new VALDIG project: 2D-SWE to detect PSVD

[Pierre-Emmanuel Rautou]

Dear VALDIG friends,
We are happy to propose a new collaborative project entitled “Liver and spleen stiffness by 2D-shear-wave elastography to detect porto-sinusoidal vascular liver disorder in patients with signs of portal hypertension”.
You can find below the project.
If you are interested, please send us an email and we will send you the CRF and the project in PDF (for the moment, we can’t add the project to VALDIG website for technical reasons).
Best wishes

Lucile Moga, lucile.moga@gmail.com
Pierre-Emmanuel Rautou, pierre-emmanuel.rautou@inserm.fr

Background
In 2019, VALDIG proposed the term of porto-sinusoidal vascular liver disease (PSVD) to describe a group of rare vascular liver entities characterized by histological lesions involving portal venules and/or sinusoids and absence of cirrhosis, with or without signs of portal hypertension (1). Recently, the Baveno VII consensus workshop preferred the term “disorder” instead of “disease” so that PSVD now stands for “porto-sinusoidal vascular liver disorder”. PSVD is defined as follows:
• Adequate liver biopsy (≥20 mm long, and not too fragmented, or considered adequate for interpretation by an expert pathologist) or liver explant without cirrhosis AND one sign specific for portal hypertension or one histological lesion specific for PSVD;
• Or adequate liver biopsy (≥20 mm long, and not too fragmented, or considered adequate for interpretation by an expert pathologist) or liver explant without cirrhosis AND one sign not specific for portal hypertension AND one histological lesion not specific for PSVD.

Histology is therefore mandatory for the diagnosis of PSVD, with a high quality liver biopsy, and an interpretation by an expert pathologist. Non-invasive tests appear useful tools to screen for PSVD. Elkrief et al. showed that liver stiffness measurement using transient elastography is able to raise suspicion of PSVD in patients with signs of portal hypertension with high accuracy (2). Ferreira-Silva et al. found that spleen stiffness measurement using transient elastography has a good performance in predicting high-risk varices in patients with non-cirrhotic portal hypertension (3), but this result was not observed by other groups (4).

Aims
• To evaluate feasibility and accuracy of two-dimensional liver and spleen shear-wave elastography (2D-SWE) to discriminate porto-sinusoidal vascular liver disorder (PSVD) from cirrhosis in patients with signs of portal hypertension.
• To compare accuracy of 2D-SWE to that of transient elastography – liver stiffness measurement (TE-LSM) to detect PSVD with signs of portal hypertension.

Design
Part I: Learning group of patients with PSVD
The learning cohort will include the 153 patients with PSVD who underwent a liver biopsy between 2012 to 2021 at Hôpital Beaujon (Clichy, France) and a liver 2D-SWE. All liver biopsies were analyzed by a pathologist expert in vascular liver diseases (Prof. Valérie Paradis, Hôpital Beaujon, Clichy, France). Diagnosis of PSVD will be based on VALDIG criteria, as stated in Baveno VII consensus.

Part II: Validation group of patients with PSVD
The validation cohort will include PSVD patients from participating VALDIG centers fulfilling the same inclusion criteria.

Part III: First control group of patients with cirrhosis
Patients with cirrhosis and signs of portal hypertension will be selected at each VALDIG centers participating in the study, matched 1:1 on ascites (absent; moderate or controlled with diuretics; tense or requiring paracentesis), with patients with PSVD.

Part IV: Second control group of patients with cirrhosis
For liver 2D-SWE: patients with cirrhosis included in the international multicentre cohort study on 2D-SWE in cirrhosis by Trebicka et al. (Gut . 2022 Feb;71(2):402-414), matched 1:1 on ascites (absent; moderate or controlled with diuretics; tense or requiring paracentesis), with patients with PSVD (from learning and validation cohorts). These patients with cirrhosis should not be part of the first control group. Investigators who provided their data for the paper mentioned above (Gut . 2022 Feb;71(2):402-414) will be contacted to ask for permission to used their data in the present study.
For spleen 2D-SWE: patients with cirrhosis included in the ongoing meta-analysis of individual participant data to determine the most performant cut-offs of spleen stiffness measurement (SSM) for the prediction of portal hypertension and/or esophageal varices in patients with compensated advanced chronic disease coordinated by Prof. Antonio Colecchia. Patients will be matched 1:1 on ascites (absent; moderate or controlled with diuretics; tense or requiring paracentesis), with patients with PSVD (from learning and validation cohorts). These patients with cirrhosis should not be part of the first control group. Investigators who provided their data for the paper mentioned above (meta-analysis of individual participant data coordinated by Prof. Antonio Colecchia) will be contacted to ask for permission to used their data in the present study.

PSVD patients
Inclusion criteria:
• Patients with PSVD and signs of portal hypertension according to VALDIG criteria (please see above). Signs of portal hypertension should be present at the time of liver biopsy (i.e. within 1 year before or after liver biopsy).
• And available liver and/or spleen stiffness measurement by 2D-SWE performed either within 3 years before liver biopsy or at any time after the liver biopsy.

Non-inclusion criteria:
• Cavernoma or complete portal vein thrombosis at the time of liver biopsy;
• Other cause of portal hypertension (Budd-Chiari syndrome, cardiac insufficiency, Fontan surgery, hereditary hemorrhagic telangiectasia, Abernethy syndrome, history of bone marrow transplantation, chronic cholestatic disease, liver infiltration by tumor cells, hepatic schistosomiasis diagnosed on liver biopsy);
• Transjugular intrahepatic portosystemic shunt at the time of stiffness measurement by 2D-SWE
• Liver or spleen stiffness measured by point-shear wave elastography.

