Reduced incidence of type 2 diabetes in patients with chronic hepatitis C virus infection cleared by direct-acting antiviral therapy: A prospective study.

AIM: To assess the effect of hepatitis C virus (HCV) eradication on type 2 diabetes mellitus (T2DM). incidence. METHODS: A prospective multicentre case-control study was performed, which included 2426 patients with HCV, 42% of whom had liver fibrosis stage F0-F2 and 58% of whom had liver fibrosis stage F3-F4. The study population consisted of a control group including 1099 untreated patients and 1327 cases treated with direct-acting antivirals (DAAs). T2DM incidence was assessed during a median (interquartile range) follow-up period of 30 (28-42) months. Risk factors for T2DM were assessed using a Cox regression model (relative risk [RR], hazard ratio [HR], Kaplan-Meier analysis). Insulin sensitivity was evaluated by homeostatic model assessment (HOMA) and changes by repeated-measures ANOVA. Factors independently associated with T2DM were assessed by multivariate analysis. RESULTS: The absolute incidence of T2DM for controls and cases was 28 and 7/1000 person-years, respectively (P = 0.001). In cases compared to controls, HCV clearance reduced the RR and HR of T2DM by 81% and 75% to 93%, respectively (P = 0.001). It was calculated that, for every 15 patients who obtained HCV clearance, one case of T2DM was saved. HCV clearance was associated with significant reductions in HOMA-insulin resistance and HOMA-ß-cell function and an increase in HOMA-insulin sensitivity, as assessed in 384 patients before and after HCV clearance. At multivariate analysis, HCV clearance emerged as independently associated with a reduced T2DM risk. CONCLUSION: The results showed that HCV clearance by DAA treatment reduces T2DM incidence probably by restoring the HCV-induced alteration of glucose homeostasis mechanisms.

Incidence and risk factors of early HCC occurrence in HCV patients treated with direct acting antivirals: a prospective multicentre study.

BACKGROUND: An unexpected increased HCC recurrence and occurrence rate among HCV patients treated with direct acting antivirals combination has been reported. Aim of the study was the evaluation of early HCC occurrence rate and its risk factors in a HCV infected population, treated with direct-acting-antivirals. METHODS: According to the Italian ministerial guidelines for direct-acting-antivirals treatment, 1022 consecutive HCV patients treated with direct-acting-antivirals were enrolled. Patients either with active HCC at imaging or history of previous treated HCC, HBV or HIV co-infection, or liver transplant recipients were excluded. The SVR, defined as the persistent absence of detectable serum HCV-RNA 12 weeks after the end of treatment (SVR12), was assessed for all enrolled patients. Abdominal ultrasound was performed before starting antiviral therapy, and repeated every 6 months. HCC was diagnosed according to the international guidelines. Patients showing either nodular patterns suggestive of HCC or with uncertain dynamic vascular behaviour were excluded from a further follow-up. RESULTS: Nine hundred and eighty-five patients completed the 48 weeks follow-up after the end of treatment. A Sofosbuvir-based regimen was administered in the 74.9% of patients, among whom, the 71.6% underwent a simultaneous Ribavirin administration. A sustained virological response at 12 weeks off treatment was documented in 966 patients (98.2%). During the post treatment follow-up HCC was detected in 35 patients, with a cumulative incidence rate of the 3.55%. At multivariate analysis, four variables resulted independently associated with HCC development, both in a cirrhosis based and a class B Child based model, respectively: cirrhosis/class B Child, therapeutic schedule including Sofosbuvir without Ribavirin, liver stiffness values, male gender and presence of diabetes. A multivariate analysis performed on Child A cirrhotic patients, showed that Sofosbuvir based therapeutic treatment without Ribavirin had a HCC occurrence 5.7 higher than Ribavirin-based schedules with or without Sofosbuvir (p < 0.0001, OR: 5.686, 95% CI 2.455-13.169). CONCLUSIONS: Our data suggest that early HCC occurrence appears more frequently related to Sofosbuvir-based therapy without Ribavirin which, indeed, seems to play a protective role on HCC onset. Therefore, a careful follow-up should be mandatory, especially in those regimens including Sofosbuvir without Ribavirin.

