Hepatitis Monthly

Published by: Kowsar

Portal Hypertension as Immune Mediate Disease

Sara Manti 1 , Lucia Marseglia 1 , Gabriella D Angelo 1 , Martina Filippelli 1 , Caterina Cuppari 1 , Eloisa Gitto 1 , Claudio Romano 1 , Teresa Arrigo 1 , * and Carmelo Salpietro 1
Authors Information
1 Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
Article information
  • Hepatitis Monthly: June 01, 2014, 14 (6); e18625
  • Published Online: June 7, 2014
  • Article Type: Review Article
  • Received: February 27, 2014
  • Accepted: April 13, 2014
  • DOI: 10.5812/hepatmon.18625

To Cite: Manti S, Marseglia L, D Angelo G, Filippelli M, Cuppari C, et al. Portal Hypertension as Immune Mediate Disease, Hepat Mon. 2014 ; 14(6):e18625. doi: 10.5812/hepatmon.18625.

Copyright © 2014, Kowsar Corp. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.
1. Context
2. Evidence Acquisition
3. Results
4. Conclusions
  • 1. Imanieh MH, Dehghani SM, Khoshkhui M, Malekpour A. Etiology of Portal Hypertension in Children: A Single Center’s Experiences. Middle East J Dig Dis . 2012; 4(4): 206-10
  • 2. Vargas HE, Gerber D, Abu-Elmagd K. Management of portal hypertension-related bleeding. Surg Clin North Am. 1999; 79(1): 1-22[PubMed]
  • 3. Gugig R, Rosenthal P. Management of portal hypertension in children. World J Gastroenterol. 2012; 18(11): 1176-84[DOI][PubMed]
  • 4. Garcia-Tsao G, Sanyal AJ, Grace ND, Carey WD, Practice Guidelines Committee of American Association for Study of Liver D, Practice Parameters Committee of American College of G. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Am J Gastroenterol. 2007; 102(9): 2086-102[DOI][PubMed]
  • 5. Gupta TK, Toruner M, Chung MK, Groszmann RJ. Endothelial dysfunction and decreased production of nitric oxide in the intrahepatic microcirculation of cirrhotic rats. Hepatology. 1998; 28(4): 926-31[DOI][PubMed]
  • 6. Aller MA, Arias JL, Cruz A, Arias J. Inflammation: a way to understanding the evolution of portal hypertension. Theor Biol Med Model. 2007; 4: 44[DOI][PubMed]
  • 7. Piascik MT, Soltis EE, Piascik MM, Macmillan LB. Alpha-adrenoceptors and vascular regulation: molecular, pharmacologic and clinical correlates. Pharmacol Ther. 1996; 72(3): 215-41[PubMed]
  • 8. Coll M, Martell M, Raurell I, Ezkurdia N, Cuenca S, Hernandez-Losa J, et al. Atrophy of mesenteric sympathetic innervation may contribute to splanchnic vasodilation in rat portal hypertension. Liver Int. 2010; 30(4): 593-602[DOI][PubMed]
  • 9. Bockx I, Verdrengh K, Vander Elst I, van Pelt J, Nevens F, Laleman W, et al. High-frequency vagus nerve stimulation improves portal hypertension in cirrhotic rats. Gut. 2012; 61(4): 604-12[DOI][PubMed]
  • 10. Valeria C, Lacquaniti A, Salpietro V, Nicoletta L, Ferrau V, Piraino B, et al. Thyroid dysfunction in thalassaemic patients: ferritin as a prognostic marker and combined iron chelators as an ideal therapy. Eur J Endocrinol. 2013; 169(6): 785-93[DOI][PubMed]
  • 11. Saito K, Nakanuma Y, Takegoshi K, Ohta G, Obata Y, Okuda K, et al. Non-specific immunological abnormalities and association of autoimmune diseases in idiopathic portal hypertension. A study by questionnaire. Hepatogastroenterology. 1993; 40(2): 163-6[PubMed]