Control patients with cirrhosis
Inclusion criteria:
– matched 1:1 on ascites (absent; moderate or controlled with diuretics; tense or requiring paracentesis) with PSVD patients,
– at least one sign of portal hypertension (specific or non-specific) among those mentioned in the Table above,
– at least one cause of cirrhosis among alcohol consumption, metabolic syndrome, and chronic viral hepatitis. At least one aetiological factor should be present – or removed (e.g. achievement of SVR in HCV; long-lasting abstinence in patients with excessive alcohol consumption) for less than 2 years- when 2D-SWE measurement was performed
– a diagnosis of cirrhosis based on one of the following 2 options:
(a) histological demonstration of cirrhosis; or
(b) a strong clinical suspicion of cirrhosis, based on clinical, laboratory and imaging features. Liver or spleen stiffness using any technique should not be taken into account to base diagnosis of cirrhosis. In that case, patients with conditions known to be associated with PSVD should not be included.

Non-inclusion criteria:
• Cavernoma or complete portal vein thrombosis at the time of liver biopsy;
• Transjugular intrahepatic portosystemic shunt at the time of stiffness measurement by 2D-SWE
• Previous history of liver transplantation
• Liver or spleen stiffness measured by point-shear wave elastography.
• Hepatocellular carcinoma at the time of 2D-SWE measurement
• Serum bilirubin > 100 µmol/L or INR > 1.7 (unless the matched PSVD patient has serum bilirubin or IRN values exceeding those thresholds)

Data collection
Data will be collected from medical records in a dedicated case report form by participating VALDIG members. The following data categories will be retrospectively collected by the local investigators, and sent to the principal investigator of the study:
– demographics data,
– histological features,
– extra-hepatic conditions associated with PSVD, classified in immunological disorder, hematological disorder, toxic, and others (genetic disorder, HIV infection, telomere disorder).
– clinical presentation,
– laboratory results,
– diagnostic imaging (liver ultrasonography, computed tomography scan, or magnetic resonance imaging),
– endoscopic data
– liver stiffness by 2D-SWE, and if available spleen stiffness, performed either within 3 years before liver biopsy or at any time after the liver biopsy
– liver and spleen stiffness by transient elastography if available, performed either within 3 years before liver biopsy or at any time after the liver biopsy.
Data will be pseudonymized with a number of inclusion assigned to each patient included in the study. Inclusion number will include the number of the center, and the patient’s number in the center.

Statistical analysis
Quantitative variables will be expressed as median and interquartile ranges (IQR) and categorical variables as absolute number (percentage). Continuous variables will be compared using the Mann-Whiney test. Comparison of categorical variables will be performed using the Chi-square or Fisher exact test, when appropriate. We will assess the ability of liver 2D-SWE alone, spleen 2D-SWE alone, spleen to liver 2D-SWE ratio, as well as platelets/spleen size to identify PSVD, by calculating area under the receiver operating characteristic curve (AUROC), sensitivity, specificity, positive predictive value, negative predictive value, positive and negative likelihood ratio and diagnostic accuracy of these tests. We will test cut-off values already published (10 kPa and 20 kPa for liver 2D-SWE; 21 kPa and 50 kPa for spleen 2D-SWE, extrapolating data obtained using TE) and identify dedicated cut-off values using Youden index. Analyses will be performed both on an intention-to-diagnose (including the entire cohort) and per-protocol (including only patients with valid 2D-SWE) basis. Sensitivity analyses will be performed restricting the analyses to patients having the same 2D-SWE machine (e.g. Airexplorer) and also matching PSVD patients with cirrhosis patients on MELD  3 on top of ascites.

Timeline
February 2022: opening of inclusions
September 2022: closure of inclusions
September-October 2022: analysis of the data
November 2022: abstract submitted to ILC

Authorship
VALDIG rules of publication will be followed http://valdig.eu/rules-of-publication/
• first and last authors are from the center coordinating the study (i.e. writes the project, the CRF and the manuscript)
• other authors are listed according to the number of patients included. Second author will be from the center that included the highest number of patients (it can be the coordinating center; in that case, the coordinating center will have 1st and 2nd authorship). Third author will be from the center that included the second highest number of patients, etc. Same rules will be followed for senior authorship.
• the number of authors per center will vary according to the overall number of patients included in the study. Usually, centers including the highest number of patients will have more authors.
Here, “to the number of patients included” refers to couples “PSVD- matched cirrhosis patients”.

References
1. De Gottardi A, Rautou P-E, Schouten J, Rubbia-Brandt L, Leebeek F, Trebicka J, et al. Porto-sinusoidal vascular disease: proposal and description of a novel entity. Lancet Gastroenterol Hepatol. mai 2019;4(5):399‑411.
2. Elkrief L, Lazareth M, Chevret S, Paradis V, Magaz M, Blaise L, et al. Liver Stiffness by Transient Elastography to Detect Porto-Sinusoidal Vascular Liver Disease With Portal Hypertension. Hepatology. juill 2021;74(1):364‑78.
3. Ferreira-Silva J, Gaspar R, Liberal R, Cardoso H, Macedo G. Transient splenic elastography predicts high-risk esophageal varices in patients with non-cirrhotic portal hypertension. Scand J Gastroenterol. déc 2021;56(12):1462‑6.
4. Cunningham ME, Parastandeh-Chehr G, Cerocchi O, Wong DK, Patel K. Noninvasive Predictors of High-Risk Varices in Patients with Non-Cirrhotic Portal Hypertension. Can J Gastroenterol Hepatol. 2019;2019:1808797.
5. Trebicka J, Gu W, de Ledinghen V, Aubé C, Krag A, Praktiknjo M, et al. Two-dimensional shear wave elastography predicts survival in advanced chronic liver disease. Gut. févr 2022;71(2):402‑14.

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