The Molecular and Cellular Underpinnings of Cirrhosis of the Liver


  • Manjeer Mitra Greenwood High School
  • Anush Swaminathan Yale University



liver, cirrhosis, hepatology, fibrosis


Cirrhosis is among the leading causes of death worldwide, making up 3.5% of global deaths. It is characterized by the replacement of the liver parenchyma with fibrotic tissue and progressively leads to complete failure of the organ. It is classified into 2 types – compensated and decompensated based on the complications such as esophageal varices, hepatic encephalopathy, asterixis, and ascites. The 2 main contributors of the disease include infection and alcohol use and these, in turn, affect 4 main cell types- Hepatic Stellate Cells, Hepatocytes, LSECs, Kupffer Cells. Commonly observed in patients with cirrhosis, stellate cells are characterized by a change in phenotype often seen in wound healing mechanisms and high proliferation whereas the apoptosis of hepatocytes is a key feature leading to inflammation. The polarization of Kupffer Cells leading to the secretion of proinflammatory cytokines is another key cause of cirrhosis and the change from a fenestrated to a smooth, capillarized phenotype is observed in Sinusoidal Endothelial Cells. The role of cirrhosis on the immunology of the liver is another important topic where changes in the concentration of complement proteins, cytokines can affect the number of dendritic cells and in turn, cause pro- and anti-inflammatory responses. Modern treatment for cirrhosis has been shaped based on these cells, complications, and molecules. In this review, we shall discuss all these topics in greater detail along with interesting ideas such as the reversibility of fibrosis as well as the future research on treatments, based on the current findings.


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Author Biography

Anush Swaminathan, Yale University


References or Bibliography

Asrani SK, Devarbhavi H, Eaton J, Kamath PS. “Burden of liver diseases in the world.” J Hepatol. 70, no. 1 (2019): 151-171. doi: 10.1016/j.jhep.2018.09.014.

Finkelstein, E. A., Khavjou, O. A., Thompson, H., Trogdon, J. G., Pan, L., Sherry, B., & Dietz, W. “Obesity and Severe Obesity Forecasts Through 2030.”. American Journal of Preventive Medicine. 42, no. 6 (2012): 563–570. doi: 10.1016/j.amepre.2011.10.026.

Ge PS, Runyon BA. “Treatment of Patients with Cirrhosis”. N Engl J Med. Aug 2016: 767-777. doi: 10.1056/NEJMra1504367.

Samonakis, Dimitrios N et al. “Clinical outcomes of compensated and decompensated cirrhosis: A long term study.” World journal of hepatology 6, no. 7 (2014): 504-512. doi: 10.4254/wjh.v6.i7.504

Axley Page, Mudumbi Sandhya, Sarker Shabnam, Kuo Yong Fang, Singal Ashwani “Patients with stage 3 compared to stage 4 liver fibrosis have lower frequency of and longer time to liver disease complications.” . PloS One . 13, no. 5 (2018): Article No. e0197117. doi: 10.1371/journal.pone.0197117

Plauth M, Cabré E, Riggio O, et al. “guidelines on enteral nutrition: liver disease” . ESPEN.Clin Nutr 25 (2006): 285-294. doi: 10.1016/j.clnu.2018.12.022

Córdoba J, López-Hellín J, Planas M,et al. “Normal protein diet for episodic hepatic encephalopathy: results of a randomized study”. J Hepatol 41 (2004): 38-43.

Pinzani M, Rombouts K. “Liver fibrosis: From the bench to clinical targets”. Dig Liver Dis 36 (2004): 231–242. doi: 10.1016/j.dld.2004.01.003

Elsharkawy AM, Oakley F, Mann DA. “The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis”. Apoptosis. 10, no. 5 (2005): 927-939. doi: 10.1007/s10495-005-1055-4.

Saile B, Matthes N, Knittel T, Ramadori G. “Transforming growth factor beta and tumor necrosis factor alpha inhibit both apoptosis and proliferation of activated rat hepatic stellate cells”. Hepatology. 30, no. 1 (1999): 196-202. doi: 10.1002/hep.510300144.

