Endoscopic Ultrasound Shear Wave vs Transient Elastography for Liver Steatosis: The RUMIPAMBA Trial

Study Overview
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Brief Summary
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Currently, there is no description of the contribution of the endoscopic ultrasound (EUS)-guided shear wave elastography (SWE) when describing liver steatosis in patients with suspicion of metabolic dysfunction-associated steatotic liver disease (MASLD). Similar research have been published but using vibration-controlled transient elastography (VCTE), recommended mainly due to its lower cost and less invasiveness. However, VCTE is limited to the anatomical proportions of the patient's body, and cannot assess the right hepatic lobe with less reliability, in opposition to the EUS-SWE.

Detailed Description
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Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly non-alcoholic fatty liver disease (NAFLD), is an umbrella term which involves simple liver steatosis, metabolic-associated steatohepatitis (MASH) and MASH-related liver cirrhosis. Liver steatosis relies on imaging or biomarkers, but liver biopsy remains the gold standard for its diagnosis and grading. It comprehends intracellular accumulation of triacylglycerol (TAG) as microvascular or macrovascular lipid droplets in at least 5% of hepatocytes. Liver biopsy is invasive, requires a high-quality biopsy sample, can mislead a diagnosis due to sampling bias, depends on pathologist interpretation variability and implies adverse events related to punction. There are non-invasive resources useful for liver steatosis screening and surveillance. Apart from serum biomarkers, non-invasive technologies designed for this purpose use ultrasound (US)-based elastography, namely: US strain, acoustic radiation force impulse (ARFI), point shear wave elastography (pSWE), two-dimension shear wave elastography (2D-SWE) and vibration-controlled transient elastography (VCTE). Although VCTE presents anatomical limitations when used in overweight patients or assessing the right hepatic lobe, it is largely accepted by international guidelines for assessing liver steatosis and fibrosis. Endoscopic ultrasound (EUS)-guided shear wave elastography (SWE) is independent of patients' anatomical proportions, and it permits a more reliable right hepatic lobe evaluation. However, it is an invasive and high-cost procedure. VCTE and EUS-SWE determine liver steatosis quantitatively through the controlled attenuation parameter (CAP) and the attenuation coefficient (ATT), respectively. The ATT is equivalent to the CAP, both expressed in decibels per meter [dB/m]. There are four important gaps in the literature. First, the diagnostic accuracy of VCTE for liver steatosis has been profoundly analysed in NAFLD, but in a wide spectrum of liver fibrosis patients, from absent to cirrhosis. These limits finding extrapolations for screening and surveillance. Second, comparisons between EUS-SWE vs. VCTE have concentrated on liver fibrosis or cirrhosis. Third, there is no determined diagnostic accuracy for liver steatosis through EUS-SWE, each day more requested procedures are. Finally, as a new proposed term, liver steatosis identification and grading still need to be described in the nowadays called MASLD patients. The present study aims to compare MASLD-related liver steatosis estimation using CAP of the VCTE and the ATT of the EUS-SWE, comparing controls vs. liver steatosis patients with absent or mild liver fibrosis determined through non-invasive methods.

Official Title
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Liver Steatosis Through Endoscopic Ultrasound-guided Shear Wave Elastography vs Vibration-controlled Transient Elastography: a Blinded Diagnostic Trial in Noninvasive Methods-determined Absent-to-mild Liver Fibrosis: The RUMIPAMBA Trial

