Analysis of the risk factors for liver dysfunction after laparoscopic gastrectomy for gastric cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LI Haojie ^1,2 , ZHOU Lang ^1,2 , ZHANG Weihan ^1,2 , LIU Kai ^1,2 ,  YANG Kun ^1,2 ,  CHEN Xiaolong ^1,2 ,  HU Jiankun ^1,2

1. Department of General Surgery & Laboratory of Gastric Cancer, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;
2. Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;

Corresponding author：

YANG Kun, Email: 626290977@qq.com; CHEN Xiaolong, Email: 626290977@qq.com; HU Jiankun, Email: 13658002983@163.com

Keywords：

gastric cancer; laparoscopic gastrectomy; abnormal liver function

DOI：

10.7507/1007-9424.202501094

Video：

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Objective To explore the influencing factors of liver dysfunction after laparoscopic gastrectomy for gastric cancer. Methods The clinical and pathological data of patients who underwent laparoscopic gastrectomy for gastric cancer at the Gastric Cancer Center of West China Hospital, Sichuan University, from June 2021 to June 2024 were collected. Results A total of 282 patients were included. Postoperative liver dysfunction occurred in 211 cases, while 71 cases had normal liver function. The results of multivariate logistic regression analysis showed that female patients [OR=4.87, 95%CI (2.28, 10.43)], increased age [OR=1.04, 95%CI (1.02, 1.07)], history of long-term alcohol consumption [OR=2.91, 95%CI (1.47, 5.76)], prolonged operation time [OR=1.01, 95%CI (1.00, 1.01)], and patients who received neoadjuvant chemotherapy [OR=2.47, 95%CI (1.09, 5.62)] had a significantly higher incidence of postoperative liver function abnormalities (P<0.05). Conclusion Female patients, older age, a history of alcohol consumption, prolonged operative duration, and receipt of neoadjuvant chemotherapy are associated with a higher incidence of abnormal liver function following laparoscopic radical gastrectomy for gastric cancer. In clinical practice, special attention should be paid to monitoring perioperative liver function changes in patients with these risk factors. Proactive measures to protect perioperative liver function are warranted to improve patients’ quality of life.