Saile B, Eisenbach C, Dudas J, El-Armouche H, Ramadori G. “Interferon-gamma acts proapoptotic on hepatic stellate cells (HSC) and abrogates the antiapoptotic effect of interferon-alpha by an HSP70-dependant pathway”. Eur J Cell Biol. 83, no. 9 (2004): 469-476. doi: 10.1078/0171-9335-00409.

Saxena NK, Titus MA, Ding X, Floyd J, Srinivasan S, Sitaraman SV, Anania FA. “Leptin as a novel profibrogenic cytokine in hepatic stellate cells: mitogenesis and inhibition of apoptosis mediated by extracellular regulated kinase (Erk) and Akt phosphorylation” . FASEB J. 18, no. 13 (2004):1612-1614. doi: 10.1096/fj.04-1847fje.

Zhou, Z., Xu, MJ. & Gao, B. “Hepatocytes: a key cell type for innate immunity”. Cell Mol Immunol 13, (2016): 301–315. doi: 10.1038/cmi.2015.97

Zhou WC, Zhang QB, Qiao L. “Pathogenesis of liver cirrhosis”. World J Gastroenterol. 20, no. 23 (2014): 7312-7324. doi: 10.3748/wjg.v20.i23.7312

Tanaka M, Miyajima A. “Liver regeneration and fibrosis after inflammation”. Inflammation and Regeneration. 36, no. 1 (2016):19-24. doi: 10.1186/s41232-016-0025-2.

Zeng T, Zhang CL, Xiao M, Yang R, Xie KQ. “Critical Roles of Kupffer Cells in the Pathogenesis of Alcoholic Liver Disease: From Basic Science to Clinical Trials”. Frontiers in Immunology. 7, no. 10 (2016): 1-14. doi: 10.3389/fimmu.2016.00538

Gordon S, Taylor PR. “Monocyte and macrophage heterogeneity”. Nat Rev Immunol 5, no. 12 (2005): 953–964. doi: 10.1038/nri1733

Dixon LJ, Barnes M, Tang H, Pritchard MT, Nagy LE. “Kupffer cells in the liver”.Compr Physiol 3, no. 2 (2013):785–797. doi: 10.1002/cphy.c120026

Hersoug LG, Moller P, Loft S. “Gut microbiota-derived lipopolysaccharide uptake and trafficking to adipose tissue: implications for inflammation and obesity”. Obes Rev 17, no. 4 (2016): 297–312. doi: 10.1111/obr.12370

Betteridge DJ. “What is oxidative stress?” Metabolism. 49, no. 2 (2000):3-8. doi: 10.1016/s0026-0495(00)80077-3.

Petrasek J, Bala S, Csak T, Lippai D, Kodys K, Menashy V, et al. “IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice” . J Clin Invest 122, no. 10 (2012): 3476–3489. doi: 10.1172/JCI60777

Baiocchini A, Del Nonno F, Taibi C, et. al. “Liver sinusoidal endothelial cells (LSECs) modifications in patients with chronic hepatitis C.” Scientific reports 9, no. 8760 (2019): 1-10. doi: 10.1038/s41598-019-45114-1

Shetty S., Lalor P. F., Adams, D. H. “Lymphocyte recruitment to the liver: molecular insights into the pathogenesis of liver injury and hepatitis”. Toxicology 254 (2008): 136–146. doi: 10.1016/j.tox.2008.08.003

Xing Y., Zhao T., Gao X., Wu Y. “Liver X receptor α is essential for the capillarization of liver sinusoidal endothelial cells in liver injury,” Scientific. Reports. 6, no. 21309 (2016): 1-11. doi: 10.1038/srep21309

Yang F, Yang XP, Liu YH, et al. “Ac-SKDP reverses inflammation and fibrosis in rats with heart failure after myocardial infarction”. Hypertension 43, no. 2 (2004): 229–236. doi: 10.1161/01.HYP.0000107777.91185.89