Role of Liver Stiffness Measurement in Predicting HCC Occurrence in Direct-Acting Antivirals Setting: A Real-Life Experience.

PURPOSE: The aim of this study was to evaluate the relationship between the liver stiffness measurement and the risk of developing hepatocellular carcinoma (HCC) in HCV cirrhotic patients undergoing new direct-acting antivirals. METHODS: From April 2015 to April 2017, all consecutive HCV cirrhotic patients treated by direct-acting antivirals were enrolled. A liver stiffness measurement was computed at baseline, and an ultrasound evaluation was provided for all patients at baseline and every 6 months until 1 year after the stopping of the antiviral therapy. The diagnosis of HCC was performed according to international guidelines by imaging technique workup. RESULTS: Two hundred and fifty-eight HCV patients with a diagnosis of cirrhosis were identified. The median liver stiffness was 25.5 kPa. Thirty-five patients developed HCC. Patients were divided into three groups, based on their liver stiffness: < 20 kPa (n = 72), between 20 and 30 kPa (n = 92) and > 30 kPa (n = 94). Compared to the < 20 kPa and 20-30 kPa groups, the > 30 kPa group showed a statistically significant increased risk of HCC (p = 0.019; HR 0.329; 95% CI 0.131-0.830). A ROC curve analysis to assess the overall predictive performance of liver stiffness measurement on the HCC risk was performed. The results allow us to identify a cutoff value of liver stiffness measurement equal to 27.8 kPa, which guarantees the highest sensitivity and specificity (respectively, 72% and 65%). CONCLUSIONS: The data underline that the baseline liver stiffness measurement and ultrasound surveillance is a valuable tool for assessing the risk of HCC in cirrhotic patients undergoing the direct-acting antivirals treatment.

Endotoxinemia contributes to steatosis, insulin resistance and atherosclerosis in chronic hepatitis C: the role of pro-inflammatory cytokines and oxidative stress.

PURPOSE: Endotoxin is a component of the outer membrane of gram-negative bacteria that live in the intestine. Endotoxinemia is reported in non-alcoholic fatty liver disease and in cirrhotic patients, causing various biological and clinical effects in the host. It is not known whether endotoxinemia occurs in chronic hepatitis C patients (CHC), therefore we evaluated the occurrence of endotoxinemia and its effect on inflammation, liver damage, insulin resistance (IR) and atherosclerosis. METHODS: Consecutive CHC patients assessed by liver biopsy were enrolled. Endotoxinemia was evaluated by LAL test. IR was estimated by HOMA-IR. Serum TNF-α, IL-8, adiponectin and MCP-1 were measured with ELISA tests. Oxidative stress was estimated by circulating IgG against malondialdehyde adducts with human serum albumin (MDA-HAS). Carotid atherosclerosis was assessed by ultrasonography. RESULTS: Endotoxinemia was found in 60% of the 126 patients enrolled. A serum level-dependent association between endotoxinemia, steatosis (p < 0.001) and HOMA-IR (p < 0.006) was observed. Patients with endotoxinemia showed significant increase in TNF-α and IL8 levels. TNF-α correlated with steatosis (p <  0.001) and HOMA-IR (p < 0.03), whereas IL8 correlated with steatosis (p =  <0.001), TNF-α (p < 0.04) and atherosclerosis (p < 0.01). The highest levels of endotoxinemia were associated with oxidative stress and a higher prevalence of carotid atherosclerosis. Multivariate logistic regression analysis showed that the independent factors associated with endotoxinemia were hepatic steatosis, HOMA-IR, IL8 and MDA-HAS. CONCLUSIONS: Endotoxinemia occurs with high frequency in CHC patients and contributes to the development of hepatic steatosis, IR and atherosclerosis through increased pro-inflammatory cytokines and oxidative stress. Anti-endotoxin treatment could be of clinical relevance.

Hepatitis C virus clearance by direct-acting antiviral treatments and impact on insulin resistance in chronic hepatitis C patients.

