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The long-term changes of liver stiffness (LS) in patients who achieve viral clearance after direct-acting anti-HCV therapy remain undefined. We conducted a multicenter prospective study to investigate this aspect. Patients with HCV infection treated with DAAs were enrolled from six Italian centers; they underwent clinical, biochemical, ultrasound, and transient elastography evaluations before treatment (T0), 12 weeks (SVR12), and 24 months (T24) after the end of therapy. Among the 516 consecutive patients enrolled, 301 had cirrhosis. LS significantly decreased from T0 to SVR (14.3 kPa vs 11.1 kPa, p=0.002), with a progressive reduction until T24 (8.7 kPa, p

Hepatitis C virus (HCV) causes a systemic infection inducing hepatic and extrahepatic diseases. These latter involve cardiovascular system, kidney, brain, endocrine, glucose, and lipid metabolism, and the immune system. HCV infection is associated with an increased risk of morbidity and mortality for both hepatic and extrahepatic events. Direct-acting antivirals (DAA), introduced in the most recent years for HCV treatment, are effective in up to 99% of cases and have changed the clinical scenarios and management of these patients.The literature on the impact of HCV clearance by DAA on both hepatic and extrahepatic disease outcomes has been analyzed and discussed in this review in order to summarize the full therapeutic potential and its weaknesses.Patients achieving HCV clearance have improved hepatic and extrahepatic diseases, quality of life and survival. They have lower incidence of cardiovascular disease, type 2 diabetes, kidney damage, and immuno-mediated manifestations. However, the improvements are related to the degree of pre-treatment organ damage. Therefore, a significant percentage of patients with advanced disease remains at risk of morbidity and mortality and must be monitored in the post-treatment. In addition, data emphasize the importance of starting treatment during the early stages of HCV infection.

Background and aims Diabetic retinopathy (DR) is the most common microvascular complication of diabetes. Diabetic macroangiopathies, particularly cardiovascular (CV) diseases, seem closely related to diabetes microvascular complications. Aspirin represents the most prescribed compound in CV prevention. Aspirin impact on DR is still object of debate. As it is already recommended among diabetics at high CV risk, aim of this study was to assess a potential relationship between DR and aspirin therapy, in a type 2 diabetes cohort of patients screened through telemedicine. Methods and results NO Blind is a cross-sectional, multicenter, observational study, which involved nine Italian outpatient clinics. Primary endpoint was the assessment of the relationship between aspirin treatment and DR. 2068 patients were enrolled in the study, subsequently split in two subpopulations according to either the presence or absence of DR. Overall, 995 subjects were under aspirin therapy. After adjusting for most common potential confounders, age and gender, aspirin reveals significantly associated with DR (OR: 1.72, 95%CI: 1.58–2.89, p = 0.002) and proliferative DR (PDR) (OR: 1.89, 95%CI: 1.24–2.84, p = 0.003). Association comes lost further adjusting for MACEs (OR: 1.28, 95%CI: 0.85–1.42, p = 0.157) (Model 4) and eGFR (OR: 0.93; 95%CI: 0.71–1.22; p = 0.591) (Model 5). Conclusion In this multicenter cross-sectional study including a large sample of outpatients with T2DM, we showed that aspirin was not associated with DR after adjustment for several cardio-metabolic confounders. However, as partially confirmed by our findings, and related to the well-known pro-hemorrhagic effect of aspirin, its use should be individually tailored, even by telemedicine tools.

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‐β, 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, In a prospective study, 343 patients with hepatitis C virus (HCV) infection who achieved sustained virologic response by direct‐acting antiviral agent (DAA) treatments were followed up for 24 weeks to evaluate the impact of viral clearance on metabolic and renal parameters. HCV clearance was independently associated with a significant reduction in serum glucose, HOMA‐IR, and HOMA‐β and an increase in HOMA‐S. Furthermore, an increase in serum cholesterol and low‐density lipoprotein cholesterol levels was observed. Renal function was improved with a significant decrease in serum creatinine levels and an increase in estimated glomerular filtration rate. Data show that HCV clearance by DAA induces significant changes in metabolic and renal parameters.

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.

Non-Alcoholic Fatty Liver Disease (NAFLD) is caused by the accumulation of fat in over 5% of hepatocytes in the absence of alcohol consumption. NAFLD is considered the hepatic manifestation of metabolic syndrome (MS). Recently, an expert consensus suggested as more appropriate the term MAFLD (metabolic-associated fatty liver disease). Insulin resistance (IR) plays a key role in the development of NAFLD, as it causes an increase in hepatic lipogenesis and an inhibition of adipose tissue lipolysis. Beyond the imbalance of adipokine levels, the increase in the mass of visceral adipose tissue also determines an increase in free fatty acid (FFA) levels. In turn, an excess of FFA is able to determine IR through the inhibition of the post-receptor insulin signal. Adipocytes secrete chemokines, which are able to enroll macrophages inside the adipose tissue, responsible, in turn, for the increased levels of TNF-α. The latter, as well as resistin and other pro-inflammatory cytokines such as IL-6, enhances insulin resistance and correlates with endothelial dysfunction and an increased cardiovascular (CV) risk. In this review, the role of diet, intestinal microbiota, genetic and epigenetic factors, low-degree chronic systemic inflammation, mitochondrial dysfunction, and endoplasmic reticulum stress on NAFLD have been addressed. Finally, the clinical impact of NAFLD on cardiovascular and renal outcomes, and its direct link with type 2 diabetes have been discussed.

