Abstract
Drug-induced liver injury (DILI) is a potentially serious clinical condition that
remains a major problem for patients, physicians and those involved in the development
of new drugs. Population and hospital-based studies have reported incidences of DILI
varying from 1.4 to 19.1/100.000. Overall, females have a 1.5- to 1.7-fold greater
risk of developing adverse drug reactions and the female/male ratio increases after
the age of 49 years, suggesting a clear susceptibility of DILI after menopause. Sex
differences in pharmacokinetics and pharmacodynamic, sex-specific hormonal effects
or interaction with signalling molecules that can influence drug efficacy and safety
and differences in abnormal immune response following drug exposure are the main probable
causes of the higher vulnerability observed among female patients. A novel phenotype
of autoimmune-mediated DILI following the use of check-point inhibitors in oncology
and haematology has been recently described. Finally, there have been increasing reports
of DILI associated with use of herbal and dietary supplements that is more frequently
reported in women.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Digestive and Liver DiseaseAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Drugs and medical devices: adverse events and the impact of women's health.Clin Ther. 2017; 39: 10-22
- The natural history of histologically proved drug-induced liver disease.Gut. 1999; 44: 731-735
- Acute and clinically relevant drug-induced liver injury: a population-based case-control studies.Br J Clin Pharmacol. 2004; 58: 71-80
- Incidence of drug-induced hepatic injuries: a French population-based study.Hepatology. 2002; 36: 451-455
- Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland.Gastroenterology. 2013; 144: 1419-1425
- Hospital admissions for drug-induced disorders in England: a study using the Hospital Episodes Statistics (HES) database.Br J Clin Pharmacol. 2005; 59: 2013-2019
- Drug-induced liver injury in a Swedish University Hospital out-patient hepatology clinic.Aliment Pharmacol Ther. 2006; 24: 1187-1195
- Incidence of drug-induced liver injury in medical inpatients.Eur J Clin Pharmacol. 2005; 61: 135-143
- Drug-induced liver injury in Japan: an analysis of 1676 cases between 1997 and 2006.Hepatol Res. 2009; 39: 427-431
- Single-center experience with drug-induced liver injury from India: causes, outcome, prognosis and predictors of mortality.Am J Gastroenterol. 2010; 105: 2396-2404
- A focus on epidemiology of drug-induced liver injury: analysis of a prospective cohort.Eur Rev Med Pharmacol Sci. 2017; 21: 112-121
- The incidence of drug- and herbal and dietary supplement-induced liver injury: preliminary findings from gastroenterologist-based surveillance in the population of the State of Delaware.Drg Saf. 2017; 40: 783-787
- Incidence and etiology of drug-induced liver injury in Mainland China.Gastroenterology. 2019; 156: 2230-2241
- Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish Registry over a 10-year period.Gastroenterology. 2005; 129: 512-521
- Features and out-comes of 899 patients with drug-induced liver injury: the DILIN prospective study.Gastroenterology. 2015; 148: 1340-1352
- When the creation of a Consortium provides useful answers: experience of the Latin American DILI Network (LATINDILIN).Clin Liver Dis. 2019; 13: 51-57
- Female gender as a susceptibility factor for drug-induced liver injury.Hum Exp Toxicol. 2014; 33: 928-939
- Gender differences in pharmacological response.Int Rev Neurobiol. 2008; 83: 1-10
- Gender differences in human pharmacokinetics and pharmacodynamics.J Adolesc Health. 1994; 15: 619-629
- The influence of sex on pharmacokinetics.Clin Pharmacokinet. 2003; 42: 107-121
- Gender differences in drug toxicity.Trends Pharmacol Sci. 2010; 31: 108-814
- Sex differences in the expression of hepatic drug metabolizing enzymes.Mol Pharmacol. 2009; 76: 215-228
- Sex-Biased Expression of Pharmacogenes across Human Tissues.Biomolecules. 2021; : 11https://doi.org/10.3390/biom11081206
- Interindividual variability in hepatic drug glucuronidation: studies into the role of age, sex, enzyme inducers, and genetic polymorphism using the human liver bank as a model system.Drug Metab Rev. 2010; 42: 209-224
- Hepatic CYP2B6 expression: gender and ethnic differences and relationship to CYP2B6 genotype and CAR (constitutive androstane receptor) expression.J Pharmacol Exp Ther. 2003; 307: 906-922
- Effect of age and gender on the activity of human hepatic CYP3A.Biochem Pharmacol. 1992; 44: 275-283
- Effects of sex steroid hormones on gastric emptying and gastrointestinal transit in rats.Am J Physiol. 1995; 268: G171-G176
- Gonadal steroids and humoral immunity.Nat Rev Endocrinol. 2013; 9: 56-62
- ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury.Am J Gastroenterol. 2014; 109: 950-966
- Drug-induced liver injury - types and phenotypes.N Engl J Med. 2019; 381: 264-273
- Oxidative stress in drug-induced liver injury (DILI): from mechanisms to biomarkers for use in clinical practice.Antioxidants. 2021; 10: 390
- Mechanisms of drug-induced liver injury.Clin Liver Dis. 2013; 17 (507-vii)
- The immunological mechanisms and immune-based biomarkers of drug-induced liver injury.Front Pharmacol. 2021; 12723940
- Drug-induced liver injury: Pathogenesis, epidemiology, clinical features, and practical management.Eur J Intern Med. 2021; https://doi.org/10.1016/j.ejim.2021.10.035
- Characterization of amoxicillin- and clavulanic acid-specific T cells in patients with amoxicillin-clavulanate-induced liver injury.Hepatology. 2015; 62: 887-899
- Clinical Characteristics and Adverse Impact of Hepatotoxicity due to Immune Checkpoint Inhibitors.Am J Gastroenterol. 2020; 115: 251-261
- Case definition and phenotype standardization in drug-induced liver injury.Clin Pharmacol Ther. 2011; 89: 806-815
- Adverse drug reactions and organ damage: the liver.Eur J Int Med. 2016; 28: 9-16
- Amoxicillin-clavulanate-induced liver injury.Dig Dis Sci. 2016; 61: 2406-2416
- Nimesulide-induced acute hepatitis: evidence from six cases.J Hepatol. 1998; 29: 135-141
- Clinical course and outcomes of drug-induced liver injury: nimesulide as the first implicated medication.Dig Liver Dis. 2010; 42: 143-148
- EASL Clinical practice guidelines: drug-induced liver injury.J Hepatol. 2019; 70: 1222-1261
- Keratin-18 and microRNA-122 complement alanine aminotransferase as novel safety biomarkers for drug-induced liver injury in two human cohorts.Liver Int. 2014; 34: 367-378
- Candidate biomarkers for the diagnosis and prognosis of drug-induced liver injury: an international collaborative effort.Hepatology. 2019; 69: 760-773
- Assessment of emerging biomarkers of liver injury in human subjects.Toxicol Sci. 2013; 132: 276-283
- Identification of specific MicroRNA biomarkers in early stages of hepatocellular injury, cholestasis, and steatosis in rats.Toxicol Sci. 2018; 166: 228-239
- Circulating microRNAs, potential biomarkers for drug-induced liver injury.Proc Natl Acad Sci USA. 2009; 106: 4402-4407
- Profiles of miRNAs in serum in severe acute drug induced liver injury and their prognostic significance.Liver Int. 2017; 37: 757-764
- Next generation DILI biomarkers:prioritization of biomarkers for qualification and best practices for biospecimen collection in drug development.Clin Pharmacol Ther. 2020; 107: 333-346
- Drug-induced autoimmune hepatitis: clinical characteristics and prognosis.Hepatology. 2010; 51: 2040-2048
- HLA-B*57:01 genotype is a major determinant of drug-induced liver injury due to flucloxacillin.Nat Genet. 2009; 41: 816-819
- Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiplae HLA class I and class II alleles.Gastroenterology. 2011; 141: 338-347
- Immune-mediated drug-induced liver injury: immunogenetics and experimental models.Int J Mol Sci. 2021; 22: 4557
Tian Y, Abu-Sbeih H, Wang Y. Immune checkpoint inhibitors-induced hepatitis. In: Naing A, Hajjar J eds. Immunotherapy. Advances in experimantal medicine and biology vol. 995, Springer 2018, pp. 159-164.
- Severe toxicity from check point protein inhibitors: what intensive care physicians need to know.Ann Int Care. 2019; 9: 1-16
- Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors.JHEP Rep. 2020; 2100170
- Hepatotoxicity from immune checkpoint inhibitors; a systematic review and management recommendation.Hepatology. 2020; 72: 315-329
- Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors.J Hepatol. 2018; 68: 1181-1190
- Drug-induced liver injury.Clin Med. 2016; 16: s104-s109
- High incidence of hepatocellular carcinoma following successful interferon-free antiviral therapy for hepatitis C associated cirrhosis.J Hepatol. 2016; 65: 1070-1071
- Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals.J Hepatol. 2016; 65: 727-733
- Unexpected high incidence of hepatocellular carcinoma in cirrhotic patients with sustained virologic response following interferon-free direct-acting antiviral treatment.J Hepatol. 2016; 65: 856-858
- Hepatocellular carcinoma mechanisms associated with chronic HCV infection and the impact of direct-acting antiviral treatment.J Hepatocell carcinoma. 2020; 7: 45-76
- DAAs rapidly reduce inflammation but increase serum VEGF level: a rationale for tumor risk during anti-HCV treatment.PLoS One. 2016; 11e0167934
- Liver angiopoietin-2 is a key predictor of de novo or recurrent hepatocellular cancer after hepatitis C virus direct-acting antivirals.Hepatology. 2018; 68: 1010-1024
- Features of patients who developed hepatocellular carcinoma after direct-acting antiviral treatment for hepatitis C virus.PLoS One. 2022; 17e0262267