BACKGROUND AND AIM: Chronic hepatitis C virus (HCV), particularly genotype 1, is associated with insulin resistance (IR) and diabetes. This study evaluated the impact of HCV clearance by all-oral direct-acting antiviral treatments on IR and glycemic control. METHODS: Included in this prospective case-control study were 133 consecutive HCV-genotype 1 patients with advance liver fibrosis (F3-F4) without type 2 diabetes. Sixty eight were treated with direct-acting antiviral and 65 were untreated. Liver fibrosis was assessed by transient elastography. Pre-treatment, end-treatment, and 3 months post-treatment withdrawal IR homeostasis was assessed by homeostatic model assessment (HOMA)-IR, HOMA-S, and HOMA-B. RESULTS: At baseline, treated, and untreated patients showed similar liver fibrosis levels, HOMA-IR was 4.90 ± 4.62 and 4.64 ± 5.62, respectively. HOMA-IR correlated with HCV RNA levels. At the end of treatment, all patients cleared HCV RNA, regardless of liver fibrosis and body mass index, and a reduction in HOMA-IR at 2.42 ± 1.85 was showed (P < 0.001); in addition, increased insulin sensitivity, decreased insulin secretion, reduction of serum glucose, and insulin levels were observed. Data were confirmed 3 months after treatment withdrawal in the 65 patients who cleared HCV. No variation occurred in untreated patients. Overall, 76.5% of sustained virologic response patients showed IR improvements, of which 41.2% normalized IR. Improvement of IR was strictly associated with HCV clearance; however, patients with the highest levels of fibrosis remain associated with some degree of IR. CONCLUSIONS: The data underline a role of HCV in development of IR and that viral eradication reverses IR and improves glycemic control and this could prevent IR-related clinical manifestations and complications.

NAFLD and NASH in HCV Infection: Prevalence and Significance in Hepatic and Extrahepatic Manifestations.

The aim of this paper is to review and up to date the prevalence of hepatitis C virus (HCV)-associated non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) and their significance in both accelerating progression of HCV-related liver disease and development of HCV-associated extrahepatic diseases. The reported mean prevalence of HCV-related NAFLD was 55%, whereas NASH was reported in 4%-10% of cases. HCV genotype 3 directly induces fatty liver deposition, namely "viral steatosis" and it is associated with the highest prevalence and degree of severity, whereas, HCV non-3 genotype infection showed lower prevalence of steatosis, which is associated with metabolic factors and insulin resistance. The host's genetic background predisposes him or her to the development of steatosis. HCV's impairment of lipid and glucose metabolism causes fatty liver accumulation; this seems to be a viral strategy to optimize its life cycle. Irrespective of insulin resistance, HCV-associated NAFLD, in a degree-dependent manner, contributes towards accelerating the liver fibrosis progression and development of hepatocellular carcinoma by inducing liver inflammation and oxidative stress. Furthermore, NAFLD is associated with the presence of metabolic syndrome, type 2 diabetes, and atherosclerosis. In addition, HCV-related "metabolic steatosis" impairs the response rate to interferon-based treatment, whereas it seems that "viral steatosis" may harm the response rate to new oral direct antiviral agents. In conclusion, a high prevalence of NAFLD occurs in HCV infections, which is, at least in part, induced by the virus, and that NAFLD significantly impacts progression of the liver disease, therapeutic response, and some extrahepatic diseases.

Metastatic melanoma: an unusual presentation.

In this report we describe a case of a malignant cutaneous melanoma metastasizing to the pleural surface and peritoneal cavity 5 years after surgical resection of the primary lesion. Malignant cutaneous melanoma is a very aggressive cancer able to metastasize anywhere in the body. Pleural secondary lesions represent a rare event described only in a small number of patients and the association with peritoneal localizations may suggest an uncommon pattern of spread that we discuss.

Metabolic and renal changes in patients with chronic hepatitis C infection after hepatitis C virus clearance by direct-acting antivirals.

