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A systematic survey evaluating 6-thioguanine-related hepatotoxicity in patients with inflammatory bowel disease

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Drug-induced liver injury was recently reported as a major complication leading to hepatic nodular regenerative hyperplasia (NRH) in patients with inflammatory bowel disease (IBD) and 6-thioguanine (6-TG) therapy. The aim of the study was to evaluate the prevalence of 6-TG-related hepatotoxicity in a large multi-centered IBD population by means of a systematic online survey. Clinical and laboratory data, imaging techniques (sonography, CT, MRI) and histology of liver biopsies were surveyed in IBD patients treated with 6-TG. The decision on whether liver imaging and/or liver biopsy were performed was exclusively at the discretion of the investigator. 6-TG use was fully documented in 296 patients (median treatment duration 56 weeks, range < 1-207). Laboratory signs of drug-induced liver injury were found in 43 patients (14.5%). Liver imaging revealed pathologic results in 68/176 patients (38.6%). Liver biopsy was performed in a subset of 60 patients; using silver-reticulin staining (n = 59), NRH was considered in 16 patients (27.1%). Age was the only independent, albeit weak, risk factor for development of NRH. This large online survey confirms the strong association between 6-TG treatment and the significant risk of development of NRH in patients with IBD. The definitive diagnosis of NRH depends solely upon liver biopsy.
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  Original Article
WIENER KLINISCHE
WOCHENSCHRIFT
The Middle European Journal
of Medicine
Printed in Austria
Wien Klin Wochenschr (2007) 119/17–18: 519–526
DOI 10.1007/s00508-007-0841-0
A systematic survey evaluating 6-thioguanine-related hepatotoxicity 
in patients with inflammatory bowel disease
Alexander Teml
1,2
, Matthias Schwab
2,3
, Daan W. Hommes
4
, Sven Almer
5
, Milan Lukas
6
, 
Thomas Feichtenschlager
7
, Timothy Florin
8
, Julia Seiderer
9
, Wolfgang Petritsch
10
, 
BerndBokemeyer
11
, Wolfgang Kreisel
12
, Klaus R.Herrlinger
13
, Peter Knoflach
14
, 
BrunoBonaz
15
, Thomas Klugmann
16
, Hans Herfarth
17
, Nikolaus Pedarnig
18
, 
andWalter Reinisch
1
1
Medical University of Vienna, Austria
2
Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology, Stuttgart, and University of Tübingen, Germany
3
Department of Clinical Pharmacology, University of Tübingen, Germany
4
Leiden University Medical Center, Leiden, The Netherlands
5
Division of Gastroenterology and Hepatology/IMK, Linköping university, Sweden
6
Charles University, Prague, Czech Republic
7
Krankenhaus Rudolfstiftung, Vienna, Austria
8
Mater Health Services’ Adult Hospital, South Brisbane, Australia
9
University-Hospital Munich-Großhadern, Munich, Germany
10
Medical University of Graz, Austria
11
Gastroenterologische Gemeinschaftspraxis Minden, Germany
12
Klinikum Freiburg, Germany
13
Robert Bosch Hospital, Stuttgart, Germany
14
Krankenhaus der Barmherzigen Schwestern, Wels, Austria
15
CHU de Grenoble, Grenoble Cedex, France
16
Internistische Gemeinschaftspraxis, Leipzig, Germany
17
University Regensburg, Germany
18
Unidata Geodesign, Vienna, Austria
Received February 28, 2007, accepted after revision June 5, 2007
© Springer-Verlag 2007
Eine systematische Studie zur Untersuchung der
6-Thioguanin-assoziierten Hepatotoxizität bei
Patienten mit chronisch-entzündlichen
Darmerkrankungen
Zusammenfassung.
Hintergrund: Vor kurzem wur-
de von Leberveränderungen im Sinne einer nodulär re-
generativen Hyperplasie (NRH) als Ausdruck einer 6-
Thioguanin (6-TG) assoziierten Hepatotoxizität bei Pati-
enten mit chronisch-entzündlichen Darmerkrankungen
(CED) berichtet.
Das Ziel dieser multi-zentrischen Internet-Studie war
es, die Prävalenz der Hepatotoxizität von 6-TG in einer
großen CED-Population zu untersuchen.
Methodik: Klinische Daten, Laborwerte, bildgebende
Untersuchungen (Sonographie, CT, MRI) und histolo-
gische Ergebnisse von Leberbiopsien wurden bei Pati-
enten mit CED unter Therapie mit 6-TG untersucht. Die
Entscheidung zur Durchführung von bildgebenden Unter-
suchungen und Leberbiopsien lag ausschließlich bei den
einzelnen Zentren.
Ergebnisse: Bei 296 Patienten wurde die Anwendung
von 6-TG über einen Zeitraum von 56 Wochen (Median,
Spannweite < 1–207) dokumentiert. Laborveränderungen
als Zeichen einer Hepatotoxizität wurden bei 43 Pati-
enten (14,5%) beobachtet. Mittels bildgebender Verfah-
ren wurden bei 68/176 Patienten (38,6%) pathologische
Ergebnisse gefunden. An 60 Patienten erfolgte eine Le-
berbiopsie. Mit Durchführung einer Silber-Retikulin Fär-
bung (n = 59) konnte bei 16 Patienten (27,1%) eine NRH
gezeigt werden. Höheres Alter war der einzige unabhän-
gige, aber schwache Risikofaktor dafür.
