Advances on the study of pathogenesis and treatment of alcohol-associated liver disease
LIANG Gaoshuang*, PENG Jinying*, LI Zhuan
Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha 410013, China
Abstract：Alcohol associated liver disease (ALD) has become a major cause of cirrhosis and liver failure across the world and its influence continues to increase. ALD encompasses a spectrum of diseases including asymptomatic liver steatosis, alcohol-associated hepatitis, alcohol associated fibrosis, cirrhosis, and even liver cancer. The progression of ALD involves in multiple cell types and even different organs including liver and gut. More importantly, there are very limited options for treatment of ALD currently due to the lack of effective diagnosis methods and clinical symptoms which resultes in patients with ALD are rarely diagnosed in the earlier phase of the disease spectrum. Therefore, it is of great strategic significance to deeply study the pathogenesis of ALD and clinical application value to develop effective diagnosis and treatment strategies. In present review, we discussed recent advances on the pathogenesis, current treatment options, and clinical trials of ALD.
梁高爽, 彭金英, 李专. 酒精相关性肝病致病机制与诊疗研究进展[J]. 湖南师范大学学报(医学版), 2023, 20(4): 1-10.
LIANG Gaoshuang, PENG Jinying, LI Zhuan. Advances on the study of pathogenesis and treatment of alcohol-associated liver disease. HuNan ShiFan DaXue XueBao(YiXueBan), 2023, 20(4): 1-10.
[1] Seitz HK, Bataller R, Cortez-pinto H, et al. Alcoholic liver disease[J]. Nat Rev Dis Primers, 2018, 4(1): 16. [2] NIAAA. Alcohol and the Human Body [EB/OL].[2023-06-10] https://www.niaaa.nih.gov/alcohols-effects-health/alcohol-topics/alcohol-facts-and-statistics/alcohol-and-human-body [3] 中国疾病控制中心. 世卫组织饮酒和健康报告发布！中国拖了全世界的后腿！全球300万死亡归因于饮酒 [EB/OL].(2018-12-19) https://www.chinacdc.cn/gwxx/201812/t20181219_198349.html [4] De Andrade K, Moura F, Dos Santos J, et al.Oxidative Stress and Inflammation in Hepatic Diseases: Therapeutic Possibilities of N-Acetylcysteine[J]. Int J Mol Sci, 2015, 16(12): 30269-30308. [5] Liu Y, Myojin T, Li K, et al.A Major Intestinal Catabolite of Quercetin Glycosides, 3-Hydroxyphenylacetic Acid, Protects the Hepatocytes from the Acetaldehyde-Induced Cytotoxicity through the Enhancement of the Total Aldehyde Dehydrogenase Activity[J]. Int J Mol Sci, 2022, 23(3): 1762. [6] Seitz H K, Neuman M G.The History of Alcoholic Liver Disease: From an Unrecognized Disease to One of the Most Frequent Diseases in Hepatology[J]. J Clin Med, 2021, 10(4): 858. [7] Lieber C S, Rubin E, Decarli LM.Hepatic microsomal ethanol oxidizing system (MEOS): differentiation from alcohol dehydrogenase and NADPH oxidase[J]. Biochem Biophys Res Commun, 1970, 40(4): 858-865. [8] Thurman RG, Handler JA.New perspectives in catalase-dependent ethanol metabolism[J]. Drug Metab Rev, 1989, 20(2-4): 679-688. [9] Neuman MG, Seitz HK, Teschke R, et al.Molecular, Viral and Clinical Features of Alcohol- and Non-Alcohol-Induced Liver Injury[J]. Curr Issues Mol Biol, 2022, 44(3): 1294-1315. [10] Lu Y, Cederbaum A I.Cytochrome P450S and Alcoholic Liver Disease[J]. Curr Pharm Des, 2018, 24(14): 1502-1517. [11] Faenza I, Blalock W L.Innate Immunity: A Balance between Disease and Adaption to Stress[J]. Biomolecules, 2022, 12(5): 737. [12] Osna N A, Donohue TM Jr.Implication of altered proteasome function in alcoholic liver injury[J]. World J Gastroenterol, 2007, 13(37): 4931-4937. [13] Ding WX, Li M, Chen X, et al.Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice[J]. Gastroenterology, 2010, 139(5): 1740-1752. [14] Linhart K, Bartsch H, Seitz H K.The role of reactive oxygen species (ROS) and cytochrome P-450 2E1 in the generation of carcinogenic etheno-DNA adducts[J]. Redox Biol, 2014, 3: 56-62. [15] Vomero M, Barbati C, Colasanti T, et al.Autophagy and Rheumatoid Arthritis: Current Knowledges and Future Perspectives[J]. Front Immunol, 2018, 9: 1577. [16] Wang Y, Millonig G, Nair J, et al.Ethanol-induced cytochrome P4502E1 causes carcinogenic etheno-DNA lesions in alcoholic liver disease[J]. Hepatology, 2009, 50(2): 453-461. [17] Druesne-pecollo N, Tehard B, Mallet Y, et al. Alcohol and genetic polymorphisms: effect on risk of alcohol-related cancer[J]. Lancet Oncol, 2009, 10(2): 173-180. [18] Chang YY, Liu YC, Kuo YH, et al.Effects of antrosterol from Antrodia camphorata submerged whole broth on lipid homeostasis, antioxidation, alcohol clearance, and anti-inflammation in livers of chronic-alcohol fed mice[J]. J Ethnopharmacol, 2017, 202: 200-207. [19] Ceni E, Mello T, Galli A.Pathogenesis of alcoholic liver disease: role of oxidative metabolism[J]. World J Gastroenterol, 2014, 20(47): 17756-17772. [20] Zhang C, Zhao J, Zhao J, et al.CYP2E1-dependent upregulation of SIRT7 is response to alcohol mediated metastasis in hepatocellular carcinoma[J]. Cancer Gene Ther, 2022, 29(12): 1961-1974. [21] Zhao J, Wozniak A, Adams A, et al.SIRT7 regulates hepatocellular carcinoma response to therapy by altering the p53-dependent cell death pathway[J]. J Exp Clin Cancer Res, 2019, 38(1): 252. [22] King AL, Swain TM, Mao Z, et al.Involvement of the mitochondrial permeability transition pore in chronic ethanol-mediated liver injury in mice[J]. Am J Physiol Gastrointest Liver Physiol, 2014, 306(4): G265-277. [23] Bailey SM, Cunningham CC.Contribution of mitochondria to oxidative stress associated with alcoholic liver disease[J]. Free Radic Biol Med, 2002, 32(1): 11-16. [24] Demeilliers C, Maisonneuve C, Grodet A, et al.Impaired adaptive resynthesis and prolonged depletion of hepatic mitochondrial DNA after repeated alcohol binges in mice[J]. Gastroenterology, 2002, 123(4): 1278-1290. [25] Wang L, Khambu B, Zhang H, et al.Autophagy in alcoholic liver disease, self-eating triggered by drinking[J]. Clin Res Hepatol Gastroenterol, 2015, 39(Suppl 1): S2-S6. [26] Thomes P G, Ehlers R A, Trambly C S, et al.Multilevel regulation of autophagosome content by ethanol oxidation in HepG2 cells[J]. Autophagy, 2013, 9(1): 63-73. [27] Sid B, Verrax J, Calderon P B.Role of AMPK activation in oxidative cell damage: Implications for alcohol-induced liver disease[J]. Biochem Pharmacol, 2013, 86(2): 200-209. [28] Ni HM, Du K, You M, et al.Critical role of FoxO3a in alcohol-induced autophagy and hepatotoxicity[J]. Am J Pathol, 2013, 183(6): 1815-1825. [29] Kharbanda KK, Mcvicker DL, Zetterman RK, et al.Ethanol consumption alters trafficking of lysosomal enzymes and affects the processing of procathepsin L in rat liver[J]. Biochim Biophys Acta, 1996, 1291(1): 45-52. [30] Schulze RJ, Rasineni K, Weller SG, et al.Ethanol exposure