BACKGROUND AND AIM: The impact of hepatitis C virus (HCV) clearance by direct-acting antiviral agents (DAAs) on HCV-related extrahepatic manifestations is not well known. We evaluated the effect of viral clearance on metabolic and renal parameters. METHODS: In this prospective study, HCV patients who achieved a sustained virologic response (SVR) by DAAs were evaluated before, at the end, and 24 weeks after treatment for glycemic (serum glucose and insulin, HOMA-IR, HOMA-ß, and HOMA-S) and lipid (serum cholesterol, triglycerides, low-density lipoprotein [LDL], high-density lipoprotein) metabolism and renal function (serum creatinine, estimated glomerular filtration rate [eGFR]). RESULTS: A total of 343 consecutive HCV patients were evaluated. At 24 weeks of post-follow-up, an increase in body mass index (BMI) was observed (P < 0.05). Regardless of hepatic fibrosis levels and BMI, a reduction in serum glucose (P = 0.001), HOMA-IR (P < 0.001) and HOMA-ß (P < 0.001) and an increase in HOMA-S (P < 0.001) values were observed at 24 weeks after HCV clearance as compared to pretreatment values; 32.4% of patients with impaired fasting glucose normalized serum glucose values and 44.6% of diabetics showed an improvement in glycemic control. In contrast, serum cholesterol (P < 0.001) and LDL cholesterol (P < 0.001) values were increased. Renal function was improved with about 10% reduction of serum creatinine values (P < 0.02) and an increase of eGFR (P < 0.001). A baseline eGFR of ≤60 mL/min/1.73 m2 was a negative predictor of renal function improvement. HCV clearance was an independent factor improving glucose metabolism and renal function. CONCLUSIONS: Our study shows an occurrence of changes in metabolic and renal parameters in HCV patients with SVR, anticipating possible future clinical scenarios that the clinician must know for proper management.

Atypical Presentation of a Rare Parasitic Infection with Fasciola hepatica: A Multidisciplinary Case Report.

BACKGROUND Fascioliasis is a zoonotic disease caused by Fasciola hepatica (F. hepatica). This infection is associated with a broad spectrum of clinical symptoms such as fever, eosinophilia, and gastrointestinal symptoms. CASE REPORT We report a case of F. hepatica abdominal mass in the peri-pancreatic region in a 58-year-old man, returned from Venezuela. The patient developed abdominal pain, nausea, anorexia, and weakness. Radiological investigations showed hepatomegaly, as well as mild intra-hepatic and extrahepatic ductal dilatation. The increase in eosinophilia, elevated total IgE titer, and anamnestic data suggested the hypothesis of parasitic infection. The diagnosis was established by high serological titer against F. hepatica. CONCLUSIONS The development of abdominal mass, with jaundice and dilation of the biliary tract, does not always suggest the presence of heteroplasia. Systemic parasitosis represents a not negligible event, especially considering the personal history of life in endemic areas.

Impact of hepatitis C virus clearance by direct-acting antiviral treatment on the incidence of major cardiovascular events: A prospective multicentre study.

BACKGROUND AND AIMS: HCV is associated with an increased risk of cardiovascular events (CV). Whether HCV clearance by direct-acting antivirals (DAA) reduces incident CV disease is poorly understood. We investigate whether HCV eradication reduces CV events. METHODS: In a prospective multicentre study, 2204 HCV patients (F0-F2:29.5%, F3-F4: 70.5%) were enrolled. Males were 48%, median age was 68 (59-74) years and BMI 25.9 (23.1-28); 24.7% were smokers, 18% had diabetes, 13.2% had cholesterol levels >200 mg/dl and 9.1% took statins, 44% had hypertension. During an overall median follow-up of 28 (24-39) months, incident CV events, such as ischemic heart disease (IHD) and ischemic cerebral stroke (ICS), were recorded. An overall of 2204 patients were evaluated as control group and 1668 patients after HCV elimination were followed as a case group. Factors associated with CV events were evaluated by uni- and multi-variate analyses. RESULTS: Incident CV rates per 100 patient years in pre-treatment and untreated controls and treated cases were 1.12, 1.14 and 0.44 (p = 0.0001 vs. controls), respectively, and a decreased of relative risk (RR = 0.379; p = 0.0002) was observed. CV risk was 2.0-3.5 times lower then in controls (HR 3.671; 95%C.I.:1.871-7.201; p < 0.001). The calculated number of patients to be treated to get a benefit in a patient was 55.26. The annual incidence reduction of CV events was 0.68%. HCV clearance was independently associated with CV events reduction (OR, 4.716; 95% C.I.:1.832-12.138; p = 0.001). CONCLUSIONS: HCV clearance by DAA reduces CV events (IHD and ICS) with both clinical and socio-economic benefits.