(1) Background: Circulating micro-RNAs (miRNAs) modulate the expression of molecules in diabetes. We evaluated the expression of serum miRNA-195-5p and -451a in diabetic patients with ischemic stroke and correlated them with two markers of brain tissue integrity. (2) Methods: Seventy-eight subjects with acute ischemic stroke (AIS) or transient ischemic attack (TIA) (40 with diabetes) were enrolled. Serum miRNA levels, brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor A (VEGF-A) were assessed at admission and 24 and 72 h after a post-ischemic stroke, and were compared to 20 controls. (3) Results: Both circulating miRNAs were two-fold up-regulated in diabetic AIS and TIA patients compared to non-diabetics. Their levels progressively decreased at 24 and 72 h in both AIS and TIA patients. Interestingly, in the non-diabetic TIA group, both circulating miRNAs, although higher than the controls, tended to achieve a complete decay after 72 h. Furthermore, miRNA-195-5p and miRNA-451a levels inversely correlated with both BDNF and VEGF-A serum levels. (4) Conclusions: These data show a different profile of both micro-RNAs in diabetic versus non-diabetic patients after acute ischemic stroke, suggesting their pivotal role in cerebrovascular ischemic attack.

Direct-acting antivirals (DAAs) induce a rapid virologic response (SVR) in up to 99% of chronic hepatitis C patients. The role of SVR by DAAs on the incidence or recurrence of hepatocellular carcinoma (HCC) is still a matter of debate, although it is known that SVR does not eliminate the risk of HCC. In this review, we made an updated analysis of the literature data on the impact of SVR by DAAs on the risk of HCC as well as an assessment of risk factors and the role of epigenetics. Data showed that SVR has no impact on the occurrence of HCC in the short–medium term but reduces the risk of HCC in the medium–long term. A direct role of DAAs in the development of HCC has not been demonstrated, while the hypothesis of a reduction in immune surveillance in response to the rapid clearance of HCV and changes in the cytokine pattern influencing early carcinogenesis remains to be further elucidated. HCV induces epigenetic alterations such as modifications of the histone tail and DNA methylation, which are risk factors for HCC, and such changes are maintained after HCV clearance. Future epigenetic studies could lead to identify useful biomarkers and therapeutic targets. Cirrhosis has been identified as a risk factor for HCC, particularly if associated with high liver stiffness and α-fetoprotein values, diabetes and the male sex. Currently, considering the high number and health cost to follow subjects’ post-HCV clearance by DAAs, it is mandatory to identify those at high risk of HCC to optimize management.

We demonstrate in 351 diabetic patients with steatosis that NAFLD fibrosis score (NFS), a rapid and affordable score to diagnose hepatic fibrosis, identifies patients at higher risk of advanced fibrosis and vascular diabetic complications (especially peripheral neuropathy), pointing NFS as a first-line vascular and hepatic screening in diabetic patients. (C) 2020 Elsevier Inc. All rights reserved.

Recently, telemedicine has become remarkably important, due to increased deployment and development of digital technologies. National and international guidelines should consider its inclusion in their updates. During the COVID-19 pandemic, mandatory social distancing and the lack of effective treatments has made telemedicine the safest interactive system between patients, both infected and uninfected, and clinicians. A few potential evidence-based scenarios for the application of telemedicine have been hypothesized. In particular, its use in diabetes and complication monitoring has been remarkably increasing, due to the high risk of poor prognosis. New evidence and technological improvements in telemedicine application in diabetic retinopathy (DR) have demonstrated efficacy and usefulness in screening. Moreover, despite an initial increase for devices and training costs, teleophthalmology demonstrated a good cost-to-efficacy ratio; however, no national screening program has yet focused on DR prevention and diagnosis. Lack of data during the COVID-19 pandemic strongly limits the possibility of tracing the real management of the disease, which is only conceivable from past evidence in normal conditions. The pandemic further stressed the importance of remote monitoring. However, the deployment of device and digital application used to increase screening of individuals and monitor progression of retinal disease needs to be easily accessible to general practitioners.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are closely associated, and liver fibrosis has been related to macrovascular complications. We examined whether liver fibrosis, diagnosed by FibroScan® , correlates with chronic vascular complications in a cohort of T2DM. METHODS: We recruited 394 outpatients with T2DM attending five Italian diabetes centres who underwent liver ultrasonography (US), FibroScan® and extensive evaluation of macrovascular and microvascular diabetic complications. RESULTS: Steatosis by US was present in 89%. Almost all patients (96%) were on hypoglycaemic drugs, 58% had at least one chronic vascular complication, 19% a macrovascular complication (prior myocardial infarction and/or ischaemic stroke) and 33% a microvascular one (26% chronic kidney disease [CKD]; 16% retinopathy; 6% neuropathy). In all, 171 (72%) patients had CAP ≥ 248dB/m (ie hepatic steatosis), whereas 83 (21%) patients had LSM ≥ 7.0/6.2 kPa (M/XL probes) (significant liver fibrosis). CAP was not associated with any macro/microvascular complications, whereas LSM ≥ 7.0/6.2 kPa was independently associated with prior cardiovascular disease (adjusted OR 3.3, 95%CI 1.2-8.8; P = .02) and presence of microvascular complications (adjusted OR 4.2, 95%CI 1.5-11.4; P = .005), mainly CKD (adjusted OR 3.6, 95%CI 1.3-10.1; P = .01) and retinopathy (adjusted OR 3.7, CI 95% 1.2-11.9; P = .02). Neither diabetes duration nor haemoglobin A1c differed according to CAP or LSM values. CONCLUSION: Significant fibrosis, detected by FibroScan® , is independently associated with increased prevalence of macrovascular and microvascular complications, thus opening a new scenario in the use of this tool for a comprehensive evaluation of hepatic and vascular complications in patients with T2DM.