inhibits hepatocyte lipophagy by inactivating the small guanosine triphosphatase Rab7[J]. Hepatol Commun, 2017, 1(2): 140-152. [31] Rasineni K, Donohue TM Jr, Thomes P G, et al.Ethanol-induced steatosis involves impairment of lipophagy, associated with reduced Dynamin2 activity[J]. Hepatol Commun, 2017, 1(6): 501-512. [32] Chao X, Wang S, Zhao K, et al. Impaired TFEB-Mediated Lysosome Biogenesis and Autophagy Promote Chronic Ethanol-Induced Liver Injury and Steatosis in Mice [J]. Gastroenterology, 2018, 155 (3): 865-879. e12. [33] Ingersoll MA, Spanbroek R, Lottaz C, et al.Comparison of gene expression profiles between human and mouse monocyte subsets[J]. Blood, 2010, 115(3): e10-19. [34] Wu X, Fan X, Miyata T, et al.Recent Advances in Understanding of Pathogenesis of Alcohol-Associated Liver Disease[J]. Annu Rev Pathol, 2023, 18: 411-438. [35] Rao R.Endotoxemia and gut barrier dysfunction in alcoholic liver disease[J]. Hepatology, 2009, 50(2): 638-644. [36] Petrasek J, Dolganiuc A, Csak T, et al.Interferon regulatory factor 3 and type I interferons are protective in alcoholic liver injury in mice by way of crosstalk of parenchymal and myeloid cells[J]. Hepatology, 2011, 53(2): 649-660. [37] Miller AM, Wang H, Bertola A, et al.Inflammation-associated interleukin-6/signal transducer and activator of transcription 3 activation ameliorates alcoholic and nonalcoholic fatty liver diseases in interleukin-10-deficient mice[J]. Hepatology, 2011, 54(3): 846-856. [38] Li Z, Zhao J, Zhang S, et al.FOXO3-dependent apoptosis limits alcohol-induced liver inflammation by promoting infiltrating macrophage differentiation[J]. Cell Death Discov, 2018, 4: 16. [39] Tilg H, Adolph T E, Trauner M.Gut-liver axis: Pathophysiological concepts and clinical implications[J]. Cell Metab, 2022, 34(11): 1700-1718. [40] Llopis M, Cassard AM, Wrzosek L, et al.Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease[J]. Gut, 2016, 65(5): 830-839. [41] Lang S, Fairfied B, Gao B, et al.Changes in the fecal bacterial microbiota associated with disease severity in alcoholic hepatitis patients[J]. Gut Microbes, 2020, 12(1): 1785251. [42] Zeng S, Rosati E, Saggau C, et al. Candida albicans-specific Th17 cell-mediated response contributes to alcohol-associated liver disease [J]. Cell Host Microbe, 2023, 31 (3): 389-404. e7. [43] 阿依木古丽·艾尼, 靳瑾. 短链脂肪酸在炎症性肠病中的作用研究进展 [J]. 现代医药卫生, 2023, 39 (10): 1727-1731+1736. [44] Canfora EE, Jocken J W, Blaak EE.Short-chain fatty acids in control of body weight and insulin sensitivity[J]. Nat Rev Endocrinol, 2015, 11(10): 577-591. [45] Wang Z, Zhang X, Zhu L, et al.Inulin alleviates inflammation of alcoholic liver disease via SCFAs-inducing suppression of M1 and facilitation of M2 macrophages in mice[J]. Int Immunopharmacol, 2020, 78: 106062. [46] Krishnan S, Ding Y, Saeidi N, et al.Gut Microbiota-Derived Tryptophan Metabolites Modulate Inflammatory Response in Hepatocytes and Macrophages[J]. Cell Rep, 2019, 28(12): 3285. [47] 覃子倩. 色氨酸微生物代谢产物的肠道免疫调节作用及其机制[J]. 轻工科技, 2021, 37(05): 11-12. [48] Hendrikx T, Duan Y, Wang Y, et al.Bacteria engineered to produce IL-22 in intestine induce expression of REG3G to reduce ethanol-induced liver disease in mice[J]. Gut, 2019, 68(8): 1504-1515. [49] Hartmann P, Hochrath K, Horvath A, et al.Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice[J]. Hepatology, 2018, 67(6): 2150-2166. [50] 张改霞, 陈海震, 黄晶. 酒精性肝病患者肠道微生态变化研究进展[J]. 实用肝脏病杂志, 2022, 25(05): 757-760. [51] Sturm R, Haag F, Janicova A, et al.Acute alcohol consumption increases systemic endotoxin bioactivity for days in healthy volunteers-with reduced intestinal barrier loss in female[J]. Eur J Trauma Emerg Surg, 2022, 48(3): 1569-1577. [52] Mukherjee S, Zheng H, Derebe MG, et al.Antibacterial membrane attack by a pore-forming intestinal C-type lectin[J]. Nature, 2014, 505(7481): 103-107. [53] Li F, Zhao C, Shao T, et al.Cathelicidin-related antimicrobial peptide alleviates alcoholic liver disease through inhibiting inflammasome activation[J]. J Pathol, 2020, 252(4): 371-383. [54] Kayama H, Okumura R, Takeda K.Interaction Between the Microbiota, Epithelia, and Immune Cells in the Intestine[J]. Annu Rev Immunol, 2020, 38: 23-48. [55] Wang L, Fouts DE, Starkel P, et al.Intestinal REG3 Lectins Protect against Alcoholic Steatohepatitis by Reducing Mucosa-Associated Microbiota and Preventing Bacterial Translocation[J]. Cell Host Microbe, 2016, 19(2): 227-239. [56] 李俊, 董荣静, 李家生, 等. 抗菌肽LL-37的抗菌和免疫调节机制[J]. 中国感染控制杂志, 2022, 21(01): 104-110. [57] Xiang X, Feng D, Hwang S, et al.Interleukin-22 ameliorates acute-on-chronic liver failure by reprogramming impaired regeneration pathways in mice[J]. J Hepatol, 2020, 72(4): 736-745. [58] Duan Y, Llorente C, Lang S, et al.Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease[J]. Nature, 2019, 575(7783): 505-511. [59] 池肇春. 肠道屏障功能障碍与酒精性肝病研究进展[J]. 世界华人消化杂志, 2019, 27(19): 1179-1192. [60] Moreno C, Mueller S, Szabo G.Non-invasive diagnosis and biomarkers in alcohol-related liver disease[J]. J Hepatol, 2019, 70(2): 273-283. [61] European Association for the Study of the Liver. Easl Clinical Practice Guidelines: Management of alcohol-related liver disease[J]. J Hepatol, 2018, 69(1): 154-181. [62] Kim BK, Bernstein N, Huang DQ, et al.Clinical and histologic factors associated with discordance between steatosis grade derived from histology vs. MRI-PDFF in NAFLD[J]. Aliment Pharmacol Ther, 2023, 58(2): 229-237. [63] Niemela O, Alatalo P.Biomarkers of alcohol consumption and related liver disease[J]. Scand J Clin Lab Invest, 2010, 70(5): 305-312. [64] Vatsalya V, Cave M C, Kong M, et al.Keratin 18 Is a Diagnostic and Prognostic Factor for Acute Alcoholic Hepatitis[J]. Clin Gastroenterol Hepatol, 2020, 18(9): 2046-2054. [65] Atkinson SR, Grove J I, Liebig S, et al.In Severe Alcoholic Hepatitis, Serum Keratin-18 Fragments Are Diagnostic, Prognostic, and Theragnostic Biomarkers[J]. Am J Gastroenterol, 2020, 115(11): 1857-1868. [66] Bissonnette J, Altamirano J, Devue C, et al.A prospective study of the utility of plasma biomarkers to diagnose alcoholic hepatitis[J]. Hepatology, 2017, 66(2): 555-563. [67] Fan X, Mccullough RL, Huang E, et al.Diagnostic and Prognostic Significance of Complement in Patients With Alcohol-Associated Hepatitis[J]. Hepatology, 2021, 73(3): 983-997. [68] Ge Y, Sun H, Xu L, et al.The amelioration of alcohol-induced liver and intestinal barrier injury by Lactobacillus rhamnosus Gorbach-Goldin (LGG) is dependent on Interleukin 22 (IL-22) expression[J]. Bioengineered, 2022, 13(5): 12650-12660. [69] Wang X, He Y, Mackowiak B, et al.MicroRNAs as regulators, biomarkers and therapeutic targets in liver diseases[J]. Gut, 2021, 70(4): 784-795. [70] Satishchandran A, Ambade A, Rao S, et al. MicroRNA 122, Regulated by GRLH2, Protects Livers of Mice and Patients From Ethanol-Induced Liver Disease [J]. Gastroenterology, 2018, 154 (1): 238-252. e7. [71] Niu L, Thiele M, Geyer PE, et al.Noninvasive proteomic biomarkers for alcohol-related liver disease[J]. Nat Med, 2022, 28(6): 1277-1287. [72] 谢廷良, 陈欣怡, 欧伟杰, 等. 