HCV genotype-3h, a difficult-to-diagnose sub-genotype in the DAA era.

BACKGROUND: No data are available on the clinical presentation and virological pattern in the case of failure of interferon (IFN)-free regimens in patients with genotype-3h. In this paper authors identified the virological and clinical characteristics of patients with genotype-3h treated with suboptimal or not indicated IFN-free regimens for the misclassification of HCV genotype. METHODS: A total of 87 consecutive patients with failure to an IFN-free regimen were re-tested for HCV genotype by HCV NS5B sequencing; the 26 patients identified as harbouring HCV-3 were enrolled. RESULTS: Of the 26 patients enrolled, 4 (15.4%) harboured sub-genotype-3h and 22 (84.6%) 3a. All patients were Italian. Patients with genotype-3a infection were younger (median age 56 years, range 47-78) compared to those with genotype-3h infection (median 74 years, range 65-79; P<0.006). With regard to the failed direct-acting antiviral (DAA)-regimens, three of the four patients with genotype-3h (75%) had been treated with an ineffective​ DAA regimen (paritaprevir, ombitasvir, dasabuvir ± ribavirin for 3 months) more frequently than those with genotype-3a (13.6%; P=0.02), because of previous erroneous identification of HCV-1 genotype. NS5A resistance-associated substitutions (RASs) were observed in 10 (45.4%) genotype-3a-infected patients and in 2 (50%) with genotype-3h. NS5B RASs were observed in only two genotype-3a-infected patients and in none of the 3h-infected patients. CONCLUSIONS: This is the first time genotype-3h has been identified in Italian patients failing an IFN-free regimen, in the majority of cases because of a misclassification of the HCV genotype.

Clinical features and natural history of cryptogenic cirrhosis compared to hepatitis C virus-related cirrhosis.

AIM: To characterize natural history of cryptogenic cirrhosis (CC) and compare its clinical features and outcomes to those of hepatitis C virus (HCV)-related cirrhosis. METHODS: A prospective cohort of 102 consecutive patients at their first diagnosis of CC were enrolled in this study. The clinical data and outcomes were compared to an age- and Child-Pugh class-matched cohort of 110 patients with HCV-related cirrhosis. Diagnosis of cirrhosis was based on compatible clinical and laboratory parameters, ultrasound/endoscopic parameters and, whenever possible, on histological grounds and transient elastography. All cases of cirrhosis without a definite etiology were enrolled in the CC group. The parameters assessed were: (1) severity of liver disease at the time of first diagnosis; (2) liver decompensation during follow-up; (3) hepatocellular carcinoma (HCC); (4) orthotopic liver transplantation; and (5) death. The independent associated factors were evaluated by multiple logistic regression analysis, and survival and its determinants by the Kaplan-Meier model, log-rank test and Cox regression. RESULTS: At the first observation, median age was 66 and 65 years and male gender was 36% and 58% for CC and HCV cirrhosis, respectively. CC showed Child-Pugh class A/B/C of 47%/31%/22%, respectively. Compared to HCV cirrhosis, CC exhibited a significantly higher prevalence of metabolic syndrome (12% vs 54%, respectively), overweight/obesity, high BMI, impaired glucose tolerance, high blood pressure, dyslipidemia, hyperuricemia, cardiovascular diseases, extrahepatic cancer, and gallstones. Over a median period of 42 mo of follow-up, liver decompensation, HCC development and death for CC and HCV-related cirrhosis were 60.8%, and 54.4%, 16.7% and 17.2%, 39.2% and 30%, respectively. The median survival was 60 mo for CC. Independent predictors of death were age and Child-Pugh class at diagnosis. CC showed an approximately twofold higher incidence of HCC in Child-Pugh class A. CONCLUSION: Undiagnosed nonalcoholic fatty liver disease has an etiologic role in CC that is associated with a poor prognosis, early HCC development, high risk of cardiovascular disease and extrahepatic cancer.

