Title: Intravenous Glutathione: A Promising Therapy for the Alcoholic Liver Disease
Authors: Dr Adarsh CK, Dr Paridhi Mathur, Dr Rajat Singal, Dr Sandip Mitra, Rajesh Kaul
DOI: https://dx.doi.org/10.18535/jmscr/v12i03.02
Abstract
Alcoholic liver disease (ALD) and sepsis are life-threatening conditions marked by severe oxidative stress. Chronic alcohol use triggers oxidative stress and inflammation that damages liver cells. Glutathione (GSH), a tripeptide consisting of gamma glutamyl cysteinyl glycine possesses a thiol group and participates in oxidation reduction reactions, acting as a principal cellular scavenger of free radicles. GSH is present in large concentrations in the liver, and its endogenous levels are depleted in ALD, exacerbating the condition. Intravenous GSH supplementation has shown promising results in improving liver function and reducing fibrosis markers in ALD patients. Intravenous GSH treatment has demonstrated the potential to reduce oxidative injury and mortality rates in patients with sepsis in the intensive care unit. The versatility of GSH in mitigating oxidative stress, inflammation, and tissue damage and proven safety and tolerability profile make it a valuable adjunct to current treatments. Further research is imperative to comprehensively unravel the therapeutic benefits of GSH injection adjunct to standard of care in patients with ALD and sepsis.
Keywords: Glutathione, Alcoholic liver disease, Sepsis, Antioxidants, Intensive care unit, Intravenous
References
- Asrani SK, Mellinger J, Arab JP, Shah VH. Reducing the Global Burden of Alcohol-Associated Liver Disease: A Blueprint for Action. Hepatol Baltim Md. 2021;73(5):2039-2050. doi:10.1002/hep.31583
- Mishra D, Dash KR, Khatua C, Panigrahi S, Parida PK, Behera SK, Barik RK, Pradhan S, Sahu SK, Thakur B, Singh SP. A Study on the Temporal Trends in the Etiology of Cirrhosis of Liver in Coastal Eastern Odisha. Euroasian J Hepato-Gastroenterol. 2020;10(1):1-6. doi:10.5005/jp-journals-10018-1312
- Gentilello LM. Alcohol and the intensive care unit: It’s not just an antiseptic*: Crit Care Med. 2007;35(2):627-628. doi:10.1097/01.CCM.0000254070.23023.34
- Wong F. Sepsis in cirrhosis: report on the 7th meeting of the International Ascites Club. Gut. 2005;54(5):718-725. doi:10.1136/gut.2004.038679
- Yan J, Li S, Li S. The Role of the Liver in Sepsis. Int Rev Immunol. 2014;33(6):498-510. doi:10.3109/08830185.2014.889129
- Nadim MK, Durand F, Kellum JA, Levitsky J, O'Leary JG, Karvellas CJ, Bajaj JS, Davenport A, Jalan R, Angeli P, Caldwell SH, Fernández J, Francoz C, Garcia-Tsao G, Ginès P, Ison MG, Kramer DJ, Mehta RL, Moreau R, Mulligan D, Olson JC, Pomfret EA, Senzolo M, Steadman RH, Subramanian RM, Vincent JL, Genyk YS. Management of the critically ill patient with cirrhosis: A multidisciplinary perspective. J Hepatol. 2016;64(3):717-735. doi:10.1016/j.jhep.2015.10.019
- Louvet A, Wartel F, Castel H, Dharancy S, Hollebecque A, Canva-Delcambre V, Deltenre P, Mathurin P. Infection in patients with severe alcoholic hepatitis treated with steroids: early response to therapy is the key factor. Gastroenterology. 2009;137(2):541-548. doi:10.1053/j.gastro.2009.04.062
- Michelena J, Altamirano J, Abraldes JG, Affò S, Morales-Ibanez O, Sancho-Bru P, Dominguez M, García-Pagán JC, Fernández J, Arroyo V, Ginès P, Louvet A, Mathurin P, Mehal WZ, Caballería J, Bataller R. Systemic inflammatory response and serum lipopolysaccharide levels predict multiple organ failure and death in alcoholic hepatitis. Hepatol Baltim Md. 2015;62(3):762-772. doi:10.1002/hep.27779
- European Association for the Study of the Liver. Electronic address: This email address is being protected from spambots. You need JavaScript enabled to view it., European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of alcohol-related liver disease. J Hepatol. 2018;69(1):154-181. doi:10.1016/j.jhep.2018.03.018
- Gao B, Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology. 2011;141(5):1572-1585. doi:10.1053/j.gastro.2011.09.002
- Dey A, Cederbaum AI. Alcohol and oxidative liver injury. Hepatol Baltim Md. 2006;43(2 Suppl 1):S63-74. doi:10.1002/hep.20957
- Fernandez-Checa JC, Ookhtens M, Kaplowitz N. Effect of chronic ethanol feeding on rat hepatocytic glutathione. Compartmentation, efflux, and response to incubation with ethanol. J Clin Invest. 1987;80(1):57-62. doi:10.1172/JCI113063
- Zakim D, Boyer TD, eds. Hepatology: A Textbook of Liver Disease. 4th ed. Saunders; 2003.
