Hepatitis C virus (HCV) infection is one of the most common chronic viral infections in the world, with a global prevalence of about 2%, and it is the leading cause of liver cirrhosis in the Western world. Chronic HCV infection is commonly associated with a number of extrahepatic complications. Type 2 diabetes mellitus (T2DM) is a chronic disease whose prevalence (about 10%) is increasing worldwide. It is associated with a high risk of severe micro- and macrovascular complications. T2DM is generally considered a polygenic disease, whose expression is favored by an inadequate lifestyle in which insulin resistance (IR) plays a key role. Epidemiological studies have suggested a linkage between T2DM and HCV-related chronic hepatitis, but the presence of additional factors such as aging, and sometimes previous or contemporaneous factors such as obesity or metabolic syndrome, prevents the establishment of a defi nite relationship between these two illnesses. the prevalence of T2DM in HCV-related cirrhosis is higher than (more than double!) that in Hepatitis B Virus (HBV)-related cirrhosis. This observation suggests that HCV infection itself can lead to IR and predispose the patient to the onset of T2DM. First, HCV core protein induces fatty liver by inhibition of microsomal triglyceride transfer protein, and fatty liver is strictly linked to IR. Second, HCV core protein inhibits, through elevation of tumor necrosis factor α and interleukin 6, the insulin signaling pathways, thus causing IR. The ability of insulin to lower the plasma glucose level has been shown to be impaired in a mouse model transgenic for the HCV core gene, as has also been observed in chronic hepatitis C patients. These results provide direct experimental evidence for a contribution of HCV to the development of IR. T2DM and impaired fasting glucose are not associated with anthropomorphic markers of obesity in HCV patients, suggesting a unique multifactorial pathogenesis of T2DM in HCV. Reports of specifi c central nervous system (CNS) involvement are not rare in HCV-infected patients Some data provide evidence that the CNS is a site of HCV replication, consistent with the recent demonstration of negative-strand HCV RNA in brain, and suggest that internal ribosomal entry site polymorphisms may be important as a viral strategy of reduced translation to favor latency in the CNS. Further, HCV is present in cerebrospinal fluid, raising the possibility that the CNS may act as a reservoir site for HCV. A defi nitive confi rmation of the role of HCV in impairment of cognitive functions comes from a study that investigated the impact of treatment-related clearance of HCV on cognitive function. The problem of depression in HCV chronic hepatitis seems far from our speculations, but it has an important role. Mood and anxiety symptoms in chronic hepatitis C patients may be related to patient awareness of the diagnosis and prognosis, to side effects induced by IFN α treatment, and to substance abuse. However, the observation of metabolic alterations in patients with chronic hepatitis C has led to the hypothesis that HCV has a direct effect on brain function. A higher lifetime prevalence of major depressive disorder (MDD) has been observed among chronic hepatitis C patients than among chronic hepatitis B patients or controls. The pathogenesis of portosystemic encephalopathy (PSE) is probably multifactorial, although the predominant causative agent appears to be ammonia. Renal dysfunction seems also to be related to cognitive impairment in patients with liver cirrhosis and might be implicated in the pathogenesis of PSE. In any case, the importance of T2DM in PSE has been confi rmed. In fact, diabetic patients have severe PSE at earlier stages of decompensation than nondiabetic patients. In conclusion, it is possible that the higher prevalence of cognitive dysfunction in HCV cirrhosis is a result of the higher prevalence of T2DM in these patients, but it is also possible that this cognitive dysfunction is HCV-mediated.

Is there a direct role of hepatitis C virus in portosystemic encephalopathy?

TARANTINO, GIOVANNI
2008

Abstract

Hepatitis C virus (HCV) infection is one of the most common chronic viral infections in the world, with a global prevalence of about 2%, and it is the leading cause of liver cirrhosis in the Western world. Chronic HCV infection is commonly associated with a number of extrahepatic complications. Type 2 diabetes mellitus (T2DM) is a chronic disease whose prevalence (about 10%) is increasing worldwide. It is associated with a high risk of severe micro- and macrovascular complications. T2DM is generally considered a polygenic disease, whose expression is favored by an inadequate lifestyle in which insulin resistance (IR) plays a key role. Epidemiological studies have suggested a linkage between T2DM and HCV-related chronic hepatitis, but the presence of additional factors such as aging, and sometimes previous or contemporaneous factors such as obesity or metabolic syndrome, prevents the establishment of a defi nite relationship between these two illnesses. the prevalence of T2DM in HCV-related cirrhosis is higher than (more than double!) that in Hepatitis B Virus (HBV)-related cirrhosis. This observation suggests that HCV infection itself can lead to IR and predispose the patient to the onset of T2DM. First, HCV core protein induces fatty liver by inhibition of microsomal triglyceride transfer protein, and fatty liver is strictly linked to IR. Second, HCV core protein inhibits, through elevation of tumor necrosis factor α and interleukin 6, the insulin signaling pathways, thus causing IR. The ability of insulin to lower the plasma glucose level has been shown to be impaired in a mouse model transgenic for the HCV core gene, as has also been observed in chronic hepatitis C patients. These results provide direct experimental evidence for a contribution of HCV to the development of IR. T2DM and impaired fasting glucose are not associated with anthropomorphic markers of obesity in HCV patients, suggesting a unique multifactorial pathogenesis of T2DM in HCV. Reports of specifi c central nervous system (CNS) involvement are not rare in HCV-infected patients Some data provide evidence that the CNS is a site of HCV replication, consistent with the recent demonstration of negative-strand HCV RNA in brain, and suggest that internal ribosomal entry site polymorphisms may be important as a viral strategy of reduced translation to favor latency in the CNS. Further, HCV is present in cerebrospinal fluid, raising the possibility that the CNS may act as a reservoir site for HCV. A defi nitive confi rmation of the role of HCV in impairment of cognitive functions comes from a study that investigated the impact of treatment-related clearance of HCV on cognitive function. The problem of depression in HCV chronic hepatitis seems far from our speculations, but it has an important role. Mood and anxiety symptoms in chronic hepatitis C patients may be related to patient awareness of the diagnosis and prognosis, to side effects induced by IFN α treatment, and to substance abuse. However, the observation of metabolic alterations in patients with chronic hepatitis C has led to the hypothesis that HCV has a direct effect on brain function. A higher lifetime prevalence of major depressive disorder (MDD) has been observed among chronic hepatitis C patients than among chronic hepatitis B patients or controls. The pathogenesis of portosystemic encephalopathy (PSE) is probably multifactorial, although the predominant causative agent appears to be ammonia. Renal dysfunction seems also to be related to cognitive impairment in patients with liver cirrhosis and might be implicated in the pathogenesis of PSE. In any case, the importance of T2DM in PSE has been confi rmed. In fact, diabetic patients have severe PSE at earlier stages of decompensation than nondiabetic patients. In conclusion, it is possible that the higher prevalence of cognitive dysfunction in HCV cirrhosis is a result of the higher prevalence of T2DM in these patients, but it is also possible that this cognitive dysfunction is HCV-mediated.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/360523
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