Ignite Creation Date:
2024-10-26 @ 3:36 PM
Last Modification Date:
2024-10-26 @ 3:36 PM
Study NCT ID:
NCT06523179
Status:
RECRUITING
Last Update Posted:
None
First Post:
2024-03-07
Brief Title:
Evaluation of Risk of hEpatocellular Carcinoma
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Study for the Evaluation of Risk of hEpatocellular Carcinoma in NonAlcoholic Fatty Liver
Status:
RECRUITING
Status Verified Date:
2024-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
PERSPECTIVE
Brief Summary:
Hepatocellular carcinoma HCC is the fifth most common solid cancer and the second cause of cancer-related mortality worldwide Nonalcoholic fatty liver disease NAFLD that is hepatic accumulation of fat in excess of 5 not explained by at risk alcohol intake is projected to become the leading cause of HCC in Western countries within 2025NAFLD is most frequently caused by insulin resistance due to unhealthy lifestyle Due to the epidemics of obesity and type 2 diabetes NAFLD now affects one in three individuals worldwide
NAFLD-HCC frequently develops without overt cirrhosis suggesting that steatosis directly promotes hepatic carcinogenesis
NAFLD-HCC frequently develops without overt cirrhosis suggesting that steatosis directly promotes hepatic carcinogenesis
Detailed Description:
The mechanisms linking NAFLD to liver disease progression towards HCC have not yet been identified Anyhow several pathways may be activated in obesity and diabetes favoring a tumor-promoting environment distinguishing the pathogenesis of NAFLD-HCC from that of other etiologies First of all increased cancer risk is associated with a low-grade of chronic inflammation a manifestation typical of obesity and metabolic syndrome Indeed adipose tissue expansion promotes the release of pro-inflammatory cytokines namely tumor necrosis factor alpha TNFα and interleukin 6 IL6 both potent activators of key oncogenic signaling pathways Furthermore obesity alters the release of adipokines reducing the level of those with anti-inflammatory effects such as adiponectin and arising the level of those with pro-inflammatory and fibrogenic effects such as leptin Overall the factors listed above collectively induce hyperinsulinemia resulting in increased bioavailability of insulin-like growth factor-1 IGF1 which in turn promotes cellular proliferation and inhibits apoptosis The activation of hepatic stellate cells HSCs is also a major step in the development of cirrhotic HCC however these cells not only secrete collagen that results in liver fibrosis but may even produce several growth factors which stimulate oncogenic pathways contributing to the expansion of neoplastic clones
Genetic factors have been shown to influence disease progression in NAFLD and family history remains the main risk factor for HCC development The common genetic polymorphism rs738409 CG encoding for the I148M variant in Patatin-like phospholipase domain-containing protein 3 PNPLA3 or adiponutrin has been established as the main common genetic determinant of hepatic fat content and of progressive NAFLD The mechanism is related to accumulation of the mutated protein which interferes with lipid droplets remodeling in hepatocytes and with retinol release by hepatic stellate cells The PNPLA3 variant predicts HCC development in European patients with NAFLD This evidence suggests that this genetic risk factors may be helpful to select high-risk individuals for screening but it has a low sensitivity to be used as single prognostic biomarker The rs58542926 E167K variant in Transmembrane 6 superfamily member 2 TM6SF2 also predisposes to progressive NAFLD by altering the secretion of very low-density lipoproteins but its direct role in HCC predisposition is disputed More recently it has been found that the rs641738 CT sequence variant in the Membrane bound O-acyltranferase domain containing 7 Transmembrane channel like 4 MBOAT7TMC4 locus involved in phospholipids remodeling predisposes to cirrhosis development in individuals with excessive alcohol intake and to the development and the progression of NAFLD in individuals of European descent We recently reported in a cross sectional cohort that the rs641738 variant is also associated with HCC risk is patients with NAFLD
Moreover loss of function germline mutations in the telomerase reverse transcriptase hTERT can predispose to a spectrum of familial liver diseases characterized by steatosis and possible evolution to cirrhosis and HCC Furthermore it has also been reported that rare mutations inducing Mendelian diseases due to severe derangements in the function of encoded proteins may predispose to NAFLD-HCC Indeed mutations in Apolipoprotein B APOB may explain some familial cases through predisposition towards development of severe steatosis caused by hepatocellular retention of lipids
Genetic factors have been shown to influence disease progression in NAFLD and family history remains the main risk factor for HCC development The common genetic polymorphism rs738409 CG encoding for the I148M variant in Patatin-like phospholipase domain-containing protein 3 PNPLA3 or adiponutrin has been established as the main common genetic determinant of hepatic fat content and of progressive NAFLD The mechanism is related to accumulation of the mutated protein which interferes with lipid droplets remodeling in hepatocytes and with retinol release by hepatic stellate cells The PNPLA3 variant predicts HCC development in European patients with NAFLD This evidence suggests that this genetic risk factors may be helpful to select high-risk individuals for screening but it has a low sensitivity to be used as single prognostic biomarker The rs58542926 E167K variant in Transmembrane 6 superfamily member 2 TM6SF2 also predisposes to progressive NAFLD by altering the secretion of very low-density lipoproteins but its direct role in HCC predisposition is disputed More recently it has been found that the rs641738 CT sequence variant in the Membrane bound O-acyltranferase domain containing 7 Transmembrane channel like 4 MBOAT7TMC4 locus involved in phospholipids remodeling predisposes to cirrhosis development in individuals with excessive alcohol intake and to the development and the progression of NAFLD in individuals of European descent We recently reported in a cross sectional cohort that the rs641738 variant is also associated with HCC risk is patients with NAFLD
Moreover loss of function germline mutations in the telomerase reverse transcriptase hTERT can predispose to a spectrum of familial liver diseases characterized by steatosis and possible evolution to cirrhosis and HCC Furthermore it has also been reported that rare mutations inducing Mendelian diseases due to severe derangements in the function of encoded proteins may predispose to NAFLD-HCC Indeed mutations in Apolipoprotein B APOB may explain some familial cases through predisposition towards development of severe steatosis caused by hepatocellular retention of lipids
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None