Tenofovir disoproxil fumarate monotherapy maintains HBV suppression achieved by a "de novo" combination of lamivudine-adefovir: a pilot study.

Chronic hepatitis B (CHB) treatment aims at long-term suppression of HBV replication and improvement in clinical outcomes. We describe the data of a pilot, non-profit study in which patients with CHB were treated with de novo combination lamivudine-adefovir (LAM-ADV) for at least four years with a view to HBV suppression and resistance prevention, and shifted to tenofovir (TDF) when new antiviral agents were available. Fifty-one HBeAg negative patients were enrolled. Histology was available for 39 patients and data of liver stiffness (LS) for 24 patients at baseline. Serum quantification of HBsAg and HBVDNA was obtained regularly during the follow-up. In 10 and 7 patients, a paired histology and LS were available at the end of LAM-ADV treatment, respectively. The de novo LAM-ADV combination was able to obtain HBVDNA suppression and ALT normalization in one year in most of the patients and in the second year in the remaining. Histology improved in patients with paired biopsy, but tissue HBsAg was present in all but one patient after 48 months of therapy. TDF maintained biochemical and virological response throughout the follow-up. Renal impairment during LAM-ADV therapy improved on shifting to TDF; only in 4 cases was a second shift to entecavir needed. TDF was safe and effective in maintaining HBV DNA suppression achieved by a long-term course of LAM-ADV de novo combination for the treatment of HBeAg-negative CHB.

Boceprevir or telaprevir in hepatitis C virus chronic infection: The Italian real life experience.

AIM: To check the safety and efficacy of boceprevir/telaprevir with peginterferon/ribavirin for hepatitis C virus (HCV) genotype 1 in the real-world settings. METHODS: This study was a non-randomized, observational, prospective, multicenter. This study involved 47 centers in Italy. A database was prepared for the homogenous collection of the data, was used by all of the centers for data collection, and was updated continuously. All of the patients enrolled in this study were older than 18 years of age and were diagnosed with chronic infection due to HCV genotype 1. The HCV RNA testing was performed using COBAS-TaqMan2.0 (Roche, LLQ 25 IU/mL). RESULTS: All consecutively treated patients were included. Forty-seven centers enrolled 834 patients as follows: Male 64%; median age 57 (range 18-78), of whom 18.3% were over 65; mean body mass index 25.6 (range 16-39); genotype 1b (79.4%); diagnosis of cirrhosis (38.2%); and fibrosis F3/4 (71.2%). The following drugs were used: Telaprevir (66.2%) and PEG-IFN-alpha2a (67.6%). Patients were naïve (24.4%), relapsers (30.5%), partial responders (14.8%) and null responders (30.3%). Overall, adverse events (AEs) occurred in 617 patients (73.9%) during the treatment. Anemia was the most frequent AE (52.9% of cases), especially in cirrhotic. The therapy was stopped for 14.6% of the patients because of adverse events or virological failure (15%). Sustained virological response was achieved in 62.7% of the cases, but was 43.8% in cirrhotic patients over 65 years of age. CONCLUSION: In everyday practice, triple therapy is safe but has moderate efficacy, especially for patients over 65 years of age, with advanced fibrosis, non-responders to peginterferon + ribavirin.

All-oral interferon-free treatments: The end of hepatitis C virus story, the dream and the reality.