Hepatitis C virus (HCV) infection is associated with extrahepatic manifestations, among these there is an increased risk of atherosclerosis and cardiovascular disease as well as an increased cardiovascular mortality. Several direct and indirect HCV pro-atherogenic mechanisms have been proposed. HCV lives and replicates within carotid plaques, promoting a local environment of pro-atherogenic factors. In addition, it causes conditions such as insulin resistance, diabetes, hepatic steatosis, cryoglobulinemia and endotoxinemia that are associated with the development of atherosclerosis and cardiovascular disease. Therapeutic regimens based on direct-acting antiviral agents (DAA) are currently available with high efficacy in HCV clearance and improvement of liver disease, but does HCV eradication also improve atherosclerosis and the risk of cardiovascular disease? Recently, a multi-center study has shown that elimination of HCV improves carotid atherosclerosis. Two studies have shown that DAA treatments significantly reduce the risk of cardiovascular events. Several studies have assessed the impact of HCV clearance on pro-atherosclerosis metabolic conditions showing improvement in cardiovascular risk biomarkers, disappearance or improvement of insulin resistance, reduction of risk of developing diabetes and improvement of glycemic control. There are also evidences that HCV clearance promotes the recovery of cytokines and inflammatory markers associated with atherosclerosis and the disappearance of cryoglobulinemia. Available data show that clearance of HCV by DAAs is associated with an improvement in atherosclerosis and metabolic and immunological conditions that promote the development of cardiovascular disease. However, the data are not sufficient to allow definitive conclusions and further studies will be needed to definitively clarify the impact of HCV clearance on atherosclerosis and cardiovascular disease.

Aims. This study is aimed at assessing the efficacy of an active search and treat strategy for HBV-infected subjects in an endemic area (Campania, Italy). To do this, we created a cooperation bundle between 24 General Practitioners (GPs) and 3 Hospital Liver Units (HLU). We assessed whether this strategy improved the detection of HBV infection in patients at risk and the overall quality of care, with the aim of reducing liver disease progression. Methods. We estimated that, among about 20,000 patients cared for by the 24 GPs, approximately 280 patients unaware of or underestimating HBV infection would be found. Identified patients were to be referred to the HLU for clinical evaluation and treatment from February 2016 for 12 months. Results. Unexpectedly, screening and enrolment were poor (48 patients only). GP workloads, patient financial difficulties, and patients' refusal were the major causes of enrolment failure according to GPs. All patients referred to HLU completed the program; most of them were HBV inactive carriers. Conclusions. This program failed to scavenge chronic HBV-infected patients in an endemic area and establish a successful clinical collaboration between GPs and HLU. Underlying reasons are diverse and call for new strategies to implement cooperation between primary care providers and hospital specialists.

In the last years new evidence has accumulated on nonalcoholic fatty liver disease (NAFLD) challenging the paradigms that had been holding the scene over the previous 30 years. NAFLD has such an epidemic prevalence as to make it impossible to screen general population looking for NAFLD cases. Conversely, focusing on those cohorts of individuals exposed to the highest risk of NAFLD could be a more rational approach. NAFLD, which can be diagnosed with either non-invasive strategies or through liver biopsy, is a pathogenically complex and clinically heterogeneous disease. The existence of metabolic as opposed to genetic-associated disease, notably including "lean NAFLD" has recently been recognized. Moreover, NAFLD is a systemic condition, featuring metabolic, cardiovascular and (hepatic/extra-hepatic) cancer risk. Among the clinico-laboratory features of NAFLD we discuss hyperuricemia, insulin resistance, atherosclerosis, gallstones, psoriasis and selected endocrine derangements. NAFLD is a precursor of type 2 diabetes (T2D) and metabolic syndrome and progressive liver disease develops in T2D patients in whom the course of disease is worsened by NAFLD. Finally, lifestyle changes and drug treatment options to be implemented in the individual patient are also critically discussed. In conclusion, this review emphasizes the new concepts on clinical and pathogenic heterogeneity of NAFLD, a systemic disorder with a multifactorial pathogenesis and protean clinical manifestations. It is highly prevalent in certain cohorts of individuals who are thus potentially amenable to selective screening strategies, intensive follow-up schedules for early identification of liver-related and extrahepatic complications and in whom earlier and more aggressive treatment schedules should be carried out whenever possible.

