1. RESEARCH QUESTIONS
The term porto-sinusoidal vascular disorder (PSVD) describes a group of vascular diseases of the liver featuring typical histologic lesions of the portal venules and hepatic sinusoids often causing portal hypertension in the absence of cirrhosis (1). Although this condition is considered a rare disease, homogenization in nomenclature and increasing awareness for this condition have fuelled recent reports on an unexpectedly high prevalence of histologic PSVD features, occuring in up to 21% of patients with cystic fibrosis (2) and in 44% of patients undergoing liver resection due to metastases, 44% (3). Interestingly, 67% of patients with unexplained gamma-glutamyltransferase elevation were found to have PSVD features in (4).
However, these reports underline the current obstacles in diagnosis of PSVD: As the disease remains asymptomatic for a long time, allowing portal hypertension to develop, most patients present and get diagnosed very late after complications have already occurred (up to 50% of patients presenting only after a complication (5-7)). If disease progresses, clinical deterioration might occur at young age and necessitate liver transplantation (median age 46 years at liver transplantation)(8).
Complicated by the heterogenous clinical presentation and incompletely understood etiological factors (7, 9), this delay may be attributed to the difficult diagnosis, requiring an invasive liver biopsy of adequate quality with associated complications and necessary patient compliance (10, 11), as well as evaluation by an expert pathologist. Despite imaging features (12-14), elastography of liver and spleen can point towards PSVD and are increasingly investigated (15-18). However, no biomarker has so far been proven sufficiently accurate to diagnose PSVD without performing a liver biopsy.
Data on the pathomechanisms driving PSVD development and progression are scarce. A co-expression gene network analysis revealed that pathways related to vascular homeostasis, coagulation and endothelial dysfunction are significantly altered in patients with PSVD (19). Also, different haematological diseases and pro-thrombotic conditions are strongly associated with PSVD development (1, 20). However, analyses of the plasma metabolome have shown promising results: Previous studies on a subgroup of PSVD patients have identified signatures that differentiate this subgroup from cirrhosis and healthy volunteers (21, 22). Specifically, the latter study identified a 5-metabolite signature including an acyl-carnitine, a bile acid, a fatty acid, a lysophosphatidylethanolamine, and sphingomyelin to discriminate patients with PSVD from patients with cirrhosis and healthy volunteers (22). Recently, we could extend this knowledge on metabolomic changes in PSVD and demonstrate distinct metabolic signatures in PSVD patients as compared to cirrhotic patients and healthy controls, including alterations in the pyrimidine, glycine, serine and threonine pathways (23). Most strikingly, taurocholic acid (TCA), a conjugated primary bile acid (BA), had the highest discriminative ability to differentiate PSVD from healthy controls (relatively elevated in PSVD) and, together with adipic acid, from cirrhosis (reduced as compared to PSVD, Figure 1), which could be confirmed in the historic metabolomics data from Barcelona, using different disease subgroups and methodology (23). Overall, 2 out of 3 tested BA were differentially expressed in PSVD, healthy controls and cirrhosis, pointing towards the potential of BA as diagnostic and prognostic biomarkers with potential link to the pathophysiology of PSVD. This is further supported by emerging data from other chronic liver diseases (CLD) linking BA to inflammation, fibrogenesis and progressive liver disease (24), but also regression after etiological cure (25).
3.1. Study design
The proposed project is a sub-study of the ongoing prospective VIenna CIrrhosis Study (VICIS; ClinicalTrials.gov ID: NCT03267615) and the Vienna VAscular LIver Disease Study (VALID; ClinicalTrials.gov ID: NCT03541057), which comprise 89 patients with PSVD (as of October 2024) and >500 patients with cirrhosis. Within these prospective registry studies with biobank, consecutive patients with cirrhosis and vascular disorders of the liver including PSVD presenting at the Vienna Hepatic Hemodynamic Lab as well as the outpatient clinic undergo extensive clinical as well as laboratory and hemodynamic phenotyping. Within these studies, a biobank including blood as well as tissue samples (especially liver tissue, as well as samples from the upper and lower gastrointestinal tract) are collected. Additionally, patients undergo a prospective clinical as well as imaging follow-up according to a structured standard operating procedure at the outpatient clinic of the Department of Gastroenterology and Hepatology, Medical University of Vienna.
Specifically, patients are recruited and characterized at the time of hepatic venous pressure gradient (HVPG) measurement within the framework of the prospective VICIS study or at the time of PSVD diagnosis within the VALID study. Blood samples for biobanking are drawn at the occasion of a routine blood draw at the outpatient clinic of the Division of Gastroenterology and Hepatology, Department of Medicine III. Only samples measured after a fasting period of at least 12 hours will be considered for this study. They are transferred to the laboratory of the Vienna Liver Study Groups immediately after blood sampling and processed by an experienced biomedical technician (centrifuged for 10 minutes at ambient temperature). Finally, blood samples are stored at -20°C/-80°C until the day of analyses.
3.2. Patients & definitions
PSVD: Patients enrolled in the prospective VALID registry with an established diagnosis of PSVD according to proposed criteria (32) will be included in this study. The first group will consist of n=40 patients with specific clinical signs of portal hypertension. Additionally, n=40 PSVD patients with only unspecific clinical signs, but additional histological signs to verify the diagnosis of PSVD will be included next to n=20 PSVD patients with only histological signs of PSVD, but without clinical signs of portal hypertension.