酒精性肝病的药物治疗最新研究进展[J]. 海峡药学, 2021, 33(10): 89-92. [73] Saberi B, Dadabhai AS, Jang YY, et al.Current Management of Alcoholic Hepatitis and Future Therapies[J]. J Clin Transl Hepatol, 2016, 4(2): 113-122. [74] Arab JP, Diaz LA, Baeza N, et al.Identification of optimal therapeutic window for steroid use in severe alcohol-associated hepatitis: A worldwide study[J]. J Hepatol, 2021, 75(5): 1026-1033. [75] Louvet A, Thursz MR, Kim DJ, et al. Corticosteroids Reduce Risk of Death Within 28 Days for Patients With Severe Alcoholic Hepatitis, Compared With Pentoxifylline or Placebo-a Meta-analysis of Individual Data From Controlled Trials [J]. Gastroenterology, 2018, 155 (2): 458-468. e8. [76] Moreno C, Langlet P, Hittelet A, et al.Enteral nutrition with or without N-acetylcysteine in the treatment of severe acute alcoholic hepatitis: a randomized multicenter controlled trial[J]. J Hepatol, 2010, 53(6): 1117-1122. [77] Thoudam T, Chanda D, Lee JY, et al.Enhanced Ca (2+) -channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease[J]. Nat Commun, 2023, 14(1): 1703. [78] Marot A, Singal AK, Moreno C, et al.Granulocyte colony-stimulating factor for alcoholic hepatitis: A systematic review and meta-analysis of randomised controlled trials[J]. JHEP Rep, 2020, 2(5): 100139. [79] Arab JP, Sehrawat TS, Simonetto DA, et al.An Open-Label, Dose-Escalation Study to Assess the Safety and Efficacy of IL-22 Agonist F-652 in Patients With Alcohol-associated Hepatitis[J]. Hepatology, 2020, 72(2): 441-453. [80] Garate I, Garcia-Bueno B, Madrigal JL, et al.Toll-like 4 receptor inhibitor TAK-242 decreases neuroinflammation in rat brain frontal cortex after stress[J]. J Neuroinflammation, 2014, 11: 8. [81] Grander C, Schaefer B, Schwarzler J, et al.Alpha-1 antitrypsin governs alcohol-related liver disease in mice and humans[J]. Gut, 2021, 70(3): 585-594. [82] 李国华, 李鹤龄, 陈智岗, 等. 酒精性肝病与肠道微生物群落研究进展[J]. 中国实验动物学报, 2022, 30(03): 423-427. [83] Duseja A, Acharya S K, Mehta M, et al.High potency multistrain probiotic improves liver histology in non-alcoholic fatty liver disease (NAFLD): a randomised, double-blind, proof of concept study[J]. BMJ Open Gastroenterol, 2019, 6(1): e000315. [84] Ragan MV, Wala SJ, Goodman SD, et al.Next-Generation Probiotic Therapy to Protect the Intestines From Injury[J]. Front Cell Infect Microbiol, 2022, 12: 863949. [85] Chen P, Miyamoto Y, Mazagova M, et al.Microbiota Protects Mice Against Acute Alcohol-Induced Liver Injury[J]. Alcohol Clin Exp Res, 2015, 39(12): 2313-2323. [86] Louvet A, Labreuche J, Dao T, et al.Effect of Prophylactic Antibiotics on Mortality in Severe Alcohol-Related Hepatitis: A Randomized Clinical Trial[J]. JAMA, 2023, 329(18): 1558-1566. [87] Bajaj JS, Gavis EA, Fagan A, et al.A Randomized Clinical Trial of Fecal Microbiota Transplant for Alcohol Use Disorder[J]. Hepatology, 2021, 73(5): 1688-1700.
2023, Vol. 20 
