Liver stiffness is a reliable non-invasive predictor of Hepatic Venous Pressure Gradient (HVPG) above 10 mm Hg. However, it failed to predict higher thresholds of HVPG. Our aim was to investigate whether liver stiffness and selected previously published non-invasive blood biomarkers could predict higher HVPG thresholds in liver transplant candidates without ongoing alcohol use. One hundred and nine liver transplant candidates with liver cirrhosis of various aetiologies underwent direct HVPG measurement, liver stiffness measurement by 2D shear-wave elastography (Aixplorer Multiwave, Supersonic Imagine, France) and assessment of blood HVPG biomarkers (osteopontin, VCAM-1, IL-6, TNF-α, IL-1ra/IL-1F3 and ELF score). The correlation between liver stiffness and HVPG was linear up to 30 mm Hg of HVPG (r = 0.765, p < 0.0001). The regression lines had similar slopes for HVPG values below and above 16 mm Hg (p > 0.05) and the correlation in patients with HVPG <16 mm Hg (r = 0.456, p = 0.01) was similar to patients with HVPG ≥ 16 mm Hg (r = 0.499, p < 0.0001). The correlation was similar in the subgroup patients with alcoholic (r = 0.718, p < 0.0001), NASH (r = 0.740, p = 0.008), cryptogenic (r = 0.648, p = 0,0377), cholestatic and autoimmune (r = 0.706, p < 0.0001) and viral cirrhosis (r = 0.756, p < 0.0001). Liver stiffness distinguished patients with HVPG above 16, and 20 mm Hg with AUROCs 0.90243, and 0.86824, sensitivity 0.7656, and 0.7027, and specificity 0.9333, and 0.8750. All studied blood biomarkers correlated better with liver stiffness than with HVPG and their AUROCs did not exceed 0.8 at both HVPG thresholds. Therefore, a composite predictor superior to liver stiffness could not be established. We conclude that liver stiffness is a clinically reliable predictor of higher HVPG thresholds in non-drinking subjects with advanced liver cirrhosis.

Anaesthesiology Resuscitation and Intensive Care Department Institute for Clinical and Experimental Medicine Prague Czech Republic

Charles University 1st Faculty of Medicine Prague Czech Republic

Department of Biostatistics Institute for Clinical and Experimental Medicine Prague Czech Republic

Department of Diagnostic and Interventional Radiology Institute for Clinical and Experimental Medicine Prague Czech Republic

Department of Hepatogastroenterology Transplant Centre Institute for Clinical and Experimental Medicine Prague Czech Republic

Department of Internal Medicine Central Military Hospital Prague Czech Republic

Laboratory of Experimental Hepatology Institute for Clinical and Experimental Medicine Prague Czech Republic

Zobrazit více v PubMed

Bosch J, Abraldes JG, Berzigotti A, Garcia-Pagan JC. The clinical use of HVPG measurements in chronic liver disease. Nat Rev Gastroenterol Hepatol. 2009;6(10):573–82. Epub 2009/09/03. 10.1038/nrgastro.2009.149 . PubMed DOI

Lebrec D, De Fleury P, Rueff B, Nahum H, Benhamou JP. Portal hypertension, size of esophageal varices, and risk of gastrointestinal bleeding in alcoholic cirrhosis. Gastroenterology. 1980;79(6):1139–44. . PubMed

Garcia-Tsao G, Groszmann RJ, Fisher RL, Conn HO, Atterbury CE, Glickman M. Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology. 1985;5(3):419–24. 10.1002/hep.1840050313 . PubMed DOI

Groszmann RJ, Garcia-Tsao G, Bosch J, Grace ND, Burroughs AK, Planas R, et al. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med. 2005;353(21):2254–61. 10.1056/NEJMoa044456 . PubMed DOI