  • 12. Carreras LO, Defreyn G, Machin SJ, Vermylen J, Deman R, Spitz B, et al. Arterial thrombosis, intrauterine death and "lupus" antiocoagulant: detection of immunoglobulin interfering with prostacyclin formation. Lancet. 1981; 1(8214): 244-6[PubMed]
  • 13. Goldschmidt I, Baumann U. Hepatic fibrosis in paediatric liver disease. Clin Res Hepatol Gastroenterol. 2012; 36(3): 268-70[DOI][PubMed]
  • 14. Malamut G, Ziol M, Suarez F, Beaugrand M, Viallard JF, Lascaux AS, et al. Nodular regenerative hyperplasia: the main liver disease in patients with primary hypogammaglobulinemia and hepatic abnormalities. J Hepatol. 2008; 48(1): 74-82[DOI][PubMed]
  • 15. Nakanuma Y, Sato Y, Kiktao A. Pathology and pathogenesis of portal venopathy in idiopathic portal hypertension: Hints from systemic sclerosis. Hepatol Res. 2009; 39(10): 1023-31[DOI][PubMed]
  • 16. Buck M, Garcia-Tsao G, Groszmann RJ, Stalling C, Grace ND, Burroughs AK, et al. Novel inflammatory biomarkers of portal pressure in compensated cirrhosis patients. Hepatology. 2014; 59(3): 1052-9[DOI][PubMed]
  • 17. Elsing C, Harenberg S, Stremmel W, Herrmann T. Serum levels of soluble Fas, nitric oxide and cytokines in acute decompensated cirrhotic patients. World J Gastroenterol. 2007; 13(3): 421-5[PubMed]
  • 18. Rizzoni D, Porteri E, Guefi D, Piccoli A, Castellano M, Pasini G, et al. Cellular hypertrophy in subcutaneous small arteries of patients with renovascular hypertension. Hypertension. 2000; 35(4): 931-5[PubMed]
  • 19. Xia Z, Wang G, Wan C, Liu T, Wang S, Wang B, et al. Expression of NALP3 in the spleen of mice with portal hypertension. J Huazhong Univ Sci Technolog Med Sci. 2010; 30(2): 170-2[DOI][PubMed]
  • 20. Prieto I, Jimenez F, Aller MA, Nava MP, Vara E, Garcia C, et al. Tumor necrosis factor-alpha, interleukin-1beta and nitric oxide: induction of liver megamitochondria in prehepatic portal hypertensive rats. World J Surg. 2005; 29(7): 903-8[DOI][PubMed]
  • 21. Mirodzhov GK, Avezov SA, Giiasov MM, Abdullaeva ZM. [The role of interleukin-6 and nitric oxide in pathogenesis of portal hypertension and decompensation of liver cirrhosis]. Klin Med (Mosk). 2012; 90(1): 47-9[PubMed]
  • 22. Trebicka J, Krag A, Gansweid S, Schiedermaier P, Strunk HM, Fimmers R, et al. Soluble TNF-alpha-receptors I are prognostic markers in TIPS-treated patients with cirrhosis and portal hypertension. PLoS One. 2013; 8(12)[DOI][PubMed]
  • 23. Tazi KA, Moreau R, Herve P, Dauvergne A, Cazals-Hatem D, Bert F, et al. Norfloxacin reduces aortic NO synthases and proinflammatory cytokine up-regulation in cirrhotic rats: role of Akt signaling. Gastroenterology. 2005; 129(1): 303-14[PubMed]
  • 24. Withers DR, Kim MY, Bekiaris V, Rossi SW, Jenkinson WE, Gaspal F, et al. The role of lymphoid tissue inducer cells in splenic white pulp development. Eur J Immunol. 2007; 37(11): 3240-5[DOI][PubMed]
  • 25. Francque S, Laleman W, Verbeke L, Van Steenkiste C, Casteleyn C, Kwanten W, et al. Increased intrahepatic resistance in severe steatosis: endothelial dysfunction, vasoconstrictor overproduction and altered microvascular architecture. Lab Invest. 2012; 92(10): 1428-39[DOI][PubMed]