Aims: To assess the correlation between diabetic retinopathy (DR) and potential risk factors, as well as the relationship between DR and the other complications of diabetes, in a real-life population of type 2 diabetes patients recruited in several centres in Italy. Methods: The NO BLIND is a cross-sectional, multicentre, observational study, which involved nine public outpatient clinics in Italy. The patients were assessed for eligibility from November 2016 till November 2017. Those enrolled underwent standard fundus oculi exam. Clinical and laboratory data were also collected. Results: 2068 T2DM underwent fundus oculi exam. 435 received diagnosis of diabetic retinopathy (21%). Diabetic retinopathy was independently associated with HDL cholesterol (O.R.: 1.042; 95% C.I.: 1.012–1.109; p = 0.004), Albumin Excretion Rate (AER) (O.R.: 1.001; 95% C.I.: 1.000–1.002; p = 0.034) and GFR (O.R.: 1.159; 95% C.I.: 1.039–1.294; p = 0.008). HDL cholesterol values were hence split in two classes according to a potential cut-off (40 mg/dL), as defined by the ROC curve. Following analysis confirmed the association between DR and high HDL values (p = 0.032). Somatic neuropathy and diabetic ulcer were independently related with DR (p < 0.001 and p = 0.012, respectively). Conclusions: A novel relationship between high HDL cholesterol and DR was observed. © 2019 Elsevier B.V. Aims: To assess the correlation between diabetic retinopathy (DR) and potential risk factors, as well as the relationship between DR and the other complications of diabetes, in a real-life population of type 2 diabetes patients recruited in several centres in Italy. Methods: The NO BLIND is a cross-sectional, multicentre, observational study, which involved nine public outpatient clinics in Italy. The patients were assessed for eligibility from November 2016 till November 2017. Those enrolled underwent standard fundus oculi exam. Clinical and laboratory data were also collected. Results: 2068 T2DM underwent fundus oculi exam. 435 received diagnosis of diabetic retinopathy (21%). Diabetic retinopathy was independently associated with HDL cholesterol (O.R.: 1.042; 95% C.I.: 1.012–1.109; p = 0.004), Albumin Excretion Rate (AER) (O.R.: 1.001; 95% C.I.: 1.000–1.002; p = 0.034) and GFR (O.R.: 1.159; 95% C.I.: 1.039–1.294; p = 0.008). HDL cholesterol values were hence split in two classes according to a potential cut-off (40 mg/dL), as defined by the ROC curve. Following analysis confirmed the association between DR and high HDL values (p = 0.032). Somatic neuropathy and diabetic ulcer were independently related with DR (p < 0.001 and p = 0.012, respectively). Conclusions: A novel relationship between high HDL cholesterol and DR was observed.

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.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.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%).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.

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

Aims To evaluate whether CB2 variants are associated with the presence of immune-mediated disorders (IMDs) in patients with chronic HCV infection. Methods One hundred and sixty-eight anti-HCV/HCV-RNA-positive patients were enrolled, 81 with signs of IMDs and 87 without. In the IMDs group, 22 (27.2%) showed ANA positivity (titers ≥1:160), 3 (3.7%) SMA positivity (titers ≥1:160), 24 (29.6%) had cryoglobulinemia, 25 (30.9%) autoimmune thyroiditis, 4 (4.9%) psoriasis, 2 (2.5%) B-cell non-Hodgkin lymphoma and 1 (1.2%) autoimmune hemolytic anemia. All patients were screened for the CNR2 rs35761398 single nucleotide polymorphism using a TaqMan Assay. Results Compared with the 87 patients without IMDs, the 81 with IMDs were more frequently females (65% vs. 45%, p = 0.01), but no significant difference was found in the initial demographic, epidemiological, serological, biochemical or virological data. Instead, the prevalence of patients with the CB2-63 RR variant was significantly higher in the IMD than in the non-IMD group (49.4% vs. 24.1%, p = 0.001). A logistic regression analysis including the CB2-63 receptor (RR vs. QR or QQ), age and sex identified the CB2-63 RR as the only independent predictor of IMDs (p = 0.005). Conclusions The data suggest a significant, previously unknown, independent association between the CB2-63 RR variant and IMDs in anti-HCV-positive patients. The study was approved by the Ethics Committee of the Azienda Ospedaliera Universitaria of the Second University of Naples (n° 214/2012).

Objective The objective of the study is to investigate the prevalence of electrolyte imbalance (EI) in the emergency department (ED) with systemic diseases in different decades of life. Methods We enrolled patients admitted to the ED. The population study included 7941 patients, subdivided in 3 groups: young group (Y), middle-aged group (MA), and elderly group (E). Results We observed EI in 13.7% of the whole population. Hyponatremia (hNa+) is the most frequent EI (44%) followed by hypokalemia (hK+) (39%), hyperkalemia (HK+) (13%), and hypernatremia (HNa+) (4.4%). In the Y group, the EI occurred in 7.1% of all patients (P< .05 vs MA and E), whereas in the MA group, they were shown in 11.5% of patients and in the E group in 22% of all patients group (P< .05 vs MA and Y). In the Y group, gastrointestinal diseases are the most frequently associated disease (24.6%; P< .05 vs MA and E). In the MA group, the most frequently associated disease was a current cardiovascular disease (29.7%; P< .05 vs Y and E). In the E group, the frequently associated diseases are cardiovascular (22.8%; P< .05 vs Y) and lung diseases (16.7%; P< .05 vs MA and Y). Conclusions In our study, 13.7% of all patients showed an EI, and only 2% of cases were alone without any associated systemic disease. Most EIs are associated to other systemic diseases. The present data also depict different age-related and disease-associated prevalence patterns of EI, thus highlighting a complex clinical scenario. © 2016

International audience; Type 2 diabetes mellitus (T2DM) has been identified as an extrahepatic manifestation of chronic HCV infection. Conversely, in the context of chronic HCV infection, T2DM can accelerate the course of HCV-induced liver disease leading to increased risk of fibrosis, cirrhosis and hepatocellular carcinoma. The presence of T2DM negatively impacts the efficacy of interferon-based antiviral therapy, but real-world data with high-efficacy direct-acting antiviral therapies suggest high viral clearance rates in T2DM patients. In HCV-infected individuals, viral eradication is associated with a reduced risk of de novo T2DM in non-diabetic patients and beneficial metabolic changes in patients with T2DM, highlighting the importance of antiviral treatment and physician awareness of this association.

