• 1.

    Messina JP, Humphreys I, Flaxman A, Brown A, Cooke GS, Pybus OG, Barnes E , 2015. Global distribution and prevalence of hepatitis C virus genotypes. Hepatology 61: 7787.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Berzigotti A, Seijo S, Reverter E, Bosch J , 2013. Assessing portal hypertension in liver diseases. Expert Rev Gastroenterol Hepatol 7: 141155.

    • Search Google Scholar
    • Export Citation
  • 3.

    Zayed RA, Omran D, Zayed AA, Elmessery LO , 2017. Determinants of infection outcome in HCV-genotype 4. Viral Immunol 8: 560567.

  • 4.

    Garcia‐Tsao G, Sanyal AJ, Grace ND, Carey W , 2007. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 46: 922938.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    D’amico G, Pagliaro L, Bosch J , 1999. Pharmacological treatment of portal hypertension: an evidence-based approach. Semin Liver Dis 19: 475505.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    De Franchis R , 2005. Evolving consensus in portal hypertension: report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol. 43: 167176.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Chandail VS, Kotwal SK, Koul S, Gupta R, Mahajan A , 2017. Non-invasive markers for prediction of varices in patients with portal hypertension. Int J Res Med Sci 5: 10071010.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Cotton PB, Hawes RH, Barkun A, Ginsberg GG, Amman S, Cohen J, Ponsky J, Rex DK, Schembre D, Wilcox CM , 2006. Excellence in endoscopy: toward practical metrics. Gastrointest Endosc 63: 286291.

    • Search Google Scholar
    • Export Citation
  • 9.

    Colli A et al.2017. Platelet count, spleen length, and platelet count-to-spleen length ratio for the diagnosis of oesophageal varices in people with chronic liver disease or portal vein thrombosis. Cochrane Database Syst Rev 4: CD008759. doi: 10.1002/14651858.CD008759.pub2.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Esmat S, Omarn D, Rashid L , 2012. Can we consider the right hepatic lobe size/albumin ratio a noninvasive predictor of oesophageal varices in hepatitis C virus-related liver cirrhotic Egyptian patients? Eur J Intern Med 23: 267272.

    • Search Google Scholar
    • Export Citation
  • 11.

    Nada L, Samira ELF, Bahija B, Adil I, Nourdine A , 2015. Noninvasive predictors of presence and grade of esophageal varices in viral cirrhotic patients. Pan Afr Med J 20: 145.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Hassan EM, Omran DA, El Beshlawey ML, Abdo M, El Askary A , 2014. Can transient elastography, Fib-4, Forns index, and Lok score predict esophageal varices in HCV related cirrhotic patients? Gastroenterol Hepatol 37: 5865.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Riggio O et al.2005. High prevalence of spontaneous portal-systemic shunts in persistent hepatic encephalopathy: a case-control study. Hepatology 42: 11581165.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Fernandez M , 2015. Molecular pathophysiology of portal hypertension. Hepatology 61: 14061415.

  • 15.

    Tiani C, Garcia-Pras E, Mejias M, De Gottardi A, Berzigotti A, Bosch J, Fernandez M , 2009. Apelin signaling modulates splanchnic angiogenesis and portosystemic collateral vessel formation in rats with portal hypertension. J Hepatol 50: 296305.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Wysocka MB, Pietraszek-Gremplewicz K, Nowak D , 2018. The role of apelin in cardiovascular diseases, obesity and cancer. Front Physiol 9: 557.

  • 17.

    Cox CM, D’Agostino SL, Miller MK, Heimark RL, Krieg PA , 2006. Apelin, the ligand for the endothelial G-protein-coupled receptor, APJ, is a potent angiogenic factor required for normal vascular development of the frog embryo. Dev Biol 296: 177189.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Melgar-Lesmes P, Pauta M, Reichenbach V, Reichenbach V, Casals G, Ros J, Bataller R, Morales-Ruiz M, Jiménez W , 2011. Hypoxia and proinflammatory factors upregulate apelin receptor expression in human stellate cells and hepatocytes. Gut 60: 14041411.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Principe A, Melgar-Lesmes P, Fernandez-Varo G, Del Arbol LR, Ros J, Morales-Ruiz M, Bernardi M, Arroyo V, Jimenez W , 2008. The hepatic apelin system: a new therapeutic target for liver disease. Hepatology 48: 11931201.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Li WW, Niu WQ, Zhang Y, Wu S, Gao PJ, Zhu DL , 2009. Family-based analysis of apelin and AGTRL1 gene polymorphisms with hypertension in Han Chinese. J Hypertens 27: 11941201.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Niu W, Wu S, Zhang Y, Li W, Ji K, Gao P, Zhu D , 2010. Validation of genetic association in apelin-AGTRL1 system with hypertension in a larger Han Chinese population. J Hypertens 28: 18541861.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Orphanides G, Reinberg D , 2002. A unified theory of gene expression. Cell 108: 439451.

  • 23.

