, Volume 46, Issue 6, pp 793–799 | Cite as

Endotoxinemia contributes to steatosis, insulin resistance and atherosclerosis in chronic hepatitis C: the role of pro-inflammatory cytokines and oxidative stress

  • Rosa Zampino
  • Aldo Marrone
  • Luca Rinaldi
  • Barbara Guerrera
  • Riccardo Nevola
  • Adriana Boemio
  • Natalina Iuliano
  • Mauro Giordano
  • Nicola Passariello
  • Ferdinando C. Sasso
  • Emanuele Albano
  • Luigi E. AdinolfiEmail author
Original Paper



Endotoxin is a component of the outer membrane of gram-negative bacteria that live in the intestine. Endotoxinemia is reported in non-alcoholic fatty liver disease and in cirrhotic patients, causing various biological and clinical effects in the host. It is not known whether endotoxinemia occurs in chronic hepatitis C patients (CHC), therefore we evaluated the occurrence of endotoxinemia and its effect on inflammation, liver damage, insulin resistance (IR) and atherosclerosis.


Consecutive CHC patients assessed by liver biopsy were enrolled. Endotoxinemia was evaluated by LAL test. IR was estimated by HOMA-IR. Serum TNF-α, IL-8, adiponectin and MCP-1 were measured with ELISA tests. Oxidative stress was estimated by circulating IgG against malondialdehyde adducts with human serum albumin (MDA-HAS). Carotid atherosclerosis was assessed by ultrasonography.


Endotoxinemia was found in 60% of the 126 patients enrolled. A serum level-dependent association between endotoxinemia, steatosis (p < 0.001) and HOMA-IR (p < 0.006) was observed. Patients with endotoxinemia showed significant increase in TNF-α and IL8 levels. TNF-α correlated with steatosis (p <  0.001) and HOMA-IR (p < 0.03), whereas IL8 correlated with steatosis (p =  <0.001), TNF-α (p < 0.04) and atherosclerosis (p < 0.01). The highest levels of endotoxinemia were associated with oxidative stress and a higher prevalence of carotid atherosclerosis. Multivariate logistic regression analysis showed that the independent factors associated with endotoxinemia were hepatic steatosis, HOMA-IR, IL8 and MDA-HAS.


Endotoxinemia occurs with high frequency in CHC patients and contributes to the development of hepatic steatosis, IR and atherosclerosis through increased pro-inflammatory cytokines and oxidative stress. Anti-endotoxin treatment could be of clinical relevance.


Endotoxin Chronic hepatitis C Steatosis Insulin resistance 


Compliance with ethical standards

Conflict of interest

There are none to declare.