Schlussfolgerung: Diese derzeit größte Studie bestä-
tigt den starken Zusammenhang zwischen der Anwen-
dung von 6-TG bei Patienten mit CED und dem signifi-
kanten Risiko für die Entwicklung einer NRH. Die defini-
tive Diagnose der NRH kann nur durch eine Leberbiopsie
gestellt werden.
Summary.
Objective: Drug-induced liver injury was
recently reported as a major complication leading to he-
520 Teml et al., 6-thioguanine-related hepatotoxicity in inflammatory bowel disease
patic nodular regenerative hyperplasia (NRH) in patients
with inflammatory bowel disease (IBD) and 6-thioguanine
(6-TG) therapy.
The aim of the study was to evaluate the prevalence
of 6-TG-related hepatotoxicity in a large multi-centered
IBD population by means of a systematic online survey.
Methods: Clinical and laboratory data, imaging tech-
niques (sonography, CT, MRI) and histology of liver bi-
opsies were surveyed in IBD patients treated with 6-TG.
The decision on whether liver imaging and/or liver biopsy
were performed was exclusively at the discretion of the
investigator.
Results: 6-TG use was fully documented in 296 pa-
tients (median treatment duration 56 weeks, range < 1–
207). Laboratory signs of drug-induced liver injury were
found in 43 patients (14.5%). Liver imaging revealed
pathologic results in 68/176 patients (38.6%). Liver bi-
opsy was performed in a subset of 60 patients; using
silver-reticulin staining (n = 59), NRH was considered in
16 patients (27.1%). Age was the only independent, al-
beit weak, risk factor for development of NRH.
Conclusion: This large online survey confirms the
strong association between 6-TG treatment and the sig-
nificant risk of development of NRH in patients with IBD.
The definitive diagnosis of NRH depends solely upon
liver biopsy.
Key words: 6-thioguanine, drug-induced liver injury,
inflammatory bowel disease, nodular regenerative hyper-
plasia, thiopurines.
Introduction
The thiopurine 6-thioguanine (6-TG) has been used
in several malignant and non-malignant diseases since its
synthesis in the early 1950s. Nowadays, it is used in che-
motherapeutic regimens in childhood acute lymphoblastic
leukemia (ALL) [1] and in acute myeloid leukemia [2].
6-TG has also been used as a treatment alternative in
patients with refractory psoriasis [3] and in inflammatory
bowel diseases (IBD) intolerant or resistant to the stan-
dard thiopurines azathioprine (AZA) or 6-mercaptopurine
(6-MP) [4–13].
A potential association between 6-TG treatment and
drug-induced liver injury (DILI) was reported for the first
time by Griner et al. in 1976 [14] when describing two
patients with hepatic veno-occlusive disease (VOD), also
termed sinusoidal obstruction syndrome. Later, two case
reports and one single-center study including children
with ALL and 6-TG treatment confirmed such a relation-
ship [15–17]. Key et al. described DILI in patients with
chronic myeloid leukemia treated with a combination of
busulfan and 6-TG [18]: four of the five patients with
clinical signs of portal hypertension and esophageal vari-
ces revealed hepatic nodular regenerative hyperplasia
(NRH). In a systematic liver biopsy study, Dubinsky et
al. made the first report on an NRH prevalence of 61.5%
(16/26) in IBD patients treated with 6-TG [19]. A high
frequency of NRH was confirmed in two subsequent liver
biopsy studies of IBD patients receiving 6-TG treatment:
16/45 (35.6%) and 20/37 (54.1%) respectively [20, 21].
In contrast, a study from the Netherlands of 13 IBD pa-
tients with long-term, low-dose 6-TG treatment did not
find any NRH in liver biopsy samples [22]. Two recent
reports raised major concerns on the outcome of 6-TG-
related liver toxicity: Piel et al. described four patients
whose signs of hepatotoxicity did not recover after 6-TG
discontinuation during a follow-up period of 1.5–4.5 years
[23], and splenomegaly and thrombocytopenia as indirect
signs for portal hypertension worsened progressively in
six patients during a follow-up of 4 months to 3 years as
described by De Bruyne et al. [24].
The Los Angeles IBD working group recommended
periodic liver biopsies in all patients under treatment with
6-TG. Such treatment should be withdrawn in NRH-posi-
tive cases [21]. A European 6-TG Working Party con-
sented on 6-TG use in IBD only under strict predefined
criteria [25]. Nevertheless 6-TG is a major drug of choice
in several leukemia treatment protocols, including those
for use in children; for example, The German Co-opera-
tive Study Group COALL [1]. Since 6-TG-related hepa-
totoxicity is of major clinical relevance, we carried out a
systematic online survey to evaluate the prevalence of
NRH in a large-scale IBD population comprising 15 gas-
troenterology centers in Europe and Australia.
