Evaluation of factors associated with drug-induced liver injury using electronic medical records

Hyewon Chung; Hyungmi An; Jieon Lee; Jaeseong Oh; Kyung-Sang Yu; Jae-Yong Chung

doi:10.12793/tcp.2016.24.2.78

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Chung, An, Lee, Oh, Yu, and Chung: Evaluation of factors associated with drug-induced liver injury using electronic medical records

Original Article

Translational and Clinical Pharmacology 2016;24(2):78-83.

Published online: 15 June 2016

DOI: https://doi.org/10.12793/tcp.2016.24.2.78

Evaluation of factors associated with drug-induced liver injury using electronic medical records

Hyewon Chung¹, Hyungmi An¹, Jieon Lee¹, Jaeseong Oh¹, Kyung-Sang Yu¹, Jae-Yong Chung^2,^∗

¹Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul 03080, Korea

²Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam 13620, Korea

^∗Correspondence: J. Y. Chung; Tel: +82-31-787-3955, Fax: +82-31-787-4045, E-mail: jychung@snubh.org

Received 13 December 201525 April 2016 Accepted 30 April 2016

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

The causes and attributing factors of drug-induced liver injury (DILI) remain unclear as a result of exclusion-based diagnosis and low incidence. The aim of this study was to explore and evaluate potential drug-related causes and factors associated with DILI. Using electronic medical records (EMR) from the Seoul National University Bundang Hospital from 2003 to 2014, patients with DILI events were identified based on liver function test results. All patients with hepatic or biliary diseases were excluded. Patient characteristics, including demographics, clinical patterns, and severity of DILI were summarized and their associations were evaluated. Drugs frequently prescribed to patients exhibiting DILI within the month before their first DILI event compared to the total patient population were identified and the probabilities of hepatotoxicity associated with their use were assessed through examination of available reports. Among the 1,835 patients with laboratory test results, 1,023 were male and 1,053 were 65 years of age or older. Moderate DILI was dominant in older or male patients and cholestatic DILI tended to be more frequently identified in older patients of either sex. Cytarabine was the most frequently prescribed drug in DILI patients, followed by aprotinin and dopamine. Among the 30 most frequently prescribed drugs in DILI patients, 15 (50%) were identified as known hepatotoxic agents. In conclusion, this study evaluated differences in features of DILI among groups based on demographics and explored candidate drugs with possible associations with DILI, which has potential value reflecting real-world clinical practice.

Keywords: Drug-induced liver injury, Electronic medical record, Hepatotoxicity

References

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Figure 1.

Inclusion and exclusion criteria and number of study patients. (SNUBH, Seoul National University Bundang Hospital; EMR, electronic medical records; DILI, drug-induced liver injury; ALT, alanine aminotransferase; ALP, alkaline phosphatase)

Figure 2.

Frequencies of drug-induced liver injury (DILI) clinical pattern and severity by age group and sex (a, clinical pattern; b, severity; p-value from Cochran-Mantel-Haenszel test).

Table 1.

Study patient characteristics

	Classification	Number of patients (%)
Demographics		1,835
	Male	1,023 (55.8%)
	Age ≥65 years	1,053 (57.4%)
Clinical pattern of drug-induced liver injury		1,420
	Cholestatic	881 (62.0%)
	Hepatocellular	344 (23.2%)
	Mixed	195 (13.7%)
Severity of drug-induced liver injury		1,835
	Mild	1,588 (86.5%)
	Moderate	247 (13.5%)

Table 2.

The frequency of clinical patterns and severity of drug-induced liver injury by age group stratified by sex

	Male		Female
	Age < 65 years	Age ≥ 65 years	Age < 65 years	Age ≥ 65 years
Clinical pattern of DILI∗
Cholestatic	169 (35.6%)	306 (64.4%)	168 (41.4%)	238 (58.6%)
Hepatocellular	94 (46.5%)	108 (53.5%)	68 (47.9%)	74 (52.1%)
Mixed	60 (56.6%)	46 (43.4%)	47 (52.8%)	42 (47.2%)
DILI severity∗∗
Mild	363 (41.7%)	507 (58.3%)	333 (46.4%)	385 (53.6%)
Moderate	50 (32.7%)	103 (67.3%)	36 (38.3%)	58 (61.7%)

^∗ Significant association between age group and clinical pattern of drug-induced liver injury (DILI) after adjusting for sex (P < 0.0001, Cochran-Mantel-Haenszel test).

^∗∗ Significant association between age group and DILI severity after adjusting for sex (P = 0.0104, Cochran-Mantel-Haenszel test).

Table 3.

Top-30 drugs frequently prescribed to patients with drug-induced liver injury compared to the total population obtained from the electronic medical record database

Drug	ATC code^a	n^b	N^c	Prescription ratio (n/N)	Known hepatotoxicity^d
Cytarabine	L01BC01	13	549	0.0237	Y
Aprotinin	B02AB01	14	614	0.0228	N
Dopamine	C01CA04	181	12591	0.0144	N
Piperacillin and enzyme inhibitor	J01CR05	81	5917	0.0137	Y
Dobutamine	C01CA07	76	5929	0.0128	N
Suxamethonium	M03AB01	33	2621	0.0126	N
Norepinephrine	C01CA03	123	9809	0.0125	N
Amiodarone	C01BD01	44	3818	0.0115	Y
Etomidate	N01AX07	72	6312	0.0114	N
Vincristine	L01CA02	11	985	0.0112	Y
Imipenem and enzyme inhibitor	J01DH51	17	1671	0.0102	Y
Piperacillin	J01CA12	21	2078	0.0101	Y
Amikacin	J01GB06	46	4774	0.0096	N
Vancomycin	J01XA01	76	8061	0.0094	N
Milrinone	C01CE02	15	1679	0.0089	Y
Phytomenadione	B02BA01	77	9157	0.0084	Y
Insulin (human)	A10AB01	138	17719	0.0078	N
Nitroprusside	C02DD01	18	2314	0.0078	N
Hydralazine	C02DB02	16	2162	0.0074	Y
Furosemide	C03CA01	292	41265	0.0071	Y
Ornithine oxoglurate	A05BA06	12	1705	0.0070	unavailable
Aztreonam	J01DF01	19	2706	0.0070	Y
Vasopressin	H01BA01	43	6380	0.0067	Y
Dolasetron	A04AA04	11	1713	0.0064	Y
Meropenem	J01DH02	17	2661	0.0064	Y
Vecuronium	M03AC03	230	38146	0.0060	N
Phenylephrine	C01CA06	98	16434	0.0060	N
Tetracosactide	H01AA02	25	4210	0.0059	N
Methotrexate	L01BA01	20	3392	0.0059	Y
Captopril	C09AA01	31	5319	0.0058	Y

^a Anatomical therapeutic chemical code;

^b Number of patients who had been prescribed with the candidate drug in the drug-induced liver injury (DILI) population;

^c Number of patients who had been prescribed with the certain drug in the total population in electronic medical record;

^d Data based on Micromedex ®.

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