An observational study in Diabetes type2, NASH - Nonalcoholic Steatohepatitis and NAFLD, sponsored by Assistance Publique - Hôpitaux de Paris. Status unknown. Open to participants aged 18 Years and older, including healthy volunteers. Per ClinicalTrials.gov, last updated 2020-01-28.
Sponsored by Assistance Publique - Hôpitaux de Paris · Observational
Non-alcoholic fatty liver diseases (NAFLD) include several entities ranging from simple steatosis to hepatic fibrosis or cirrhosis. Steatosis, considered benign and the first stage of the disease, is characterized by the accumulation of triglycerides in the liver. It may in some cases progress to nonalcoholic steatohepatitis (NASH), which is characterized by the presence of a marked inflammation with or without fibrosis. NAFLD is the most common liver disease in the world and is particularly associated with type 2 diabetes (T2D) (80% in the diabetic population). While NASH is characterized by a higher prevalence of mortality from a cardiac and hepatic (cirrhosis and cancer) origin, therapeutic resources are almost non-existent.
RANK (receptor activator of NF-kB) and its ligand RANKL (a member of the TNFalpha family) have emerged in recent years as new players in bone pathophysiology. By binding to its receptor, RANKL induces a number of signaling pathway and in particular the NF-kB pathway (Nuclear factor-kB), a major player in inflammation. Recent literature shows that the role of RANK / RANKL is not confined to the bone but may be involved in the genesis of inflammation in other tissues. It has been shown recently that a high circulating level of RANKL was a risk factor predictor of T2DM. Furthermore, the invalidation of RANK specifically in hepatocytes protects from insulin resistance and hepatic steatosis induced by a high fat diet in mice.
The aim of our project is to provide a proof of concept that the RANKL / RANK system plays an important role in the pathogenesis of NAFLD and in the progression of this disease to NASH. The aim of our project is to provide a proof of concept that the RANKL / RANK system plays an important role in the pathogenesis of NAFLD and in the progression of this disease to NASH.
The investigator propose to study the RANKL / RANK expression in serum and liver biopsies of type 2 diabetic patients at different stages of NAFLD.
Objectives:
To show that (i) expression of mRNA and proteins of the RANKL pathway (RANK, RANKL, OPG) in liver and (ii) serum concentration of RANKL/OPG proteins are correlated with the gravity of the NAFLD.
Study protocol:
Identify patients with different stages of NAFLD (mere steatosis, NASH, and moderate or advanced fibrosis) from the database of patients who have undergone liver biopsy in the hepatology department of the Pitié-Salpêtrière Hospital . From the hepatic tissue, the paraffin-embedded liver biopsies and the serum of these patients, study of the expression of mRNA (quantitative RtPCR) and proteins (immunohistochemistry, western blots) of the RANKL pathway (RANK, RANKL, OPG) in liver. In the serum of these patients, measure of concentration of RANKL and OPG proteins as described above.
Study Type: monocentric, observational, case-control, analytical study Study duration: 18 months (time for data collection, for cellular biological experimentations and for data analysis)
Patient Population:
5 groups of patients very well phenotyped and with liver biopsy (with at our disposal frozen liver tissue, paraffin-embedded liver tissue and serum for all the patients):
1,451 studies on the registry are indexed under Fatty Liver; 292 are open to participants now.
This study's planned enrollment of 50 is below the median of 140 across 397 observational studies indexed under Fatty Liver.
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We will constitute 5 groups of patients very well phenotyped and with liver biopsy (with at our disposal frozen liver tissue, paraffin-embedded liver tissue and serum for all the patients):
Patients with one of the following criteria:
Exclusion Criteria:
Steatosis group
Biological: "Collection of additional blood tubes; Biobanking (plasma, liver tissue).
NASH group without fibrosis
Biological: "Collection of additional blood tubes; Biobanking (plasma, liver tissue).
Moderate fibrosis
Biological: "Collection of additional blood tubes; Biobanking (plasma, liver tissue).
Advanced fibrosis
Biological: "Collection of additional blood tubes; Biobanking (plasma, liver tissue).
Control group
Biological: "Collection of additional blood tubes; Biobanking (plasma, liver tissue).
* Preservation of liver tissue obtain by liver biopsy, constitution of a collection * Sampling of additional blood tubes for a biological collection (serum): Serum biomarker research and genetic research
Measure of RANKL mRNA expression in the liver
Expression of RANKL mRNA in liver of patients with NASH or NAFLD with fibrosis comparatively to patients with mere steatosis.
Time frame: Baseline
Serum concentrations of RANKL
Measure of Serum RANKL concentration in patients with NASH or NAFLD with fibrosis comparatively to patients with mere steatosis and in NAFLD patients comparatively to healthy controls.
Time frame: Baseline
Serum osteoprotegerin concentrations
Measure of serum osteoprotegerin concentrations in type 2 diabetic patients with NASH or NAFLD with fibrosis compared to type 2 diabetic patients with simple steatosis and in patients with type 2 diabetes with NAFLD compared to healthy controls.
Time frame: Baseline
HOMA-IR
Correlation between RANK and RANKL protein expression and insulin resistance and correlation between serum concentrations of RANKL / osteoprotegerin and insulin resistance in type 2 diabetic patients with NASH and NAFLD with fibrosis compared to type 2 diabetic patients with simple steatosis and in patients with type 2 diabetes with NAFLD compared to healthy controls
Time frame: Baseline
Measure of RANKL mRNA
Expression of RANKL mRNA and RANKL protein in liver tissue of NAFLD patients comparatively to healthy controls.
Time frame: Baseline
Measure of RANKL protein levels
Expression of RANKL protein in liver of patients with NASH or NAFLD with fibrosis comparatively to patients with mere steatosis.
Time frame: Baseline
Measure of RANK mRNA
Expression of RANK mRNA and protein in liver of patients with NASH or NAFLD with fibrosis comparatively to patients with mere steatosis and in liver tissue of NAFLD patients comparatively to healthy controls
Time frame: Baseline
Measure of RANK protein levels
Expression of RANK protein in liver of patients with NASH or NAFLD with fibrosis comparatively to patients with mere steatosis and in liver tissue of NAFLD patients comparatively to healthy controls.
Time frame: Baseline
RANK/RANKL genes polymorphisms
Association between RANK/RANKL gene polymorphisms and NAFLD development To highlight association between RANK/RANKL genes polymorphisms and NAFLD development.
Time frame: Baseline
NF-kB pathway in hepatocytes and Kupffer cells
Correlation of liver RANKL and RANK proteins expression with activation of NF-kB pathway in hepatocytes and Kupffer cells of patients with NASH or NAFLD with fibrosis comparatively to patients with mere steatosis and in NAFLD patients comparatively to healthy controls and correlation of serum RANKL and osteoprotegerin concentrations with activation of NF-kB pathway in hepatocytes and Kupffer cells in NAFLD patients comparatively to healthy controls and in NAFLD patients comparatively to patients with mere steatosis.
Time frame: Baseline
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Assistance Publique - Hôpitaux de Paris