  1. 1.
    Glaros TG, Chang S, Gilliam EA, Maitra U, Deng H, Li L. Causes and consequences of low grade endotoxemia and inflammatory diseases. Front Biosci. 2013;5:754–65.CrossRefGoogle Scholar
  2. 2.
    Gaeta GB, Perna P, Adinolfi LE, et al. Endotoxemia in a series of 104 patients with chronic liver diseases: prevalence and significance. Digestion. 1982;23:239–44.CrossRefGoogle Scholar
  3. 3.
    Pascual S, Such J, Esteban A, et al. Intestinal permeability is increased in patients with advanced cirrhosis. Hepatogastroenterology. 2003;50:1482–86.PubMedGoogle Scholar
  4. 4.
    Pendyala S, Walker JM, Holt PR. A high-fat diet is associated with endotoxemia that originates from the gut. Gastroenterology. 2012;142:1100–101.CrossRefGoogle Scholar
  5. 5.
    Thuy S, Ladurner R, Volynets V, et al. Nonalcoholic fatty liver disease in humans is associated with increased plasma endotoxin and plasminogen activator inhibitor 1 concentrations and with fructose intake. J Nutr. 2008;138:1452–55.CrossRefGoogle Scholar
  6. 6.
    Yuan J, Baker SS, Liu W, et al. Endotoxemia unrequired in the pathogenesis of pediatric nonalcoholic steatohepatitis. J Gastroenterol Hepatol. 2014;29:1292–8.CrossRefGoogle Scholar
  7. 7.
    Anderson PD, Mehta NN, Wolfe ML, et al. Innate immunity modulates adipokines in humans. J Clin Endocrinol Metab. 2007;92:2272–279.CrossRefGoogle Scholar
  8. 8.
    Boroni Moreira AP, de Cássia Gonçalves Alfenas R. The influence of endotoxemia on the molecular mechanisms of insulin resistance. Nutr Hosp. 2012;27:382–90.PubMedGoogle Scholar
  9. 9.
    Adinolfi LE, Gambardella M, Andreana A, Tripodi MF, Utili R, Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology. 2001;33:1358–364.CrossRefGoogle Scholar
  10. 10.
    Lonardo A, Adinolfi LE, Loria P, Carulli N, Ruggiero G, Day CP. Steatosis and hepatitis C: mechanisms and significance for hepatic and extrahepatic disease. Gastroenterology. 2004;126:586–97.CrossRefGoogle Scholar
  11. 11.
    Adinolfi LE, Restivo L, Zampino R, et al. Chronic HCV infection is a risk of atherosclerosis. Role of HCV and HCV-related steatosis. Atherosclerosis. 2012;221:496–502.CrossRefGoogle Scholar
  12. 12.
    Ishak K, Baptista A, Bianchi L, et al. Histological grading and staging of chronic hepatitis. J Hepatol. 1995;22:696–99.CrossRefGoogle Scholar
  13. 13.
    Vidali M, Tripodi MF, Ivaldi A, et al. Interplay between oxidative stress and hepatic steatosis in the progression of chronic hepatitis C. J Hepatol. 2008;48:399–406.CrossRefGoogle Scholar
  14. 14.
    Tsui JI, Whooley MA, Monto A, Seal K, Tien PC, Shlipak M. Association of hepatitis C virus seropositivity with inflammatory markers and heart failure in persons with coronary heart disease: data from the Heart and Soul study. J Card Fail. 2009;15:451–56.CrossRefGoogle Scholar
  15. 15.
    Oliveira CP, Kappel CR, Siqueira ER, et al. Effects of hepatitis C virus on cardiovascular risk in infected patients: a comparative study. Int J Cardiol. 2013;164:221–26.CrossRefGoogle Scholar
  16. 16.
    Cani PD, Amar J, Iglesias MA, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56:1761–72.CrossRefGoogle Scholar
  17. 17.
    Sakaguchi S, Furusawa S. Oxidative stress and septic shock: metabolic aspects of oxygen-derived free radicals generated in the liver during endotoxemia. FEMS Pathog Dis. 2006;47:167–77.Google Scholar
  18. 18.
    Baffy G. Kupffer cells in non-alcoholic fatty liver disease: the emerging view. J Hepatol. 2009;51:212–23.CrossRefGoogle Scholar
  19. 19.
    Rabelo F, Oliveira CP, Faintuch J, et al. Pro- and anti-inflammatory cytokines in steatosis and steatohepatitis. Obes Surg. 2010;20:906–12.CrossRefGoogle Scholar
  20. 20.
    Miele L, Valenza V, La Torre G, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology. 2009;49:1877–887.CrossRefGoogle Scholar
  21. 21.
    Brun P, Castagliuolo I, Pinzani M, Palù G, Martines D. Exposure to bacterial cell wall products triggers an inflammatory phenotype in hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2005;289:G571–8.CrossRefGoogle Scholar
  22. 22.
    Schnabl B, Brandl K, Fink M, et al. A TLR4/MD2 fusion protein inhibits LPS-induced pro-inflammatory signaling in hepatic stellate cells. Biochem Biophys Res Commun. 2008;375:210–14.CrossRefGoogle Scholar
  23. 23.
    Henao-Mejia J, Elinav E, Jin C, et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature. 2012;482:179–85.CrossRefGoogle Scholar
  24. 24.