Bureau C, Metivier S, Peron JM, Selves J, Robic MA, Gourraud PA, et al. Transient elastography accurately predicts presence of significant portal hypertension in patients with chronic liver disease. Aliment Pharmacol Ther. 2008;27(12):1261–8. 10.1111/j.1365-2036.2008.03701.x . PubMed DOI

Ripoll C, Groszmann R, Garcia-Tsao G, Grace N, Burroughs A, Planas R, et al. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology. 2007;133(2):481–8. 10.1053/j.gastro.2007.05.024 . PubMed DOI

Silva-Junior G, Baiges A, Turon F, Torres F, Hernandez-Gea V, Bosch J, et al. The prognostic value of hepatic venous pressure gradient in patients with cirrhosis is highly dependent on the accuracy of the technique. Hepatology. 2015;62(5):1584–92. 10.1002/hep.28031 . PubMed DOI

Abraldes JG, Villanueva C, Banares R, Aracil C, Catalina MV, Garci APJC, et al. Hepatic venous pressure gradient and prognosis in patients with acute variceal bleeding treated with pharmacologic and endoscopic therapy. J Hepatol. 2008;48(2):229–36. 10.1016/j.jhep.2007.10.008 . PubMed DOI

de Franchis R, Baveno VIF. Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol. 2015;63(3):743–52. 10.1016/j.jhep.2015.05.022 . PubMed DOI

Maurice JB, Brodkin E, Arnold F, Navaratnam A, Paine H, Khawar S, et al. Validation of the Baveno VI criteria to identify low risk cirrhotic patients not requiring endoscopic surveillance for varices. J Hepatol. 2016;65(5):899–905. 10.1016/j.jhep.2016.06.021 . PubMed DOI

Augustin S, Pons M, Maurice JB, Bureau C, Stefanescu H, Ney M, et al. Expanding the Baveno VI criteria for the screening of varices in patients with compensated advanced chronic liver disease. Hepatology. 2017;66(6):1980–8. 10.1002/hep.29363 . PubMed DOI

Procopet B, Berzigotti A, Abraldes JG, Turon F, Hernandez-Gea V, Garcia-Pagan JC, et al. Real-time shear-wave elastography: applicability, reliability and accuracy for clinically significant portal hypertension. J Hepatol. 2015;62(5):1068–75. 10.1016/j.jhep.2014.12.007 . PubMed DOI

Choi SY, Jeong WK, Kim Y, Kim J, Kim TY, Sohn JH. Shear-wave elastography: a noninvasive tool for monitoring changing hepatic venous pressure gradients in patients with cirrhosis. Radiology. 2014;273(3):917–26. 10.1148/radiol.14140008 . PubMed DOI

Jansen C, Bogs C, Verlinden W, Thiele M, Moller P, Gortzen J, et al. Algorithm to rule out clinically significant portal hypertension combining Shear-wave elastography of liver and spleen: a prospective multicentre study. Gut. 2016;65(6):1057–8. 10.1136/gutjnl-2016-311536 . PubMed DOI

Jansen C, Bogs C, Verlinden W, Thiele M, Moller P, Gortzen J, et al. Shear-wave elastography of the liver and spleen identifies clinically significant portal hypertension: A prospective multicentre study. Liver Int. 2017;37(3):396–405. 10.1111/liv.13243 . PubMed DOI

Elkrief L, Rautou PE, Ronot M, Lambert S, Dioguardi Burgio M, Francoz C, et al. Prospective comparison of spleen and liver stiffness by using shear-wave and transient elastography for detection of portal hypertension in cirrhosis. Radiology. 2015;275(2):589–98. 10.1148/radiol.14141210 . PubMed DOI

Elkrief L, Ronot M, Andrade F, Dioguardi Burgio M, Issoufaly T, Zappa M, et al. Non-invasive evaluation of portal hypertension using shear-wave elastography: analysis of two algorithms combining liver and spleen stiffness in 191 patients with cirrhosis. Aliment Pharmacol Ther. 2018;47(5):621–30. 10.1111/apt.14488 . PubMed DOI