    Mishra A, Kohli S, Dua S, Thinlas T, Mohammad G, Pasha MAQ , 2015. Genetic differences and aberrant methylation in the apelin system predict the risk of high-altitude pulmonary edema. Proc Natl Acad Sci USA 112: 61346139.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24.

    Ganne-Carrié N, Ziol M, de Ledinghen V, Douvin C, Marcellin P, Castera L, Dhumeaux D, Trinchet JC, Beaugrand M , 2006. Accuracy of liver stiffness measurement for the diagnosis of cirrhosis in patients with chronic liver diseases. Hepatology 44: 15111517.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    Chen W, Oue T, Ueno T, Uehara S, Usui N, Fukuzawa M , 2013. Apelin is a marker of the progression of liver fibrosis and portal hypertension in patients with biliary atresia. Pediatr Surg Int 29: 7985.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26.

    Paquet KJ , 1982. Prophylactic endoscopic sclerosing treatment of the esophageal wall in varices: a prospective controlled randomized trial. Endoscopy 14: 45.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27.

    Omran D et al.2018. Evaluating diagnostic accuracy of noninvasive tests in assessment of significant liver fibrosis in chronic hepatitis C Egyptian patients. Viral Immunol 31: 315320.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28.

    De Souza-Cruz S et al.2016. Liver and blood cytokine microenvironment in HCV patients is associated to liver fibrosis score: a proinflammatory cytokine ensemble orchestrated by TNF and tuned by IL-10. BMC Microbiol 16: 3.

    • Search Google Scholar
    • Export Citation
  • 29.

    The Human Protein Atlas. https://www.proteinatlas.org/ENSG00000171388-APLN. Accessed November 20, 2019.

    • Crossref
    • Export Citation
  • 30.

    Zakaria MK, Sankhyan A, Ali A, Fatima K, Azhar E, Qadri I , 2014. HBV/HCV infection and inflammation. J Genet Syndr Gene Ther 5: 241.

  • 31.

    Friedman SL , 2000. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem 275: 22472250.

  • 32.

    Hammam O, Mahmoud O, Zahran M, Sayed A, Salama R, Hosny K, Farghly A, 2000. A possible role for TNF-alpha in coordinating inflammation and angiogenesis in chronic liver disease and hepatocellular carcinoma. Gastrointest Cancer Res 6: 107114.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33.

    Daviaud D et al.2006. TNFalpha up-regulates apelin expression in human and mouse adipose tissue. FASEB J 20: 15281530.

  • 34.

    Kandeel A, Genedy M, El-Refai S, Funk AL, Fontanet A, Talaat M , 2017. The prevalence of hepatitis C virus infection in Egypt 2015: implications for future policy on prevention and treatment. Liver Int 37: 4553.

    • Search Google Scholar
    • Export Citation
  • 35.

    Omran D et al.2018. Towards hepatitis C virus elimination: Egyptian experience, achievements and limitations. World J Gastroenterol 24: 43304340.

    • Search Google Scholar
    • Export Citation
  • 36.

     The allele frequency net database. Available at: http://www.allelefrequencies.net/. Accessed November 20, 2018.

    • Crossref
    • Export Citation
  • 37.

    HGVS , n.d. HGVS Simple. Available at: http://varnomen.hgvs.org/bg-material/simple/. Accessed April 1, 2022.

    • Crossref
    • Export Citation
  • 38.

    Tiani C, Garcia-Pras E, Mejias M, De Gottardi A, Berzigotti A, Bosch J, Fernandez M , 2009. Apelin signaling modulates splanchnic angiogenesis and portosystemic collateral vessel formation in rats with portal hypertension. J Hepatol 50: 296305.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 39.

    Lv SY, Cui B, Chen WD, Wang YD , 2017. Apelin/APJ system: a key therapeutic target for liver disease. Oncotarget 8: 112145112151.

  • 40.

    Jin W, Su X, Xu M, Liu Y, Shi J, Lu L, Niu W , 2012. Interactive association of five candidate polymorphisms in apelin/APJ pathway with coronary artery disease among Chinese hypertensive patients. PLoS One 7: e51123.

    • Search Google Scholar
    • Export Citation
  • 41.

    Melgar-Lesmes P, Casals G, Pauta M, Ros J, Reichenbach V, Bataller R, Morales-Ruiz M, Jimenez W , 2010. Apelin mediates the induction of profibrogenic genes in human hepatic stellate cells. Endocrinology 151: 53065314.

    • Search Google Scholar
    • Export Citation
  • 42.

    El-Mesallamy HO, Hamdy NM, Rizk HH, El-Zayadi AR , 2011. Apelin serum level in Egyptian patients with chronic hepatitis C. Mediators Inflamm. http://dx.doi.org/10.1155/2011/703031.

    • Search Google Scholar
    • Export Citation
  • 43.

    Mandal L, Mandal SK, Bandyopadhyay D, Datta S , 2011. Correlation of portal vein diameter and splenic size with gastro-oesophageal varices in cirrhosis of liver. J Indian Acad Clin Med 12: 266270.

