Differences in the Adverse Effects of Azathioprine between Inflammatory Bowel Disease and Autoimmune Hepatitis in Korean Patients

Yoo Jin Lee; Wang Yong Choi; Kyung Sik Park; Yun Jung Kim; Kwang Bum Cho; Eun Soo Kim; Byoung Kuk Jang; Woo Jin Chung; Jae Seok Hwang

doi:10.4166/kjg.2014.64.6.348

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Lee, Choi, Park, Kim, Cho, Kim, Jang, Chung, and Hwang: Differences in the Adverse Effects of Azathioprine between Inflammatory Bowel Disease and Autoimmune Hepatitis in Korean Patients

Original Article

Korean J Gastroenterol 2014;64(6):348-355.

Published online: 4 October 2014

DOI: https://doi.org/10.4166/kjg.2014.64.6.348

Differences in the Adverse Effects of Azathioprine between Inflammatory Bowel Disease and Autoimmune Hepatitis in Korean Patients

Yoo Jin Lee^∗,, Wang Yong Choi^∗,, Kyung Sik Park, Yun Jung Kim, Kwang Bum Cho, Eun Soo Kim, Byoung Kuk Jang, Woo Jin Chung, Jae Seok Hwang

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea

Correspondence to: Kyung Sik Park, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keimyung University School of Medicine, 56 Dalseong-ro, Jung-gu, Daegu 700-712, Korea. Tel: +82-53-250-7088, Fax: +82-53-250-7442, E-mail: seenae99@dsmc.or.kr

^∗ These two authors have equally contributed to this work.

Received 12 May 20146 October 2014 Accepted 6 October 2014

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background/Aims

Azathioprine (AZA) has been widely used in the therapy of inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH). However, studies evaluating the adverse effects of AZA in these two diseases are lacking. The aim of this study was to compare the adverse effects of AZA in Korean IBD and AIH patients.

Methods

Patients with IBD or AIH who were treated with AZA at Keimyung University Dongsan Medical Center (Daegu, Korea) between January 2002 and March 2011 were enrolled. Their medical records were reviewed retrospectively in terms of clinical characteristics and adverse effects of AZA.

Results

A total of 139 IBD patients and 55 AIH patients were finally enrolled. Thirty IBD patients (21.6%) and eight AIH patients (14.5%) experienced adverse effects of AZA. In particular, the prevalence of leukopenia was significantly higher in the IBD group than in the AIH group (p=0.026). T474C mutation was observed in three of 10 patients who were assessed for thiopurine methyltransferase (TPMT) genotype.

Conclusions

IBD patients are at increased risk for the adverse effects of AZA compared with AIH patients, of which leukopenia was the most commonly observed. Therefore, IBD patients receiving AZA therapy should be carefully monitored.

Keywords: Azathioprine, Inflammatory bowel diseases, Hepatitis, autoimmune, Adverse effects

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Fig. 1.

Flow diagram of enrolled patients. AZA, azathioprine; IBD, inflammatory bowel disease; AIH, autoimmune hepatitis; 6-MP, 6-mercaptopurine; CD, Crohn's disease; UC, ulcerative colitis.

Fig. 2.

Electropherogram showing the alteration of a single nucleotide in the 7th exon. Genotyping of the 7th exon shows that three patients have two different alleles of thymine (T) and cytosine (C). This heterozygous T474C silent mutation was confirmed for TPMT∗1S. G, guanine; A, adenine.

Table 1.

Characteristics of the Studied Population Treated with Azathioprine

Characteristic	IBD (n=139 ^a)	AIH (n=55)	p-value
Age at diagnosed (yr)	32.23±14.74	49.34±15.39	0.001
	(19–80)	(18–78)
Sex			0.001
Male	89 (64.0)	12 (21.8)
Female	50 (36.0)	43 (78.2)
Duration of AZA treatment (mo)	23.0 (0–93)	24.57 (0–81)	0.186
Initial combination therapy with steroid	77 (55.4)	55 (100)	0.001
TPMT genotype ^b			1.000
TPMT∗1	3 (60.0)	4 (80.0)
TPMT∗1S	2 (40.0)	1 (20.0)

Values are presented as mean±SD (range), n (%), or median (range).