1.	Smyth EC, Nilsson M, Grabsch HI, et al. Gastric cancer. Lancet, 2020, 396(10251): 635-648.
2.	Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2024, 74(3): 229-263.
3.	李茁钰, 刘凯, 张维汉, 等. 全球及中国胃癌的流行病学特点及趋势: 2018–2022《全球癌症统计报告》解读. 中国普外基础与临床杂志, 2024, 31(10): 1236-1245.
4.	姚一菲, 孙可欣, 郑荣寿. 《2022全球癌症统计报告》解读: 中国与全球对比. 中国普外基础与临床杂志, 2024, 31(7): 769-780.
5.	Huang C, Liu H, Hu Y, et al. Laparoscopic vs open distal gastrectomy for locally advanced gastric cancer: five-year outcomes from the CLASS-01 randomized clinical trial. JAMA Surg, 2022, 157(1): 9-17.
6.	Yu J, Huang C, Sun Y, et al. Effect of laparoscopic vs open distal gastrectomy on 3-year disease-free survival in patients with locally advanced gastric cancer: the CLASS-01 randomized clinical trial. JAMA, 2019, 321(20): 1983-1992.
7.	Park SH, Hyung WJ, Yang HK, et al. Standard follow-up after curative surgery for advanced gastric cancer: secondary analysis of a multicentre randomized clinical trial (KLASS-02). Br J Surg, 2023, 110(4): 449-455.
8.	Son SY, Hur H, Hyung WJ, et al. Laparoscopic vs open distal gastrectomy for locally advanced gastric cancer: 5-year outcomes of the KLASS-02 randomized clinical trial. JAMA Surg, 2022, 157(10): 879-886.
9.	Kim W, Kim HH, Han SU, et al. Decreased morbidity of laparoscopic distal gastrectomy compared with open distal gastrectomy for stage Ⅰ gastric Cancer: short-term outcomes from a multicenter randomized controlled trial (KLASS-01). Ann Surg, 2016, 263(1): 28-35.
10.	Zaninotto G, Costantini M. Are elevated liver enzymes and bilirubin levels significant after laparoscopic cholecystectomy in the absence of bile duct injury?. Ann Surg, 1995, 221(4): 433.
11.	Guven HE, Oral S. Liver enzyme alterations after laparoscopic cholecystectomy. J Gastrointestin Liver Dis, 2007, 16(4): 391-394.
12.	Hasukic S, Kosuta D, Muminhodzic K. Comparison of postoperative hepatic function between laparoscopic and open cholecystectomy. Med Princ Pract, 2005, 14(3): 147-150.
13.	Koirala R, Shakya VC, Khania S, et al. Rise in liver enzymes after laproscopic cholecystectomy: a transient phenomenon. Nepal Med Coll J, 2012, 14(3): 223-226.
14.	Sakorafas G, Anagnostopoulos G, Stafyla V, et al. Elevation of serum liver enzymes after laparoscopic cholecystectomy. N Z Med J, 2005, 118(1210): U1317.
15.	Etoh T, Shiraishi N, Tajima M, et al. Transient liver dysfunction after laparoscopic gastrectomy for gastric cancer patients. World J Surg, 2007, 31(5): 1115-1120.
16.	Kim SG, Song KY, Kim SN, et al. Alterations in hepatic function after laparoscopic assisted distal gastrectomy: a prospective study. J Korean Surg Soc, 2007, 72(1): 46-50.
17.	Nguyen NT, Braley S, Fleming NW, et al. Comparison of postoperative hepatic function after laparoscopic versus open gastric bypass. Am J Surg, 2003, 186(1): 40-44.
18.	Wu J, Feng H, Wang ZY, et al. Factors affecting liver function abnormalities after laparoscopic esophageal hiatal hernia repair. Surg Laparosc Endosc Percutan Tech, 2025, 35(2): e1350. doi: 10.1097/SLE.0000000000001350.
19.	Jeong GA, Cho GS, Shin EJ, et al. Liver function alterations after laparoscopy-assisted gastrectomy for gastric cancer and its clinical significance. World J Gastroenterol, 2011, 17(3): 372-378.
20.	Guerrini GP, Esposito G, Magistri P, et al. Robotic versus laparoscopic gastrectomy for gastric cancer: the largest meta-analysis. Int J Surg, 2020, 82: 210-228.
