Portal Hypertension in Non-alcoholic Fatty Liver Disease: Association With Cardiovascular Risk and Identification of Non-invasive Biomarkers (THESIS) (THESIS)

Portal Hypertension in Non-alcoholic Fatty Liver Disease: Association With Cardiovascular Risk and Identification of Non-invasive Biomarkers

Non-alcoholic fatty liver disease (NAFLD) is the most frequent cause of chronic liver disease in our environment. Preliminary data suggest that portal hypertension may exist in the initial phases of NAFLD due to mechanisms that have not yet been elucidated. The clinical relevance of its development in these initial phases is unknown, while in more advanced phases new data are required to confirm the close relationship between portal hypertension and the risk of decompensation described in other etiologies. Likewise, the influence of fibrosis and portal hypertension on the cardiovascular risk of patients with NAFLD is unknown. The aim of the present multicenter project is to characterize the presence of portal hypertension and the mechanisms involved in its development in the different stages of NAFLD, to assess the association between the degree of portal hypertension and the development of portal hypertension-related complications, to know the early cardiovascular risk in the different stages of the disease, and to identify noninvasive biomarkers of the presence and severity of portal hypertension.

Study Overview

• Status: Unknown
• Conditions: Fatty Liver Disease
• Intervention / Treatment: Other: A complete cardiovascular and liver characterization will be carried out

• Study Type: Observational
• Enrollment (Anticipated): 170

Contacts and Locations

• Study Contact: Name: Jose Ignacio Fortea; Phone Number: +34 942 204084; Email: jifortea@gmail.com
• Study Contact Backup: Name: Lucia Lavin Alconero; Phone Number: +34 942 204084; Email: eclinicos5@idival.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Non-alcoholic fatty liver disease.

Description

Inclusion Criteria:

• Age between 18 and 65 years.
• Clinical suspicion of NAFLD.
• Severe (controlled attenuation parameter (CAP) ≥330 dB/m) or mild steatosis (CAP: 298-317 dB / m), and FibroScan® grade 2 fibrosis (M probe: 7-9 kpa; XL probe: 5-7.5 kpa) in patients with grade 1 or 2 obesity and insulin resistance (HOMA index> 2.6) or diabetes mellitus.
• Fibroscan® grade 3 or 4 fibrosis (M probe:> 9 kpa; XL probe:> 7.5 kpa).
• Decompensated NAFLD cirrhosis (i.e. development of ascites, variceal hemorrhage, and/or hepatic encephalopathy) up to Child B (9 points).
• Signature of informed consent.

Exclusion Criteria:

• Concomitant liver disease and patients with acute on chronic liver failure.
• Excessive alcohol consumption (≥ 30 grams per day in men and ≥ 20 grams per day in women).
• Comorbidities (HIV infection, connective diseases, prothrombotic disorders) and/or drugs (didanosine, azathioprine, oxaliplatin) associated with the presence of idiopathic non-cirrhotic portal hypertension.
• Clinical history of cardiovascular disease (ischemic cardiomyopathy, atrial fibrillation, valvular defects, severe arterial hypertension, previous hospitalizations secondary to heart failure, cerebrovascular disease).
• Severe renal impairment, defined by creatinine clearance <15 ml/min/1.73m2.
• Any previous or current thrombosis in any venous territory.
• Uncontrolled psychiatric illness
• Contraindication to liver biopsy or any of the complementary tests included in the project.
• Hepatocellular carcinoma that does not meet Milan criteria.
• Pregnancy or breastfeeding
• Significant comorbidities that entail a functional limitation and/or a life expectancy of less than 12 months.