Patients and methods
Data management
Internet technology was used for data input and transfer,
and online questionnaires were programmed using Microsoft
Visual Basic.Net (Microsoft Corporation, Redmond, Washing-
ton, USA). Checkboxes and multiple-choice menus were used
for standardization and validation of data, and patients les
were automatically checked for contradictory or missing man-
datory data. The questionnaires were hosted on a web-server
of Unidata Geodesign (Pedarnig & Ortner Unidata Geodesign
OEG, Vienna, Austria). The final database was located on a
dedicated server. To protect data from unauthorized access, all
study investigators received an individual password and patient
data were entered anonymously.
Gastroenterologists from several countries known to have
used 6-TG in open clinical trials were invited to participate in
this survey. The participating centers committed to include all
their IBD patients ever treated with 6-TG, independent of
whether the patients were still under treatment or not. The in-
vestigators registered online and data were submitted between
August 2003 and December 2004.
Items of the questionnaire
Clinical descriptive data and pathologic changes in labora-
tory parameters including liver enzymes were surveyed, to-
gether with imaging techniques and histology of liver biopsies.
The clinical data consisted of demographics, previous immu-
nosuppression, indication for and duration of 6-TG treatment,
adverse drug reactions and concomitant medication. Observed
changes in laboratory data were graded 1–4 according the
recommendations of the World Health Organization (WHO)
for drug-related toxicity [26]. Only patients with a documented
WHO score were analyzed. Laboratory hepatotoxicity was de-
fined as elevation of alanine aminotransferase (ALAT), aspar-
tate aminotransferase (ASAT), alkaline phosphatase and/or
bilirubin > 1.25 times the upper limit of normal range.
Liver imaging techniques comprised abdominal sonogra-
phy, computed tomography (CT) and magnetic resonance im-
aging (MRI). The presence of liver pathologies was surveyed
521Teml et al., 6-thioguanine-related hepatotoxicity in inflammatory bowel disease
in general (‘any pathology’) and in particular (hepatic steatosis,
cirrhosis, regenerative nodules, hepatocellular carcinoma,
VOD, focal lesions, cholangiocellular carcinoma, peribiliary
cysts, confluent fibrosis or splenomegaly).
Liver biopsy results from the respective pathologist at each
center reflect both common hepatic pathology (e.g. adenoma,
carcinoma) and specific findings assessed using silver-reticulin
staining, a prerequisite for a definite histological diagnosis of
NRH. Nevertheless diagnosis of NRH on the basis of a single
needle biopsy of the liver might be difficult; for example, be-
cause of limited tissue material [27]. Thus in some cases in the
survey, NRH could not histologically be definitively excluded
and therefore we stratified liver biopsy reports into two groups:
‘NRH positive’ (unambiguous and most likely cases) and ‘non-
NRH’ (unlikely and definite exclusion of NRH). The decision
on whether laboratory examinations, liver imaging and/or liver
biopsy were performed was exclusively at the discretion of the
respective physician and was independent of the survey.
Data analysis and statistical analysis
After closure of the database, all records were reviewed
again for accuracy and comprehensiveness, in addition to the
automated validation of data. Where there was inconsistency,
the responsible investigator was contacted for further clarifica-
tion. Insufficient datasets were excluded from further analy-
sis.
Data were analyzed using the SPSS
®
software package
Release 11.0 (SPSS Inc., Chicago, Illinois, USA). Continuous
data are given as the median and the range.
Unpaired t-tests, the Mann-Whitney test, χ
2
analysis or
Fisher’s exact test were used where appropriate to assess dif-
ferences or proportions of data between the patient groups. A
paired t-test or the Wilcoxon test was used to test whether
variables in each patient at various time points differed sig-
nificantly. A multivariate model was used to analyze the rela-
tion between development of NRH and candidate covariates by
forward and backward stepwise logistic regression analysis
according to Wald. A P value of less than 0.05 was considered
statistically significant.
Results
A total of 304 patients were included in the 6-TG
online survey from 15 centers: six centers in Germany,
four in Austria and one each in The Netherlands, Sweden,
Czech Republic, France and Australia. Eight patients were
excluded because of incomplete documentation, thus the
final study population comprised 296 patients (median 15
patients/center; range 7–74) treated for 370 patient-years.
Baseline data are given in Table 1 and a flow chart show-
ing the progress of the patients throughout the study is
given in Fig. 1.
Previous treatments
AZA and/or 6-MP had been previously used for dis-
ease control in 277/296 patients (93.6%), of whom 70.2%
and 91.0%, respectively, were thiopurine intolerant. Be-
fore commencement of 6-TG, only 51/296 patients
(17.2%) received methotrexate treatment, and 16/296 pa-
tients (5.4%) were naïve for immunosuppressants. Steroid
dependence occurred in 156/296 patients (52.7%), steroid
refractoriness in 43/296 (14.5%), and 92/296 patients
(31.1%) had been treated with infliximab before 6-TG use
(median 3 infusions, range 1–25). Other immunosuppres-
sive therapy (mycophenolate mofetil, cyclosporine A, ta-
crolimus) was used less frequently (< 10%).