Tripodi, A et al. “Hypercoagulability in cirrhosis: causes and consequences.” Journal of thrombosis and haemostasis 9, no. 9 (2011): 1713-1723. doi: 10.1111/j.1538-7836.2011.04429.x

Vaquero Javier, and Bañares Rafael. “A gut solution for hepatic encephalopathy.” Hepatology 61, no. 6 (2015): 2107-2109. doi: 10.1002/hep.27784

Koo Hoonmo L, and DuPont Herbert L. “Rifaximin: a unique gastrointestinal-selective antibiotic for enteric diseases.” Current Opinion in Gastroenterology 26, no. 1 (2010): 17-25. doi: 10.1097/MOG.0b013e328333dc8d

Northup PG, Wanamaker RC, Lee VD, Adams RB, Berg CL. “Model for End-Stage Liver Disease (MELD) predicts nontransplant surgical mortality in patients with cirrhosis”. Ann Surg 242 (2005): 244-251. doi: 10.1097/01.sla.0000171327.29262.e0

Fernández J, Ruiz del Arbol L, Gómez C, et al. Norfloxacin vs ceftriaxone in the prophylaxis of infections in patients withadvanced cirrhosis and hemorrhage. Gastroenterology 131, no. 4, (2006): 1049-1056. doi: 10.1053/j.gastro.2006.07.010

Mellinger, Jessica L et al. “Misconceptions, preferences and barriers to alcohol use disorder treatment in alcohol-related cirrhosis.” Journal of Substance Abuse Treatment 91 (2018): 20-27. doi: 10.1016/j.jsat.2018.05.003

Noor Mohd Talha, and Manoria Piyush. “Immune Dysfunction in Cirrhosis.” Journal of Clinical and Translational Hepatology 5, no. 1 (2017): 50-58. doi: 10.14218/JCTH.2016.00056

Albillos, Agustín et al. “Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance.” Journal of Hepatology 61, no. 6 (2014): 1385-1396. doi: 10.1016/j.jhep.2014.08.010

Sipeki N, Antal-Szalmas P, Lakatos PL, Papp M. “Immune dysfunction in cirrhosis”. World J Gastroenterology 20 (2014):2564–2577. doi: 10.3748/wjg. v20.i10.2564.

Neish AS. “Microbes in gastrointestinal health and disease”. Gastroenterology 136 (2009):65–80. doi: 10.1053/j.gastro.2008.10.080.

Newton K, Dixit VM. “Signaling in innate immunity and inflammation”. Cold Spring Harb Perspect Biol 4 (2012). doi: 10.1101/cshperspect. a006049.

Thompson AJ, Locarnini SA, Lau GK, Naoumov NV, Desmond PV, Mommeja- Marin H, et al. “Quantitative HBeAg levels and patterns of TLR2 and TLR4 expression on CD14+ monocytes during potent antiviral therapy for chronic hepatitis” B. J Gastroenterol Hepatol 20, no. A83 (2005). doi: 10.14218/JCTH.2016.00056

Hillebrandt S, Wasmuth HE, Weiskirchen R, Hellerbrand C, Keppeler H, Werth A, et al. “Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans”. Nat Genet 37 (2005):835–843. doi: 10.1038/ng1599.

Fleming KM, Aithal GP, Card TR, West J. “All-cause mortality in people with cirrhosis compared with the general population:a population-based cohort study”. Liver Int 32 (2012): 79-84. doi : 10.1111/j.1478-3231.2011.02517.x

Zeng, Tao et al. “Critical Roles of Kupffer Cells in the Pathogenesis of Alcoholic Liver Disease: From Basic Science to Clinical Trials.” Frontiers in Immunology 7 (2016): 538. doi:10.3389/fimmu.2016.00538

Tsutsui, Hiroko, and Shuhei Nishiguchi. “Importance of Kupffer cells in the development of acute liver injuries in mice.” International Journal of Molecular Sciences 15, no. 5 (2014): 7711-7730. doi:10.3390/ijms15057711



How to Cite

Mitra, M., & Swaminathan, A. (2022). The Molecular and Cellular Underpinnings of Cirrhosis of the Liver. Journal of Student Research, 11(2).



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