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Non-invasive Assessment of Portal Hypertension

APASL2014, consensus development meeting. Non-invasive Assessment of Portal Hypertension. Department of Gastroenterology Chiba University Graduate School of Medicine, Chiba, Japan Hitoshi Maruyama, M.D., PhD. Non-invasive Tools for the Evaluation of Portal Hypertension.

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Non-invasive Assessment of Portal Hypertension

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  1. APASL2014, consensus development meeting Non-invasive Assessment of Portal Hypertension Department of Gastroenterology Chiba University Graduate School of Medicine, Chiba, Japan Hitoshi Maruyama, M.D., PhD

  2. Non-invasive Tools for the Evaluation of Portal Hypertension Evaluation of the pathogenic factors of portal hypertension • Evaluation of hyperkinetic syndrome • Measurement of cardiac output • Measurement of splanchnic circulation • Evaluation of baroreflex sensitivity • Evaluation of portal blood flow • Evaluation of increased intrahepatic vascular resistance • Measurement of vasoconstriction and vascular injury • Evaluation of hepatic fibrosis • Assessment of biochemical parameters • Assessment of liver stiffness • Determination of liver failure Evaluation of clinical complications of portal hypertension • Evaluation of the presence of varices • Assessment by endoscopy • Assessment by biochemical parameters • Assessment by abdominal CT scan • Assessment by video capsule endoscopy • Measurement of variceal pressure • Spleen stiffness • Evaluation of modifications in the splanchnic circulation • Detection of portal vein enlargement and collaterals • Measurement of splenic pulsatility • Evaluation of hepatic vein waveforms Thabut D, et al. Non-invasive assessment of portal hypetension in patients with cirrhosis. Hepatology 2011;53:683-694

  3. Performance of Transient Elastography (TE) for Liver Stiffness (LS) to assess HVPG Study Pt (n) Etiology Prevalence AUROC Accuracy Cutoff Sensitivity/Specificity HVPG cutoff Vizzutti et al. 61* HCV 57 0.99 95 13.4 kPa 97 / 92 10 0.92 90 17.6 kPa 94 / 81 12 Lemoine et al. 44 HCV 77 0.76 98 20.5 kPa 63 / 70 10 48 Alcohol 83 0.94 98 34.9 kPa 90 / 88 Bureau et al. 144† Mix 51 0.95 92 21 kPa 90 / 93 10 Carrion et al. 124 HCV 21 0.93 85 8.74 90 / 81 6 SanchesConde et al 38 HIV-HCV 74 0.80 14 93 / 50 10 0.80 23 83 / 67 12 *: 47 / 61 cirrhosis Correlation between LS and HVPG was not dominant in case >HVPG12mmHg † :Only 89 patients had cirrhosis

  4. Performance of Non-invasive Markers for HVPG Pt (n) Etiology HVPG cutoff Prevalence AUROC LS LSPS PH risk score 117, training Mix 10mmHg 67% 0.883 0.918 0.935 56, validation Mix 10mmHg 86% 0.901 0.906 0.932 LSPS: LS×spleen size/platelet count PH risk score : -5.953+0.188 ×LS +1.583 ×sex (1:male; 0: female) + 26.705 ×spleen diameter/platelet count ratio Berzigotti et al. Elastography, Spleen Size, and Platelet Count Identify Portal Hypertension in Patients With Compensated Cirrhosis. Gastroenterology 2013;144:102–111.

  5. Performance of Spleen Stiffness (TE/MRE) as a predictive marker of HVPG Study Pt (n) Etiology HVPG Prevalence (%) AUROC SS LSPS Plt/Spl TE Colecchiaet al. 100 HCV >10mmHg 65 0.966*,** 0.907* 0.847** >12 mmHg 54 0.959† 0.899†,†† 0.828†† MRE Storage Loss moduli Ronot et al. 36 Mix > 12 mmHg 69 0.81 0.81 *:p=0.05, **:p=0.007, †: p=0.048, † † : p=0.003

  6. Performance of Non-invasive Markers for HVPG Parameters Study Pt (n) Etiology Prevalence AUROC Accuracy Cutoff Sensitivity/Specificity HVPG cutoff (mmHg) Laminin and Kropf et al. 45 Mix NA NA 82 NA 83 / 82 5 Hyaluronate 39 Alcohol 88 NA 84 / 90 Index FibroTest Thabut et al. 92 Mix 92 0.79 91 0.93 88 / 50 12