Treatment with 6-TG
Treatment with 6-TG was started between November
2001 and July 2004, mainly for the induction of remission
in chronic-active, AZA- or 6-MP-intolerant, steroid-de-
pendent or steroid-refractory IBD. The median duration
of 6-TG treatment was 56 weeks (range < 1–207) for all
patients included in the survey. In contrast, patients who
discontinued 6-TG use received the drug for a median of
only 12 weeks (Fig. 1). The median 6-TG dosage of 20 mg
in patients without discontinuation after a treatment pe-
riod of 93 weeks was significantly lower than the median
dosage at commencement of 6-TG therapy (40 mg,
P < 0.001).
Table 1.Demographic data
Sex no. (%)
Male
Female
118 (39.9)
178 (60.1)
Age (years) at start of 6-thioguanine
treatment median (range)
37 (16–82)
Diagnosis no. (%)
Crohn’s disease
Ulcerative colitis
Indeterminate colitis
1
239 (80.7)
48 (16.2)
9 (3.0)
Age (years) at disease onset median (range) 27 (7–65)
Crohn’s disease: location
2
no. (%)
Ileal
Colonic
Ileocolonic
Upper gastrointestinal tract
Unknown
32 (13.4)
52 (21.8)
131 (54.8)
23 (9.6)
1 (0.4)
Crohn’s disease: behavior
2
no. (%)
Non-stricturing, non-penetrating
Stricturing
Penetrating
Unknown
77 (32.2)
66 (27.6)
90 (37.7)
6 (2.5)
Ulcerative colitis: extent
3
no. (%)
Proctitis
Left-sided colitis
Extensive colitis
3 (6.3)
18 (37.5)
27 (56.3)
Previous intestinal resections no. (%)
Ever
N = 1
N = 2
N = 3
120 (40.5)
61 (20.6)
33 (11.1)
26 (8.8)
Smoking habits no. (%)
Smoker
Ex-smoker
Never-smoker
Unknown
96 (32.4)
49 (16.6)
111 (37.5)
40 (13.5)
Smokers: Number of cigarettes/day
median (range)
10 (2–60)
1
Subsuming indeterminate colitis and colonic IBD type unclas-
sified according to the Montreal classification.
2
According to
the Vienna classification.
3
According to the Montreal classifi-
cation.
522 Teml et al., 6-thioguanine-related hepatotoxicity in inflammatory bowel disease
The most frequent co-medication comprised steroids
in 171/296 patients (57.8%) for a median duration of
4 months (range < 1–34), followed by 5-aminosalicylates
(95/296, 32.1%), and infliximab (65/296, 22.0%; median
number of infusions 3, range 1–14).
Treatment outcome
Treatment with 6-TG was stopped in 161/296 patients
(54.4%), mainly because of adverse drug reactions
(71/161, 44.1%, Table 2), treatment failure (39/161,
24.2%), safety concerns expressed by the patients them-
selves and/or their physicians (35/161, 21.7%), or for
unknown reasons (16/161, 9.9%). Elevated liver enzymes
suggesting DILI were reported in 43/296 patients (14.5%)
leading to a 6-TG dosage reduction in 15 of these patients
and 6-TG withdrawal in seven. Of the 15 patients with
dose reduction, 6-TG was subsequently stopped in three
patients, laboratory changes were reversible in seven pa-
tients but irreversible during the observation period in
four patients, and in one patient the outcome was un-
known. Of the seven patients in whom treatment was
stopped, pathological laboratory values normalized in four
(57.1%) with 6-TG discontinuation after a median dura-
tion of 25 weeks (range 4–40), but in the remaining three
patients elevated liver enzymes failed to recover by the
end of the follow-up period of median 39 weeks (range
13–113).
Hematological toxicity was observed in 41/296 pa-
tients (13.9%), with leukopenia in 24, anemia in 15 and/or
thrombocytopenia in 13 patients. As a consequence, 6-TG
was discontinued in 14 of these 41 patients. Leukopenia
and/or anemia recovered in all cases with complete fol-
low-up (6/8), but thrombocytopenia was irreversible in
2/8 patients (25.0%) during follow-up periods of 106 and
107 weeks, respectively.
At least one adverse drug reaction (WHO grades 1–4)
was recorded in 137/296 patients (46.3%), whereas 142
patients (48.0%) did not have any side effects during 6-TG
treatment. In 17 patients (5.7%), exact assignment to a
WHO grade was not done. The type and frequency distri-
bution of 6-TG-related side effects in patients with 6-TG
withdrawal were substantially different when compared
with patients with adverse drug reactions and continuation
of 6-TG use (Table 2). For example, 6-TG therapy was
stopped in 18 of 31 patients (58.1%) with ‘pain’ (e.g.
abdominal pain, arthralgia) whereas infections’ (e.g. up-
per respiratory infection) possibly related to 6-TG therapy
did not result in 6-TG withdrawal in any patient (n = 36).
This may be explained by the fact that 91.7% of these
patients showed only mild-to-moderate infection accord-
ing to the WHO classification (grades 1 and 2).