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. 10.1002/hep.26755 . PubMed DOI

Bruha R, Jachymova M, Petrtyl J, Dvorak K, Lenicek M, Urbanek P, et al. Osteopontin: A non-invasive parameter of portal hypertension and prognostic marker of cirrhosis. World J Gastroenterol. 2016;22(12):3441–50. 10.3748/wjg.v22.i12.3441 PubMed DOI PMC

Kim TY, Jeong WK, Sohn JH, Kim J, Kim MY, Kim Y. Evaluation of portal hypertension by real-time shear wave elastography in cirrhotic patients. Liver Int. 2015;35(11):2416–24. Epub 2015/04/16. 10.1111/liv.12846 . PubMed DOI

Gouya H, Grabar S., Vignaux O., Saade A., Pol S. Legmann P., Sogni P. Portal hypertension in patients with cirrhosis: indirect assessment of hepatic venous pressure gradient by measuring azygos flow with 2D-cine phase-contrast magnetic resonance imaging. Eur Radiol. 2016;26(7):1981–90. Epub 2015 Sep 15. 10.1007/s00330-015-3991-x PubMed DOI

Stefanescu H, Rusu C, Lupsor-Platon M, Nicoara Farcau O, Fischer P, Grigoras C, et al. Liver Stiffness Assessed by Ultrasound Shear Wave Elastography from General Electric Accurately Predicts Clinically Significant Portal Hypertension in Patients with Advanced Chronic Liver Disease. Ultraschall Med. 2019. 10.1055/a-0965-0745 . PubMed DOI

Mandorfer M, Hernandez-Gea V, Garcia-Pagan JC, Reiberger T. Noninvasive Diagnostics for Portal Hypertension: A Comprehensive Review. Semin Liver Dis. 2020;40(3):240–55. Epub 2020/06/20. 10.1055/s-0040-1708806 . PubMed DOI

Reiberger T, Ferlitsch A, Payer BA, Pinter M, Homoncik M, Peck-Radosavljevic M, et al. Non-selective beta-blockers improve the correlation of liver stiffness and portal pressure in advanced cirrhosis. J Gastroenterol. 2012;47(5):561–8. Epub 2011/12/16. 10.1007/s00535-011-0517-4 . PubMed DOI

Ling L, Li G, Meng D, Wang S, Zhang C. Carvedilol Ameliorates Intrahepatic Angiogenesis, Sinusoidal Remodeling and Portal Pressure in Cirrhotic Rats. Med Sci Monit. 2018;24:8290–7. Epub 2018/11/19. 10.12659/MSM.913118 PubMed DOI PMC

Semmler G, Scheiner B, Schwabl P, Bucsics T, Paternostro R, Chromy D, et al. The impact of hepatic steatosis on portal hypertension. PLoS One. 2019;14(11):e0224506 Epub 2019/11/07. 10.1371/journal.pone.0224506 PubMed DOI PMC

Conti CB, Weiler N, Casazza G, Schrecker C, Schneider M, Mucke MM, et al. Feasibility and reproducibility of liver and pancreatic stiffness in patients with alcohol-related liver disease. Dig Liver Dis. 2019;51(7):1023–9. 10.1016/j.dld.2018.12.017 . PubMed DOI

Powell EE, Cooksley WG, Hanson R, Searle J, Halliday JW, Powell LW. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology. 1990;11(1):74–80. 10.1002/hep.1840110114 . PubMed DOI

Caldwell SH, Lee VD, Kleiner DE, Al-Osaimi AM, Argo CK, Northup PG, et al. NASH and cryptogenic cirrhosis: a histological analysis. Ann Hepatol. 2009;8(4):346–52. . PubMed PMC

Kleine M, Riemer M, Krech T, DeTemple D, Jager MD, Lehner F, et al. Explanted diseased livers—a possible source of metabolic competent primary human hepatocytes. PLoS One. 2014;9(7):e101386 Epub 2014/07/08. 10.1371/journal.pone.0101386 PubMed DOI PMC

