Title: Novel applications of magnetic resonance imaging for the evaluation of portal hypertension and liver function
Funder: Department of Health and Social Care

Abstract: Background Liver-related deaths increased 4-fold in the United Kingdom since 1970, despite all other causes of death declining. Portal hypertension and liver dysfunction are major causes of liver mortality and morbidity, including oesophageal variceal bleeding, ascites and hepatic encephalopathy. Portal pressure is usually measured using invasive venous catheterisation to measure the hepatic venous pressure gradient (HVPG) and oesophageal varices are assessed by gastroscopy. Non-invasive, cheaper, safer methods of assessment are needed. A non-invasive, novel magnetic resonance imaging (MRI) technique created in Oxford accurately evaluates liver fibrosis, fat and iron content, as an alternative to liver biopsy. We propose additionally to develop new candidate predictors of portal hypertension and liver biochemical function. T1 relaxation time is an intrinsic property of tissues affected primarily by extracellular water content. Oxford researchers find that native spleen T1 has excellent correlation with HVPG (r=0.83; R2=0.69; p=0.0008, n=12; unpublished data). This may be because increasing portal pressure increases splenic venous congestion. Changes in T1 after injection of intravenous contrast, combined with blood hematocrit allow calculation of extracellular volume (ECV) fraction. This is used widely in cardiovascular applications and has excellent correlation with histology (White et al., 2013)18. ECV includes plasma volume within blood vessels and thus may be another independent marker of splenic venous congestion and portal hypertension. Liver function will be assessed by liver T1 reduction with Gd-EOB-DTPA (clinically approved, liver-excreted Gadolinium-based contrast) administration, correlated previously by Haimerl et al. (2014)19. The proposal, therefore, is to test the added value of the above assessments to our current diagnostic tests. Aims This study aims to develop existing MRI technology by adding portal hypertension and liver function evaluations to its capabilities. Specifically, this project will explore whether spleen and liver T1 and their responses to Gd-EOB-DTPA administration can: 1) quantify portal hypertension and liver function; 2) assess the relative contribution of pathological phenotype (liver fibrosis, portal hypertension, liver function) to clinical phenotype (varices, ascites, hepatic encephalopathy); 3) predict specific clinical events; 4) assess dynamic changes in portal hypertension in response to therapy. Plan of investigation The 3-year study will take place at the Oxford Centre for Clinical Magnetic Resonance Research (OCMR) and Southampton General Hospital. Healthy volunteers (controls, n=20) and patients with acute liver dysfunction (n=20), compensated cirrhosis (n=80) and decompensated cirrhosis (n=80) will be recruited. The last group will be subdivided by clinical phenotype into those with impaired liver function blood parameters alone (n=20), ascites (n=20), hepatic encephalopathy (n=20) and awaiting transjugular porto-systemic shunt (TIPSS) (n=20). All causes of liver disease will be included. All participants will undergo clinical assessment, liver-related blood tests, transient elastography and MRI including Gd-EOB-DTPA administration. Patients will be followed up for 6-36 months for liver-related clinical events (varices, variceal bleeds, ascites, hepatic encephalopathy, hepatocellular carcinoma, death). Results will be analysed for correlation of spleen T1, spleen ECV fraction and liver T1 reduction with Gd-EOB-DTPA enhancement with clinical phenotype, HVPG and follow-up events. Optimal cut off scores will be defined for each parameter and predictive value assessed. Benefits to patients/NHS If these MRI techniques allow prediction of clinical outcomes, MRI would provide a non-invasive, safe, cost effective alternative to: 1) gastroscopy screening for oesophageal varices 2) hepatic catheterisation for HVPG measurement 3) liver biopsy to identify significant fibrosis. Risk stratification by MRI could identify patients likely to develop post-TIPSS encephalopathy or liver transplant candidates. Disease progression and treatment effectiveness could also be monitored. The MRI techniques will be possible on the vast majority of existing MRI scanners, making the findings readily translatable into NHS care.CHAR(13) + CHAR(10)

Lay abstract: Background Liver-related deaths have increased 4-fold in the United Kingdom since 1970, despite a decline in all other causes of death. Liver disease particularly affects people of working age. Liver disease causes progressive accumulation of scarring in the liver, which in turn leads to increased resistance to blood flow through the liver. This causes congestion and raises the pressure in the veins that carry blood from the gut and spleen to the liver (portal hypertension). Also, as liver disease progresses, more liver cells die, so the liver is not able to carry out its vital biochemical functions properly (liver dysfunction). Liver dysfunction and portal hypertension cause the majority of problems in the later stages of liver disease. Measures of portal hypertension are known to predict liver-related complications and death. To date the most accurate tests to assess portal hypertension require invasive procedures (e.g. passing wires from the neck to the liver vein). These are uncomfortable, expensive and pose risks to the patient. Liver function is usually measured using blood tests, but these can be affected by other diseases or medications and so are not specific to the liver. Alternative tests that are non-invasive, cheap and accurate are therefore needed urgently. Indeed the need for better diagnostic tests for liver disease has been highlighted by the American Association for the Study of the Liver and the international consensus group for the management of portal hypertension (Baveno). An Oxford research group has developed new magnetic resonance imaging (MRI) scan techniques for quantitative assessment of the heart. These have been used successfully to assess the amount of scarring, fat and iron in the liver. The results aid diagnosis without the need for liver biopsy in many circumstances. MRI is safe, non-invasive and widely available. There is also evidence that spleen MRI measures (T1 relaxation times) increase with worsening liver scarring and portal hypertension. We therefore hypothesize that worsening portal hypertension causes more venous congestion in the spleen resulting in higher T1 relaxation times. The observed effects appear large enough for non-invasive assessment of portal hypertension directly on the MRI scanner. The addition of an injectable, liver-excreted contrast agent during the MRI scans may allow better interpretation of the observed phenomenon and provide additional evaluation of liver function. Aims This study aims to investigate the use and value of novel quantitative MRI methods (spleen and liver T1 relaxation time mapping and their responses to contrast administration) to: 1) evaluate portal hypertension and liver function 2) predict which patients are at risk of developing serious complications or dying from liver disease It is hoped that in the long term this use of MRI scans could avoid multiple unnecessary invasive procedures, guide the clinical management of liver disease and predict its complications. Design and methods Over three years, three patients groups with different clinical stages of liver disease and a healthy control group will be recruited. All participants will have a clinical assessment, liver-related blood tests, transient elastography and an MRI scan optimised to cover liver and spleen. During the scan, participants will have an injection of a contrast agent. Transient elastography is similar to an ultrasound scan and takes about 5 minutes to perform. Patients will be followed up for 6-36 months to establish whether they have developed any complications from their liver disease. From the MRI I will measure novel markers of portal hypertension and liver function. I will determine how accurate the MRI measurements are at predicting significant portal hypertension, liver dysfunction and liver-related complications. Patient and public involvement The research idea has been supported by the Primary Biliary Cirrhosis Foundation and Liver4Life liver disease charities. Two patients (one already committed) will be involved in design aspects, patient literature and management of the study. Along with the charities they will also be key to the dissemination of the study findings in plain English. A dedicated study website will also keep the public informed of the study progress and results. Dissemination of study findings Study results will be presented at international meetings, published in scientific journals and on public media. The necessary equipment already exists within the NHS and so the results could be applied in standard care within 5 years.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: ORAL AND GASTROINTESTINAL