BACKGROUND AND AIM: Recent studies suggest an association between HCV infection and cardiovascular damage, including carotid atherosclerosis, with a possible effect of HCV clearance on cardiovascular outcomes. We aimed to examine whether HCV eradication by direct antiviral agents (DAA) improves carotid atherosclerosis in HCV-infected patients with advanced fibrosis/compensated cirrhosis. MATERIALS AND METHODS: One hundred eighty-two consecutive HCV patients with advanced fibrosis or compensated cirrhosis were evaluated by virological, anthropometric and metabolic measurements. All patients underwent DAA-based antiviral therapy according to AISF/EASL guidelines. Intima-media thickness (IMT), carotid thickening (IMT≥1 mm) and carotid plaques, defined as focal thickening of ≥ 1.5 mm at the level of common carotid, were evaluated by ultrasonography (US) at baseline and 9-12 months after the end of therapy. RESULTS: Fifty-six percent of patients were males, mean age was 63.1±10.4 years and 65.9% had compensated cirrhosis. One patient out of five had diabetes, 14.3% were obese, 41.8% had arterial hypertension and 35.2% were smokers. Mean IMT was 0.94±0.29 mm, 42.9% had IMT≥1 mm, and 42.9% had carotid plaques. All patients achieved a 12-weeks sustained virological response. IMT significantly decreased from baseline to follow-up (0.94±0.29 mm vs. 0.81±0.27, p

Chronic hepatitis C virus (HCV) infection has been associated with myriad extrahepatic manifestations, often resulting from aberrant immune responses. Among the most common immune-mediated manifestations of HCV infection, mixed cryoglobulinemia is the best known extra-hepatic complication. Areas covered: Here we review less common extrahepatic manifestations of HCV infection, with ascertained or presumed immune pathogenesis and the role of the new all oral direct-acting antiviral agents. Rheumatologic, dermatologic, ophthalmologic, renal, pulmonary, hematologic, cardiovascular, and neuropsychiatric manifestations of HCV infection have been considered. Expert commentary: Pathogenesis of HCV-induced aberrant immune responses resulting in peculiar clinical manifestations is not restricted to a single mechanism. A sound approach would therefore consider implementation of an etiologic treatment, through use of antiviral medications, to stop upstream in the pathogenic process all the immune mechanisms leading to hepatic and extrahepatic abnormalities. With the recent introduction of interferon-free, direct antiviral agents, capable of warranting cure for nearly all HCV-infected patients subjected to therapy, both common and uncommon extrahepatic manifestations of chronic hepatitis C are expected to no longer constitute a matter of comorbidity in the course of HCV infection.

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.

We investigated seasonal prevalence of hyponatremia in the emergency department (ED).A cross-sectional study using clinical chart review.University Hospital ED, with approximately 28 000 patient visits a year.We reviewed 15 049 patients, subdivided in 2 groups: the adult group consisting of 9822 patients aged between 18 and 64years old and the elderly group consisting of 5227 patients aged over 65years presenting to the ED between January 1st, 2014 and December 31st, 2015.Emergency patients were evaluated for the presence of hyponatremia by clinical chart review.Hyponatremia was defined as a serum sodium level135mmol/l. Mean monthly prevalence of hyponatremia was of 3.74±0.5% in the adult group and it was significantly increased to 10.3±0.7% in the elderly group (p0.05 vs adults). During the summer, hyponatremia prevalence was of 4.14±0.2% in adult and markedly increased to 12.52±0.7% (zenith) in elderly patients (p0.01 vs adult group; p0.05 vs other seasons in elderly group). In the elderly group, we reported a significant correlation between weather temperature and hyponatremia prevalence (r: 0.491; p0.05).We observed a major influence of climate on the prevalence of hyponatremia in the elderly in the ED. Decline in renal function, salt loss, reduced salt intake and increased water ingestion could all contribute to developing hyponatremia in elderly patients during the summer. These data could be useful for emergency physicians to prevent hot weather-induced hyponatremia in the elderly.

The purpose of this investigation was to evaluate the role of IL28-B polymorphism in the clearance of hepatitis C virus (HCV) in chronic hepatitis B virus (HBV)/HCV coinfection during a long-term follow-up. Thirty-four consecutive patients with HBV surface antigen (HBsAg)-positive/anti-HCV-positive chronic hepatitis were retrospectively enrolled at their first liver biopsy (LB). For all patients, a documented clinical, serological and virological follow-up of at least 3 years (range 3-16 years) after LB and a sample of whole blood for genetic evaluation were available. Of the 24 patients with detectable serum HBV-DNA and HCV-RNA at their first observation, three cleared both HBV-DNA and HCV-RNA, 12 HCV-RNA and five HBV-DNA. Of the seven HBV DNA-positive/HCV RNA-negative patients at enrolment, three cleared HBV-DNA and one remained HBV DNA-positive and became HCV RNA-positive. All three HBV DNA-negative/HCV RNA-positive patients remained unchanged. Compared with the 12 patients with HCV persistence, the 15 patients who cleared HCV were younger, had lower serum alanine aminotransferase (ALT), HCV load, and histological activity index (HAI) and fibrosis score, more frequently had IL28-B CC variant, had been receiving an interferon-based treatment and less frequently cleared serum HBV-DNA. To investigate the relationship between the IL28-B variants and clearance of HCV, excluding the confounding effect of interferon-based treatment, the Mantel-Haenszel test was used, which indicated an association between HCV clearance and IL28-B variants (p=0.009). In chronic HBV/HCV coinfection, a long-term follow-up showed a frequent spontaneous or treatment-related clearance of active replication of one or both viruses and identified the IL28-B CC genotype as an independent predictor of HCV clearance. © 2013 Springer-Verlag.