Conditions
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Liver Steatosis

Intervention / Treatment
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* Device: Transparietal ultrasound (US)-based shear wave elastography (SWE)
* Device: Vibration-controlled transient elastography (VCTE)
* Device: Endoscopic ultrasound (EUS)-guided shear wave elastography (SWE)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients referred for any kind of endoscopic procedure. Without clinical suspicion of advanced liver fibrosis. Acceptance to participate in the study. Exclusion Criteria: History of greater amounts of alcohol per week (140 g/week and 210 g/week for females and males respectively). Significant or advanced fibrosis in accordance with FIB4 or APRI scores. Any liver space-occupying lesion in the US. Comorbidities or conditions related to avoidance of interventional procedures, namely: pregnancy or nursing, coagulopathy or any risk of bleeding, ASA IV or higher, NYHA III or IV.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Liver steatosis<br>Patients with requirements of screening following the European Association for the Study of the Liver (EASL) 2016 recommendations. The liver steatosis group will be compounded by patients with at least one of the following criteria: Over fifty years old; Body mass index (BMI) over 25 kg/m2; Diabetes mellitus type 2; Metabolic syndrome; or Persistently elevated liver enzymes. | Device: Transparietal ultrasound (US)-based shear wave elastography (SWE)<br>* The operator will be blinded to any clinical record. Before US-SWE, the patient must be fasted for a minimum of 4 hours and must remain alcohol-free for 7 days. Using an Aloka Arietta 850 (Olympus America, PA, USA), each patient must be supine. Upon breath-hold at the end of expiration, ten measurements will be obtained with the probe placed in the area of the right hepatic lobe through an intercostal space.<br>* Other names: US-SWE;Device: Vibration-controlled transient elastography (VCTE)<br>* The operator will be blinded to any clinical record. Before VCTE, the patient must be fasted for a minimum of 4 hours and must remain alcohol-free for 7 days. Using the FibroScan® Compact 530 (Echosens, Paris, France), each patient must be supine with the right arm in abduction and the ipsilateral hand resting under the head. Upon breath-hold at the end of expiration, ten measurements will be obtained with the M-probe placed in the area of the right hepatic lobe through an intercostal space. Transition to an XL probe will be based on a VCTE automatic probe selection tool prompt.<br>* Other names: VCTE;Device: Endoscopic ultrasound (EUS)-guided shear wave elastography (SWE)<br>* EUS-SWE will be performed by an experienced endoscopist, who will be blinded to any clinical records. The expert will use the ArrietaTM 850 EUS console (Fujifilm, Tokyo, Japan) using a linear ultrasound video gastroscope EUS-J10 (Pentax Medical, Hoya Corp, Japan). The patient must be lying in the supine position. Based on the premise that as fibrosis progresses the distribution becomes heterogeneous, both lobes will be evaluated. The transducer will be positioned in the gastric window to visualize right liver segment number five and left liver segment two or three. After the patient suspended respiration for a few seconds, the elastogram region of interest (ROI) will be placed within the liver tissue at a distance ≥10 mm beneath the hepatic capsule in an area free of vessels and artefacts. A 10-mm circular ROI will be placed within the elastogram at a depth of 4-5 cm from the skin, and a minimum of ten successful kPa measurements will be obtained.<br>* Other names: EUS-SWE;|
| Other: Controls<br>Patients without requirements of screening following the European Association for the Study of the Liver (EASL) 2016 recommendations. The liver steatosis group will be compounded by patients who will not present any of the following criteria: Over fifty years old; Body mass index (BMI) over 25 kg/m2; Diabetes mellitus type 2; Metabolic syndrome; and Persistently elevated liver enzymes. To be a control participant does not mean that the patient is a healthy participant. The control participants are patients who request any type of endoscopy and fulfil the criteria not to screen for liver steatosis. For example, a 48-year-old male with 21 kg/m2 BMI, without diabetes mellitus type 2, any metabolic syndrome-related comorbidities, with normal liver enzymes and who refused an episode of persistently elevated liver enzymes, with persistent reflux disease after two months of proton pump inhibitor therapy, | Device: Transparietal ultrasound (US)-based shear wave elastography (SWE)<br>* The operator will be blinded to any clinical record. Before US-SWE, the patient must be fasted for a minimum of 4 hours and must remain alcohol-free for 7 days. Using an Aloka Arietta 850 (Olympus America, PA, USA), each patient must be supine. Upon breath-hold at the end of expiration, ten measurements will be obtained with the probe placed in the area of the right hepatic lobe through an intercostal space.