  7. Novel Inflammatory Biomarkers of Portal Pressure Inflammatory Biomarkers Pearson’s P Value VCAM-1 0.0007* IL-1b 0.0052* IL-1Ra 0.0085* Fas-R 0.0354* ICAM-1 0.0609 CD-163 0.0739 Thrombospondin-1 0.0950 Elastase-2 0.4105 Lactoferrin 0.7008 LBP 0.6297 IL-1a 0.0772 IL-2 0.7130 IL-4 0.4357 IL-5 0.3703 IL-6 0.2943 IL-8 0.3585 IL-10 0.5814 IL-12 0.3990 IL-13 0.7905 IL-17 0.3132 IFN-c 0.5065 IL-1RA 0.8545 CCL-22 0.0955 CCL-17 0.0905 TNF-a 0.0955 TNF-b 0.0905 Fas-L 0.0894 Granzyme-B 0.6713 HSP-70 0.0894 MIP-1a 0.7681 MIP-1b 0.1162 MMP-8 0.1183 N-Gal 0.5171 Resistin 0.3517 MIF 0.1662 Resistin 0.3517 MIF 0.1662 • N=90 • Compensated cirrhosis • (N Engl J Med 2005;353:2254) • 52%, HCV • No varices Buck M et al. Novel Inflammatory Biomarkers of Portal Pressure in Compensated Cirrhosis Patients. Hepatology 2014;59:1052–1059.

  8. Logistic Regression Analysis of HVPG Biomarkers HVPG <12 mmHg HVPG ≥12 mmHg Measure Mean/N SD/% Mean/N SD/% P Values HSP70 4.23 1.12 3.64 1.32 0.030* TNF-β 412.08 336.82 594.58 350.18 0.019* At-risk alcohol use 19 33 % 21 66% 0.003* Child class B 5 9% 8 25% 0.034* Predictive Value of the Composite Test for HVPG Equal or > 12 mmHg Test Variable Percent 95% Confidence Intervals Sensitivity 87.09 69.68 96.34 Specificity 43.86 30.93 57.56 Negative Predictive Value 86.21 67.78 96.16 Positive Predictive Value 45.76 32.89 59.14 Buck M et al. Novel Inflammatory Biomarkers of Portal Pressure in Compensated Cirrhosis Patients. Hepatology 2014;59:1052–1059.

  9. Performance of TE for Esophageal Varices Study Pt (n) Etiology Prevalence of EV (%) AUROC Accuracy Cutoff Sensitivity/Specificity Endpoint Vizzutti et al. 61 HCV 63.7 0.76 90 17.6 90 / 43 Any EV Kazemi et al. 165 Mix 41.2 0.84 95 19 95 / 43 Any EV 0.83 91 13.9 Large EV Bureau et al. 150 Mix 72 0.85 NA 21.1 84 / 71 Any EV Mix 48 0.76 NA 29.3 81 / 61 Large EV Castera et al.3 70 HCV 36 0.84 73 21.5 76 / 78 Any EV 19 0.87 79 30.5 77 / 85 Large EV Pritchett et al. 211 Mix 62.6, F0-F1 0.74 19.5 76 / 66 Any EV 37.4, large 0.76 19.8 91 / 56 Large (vs small) Nguyen-Khac et al. 183 Mix 22.4, large 0.75 48 73.2 / 73.2 Large EV Malik et al. 404 Mix 50.8 (in cirrhosis ) 0.85 NA 20 NA Any EV (cirrhosis, 70%)

  10. Performance of TE for Esophageal Varices Study Pt (n) Etiology Prevalence of EV (%) AUROC Accuracy Cutoff Sensitivity/Specificity Endpoint Vizzutti et al. 61 HCV 63.7 0.76 90 17.6 90 / 43 Any EV Kazemi et al. 165 Mix 41.2 0.84 95 19 95 / 43 Any EV 0.83 91 13.9 Large EV Bureau et al. 150 Mix 72 0.85 NA 21.1 84 / 71 Any EV Mix 48 0.76 NA 29.3 81 / 61 Large EV Castera et al.3 70 HCV 36 0.84 73 21.5 76 / 78 Any EV 19 0.87 79 30.5 77 / 85 Large EV Pritchett et al. 211 Mix 62.6, F0-F1 0.74 19.5 76 / 66 Any EV 37.4, large 0.76 19.8 91 / 56 Large (vs small) Nguyen-Khac et al. 183 Mix 22.4, large 0.75 48 73.2 / 73.2 Large EV Malik et al. 404 Mix 50.8 (in cirrhosis ) 0.85 NA 20 NA Any EV (cirrhosis, 70%)

  11. Performance of Transient Elastography for Esophageal Varices :A meta-analysis in 18 studies Study Pt (n) Etiology Prevalence of EV (%) HSROC Accuracy Cutoff Sensitivity/Specificity Endpoint Shi, et al. 3644 Mix NA 0.84 NA 15.1-28 kPa 87 / 53 Any EV 0.78 NA 17.8-48 kPa 86 / 59 Large EV Shi et al. Transient elastography: a meta-analysis of diagnostic accuracy in evaluation of portal hypertension in chronic liver disease. Liver Int. 2013 Jan;33:62-71.