  • 26. Tokushige K, Yamauchi K, Komatsu T, Takasaki K, Hayashi N. Predominant T helper 1 cells in patients with idiopathic portal hypertension. J Gastroenterol Hepatol. 2000; 15(11): 1312-7[PubMed]
  • 27. Muschen M, Warskulat U, Peters-Regehr T, Bode JG, Kubitz R, Haussinger D. Involvement of CD95 (Apo-1/Fas) ligand expressed by rat Kupffer cells in hepatic immunoregulation. Gastroenterology. 1999; 116(3): 666-77[PubMed]
  • 28. Lemaigre F, Zaret KS. Liver development update: new embryo models, cell lineage control, and morphogenesis. Curr Opin Genet Dev. 2004; 14(5): 582-90[DOI][PubMed]
  • 29. Li ZF, Zhang S, Lv GB, Huang Y, Zhang W, Ren S, et al. Changes in count and function of splenic lymphocytes from patients with portal hypertension. World J Gastroenterol. 2008; 14(15): 2377-82[PubMed]
  • 30. Ziol M, Poirel H, Kountchou GN, Boyer O, Mohand D, Mouthon L, et al. Intrasinusoidal cytotoxic CD8+ T cells in nodular regenerative hyperplasia of the liver. Hum Pathol. 2004; 35(10): 1241-51[PubMed]
  • 31. Guo Y, Wu CZ, Liao Y, Zhang QY. The expression and significance of CD4+CD25+CD127low/- regulatory T cells and Foxp3 in patients with portal hypertension and hypersplenism. Hepatogastroenterology. 2013; 60(123): 581-4[DOI][PubMed]
  • 32. Merino J, Aller MA, Rubio S, Arias N, Nava MP, Loscertales M, et al. Gut-brain chemokine changes in portal hypertensive rats. Dig Dis Sci. 2011; 56(8): 2309-17[DOI][PubMed]
  • 33. Aller MA, de las Heras N, Nava MP, Regadera J, Arias J, Lahera V. Splanchnic-aortic inflammatory axis in experimental portal hypertension. World J Gastroenterol. 2013; 19(44): 7992-9[DOI][PubMed]
  • 34. Ebe Y, Hasegawa G, Takatsuka H, Umezu H, Mitsuyama M, Arakawa M, et al. The role of Kupffer cells and regulation of neutrophil migration into the liver by macrophage inflammatory protein-2 in primary listeriosis in mice. Pathol Int. 1999; 49(6): 519-32[PubMed]
  • 35. Salpietro C, Rigoli L, Miraglia Del Giudice M, Cuppari C, Di Bella C, Salpietro A, et al. TLR2 and TLR4 gene polymorphisms and atopic dermatitis in Italian children: a multicenter study. Int J Immunopathol Pharmacol. 2011; 24(4 Suppl): 33-40[PubMed]
  • 36. McHutchison J, Goodman Z, Patel K, Makhlouf H, Rodriguez-Torres M, Shiffman M, et al. Farglitazar lacks antifibrotic activity in patients with chronic hepatitis C infection. Gastroenterology. 2010; 138(4): 1365-73[DOI][PubMed]
  • 37. Zhu Q, Zou L, Jagavelu K, Simonetto DA, Huebert RC, Jiang ZD, et al. Intestinal decontamination inhibits TLR4 dependent fibronectin-mediated cross-talk between stellate cells and endothelial cells in liver fibrosis in mice. J Hepatol. 2012; 56(4): 893-9[DOI][PubMed]
  • 38. Li ZF, Zhang Y, Gao J, Zhang PJ, Wang JX, Liu XG. [Expression and significance of Toll-like receptor 4 of splenic macrophage in patients with hypersplenism due to portal hypertension]. Zhonghua Yi Xue Za Zhi. 2004; 84(13): 1088-91[PubMed]