- Buchanan R, Sinclair JMA. Alcohol use disorder and the liver. Addiction. 2021;116(5):1270-1278. doi:10.1111/add.15204
- Stickel F, Datz C, Hampe J, Bataller R. Pathophysiology and Management of Alcoholic Liver Disease: Update 2016. Gut Liver. 2017;11(2):173-188. doi:10.5009/gnl16477
- Seitz HK, Stickel F. Molecular mechanisms of alcohol-mediated carcinogenesis. Nat Rev Cancer. 2007;7(8):599-612. doi:10.1038/nrc2191
- Tuma DJ, Thiele GM, Xu D, Klassen LW, Sorrell MF. Acetaldehyde and malondialdehyde react together to generate distinct protein adducts in the liver during long-term ethanol administration. Hepatol Baltim Md. 1996;23(4):872-880. doi:10.1002/hep.510230431
- Galicia-Moreno M, Gutiérrez-Reyes G. The role of oxidative stress in the development of alcoholic liver disease. Rev Gastroenterol México Engl Ed. 2014;79(2):135-144. doi:10.1016/j.rgmxen.2014.06.007
- García-Ruiz C, Morales A, Ballesta A, Rodés J, Kaplowitz N, Fernández-Checa JC. Effect of chronic ethanol feeding on glutathione and functional integrity of mitochondria in periportal and perivenous rat hepatocytes. J Clin Invest. 1994;94(1):193-201. doi:10.1172/JCI117306
- Nguyen-Khac E, Thevenot T, Piquet MA, Benferhat S, Goria O, Chatelain D, Tramier B, Dewaele F, Ghrib S, Rudler M, Carbonell N, Tossou H, Bental A, Bernard-Chabert B, Dupas JL. Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis. N Engl J Med. 2011;365(19):1781-1789. doi:10.1056/NEJMoa1101214
- Louvet A, Mathurin P. Alcoholic liver disease: mechanisms of injury and targeted treatment. Nat Rev Gastroenterol Hepatol. 2015;12(4):231-242. doi:10.1038/nrgastro.2015.35
- Pizzorno JE, Katzinger JJ. Glutathione: Physiological and Clinical Relevance. J Restor Med. 2012;1(1):24-37. doi:10.14200/jrm.2012.1.1002
- Garcia-Ruiz C, Fernandez-Checa JC. Mitochondrial glutathione: hepatocellular survival-death switch. J Gastroenterol Hepatol. 2006;21 Suppl 3:S3-6. doi:10.1111/j.1440-1746.2006.04570.x
- Colell A, Coll O, García-Ruiz C, París R, Tiribelli C, Kaplowitz N, Fernández-Checa JC. Tauroursodeoxycholic acid protects hepatocytes from ethanol-fed rats against tumor necrosis factor-induced cell death by replenishing mitochondrial glutathione. Hepatol Baltim Md. 2001;34(5):964-971. doi:10.1053/jhep.2001.28510
- Ballatori N, Krance SM, Notenboom S, Shi S, Tieu K, Hammond CL. Glutathione dysregulation and the etiology and progression of human diseases. Biol Chem. 2009;390(3):191-214. doi:10.1515/BC.2009.033
- Johnson WM, Wilson-Delfosse AL, Mieyal JohnJ. Dysregulation of Glutathione Homeostasis in Neurodegenerative Diseases. Nutrients. 2012;4(10):1399-1440. doi:10.3390/nu4101399
- Labarrere CA, Kassab GS. Glutathione: A Samsonian life-sustaining small molecule that protects against oxidative stress, ageing and damaging inflammation. Front Nutr. 2022;9:1007816. doi:10.3389/fnut.2022.1007816
- Matuz-Mares D, Riveros-Rosas H, Vilchis-Landeros MM, Vázquez-Meza H. Glutathione Participation in the Prevention of Cardiovascular Diseases. Antioxidants. 2021;10(8):1220. doi:10.3390/antiox10081220
