Hepatic Venous Pressure Gradient and Elastography in Porto-sinusoidal Vascular Disorder

Diagnostic Role of the Hepatic Venous Pressure Gradient and Elastography in Porto-sinusoidal Vascular Disorder With Portal Hypertension

Porto-sinusoidal vascular disorder (PSVD) is considered a rare cause of portal hypertension (PH), resulting from specific histological alterations that essentially affect the small portal branches and sinusoids, in the absence of cirrhosis. In recent years, the recognition and importance of PSVD has increased, notably due to the widespread use of transient elastography (TE). However, the definitive diagnosis of PSVD can only be established through liver biopsy. Recent data show that PSVD should be suspected in patients with PH and TE ≤ 20 kPa and liver biopsy should be considered in this context. The investigators hypothesize that hepatic venous pressure gradient (HVPG) and magnetic resonance liver elastography (MRE) may help in the selection of liver biopsy candidates for the diagnosis of PSVD. The primary objective of the study is to describe HVPG and MRE values and liver biopsy findings in patients with PH and TE ≤ 20 kPa. The search for serum markers that can distinguish these patients from those with cirrhotic portal hypertension without the need for liver biopsy will also be the object of this study. 50 patients will be included, prospectively and retrospectively, in a comparative study between diagnostic methods, with a cross-sectional design.

Porto-sinusoidal vascular disorder (PSVD) is considered a rare cause of portal hypertension (PH), resulting from specific histological alterations that essentially affect the small portal branches and sinusoids, in the absence of cirrhosis. In recent years, the recognition and importance of PSVD has increased, notably due to the widespread use of transient elastography (TE). However, the definitive diagnosis of PSVD can only be established through liver biopsy. Recent data show that PSVD should be suspected in patients with PH and TE ≤ 20 kPa and liver biopsy should be considered in this context. The investigators hypothesize that hepatic venous pressure gradient (HVPG) and magnetic resonance liver elastography (MRE) may help in the selection of liver biopsy candidates for the diagnosis of PSVD. Primary objectives are: To describe the measurement of the hepatic venous pressure gradient (in mmHg) in patients with portal hypertension and transient hepatic elastography ≤ 20 kPa. To describe hepatic (in kPa) and splenic (in kPa) stiffness measured by magnetic resonance elastography in patients with portal hypertension and transient hepatic elastography ≤ 20 kPa. To describe the frequency of major histological findings for the diagnosis of portal sinusoidal vascular disorder (obliterative portal venopathy, regenerative nodular hyperplasia and incomplete septal cirrhosis) in patients with portal hypertension and transient hepatic elastography ≤ 20 kPa. Secondary objectives are: To describe the frequency of hepatic vein-to-vein communications in patients with portal hypertension and transient hepatic elastography ≤ 20 kPa. To describe the frequency of minor histological findings for the diagnosis of portal sinusoidal vascular disease (portal tract abnormalities, architectural disturbances, nonzonal sinusoidal dilatation, mild perisinusoidal fibrosis) in patients with portal hypertension and transient hepatic elastography ≤ 20 kPa. To compare the serum values of von Willebrand antigen factor (IU/mL) between patients diagnosed with porto-sinusoidal vascular disorder and those diagnosed with cirrhosis, after analysis of liver biopsy. To compare the serum titers of procollagen III amino-terminal peptide (mcg/l) between patients diagnosed with portosinusoidal vascular disorder and those diagnosed with cirrhosis, after analysis of liver biopsy. To compare the serum titers of anti-endothelial cell antibodies between patients diagnosed with portosinusoidal vascular disorder and those diagnosed with cirrhosis, after analysis of liver biopsy. 50 patients will be included, prospectively and retrospectively, in a comparative study between diagnostic methods, with a cross-sectional design.