Steatosis is a complication of hepatitis C virus (HCV) infection and the mechanisms of its development are complex, involving viral and host factors. Steatosis that is prevalently viral is associated with HCV genotype 3, and steatosis that is prevalently metabolic is associated with non-3 genotypes. Viral steatosis is correlated with the level of HCV replication, whereas metabolic steatosis is related to insulin resistance. The two types of steatosis have a different impact on HCV disease and may have an additive effect. HCV infection is a multifaceted disease with hepatic and extrahepatic manifestations. There is a body of evidence indicating that HCV-related steatosis plays a role in many HCV manifestations and, thus, the presence of steatosis is a predictive factor for the development of such events. The current data show that HCV-related steatosis predicts an advanced liver disease and a more rapid progression of fibrosis, as well as an increased risk of development of hepatocellular carcinoma. Moreover, the presence of steatosis in a HCV patient has a high predictive value that the subject may have or may develop insulin resistance, diabetes and metabolic syndrome. Recently, a strict association between HCV-related steatosis and development of atherosclerosis has been demonstrated. In addition, steatosis negatively impacts response rate to interferon-based treatment, even in HCV genotype-3 infection. Therapeutic strategies to improve steatosis and, consequently, response to standard antiviral therapy and outcome of disease are wanted. The authors summarize current knowledge of impact of steatosis on the above reported clinical conditions associated with HCV infection.

SummaryAtrial fibrillation (AF) patients are at high risk for thrombotic and vascular events related to their cardiac arrhythmia and underlying systemic atherosclerosis. Ankle-Brachial Index (ABI) is a non-invasive tool in evaluating systemic atherosclerosis, useful in predicting cardiovascular events in general population; no data are available in AF patients. ARAPACIS is a prospective multicentre observational study performed by the Italian Society of Internal Medicine, analysing association between low ABI (≤0.90) and vascular events in NVAF out- or in-patients, enrolled in 136 Italian centres. A total of 2,027 non-valvular AF (NVAF) patients aged > 18 years from both sexes followed for a median time of 34.7 (interquartile range: 22.0–36.0) months, yielding a total of 4,614 patient-years of observation. Mean age was 73 ± 10 years old with 55% male patients. A total of 176 patients (8.7%) experienced a vascular event, with a cumulative incidence of 3.81%/patient-year. ABI≤ 0.90 was more prevalent in patients with a vascular event compared with patients free of vascular events (32.2 vs 20.2%, p< 0.05). On Cox proportional hazard analysis, ABI≤ 0.90 was an independent predictor of vascular events (hazard ratio (HR): 1.394, 95% confidence interval (CI): 1.042–1.866; p=0.02), vascular death (HR: 2.047, 95% CI: 1.255-3.338; p=0.004) and MI (HR: 2.709, 95%> CI: 1.485-5.083; p=0.001). This latter association was also confirmed after excluding patients with previous MI (HR: 2.901, 95% CI: 1.408-5.990, p=0.004). No association was observed between low ABI and stroke/transient ischaemic attack (p=0.91). In conclusion, low ABI is useful to predict MI and vascular death in NVAF patients and may independently facilitate cardiovascular risk assessment in NVAF patients.Note: The review process for this paper was fully handled by C. Weber, Editor in Chief.Listed in the Supplementary Online Appendix Material which is available online at www.thrombosis-online.com.

Our patient is a 42-year-old woman with muscle paralysis, muscle weakness, and fever. On admission, a neurologic examination showed proximal and distal weakness in the leg. Serum creatine phosphokinase and serum myoglobin level were markedly increased (5600 UI/L and 5197 UI/L, respectively). There was no sign of renal failure. Nerve conduction study was negative. Serologic studies for virus titers showed the antibody immunoglobulin M cytomegalovirus. Muscle weakness and its paralysis, fever, and serum creatine kinase level gradually improved after the administration of methylprednisolone intravenous. Cytomegalovirus infection was thought to have played a central role in this case, leading to an acute but reversible peripheral muscle paralysis.

OBJECTIVE: Carotid intima-media thickness (cIMT) is a surrogate marker of subclinical atherosclerosis and it is able to predict both coronary and cerebral vascular events. No data exist on the association between cIMT and non valvular atrial fibrillation (NVAF) type. We conduct this study with the aim to analyze the association between abnormal cIMT and NVAF type. METHODS: A cross-sectional study of the "Atrial fibrillation Registry for Ankle-brachial index Prevalence Assessment-Collaborative Italian Study (ARAPACIS)" has been performed. Among 2027 patients enrolled in the ARAPACIS, 673 patients, who underwent carotid ultrasound examination to assess cIMT, were included in the study. RESULTS: Among the entire population, 478 patients (71%) had cIMT > 0.90 mm. Patients with an abnormal cIMT (>0.90 mm) were significantly older and more likely hypertensive, diabetic and with a previous history of stroke than those with normal cIMT (≤0.90 mm). These patients had more permanent/persistent NVAF and CHA2DS2-VASc score ≥ 2 (p < 0.0001) compared to those with cIMT