Liver imaging
Liver imaging was performed in 176/296 patients
(59.5%): sonography in 149 patients (50.3%) 9 months
(median, range < 1–37) after 6-TG commencement, CT in
16 (5.4%) after 10 months (range 1–31) and MRI in 53
(17.9%) after 17 months (range 3–47). Forty patients re-
ceived more than one imaging examination: sonography
plus CT in five patients, sonography plus MRI in 31, CT
plus MRI in one and sonography plus CT plus MRI in
three. Liver pathology, mainly hepatic steatosis (76.5%)
and/or splenomegaly (20.6%), was diagnosed in 68 pa-
tients (38.6%). Signs of liver cirrhosis were identified in
two patients; this was subsequently confirmed histologi-
cally and/or clinically. Cirrhosis most probably arose as a
consequence of chronic alcohol abuse in one of these
patients the patient also had a hepatocellular carcinoma
(HCC) and as the result of chronic hepatitis B infection
in the other patient. MRI findings suggested liver fibrosis
and cirrhosis in two further patients; this was later diag-
nosed histologically as arising from unambiguous NRH.
Hepatic VOD was not diagnosed in any patient.
Liver biopsy
Overall, 60 liver biopsies were performed in six of
the 15 centers after a median treatment duration of 18
months (range < 1–32). Liver biopsy disclosed pathology
in 34/60 (56.7%) patients: acute hepatotoxicity in eight
(13.3%), chronic hepatotoxicity in 23 (38.3%) and an
adenoma in one patient. An HCC was revealed in one
patient, as mentioned above. In the 59 other patients, in
addition to standard histological procedure, silver-reticu-
lin staining was performed to ascertain the diagnosis of
Fig. 1.  Flow chart showing the progress of 6-thioguanine-treated patients throughout the study. The median treatment duration
in weeks is given with ranges in parentheses
523Teml et al., 6-thioguanine-related hepatotoxicity in inflammatory bowel disease
NRH and resulted in unambiguous NRH in six patients
(10.2%) and most likely NRH in 10 (16.9%). These pa-
tients received 6-TG for a median treatment duration of
118 weeks (range 21–169). NRH was unlikely in 15 of
the 59 patients (25.4%) and could be excluded in 28
(47.5%); the median 6-TG treatment duration was 103
weeks (range 12–163).
Risk factors for development of NRH
In univariate analysis, a patient’s age was the only
risk factor for development of NRH (P = 0.002, Table 3),
whereas disease duration, disease phenotype, indications
for 6-TG treatment (i.e. AZA intolerance vs. resistance),
sex and 6-TG duration were not significantly different
between the NRH-positive and non-NRH groups. The
multivariate analysis using a binary logistic regression
model confirmed patients’ age as the only independent but
weak risk factor for NRH (OR 1.10, 95% CI 1.03–1.17,
P = 0.005).
In an attempt to identify laboratory parameters for
prediction of NRH in the NRH-positive group, we esti-
mated the sensitivity, specificity, and positive and nega-
tive predictive values (PPV/NPV) for parameters discrim-
inating for hematological toxicity and/or hepatotoxicity.
The sensitivity was highest (68.8%) when combining
laboratory signs of hematological toxicity and hepatotox-
icity (Table 4).
Discussion
To the best of our knowledge, the present clinical
data, laboratory parameters, and data on liver imaging and
liver biopsies represent the largest IBD population treated
with 6-TG. Our surveillance data comprised 370 treat-
ment-years. We used a systematic online survey because
this reporting system presents a unique tool in clinical
research for acquiring data in a cost- and time-saving way
with the advantage of automated data validation and stan-
dardization [28, 29]. The participating centers were obli-
gated to include all IBD patients ever treated with 6-TG,
independently of whether the patients were still receiving
treatment or not at time of data collection. This was nec-
essary in order to minimize the risk that only patients
tolerant for 6-TG were systematically recorded and pa-
tients with discontinuation of 6-TG treatment before data
collection (August 2003) were under-represented.
In this study of patients with IBD we confirmed the
major relevance of 6-TG-related DILI and the high risk for
development of NRH. Unambiguous or most likely NRH
was diagnosed on the basis of histological examination in
27.1% of the 59 patients with liver biopsy and silver-re-
ticulin staining. Although the prevalence of NRH appeared
to be high in our survey, it was even higher in two studies
by the Los Angeles working group in IBD patients under
6-TG therapy (61.5% and 54.1%, respectively) [19, 21].