  12. Performance of Non-invasive Markers for Esophageal Varices Pt (n) Etiology EV Prevalence Performance LSPS Varices risk score 117, training Mix Any 37/117 AUROC 0.882 0.909 Se (cutoff >80%) 81.1 NA Se (cutoff >90%)) 91.9 NA Sp (cutoff >80%) 86.3 NA Sp (cutoff >90%) 65.0 NA 56, validation Mix Any 33/56 AUROC 0.808 0.759 Se (cutoff >80%) 81.1 NA Se (cutoff >90%) 91.9 NA Sp (cutoff >80%) 86.3 NA Sp (cutoff >90%) 77.5 NA LSPS: LS×spleen size/platelet count Varices risk score : -4.364+0.538×spleen diameter-0.049×platelet count-0.044×LS+0.001×(LS×platelet count). Berzigotti et al. Elastography, Spleen Size, and Platelet Count Identify Portal Hypertension in Patients With Compensated Cirrhosis. Gastroenterology 2013;144:102–111.

  13. Performance of Non-invasive Markers for Esophageal Varices in Cirrhosis Study Pt (n) Etiology Prevalence of EV AUROC Accuracy Cutoff Sensitivity/Specificity Endpoint TE (SS) Sharma et al. 174 Mix 71.3% 0.898 89 40.8 94/76 Any EV TE (SS) Colecchiaet al. 100 HCV 53% 0.941 55 71.7 / 95.7 Any EV ARFI (SS) Takuma et al. 340 Mix 38.8% 0.933 75 3.18 m/s 98.5 / 60.1 Any EV 25.6% 0.930 72.1 3.30 m/s 98.9 / 62.9 High-risk EV MRE (spleen) Ronot et al. 36 Mix 75% (EV), 72% risk 0.93 NA 4.2kPa 54 / 100 High-risk EV Loss moduli (84Hz) CT Kim et al 67 Mix 63 0.77-0.80 72-73 NA 64-69 / 76-88 Any EV CT Kim et al 90 Mix 59 0.93-0.96 90-93 NA 74-78 / 70-89 Large EV CT Perri et al. 101 Mix 78 NA 34-44 5mm 75-85 / 62-75 Any EV VCE de Franchis et al 288 Mix 63 NA 94 NA 84 / 88 Any EV 27 88 78 / 96 Large EV VCE Lapalus et al 120 Mix 62 NA NA NA 77 / 86 Any EV 29 NA 85 NA 77 / 88 Large EV

  14. Performance of Non-invasive Markers for Esophageal Varices Study Pt (n) Etiology Prevalence of EV AUROC Accuracy Cutoff Sensitivity/Specificity Endpoint FibroTest Thabut et al. 99 Mix 72% 0.77 92 0.85 85/53 Large EV Plt Sebastiani G et al. 510 , retro Mix 56.9% 0.72 72 100 60 / 33 Any EV AAR 510 , retro Mix 56.9% 0.64 63 1 62 / 66 Any EV APRI 510 , retro Mix 56.9% 0.63 63 1.4 54 / 69 Any EV Forns’ index 510 , retro Mix 56.9% 0.74 73 8.5 68 / 72 Any EV Lok index 510 , retro Mix 56.9% 0.724 75 0.9 75 / 65 Any EV 110, pros Mix 51.8% 0.69 71 1.5 70 / 60 Large EV FIB4 510 , retro Mix 56.9% 0.64 66 3.5 70 / 59 Any EV Fibroindex 510 , retro Mix 56.9% 0.70 68 2.2 57 / 79 Any EV Plt/Spl Giannini EG, et al. 145, training Mix 61% NA 0.981 (c-index) 909 100 / 93 Any EV Plt/Spl Giannini EG, et al 218 Mix 54.1% 0.86 0.836 (c-index) 909 91.5 / 67 Any EV Risk score Berzigotti et al. 60 training Mix 46.7% NA 0.779 (c-index) -1.02 93 / 37 Any EV 74 validation Mix 47.3% 0.795 NA -1.02 88 / 56 Any EV

  15. Recommendations • Liver stiffness has been proven as an effective non-invasive assessment tool to predict clinically significant portal hypertension [A1]. • Non-invasive markers to predict esophageal varices have suffered from insufficient diagnostic ability, and none could replace endoscopy at present. Further study is needed to overcome this issue [A1]. • Spleen stiffness is a promising parameter to estimate the severity of portal hypertension. However, optimal imaging method need to be determined [B1]. • Calculation-based non-invasive markers have increased the diagnostic ability of portal hypertension, and may have a possibility to make a further improvement [B1]. • Non-invasive markers for portal hypertension have yet to be determined in patients with non-cirrhotic portal hypertension [C2].

  16. Chiba University Thank you for your kind attention

  17. Consensus Statement Consensus statement and evidence level • Stiffness measurement of the liver and spleen is effective to identify clinically significant portal hypertension [B, 1]. • Although recent research achieved a certain level of improvement, there are still problem in the non-invasive assessment of esophageal [1a, A].

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