<br>* Other names: US-SWE;Device: Vibration-controlled transient elastography (VCTE)<br>* The operator will be blinded to any clinical record. Before VCTE, the patient must be fasted for a minimum of 4 hours and must remain alcohol-free for 7 days. Using the FibroScan® Compact 530 (Echosens, Paris, France), each patient must be supine with the right arm in abduction and the ipsilateral hand resting under the head. Upon breath-hold at the end of expiration, ten measurements will be obtained with the M-probe placed in the area of the right hepatic lobe through an intercostal space. Transition to an XL probe will be based on a VCTE automatic probe selection tool prompt.<br>* Other names: VCTE;Device: Endoscopic ultrasound (EUS)-guided shear wave elastography (SWE)<br>* EUS-SWE will be performed by an experienced endoscopist, who will be blinded to any clinical records. The expert will use the ArrietaTM 850 EUS console (Fujifilm, Tokyo, Japan) using a linear ultrasound video gastroscope EUS-J10 (Pentax Medical, Hoya Corp, Japan). The patient must be lying in the supine position. Based on the premise that as fibrosis progresses the distribution becomes heterogeneous, both lobes will be evaluated. The transducer will be positioned in the gastric window to visualize right liver segment number five and left liver segment two or three. After the patient suspended respiration for a few seconds, the elastogram region of interest (ROI) will be placed within the liver tissue at a distance ≥10 mm beneath the hepatic capsule in an area free of vessels and artefacts. A 10-mm circular ROI will be placed within the elastogram at a depth of 4-5 cm from the skin, and a minimum of ten successful kPa measurements will be obtained.<br>* Other names: EUS-SWE;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vibration-controlled transient elastrography (VCTE) liver steatosis grade | Liver steatosis will be defined by elastography using the controlled attenuation parameter (CAP), measured in decibels per meter [db/m]. | Six months | 
| Transparietal ultrasound (US)-based shear wave elastography (SWE) liver steatosis grade | Liver steatosis will be defined by elastography using the attenuation coefficient (ATT), measured in decibels per meter [db/m]. The ATT corresponds to the VCTE CAP measurement. | Six months | 
| Endoscopic ultrasound (EUS)-guided shear wave elastography (SWE) liver steatosis grade | Liver steatosis per hepatic lobe will be defined by elastography using the attenuation coefficient (ATT) measurement [db/m]. The ATT corresponds to the VCTE CAP measurement. | Six months | 
| Endoscopic ultrasound (EUS)-guided liver biopsy steatosis grade | The EUS-guided liver biopsy findings, per hepatic lobe, will be standardised through the steatosis-Activity-Fibrosis (SAF) score. The SAF scores steatosis (0-3), ballooning degeneration (0-2), lobular inflammation (0-2), and fibrosis (0-4). Liver steatosis is present when proper steatosis is present, and when both features of activity (ballooning and lobular inflammation) display at least grade 1. | Six months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vibration-controlled transient elastrography (VCTE) liver fibrosis grade | Liver steatosis will be defined by elastography using kilopascals [kPa]. | Six months | 
| Transparietal ultrasound (US)-based shear wave elastography (SWE) liver fibrosis grade | Liver steatosis will be defined by elastography using kilopascals [kPa]. | Six months | 
| Endoscopic ultrasound (EUS)-guided shear wave elastography (SWE) liver fibrosis grade | Liver steatosis per hepatic lobe will be defined by elastography using kilopascals [kPa]. | Six months | 
| Endoscopic ultrasound (EUS)-guided liver biopsy fibrosis grade | The EUS-guided liver biopsy findings, per hepatic lobe, will be standardised through the Brunt system. | Six months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver steatosis, Fatty liver, Endosonography, Elastography