  • 39. Steib CJ, Bilzer M, op den Winkel M, Pfeiler S, Hartmann AC, Hennenberg M, et al. Treatment with the leukotriene inhibitor montelukast for 10 days attenuates portal hypertension in rat liver cirrhosis. Hepatology. 2010; 51(6): 2086-96[DOI][PubMed]
  • 40. Cavasin MA, Semus H, Pitts K, Peng Y, Sandoval J, Chapo J, et al. Acute effects of endothelin receptor antagonists on hepatic hemodynamics of cirrhotic and noncirrhotic rats. Can J Physiol Pharmacol. 2010; 88(6): 636-43[DOI][PubMed]
  • 41. Gemelli M, Manganaro R, Mami C, Buemi M, Paolata A, Marrone T, et al. Endothelin-1 concentrations in cord blood of neonates with meconium-stained amniotic fluid. J Perinat Med. 2005; 33(3): 259-61[DOI][PubMed]
  • 42. Iwakiri Y, Groszmann RJ. The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule. Hepatology. 2006; 43(2 Suppl 1)-31[DOI][PubMed]
  • 43. Vorobioff J, Bredfeldt JE, Groszmann RJ. Increased blood flow through the portal system in cirrhotic rats. Gastroenterology. 1984; 87(5): 1120-6[PubMed]
  • 44. Gitto E, Pellegrino S, Aversa S, Romeo C, Trimarchi G, Barberi I, et al. Oxidative stress and persistent pulmonary hypertension of the newborn treated with inhaled nitric oxide and different oxygen concentrations. J Matern Fetal Neonatal Med. 2012; 25(9): 1723-6[DOI][PubMed]
  • 45. Snowdon VK, Guha N, Fallowfield JA. Noninvasive evaluation of portal hypertension: emerging tools and techniques. Int J Hepatol. 2012; 2012: 691089[DOI][PubMed]
  • 46. Chen YC, Gines P, Yang J, Summer SN, Falk S, Russell NS, et al. Increased vascular heme oxygenase-1 expression contributes to arterial vasodilation in experimental cirrhosis in rats. Hepatology. 2004; 39(4): 1075-87[DOI][PubMed]
  • 47. Iwakiri Y, Tsai MH, McCabe TJ, Gratton JP, Fulton D, Groszmann RJ, et al. Phosphorylation of eNOS initiates excessive NO production in early phases of portal hypertension. Am J Physiol Heart Circ Physiol. 2002; 282(6)-90[DOI][PubMed]
  • 48. Fiorucci S, Antonelli E, Mencarelli A, Orlandi S, Renga B, Rizzo G, et al. The third gas: H2S regulates perfusion pressure in both the isolated and perfused normal rat liver and in cirrhosis. Hepatology. 2005; 42(3): 539-48[DOI][PubMed]
  • 49. Gronbaek H, Sandahl TD, Mortensen C, Vilstrup H, Moller HJ, Moller S. Soluble CD163, a marker of Kupffer cell activation, is related to portal hypertension in patients with liver cirrhosis. Aliment Pharmacol Ther. 2012; 36(2): 173-80[DOI][PubMed]
  • 50. Kolios G, Valatas V, Kouroumalis E. Role of Kupffer cells in the pathogenesis of liver disease. World J Gastroenterol. 2006; 12(46): 7413-20[PubMed]
  • 51. Oakley F, Meso M, Iredale JP, Green K, Marek CJ, Zhou X, et al. Inhibition of inhibitor of kappaB kinases stimulates hepatic stellate cell apoptosis and accelerated recovery from rat liver fibrosis. Gastroenterology. 2005; 128(1): 108-20[PubMed]
  • 52. Li T, Eheim AL, Klein S, Uschner FE, Smith AC, Brandon-Warner E, et al. Novel role of nuclear receptor rev-erbalpha in hepatic stellate cell activation: Potential therapeutic target for liver injury. Hepatology. 2014; [DOI][PubMed]
