Univariate analysis of risk factors for chronic DILI
Variable
Recovered
(n = 236)
Chronicity
(n = 61)
P value
Gender [n (%)]
Male
91 (38.6)
24 (39.3)
0.911
Female
145 (61.4)
37 (60.7)
Age [M (IQR)]
55 (43–65)
59 (51–65)
0.026
Clinical classification
Hepatocellular
156 (66.1)
15 (24.6)
< 0.001
Cholestatic
10 (4.2)
8 (13.1)
Mixed type
14 (5.9)
3 (4.9)
Abnormal liver biochemical examinations
56 (23.7)
35 (57.4)
Latency (days)
< 5
12 (5.1)
2 (3.3)
0.731
5–90
185 (78.4)
47 (77.0)
> 90
39 (16.5)
12 (19.7)
Comorbidities [n (%)]
Hypertension
Yes
62 (26.3)
20 (32.8)
0.310
No
174 (73.7)
41 (67.2)
Diabetes
Yes
14 (5.9)
3 (4.9)
0.761
No
222 (94.1)
58 (95.1)
Coronary heart disease
Yes
14 (5.9)
7 (11.5)
0.220
No
222 (94.1)
54 (88.5)
Gallbladder lesion
Yes
84 (35.6)
16 (26.2)
0.168
No
152 (64.4)
45 (73.8)
Fatty liver
Yes
52 (22.0)
21 (34.4)
0.045
No
184 (78.0)
40 (65.6)
Chronic hepatitis B
Yes
13 (5.5)
1 (1.6)
0.351
No
223 (94.5)
60 (98.4)
Malignant tumor
Yes
76 (32.2)
38 (62.3)
< 0.001
No
160 (67.8)
23 (37.7)
ANA
Negative
142 (60.2)
38 (62.3)
0.503
1:100
65 (27.5)
13 (21.3)
≥ 1:320
29 (12.3)
10 (16.4)
Drug categories [n (%)]
CM
121 (51.3)
19 (31.1)
0.005
Antimicrobial
8 (3.4)
1 (1.6)
0.770
NSAIDs
12 (5.1)
1 (1.6)
0.411
Anti-tumor
53 (22.5)
35 (57.4)
< 0.001
Anti-tuberculosis
5 (2.1)
0 (0.0)
0.587
Cardiovascular
5 (2.1)
1 (1.6)
0.813
CM-WM
21 (8.9)
3 (4.9)
0.451
Others
11 (4.7)
1 (1.6)
0.482
Therapeutic drugs [n (%)]
Single
19 (8.1)
10 (16.4)
0.094
Two drugs
42 (17.8)
13 (21.3)
Three drugs or more
175 (74.2)
38 (62.3)
Glucocorticoids [n (%)]
Yes
84 (35.6)
16 (26.2)
0.168
No
152 (64.4)
45 (73.8)
T0.5TBIL (day) [M (IQR)]
6 (0–12)
0 (0–13)
0.186
T0.5ALT (day) [M (IQR)]
8 (5–14)
20 (8–62)
< 0.001
T0.5AST (day) [M (IQR)]
7 (4–12)
19 (8–76)
< 0.001
T0.5ALP (day) [M (IQR)]
7 (0–15)
7 (0–30)
0.288
T0.5GGT (day) [M (IQR)]
15 (8–27)
30 (10–75)
0.001
M (IQR): median (interquartile range); n (%): number of cases (percentage); T0.5TBIL, T0.5ALT, T0.5AST, T0.5ALP, T0.5GGT: time when TBIL, ALT, AST, ALP, and GGT decrease from peak to below 50%, respectively
Declarations
Author contributions
QW: Data curation, Investigation, Methodology, and Writing—original draft. LL: Methodology and Writing—review & editing. XZ and JY: Data curation, Writing—original draft, and Writing—review & editing. JG: Methodology, Writing—original draft and Writing—review & editing. All authors read and approved the submitted version.
