usada em politerapias, o 
que dificulta a elucidação da causa de efeitos colaterais relacionados à terapia medicamentosa. Propomos 
que o monitoramento de drogas terapêuticas de metabólitos AZA é útil para o diagnóstico diferencial das 
causas de efeitos colaterais relacionados à droga, como pancreatite aguda.
Unitermos: Azatioprina; transplante renal; pancreatite; 6-TGN; imunossupressão.
©2012 Elsevier Editora Ltda. Todos os direitos reservados
MAURÍLIO PACHECO-NETO ET AL.
40 Rev Assoc Med Bras 2012; 58(Suppl 1):S39-41
INTRODUCTION
Azathioprine (AZA) is an immunosuppressant widely used 
to prevent rejection in organ transplant recipients and to 
treat auto-immune diseases such as inflammatory bowel dis-
ease, lupus, and auto-immune hepatitis. After uptake, AZA 
is rapidly converted by the action of glutathione to 6-mer-
captopurine, then undergoes extensive metabolism follow-
ing three different routes. The anabolic pathway of hypo-
xanthine phosphoribosyl transferase converts 6-MP to the 
active metabolite 6-thioguanine nucleotide (6-TGN), a pu-
rine analogue of GTP. Two pathways are catabolic: xanthine 
oxidase (XO) and thiopurine methyltransferase (TPMT); 
these are primarily responsible for the inactivation of thio-
purines, and the variability in their activity is responsible 
for either therapeutic ineffectiveness or increased toxicity1,2. 
Individuals with high TPMT activity may have low 6-TGN 
levels and poor clinical outcome, while patients with very 
low TPMT activity may have 6-TGN levels above therapeu-
tic levels and are more susceptible to myelotoxicity,  a major 
side effect associated with the use of AZA in transplantation, 
while side effects such as rash, nausea, flu-like symptoms, di-
arrhea, hepatitis, and pancreatitis are relatively uncommon.
Pancreatitis is more frequent in patients with inflamma-
tory bowel diseases3-5, but has also been reported in patients 
with other diseases6 and occasionally in renal transplant re-
cipients7. We describe here the evolution, in a kidney trans-
plant recipient, of recurrent acute pancreatitis related to the 
use of AZA and high levels of 6-TGN. According to our 
knowledge, this is the first report of recurrent acute pancre-
atitis simultaneously with high levels of 6-TGN.
CASE PRESENTATION
The patient was a 57-year-old Brazilian Caucasian man 
who underwent a renal transplant in 1978, and whose con-
dition had been stable on a maintenance immunosuppres-
sive regimen consisting of 150 mg of AZA (1.6 mg/kg) and 
5 mg of prednisone daily. He presented with an episode of 
mild acute pancreatitis in 2004 with moderate evolution 
that was not suspected of having AZA as the causal agent.
The patient continued on an uncomplicated course un-
til the beginning of 2007, when he presented with a new 
episode of acute pancreatitis, which was also mild. On that 
occasion, it was suspected that the pancreatitis was in-
duced by acitretin, a rare cause of pancreatitis, which was 
then withdrawn8. No other known factor was found de-
spite intensive investigation, and once again AZA was not 
suspected as the causal agent of pancreatitis. After AZA 
metabolite assays were performed in 2007 in São Paulo, a 
routine analysis in October 2008 found elevated levels of 
6-TGN and 6-MMP of 1,549 and 6,053 nmol/8x108 RBC, 
respectively. On that occasion, AZA was then suspected of 
being the cause of the two previous episodes of pancreati-
tis and its withdrawal was suggested.
In December 2008, before AZA withdrawal, the pa-
tient presented with a new episode of mild acute pancre-
atitis, with full and fast resolution. On that occasion AZA 
was interrupted. Two months later AZA was withdrawn, 
which was accompanied by a decrease in MCV and in-
crease in his leukocyte count (Figure 1). Investigations 
were again negative for other known causes of acute pan-
creatitis.
Figure 1 – Patient outcome showing pancreatitis episodes, 6-TGN and 6-MMP levels (nmol/8 ×108 RBC), MCV (fL) and 
leukocyte counts (× 1,000/mm3). Note changes after withdrawal of 150 mg/day of azathioprine.
150
100
50
110
117
114115
Acute
Pancreatitis
(2nd episode)
Acute
Pancreatitis
(3rd episode)
6-TNG: 1,549 pmol/8 × 108 RBC
6-MMP: 6,053 pmol/8 × 108 RBC
5.1 5.3 5.2 5.3
86
11.9
MCV
Leukocytes
12.4
81
Leokocytes (×1,000)
Azathioprine
(mg/day)
MCV (fL)
7
12
2
110
120
100
90
80
70
60
2008
J F M A A O N DSM
1.56 mg/kg
J J
2009
J F M A M
A CASE REPORT OF AZATHIOPRINE-INDUCED RECURRENT ACUTE PANCREATITIS ASSOCIATED WITH HIGH LEVELS OF 6-THIOGUANINE NUCLEOTIDES IN A RENAL TRANSPLANT RECIPIENT
41Rev Assoc Med Bras 2012; 58(Suppl 1):S39-41
Throughout this time, the patient maintained normal 
renal function with plasma creatinine ranging between 1.0 
and 1.5 mg/dL and unremarkable further biochemical and 
clinical parameters. His current maintenance immunosup-
pression regimen consists of 1,000 mg of mycophenolate 
mofetil, 2 mg of tacrolimus and 5 mg of prednisone daily. 
DISCUSSION
AZA has been used for almost 50 years in renal transplant 
recipients and despite that, its mechanism of action remains 
still poorly understood. Even today it is used empirically, i.e. 
mg/kg, even though the pharmacokinetics is demonstrably 
variable among individuals, without any correlation with 
body weight, but related to TPMT genetic status. This case 
provides the first description of the evolution of recurrent 
acute pancreatitis in a patient on standard dose AZA ac-
companied by high levels of 6-TGN.
AZA is used in the treatment of serious illnesses that 
often require polytherapy, a fact that complicates the eluci-
dation of the cause of drug-related side effects. In the case 
reported here, the only suspected cause of recurrent acute 
pancreatitis following extensive investigation was the ab-
normal result for 6-TGN, apparently disproportionate to 
the dose used - about 1.5 mg/kg daily for almost thirty years.
This report shows that therapeutic drug monitoring of 
AZA metabolites can be useful for differential diagnosis 
of the causes of side effects such as acute pancreatitis and 
other drug-related side effects, notwithstanding the use of 
weight-based dosage.
ACKNOWLEDGMENTS
This study was presented in part to the III International 
Thiopurine Symposium, held at the Instituto de Educação 
e Ciências, Hospital Alemão Oswaldo Cruz, São Paulo, 
September 30th – October 2nd, 2010.
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5. Paloyan D, Levin B, Simonowitz D. Azathioprine-associated acute 
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A case report of azathioprine-induced recurrent acute pancreatitis associated with high levels of 6-thioguanine nucleotides in a renal transplant recipient

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A case report of azathioprine-induced recurrent acute pancreatitis associated with high levels of 6-thioguanine nucleotides in a renal transplant recipient

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