Portal hypertension in cirrhosis and its associated pulmonary vascular disorders

Liver disease is the third most common cause of premature death and is the only condition with mortality increasing year on year. Cirrhosis, through portal hypertension (PH), leads to complications, including pulmonary vascular disorders, portopulmonary hypertension (PoPH), and hepatopulmonary syndrome (HPS). PoPH and HPS are poorly characterised and associated with a worse prognosis in cirrhosis. There is no consensus on screening, and they are challenging to diagnose, requiring invasive tests. Current drugs used in PH to prevent variceal bleeding in the chronic setting, are limited to β-adrenoreceptor blockers, with many patients failing to respond. There is a current unmet need to identify new therapeutic targets for drug treatments. This research aimed to identify novel clinical and biochemical markers for patients with PoPH and HPS in a prospective case-control study. Secondly, to identify new potential therapeutic targets for PH by comparing differences in RNA expression in the human portal vein from patients with cirrhosis versus healthy controls. N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, in addition to the echocardiographic measure, right ventricular systolic pressure, correlated strongly with mean pulmonary artery pressure, suggesting NT-proBNP may have a role in identifying cirrhotic patients who require right heart catheterisation. The arterio-alveolar gradient was a more sensitive method of identifying patients that would benefit from investigations for HPS, compared to measuring oxygen saturation. Among cirrhotics, circulating bone morphogenetic protein (BMP) 9 and 10 levels were normal in compensated individuals but undetectable in those with decompensated disease. This loss of BMP9/10 suggests these ligands have a significant role in maintaining endothelial homeostasis in PH, and treatment with BMP9/10 could be a new therapeutic strategy for PH. In cirrhotic compared to control portal veins, ~3,500 genes were downregulated; ~1,200 upregulated with 49 pathways identified as statistically significant, including potential drug targets. Inflammatory pathways featured highly with the interleukin (IL) 4 and 6 pathways in the top 10, and the IL-6 pathway with the highest level of significance. Current approved drugs could be repurposed to treat dysregulation of pro-inflammatory cytokines. The endothelin pathway (ranked 10) demonstrated upregulation of endothelin-1 that could be blocked by endothelin receptor A antagonists.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2021

Author dc:creator

• Owen, Nicola

Advisor dc:contributor.advisor

• Davenport, Anthony

• portal hypertension
• portopulmonary hypertension
• hepatopulmonary syndrome
• bone morphogenetic protein
• brain natriuretic peptide
• endoglin

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/4fdd7cc9-6170-40e6-9009-837b023d77ff/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

Author Identifier

0000-0002-2096-3117

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/329856