Conflicts of interest
The authors declare that they have no conflicts of interest.
Ethical approval
The study was approved by the ethical committee of Zhongshan Hospital affiliated to Fudan University, Shanghai, China. The study protocol conformed to the provisions of the Declaration of Helsinki.
Consent to participate
Informed consent to participate in the study was obtained from all participants.
Consent to publication
Informed consent to publication was obtained from relevant participants.
Availability of data and materials
All the citations and data included in this manuscript are available upon request by contact with the corresponding author.
Funding
This work was funded by the National Fund of Nature Science of P.R. China [91129705, 81070340] and Shanghai Pujiang Talent Program [09PJ1402600]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases. LiverTox: clinical and research information on drug-induced liver injury [Internet]. [cited 2023 May 18]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK547852/
Ostapowicz G, Fontana RJ, Schiødt FV, Larson A, Davern TJ, Han SHB, et al.; U. S. Acute Liver Failure Study Group. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States.Ann Intern Med. 2002;137:947–54. [DOI] [PubMed]
Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study.Hepatology. 2010;52:2065–76. [DOI] [PubMed] [PMC]
Wei G, Bergquist A, Broomé U, Lindgren S, Wallerstedt S, Almer S, et al. Acute liver failure in Sweden: etiology and outcome.J Intern Med. 2007;262:393–401. [DOI] [PubMed]
Björnsson E, Jerlstad P, Bergqvist A, Olsson R. Fulminant drug-induced hepatic failure leading to death or liver transplantation in Sweden.Scand J Gastroenterol. 2005;40:1095–101. [DOI] [PubMed]
Ohmori S, Shiraki K, Inoue H, Okano H, Yamanaka T, Deguchi M, et al. Clinical characteristics and prognostic indicators of drug-induced fulminant hepatic failure.Hepatogastroenterology. 2003;50:1531–4. [PubMed]
Jiménez-Pérez M, González-Grande R, García-Cortés M, Andrade RJ. Drug-induced liver injury after liver transplantation.Liver Transpl. 2020;26:1167–76. [DOI] [PubMed]
Sgro C, Clinard F, Ouazir K, Chanay H, Allard C, Guilleminet C, et al. Incidence of drug-induced hepatic injuries: a French population-based study.Hepatology. 2002;36:451–5. [DOI] [PubMed]
Shen T, Liu Y, Shang J, Xie Q, Li J, Yan M, et al. Incidence and etiology of drug-induced liver injury in mainland China.Gastroenterology. 2019;156:2230–41.e11. [DOI] [PubMed]
Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug induced liver injury in the United States.Liver Transpl. 2004;10:1018–23. [DOI] [PubMed]
European Association for the Study of the Liver; Clinical Practice Guideline Panel: Chair:; Panel members; EASL Governing Board representative:. EASL Clinical Practice Guidelines: drug-induced liver injury.J Hepatol. 2019;70:1222–61. [DOI] [PubMed]
Danan G, Benichou C. Causality assessment of adverse reactions to drugs—I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries.J Clin Epidemiol. 1993;46:1323–30. [DOI] [PubMed]
Benichou C, Danan G, Flahault A. Causality assessment of adverse reactions to drugs—II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge.J Clin Epidemiol. 1993;46:1331–6. [DOI] [PubMed]
Chalasani NP, Maddur H, Russo MW, Wong RJ, Reddy KR; Practice Parameters Committee of the American College of Gastroenterology. ACG Clinical Guideline: diagnosis and management of idiosyncratic drug-induced liver injury.Am J Gastroenterol. 2021;116:878–98. [DOI] [PubMed]
Yu YC, Mao YM, Chen CW, Chen JJ, Chen J, Cong WM, et al.; Drug-induced Liver Injury (DILI) Study Group; Chinese Society of Hepatology (CSH); Chinese Medical Association (CMA). CSH guidelines for the diagnosis and treatment of drug-induced liver injury.Hepatol Int. 2017;11:221–41. [DOI] [PubMed] [PMC]
Ma Z, Zhao JR, Dong RR, Cui Y, Wang M, Zhu Y. Hepatotoxicity study of extracts and main components in Polygonum multijiorum using high content analysis.Chin Tradit Herb Drugs. 2016;47:4021–9. Chinese.