    Ceccarelli S, Panera N, Mina M, et al. LPS-induced TNF-α factor mediates pro-inflammatory and pro-fibrogenic pattern in non-alcoholic fatty liver disease. Oncotarget. 2015;6:41434–52.CrossRefGoogle Scholar
  25. 25.
    Ruiz AG, Casafont F, Crespo J, et al. Lipopolysaccharide-binding protein plasma levels and liver TNF-alpha gene expression in obese patients: evidence for the potential role of endotoxin in the pathogenesis of non-alcoholic steatohepatitis. Obes Surg. 2007;17:1374–380.CrossRefGoogle Scholar
  26. 26.
    Durante-Mangoni E, Zampino R, Marrone A, et al. Hepatic steatosis and insulin resistance are associated with serum imbalance of adiponectin/tumour necrosis factor-alpha in chronic hepatitis C patients. Aliment Pharmacol Ther. 2006;24:1349–457.CrossRefGoogle Scholar
  27. 27.
    Ashour E, Samy N, Sayed M, Imam A. The relationship between serum adiponectin and steatosis in patients with chronic hepatitis C genotype-4. Clin Lab. 2010;56:103–10.PubMedGoogle Scholar
  28. 28.
    Dolganiuc A, Norkina O, Kodys K, et al. Viral and host factors induce macrophage activation and loss of toll-like receptor tolerance in chronic HCV infection. Gastroenterology. 2007;133:1627–636.CrossRefGoogle Scholar
  29. 29.
    Sandler NG, Koh C, Roque A, et al. Host response to translocated microbial products predicts outcomes of patients with HBV or HCV infection. Gastroenterology. 2011;141:1220–230.CrossRefGoogle Scholar
  30. 30.
    Sakaguchi S, Furusawa S. Oxidative stress and septic shock. FEMS Immunol Med Microbiol. 2006;47:167–77.CrossRefGoogle Scholar
  31. 31.
    González-Gallego J, García-Mediavilla MV, Sánchez-Campos S. Hepatitis C, Virus. Oxidative stress and steatosis: current status and perspectives. Curr Mol Med. 2011;11:373–90.CrossRefGoogle Scholar
  32. 32.
    Lonardo A, Nascimbeni F, Maurantonio M, Marrazzo A, Rinaldi L, Adinolfi LE. Non-alcoholic fatty liver disease: evolving paradigms. World J Gastroenterol. 2017;23:6571–92.CrossRefGoogle Scholar
  33. 33.
    Suganami T, Tanimoto-Koyama K, Nishida J, et al. Role of the Toll-like receptor 4/NF-kappaB pathway in saturated fatty acid-induced inflammatory changes in the interaction between adipocytes and macrophages. Arterioscler Thromb Vasc Biol. 2007;27:84–91.CrossRefGoogle Scholar
  34. 34.
    Carreau A, Kieda C, Grillon C. Nitric oxide modulates the expression of endothelial cell adhesion molecules involved in angiogenesis and leukocyte recruitment. Exp Cell Res. 2011;317:29–41.CrossRefGoogle Scholar
  35. 35.
    Xi H, Akishita M, Nagai K, et al. Potent free radical scavenger, edaravone, suppresses oxidative stress-induced endothelial damage and early atherosclerosis. Atherosclerosis. 2007;191:281–89.CrossRefGoogle Scholar
  36. 36.
    Remick GD. Interleukin-8. Crit Care Med. 2005;33:s646–s647.CrossRefGoogle Scholar
  37. 37.
    De Forg LE, Preston AM, Takeuchi E, Kenney J, Boxer LA, Remick DG. Regulation of interleukin 8 gene expression by oxidant stress. J Biol Chem. 1993;268:568–76.Google Scholar
  38. 38.
    Apostolakis S, Vogiatzi K, Amanatidou V, Spandidos DA. Interleukin 8 and cardiovascular disease. Cardiovasc Res. 2009;84:353–60.CrossRefGoogle Scholar
  39. 39.
    Weber KS, von Hundelshausen P, Clark-Lewis I, Weber PC, Weber C. Differential immobilization and hierarchical involvement of chemokines in monocyte arrest and transmigration on inflamed endothelium in shear flow. Eur J Immunol. 1999;29:700–12.CrossRefGoogle Scholar
  40. 40.
    Simonini A, Moscucci M, Muller DWM, et al. IL-8 is an angiogenic factor in human coronary atherectomy tissue. Circulation. 2000;101:1519–26.CrossRefGoogle Scholar
  41. 41.
    Ait-Belgnaoui A, Durand H, Cartier C, et al. Prevention of gut leakiness by a probiotic treatment leads to attenuated HPA response to an acute psychological stress in rats. Psychoneuroendocrinology. 2012;37:1885–95.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Rosa Zampino
    • 1
  • Aldo Marrone
    • 1
  • Luca Rinaldi
    • 1
  • Barbara Guerrera
    • 1
  • Riccardo Nevola
    • 1
  • Adriana Boemio
    • 1
  • Natalina Iuliano
    • 1
  • Mauro Giordano
    • 1
  • Nicola Passariello
    • 1
  • Ferdinando C. Sasso
    • 1
  • Emanuele Albano
    • 2
  • Luigi E. Adinolfi
    • 1
    Email author
  1. 1.Department of Medical, Surgical, Neurological, Metabolic, and Aging SciencesUniversity of Campania “L. Vanvitelli”NaplesItaly
  2. 2.Department of Health Sciences and Interdisciplinary Research Center for Autoimmune DiseasesUniversity Amedeo Avogadro of East PiedmontNovaraItaly

Personalised recommendations