  • 53. Saiman Y, Agarwal R, Hickman DA, Fausther M, El-Shamy A, Dranoff JA, et al. CXCL12 induces hepatic stellate cell contraction through a calcium-independent pathway. Am J Physiol Gastrointest Liver Physiol. 2013; 305(5)-82[DOI][PubMed]
  • 54. Klein S, Van Beuge MM, Granzow M, Beljaars L, Schierwagen R, Kilic S, et al. HSC-specific inhibition of Rho-kinase reduces portal pressure in cirrhotic rats without major systemic effects. J Hepatol. 2012; 57(6): 1220-7[DOI][PubMed]
  • 55. Lee S, Chen TT, Barber CL, Jordan MC, Murdock J, Desai S, et al. Autocrine VEGF signaling is required for vascular homeostasis. Cell. 2007; 130(4): 691-703[DOI][PubMed]
  • 56. Marques C, Licks F, Zattoni I, Borges B, de Souza LE, Marroni CA, et al. Antioxidant properties of glutamine and its role in VEGF-Akt pathways in portal hypertension gastropathy. World J Gastroenterol. 2013; 19(28): 4464-74[DOI][PubMed]
  • 57. Fernandez M, Mejias M, Garcia-Pras E, Mendez R, Garcia-Pagan JC, Bosch J. Reversal of portal hypertension and hyperdynamic splanchnic circulation by combined vascular endothelial growth factor and platelet-derived growth factor blockade in rats. Hepatology. 2007; 46(4): 1208-17[DOI][PubMed]
  • 58. Ward NL, Haninec AL, Van Slyke P, Sled JG, Sturk C, Henkelman RM, et al. Angiopoietin-1 causes reversible degradation of the portal microcirculation in mice: implications for treatment of liver disease. Am J Pathol. 2004; 165(3): 889-99[DOI][PubMed]
  • 59. Popov Y, Patsenker E, Stickel F, Zaks J, Bhaskar KR, Niedobitek G, et al. Integrin alphavbeta6 is a marker of the progression of biliary and portal liver fibrosis and a novel target for antifibrotic therapies. J Hepatol. 2008; 48(3): 453-64[DOI][PubMed]
  • 60. Munoz-Luque J, Ros J, Fernandez-Varo G, Tugues S, Morales-Ruiz M, Alvarez CE, et al. Regression of fibrosis after chronic stimulation of cannabinoid CB2 receptor in cirrhotic rats. J Pharmacol Exp Ther. 2008; 324(2): 475-83[DOI][PubMed]
  • 61. Arrigo T, Chirico V, Salpietro V, Munafo C, Ferrau V, Gitto E, et al. High-mobility group protein B1: a new biomarker of metabolic syndrome in obese children. Eur J Endocrinol. 2013; 168(4): 631-8[DOI][PubMed]
  • 62. Fallowfield JA. Therapeutic targets in liver fibrosis. Am J Physiol Gastrointest Liver Physiol. 2011; 300(5)-15[DOI][PubMed]
  • 63. Salpietro C, Cuppari C, Grasso L, Tosca MA, Miraglia Del Giudice M, La Rosa M, et al. Nasal high-mobility group box-1 protein in children with allergic rhinitis. Int Arch Allergy Immunol. 2013; 161(2): 116-21[DOI][PubMed]
  • 64. Chen W, Oue T, Ueno T, Uehara S, Usui N, Fukuzawa M. Apelin is a marker of the progression of liver fibrosis and portal hypertension in patients with biliary atresia. Pediatr Surg Int. 2013; 29(1): 79-85[DOI][PubMed]
  • 65. Meyer DH, Bachem MG, Gressner AM. Modulation of hepatic lipocyte proteoglycan synthesis and proliferation by Kupffer cell-derived transforming growth factors type beta 1 and type alpha. Biochem Biophys Res Commun. 1990; 171(3): 1122-9[PubMed]
  • 66. Leeming DJ, Karsdal MA, Byrjalsen I, Bendtsen F, Trebicka J, Nielsen MJ, et al. Novel serological neo-epitope markers of extracellular matrix proteins for the detection of portal hypertension. Aliment Pharmacol Ther. 2013; 38(9): 1086-96[DOI][PubMed]