Vizzutti F, Arena U, Romanelli RG, Rega L, Foschi M, Colagrande S, et al. Liver stiffness measurement predicts severe portal hypertension in patients with HCV-related cirrhosis. Hepatology. 2007;45(5):1290–7. Epub 2007/04/28. 10.1002/hep.21665 . PubMed DOI

European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol. 2018;69(2):406–60. Epub 2018/04/15. 10.1016/j.jhep.2018.03.024 . PubMed DOI

Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334(11):693–9. 10.1056/NEJM199603143341104 . PubMed DOI

European Association for the Study of the Liver. Electronic address eee. EASL Clinical Practice Guidelines: Liver transplantation. J Hepatol. 2016;64(2):433–85. Epub 2015/11/26. 10.1016/j.jhep.2015.10.006 . PubMed DOI

Kamath PS, Kim WR, Advanced Liver Disease Study G. The model for end-stage liver disease (MELD). Hepatology. 2007;45(3):797–805. 10.1002/hep.21563 . PubMed DOI

Hoffman DH, Ayoola A, Nickel D, Han F, Chandarana H, Babb J, et al. MR elastography, T1 and T2 relaxometry of liver: role in noninvasive assessment of liver function and portal hypertension. Abdom Radiol (NY). 2020;45(9):2680–7. 10.1007/s00261-020-02432-7 . PubMed DOI

Conejo I, Guardascione MA, Tandon P, Cachero A, Castellote J, Abraldes JG, et al. Multicenter External Validation of Risk Stratification Criteria for Patients With Variceal Bleeding. Clin Gastroenterol Hepatol. 2018;16(1):132–9 e8. 10.1016/j.cgh.2017.04.042 . PubMed DOI

Wiesner RH, McDiarmid SV, Kamath PS, Edwards EB, Malinchoc M, Kremers WK, et al. MELD and PELD: application of survival models to liver allocation. Liver Transpl. 2001;7(7):567–80. 10.1053/jlts.2001.25879 . PubMed DOI

Wiesner R, Edwards E, Freeman R, Harper A, Kim R, Kamath P, et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology. 2003;124(1):91–6. 10.1053/gast.2003.50016 . PubMed DOI

Berzigotti A, Seijo S, Arena U, Abraldes JG, Vizzutti F, Garcia-Pagan JC, et al. Elastography, spleen size, and platelet count identify portal hypertension in patients with compensated cirrhosis. Gastroenterology. 2013;144(1):102–11 e1. 10.1053/j.gastro.2012.10.001 . PubMed DOI

Luo B, Liu L, Tang L, Zhang J, Ling Y, Fallon MB. ET-1 and TNF-alpha in HPS: analysis in prehepatic portal hypertension and biliary and nonbiliary cirrhosis in rats. Am J Physiol Gastrointest Liver Physiol. 2004;286(2):G294–303. 10.1152/ajpgi.00298.2003 . PubMed DOI

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. 10.1007/s00268-005-7757-5 . PubMed DOI

Parkes J, Guha IN, Roderick P, Harris S, Cross R, Manos MM, et al. Enhanced Liver Fibrosis (ELF) test accurately identifies liver fibrosis in patients with chronic hepatitis C. J Viral Hepat. 2011;18(1):23–31. 10.1111/j.1365-2893.2009.01263.x . PubMed DOI

Parkes J, Roderick P, Harris S, Day C, Mutimer D, Collier J, et al. Enhanced liver fibrosis test can predict clinical outcomes in patients with chronic liver disease. Gut. 2010;59(9):1245–51. 10.1136/gut.2009.203166 . PubMed DOI

Miele L, De Michele T, Marrone G, Antonietta Isgro M, Basile U, Cefalo C, et al. Enhanced liver fibrosis test as a reliable tool for assessing fibrosis in nonalcoholic fatty liver disease in a clinical setting. Int J Biol Markers. 2017;32(4):e397–e402. 10.5301/ijbm.5000292 . PubMed DOI