    • Search Google Scholar
    • Export Citation
  • 44.

    Prihatini J, Lesmanal A, Manan C, Gani RA , 2005. Detection of esophageal varices in liver cirrhosis using non-invasive parameters. Acta Med Indones 37: 126131.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 45.

    Dib N, Konate A, Oberti F, Cales P , 2005. Non-invasive diagnosis of portal hypertension in cirrhosis: application to the primary prevention of varices. Gastroenterol Clin Biol 29: 975987.

    • Search Google Scholar
    • Export Citation
  • 46.

    Thomopoulos KC, Labropoulou-Karatza C, Mimidis KP, Katsakoulis EC, Iconomou G, Nikolopoulou VN , 2003. Non-invasive predictors of the presence of large oesophageal varices in patients with cirrhosis. Dig Liver Dis 35: 473478.

    • Search Google Scholar
    • Export Citation
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Apelin Association with Hepatic Fibrosis and Esophageal Varices in Patients with Chronic Hepatitis C Virus

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  • 1 Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt;
  • | 2 Department of Endemic Medicine and Hepatogastroenterology, Faculty of Medicine, Cairo University, Cairo, Egypt;
  • | 3 Department of Microbiology and Immunology, Faculty of Pharmacy, Port Said University, Port Said, Egypt;
  • | 4 Department of Tropical Medicine, Ain Shams University, Cairo, Egypt;
  • | 5 Department of Biochemistry, Faculty of Pharmacy, Ahram Canadian University, Cairo, Egypt
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ABSTRACT.

Portal hypertension and esophageal varices complicating hepatitis C virus (HCV)-related chronic liver diseases are some of the most devastating sequelae. Angiogenesis is the hallmark of their pathogenesis. Apelin is one of the recently identified angiogenic and fibrogenic peptides. We studied apelin gene expression, apelin (rs3761581) single-nucleotide polymorphism (SNP), and serum apelin level in patients with chronic HCV, and their association with liver fibrosis and esophageal varices in 112 patients with HCV-related chronic liver disease (40 with liver cirrhosis [LC]/low-grade varices, 33 with LC/high-grade varices, and 39 with fibrotic non-cirrhotic liver/no varices) and 80 healthy control subjects. Real-time polymerase chain reaction was used for apelin gene expression assay and apelin rs3761581 SNP analysis in peripheral blood samples. The serum apelin level was measured by ELISA. Apelin gene expression was undetectable in the studied samples. The SNP analysis revealed a greater frequency of the C (mutant) allele among patients compared with control subjects (P = 0.012; odds ratio, 3.67). The serum apelin level was significantly greater in patients with LC/varices (median, 31.6 ng/L) compared with patients without LC/varices (median, 2.9 ng/L; P < 0.001). A serum apelin level cutoff value of 16.55 ng/L predicted the presence of varices, with an area under the receiver operating characteristic curve value of 0.786. A positive correlation was found between serum apelin level and grade of liver fibrosis (r = 0.346, P < 0.001) and portal hypertension (r = 0.438, P < 0.001). In conclusion, the apelin rs3761581-C allele may be associated with the progression of HCV-related chronic liver disease and varices formation, and can be considered a potential therapeutic target to control fibrosis progression. The serum apelin level provided an accurate prediction of the presence of esophageal varices.

Author Notes

Address correspondence to Rania A. Zayed, Cairo University, El Saraya St., Infront of El Manial Palace, Cairo 11451, Egypt. E-mail: rania.zayed@medicine.cu.edu.eg

Financial support: This research was funded in part by Cairo University.

Authors’ addresses: Lamyaa Abdellatif Soliman, Rania A. Zayed, Fadwa Said, Doaa Mohamed Ghaith, and Iman Rifaat Elmahgoub, Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt, E-mails: lelbialy@gmail.com, rania.zayed@medicine.cu.edu.eg, f2said@yahoo.com, doaaghaith@gmail.com, and imanelmahgoub@gmail.com. Dalia Omran, Samar Kamal Darweesh, Rasha Eletreby, and Mahmoud Salama Barakat, Department of Endemic Medicine and Hepatogastroenterology, Faculty of Medicine, Cairo University, Cairo, Egypt, E-mails: daliaomran@kasralainy.edu.eg, samarkad@hotmail.com, r_m_tawfik@yahoo.com, and dr.mahmoudsala1987@gmail.com. Mahmoud M. Bendary, Department of Microbiology and Immunology, Faculty of Pharmacy, Port Said University, Port Said, Egypt, E-mail: m.pendary@pharm.psu.edu.eg. Doaa Zakaria Zaky, Department of Tropical Medicine, Ain Shams University, Cairo, Egypt, E-mail: drdoaazakaria@gmail.com. Eman Amer, Department of Biochemistry, Faculty of Pharmacy, Ahram Canadian University, Cairo, Egypt, E-mail: dr_eman_amer@yahoo.com.

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