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

Fatty Liver Disease Clinical Trial

— THESIS  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04191044
• Other study ID #: THESIS
• Status: Not yet recruiting
• Start date: January 10, 2020
• Est. completion date: July 10, 2020

Study information

• Verified date: December 2019
• Source: Instituto de Investigación Marqués de Valdecilla
• Contact: Jose Ignacio Fortea
• Phone: +34 942 204084
• Email: jifortea[@]gmail.com
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 170
• Est. completion date: July 10, 2020
• Est. primary completion date: January 10, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Fatty Liver
• Fatty Liver Disease
• Hypertension
• Hypertension, Portal
• Liver Diseases
• Non-alcoholic Fatty Liver Disease

Intervention

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.

Locations

Country	Name	City	State
n/a

Sponsors (4)

Lead Sponsor	Collaborator
Instituto de Investigación Marqués de Valdecilla	Hospital General Universitario Gregorio Marañon, Hospital Universitario Ramon y Cajal, Puerta de Hierro University Hospital

References & Publications (4)

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. Review. — View 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. — View 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. — View Citation

Rodrigues SG, Montani M, Guixé-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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of patients with NAFLD without advanced fibrosis and severe steatosis with portal hypertension		1 months
Primary	Number of patients with NAFLD and advanced fibrosis with portal hypertension		1 months
Primary	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
Primary	Threshold of portal hypertension leading to portal hypertension-related complications in patients with NAFLD		1months
Secondary	Impact of portal hypertension and hepatic fibrosis on early cardiovascular risk and the degree of liver and kidney function.		1 months
Secondary	Non-invasive biomarkers of the presence and severity of portal hypertension through metabolomics, extracellular vesicles and / or other analytical markers	liquid biopsy	1 months