Portal Hypertension, Non-Cirrhotic Portal Hypertension, Non-Cirrhotic Portal Fibrosis, Regenerative Nodular Hyperplasia, Incomplete Septal Cirrhosis, Obliterative Portal Venopathy, Idiopathic Non-Cirrhotic Portal Hypertension, Hepatoportal Sclerosis, Idiopathic Portal Hypertension, Vascular Disorder of Liver

All patients included will undergo HVPG measurement and US-guided percutaneous liver biopsy. The exams will be performed in sequence, in the laboratory of hepatic hemodynamics. Within 4 to 8 weeks, a multiparametric magnetic resonance imaging of the abdomen with elastography will be performed, concluding the protocol.

HVPG will be performed after light conscious sedation and with noninvasive vital sign monitoring. The right jugular vein will be catheterized with ultrasound assistance and after local anesthesia. Then a venous introducer will be placed and a balloon-tipped catheter will be advanced under fluoroscopic control into the right hepatic vein. Free hepatic pressure will be obtained with the balloon deflated, keeping the catheter tip in the right hepatic vein. Then, wedged venous pressure will be measured by inflating the balloon with 2 ml of air. At this moment, complete occlusion of the catheterized hepatic vein can be confirmed by injecting iodinated contrast and observing its retention. The presence of veno-venous communications can be detected during the test. To calculate the gradient, we perform the simple difference between the two measurements. Measurements will be performed in triplicate and the average used as the final value.

Percutaneous liver biopsy will be performed with the aid of US to choose the best site for the procedure, minimizing the incidence of complications. With the patient in dorsal decubitus, venous analgesia with fentanyl 25-50 mcg will be performed. After marking the appropriate site, skin asepsis and antisepsis will be performed with Chlorhexidine® and topical anesthesia with 1% lidocaine. Then, the liver will be punctured using a 14G semi-automatic tru-cut single-use liver biopsy needle. The recovered material will be stored in a 50 ml flask with 10% formaldehyde. Patients will remain at rest supervised for 4 hours, with hourly measurement of blood pressure (BP), heart rate (HR) and assessment of symptoms (abdominal pain, nausea, etc.). In the absence of any complications, patients will be discharged from the hospital.

The evaluation of the abdomen by MRI, with special interest to the liver and spleen, will be performed in a Siemens 3.0T Magnetom Prisma MR system. In addition to the routine protocol without contrast administration, MR elastography will be performed to assess liver stiffness and spleen stiffness. Data processing will be carried out at a Syngovia workstation.

To describe the measurement of the hepatic venous pressure gradient (in mmHg) in patients with portal hypertension and transient hepatic elastography ≤ 20 kPa.

To describe hepatic (in kPa) and splenic (in kPa) stiffness measured by magnetic resonance elastography in patients with portal hypertension and transient hepatic elastography ≤ 20 kPa.

To describe the frequency of major histological findings for the diagnosis of portal sinusoidal vascular disorder (obliterative portal venopathy, regenerative nodular hyperplasia and incomplete septal cirrhosis) in patients with portal hypertension and transient hepatic elastography ≤ 20 kPa.

To describe the frequency of hepatic vein-to-vein communications in patients with portal hypertension and transient hepatic elastography ≤ 20 kPa.

To describe the frequency of minor histological findings for the diagnosis of portal sinusoidal vascular disease (portal tract abnormalities, architectural disturbances, nonzonal sinusoidal dilatation, mild perisinusoidal fibrosis) in patients with portal hypertension and transient hepatic elastography ≤ 20 kPa.

To compare the serum values of von Willebrand antigen factor (IU/mL) between patients diagnosed with porto-sinusoidal vascular disorder and those diagnosed with cirrhosis, after analysis of liver biopsy.

To compare the serum titers of procollagen III amino-terminal peptide (mcg/l) between patients diagnosed with portosinusoidal vascular disorder and those diagnosed with cirrhosis, after analysis of liver biopsy.

To compare the serum titers of anti-endothelial cell antibodies between patients diagnosed with portosinusoidal vascular disorder and those diagnosed with cirrhosis, after analysis of liver biopsy.

