Challenges and opportunities in the management of portal hypertension

Abstract

Portal hypertension and Gastro-Oesophageal varices (GOV) can occur in early stage Primary Biliary Cirrhosis (PBC) and are associated with a poor prognosis. Screening with endoscopy however, is only recommended in advanced disease. Transjugular-intrahepatic-portosystemic shunting (TIPS) is a life saving procedure in patients with decompensated portal hypertension. Serial TIPS patency checks using a venogram, in stable patients, offers a unique opportunity to sample portal venous blood, and in doing so to study the role of the human intestinal mucosa in bio-transforming essential nutrients. The aim of this work was to create a non invasive, inexpensive, externally validated screening tool to identify PBC patients with GOV and to use in-situ TIPS as a novel route of access to sample portal venous blood to define the exact site of bio-transformation of folates in humans. A cross-sectional retrospective study of 330 PBC patients who underwent an OGD at Newcastle was used to create a predictive tool that was externally validated in PBC patients from Cambridge and Toronto. 48% of the Newcastle, 31% of the Cambridge and 22% of the Toronto cohorts of PBC patients had GOV. 25% (95% CI 18–32%) of the Newcastle cohort had GOV diagnosed at an index variceal bleed. Of the others, 37% (95% CI 28–46%) bled after a median of 1.5 years (IQR 3.75). Transplant-free survival was significantly better in those without GOV vs. those with GOV (p <0.001), but similar in patients with GOV that bled and those that did not (p = 0.1). The NVP score (%Probability of GOV) = 1 / [1+exp ^ − (9.186 + 0.001 * alkaline phosphatase in IU − 0.178*albumin in g/L − 0.015*platelet×109) was validated in external cohorts ii (AUROC 0.86). Cost consequences analyses revealed the NVP score to be as accurate as, but more economical than using either OGD directly or other risk scores for screening. A prospective cross-over study of portal and peripheral venous labelled folate concentrations following oral dosing with physiological doses of stable-isotopelabelled folic acid (FA) or 5-formyltetrahydrofolic acid (5-FTHF) in six subjects with a TIPS in situ was set up. At 15 minutes, a median 86% [range 60-88%] of labelled folate in the hepatic portal vein following a dose of FA was unmodified FA. In contrast, following a dose of 5-FTHF, only a median 3% [range 2-6%] of labelled folate in the portal vein was unmodified 5-FTHF; the rest being methylated to 5-MTHF, suggesting limited gut wall dihydrofolate reductase capacity and suggesting that the liver in humans, rather than the intestinal mucosa as previously thought, is the organ responsible for this process.