21.	Xiong J, Nunes QM, Tan C, et al. Comparison of short-term clinical outcomes between robotic and laparoscopic gastrectomy for gastric cancer: a meta-analysis of 2 495 patients. J Laparoendosc Adv Surg Tech A, 2013, 23(12): 965-976.
22.	Singal AK, Bataller R, Ahn J, et al. ACG clinical guideline: alcoholic liver disease. Am J Gastroenterol, 2018, 113(2): 175-194.
23.	Yan C, Hu W, Tu J, et al. Pathogenic mechanisms and regulatory factors involved in alcoholic liver disease. J Transl Med, 2023, 21(1): 300. doi: 10.1186/s12967-023-04166-8.
24.	Ceni E, Mello T, Galli A. Pathogenesis of alcoholic liver disease: role of oxidative metabolism. World J Gastroenterol, 2014, 20(47): 17756-17772.
25.	Osna NA, Donohue TM Jr, Kharbanda KK. Alcoholic liver disease: pathogenesis and current management. Alcohol Res, 2017, 38(2): 147-161.
26.	于小会. 乳腺癌患者化疗后肝功能异常的危险因素分析. 锦州医科大学学报, 2024, 45(2): 66-70.
27.	Smith NJ, Watchalotone S, Sandhu S. Drug-induced liver injury secondary to endocrine therapy with aromatase inhibitors: a case report. Cureus, 2025, 17(3): e80795. doi: 10.7759/cureus.80795.
28.	杜晨牧. 急性白血病化疗对肝功能的影响. 杭州: 浙江大学, 2011.
29.	朱聚龙, 翟景明, 范永刚. 胃癌术后化疗患者肝功能异常因素分析. 医学研究杂志, 2019, 48(9): 169-173.
30.	Agostini J, Benoist S, Seman M, et al. Identification of molecular pathways involved in oxaliplatin-associated sinusoidal dilatation. J Hepatol, 2012, 56(4): 869-876.
31.	Robinson SM, Mann J, Vasilaki A, et al. Pathogenesis of FOLFOX induced sinusoidal obstruction syndrome in a murine chemotherapy model. J Hepatol, 2013, 59(2): 318-326.
32.	Cheng X, Zhu C, Chen Y, et al. Huaier relieves oxaliplatin-induced hepatotoxicity through activation of the PI3K/AKT/Nrf2 signaling pathway in C57BL/6 mice. Heliyon, 2024, 10(17): e37010. doi: 10.1016/j.heliyon.2024.e37010.
33.	Remash D, Prince DS, McKenzie C, et al. Immune checkpoint inhibitor-related hepatotoxicity: a review. World J Gastroenterol, 2021, 27(32): 5376-5391.
34.	Wang DY, Salem JE, Cohen JV, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol, 2018, 4(12): 1721-1728.
35.	Martins F, Sofiya L, Sykiotis GP, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol, 2019, 16(9): 563-580.
36.	Yin Q, Wu L, Han L, et al. Immune-related adverse events of immune checkpoint inhibitors: a review. Front Immunol, 2023, 14: 1167975. doi: 10.3389/fimmu.2023.1167975.
37.	Tao G, Huang J, Moorthy B, et al. Potential role of drug metabolizing enzymes in chemotherapy-induced gastrointestinal toxicity and hepatotoxicity. Expert Opin Drug Metab Toxicol, 2020, 16(11): 1109-1124.
38.	Liu J, Xiao Q, Xiao J, et al. Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduct Target Ther, 2022, 7(1): 3. doi: 10.1038/s41392-021-00762-6.
39.	Hagström H, Tynelius P, Rasmussen F. High BMI in late adolescence predicts future severe liver disease and hepatocellular carcinoma: a national, population-based cohort study in 1. 2 million men. Gut, 2018, 67(8): 1536-1542.
40.	Kroh A, Schmitz S, Köhne S, et al. Sleeve-gastrectomy results in improved metabolism and a massive stress response of the liver proteome in a mouse model of metabolic dysfunction-associated steatohepatitis. Heliyon, 2024, 10(21): e38678. doi: 10.1016/j.heliyon.2024.e38678.
