Liver cirrhosis is the consequence of chronicisation and of the evolution of untreated liver diseases. The complexity of the disease and the complications it can cause have been and are still intensively researched, aiming to discover new therapies or improve existing ones for the effective management of liver cirrhosis. Currently, the treatment used is directed against the cause that caused the disease, if it is known; in advanced cases, liver transplantation is the only valid therapeutic option. Hepatoprotectors that are currently on the market are numerous, having as common properties the antioxidant, anti-inflammatory, stabilizing properties of the hepatocytic membrane; A few examples: the ethanolic extract of Curcuma longa, the extract from the plant called Sophora flavescens, the extract of Glycyrrhiza glabra, silymarin (extracted from Sylibum marianum), the extract of Ganoderma lucidum, etc. Liver cirrhosis is accompanied by generalized hypovitaminosis, so supplementing the diet with hydro- and liposoluble vitamins is mandatory. Protein-caloric malnutrition can be prevented by a hyperprotein diet, especially beneficial being the supplementation with branched-chain amino acids, which are also applicable in the prophylaxis and treatment of hepatic encephalopathy. Nanoparticles are a state-of-the-art therapeutic option, proving increased bioavailability, for example polydopamine nanoparticles loaded with l-arginine have been tested as therapy in liver cirrhosis. Among the innovative treatment directions in liver cirrhosis are hybrid products (e.g. hybrid polymer nanoparticles loaded with caffeic acid), cell cultures and artificial or bioartificial liver support.
Tsochatzis EA, Bosch J, Burroughs AK. Liver cirrhosis. Lancet 2014 May 17; 383(9930): 1749–61. https://doi.org/10.1016/S0140-6736(14)60121-5.
Wiegand J, Berg T. The etiology, diagnosis and prevention of liver cirrhosis: part 1 of a series on liver cirrhosis. Dtsch Arztebl Int 2013 Feb; 110(6): 85–91. https://doi.org/10.3238/arztebl.2013.0085.
Kim SU, Oh HJ, Wanless IR, Lee S, Han KH, Park YN. The Laennec staging system for histological sub-classification of cirrhosis is useful for stratification of prognosis in patients with liver cirrhosis. J Hepatol 2012 Sep; 57(3): 556–63. https://doi.org/10.1016/j.jhep.2012.04.029.
Lee SJ, Kim KH, Park KK. Mechanisms of fibrogenesis in liver cirrhosis: the molecular aspects of epithelial-mesenchymal transition. World J Hepatol 2014 Apr 27; 6(4): 207–16. https://doi.org/10.4254/wjh.v6.i4.207.
Cichoz-Lach H, Celiński K, Słomka M, Kasztelan-Szczerbińska B. Pathophysiology of portal hypertension. J Physiol Pharmacol 2008 Aug; 59(Suppl 2): 231–8.
Schuppan D, Afdhal NH. Liver cirrhosis. Lancet 2008 Mar 8; 371(9615): 838–51. https://doi.org/10.1016/S0140-6736(08)60383-9.
Merion RM. Current status and future of liver transplantation. Semin Liver Dis 2010 Nov; 30(4): 411–21. https://doi.org/10.1055/s-0030-1267541.
Hartl J, Scherer MN, Loss M, Schnitzbauer A, Farkas S, Baier L, et al. Strong predictors for alcohol recidivism after liver transplantation: non-acceptance of the alcohol problem and abstinence of <3 months. Scand J Gastroenterol 2011 Oct; 46(10): 1257–66. https://doi.org/10.3109/00365521.2011.603160.
Kornberg A, Küpper B, Tannapfel A, Katenkamp K, Thrum K, Habrecht O, et al. Long-term survival after recurrent hepatocellular carcinoma in liver transplant patients: clinical patterns and outcome variables. Eur J Surg Oncol 2010 Mar; 36(3): 275–80. https://doi.org/10.1016/j.ejso.2009.10.001.
Carbone M, Neuberger JM. Autoimmune liver disease, autoimmunity and liver transplantation. J Hepatol 2014 Jan; 60(1): 210–23. https://doi.org/10.1016/j.jhep.2013.09.020.