The year 2014 marked the beginning of the end of the interferon era and the triumph of the all-oral interferon-free regimens for treatment of hepatitis C virus (HCV) infection. These innovative therapies are safe and yield a cure rate of over 90%. The scientific hepatology community is euphoric about the possibility of elimination and even eradication of HCV infection. However, the current high cost of the new all-oral regimens allows access to treatment only for a restricted number of HCV-infected patients. In addition, many other conditions such as modality of access and delivery of care, inadequate knowledge of HCV epidemiology and political commitments to be undertaken, hamper the fulfillment of the dream to eliminate the virus. Since, such conditions are not impossible to overcome, a global urgent effort must be made to allow a widespread access to the new treatments which will permit in the next years to avoid million of HCV-related deaths.

Chronic hepatitis C virus infection and neurological and psychiatric disorders: an overview.

Hepatitis C virus (HCV) infection is considered a systemic disease because of involvement of other organs and tissues concomitantly with liver disease. Among the extrahepatic manifestations, neuropsychiatric disorders have been reported in up to 50% of chronic HCV infected patients. Both the central and peripheral nervous system may be involved with a wide variety of clinical manifestations. Main HCV-associated neurological conditions include cerebrovascular events, encephalopathy, myelitis, encephalomyelitis, and cognitive impairment, whereas "brain fog", depression, anxiety, and fatigue are at the top of the list of psychiatric disorders. Moreover, HCV infection is known to cause both motor and sensory peripheral neuropathy in the context of mixed cryoglobulinemia, and has also been recently recognized as an independent risk factor for stroke. These extrahepatic manifestations are independent of severity of the underlying chronic liver disease and hepatic encephalopathy. The brain is a suitable site for HCV replication, where the virus may directly exert neurotoxicity; other mechanisms proposed to explain the pathogenesis of neuropsychiatric disorders in chronic HCV infection include derangement of metabolic pathways of infected cells, alterations in neurotransmitter circuits, autoimmune disorders, and cerebral or systemic inflammation. A pathogenic role for HCV is also suggested by improvement of neurological and psychiatric symptoms in patients achieving a sustained virologic response following interferon treatment; however, further ad hoc trials are needed to fully assess the impact of HCV infection and specific antiviral treatments on associated neuropsychiatric disorders.

Chronic hepatitis C virus infection and atherosclerosis: clinical impact and mechanisms.

Hepatitis C virus (HCV) infection represents a major health issue worldwide due to its burden of chronic liver disease and extrahepatic manifestations including cardiovascular diseases, which are associated with excess mortality. Analysis of published studies supports the view that HCV infection should be considered a risk factor for the development of carotid atherosclerosis, heart failure and stroke. In contrast, findings from studies addressing coronary artery disease and HCV have yielded conflicting results. Therefore, meta-analytic reviews and prospective studies are warranted. The pathogenic mechanisms connecting HCV infection, chronic liver disease, and atherogenesis are not completely understood. However, it has been hypothesized that HCV may promote atherogenesis and its complications through several direct and indirect biological mechanisms involving HCV colonization and replication within arterial walls, liver steatosis and fibrosis, enhanced and imbalanced secretion of inflammatory cytokines, oxidative stress, endotoxemia, mixed cryoglobulinemia, perturbed cellular and humoral immunity, hyperhomocysteinemia, hypo-adiponectinaemia, insulin resistance, type 2 diabetes and other components of the metabolic syndrome. Understanding these complex mechanisms is of fundamental importance for the development of novel therapeutic approaches to prevent and to treat vascular complications in patients with chronic HCV infection. Currently, it seems that HCV clearance by interferon and ribavirin treatment significantly reduces non-liver-related mortality; moreover, interferon-based treatment appears to decrease the risk of ischemic stroke.

Chronic HCV infection is a risk factor of ischemic stroke.

