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

Study Overview
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Brief Summary
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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.

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

Conditions
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Fatty Liver Disease

Intervention / Treatment
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* Other: A complete cardiovascular and liver characterization will be carried out


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| NAFLD with mild steatosis and grade <3 fibrosis in patients<br>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<br>* 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.<br>|
| NAFLD with severe steatosis and grade <3 fibrosis in patients<br>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<br>* 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.<br>|
| NAFLD with advanced fibrosis<br>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<br>* 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.<br>|
| Decompensated NAFLD cirrhosis<br>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<br>* 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.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-alcoholic fatty liver disease