Tasdogan BE, Ma M, Simsek C, Saberi B, Gurakar A. Update on immunosuppression in liver transplantation. Euroasian J Hepatogastroenterol 2019 Jul-Dec; 9(2): 96–101. https://doi.org/10.5005/jp-journals-10018-1301.
Valour F, Conrad A, Ader F, Launay O. Vaccination in adult liver transplantation candidates and recipients. Clin Res Hepatol Gastroenterol 2020 Apr; 44(2): 126–134. https://doi.org/10.1016/j.clinre.2019.08.007.
de la Riva GA, López Mendoza FJ, Agüero-Chapin G. Known hepatoprotectors act as antioxidants and immune stimulators in stressed mice: perspectives in animal health care. Curr Pharm Des 2018; 24(40): 4825–4837. https://doi.org/10.2174/1381612825666190116151628.
Salama SM, Abdulla MA, AlRashdi AS, Ismail S, Alkiyumi SS, Golbabapour S. Hepatoprotective effect of ethanolic extract of Curcuma longa on thioacetamide induced liver cirrhosis in rats. BMC Complement Altern Med 2013 Mar 5; 13: 56. https://doi.org/10.1186/1472-6882-13-56.
Sengupta M, Sharma GD, Chakraborty B. Hepatoprotective and immunomodulatory properties of aqueous extract of Curcuma longa in carbon tetra chloride intoxicated Swiss albino mice. Asian Pac J Trop Biomed 2011 Jun; 1(3): 193–9. https://doi.org/10.1016/S2221-1691(11)60026-9.
Ibrahim J, Yusuf A, Abdulrasheed-Adeleke T, Lawal B, Adewuyi A. Antioxidant and hepatoprotective potentials of curcuminoid isolates from turmeric (Curcuma longa) rhizome on CCl 4 -induced hepatic damage in Wistar rats. J Taibah Univ Sci 2020; 14(1): 908–915. https://doi.org/10.1080/16583655.2020.1790928.
Wan XY, Luo M, Li XD, He P. Hepatoprotective and anti-hepatocarcinogenic effects of glycyrrhizin and matrine. Chem Biol Interact 2009 Sep 14; 181(1): 15–9. https://doi.org/10.1016/j.cbi.2009.04.013.
Féher J, Lengyel G. Silymarin in the prevention and treatment of liver diseases and primary liver cancer. Curr Pharm Biotechnol 2012 Jan; 13(1): 210–7. https://doi.org/10.2174/138920112798868818.
Gillessen A, Schmidt HH. Silymarin as supportive treatment in liver diseases: a narrative review. Adv Ther 2020 Apr; 37(4): 1279–1301. https://doi.org/10.1007/s12325-020-01251-y.
Ahmad MF, Ahmad FA, Zeyaullah M, Alsayegh AA, Mahmood SE, AlShahrani AM, et al. Ganoderma lucidum: novel insight into hepatoprotective potential with mechanisms of action. Nutrients 2023 Apr 13; 15(8): 1874. https://doi.org/10.3390/nu15081874.
Rocchi E, Borghi A, Paolillo F, Pradelli M, Casalgrandi G. Carotenoids and liposoluble vitamins in liver cirrhosis. J Lab Clin Med 1991 Aug; 118(2): 176–85.
Carroll ML, Herman B, Willem T, Oscar F, Gilbert RC. B-complex vitamins in liver disease of the alcoholic. The Am J Clin Nutr 1965; 16(4): 339–46. https://doi.org/10.7326/0003-4819-60-4-721_1.
Türkdoğan MK, Ağaoğlu Z, Yener Z, Sekeroğlu R, Akkan HA, Avci ME. The role of antioxidant vitamins (C and E), selenium and Nigella sativa in the prevention of liver fibrosis and cirrhosis in rabbits: new hopes. Dtsch Tierarztl Wochenschr 2001 Feb; 108(2): 71–3.