OBJECTIVES: Cerebrovascular diseases are leading cause of death worldwide. Plaque rupture and embolization account for one-third of ischemic stroke. The causes are not fully known, but inflammation plays a pathogenic role. Recently, HCV infection has been identify as risk of atherosclerosis. HCV replicates within carotid plaques and brain endothelia cells; moreover, HCV patients showed higher levels of inflammation. Thus, we hypothesized that subjects carrying HCV are at higher risk of stroke. Accordingly, we evaluated prevalence and role of HCV infection in patients with stroke. METHODS: A priori sample size was calculated. Overall, 820 consecutive patients were enrolled, 123 with stroke and, as control, 697 age- and gender-matched (295 with COPD; 402 with diseases other than HCV-associated). Patients were evaluated for HCV and conventional risk of stroke. RESULTS: Prevalence of HCV was higher in patients with stroke than that observed in control (26.8% vs. 6.6%, p = 0.0001). An analysis of stroke patients showed that those HCV positive were younger (p = 0.017) had lower serum levels of cholesterol (p = 0.001), triglycerides (p = 0.045), and higher serum levels of inflammation markers (ESR, p = 0.001; CRP, p = 0.0001; fibrinogen, p = 0.012). A multivariate analysis showed that HCV infection was an independent risk factor of stroke (O.R. 2.04, 95% C.I. 1.69-2.46; p = 0.0001). A secondary analysis showed that HCV patients had higher (p = 0.031) prevalence of past ischemic heart disease. CONCLUSIONS: HCV infected patients are at higher and earlier risk of stroke. Inflammation is a key mediator. Clinicians in clinical practice and researchers in future trials should take into account these new findings.

Chronic HCV infection and inflammation: Clinical impact on hepatic and extra-hepatic manifestations.

The liver has a central role in regulating inflammation by its capacity to secrete a number of proteins that control both local and systemic inflammatory responses. Chronic inflammation or an exaggerated inflammatory response can produce detrimental effects on target organs. Chronic hepatitis C virus (HCV) infection causes liver inflammation by complex and not yet well-understood molecular pathways, including direct viral effects and indirect mechanisms involving cytokine pathways, oxidative stress and steatosis induction. An increasing body of evidence recognizes the inflammatory response in chronic hepatitis C as pathogenically linked to the development of both liver-limited injury (fibrosis, cirrhosis and hepatocellular carcinoma) and extrahepatic HCV-related diseases (lymphoproliferative disease, atherosclerosis, cardiovascular and brain disease). Defining the complex mechanisms of HCV-induced inflammation could be crucial to determine the global impact of infection, to estimate progression of the disease, and to explore novel therapeutic approaches to avert HCV-related diseases. This review focuses on HCV-related clinical conditions as a result of chronic liver and systemic inflammatory states.

Chronic HCV infection is a risk of atherosclerosis. Role of HCV and HCV-related steatosis.

OBJECTIVES: HCV and NAFLD are associated with atherosclerosis in general population. The prevalence of atherosclerosis in chronic hepatitis C (CHC) patients is unknown. We hypothesized that HCV per se and HCV-related steatosis could favour atherosclerosis. Thus, in CHC patients we assessed: (a) the prevalence of atherosclerosis; (b) the role of HCV, cardio-metabolic risk factors and hepatic histology. METHODS: Overall, 803 subjects were enrolled: (A) 326 patients with liver biopsy-proven treatment naive CHC (175 with and 151 without steatosis); (B) 477 age and gender matched controls, including 292 healthy subjects without steatosis (B1) and 185 with NAFLD (B2). Carotid atherosclerosis (CA), assessed by high-resolution B-mode ultrasonography, was categorized as either intima-media thickness (IMT: >1mm) or plaques (≥ 1.5mm). RESULTS: CHC patients had a higher prevalence of CA than controls (53.7% vs 34.3%; p<0.0001). Younger CHC (<50 years) had a higher prevalence of CA than controls (34.0% vs 16.0%; p<0.04). CHC patients without steatosis had a higher prevalence of CA than B1 controls (26.0% vs 14.8%; p<0.02). CHC with steatosis had a higher prevalence of CA than NAFLD patients (77.7% vs 57.8%, p<0.0001). Viral load was associated with serum CRP and fibrinogen levels; steatosis with metabolic syndrome, HOMA-IR, hyperhomocysteinemia and liver fibrosis. Viral load and steatosis were independently associated with CA. Diabetes and metabolic syndrome were associated with plaques. CONCLUSION: HCV infection is a risk factor for earlier and facilitated occurrence of CA via viral load and steatosis which modulate atherogenic factors such as inflammation and dysmetabolic milieu.