41.	Li X, Gao P, Niu J. Metabolic comorbidities and risk of development and severity of drug-induced liver injury. Biomed Res Int, 2019, 2019: 8764093. doi: 10.1155/2019/8764093.
42.	Lucena MI, Andrade RJ, Kaplowitz N, et al. Phenotypic characterization of idiosyncratic drug-induced liver injury: the influence of age and sex. Hepatology, 2009, 49(6): 2001-2009.
43.	Weersink RA, Alvarez-Alvarez I, Medina-Cáliz I, et al. Clinical characteristics and outcome of drug-induced liver injury in the older patients: from the young-old to the oldest-old. Clin Pharmacol Ther, 2021, 109(4): 1147-1158.
44.	Han YZ, Guo YM, Xiong P, et al. Age-associated risk of liver-related adverse drug reactions. Front Med (Lausanne), 2022, 9: 832557. doi: 10.3389/fmed.2022.832557.
45.	Kurt Z, Barrere-Cain R, LaGuardia J, et al. Tissue-specific pathways and networks underlying sexual dimorphism in non-alcoholic fatty liver disease. Biol Sex Differ, 2018, 9(1): 46. doi: 10.1186/s13293-018-0205-7.
46.	Gurka MJ, Vishnu A, Santen RJ, et al. Progression of metabolic syndrome severity during the menopausal transition. J Am Heart Assoc, 2016, 5(8): e003609. doi: 10.1161/JAHA.116.003609.
47.	Palatini P, Orlando R, De Martin S. The effect of liver disease on inhibitory and plasma protein-binding displacement interactions: an update. Expert Opin Drug Metab Toxicol, 2010, 6(10): 1215-1230.
48.	Roelfsema F, Veldhuis JD. Growth hormone dynamics in healthy adults are related to age and sex and strongly dependent on body mass index. Neuroendocrinology, 2016, 103(3-4): 335-344.
49.	Hunt CM, Westerkam WR, Stave GM. Effect of age and gender on the activity of human hepatic CYP3A. Biochem Pharmacol, 1992, 44(2): 275-283.
50.	George N, Chen M, Yuen N, et al. Interplay of gender, age and drug properties on reporting frequency of drug-induced liver injury. Regul Toxicol Pharmacol, 2018, 94: 101-107.
51.	Fattinger K, Roos M, Vergères P, et al. Epidemiology of drug exposure and adverse drug reactions in two swiss departments of internal medicine. Br J Clin Pharmacol, 2000, 49(2): 158-167.
52.	Hallajzadeh J, Khoramdad M, Izadi N, et al. Metabolic syndrome and its components in premenopausal and postmenopausal women: a comprehensive systematic review and meta-analysis on observational studies. Menopause, 2018, 25(10): 1155-1164.
53.	Friedman SL, Neuschwander-Tetri BA, Rinella M, et al. Mechanisms of NAFLD development and therapeutic strategies. Nat Med, 2018, 24(7): 908-922.
54.	Ballestri S, Nascimbeni F, Baldelli E, et al. NAFLD as a sexual dimorphic disease: role of gender and reproductive status in the development and progression of nonalcoholic fatty liver disease and inherent cardiovascular risk. Adv Ther, 2017, 34(6): 1291-1326.
55.	Cho J, Kim L, Li Z, et al. Sex bias in experimental immune-mediated, drug-induced liver injury in BALB/c mice: suggested roles for Tregs, estrogen, and IL-6. PLoS One, 2013, 8(4): e61186. doi: 10.1371/journal.pone.0061186.
56.	Toyoda Y, Miyashita T, Endo S, et al. Estradiol and progesterone modulate halothane-induced liver injury in mice. Toxicol Lett, 2011, 204(1): 17-24.
57.	Court MH. 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(1): 209-224.
58.	Taylor RM, Tujios S, Jinjuvadia K, et al. Short and long-term outcomes in patients with acute liver failure due to ischemic hepatitis. Dig Dis Sci, 2012, 57(3): 777-785.