The reasons for this discrepancy are unknown. We can
Table  2.  Adverse drug reactions (ADR) graded according to the WHO classification with and without subsequent withdrawal
of 6-thioguanine treatment
Adverse drug reaction ADR with treatment withdrawal ADR without treatment withdrawal
Grade 1 Grade 2 Grade 3 Grade 4 Grade 1 Grade 2 Grade 3 Grade 4
Pain 4 6 8 0 7 6 0 0
Nausea/vomiting 7 5 0 0 16 11 0 0
Leukopenia 1 5 2 0 13 3 0 0
Thrombocytopenia 5 2 1 0 2 2 1 0
Hepatotoxicity
1
5 2 0 0 31 2 0 0
Headache 2 3 0 0 10 2 0 0
Anemia 1 1 0 1 5 6 1 0
Elevation of γ-GT 0 2 1 0 14 6 1 1
Diarrhea 0 1 1 1 0 2 0 0
Drug-induced fever 0 3 0 0 0 0 0 0
Cutaneous toxicity 2 0 0 0 15 1 0 0
Hair loss 2 0 0 0 7 0 0 0
Cardiac dysfunction 0 0 1 0 0 0 0 0
Pericarditis 0 1 0 0 0 0 0 0
Infection 0 0 0 0 30 3 3 0
Elevation of blood urea
nitrogen
0 0 0 0 2 0 0 0
Neurological toxicity 0 0 0 0 1 1 0 0
Hemorrhage 0 0 0 0 0 0 1 0
Stomatitis 0 0 0 0 1 0 0 0
Elevation of creatinine 0 0 0 0 0 1 0 0
Cardiac arrhythmias 0 0 0 0 1 0 0 0
Constipation 0 0 0 0 1 0 0 0
1
Hepatotoxicity: elevation of ALAT, ASAT, alkaline phosphatase or bilirubin; the highest grade of toxicity is given; γ-GT
γ-glutamyltransferase.
524 Teml et al., 6-thioguanine-related hepatotoxicity in inflammatory bowel disease
definitely exclude treatment duration as a major confound-
er since 6-TG was used for a median 18 months before
liver biopsy in our population, compared with only 8.5
months in the work by Dubinsky et al. [19]. Since the
diagnosis of NRH is difficult to establish through the use
of hematoxylin and eosin staining alone, silver-reticulin
staining was also used, as suggested by several authors
[21, 27]. Nevertheless, inter-observer disagreement be-
tween experienced pathologists may be a substantial limi-
tation in diagnosis of NRH, and we have recently shown
that pathological diagnosis of NRH differed even between
two experienced pathologists [20]. Moreover, because the
quality of biopsy samples may be limited in some cases,
ultimate histological exclusion of NRH might be difficult.
The use of different dosages of 6-TG in the European and
USA patient cohorts may also be important for the differ-
ent rates of NRH; for example, 6-TG was used in doses
up to 100 mg/day in one study in the USA [4], whereas the
median initiation dose was 40 mg/day in our patient group.
Unfortunately, detailed information with respect to daily
doses in the two USA liver biopsy studies is unavailable
[19, 21]. The assumption that 6-TG dosage relates to NRH
rates has been corroborated by the experiences of a Dutch
working group who found only slight hepatic regenerative
changes in 23% of IBD patients treated with low doses of
6-TG (median 20 mg) over a long-term duration of 39
months (range 30–53) [30, 31]. In addition, Gilissen et al.
did not find NRH in 13 IBD patients treated with long-
term, low-dose 6-TG (mean 0.28 mg/kg per day) [22].
The pathogenesis of 6-TG-associated NRH remains to
be elucidated. Some authors propose development of NRH
to be dependent on high levels of 6-TG nucleotides (6-
TGN), the active principle of thiopurine treatment [32, 33].
In general, red blood cells (RBC) of patients on 6-TG ac-
cumulate far higher levels of 6-TGN than for correspond-
ing doses of azathioprine/6-MP in both IBD and ALL pa-
tients [4, 6, 12, 34]. This may be due to the different
metabolic capacity of RBC to convert 6-MP and 6-TG into
6-TGN: these cells are able to directly metabolize 6-TG
into 6-TGN, but conversion of 6-MP to 6-TGN needs bio-
activation via the enzyme inosine 5’-monophosphate dehy-
drogenase (IMPDH) [35, 36]. The IMPDH activity in RBC
in a large number of patients with untreated ALL and in
healthy adult volunteers, although wide-ranging [37], was
low compared with IMPDH enzyme activity in white blood
cells. Thus, the higher 6-TGN levels in RBC after 6-TG
Table 4.  Sensitivity, specificity, and positive and negative predictive values (PPV, NPV) of laboratory parameters for diagnosis
of nodular regenerative hyperplasia
Parameter Sensitivity (%) Specificity (%) PPV (%) NPV (%)
Hepatotoxicity 56.3 74.4 45.0 82.1
Hematotoxity 43.8 86.0 53.8 80.4
Hepato- and/or hematotoxicity 68.8 65.1 42.3 84.8
Table  3. 