- Santacroce G, Gentile A, Soriano S, Novelli A, Lenti MV, Di Sabatino A. Glutathione: Pharmacological aspects and implications for clinical use in non-alcoholic fatty liver disease. Front Med. 2023;10:1124275. doi:10.3389/fmed.2023.1124275
- Causer AJ, Shute JK, Cummings MH, Shepherd AI, Gruet M, Costello JT, Bailey S, Lindley M, Pearson C, Connett G, Allenby MI, Carroll MP, Daniels T, Saynor ZL. Circulating biomarkers of antioxidant status and oxidative stress in people with cystic fibrosis: A systematic review and meta-analysis. Redox Biol. 2020;32:101436. doi:10.1016/j.redox.2020.101436
- Iskusnykh IY, Zakharova AA, Pathak D. Glutathione in Brain Disorders and Aging. Molecules. 2022;27(1):324. doi:10.3390/molecules27010324
- Vairetti M, Di Pasqua LG, Cagna M, Richelmi P, Ferrigno A, Berardo C. Changes in Glutathione Content in Liver Diseases: An Update. Antioxid Basel Switz. 2021;10(3):364. doi:10.3390/antiox10030364
- Dentico P, Volpe A, Buongiorno R, Grattagliano I, Altomare E, Tantimonaco G, Scotto G, Sacco R, Schiraldi O. [Glutathione in the treatment of chronic fatty liver diseases]. Recenti Prog Med. 1995;86(7-8):290-293.
- Singh SK , Bhattacharjee M , Singh TG , NingthoukhongjamReema, Singh LR, Marak CB. To determine the effect of treatment with glutathione in acute hepatitis. 2022;21(7). doi:10.9790/0853-2107040612
- I.M.S, Wairokpam DT. Role of Intravenous Glutathione in Alcoholic Hepatitis. J Med Sci Clin Res. 2017;05(03):18923-18926. doi:10.18535/jmscr/v5i3.101
- Qian L, Wang W, Zhou Y, Ma J. Effects of reduced glutathione therapy on chronic hepatitis B. Cent-Eur J Immunol. 2017;42(1):97-100. doi:10.5114/ceji.2016.65894
- Nagai H, Sumino Y. Therapeutic strategy of advanced hepatocellular carcinoma by using combined intra-arterial chemotherapy. Recent Patents Anticancer Drug Discov. 2008;3(3):220-226. doi:10.2174/157489208786242296
- Friesen C, Kiess Y, Debatin KM. A critical role of glutathione in determining apoptosis sensitivity and resistance in leukemia cells. Cell Death Differ. 2004;11 Suppl 1:S73-85. doi:10.1038/sj.cdd.4401431
- Momiyama K, Nagai H, Ogino Y, Mukozu T, Matsui D, Matsui T, Wakui N, Shinohara M, Igarashi Y, Sumino Y. Glutathione for Hepatotoxicity in Patients with Liver Cirrhosis and Advanced Hepatocellular Carcinoma Receiving Hepatic Arterial Infusion Chemotherapy. Clin Cancer Drugs. 2015;2(1):54-60. doi:10.2174/2212697X02666150313003755
- Honda Y, Kessoku T, Sumida Y, Kobayashi T, Kato T, Ogawa Y, Tomeno W, Imajo K, Fujita K, Yoneda M, Kataoka K. Efficacy of glutathione for the treatment of nonalcoholic fatty liver disease: an open-label, single-arm, multicenter, pilot study. BMC Gastroenterol. 2017;17(1):96. doi:10.1186/s12876-017-0652-3
- Mardinoglu A, Bjornson E, Zhang C, Klevstig M, Söderlund S, Ståhlman M, Adiels M, Hakkarainen A, Lundbom N, Kilicarslan M, Hallström BM, Lundbom J, Vergès B, Barrett PH, Watts GF, Serlie MJ, Nielsen J, Uhlén M, Smith U, Marschall HU, Taskinen MR, Boren J. Personal model-assisted identification of NAD+ and glutathione metabolism as intervention target in NAFLD. Mol Syst Biol. 2017;13(3):916. doi:10.15252/msb.20167422