  • 67. Wang D, Lu JG, Wang Q, Du XL, Dong R, Wang P, et al. Increased immunohistochemical expression of YKL-40 in the spleen of patients with portal hypertension. Braz J Med Biol Res. 2012; 45(3): 264-72[PubMed]
  • 68. Parfieniuk A, Flisiak R. Role of cannabinoids in chronic liver diseases. World J Gastroenterol. 2008; 14(40): 6109-14[PubMed]
  • 69. Rodriguez-Vilarrupla A, Lavina B, Garcia-Caldero H, Russo L, Rosado E, Roglans N, et al. PPARalpha activation improves endothelial dysfunction and reduces fibrosis and portal pressure in cirrhotic rats. J Hepatol. 2012; 56(5): 1033-9[DOI][PubMed]
  • 70. Ryan P, Berenguer J, Michelaud D, Miralles P, Bellon JM, Alvarez E, et al. Insulin resistance is associated with advanced liver fibrosis and high body mass index in HIV/HCV-coinfected patients. J Acquir Immune Defic Syndr. 2009; 50(1): 109-10[DOI][PubMed]
  • 71. d'Annunzio G, Vanelli M, Pistorio A, Minuto N, Bergamino L, Lafusco D, et al. Insulin resistance and secretion indexes in healthy Italian children and adolescents: a multicentre study. Acta Biomed. 2009; 80(1): 21-8[PubMed]
  • 72. Aleffi S, Petrai I, Bertolani C, Parola M, Colombatto S, Novo E, et al. Upregulation of proinflammatory and proangiogenic cytokines by leptin in human hepatic stellate cells. Hepatology. 2005; 42(6): 1339-48[DOI][PubMed]
  • 73. Arrigo T, Gitto E, Ferrau V, Munafo C, Alibrandi A, Marseglia GL, et al. Effect of weight reduction on leptin, total ghrelin and obestatin concentrations in prepubertal children. J Biol Regul Homeost Agents. 2012; 26(1 Suppl)-103[PubMed]
  • 74. Chirico V, Cannavo S, Lacquaniti A, Salpietro V, Mandolfino M, Romeo PD, et al. Prolactin in obese children: a bridge between inflammation and metabolic-endocrine dysfunction. Clin Endocrinol (Oxf). 2013; 79(4): 537-44[DOI][PubMed]
  • 75. Mami C, Manganaro R, Marseglia L, Saitta G, Gemelli M, Martino F. Plasma leptin, insulin, and neuropeptide Y response to feeding in newborn infants. Arch Dis Child Fetal Neonatal Ed. 2006; 91(5)[DOI][PubMed]
  • 76. Delgado MG, Gracia-Sancho J, Marrone G, Rodriguez-Vilarrupla A, Deulofeu R, Abraldes JG, et al. Leptin receptor blockade reduces intrahepatic vascular resistance and portal pressure in an experimental model of rat liver cirrhosis. Am J Physiol Gastrointest Liver Physiol. 2013; 305(7)-502[DOI][PubMed]
  • 77. Eslam M, Ampuero J, Jover M, Abd-Elhalim H, Rincon D, Shatat M, et al. Predicting portal hypertension and variceal bleeding using non-invasive measurements of metabolic variables. Ann Hepatol. 2013; 12(4): 588-98[PubMed]
  • 78. Fallowfield JA, Hayden AL, Snowdon VK, Aucott RL, Stutchfield BM, Mole DJ, et al. Relaxin modulates human and rat hepatic myofibroblast function and ameliorates portal hypertension in vivo. Hepatology. 2014; 59(4): 1492-504[DOI][PubMed]
Creative Commons License Except where otherwise noted, this work is licensed under Creative Commons Attribution Non Commercial 4.0 International License .

Search Relations:



Create Citiation Alert
via Google Reader

Readers' Comments