Zhang YN, Huang YY, Bao ZY, Huang W, Sun R. Experimental study on the “dosage-time-toxicity” relationship of acute hepatotoxicity induced by percolation liquid of acid from Rhizoma Pinelliae in mice.Chin J Pharmacovigilance. 2011;8:15–9. Chinese.
Yu HL, Zhao TF, Wu H, Pan YZ, Zhang Q, Wang KL, et al. Pinellia ternata lectin exerts a pro-inflammatory effect on macrophages by inducing the release of pro-inflammatory cytokines, the activation of the nuclear factor-κB signaling pathway and the overproduction of reactive oxygen species.Int J Mol Med. 2015;36:1127–35. [DOI] [PubMed]
Liu Q, Guo YL, Dong TW, Gao F, Li M, Ou L, et al. Research progress on hepatotoxicity mechanism and attenuation methods of Psoraleae Fructus.Chin J Exp Tradit Med Formulae. 2021;27:233–9. Chinese.
Yao Y, Jia YJ, Deng RF, Xie HX, Li XJ, Kong FM. Based on the hepatotoxicity of rhubarb to explore its rational clinical application.Chin J Surg Integr Tradit West Med. 2020;26:1180–3. Chinese.
Hu DH, Wang YG, Chen ZW, Ma ZC, Liang QD, Xiao CY, et al. Effect of compound danshen dripping pills on rat hepatic cytochrome P450.Chin J Pharmacol Toxicol. 2013;27:678–84. Chinese.
Huang W, Lv Z, Sun R. Research development on chemincal compositions in Bupleurum Chinense related with efficacy and toxicity.Chin J Pharmacovigilance. 2013;10:545–8. Chinese.
Li XY, Sun R. Experimental study on the “dose-time-toxicity” relationship of hepatotoxicity induced by different components from Herba Menthae in mice.Chin J Pharmacovigilance. 2012;9:129–33. Chinese.
Lin G, Wang JY, Li N, Li M, Gao H, Ji Y, et al. Hepatic sinusoidal obstruction syndrome associated with consumption of Gynura segetum.J Hepatol. 2011;54:666–73. [PubMed]
Chen XQ, Yu WN, Ma ZC, Long ZH. Observation of acute toxic effects of six kinds of Chinese herbal extracts including Alisma orientalis and Pueraria lobata.Zhejiang J Tradit Chin Med. 2011;46:848–9. Chinese.
Guo JP, Sun QR. General situation of research on chemical constituents and clinical application of Pueraria lobata.J Pharm Pract. 1996;3:146–8.
Huang ZY, Zhao YT, Li Y. Progress of Pueraria lobata in pharmacological effect and clinical application.Guangming J Chin Med. 2007;22:63–7. Chinese.