Zaidi SM, Al-Qirim TM, Banu N. Effects of antioxidant vitamins on glutathione depletion and lipid peroxidation induced by restraint stress in the rat liver. Drugs R D 2005; 6(3): 157–65. https://doi.org/10.2165/00126839-200506030-00004.
Veraldi S, Pietrobattista A, Liccardo D, Basso MS, Mosca A, Alterio T, et al. Fat soluble vitamins deficiency in pediatric chronic liver disease: the impact of liver transplantation. Dig Liver Dis 2020 Mar; 52(3): 308–313. https://doi.org/10.1016/j.dld.2019.10.005.
Adikwu E, Deo O. Hepatoprotective effect of vitamin C (ascorbic acid). Pharmacol Pharm 2013; 4(1): 84–92. https://doi.org/10.4236/pp.2013.41012.
Moriwaki H, Miwa Y, Tajika M, Kato M, Fukushima H, Shiraki M. Branched-chain amino acids as a protein- and energy-source in liver cirrhosis. Biochem Biophys Res Commun 2004 Jan 9; 313(2): 405–9. https://doi.org/10.1016/j.bbrc.2003.07.016.
Nishitani S, Takehana K, Fujitani S, Sonaka I. Branched-chain amino acids improve glucose metabolism in rats with liver cirrhosis. Am J Physiol Gastrointest Liver Physiol 2005 Jun; 288(6): G1292–300. https://doi.org/10.1152/ajpgi.00510.2003.
Muto Y, Sato S, Watanabe A, Moriwaki H, Suzuki K, Kato A, et al. Overweight and obesity increase the risk for liver cancer in patients with liver cirrhosis and long-term oral supplementation with branched-chain amino acid granules inhibits liver carcinogenesis in heavier patients with liver cirrhosis. Hepatol Res 2006 Jul; 35(3): 204–14. https://doi.org/10.1016/j.hepres.2006.04.007.
Kawaguchi T, Taniguchi E, Sata M. Effects of oral branched-chain amino acids on hepatic encephalopathy and outcome in patients with liver cirrhosis. Nutr Clin Pract 2013 Oct; 28(5): 580–8. https://doi.org/10.1177/0884533613496432.
Yoshida T, Muto Y, Moriwaki H, Yamato M. Effect of long-term oral supplementation with branched-chain amino acid granules on the prognosis of liver cirrhosis. Gastroenterol Jpn 1989 Dec; 24(6): 692–8. https://doi.org/10.1007/BF02774169.
Nikolova M, Slavchov R, Nikolova G. Nanotechnology in medicine. In: Hock F, Gralinski M, editors. Drug discovery and evaluation: methods in clinical pharmacology; 2020. p. 533–46.
Pulavendran S, Rose C, Mandal AB. Hepatocyte growth factor incorporated chitosan nanoparticles augment the differentiation of stem cell into hepatocytes for the recovery of liver cirrhosis in mice. J Nanobiotechnology 2011 Apr 28; 9: 15. https://doi.org/10.1186/1477-3155-9-15.
Zhang J, Shen H, Xu J, Liu L, Tan J, Li M, et al. Liver-targeted siRNA lipid nanoparticles treat hepatic cirrhosis by dual antifibrotic and anti-inflammatory activities. ACS Nano 2020 May 26; 14(5): 6305–6322. https://doi.org/10.1021/acsnano.0c02633.
Wang Y, Liu Y, Liu Y, Zhong J, Wang J, Sun L, et al. Remodeling liver microenvironment by L-arginine loaded hollow polydopamine nanoparticles for liver cirrhosis treatment. Biomaterials 2023 Apr; 295: 122028. https://doi.org/10.1016/j.biomaterials.2023.122028.
Wang M, Zhang M, Fu L, Lin J, Zhou X, Zhou P, et al. Liver-targeted delivery of TSG-6 by calcium phosphate nanoparticles for the management of liver fibrosis. Theranostics 2020 Jan 1; 10(1): 36–49. https://doi.org/10.7150/thno.37301.
