Development of 4D Flow MRI for Risk Stratification of Variceal Bleeding in Cirrhosis
- Conditions
- Gastroesophageal VaricesCirrhosis, Liver
- Interventions
- Other: Pre-clinical validation contrast enhanced MRIOther: Ensure Plus®Other: Pre-clinical validation contrast enhanced MRI + fastingOther: Clinical validation MRI
- Registration Number
- NCT04867954
- Lead Sponsor
- University of Wisconsin, Madison
- Brief Summary
The goal of this research is to validate novel non-invasive Magnetic resonance imaging (MRI) biomarkers to detect Gastroesophageal varices (GEV) in patients with cirrhosis, including fractional flow change in the portal vein and elevated azygos flow.
End-stage liver disease (cirrhosis) is characterized by advanced fibrosis, liver failure, and portal hypertension. There are many causes of cirrhosis, including viral hepatitis, alcohol abuse, and perhaps most importantly, non-alcoholic fatty liver disease (NAFLD) and its aggressive subset, non-alcoholic steatohepatitis (NASH). 3 million new cases of end-stage liver disease (cirrhosis) are expected over the next decade. In cirrhosis, portosystemic collaterals that shunt blood away from the liver develop due to increased portal pressure. Gastroesophageal varices (GEV) are the most clinically relevant because they can cause fatal internal bleeding. GEV bleeding carries \~20% mortality at 6 weeks, and \~34% overall mortality. Identification of at-risk varices, prior to bleeding, is of paramount importance to initiate primary prophylaxis. To identify and treat at-risk patients, current guidelines recommend regular esophagogastroduodenoscopy (EGD) and variceal band ligation. Detection of high-risk GEV is key to initiating primary prophylaxis, which can reduce mortality by 50-70%.
However, endoscopy is invasive and often unnecessary when no treatment is required. Therefore, the American Association for the Study of Liver Diseases has identified the development of "non-invasive markers that predict the presence of high-risk varices" as a major unmet need.
- Detailed Description
The overall goal of this research is to implement advanced non-invasive 4D flow MRI biomarkers to predict the presence of treatable but potentially lethal GEV in patients with cirrhosis. This would facilitate the triage of patients with high-risk GEV to therapeutic EGD, while reducing unnecessary EGD procedures in patients without them.
The primary biological mechanism for development of GEV is elevated portal pressure and reversal of flow in the left gastric vein (LGV). Applying 4D flow MRI, investigators aim to detect and quantify reversed flow in the LGV to detect GEV at risk for bleeding.
Aim 1: Perform pre-clinical validations of an optimized, accelerated radial 4D flow MRI strategy, and of fat mitigation strategies for radial 4D flow MRI.
Aim 2: Determine the diagnostic performance of radial 4D flow MRI, in cirrhotic adults including
1. diagnostic accuracy to identify high-risk GEV using EGD as reference standard, and
2. test-retest repeatability Aim 3: Evaluate the effects and added value of a meal challenge to assess for high-risk GEV.
Aim 4: Compare the accuracy of 4D flow MRI to current non-invasive markers of liver disease.
Research Procedures
Pre-Clinical Validation (Phase 1): A total of 21 participants (7 healthy volunteers, 14 patients with GEV) to evaluate the optimized 4D flow methods, and 20 obese subjects to evaluate fat-mitigation strategies, will be enrolled. Participants will be asked to complete a single research visit that will include a contrast enhanced MRI scan lasting up to 1 hour. Participants will be asked to fast for at least 5 hours prior to the exam. Participants will be screening a final time for contraindications to contrast enhanced MR imaging; an IV will be placed; and participants will be positioned in the MR scanner, asked to lie as still as possible and to follow some breath hold instructions.
Clinical Validation (Phase 2-3): A total of 100 patients diagnosed with cirrhosis will be enrolled. Participants will be asked to complete a single research visit, lasting approximately 2 hours, that will include the following procedures:
* Participants will be asked to fast for 12 hours prior to arriving.
* An IV will be placed for tracer administration
* Participants will undergo a research MRI lasting approximately 1.5 hours (up to 1 hour of total scan time)
* All participants will be positioned in the MRI scanner for the initial scanning session (30 min) during which the first dose of GBCA (3/4 of total dose) or the total dose of Ferumoxytol will be administered.
* 50 participants will be removed from the scanner bore, repositioned, and scanned for an additional 15 minutes (repeatability testing).
