Clinical trial NCT04036357: Liver Damage and Cardiometabolic Disorders in NAFLD
Official title: Progression of LIver Damage and Cardiometabolic Disorders in Non-alcoholic Fatty Liver dIsease: an Observational Cohort STUDY. The Plinio Study
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: NAFLD
Liver Fibroses
Cardiovascular Diseases
Cardiovascular Risk Factor
Keywords: NAFLD
Liver fibrosis
Cardiovascular
Lead sponsor: University of Roma La Sapienza
Sponsor class: OTHER
First posted: 2019-07-29
Enrollment: 2000
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Consecutive outpatients referring to the Day Service of Internal Medicine and Metabolic Diseases of the Department of Internal Medicine of Sapienza University of Rome for the management of cardio-metabolic risk factors, such as metabolic syndrome, dyslipidemia, hypertension, diabetes.

Brief summary: Liver fibrosis is the most important prognostic factor in patients with non-alcoholic factor disease. Clinical and biological condition, as diabetes or mutation for PNPLA3, are well known factors associated with liver fibrosis onset and progression. However, little is known about biochemical factors predicting liver fibrosis evolution in large NAFLD populations.

Detailed description: Non-alcoholic fatty liver disease (NAFLD) is a common liver disease worldwide. NAFLD includes a spectrum of diseases raging from simple steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma.

The prevalence of NAFLD ranges from 20% in the general population to 80-90% in obese and/or diabetic patients. Type 2 diabetes is also associated with disease progression. Some genetic conditions are known to be related with NAFLD pathophysiology. Mutation of patatin like phospholipase domain containing 3 (PNPLA3) is the most frequent genetic disorder associated with NAFLD onset and its accelerated progression. Both type 2 diabetes and PNPL3 mutation are the better-known factors associated with liver fibrosis.

More than the amount of lipid accumulation in the hepatocytes or of liver inflammation, the most important prognostic factors in NAFLD is fibrosis, which can occur in all stage of NAFLD disease, also in simple steatosis without inflammation or ballooning. Advanced fibrosis (F stage ≥ 3) has been related not only with liver-related death but also with death from all causes.

In 2007 a noninvasive system, the NAFLD fibrosis score (NFS), was validated to identify NAFLD patients with advanced fibrosis. NFS ≥ 0.676 detects an advanced fibrosis (F3-F4) with a positive predictive value of 90%-82% while NFS ≤ -1.455 excludes advanced fibrosis with a negative predictive value of 93%-88%.

In addition, in different settings, a score named Fibrosis-4 (FIB-4) was also validated to detect advanced fibrosis in patients with hepatitis B virus and hepatitis C virus /human immunodeficiency virus coinfection. Fib-4 ≤ 1.45 excludes advanced fibrosis with a negative predictive value of 90%, while Fib-4 ≥ 3.25 detects advanced fibrosis with a positive predictive value of 65%.

Currently, little is known about biochemical and pharmacological factors predicting liver fibrosis evolution in large cohorts of NAFLD patients.

Therefore, the primary aim of the study Is to investigate biochemical and pharmacological factors associated with fibrosis progression, identified as variations in noninvasive fibrosis scores, in a large population of patients with ultrasonography diagnosis of fatty liver disease.

A growing number of evidences show a higher cardiovascular risk in patients with NAFLD. Most of the data are derived from diabetic patients and there are not data derived from ad hoc studies. In addition, there are only few data on factors predicting incident cardiovascular (CV) events in patients with NAFLD.

Therefore, the secondary objective of the study is to investigate the association between NAFLD and CV events and to detect factors predicting CV events inception.

Eligibility criteria: Inclusion Criteria:

* Patients aged 18 years old or more
* Patients with at least on of the following metabolic disorders

  * Obesity
  * Diabetes
  * Arterial hypertension
  * Dyslipidemia

Exclusion Criteria:

* Average daily consumption of alcohol \>20 g in women and of \>30 g in men (assessed by Alcohol Use Disorders Identification Test, AUDIT;
* presence of hepatitis B surface antigen and antibody to hepatitis C virus;
* positive tests for autoimmune hepatitis;
* cirrhosis and other chronic liver diseases;
* diagnosis of oncological diseases
* concomitant therapy with drugs known to promote liver steatosis (e.g. amiodarone);
* other chronic infectious or autoimmune disease;

Primary outcomes:
measure: Clinical, biochemical and genetic factors associated to progression of liver fibrosis in a large cohort of patients with NAFLD
timeFrame: Patients will be followed for an expected mean time of 120 months
Secondary outcomes:
measure: The predictive role of non-invasive markers of fibrosis on the incidence of major cardiovascular events.
timeFrame: Patients will be followed for an expected mean time of 60 months
measure: Nutritional factors associated to NAFLD
timeFrame: At Baseline
measure: Platelet activation in NAFLD and NASH
timeFrame: At Baseline
measure: The predictive role of systemic markers of oxidative stress and antioxidant status on the incidence of cardiovascular events in NAFLD patients
timeFrame: Patients will be followed for an expected mean time of 120 months
measure: Factors associated with chronic kidney disease in NAFLD patients
timeFrame: At Baseline
measure: Predictors of kidney disease progression in patients with NAFLD
timeFrame: Patients will be followed for an expected mean time of 60 months
measure: Role of gut microbiota in NAFLD
timeFrame: At Baseline
measure: Echocardiographic changes in patients with NAFLD
timeFrame: At Baseline
measure: Score of cardiovascular risk in patients with NAFLD
timeFrame: Patients will be followed for an expected mean time of 120 months
measure: Dyslipidemia and cardiovascular events in patients with NAFLD
timeFrame: Patients will be followed for an expected mean time of 120 months
measure: Plasmatic and urinary isoprostanes
timeFrame: At Baseline
measure: Reactive species of oxygen in NAFLD and NASH
timeFrame: At Baseline
measure: Nadph oxidase (nox2) activation in NAFLD and NASH
timeFrame: At Baseline
Other outcomes:
Locations:
city: Rome
country: Italy
facility: Day Service of Internal Medicine and Metabolic Disorders - Policlinico Umberto I - Sapienza University of Rome
Study officials:
affiliation: University of Roma La Sapienza
name: Maria Del Ben, MD
role: STUDY_DIRECTOR
affiliation: University of Roma La Sapienza
name: Daniele Pastori, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Roma La Sapienza
name: Francesco Baratta, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Roma La Sapienza
name: Francesco Angelico, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Baratta F, D'Erasmo L, Di Costanzo A, Umbro I, Pastori D, Angelico F, Del Ben M. Metabolic Syndrome but Not Fatty Liver-Associated Genetic Variants Correlates with Glomerular Renal Function Decline in Patients with Non-Alcoholic Fatty Liver Disease. Biomedicines. 2022 Mar 19;10(3):720. doi: 10.3390/biomedicines10030720.
citation: Baratta F, Pastori D, Angelico F, Balla A, Paganini AM, Cocomello N, Ferro D, Violi F, Sanyal AJ, Del Ben M. Nonalcoholic Fatty Liver Disease and Fibrosis Associated With Increased Risk of Cardiovascular Events in a Prospective Study. Clin Gastroenterol Hepatol. 2020 Sep;18(10):2324-2331.e4. doi: 10.1016/j.cgh.2019.12.026. Epub 2019 Dec 27.