1. Smyth EC, Nilsson M, Grabsch HI, et al. Gastric cancer. Lancet, 2020, 396(10251): 635-648.
2. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2024, 74(3): 229-263.
3. 李茁钰, 刘凯, 张维汉, 等. 全球及中国胃癌的流行病学特点及趋势: 2018–2022《全球癌症统计报告》解读. 中国普外基础与临床杂志, 2024, 31(10): 1236-1245.
4. 姚一菲, 孙可欣, 郑荣寿. 《2022全球癌症统计报告》解读: 中国与全球对比. 中国普外基础与临床杂志, 2024, 31(7): 769-780.
5. Huang C, Liu H, Hu Y, et al. Laparoscopic vs open distal gastrectomy for locally advanced gastric cancer: five-year outcomes from the CLASS-01 randomized clinical trial. JAMA Surg, 2022, 157(1): 9-17.
6. Yu J, Huang C, Sun Y, et al. Effect of laparoscopic vs open distal gastrectomy on 3-year disease-free survival in patients with locally advanced gastric cancer: the CLASS-01 randomized clinical trial. JAMA, 2019, 321(20): 1983-1992.
7. Park SH, Hyung WJ, Yang HK, et al. Standard follow-up after curative surgery for advanced gastric cancer: secondary analysis of a multicentre randomized clinical trial (KLASS-02). Br J Surg, 2023, 110(4): 449-455.
8. Son SY, Hur H, Hyung WJ, et al. Laparoscopic vs open distal gastrectomy for locally advanced gastric cancer: 5-year outcomes of the KLASS-02 randomized clinical trial. JAMA Surg, 2022, 157(10): 879-886.
9. Kim W, Kim HH, Han SU, et al. Decreased morbidity of laparoscopic distal gastrectomy compared with open distal gastrectomy for stage Ⅰ gastric Cancer: short-term outcomes from a multicenter randomized controlled trial (KLASS-01). Ann Surg, 2016, 263(1): 28-35.
10. Zaninotto G, Costantini M. Are elevated liver enzymes and bilirubin levels significant after laparoscopic cholecystectomy in the absence of bile duct injury?. Ann Surg, 1995, 221(4): 433.
11. Guven HE, Oral S. Liver enzyme alterations after laparoscopic cholecystectomy. J Gastrointestin Liver Dis, 2007, 16(4): 391-394.
12. Hasukic S, Kosuta D, Muminhodzic K. Comparison of postoperative hepatic function between laparoscopic and open cholecystectomy. Med Princ Pract, 2005, 14(3): 147-150.
13. Koirala R, Shakya VC, Khania S, et al. Rise in liver enzymes after laproscopic cholecystectomy: a transient phenomenon. Nepal Med Coll J, 2012, 14(3): 223-226.
14. Sakorafas G, Anagnostopoulos G, Stafyla V, et al. Elevation of serum liver enzymes after laparoscopic cholecystectomy. N Z Med J, 2005, 118(1210): U1317.
15. Etoh T, Shiraishi N, Tajima M, et al. Transient liver dysfunction after laparoscopic gastrectomy for gastric cancer patients. World J Surg, 2007, 31(5): 1115-1120.
16. Kim SG, Song KY, Kim SN, et al. Alterations in hepatic function after laparoscopic assisted distal gastrectomy: a prospective study. J Korean Surg Soc, 2007, 72(1): 46-50.
17. Nguyen NT, Braley S, Fleming NW, et al. Comparison of postoperative hepatic function after laparoscopic versus open gastric bypass. Am J Surg, 2003, 186(1): 40-44.
18. Wu J, Feng H, Wang ZY, et al. Factors affecting liver function abnormalities after laparoscopic esophageal hiatal hernia repair. Surg Laparosc Endosc Percutan Tech, 2025, 35(2): e1350. doi: 10.1097/SLE.0000000000001350.
19. Jeong GA, Cho GS, Shin EJ, et al. Liver function alterations after laparoscopy-assisted gastrectomy for gastric cancer and its clinical significance. World J Gastroenterol, 2011, 17(3): 372-378.
20. Guerrini GP, Esposito G, Magistri P, et al. Robotic versus laparoscopic gastrectomy for gastric cancer: the largest meta-analysis. Int J Surg, 2020, 82: 210-228.
21. Xiong J, Nunes QM, Tan C, et al. Comparison of short-term clinical outcomes between robotic and laparoscopic gastrectomy for gastric cancer: a meta-analysis of 2 495 patients. J Laparoendosc Adv Surg Tech A, 2013, 23(12): 965-976.
22. Singal AK, Bataller R, Ahn J, et al. ACG clinical guideline: alcoholic liver disease. Am J Gastroenterol, 2018, 113(2): 175-194.
23. Yan C, Hu W, Tu J, et al. Pathogenic mechanisms and regulatory factors involved in alcoholic liver disease. J Transl Med, 2023, 21(1): 300. doi: 10.1186/s12967-023-04166-8.
24. Ceni E, Mello T, Galli A. Pathogenesis of alcoholic liver disease: role of oxidative metabolism. World J Gastroenterol, 2014, 20(47): 17756-17772.
25. Osna NA, Donohue TM Jr, Kharbanda KK. Alcoholic liver disease: pathogenesis and current management. Alcohol Res, 2017, 38(2): 147-161.
26. 于小会. 乳腺癌患者化疗后肝功能异常的危险因素分析. 锦州医科大学学报, 2024, 45(2): 66-70.
27. Smith NJ, Watchalotone S, Sandhu S. Drug-induced liver injury secondary to endocrine therapy with aromatase inhibitors: a case report. Cureus, 2025, 17(3): e80795. doi: 10.7759/cureus.80795.
28. 杜晨牧. 急性白血病化疗对肝功能的影响. 杭州: 浙江大学, 2011.
29. 朱聚龙, 翟景明, 范永刚. 胃癌术后化疗患者肝功能异常因素分析. 医学研究杂志, 2019, 48(9): 169-173.
30. Agostini J, Benoist S, Seman M, et al. Identification of molecular pathways involved in oxaliplatin-associated sinusoidal dilatation. J Hepatol, 2012, 56(4): 869-876.
31. Robinson SM, Mann J, Vasilaki A, et al. Pathogenesis of FOLFOX induced sinusoidal obstruction syndrome in a murine chemotherapy model. J Hepatol, 2013, 59(2): 318-326.