Navarro VJ, Barnhart H, Bonkovsky HL, Davern T, Fontana RJ, Grant L, et al. Liver injury from herbals and dietary supplements in the U.S. Drug-Induced Liver Injury Network.Hepatology. 2014;60:1399–408. [DOI] [PubMed] [PMC]
Andrade RJ, Medina-Caliz I, Gonzalez-Jimenez A, Garcia-Cortes M, Lucena MI. Hepatic damage by natural remedies.Semin Liver Dis. 2018;38:21–40. [DOI] [PubMed]
Andrade RJ, Lucena MI, Fernández MC, Pelaez G, Pachkoria K, García-Ruiz E, et al.; Spanish Group for the Study of Drug-Induced Liver Disease. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period.Gastroenterology. 2005;129:512–21.Erratum in: Gastroenterology. 2005;129:1808. [DOI] [PubMed]
Lucena MI, Andrade RJ, Kaplowitz N, García-Cortes M, Fernández MC, Romero-Gomez M, et al.; Spanish Group for the Study of Drug-Induced Liver Disease. Phenotypic characterization of idiosyncratic drug-induced liver injury: the influence of age and sex.Hepatology. 2009;49:2001–9. [DOI] [PubMed]
Grewal P, Ahmad J. Severe liver injury due to herbal and dietary supplements and the role of liver transplantation.World J Gastroenterol. 2019;25:6704–12. [DOI] [PubMed] [PMC]
Suk KT, Kim DJ, Kim CH, Park SH, Yoon JH, Kim YS, et al. A prospective nationwide study of drug-induced liver injury in Korea.Am J Gastroenterol. 2012;107:1380–7. [DOI] [PubMed]
Wai CT. Presentation of drug-induced liver injury in Singapore.Singapore Med J. 2006;47:116–20. [PubMed]
Gao H, Li N, Wang JY, Zhang SC, Lin G. Definitive diagnosis of hepatic sinusoidal obstruction syndrome induced by pyrrolizidine alkaloids.J Dig Dis. 2012;13:33–9. [DOI] [PubMed]
Liu WP. Modern research progress of Banxia Xiexin decoction.Sci Tech Inf Gansu. 2020;49:6–9.
Tao YF. Clinical application of Rhizoma Pinelliae in ancient time.Shanghai J Tradit Chin Med. 2001;35:14–5. Chinese.
Ji X, Huang B, Wang G, Zhang C. The ethnobotanical, phytochemical and pharmacological profile of the genus Pinellia.Fitoterapia. 2014;93:1–17. [DOI] [PubMed]
Guo S, Zhang S, Liu L, Yang P, Dang X, Wei H, et al. Pinelliae Rhizoma Praeparatum involved in the regulation of bile acids metabolism in hepatic injury.Biol Pharm Bull. 2018;41:869–76. [DOI] [PubMed]
Zhang LM, Bao ZY, Huang YY, Huang W, Zhang YN, Sun R. Experimental study on the “dosage-time-toxicity” relationship of acute hepatotoxicity induced by water extraction from Rhizoma Pinelliae in mice.Chin J Pharmacovigilance. 2011;8:11–5.
Wu J, Cheng Z, He S, Shi J, Liu S, Zhang G, et al. Pinelliae rhizoma, a toxic chinese herb, can significantly inhibit CYP3A activity in rats.Molecules. 2015;20:792–806. [DOI] [PubMed] [PMC]
Ingelman-Sundberg M. Pharmacogenetics of cytochrome P450 and its applications in drug therapy: the past, present and future.Trends Pharmacol Sci. 2004;25:193–200. [DOI] [PubMed]
Shen T, Huang X, Wang YY, Zhuang H. Current status of epidemiological studies on drug-induced liver injury in China.J Clin Hepatol. 2018;34:1152–5. [DOI]
Takeda M, Okamoto I, Nakagawa K. Pooled safety analysis of EGFR-TKI treatment for EGFR mutation-positive non-small cell lung cancer.Lung Cancer. 2015;88:74–9. [DOI] [PubMed]
Nagano T, Kotani Y, Kobayashi K, Katsurada M, Hatakeyama Y, Hori S, et al. Successful erlotinib treatment for a patient with gefitinib-related hepatotoxicity and lung adenocarcinoma refractory to intermittently administered gefitinib.Case Rep Pulmonol. 2011;2011:812972. [DOI] [PubMed] [PMC]
Zhang Y, Cai Y, Zhang SR, Li CY, Jiang LL, Wei P, et al. Mechanism of hepatotoxicity of first-line tyrosine kinase inhibitors: gefitinib and afatinib.Toxicol Lett. 2021;343:1–10. [DOI] [PubMed]
