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Liver Damage and Cardiometabolic Disorders in NAFLD (PLINIO)

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ClinicalTrials.gov Identifier: NCT04036357
Recruitment Status : Recruiting
First Posted : July 29, 2019
Last Update Posted : August 16, 2019
Sponsor:
Information provided by (Responsible Party):
Francesco Violi, University of Roma La Sapienza

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.

Condition or disease
NAFLD Liver Fibroses Cardiovascular Diseases Cardiovascular Risk Factor

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.


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Study Type : Observational
Estimated Enrollment : 2000 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Progression of LIver Damage and Cardiometabolic Disorders in Non-alcoholic Fatty Liver dIsease: an Observational Cohort STUDY. The Plinio Study
Actual Study Start Date : November 2011
Estimated Primary Completion Date : December 31, 2036
Estimated Study Completion Date : December 31, 2036





Primary Outcome Measures :
  1. Clinical, biochemical and genetic factors associated to progression of liver fibrosis in a large cohort of patients with NAFLD [ Time Frame: Patients will be followed for an expected mean time of 120 months ]
    To detect non conventional factors associated with the progression of liver fibrosis in patients with NAFLD. Progression of liver fibrosis will be assessed by non invasive markers (such as FIB-4, Nafld Fibrosis Score e liver elastography). The predictive role of the following factors will be assessed: plasmatic and urinary isoprostanes, thromboxane, platelet recruitment, reactive species of oxygen, nadph oxidase (nox2). Genes of interested will be sequenced.


Secondary Outcome Measures :
  1. The predictive role of non-invasive markers of fibrosis on the incidence of major cardiovascular events. [ Time Frame: Patients will be followed for an expected mean time of 60 months ]
    Non invasive score of liver fibrosis (such as NAFLD fibrosis score, AST-to-Platelets index and FIB-4) will be calculated at baseline and their predictive role on the incidence of major cardiovascular events will be tested

  2. Nutritional factors associated to NAFLD [ Time Frame: At Baseline ]
    Data on mediterranean diet adherence and on nutrients consumption will be collected and related to NAFLD severity. Data on circulating free fatty acid will be collected.

  3. Platelet activation in NAFLD and NASH [ Time Frame: At Baseline ]
    Plasmatic and urinary thromboxane and platelet recruitment will be measured as markers of platelets activation. Differences of these markers in different degree of NAFLD severity will be investigated

  4. The predictive role of systemic markers of oxidative stress and antioxidant status on the incidence of cardiovascular events in NAFLD patients [ Time Frame: Patients will be followed for an expected mean time of 120 months ]
    Oxidative stress markers such as plasmatic and urinary isoprostanes, thromboxane, platelet recruitment, reactive species of oxygen, nadph oxidase(nox2) will be measured. The predictive role of these markers on the incidence of cardiovascular events will be tested

  5. Factors associated with chronic kidney disease in NAFLD patients [ Time Frame: At Baseline ]
    To investigate the prevalence of chronic renal failure in Patients with NAFLD. Moreover, genetic, pharmacological and biochemical factors associated with estimated glomerular filtration rate (eGFR) < 90 and with eGFR < 60 will be investigated.

  6. Predictors of kidney disease progression in patients with NAFLD [ Time Frame: Patients will be followed for an expected mean time of 60 months ]
    The rate of Kidney disease progression in patients with NAFLD will be measured and will and compared to that in general populations. Predictors of kidney disease progression will be investigated.

  7. Role of gut microbiota in NAFLD [ Time Frame: At Baseline ]
    Serum Lipopolysaccharide (LPS) and serum zonulin will be measured in NAFLD patients and the correlation between LPS and NAFLD severity will be tested

  8. Echocardiographic changes in patients with NAFLD [ Time Frame: At Baseline ]
    Measures of systolic and diastolic function will be collected at baseline and correlated with the severity of NAFLD, of metabolic disorders and with genetic mutations correlated with NAFLD.

  9. Score of cardiovascular risk in patients with NAFLD [ Time Frame: Patients will be followed for an expected mean time of 120 months ]
    Performance of classical scores of cardiovascular risk will be tested in patients of NAFLD. In particular, the 2MACE score and the Systemic Coronary Risk Estimation (SCORE) will be tested. 2MACE score will be calculated assigning 2 points for Metabolic Syndrome and Age ≥75, 1 point for MI/revascularization, Congestive heart failure (ejection fraction ≤40 %), thrombo-Embolism (stroke/transient ischemic attack. The score, ranging from 0 to 7 points, will be considered positive for values higher than 2. SCORE will be calculated using age, sex, systolic blood pressure, smoking status, total and HDL cholesterol. The SCORE system estimates the 10-year cumulative risk of a first fatal atherosclerotic event. In absence of a good performance of pre-existing scores, we'll try to assess a specific cardiovascular risk score in NAFLD patients.

  10. Dyslipidemia and cardiovascular events in patients with NAFLD [ Time Frame: Patients will be followed for an expected mean time of 120 months ]
    The predictive role of triglycerides rich lipoproteins and cholesterol remnants will be evaluated.

  11. Plasmatic and urinary isoprostanes [ Time Frame: At Baseline ]
    Plasmatic and urinary isoprostanes will be measured as markers of systemic oxidative stress and of antioxidant status in NAFLD and NASH. Differences of these markers in different degree of NAFLD severity will be investigated

  12. Reactive species of oxygen in NAFLD and NASH [ Time Frame: At Baseline ]
    Reactive species of oxygen will be measured as markers of systemic oxidative stress and of antioxidant status in NAFLD and NASH. Differences of these markers in different degree of NAFLD severity will be investigated

  13. Nadph oxidase (nox2) activation in NAFLD and NASH [ Time Frame: At Baseline ]
    Nadph oxidase (nox2) activation will be estimated as markers of systemic oxidative stress and of antioxidant status in NAFLD and NASH. Differences of these markers in different degree of NAFLD severity will be investigated



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
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;

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04036357


Contacts
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Contact: Francesco Baratta, MD, PI. +390649972249 francesco.baratta@uniroma1.it
Contact: Daniele Pastori, MD, PI. +390649972249 daniele.pastori@uniroma1.it

Locations
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Italy
Day Service of Internal Medicine and Metabolic Disorders - Policlinico Umberto I - Sapienza University of Rome Recruiting
Rome, Italy, 00100
Contact: Maria Del Ben, MD    +390649972249    maria.delben@uniroma1.it   
Contact: Francesco Baratta, MD    +390649972249    francesco.baratta@uniroma1.it   
Sponsors and Collaborators
University of Roma La Sapienza
Investigators
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Study Director: Maria Del Ben, MD Sapienza University of Rome
Principal Investigator: Daniele Pastori, MD Sapienza University of Rome
Principal Investigator: Francesco Baratta, MD Sapienza University of Rome
Principal Investigator: Francesco Angelico, MD Sapienza University of Rome

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Responsible Party: Francesco Violi, Department Head, University of Roma La Sapienza
ClinicalTrials.gov Identifier: NCT04036357     History of Changes
Other Study ID Numbers: 2277/2011
First Posted: July 29, 2019    Key Record Dates
Last Update Posted: August 16, 2019
Last Verified: August 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Francesco Violi, University of Roma La Sapienza:
NAFLD
Liver fibrosis
Cardiovascular
Additional relevant MeSH terms:
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Liver Cirrhosis
Fibrosis
Cardiovascular Diseases
Pathologic Processes
Liver Diseases
Digestive System Diseases