Inclusion Criteria: Age ≥ 18 years; Patients with specific signs of portal hypertension: Endoscopic: esophagogastric/ectopic varices; On imaging (US, CT or MRI): portosystemic collateral veins; Transient hepatic elastography with valid values ≤ 20 kPa; Signed written informed consent form. Exclusion Criteria: Contraindications to HVPG or percutaneous liver biopsy: Pregnancy Allergy to iodine Chronic kidney disease with creatinine clearance < 50 ml/min Anticoagulation RNI > 1.5 Platelets < 50,000/mm3 Confounding factors: 1. Hepatitis C treated with SVR Conditions that exclude the diagnosis of PSVD: History of bone marrow transplant Budd-Chiari Congestive heart failure or Fontan surgery Abernethy's Syndrome Hereditary hemorrhagic telangiectasia Chronic cholestatic diseases Neoplastic hepatic infiltration Sarcoidosis Congenital hepatic fibrosis Hepatosplenic schistosomiasis Portal cavernoma / thrombosis with complete occlusion of the main portal vein.

Huwart L, Sempoux C, Vicaut E, Salameh N, Annet L, Danse E, Peeters F, ter Beek LC, Rahier J, Sinkus R, Horsmans Y, Van Beers BE. Magnetic resonance elastography for the noninvasive staging of liver fibrosis. Gastroenterology. 2008 Jul;135(1):32-40. doi: 10.1053/j.gastro.2008.03.076. Epub 2008 Apr 4.

Berzigotti A, Seijo S, Reverter E, Bosch J. Assessing portal hypertension in liver diseases. Expert Rev Gastroenterol Hepatol. 2013 Feb;7(2):141-55. doi: 10.1586/egh.12.83.

Cerda Reyes E, Gonzalez-Navarro EA, Magaz M, Munoz-Sanchez G, Diaz A, Silva-Junior G, Triguero A, Lafoz E, Camprecios G, Orts L, Perez-Campuzano V, Seijo S, Rubio L, Turon F, Baiges A, Hernandez-Gea V, Alvarez-Larran A, Juan M, Garcia-Pagan JC. Autoimmune biomarkers in porto-sinusoidal vascular disease: Potential role in its diagnosis and pathophysiology. Liver Int. 2021 Sep;41(9):2171-2178. doi: 10.1111/liv.14997. Epub 2021 Jul 11.

D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol. 2006 Jan;44(1):217-31. doi: 10.1016/j.jhep.2005.10.013. Epub 2005 Nov 9. No abstract available.

de Franchis R; Baveno VI Faculty. Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol. 2015 Sep;63(3):743-52. doi: 10.1016/j.jhep.2015.05.022. Epub 2015 Jun 3. No abstract available.

De Gottardi A, Rautou PE, Schouten J, Rubbia-Brandt L, Leebeek F, Trebicka J, Murad SD, Vilgrain V, Hernandez-Gea V, Nery F, Plessier A, Berzigotti A, Bioulac-Sage P, Primignani M, Semela D, Elkrief L, Bedossa P, Valla D, Garcia-Pagan JC; VALDIG group. Porto-sinusoidal vascular disease: proposal and description of a novel entity. Lancet Gastroenterol Hepatol. 2019 May;4(5):399-411. doi: 10.1016/S2468-1253(19)30047-0.

Elkrief L, Lazareth M, Chevret S, Paradis V, Magaz M, Blaise L, Rubbia-Brandt L, Moga L, Durand F, Payance A, Plessier A, Chaffaut C, Valla D, Malphettes M, Diaz A, Nault JC, Nahon P, Audureau E, Ratziu V, Castera L, Garcia Pagan JC, Ganne-Carrie N, Rautou PE; ANRS CO12 CirVir Group. Liver Stiffness by Transient Elastography to Detect Porto-Sinusoidal Vascular Liver Disease With Portal Hypertension. Hepatology. 2021 Jul;74(1):364-378. doi: 10.1002/hep.31688. Epub 2021 Jun 11.

European Association for Study of Liver; Asociacion Latinoamericana para el Estudio del Higado. EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. J Hepatol. 2015 Jul;63(1):237-64. doi: 10.1016/j.jhep.2015.04.006. Epub 2015 Apr 21. No abstract available.