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
NAFLD with mild steatosis and grade <3 fibrosis in patients; NAFLD with mild steatosis and grade <3 fibrosis in patients with grade 1 or 2 obesity and insulin resistance (HOMA index> 2.6) or diabetes mellitus.	Other: A complete cardiovascular and liver characterization will be carried out; A complete cardiovascular and liver characterization will be carried out, including some supplementary tests with minimal risks (e.g. hemodynamic study). If any disease is detected, patients will be referred to the corresponding specialized care following the usual clinical practice.
NAFLD with severe steatosis and grade <3 fibrosis in patients; NAFLD with severe steatosis and grade <3 fibrosis in patients with grade 1 or 2 obesity and insulin resistance (HOMA index> 2.6) or diabetes mellitus.	Other: A complete cardiovascular and liver characterization will be carried out; A complete cardiovascular and liver characterization will be carried out, including some supplementary tests with minimal risks (e.g. hemodynamic study). If any disease is detected, patients will be referred to the corresponding specialized care following the usual clinical practice.
NAFLD with advanced fibrosis; NAFLD with advanced fibrosis (i.e. grade 3 or 4 fibrosis) without previous portal hypertension-related complications	Other: A complete cardiovascular and liver characterization will be carried out; A complete cardiovascular and liver characterization will be carried out, including some supplementary tests with minimal risks (e.g. hemodynamic study). If any disease is detected, patients will be referred to the corresponding specialized care following the usual clinical practice.
Decompensated NAFLD cirrhosis; Decompensated NAFLD cirrhosis (i.e. development of ascites, variceal hemorrhage, and/or hepatic encephalopathy) up to Child B (9 points)	Other: A complete cardiovascular and liver characterization will be carried out; A complete cardiovascular and liver characterization will be carried out, including some supplementary tests with minimal risks (e.g. hemodynamic study). If any disease is detected, patients will be referred to the corresponding specialized care following the usual clinical practice.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with NAFLD without advanced fibrosis and severe steatosis with portal hypertension		1 months
Number of patients with NAFLD and advanced fibrosis with portal hypertension		1 months
number of the mechanisms responsible for the appearance of portal hypertension by specifically assessing the following	An increase in sinusoidal vascular resistance and the relative importance of its structural (sinusoidal compression) and functional (endothelial dysfunction and activation of starry cells) components, Splanchnic vasodilatation leading to portal hyperflow and hyperdynamic circulation, proinflammatory state and Activation of angiogenesis.	1 months
Threshold of portal hypertension leading to portal hypertension-related complications in patients with NAFLD		1months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Impact of portal hypertension and hepatic fibrosis on early cardiovascular risk and the degree of liver and kidney function.		1 months
Non-invasive biomarkers of the presence and severity of portal hypertension through metabolomics, extracellular vesicles and / or other analytical markers	liquid biopsy	1 months

Collaborators and Investigators

• Sponsor: Instituto de Investigación Marqués de Valdecilla
• Collaborators: Hospital General Universitario Gregorio Marañon; Hospital Universitario Ramon y Cajal; Puerta de Hierro University Hospital

Publications and helpful links

General Publications

• Baffy G. Origins of Portal Hypertension in Nonalcoholic Fatty Liver Disease. Dig Dis Sci. 2018 Mar;63(3):563-576. doi: 10.1007/s10620-017-4903-5. Epub 2018 Jan 22.
• Francque S, Verrijken A, Mertens I, Hubens G, Van Marck E, Pelckmans P, Van Gaal L, Michielsen P. Noncirrhotic human nonalcoholic fatty liver disease induces portal hypertension in relation to the histological degree of steatosis. Eur J Gastroenterol Hepatol. 2010 Dec;22(12):1449-57. doi: 10.1097/MEG.0b013e32833f14a1.
• Mendes FD, Suzuki A, Sanderson SO, Lindor KD, Angulo P. Prevalence and indicators of portal hypertension in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2012 Sep;10(9):1028-33.e2. doi: 10.1016/j.cgh.2012.05.008. Epub 2012 May 18.
• Rodrigues SG, Montani M, Guixe-Muntet S, De Gottardi A, Berzigotti A, Bosch J. Patients With Signs of Advanced Liver Disease and Clinically Significant Portal Hypertension Do Not Necessarily Have Cirrhosis. Clin Gastroenterol Hepatol. 2019 Sep;17(10):2101-2109.e1. doi: 10.1016/j.cgh.2018.12.038. Epub 2019 Jan 6.

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): January 10, 2020
• Primary Completion (ANTICIPATED): January 10, 2020
• Study Completion (ANTICIPATED): July 10, 2020

Study Registration Dates

• First Submitted: December 5, 2019
• First Submitted That Met QC Criteria: December 5, 2019
• First Posted (ACTUAL): December 9, 2019

Study Record Updates

• Last Update Posted (ACTUAL): December 12, 2019
• Last Update Submitted That Met QC Criteria: December 10, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Keywords: Non-alcoholic fatty liver disease
• Additional Relevant MeSH Terms: Digestive System Diseases; Cardiovascular Diseases; Vascular Diseases; Liver Diseases; Hypertension; Fatty Liver; Non-alcoholic Fatty Liver Disease; Hypertension, Portal
• Other Study ID Numbers: THESIS

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No