^a Crohn's disease=77, ulcerative colitis=62.

^b The results for patients whose samples were available for genotyping. Five patients in IBD and five patients in AIH were included in this analysis. Among patients with adverse effects, TPMT∗1S was found in one patient with IBD and one patient with AIH with no significant difference.

IBD, inflammatory bowel disease; AIH, autoimmune hepatitis; AZA, azathioprine.

Table 2.

Clinical Details of Patients Who Developed Adverse Effects of Azathioprine

Characteristic	IBD (n=30)	AIH (n=8)	p-value
Concomitant steroid therapy at the time of adverse effects occurrence	22 (73.3)	5 (62.5)	0.667
Interval of adverse effects occurrence after AZA initiation (mo)	7.16 (0–67)	6.11 (0–22)	0.548
Discontinuation of AZA	21 (70.0)	5 (62.5)	0.587
Require hospitalization	7 (23.3)	2 (25.0)	0.214

Values are presented as n (%) or median (range).

IBD, inflammatory bowel disease; AIH, autoimmune hepatitis; AZA, azathioprine.

Table 3.

Adverse Effects of Azathioprine by Disease

Variable	IBD (n=139)	AIH (n=55)	p-value
Total adverse effects ^a	30 (21.6)	8 (14.5)	0.266
Bone marrow suppression
Leukopenia	21 (15.1)	2 (3.6)	0.026
Anemia	6 (4.3)	2 (3.6)	1.000
Thrombocytopenia	2 (1.4)	3 (5.5)	0.141
Acute pancreatitis	3 (2.2)	0	0.564
Nausea/vomiting	4 (2.9)	1 (1.8)	1.000
Skin rash	1 (0.7)	1 (1.8)	0.488

Values are presented as n (%).

^a The number of patients who developed more than one adverse effect. Thirty seven adverse events occurred in 30 IBD patients.

Nine adverse events developed in eight AIH patients.

IBD, inflammatory bowel disease; AIH, autoimmune hepatitis.

Table 4.

Comparisons of Patients with IBD and AIH Who Developed Leukopenia While Taking AZA

Characteristic	IBD (n=21)	AIH (n=2)	p-value
Age (yr)	38.05±10.31	74.00±1.41	0.001
Sex			0.178
Male	13 (61.9)	0
Female	8 (38.1)	2 (100)
Initial combination therapy with steroid and AZA	11 (52.4)	2 (100)	0.486
Concomitant steroid therapy at the time of leukopenia occurrence	9 (42.9)	1 (50.0)	1.000
Concomitant mesalazine therapy at the time of leukopenia occurrence	16 (76.2)	0	0.083
Interval of leukopenia occurrence after	5.1 (0.12-24)	0.93 (0.23-1.63)	0.376
AZA initiationa ^a (mo)
Initial WBC count (/mm³)	6,541.90±2,498.02	5,785.00±2,340.52	0.685
Leukopenic WBC count (/mm³)	2,360.50±655.51	2,160.00±367.70	0.679
Required hospitalization	4 (19.0)	1 (50.0)	0.395

Values are presented as mean±SD, n (%), or median (range).

IBD, inflammatory bowel disease; AIH, autoimmune hepatitis; AZA, azathioprine; WBC, white blood cell.

Table 5.

Characteristics of Patients Who Were Admitted to Hospital due to Leukopenia

Case	Age (yr)/sex	Disease	Time to leukopenia (mo)	Clinical manifestation	Concomitant steroid therapy	Concomitant mesalazine therapy	Recover after discontinuation
1	20/male	IBD	1.13	Pneumonia	Yes	Yes	Yes
2	25/male	IBD	3.8	Fever and chills	Yes	Yes	Yes
3	36/male	IBD	3.51	Pneumonia	Yes	No	Yes
4	31/female	IBD	4.27	Fever and chills	Yes	Yes	Yes
5	51/female	AIH	0.83	Fever and chills	Yes	No	Yes

IBD, inflammatory bowel disease; AIH, autoimmune hepatitis.

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