- Hepatocellular carcinoma recurrence after direct-acting antiviral therapy: an individual patient data meta-analysis.Gut. 2021; https://doi.org/10.1136/gutjnl-2020-323663
- Malignant transformation of hepatocellular adenomas into hepatocellular carcinomas: a systematic review including more than 1600 adenoma cases.HPB. 2010; 12: 509-522
- Development of hepatocellular carcinoma associated with anabolic androgenic steroid abuse in a young bodybuilder: a case report.Case Rep Pathol. 2012; 195607
- Testosterone-receptor positive hepatocellular carcinoma in a 29-year old bodybuilder with a history of anabolic androgenic steroid abuse: a case report.BMC Gastroenterol. 2015; 15: 60
- The changing epidemiology of liver diseases in the Asia-Pacific region.Nat Rev Gastroenterol Hepatol. 2019; 16: 57-73
- Hepatocellular carcinoma in body builders; an emerging rare but serious complication of androgenic anabolic steroid use.Ann Hepatobiliary Pancreat Surg. 2019; 23: 174-177
- Endocrine-disrupting chemicals and fatty liver disease.Nat Rev Endocrinol. 2017; 13: 445-457
- Molecular initiating events associated with drug-induced liver malignant tumors: an integrated study of the FDA adverse event reporting system and toxicity predictions.Biomolecules. 2021; 11: 944https://doi.org/10.3390/biom11070944
- Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC.Hepatology. 2006; 43: 515-524
- A single-center surgical experience of 122 patients with single and multiple hepatocellular adenomas.Gastroenterology. 2009; 137: 1698-1705
- Sex hormone dependency of diethylnitrosamine-induced liver tumors in mice and chemoprevention by leuprorelin.Jpn J Cancer Res. 2001; 92: 249-256
- Sex-dependent differences in inflammatory responses during liver regeneration in a murine model of acute liver injury.Clin Sci (Lond). 2018; 132: 255-279
- Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production.Science. 2007; 317: 121-124
- The Lancet Gastroenterology & Hepatology. Herbal assault: liver toxicity of herbal and dietary supplements.Lancet Gastroenterol Hepatol. 2018; 3: 141
- Herbal and dietary supplement induced liver injury: Highlights from the recent literature.World J Hepatol. 2021; 13: 1019-1041
- Dietary supplements and herbal medicine toxicities-when to anticipate them and how to manage them.Int J Emerg Med. 2009; 2: 69-76
- Liver injury from herbal and dietary supplements.Hepatology. 2017; 65: 363-373
- Herb-induced liver injuries in developing nations: an update.Toxics. 2018; 6: 24https://doi.org/10.3390/toxics6020024
- Herb-induced liver injury: systematic review and meta-analysis.World J Clin Cases. 2021; 9: 5490-5513
- Distinct phenotype of hepatotoxicity associated with illicit use of anabolic androgenic steroids.APT. 2015; 41: 116-125
- Drug induced liver injury. Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.Gastroenterology. 2008; 135: 1924-1934
- Liver injury from herbals and dietary supplements in the U.S. Drug-Induced Liver Injury Network.Hepatology. 2014; 60: 1399-1408
- Clinical features and outcomes of complementary and alternative medicine induced acute liver failure and injury.Am J Gastroenterol. 2016; 111: 958-965
- A nationwide study of the incidence rate of herb-induced liver injury in Korea.Arch Toxicol. 2017; 91: 4009-4015
- Herbal and dietary supplement-induced liver injuries in the Spanish DILI registry.Clin Gastroenterol Hepatol. 2018; 16: 1495-1502
- Herbal and dietary supplements-induced liver injury in Latin America: experience from the LATINDILI network.Clin Gastroenterol Hepatol. 2021; : S1542-S3565https://doi.org/10.1016/j.cgh.2021.01.011
- Why US adults use dietary supplements.JAMA Intern Med. 2013; 173: 355-361
- Liver injury from herbals and dietary supplements in the U.S. Drug-Induced Liver Injury Network.Hepatology. 2014; 60: 1399-1408
- Liver injury from herbal, dietary, and weight loss supplements: a review.J Clin Transl Hepatol. 2015; 3: 93-98
- Herbal toxicity: a hidden epidemic.Intern Emerg Med. 2013; 8: 13-22
- Suspected adverse reactions associated with herbal products used for weight loss: a case series reported to the Italian Institute of Health.Eur J Clin Pharmacol. 2011; 67: 215-224
- Herbal hepatotoxicity: clinical characteristics and listing compilation.Int J Mol Sci. 2016; 17: 588https://doi.org/10.3390/ijms17050588
- Legal requirements for the quality of herbal substances and herbal preparations for the manufacturing of herbal medicinal products in the European union.Planta Med. 2009; 75: 683-688
Article info
Publication history
Published online: July 14, 2022
Accepted:
June 21,
2022
Received:
April 6,
2022
Identification
Copyright
© 2022 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