European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; Clinical Practice Guideline Panel; Chair:; EASL Governing Board representative:; Panel members:. EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis - 2021 update. J Hepatol. 2021 Sep;75(3):659-689. doi: 10.1016/j.jhep.2021.05.025. Epub 2021 Jun 21.

Ferlitsch M, Reiberger T, Hoke M, Salzl P, Schwengerer B, Ulbrich G, Payer BA, Trauner M, Peck-Radosavljevic M, Ferlitsch A. von Willebrand factor as new noninvasive predictor of portal hypertension, decompensation and mortality in patients with liver cirrhosis. Hepatology. 2012 Oct;56(4):1439-47. doi: 10.1002/hep.25806. Epub 2012 Aug 27.

Goel A, Ramakrishna B, Muliyil J, Madhu K, Sajith KG, Zachariah U, Ramachandran J, Keshava SN, Selvakumar R, Chandy GM, Elias E, Eapen CE. Use of serum vitamin B12 level as a marker to differentiate idiopathic noncirrhotic intrahepatic portal hypertension from cryptogenic cirrhosis. Dig Dis Sci. 2013 Jan;58(1):179-87. doi: 10.1007/s10620-012-2361-7. Epub 2012 Aug 24.

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 Jul;36(2):173-80. doi: 10.1111/j.1365-2036.2012.05134.x. Epub 2012 May 16.

Khanna R, Sarin SK. Noncirrhotic Portal Hypertension: Current and Emerging Perspectives. Clin Liver Dis. 2019 Nov;23(4):781-807. doi: 10.1016/j.cld.2019.07.006.

La Mura V, Reverter JC, Flores-Arroyo A, Raffa S, Reverter E, Seijo S, Abraldes JG, Bosch J, Garcia-Pagan JC. Von Willebrand factor levels predict clinical outcome in patients with cirrhosis and portal hypertension. Gut. 2011 Aug;60(8):1133-8. doi: 10.1136/gut.2010.235689. Epub 2011 Mar 22.

Morikawa H, Tamori A, Nishiguchi S, Enomoto M, Habu D, Kawada N, Shiomi S. Expression of connective tissue growth factor in the human liver with idiopathic portal hypertension. Mol Med. 2007 May-Jun;13(5-6):240-5. doi: 10.2119/2006-00093.Morikawa.

Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD; American Association for the Study of Liver Diseases. Liver biopsy. Hepatology. 2009 Mar;49(3):1017-44. doi: 10.1002/hep.22742. No abstract available.

Seijo S, Reverter E, Miquel R, Berzigotti A, Abraldes JG, Bosch J, Garcia-Pagan JC. Role of hepatic vein catheterisation and transient elastography in the diagnosis of idiopathic portal hypertension. Dig Liver Dis. 2012 Oct;44(10):855-60. doi: 10.1016/j.dld.2012.05.005. Epub 2012 Jun 19.

Sharma P, Agarwal R, Dhawan S, Bansal N, Singla V, Kumar A, Arora A. Transient Elastography (Fibroscan) in Patients with Non-cirrhotic Portal Fibrosis. J Clin Exp Hepatol. 2017 Sep;7(3):230-234. doi: 10.1016/j.jceh.2017.03.002. Epub 2017 Mar 14.

Siramolpiwat S, Seijo S, Miquel R, Berzigotti A, Garcia-Criado A, Darnell A, Turon F, Hernandez-Gea V, Bosch J, Garcia-Pagan JC. Idiopathic portal hypertension: natural history and long-term outcome. Hepatology. 2014 Jun;59(6):2276-85. doi: 10.1002/hep.26904. Epub 2014 Feb 28.

Waidmann O, Brunner F, Herrmann E, Zeuzem S, Piiper A, Kronenberger B. Macrophage activation is a prognostic parameter for variceal bleeding and overall survival in patients with liver cirrhosis. J Hepatol. 2013 May;58(5):956-61. doi: 10.1016/j.jhep.2013.01.005. Epub 2013 Jan 16.