Ferrusquía-Acosta J BO, Turco L, Reverter E, Pellone M, Bianchini M, Campuzano V, Ripoll E, García-Criado Á, Graupera I, García-Pagán JC, Schepis F, Senzolo M, Hernández-Gea V. Agreement between wedged hepatic venous pressure and portal pressure in non-alcoholic steatohepatitis-related cirrhosis. J Hepatol. 2020. 10.1016/j.jhep.2020.10.003 PubMed DOI

Nadebaum DP, Nicoll AJ, Sood S, Gorelik A, Gibson RN. Variability of Liver Shear Wave Measurements Using a New Ultrasound Elastographic Technique. J Ultrasound Med. 2018;37(3):647–56. 10.1002/jum.14375 . PubMed DOI

Sandrin L, Fourquet B, Hasquenoph JM, Yon S, Fournier C, Mal F, et al. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol. 2003;29(12):1705–13. Epub 2003/12/31. 10.1016/j.ultrasmedbio.2003.07.001 . PubMed DOI

European Association for Study of L, Asociacion Latinoamericana para el Estudio del H. EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. J Hepatol. 2015;63(1):237–64. Epub 2015/04/26. 10.1016/j.jhep.2015.04.006 . PubMed DOI

Berzigotti A. Non-invasive evaluation of portal hypertension using ultrasound elastography. J Hepatol. 2017;67(2):399–411. Epub 2017/02/23. 10.1016/j.jhep.2017.02.003 . PubMed DOI

Takuma Y, Nouso K, Morimoto Y, Tomokuni J, Sahara A, Takabatake H, et al. Portal Hypertension in Patients with Liver Cirrhosis: Diagnostic Accuracy of Spleen Stiffness. Radiology. 2016;279(2):609–19. Epub 2015/11/21. 10.1148/radiol.2015150690 . PubMed DOI

Attia D, Schoenemeier B, Rodt T, Negm AA, Lenzen H, Lankisch TO, et al. Evaluation of Liver and Spleen Stiffness with Acoustic Radiation Force Impulse Quantification Elastography for Diagnosing Clinically Significant Portal Hypertension. Ultraschall Med. 2015;36(6):603–10. Epub 2015/11/14. 10.1055/s-0041-107971 . PubMed DOI

Kim HY, So YH, Kim W, Ahn DW, Jung YJ, Woo H, et al. Non-invasive response prediction in prophylactic carvedilol therapy for cirrhotic patients with esophageal varices. J Hepatol. 2019;70(3):412–22. Epub 2018/11/06. 10.1016/j.jhep.2018.10.018 . PubMed DOI

Marasco G, Dajti E, Ravaioli F, Alemanni LV, Capuano F, Gjini K, et al. Spleen stiffness measurement for assessing the response to beta-blockers therapy for high-risk esophageal varices patients. Hepatol Int. 2020;14(5):850–7. Epub 2020/06/20. 10.1007/s12072-020-10062-w . PubMed DOI

Jabor A, Kubicek Z, Frankova S, Senkerikova R, Franekova J. Enhanced liver fibrosis (ELF) score: Reference ranges, biological variation in healthy subjects, and analytical considerations. Clin Chim Acta. 2018;483:291–5. 10.1016/j.cca.2018.05.027 . PubMed DOI

Simbrunner B, Marculescu R, Scheiner B, Schwabl P, Bucsics T, Stadlmann A, et al. Non-invasive detection of portal hypertension by enhanced liver fibrosis score in patients with different aetiologies of advanced chronic liver disease. Liver Int. 2020;40(7):1713–24. Epub 2020/05/03. 10.1111/liv.14498 PubMed DOI PMC

Mechanical Regulation of Mitochondrial Dynamics and Function in a 3D-Engineered Liver Tumor Microenvironment

Portal hypertension is the main driver of liver stiffness in advanced liver cirrhosis