Clinical trial NCT04191044: Portal Hypertension in Non-alcoholic Fatty Liver Disease: Association With Cardiovascular Risk and Identification of Non-invasive Biomarkers (THESIS)
Official title: Portal Hypertension in Non-alcoholic Fatty Liver Disease: Association With Cardiovascular Risk and Identification of Non-invasive Biomarkers
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Fatty Liver Disease
Keywords: Non-alcoholic fatty liver disease
Lead sponsor: Instituto de Investigación Marqués de Valdecilla
Sponsor class: OTHER
Collaborators: name: Hospital Universitario Ramon y Cajal
name: Hospital General Universitario Gregorio Marañon
name: Puerta de Hierro University Hospital
First posted: 2019-12-09
Enrollment: 170
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Non-alcoholic fatty liver disease.

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Number of patients with NAFLD without advanced fibrosis and severe steatosis with portal hypertension
timeFrame: 1 months
measure: Number of patients with NAFLD and advanced fibrosis with portal hypertension
timeFrame: 1 months
measure: number of the mechanisms responsible for the appearance of portal hypertension by specifically assessing the following
timeFrame: 1 months
measure: Threshold of portal hypertension leading to portal hypertension-related complications in patients with NAFLD
timeFrame: 1months
Secondary outcomes:
measure: Impact of portal hypertension and hepatic fibrosis on early cardiovascular risk and the degree of liver and kidney function.
timeFrame: 1 months
measure: Non-invasive biomarkers of the presence and severity of portal hypertension through metabolomics, extracellular vesicles and / or other analytical markers
timeFrame: 1 months
Other outcomes:
Locations:
Study officials:
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.