Background & Aims: A common non-synonymous polymorphism, E167K, in transmembrane six superfamily member 2 (TM6SF2) gene has been recently associated with an increased hepatic triglyceride content, dyslipidemia and liver fibrosis in NAFLD patients. We investigated possible associations between the TM6SF2 variants and liver lesions in chronic hepatitis C. Patients and Methods: 148 consecutive patients with biopsy proven anti-HCV/HCV-RNA-positive chronic hepatitis, naive for antiviral therapy, were genotyped for TM6SF2 E167K and PNPLA3 I148M variants. Results: The score of liver steatosis was higher in the 18 patients with TM6SF2 E167K variant (mean 1.9 ± 1.3) than in the 130 homozygotes for TM6SF2 167E allele (1.1 ± 1.1, P = 0.02), and the prevalence of a steatosis score ≥ 3 was 33.3% vs. 12.3% respectively (P = 0.02). No difference in necroinflammatory or fibrosis scores was found between the two groups. A general linear model identified as independent predictors of steatosis TM6SF2 E167K and PNPLA3 M148M variants and waist circumference (P = 0.0376, P = 0.0069 and P = 0.0273 respectively). Conclusions: This is the first demonstration that TM6SF2 E167K variant is an independent predictor of liver steatosis in chronic hepatitis C. © 2015 John Wiley & Sons A/S

Summary Background Steatosis and insulin resistance (IR) have a pathogenic role in chronic hepatitis C (HCV). Adipocytokines balance modulates hepatic lipid content and IR. Aim To evaluate serum adipocytokines and relationship with virological, histological and metabolic parameters in chronic HCV. Methods Adiponectin and tumour necrosis factor-α (TNF-α) levels, HCV genotypes, HCV-RNA, IR (HOMA-IR), body mass index and liver steatosis and fibrosis were assessed in 161 non-diabetic chronic HCV patients. Results Chronic HCV patients with steatosis showed lower serum adiponectin levels and higher levels of TNF-α, HOMA, alanine aminotransferase, γ-glutamiltransferase and Histological Activity Index (HAI) and fibrosis scores. Low adiponectin levels were independently associated with grades of steatosis and HOMA-IR. Higher tumour necrosis factor-α levels were observed in patients with low adiponectin levels. The extension of steatosis was inversely correlated with adiponectin levels. A correlation between grade of steatosis with HOMA-IR and fibrosis was observed. HCV genotype 3-infected patients showed lower adiponectin levels than those with other genotypes. An independent predictor of low adiponectin levels in genotype 3 infection was the extension of steatosis. Liver fibrosis score was associated with steatosis, HAI and age. Conclusions Chronic HCV patients with steatosis showed a serum adiponectin/TNF-α imbalance that is associated with IR. Reduced adiponectin levels may be involved in the pathogenesis of steatosis, which in turn accelerates progression of fibrosis in chronic HCV.

Chronic hepatitis B is an important clinical problem often leading to severe complications. In this review, the results obtained in the last few years with the use of current drugs, such as interferon and nucleo(t)side analogues, are summarized and the problems of obtaining a sustained remission, which is only achieved in a small number of patients, are discussed. The new approaches, such as the use of combinations of drugs, to optimize long-term tolerable treatment are also considered.

Steatosis is a common feature of chronic hepatitis C, and may be caused directly by the virus, as in genotype 3 infection, or be associated with host metabolic factors. The interaction of hepatitis C virus core protein with the lipoprotein secretion pathways causes the characteristic alterations of lipid metabolism observed in hepatitis C virus-related steatosis. Several pathogenic mechanisms are likely involved into the pathogenesis of hepatitis C virus-related steatosis, including hyper-homocysteinaemia, hypoadiponectinaemia and insulin resistance. Steatosis is a major determinant of the liver damage progression in chronic hepatitis C (CHC), and negatively affects the response rate to the interferon (IFN)-based anti-viral treatment. Moreover, recent evidence suggests that steatosis may contribute to liver carcinogenesis. Chronic hepatitis C is a recognized risk factor for type 2 diabetes and it could be implicated into the pathogenesis of atherosclerosis. The role of hepatitis C virus (HCV)-related steatosis in these epidemiological associations remains to be determined.

The factors and mechanisms implicated in the development of hepatitis C virus (HCV)-related steatosis are unknown. Hyperhomocysteinemia causes steatosis, and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism induces hyperhomocysteinemia. We investigated the role of these factors in the development of HCV-related steatosis and in the progression of chronic hepatitis C (CHC). One hundred sixteen CHC patients were evaluated for HAI, fibrosis and steatosis grades, body mass index, HCV genotypes, HCV RNA levels, homocysteinemia, and the MTHFR C677T polymorphism. Hyperhomocysteinemia was associated with the TT genotype of MTHFR (r = 0.367; P = .001). Median values of homocysteine in the CC, CT, and TT genotypes of the MTHFR gene were 9.3, 12.2, and 18.6 μmol/L, respectively (P = .006). Steatosis correlated with the MTHFR polymorphism, homocysteinemia, HAI and fibrosis. Steatosis above 20% was significantly associated with fibrosis. Prevalence and high grade (>20%) of steatosis were 41% and 11% in CC, 61% and 49% in CT, and 79% and 64% in TT, respectively (P = .01). Relative risk of developing high levels of steatosis was 20 times higher for TT genotypes than CC genotypes. According to multivariate analysis, steatosis was independently associated with hyperhomocysteinemia (OR = 7.1), HAI (OR = 3.8), liver fibrosis (OR = 4.0), and HCV genotype 3 (OR = 4.6). On univariate analysis, fibrosis was associated with age, steatosis, MTHFR, homocysteinemia and HAI; however, on multivariate analysis, liver fibrosis was independently associated with age (P = .03), HAI (P = .0001), and steatosis (P = .007). In conclusion, a genetic background such as the MTHFR C677T polymorphism responsible for hyperhomocysteinemia plays a role in the development of higher degree of steatosis, which in turn accelerates the progression of liver fibrosis in CHC. (HEPATOLOGY 2005.)