Demographic, clinical, laboratory and imaging data in patients with and without nodular regenerative hyperplasia
(NRH): only patients with liver biopsy and silver reticulin staining included
Parameter NRH-positive Non-NRH Probability
Female sex
Male sex
111/16 (68.8)
115/16 (31.3)
119/43 (44.2)
124/43 (55.8)
0.09
1
Age (years) median (range) 144 (28–73) 135 (19–57) 0.002
Disease duration (years) median (range) 110 (<1–34) 118 (1–24) 0.60
Azathioprine intolerance
Azathioprine resistance
112/16 (75.0)
114/16 (25.0)
126/39 (66.7)
113/39 (33.3)
0.75
2
Dose at the beginning (mg/d)
Dose at data entry (mg/d)
120 (20–60)
119 (6–40)
140 (10–60)
120 (6–40)
0.39
0.01
Therapy duration (wks) 118 (21–169) 103 (12–163) 0.37
Any pathology by
Any liver imaging
Sonography
Computed tomography
Magnetic resonance
113/15 (86.7)
111/12 (91.7)
110/2 (0)
115/13 (38.5)
120/39 (51.3)
116/27 (59.3)
112/2 (100.0)
115/23 (21.7)
0.02
0.06
0.33
0.44
Occurrence of
Any ADR
3
Any ADR
3
except hepato- or hematotoxicity
4
Hepatotoxicity
4
Hematotoxicity
4
Hepato- and/or hematotoxicity
4
112/16 (75.0)
118/16 (50.0)
119/16 (56.3)
117/16 (43.8)
111/16 (68.8)
121/43 (48.8)
112/43 (27.9)
111/43 (25.6)
116/43 (14.0)
115/43 (34.9)
0.07
0.11
0.03
0.03
0.02
1
Female versus male sex.
2
Azathioprine intolerance versus resistance.
3
Adverse drug reactions (ADR) with a toxicity grade 1.
4
Hepatotoxicity: elevation of ALAT, ASAT, alkaline phosphatase or bilirubin; hematotoxicity: toxicity in hemoglobin, leucocytes
or platelets.
525Teml et al., 6-thioguanine-related hepatotoxicity in inflammatory bowel disease
therapy, in comparison with 6-MP therapy, appear to be of
limited value in explaining an increased frequency of NRH
under 6-TG treatment [38]. Of note, high 6-TGN levels
have not been associated with development of NRH in IBD
patients treated with AZA [39] and vice versa [40].
In the multivariate analysis, patients’ age was identi-
fied as an independent but weak risk factor for develop-
ment of NRH in our population (Table 3). This observa-
tion is in line with a report by Wanless, who found a
higher prevalence of NRH in older patients in a general
population of 2500 autopsies [41]. The reason for this
relationship is unknown but, as one might assume, longer
disease duration in older patients was excluded as a con-
founding factor since there was no difference in disease
duration between patients with and without NRH. Male
sex was identified as a significant parameter in one series
[40], but we did not find this in our series where there was
a trend for more females. Differences between study pop-
ulations (children vs. adults) and underlying disease (ALL
vs. IBD) may be relevant.
The type of thiopurine therapy appears important.
NRH has also been observed in patients treated with AZA
but, compared with 6-TG, there appears to be a substan-
tially lower prevalence of AZA-related NRH [38]. In fact
NRH might be underestimated in IBD patients treated
with AZA because of missing systematic data [40], but in
principle it remains unclear whether IBD patients or a
subgroup are per se more susceptible for developing NRH,
and that 6-TG works only as a specific trigger. Notably,
NRH was recently reported in ALL patients treated with
6-TG, but only in single cases [23, 24], and 6-mercapto-
purine, used as cornerstone of long-term maintenance
treatment in ALL chemotherapeutic protocols over de-
cades, is not associated with hepatic NRH [23, 24].
Establishing the diagnosis of NRH is a major issue.
MRI has been systematically evaluated in the diagnosis of
NRH in our recent prospective clinical trial, with esti-
mates of 77% sensitivity, 72% specificity, 67% PPV and
81% NPV [20]. Separate evaluation of magnetic reso-
nance techniques could further improve these values [42].
In the present survey, various liver imaging techniques
were used to screen for liver pathology. Abdominal ultra-
sound was the main technique, revealing hepatic steatosis
and/or splenomegaly in 33.6% of cases. Interestingly,
86.7% of the patients with histologically-proven NRH had
pathology in at least one of the three imaging techniques.
Thus, imaging techniques may be helpful to suspect he-
patic NRH, but currently liver biopsy is the only appropri-
ate method for its diagnosis [27].
We analyzed abnormal hematological and/or hepato-
logical laboratory values as an additional screening param-
eter for identification of patients at risk of developing
NRH. Abnormal laboratory findings were observed in
68/296 (23.0%), which is in line with data of Dubinsky et
al. (26.1%) [19]. Nevertheless, although sensitivity (68.8%)
and specificity (65.1%) of laboratory changes in hepato-
logical and/or hematological parameters appeared promis-
ing in our study, the disappointing PPV of 42.3% limits
their clinical value as a surrogate marker for NRH.
A shortcoming of the present study is that patients’
history of hepatic diseases or hepatotoxicity before 6-TG
treatment was not documented and therefore the presence
of hepatic changes before treatment cannot be definitely
excluded, which could have led to overestimation of the
risk associated with 6-TG treatment.
Unfortunately, specific and sensitive serological
markers for identifying patients at risk of NRH are lack-
ing, and therefore liver biopsy is still required for the
definitive diagnosis of NRH. Accordingly, the European
consensus on 6-TG treatment of patients with IBD recom-
mends rigorous monitoring with regular liver biopsies
[25] at predefined intervals. Since 6-TG-related NRH ap-
pears not to be restricted to IBD only, there is an ultimate
need to identify underlying mechanisms.
