Rationale: PCSK9 has been shown to affect cardiovascular system beyond its involvement in lipid metabolism. Recent studies raised the hypothesis that elevated PCSK9 may represent a novel risk factor for cardiovascular events.
Working hypothesis: Our hypothesis is that elevated levels of PCSK9 may increase the risk of major adverse cardiovascular and cerebrovascular events (MACCE) in patients with non-alcoholic fatty liver disease (NAFLD).
Main objectives: Primary endpoint will be to investigate the association between PCSK9 levels and the occurrence of major adverse cardiovascular and cerebrovascular events (MACCE) during follow-up. Secondary endpoints will be the identification of factors affecting circulating levels of PCSK9, to correlate PCSK9 to non-invasive markers liver fibrosis and steatosis and to investigate the association between adherence to Mediterranean Diet and PCSK9. Furthermore, in a subgroup of patients with biopsy-proven NASH, the association between PCSK9 and histological features will be investigated.
Experimental design: We will perform a prospective observational cohort study including 950 patients with ultrasonography evidence of liver steatosis. At baseline a blood sample will be collected for all patients to measure PCSK9 levels. After enrollment, patients will be followed for 1 year to see the occurrence of MACCE.
Several pathophysiological and therapeutic issues regarding NAFLD are yet to be explored. In particular, there are still no drugs approved for the treatment of this disease. This is essentially due to a lack of knowledge of factors associated to the progression from simple fatty liver to steato-hepatitis.
In this context, a deeper knowledge of clinical and biochemical factors involved in the alteration in lipid metabolism may favour the development of new therapeutic and prevention strategies. Thus, approaches aimed at reducing hepatic accumulation of lipids may reduce the onset of liver-related complications and in turn, cardiovascular outcomes. In this context, investigation of PCSK9, the coreceptor
of LDL cholesterol receptor, may provide novel insights in the pathogenesis of NAFLD. Of note, the involvement of PCSK9 in the pathogenesis of NAFLD has not been studied before. Recent large interventional trials with monoclonal antibodies inhibitors of PCSK9 showed a great benefit in terms of reduction of LDL cholesterol and cardiovascular outcomes in patients suffering from genetic hypercholesterolemia. If we will find increased levels of PCKS9 in patients with NAFLD, in association with the severity of liver disease, this finding would provide the rationale for the use of PCSK9 inhibitors in this clinical setting, with a potential great benefit for NAFLD patients.