Chen J, Zheng X, Liu DY, Zhao Q, Wu YW, Tan FL, et al. Therapeutic effects and adverse drug reactions are affected by icotinib exposure and CYP2C19 and EGFR genotypes in Chinese non-small cell lung cancer patients.Asian Pac J Cancer Prev. 2014;15:7195–200. [DOI] [PubMed]
Martins F, Sofiya L, Sykiotis GP, Lamine F, Maillard M, Fraga M, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance.Nat Rev Clin Oncol. 2019;16:563–80. [DOI] [PubMed]
Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al.; IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.N Engl J Med. 2020;382:1894–905. [DOI] [PubMed]
Kansara RR, Speziali C. Immunotherapy in hematologic malignancies.Curr Oncol. 2020;27:124–31. [DOI] [PubMed] [PMC]
Hofmann L, Forschner A, Loquai C, Goldinger SM, Zimmer L, Ugurel S, et al. Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy.Eur J Cancer. 2016;60:190–209. [DOI] [PubMed]
Charles EC, Olson KL, Sandhoff BG, McClure DL, Merenich JA. Evaluation of cases of severe statin-related transaminitis within a large health maintenance organization.Am J Med. 2005;118:618–24. [DOI] [PubMed]
Suzman DL, Pelosof L, Rosenberg A, Avigan MI. Hepatotoxicity of immune checkpoint inhibitors: an evolving picture of risk associated with a vital class of immunotherapy agents.Liver Int. 2018;38:976–87. [DOI] [PubMed]
Haanen JBAG, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, et al.; ESMO Guidelines Committee. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2017;28:iv119–42.Erratum in: Ann Oncol. 2018;29:iv264–6. [DOI] [PubMed]
Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.N Engl J Med. 2015;373:23–34.Erratum in: N Engl J Med. 2018;379:2185. [DOI] [PubMed] [PMC]
Larkin J, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.N Engl J Med. 2015;373:1270–1.Erratum in: N Engl J Med. 2018;379:2185. [DOI] [PubMed]
Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma.N Engl J Med. 2013;369:122–33.Erratum in: N Engl J Med. 2018;379:2185. [DOI] [PubMed] [PMC]
Sawada K, Hayashi H, Nakajima S, Hasebe T, Fujiya M, Okumura T. Non-alcoholic fatty liver disease is a potential risk factor for liver injury caused by immune checkpoint inhibitor.J Gastroenterol Hepatol. 2020;35:1042–8. [DOI] [PubMed]
Portincasa P, Moschetta A, Palasciano G. Cholesterol gallstone disease.Lancet. 2006;368:230–9. [DOI] [PubMed]
Méndez-Sánchez N, Bahena-Aponte J, Chávez-Tapia NC, Motola-Kuba D, Sánchez-Lara K, Ponciano-Radríguez G, et al. Strong association between gallstones and cardiovascular disease.Am J Gastroenterol. 2005;100:827–30. [DOI] [PubMed]
Koller T, Kollerova J, Hlavaty T, Huorka M, Payer J. Cholelithiasis and markers of nonalcoholic fatty liver disease in patients with metabolic risk factors.Scand J Gastroenterol. 2012;47:197–203. [DOI] [PubMed]
Housset C, Chrétien Y, Debray D, Chignard N. Functions of the gallbladder.Compr Physiol. 2016;6:1549–77. [DOI] [PubMed]
Cortés V, Quezada N, Uribe S, Arrese M, Nervi F. Effect of cholecystectomy on hepatic fat accumulation and insulin resistance in non-obese Hispanic patients: a pilot study.Lipids Health Dis. 2017;16:129. [DOI] [PubMed] [PMC]
Pang L, Yang W, Hou F. Features and outcomes from a retrospective study of 570 hospitalized Chinese patients with drug-induced liver injury.Clin Res Hepatol Gastroenterol. 2018;42:48–56. [DOI] [PubMed]
Andrade RJ, Chalasani N, Björnsson ES, Suzuki A, Kullak-Ublick GA, Watkins PB, et al. Drug-induced liver injury.Nat Rev Dis Primers. 2019;5:58. [DOI] [PubMed]