Acknowledgements
This study was supported by Dr. Falk Pharma GmbH,
Freiburg, Germany. AT, MS and KRH were supported by the
Robert Bosch Foundation, Stuttgart, Germany.
The contribution of T. Ochsenkuehn (Munich) and X.
Roblin (Grenoble) to this work is highly acknowledged.
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Approximately 10% of inflammatory bowel disease (IBD) patients receiving 6-mercaptopurine (6-MP) or azathioprine (AZA) develop drug hypersensitivity reactions necessitating early discontinuation of these traditional thiopurines. These allergic reactions typically reoccur upon rechallenge. Our recently published pilot study suggested that thioguanine (6-TG), a closely related thiopurine, was efficacious and well tolerated in IBD patients resistant to 6-MP/AZA. The aim of this study was to determine if hypersensitivity reactions to 6-MP/AZA reoccur with 6-TG therapy.
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Background and AimsA substantial number of patients with inflammatory bowel disease (IBD) fail to achieve a complete clinical response with 6-mercaptopurine (6-MP) and azathioprine (AZA). Inability to achieve therapeutic 6-thioguanine nucleotide (6-TGN) levels due to the preferential overproduction of 6-methylmercaptopurine ribonucleotides (6-MMPR) upon dose escalation characterizes a newly described subgroup of IBD patients resistant to 6-MP/AZA therapy. Treatment with 6-thioguanine (6-TG), a related thiopurine, which forms 6-TGNs more directly may be beneficial in such patients. This pilot study evaluated the safety, tolerance, and efficacy of 6-TG in the subgroup of Crohn's disease (CD) patients failing to attain adequate disease control with traditional 6-MP/AZA therapy.Methods Ten CD patients with preferential 6-MMPR production upon 6-MP/AZA dose escalation were enrolled in an open-label pilot study. Seven of 10 patients had experienced dose-related 6-MP toxicities.ResultsSeventy percent of the patients (7 of 10) responded or were in remission at week 16. Clinical response was evident by week 4 in most. 6-TGN levels were nine-fold higher with 6-TG treatment than with 6-MP, whereas 6-MMPR levels were undetectable. No patient developed a recurrence of hepatic or hematological toxicity.Conclusions6-TG was a safer and more efficacious thiopurine in this subgroup of IBD patients resistant to 6-MP therapy. Larger controlled trials are warranted to further evaluate both the short-and long-term safety and efficacy in this subgroup of patients as well as a broader spectrum of IBD patients.
Article
Two adult male patients with acute leukemia developed a fatal Budd-Chiari-like illness while receiving 6-thioguanine. Both had previously received cytosine arabinoside. Antemortem and postmortem specimens of liver showed changes characteristic of toxic veno-occlusive disease. Similar findings have been described after ingestion of certain plant alkaloids and after treatment with arsphenamine, urethane, and ionizing radiation to the liver. We are unaware of any published reports of veno-occlusive disease of the liver after treatment with either 6-thioguanine or cytosine arabinoside. Although 6-thioguanine was most likely responsible for this syndrome, it is not possible to eliminate cytosine arabinoside as the causative agent. Since both drugs are occasionally used for benign conditions, physicians should be aware of this possible complication.
Article
Nodular regenerative hyperplasia is defined by he-patocellular nodules distributed throughout the liver in the absence of fibrous septa between the nodules. Most reports have been single cases so that the prevalencend clinical significance of nodular regenerative hyperplasia is uncertain. In this study, the hepatic histology of 2,500 consecutive autopsies was reviewed. A spectrum of nodular regenerative hyperplasia present in 2.6% of autopsy livers and qualitatively similar but lesser degrees of noduler transformation was found with nodular regenerative hyperplasia present in 2.6% of autopsy livers and qualitatively similar but lesser degrees of nodular transformation in a further 10.2%. Nodular transformation was also seen in 47% of livers with cirrhosis and 69% with portal veins was seen in all cases with nodlular regenerative byperplasal, but only 4.7% of these had evidence of portal hypertension. The prevalence of various clinical states was compared in nodular regenerative hyperplasia and in controls. The reslults confirm, extend and quantify the spectrum of associated diseases. Nodular regenerative hyperplasia occurs in 5. 6% of individuals over age 80 and with increased frequency in patients with arteritis, polymyalgia rheumatica, massive tumor infiltration and mineral oil deposition. Nodular tumor infiltrtion and mineral oil deposition. Noduler regenerative hyperplasia appears to be the hepatic analogue of arterial and arteriolar nephrosclerosis. A new classification of nodular transformation is proposed that encompasses the specturm of lessions described here and the previously defined entities of focal nodular hyperplasia, parial nodular transformation and “cirrhosis telangiectasia hepatis.” The major conclusion is that nodular regenerative yperplasia is a secendary and nonspecific tissue adaptation to tation to heterogeneous distribution of blood flow and does not represent a specific entity.(HEPATOLOGY 1990; 11:787-797.)