- Zhou X, Han D, Xu R, Wu H, Qu C, Wang F, Wang X, Zhao Y. Glycine protects against high sucrose and high fat-induced non-alcoholic steatohepatitis in rats. Oncotarget. 2016;7(49):80223-80237. doi:10.18632/oncotarget.12831
- Abelli J, Méndez-Valdés G, Gómez-Hevia F, Bragato MC, Chichiarelli S, Saso L, Rodrigo R. Potential Antioxidant Multitherapy against Complications Occurring in Sepsis. Biomedicines. 2022;10(12):3088. doi:10.3390/biomedicines10123088
- Macdonald J, Galley HF, Webster NR. Oxidative stress and gene expression in sepsis. Br J Anaesth. 2003;90(2):221-232. doi:10.1093/bja/aeg034
- Biolo G, Antonione R, De Cicco M. Glutathione metabolism in sepsis. Crit Care Med. 2007;35(9 Suppl):S591-595. doi:10.1097/01.CCM.0000278913.19123.13
- Keller GA, Barke R, Harty JT, Humphrey E, Simmons RL. Decreased hepatic glutathione levels in septic shock. Predisposition of hepatocytes to oxidative stress: an experimental approach. Arch Surg Chic Ill 1960. 1985;120(8):941-945. doi:10.1001/archsurg.1985.01390320065013
- Lyons J, Rauh-Pfeiffer A, Ming-Yu Y, Lu XM, Zurakowski D, Curley M, Collier S, Duggan C, Nurko S, Thompson J, Ajami A, Borgonha S, Young VR, Castillo L. Cysteine metabolism and whole blood glutathione synthesis in septic pediatric patients. Crit Care Med. 2001;29(4):870-877. doi:10.1097/00003246-200104000-00036
- Fläring UB, Rooyackers OE, Hebert C, Bratel T, Hammarqvist F, Wernerman J. Temporal changes in whole-blood and plasma glutathione in ICU patients with multiple organ failure. Intensive Care Med. 2005;31(8):1072-1078. doi:10.1007/s00134-005-2687-0
- Ortolani O, Conti A, De Gaudio AR, Moraldi E, Cantini Q, Novelli G. The effect of glutathione and N-acetylcysteine on lipoperoxidative damage in patients with early septic shock. Am J Respir Crit Care Med. 2000;161(6):1907-1911. doi:10.1164/ajrccm.161.6.9903043
- Witschi A, Reddy S, Stofer B, Lauterburg BH. The systemic availability of oral glutathione. Eur J Clin Pharmacol. 1992;43(6):667-669. doi:10.1007/BF02284971
- Milla P, Airoldi M, Weber G, Drescher A, Jaehde U, Cattel L. Administration of reduced glutathione in FOLFOX4 adjuvant treatment for colorectal cancer: effect on oxaliplatin pharmacokinetics, Pt-DNA adduct formation, and neurotoxicity. Anticancer Drugs. 2009;20(5):396-402. doi:10.1097/CAD.0b013e32832a2dc1
- Cascinu S, Cordella L, Del Ferro E, Fronzoni M, Catalano G. Neuroprotective effect of reduced glutathione on cisplatin-based chemotherapy in advanced gastric cancer: a randomized double-blind placebo-controlled trial. J Clin Oncol Off J Am Soc Clin Oncol. 1995;13(1):26-32. doi:10.1200/JCO.1995.13.1.26
- Sechi G, Deledda MG, Bua G, Satta WM, Deiana GA, Pes GM, Rosati G. Reduced intravenous glutathione in the treatment of early parkinson’s disease. Prog Neuropsychopharmacol Biol Psychiatry. 1996;20(7):1159-1170. doi:10.1016/S0278-5846(96)00103-0
- Horowitz RI, Freeman PR, Bruzzese J. Efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia: A report of 2 cases. Respir Med Case Rep. 2020;30:101063. doi:10.1016/j.rmcr.2020.101063
- Pizzorno J. Glutathione! Integr Med Encinitas Calif. 2014;13(1):8-12.