Wang H, Thorling CA, Liang X, Bridle KR, Grice JE, Zhu Y, et al. Diagnostic imaging and therapeutic application of nanoparticles targeting the liver. J Mater Chem B 2015 Feb 14; 3(6): 939–958. https://doi.org/10.1039/C4TB01611D.
Zhao H, Achreja A, Iessi E, Logozzi M, Mizzoni D, Di Raimo R, et al. The key role of extracellular vesicles in the metastatic process. Biochim Biophys Acta Rev Cancer 2018 Jan; 1869(1): 64–77. https://doi.org/10.1016/j.bbcan.2017.11.005.
Saadeh HA, Mubarak MS. Hybrid drugs as potential combatants against drug-resistant microbes: a review. Curr Top Med Chem 2017; 17(8): 895–906. https://doi.org/10.2174/1568026616666160927155251.
Zai W, Chen W, Wu Z, Jin X, Fan J, Zhang X, et al. Targeted interleukin-22 gene delivery in the liver by polymetformin and penetratin-based hybrid nanoparticles to treat nonalcoholic fatty liver disease. ACS Appl Mater Inter 2019 Feb 6; 11(5): 4842–4857. https://doi.org/10.1021/acsami.8b19717.
Ansari M, Rahman M, Alrobaian M, Almalki WH, Alharbi KS, Altowayan WM, et al. Caffeic acid loaded lipid polymer hybrid nanoparticles: ex vivo and pre-clinical evaluation against liver cirrhosis. J Cluster Sci 2023; 34: 1757–1768. https://doi.org/10.1007/s10876-022-02283-w.
Stadlbauer V, Wright G, Jalan R. Role of artificial liver support in hepatic encephalopathy. Metab Brain Dis 2009; 24: 15–26. https://doi.org/10.1007/s11011-008-9117-2.
Mazariegos GV, Patzer JF II, Lopez RC, Giraldo M, Grogan TA, Devera ME, et al. First clinical use of a novel bioartificial liver support system (BLSS). Am J Transpl 2002; 2: 260–266. https://doi.org/10.1034/j.1600-6143.2002.20311.x.
Miwa Y, Ellis AJ, Hughes RD, Langley PG, Wendon JA, Williams R. Effect of ELAD liver support on plasma HGF and TGF-beta 1 in acute liver failure. Int J Artif Organs 1996; 19: 240–244. https://doi.org/10.1177/039139889601900406.
Stadlbauer V, Wright GA, Banaji M, Mukhopadhya A, Mookerjee RP, Moore K, et al. Relationship between activation of the sympathetic nervous system and renal blood flow autoregulation in cirrhosis. Gastroenterology 2008 Jan; 134(1): 111–9. https://doi.org/10.1053/j.gastro.2007.10.055.
Sen S, Rose C, Ytrebo LM. Effect of albumin dialysis on intracranial pressure increase in pigs with acute liver failure: a randomized study. Crit Care Med 2006; 34: 158–164. https://doi.org/10.1097/01.CCM.0000196203.39832.3C.
Doria C, Marino IR. Bacteremia using the molecular adsorbent recirculating system in patients bridged to liver transplantation. Exp Clin Transpl 2005; 3: 289–292.
Hughes RD, Nicolaou N, Langley PG, Ellis AJ, Wendon JA, Williams R. Plasma cytokine levels and coagulation and complement activation during use of the extracorporeal liver assist device in acute liver failure. Artif Organs 1998; 22: 854–858. https://doi.org/10.1046/j.1525-1594.1998.06162.x.
Lanza RP, Chung HY, Yoo JJ, Wettstein PJ, Blackwell C, Borson N, et al. Generation of histocompatible tissues using nuclear transplantation. Nat Biotechnol 2002 Jul; 20(7): 689–96. https://doi.org/10.1038/nbt703.
Aebischer P, Ip TK, Panol G, Galletti PM. The bioartificial kidney: progress towards an ultrafiltration device with renal epithelial cells processing. Life Support Syst 1987 Apr-Jun; 5(2): 159–68.