* All participants will then be removed from the scanner and asked to consume 16 ounces of Ensure Plus®. After 20 minutes, they will be repositioned in the scanner for an additional scanning session (15 min) during which, a second dose of GBCA (1/4 of total dose) will be administered if required.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 141
Not provided
Not provided
Study & Design
- Study Type
- OBSERVATIONAL
- Study Design
- Not specified
- Arm && Interventions
Group Intervention Description Healthy volunteers Pre-clinical validation contrast enhanced MRI 7 healthy participants will be recruited. Patients with large, high-risk GEV Pre-clinical validation contrast enhanced MRI Patients with large, high-risk Gastroesophageal varices (GEV) will be recruited. Patients scheduled for screening or surveillance esophagogastroduodenoscopy (EGD) Ensure Plus® 100 patients diagnosed with cirrhosis and scheduled for screening or surveillance esophagogastroduodenoscopy (EGD) procedure will be recruited. Participants will complete a single research visit, lasting approximately 2 hours, that will include the following procedures: * Participants will fast for 12 hours prior to arriving. * An IV will be placed and a blood sample collected (\~11 mL, if necessary). * All participants will undergo research MRI lasting approximately 1.5 hours Patients with small, low-risk GEV Pre-clinical validation contrast enhanced MRI Patients with small, low-risk Gastroesophageal varices (GEV) will be recruited. Patients scheduled for screening or surveillance esophagogastroduodenoscopy (EGD) Clinical validation MRI 100 patients diagnosed with cirrhosis and scheduled for screening or surveillance esophagogastroduodenoscopy (EGD) procedure will be recruited. Participants will complete a single research visit, lasting approximately 2 hours, that will include the following procedures: * Participants will fast for 12 hours prior to arriving. * An IV will be placed and a blood sample collected (\~11 mL, if necessary). * All participants will undergo research MRI lasting approximately 1.5 hours Obese patients Pre-clinical validation contrast enhanced MRI + fasting 20 obese patients will be recruited
- Primary Outcome Measures
Name Time Method Receiver operation characteristic (ROC) curve analysis to determine diagnostic accuracy 2 hours Receiver operation characteristic (ROC) curve analysis will be performed to determine the diagnostic accuracy of 4D flow MRI to differentiate high-risk GEV from absent or low-risk GEV. The area under the curve (AUC) will be estimated for each flow measurement with 95% confidence intervals. The primary analysis is based on fractional flow change in the portal vein.
Variation in postprandial flow after Meal Challenge pre and post meal (approximately 2 hours) Variations in flow after a meal will be analyzed under(log-)linear mixed effects (LME) models.
Repeatability of 4D flow MRI: measured by summary measures of test-retest agreement with 95% Confidence intervals(CIs). 2 hours Repeatability of all flow measurements and fractional flow changes will be measured using intra-class correlation coefficient (ICC), and the wishing-subject coefficient of variation (wCV) will be estimated as summary measures of test-retest agreement with 95% CIs.
- Secondary Outcome Measures
Name Time Method Liver and spleen stiffness measurement by 2D spin-echo MR elastography Within 3 months 2D spin-echo MR elastography will be acquired to assess liver and spleen stiffness, using a single or dual-paddle system to ensure adequate wave-propagation in the liver and spleen
Liver proton density fat fraction (PDFF) as assessed by chemical shift encoded MRI (CSE-MRI) Within 3 months Liver proton density fat fraction (PDFF) is a biomarker of hepatic steatosis. It will be measured by Chemical shift encoded MRI (CSE-MRI; IDEAL IQ, GE Healthcare),pioneered at UW-Madison. It will help characterizing the possible confounders affecting 4D flow MRI
Aspartate aminotransferase-to-platelet ratio index (APRI) Within 3 months APRI is a way for doctors to measure how healthy a patient's liver is when they have a liver disease.
APRI = \[(AST/upper limit of normal)/platelet count\]x100Child-Turcotte-Pugh (CTP) score for prognosis of cirrhosis Within 3 months The Child-Turcotte-Pugh (CTP) score is used to assess the severity of cirrhosis. Parameters included are Encephalopathy, Ascites, Bilirubin levels, Albumin levels, Prothrombin Time and International Normalized Ratio (PT/INR) . Parameters are scored on point 1-3. CTP score is obtained by adding the score for each parameter. CTP scores can be categorized into A= 5-6 points, B=7-9 points and C=10-15 points. Higher points correspond to more severe cirrhosis state.
Fibrosis 4 (FIB-4) index Within 3 months The Fibrosis-4 score helps to estimate the amount of scarring in the liver. FIB-4 = age (years) × AST \[IU/L\] / \[platelet count × sqr(ALT \[IU/L\])\]
Hepatic iron level quantitation by in vivo R2* MRI method Within 3 months R2\* is an imaging method used in MRI. R2\* = (1/T2\*) where R2\* is a relaxation rate measured in units of Hz (\[1/sec\]). R2\* is commonly used to look at iron levels by measuring the relaxation times of hydrogen nuclei affected by iron. The presence of the iron results in the shortening of proton relaxation times (T2\*), thus increasing R2\*. R2\* will be measured by Chemical shift encoded MRI (CSE-MRI; IDEAL IQ, GE Healthcare), pioneered at University of Wisconsin (UW)-Madison. It will help characterizing the possible confounders affecting 4D flow MRI
Trial Locations
- Locations (1)
University of Wisconsin, Madison
🇺🇸Madison, Wisconsin, United States