32. Cheng X, Zhu C, Chen Y, et al. Huaier relieves oxaliplatin-induced hepatotoxicity through activation of the PI3K/AKT/Nrf2 signaling pathway in C57BL/6 mice. Heliyon, 2024, 10(17): e37010. doi: 10.1016/j.heliyon.2024.e37010.
33. Remash D, Prince DS, McKenzie C, et al. Immune checkpoint inhibitor-related hepatotoxicity: a review. World J Gastroenterol, 2021, 27(32): 5376-5391.
34. Wang DY, Salem JE, Cohen JV, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol, 2018, 4(12): 1721-1728.
35. Martins F, Sofiya L, Sykiotis GP, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol, 2019, 16(9): 563-580.
36. Yin Q, Wu L, Han L, et al. Immune-related adverse events of immune checkpoint inhibitors: a review. Front Immunol, 2023, 14: 1167975. doi: 10.3389/fimmu.2023.1167975.
37. Tao G, Huang J, Moorthy B, et al. Potential role of drug metabolizing enzymes in chemotherapy-induced gastrointestinal toxicity and hepatotoxicity. Expert Opin Drug Metab Toxicol, 2020, 16(11): 1109-1124.
38. Liu J, Xiao Q, Xiao J, et al. Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduct Target Ther, 2022, 7(1): 3. doi: 10.1038/s41392-021-00762-6.
39. Hagström H, Tynelius P, Rasmussen F. High BMI in late adolescence predicts future severe liver disease and hepatocellular carcinoma: a national, population-based cohort study in 1. 2 million men. Gut, 2018, 67(8): 1536-1542.
40. Kroh A, Schmitz S, Köhne S, et al. Sleeve-gastrectomy results in improved metabolism and a massive stress response of the liver proteome in a mouse model of metabolic dysfunction-associated steatohepatitis. Heliyon, 2024, 10(21): e38678. doi: 10.1016/j.heliyon.2024.e38678.
41. Li X, Gao P, Niu J. Metabolic comorbidities and risk of development and severity of drug-induced liver injury. Biomed Res Int, 2019, 2019: 8764093. doi: 10.1155/2019/8764093.
42. Lucena MI, Andrade RJ, Kaplowitz N, et al. Phenotypic characterization of idiosyncratic drug-induced liver injury: the influence of age and sex. Hepatology, 2009, 49(6): 2001-2009.
43. Weersink RA, Alvarez-Alvarez I, Medina-Cáliz I, et al. Clinical characteristics and outcome of drug-induced liver injury in the older patients: from the young-old to the oldest-old. Clin Pharmacol Ther, 2021, 109(4): 1147-1158.
44. Han YZ, Guo YM, Xiong P, et al. Age-associated risk of liver-related adverse drug reactions. Front Med (Lausanne), 2022, 9: 832557. doi: 10.3389/fmed.2022.832557.
45. Kurt Z, Barrere-Cain R, LaGuardia J, et al. Tissue-specific pathways and networks underlying sexual dimorphism in non-alcoholic fatty liver disease. Biol Sex Differ, 2018, 9(1): 46. doi: 10.1186/s13293-018-0205-7.
46. Gurka MJ, Vishnu A, Santen RJ, et al. Progression of metabolic syndrome severity during the menopausal transition. J Am Heart Assoc, 2016, 5(8): e003609. doi: 10.1161/JAHA.116.003609.
47. Palatini P, Orlando R, De Martin S. The effect of liver disease on inhibitory and plasma protein-binding displacement interactions: an update. Expert Opin Drug Metab Toxicol, 2010, 6(10): 1215-1230.
48. Roelfsema F, Veldhuis JD. Growth hormone dynamics in healthy adults are related to age and sex and strongly dependent on body mass index. Neuroendocrinology, 2016, 103(3-4): 335-344.
49. Hunt CM, Westerkam WR, Stave GM. Effect of age and gender on the activity of human hepatic CYP3A. Biochem Pharmacol, 1992, 44(2): 275-283.
50. George N, Chen M, Yuen N, et al. Interplay of gender, age and drug properties on reporting frequency of drug-induced liver injury. Regul Toxicol Pharmacol, 2018, 94: 101-107.
51. Fattinger K, Roos M, Vergères P, et al. Epidemiology of drug exposure and adverse drug reactions in two swiss departments of internal medicine. Br J Clin Pharmacol, 2000, 49(2): 158-167.
52. Hallajzadeh J, Khoramdad M, Izadi N, et al. Metabolic syndrome and its components in premenopausal and postmenopausal women: a comprehensive systematic review and meta-analysis on observational studies. Menopause, 2018, 25(10): 1155-1164.
53. Friedman SL, Neuschwander-Tetri BA, Rinella M, et al. Mechanisms of NAFLD development and therapeutic strategies. Nat Med, 2018, 24(7): 908-922.
54. Ballestri S, Nascimbeni F, Baldelli E, et al. NAFLD as a sexual dimorphic disease: role of gender and reproductive status in the development and progression of nonalcoholic fatty liver disease and inherent cardiovascular risk. Adv Ther, 2017, 34(6): 1291-1326.
55. Cho J, Kim L, Li Z, et al. Sex bias in experimental immune-mediated, drug-induced liver injury in BALB/c mice: suggested roles for Tregs, estrogen, and IL-6. PLoS One, 2013, 8(4): e61186. doi: 10.1371/journal.pone.0061186.
56. Toyoda Y, Miyashita T, Endo S, et al. Estradiol and progesterone modulate halothane-induced liver injury in mice. Toxicol Lett, 2011, 204(1): 17-24.
57. Court MH. 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(1): 209-224.
58. Taylor RM, Tujios S, Jinjuvadia K, et al. Short and long-term outcomes in patients with acute liver failure due to ischemic hepatitis. Dig Dis Sci, 2012, 57(3): 777-785.

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