Clinical and epidemiological characteristics of Streptococcus bovis endocarditis were prospectively studied among 199 patients with definite endocarditis. Thirty patients (15.1%) had S. bovis endocarditis. Compared with patients with non–S. bovis endocarditis, these 30 patients were older (mean age, 58.6*12.4 years vs. 46.0*17.0 years; P < .001) and had higher rates of bivalvular involvement (43.3% vs. 7.7%; P

Antibodies against envelope glycoprotein 1 and 2 (anti-E1/E2) have been suggested to influence HCV replication levels. Hepatitis B virus (HBV) may interfere with hepatitis C virus (HCV) replication. At present there are no data on anti-E1/E2 antibody responses or on the effect of interferon (IFN) treatment in HBV–HCV co-infection. Accordingly, we evaluated serum anti-E1/E2 antibodies in 50 patients (median age, 26.5; males, 30) with chronic hepatitis, 38 with HCV and 12 with HBV–HCV co-infection, who had undergone α-IFN treatment. Before starting IFN, the HCV group showed higher HCV-RNA levels (bDNA assay) than the HBV–HCV group (median 3.75 vs. 0.64 × 106 Eq/ml, respectively; P

The patatin-like phospholipase domain-containing 3 gene (PNPLA3) has been associated with liver steatosis and disease progression in nonalcoholic steatohepatitis and chronic hepatitis C.The aim of the present study was to evaluate the influence of the PNPLA3 I148M polymorphisms on the clinical, histological, viral, and host parameters in Italian patients with chronic hepatitis B (CHB).Ninety-nine patients with CHB entered the study and underwent a clinical, histological, virological, and biochemical evaluation. PNPLA3 (p.I148M) variants were genotyped.PNPLA3 rare variant (148M) was significantly associated with liver steatosis (p = 0.0019) and cholesterol (p = 0.04) levels, but not with fibrosis or histological activity index. The 13 patients with severe liver steatosis (score3) (38%) were more frequently homozygous for PNPLA3 148M variant than the 86 without (6%, p = 0.003). At logistic regression analysis, severe steatosis was independently associated with the rare allele (p = 0.001) and waist circumference, but not with body mass index (BMI).In our CHB patients, the PNPLA3 polymorphisms influenced the development of liver steatosis, but not fibrosis status. The association of PNPLA3 p.I148M with liver steatosis increased with the greater amount of abdominal fat, irrespective of BMI.

Background and aimTo evaluate in anti-HCV-positive patients the clinical impact of the rs35761398 variant of the CNR2 gene leading to the substitution of Gln (Q) of codon 63 of the cannabinoid receptor 2 (CB2) with Arg (R).Patients and methods253 consecutive anti-HCV-/HCV-RNA-positive patients were enrolled, of whom 53 were HCV carriers with persistently normal ALT (PNALT group) and 200 had a history of steadily abnormal serum ALT values (abnormal ALT group). All patients were naive for antiviral therapy and were screened for the CNR2 rs35761398 polymorphism by a TaqMan assay.ResultsSubjects in the PNALT group, compared with those in the abnormal ALT group were older (58.5±12 vs. 50.7±12.4 years, p = 0.001), more frequently female (66% vs. 42%, p = 0.003), with lower body mass index (BMI) (24.5±3.1 vs. 26.6±4.6, p = 0.003), and more frequently with HCV genotype 2 (43.1% vs 17.7%, p = 0.0002) and CB2-63 QQ variant (34% vs. 11%, p = 0.0001). Considering all 253 patients, no difference in the demographic, biochemical, or virological data was observed between patients in the different CB2-63 variants. The logistic regression analysis identified CB2-63 QQ, HCV genotype 2, older age and lower BMI as independent predictors of PNALT (pDiscussionThe CB2-63 QQ variant in HCV patients was independently associated with the PNALT status.

AIM: To evaluate steatosis, insulin resistance (IR) and patatin-like phospholipase domain-containing 3 (PNPLA3) and their relation to disease progression in hepatitis B and C viruses (HCV-HBV) co-infected patients. METHODS: Three hundred and thirty patients with biopsy proven chronic hepatitis were enrolled: 66 had HBV-HCV, 66 HBV and 198 HCV infection. Prevalence of steatosis, IR and PNPLA3 polymorphisms and their relation to anthropometric, biochemical, virological and histological parameters were evaluated. RESULTS: Prevalence of steatosis in group HBV-HCV was similar to that in HCV (47.0% vs 49.5%, respectively); group HBV showed the lowest steatosis (33.3%). Group HBV-HCV had a lesser degree of steatosis than HCV (P = 0.016), lower HCV RNA levels (P = 0.025) and lower prevalence and degree of IR (P = 0.01). PNPLA3 polymorphisms were associated with steatosis. Group HBV-HCV showed higher levels of liver fibrosis than group HCV (P = 0.001), but similar to that observed in HBV group. In HBV-HCV group, liver fibrosis was not associated with steatosis, IR or PNPLA3. HBV infection was the independent predictor of advanced liver fibrosis. CONCLUSION: HBV-HCV co-infected patients have lower degree of hepatic steatosis, IR and HCV RNA than HCV mono-infected; co-infected patients showed a more rapid liver fibrosis progression that seems to be due to the double infection and/or HBV dominance.

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.

We conducted a long-term prospective study of 89 cancer survivor children who had acquired hepatitis B virus (HBV) and/or hepatitis C virus (HCV) during treatment for neoplasia, the aim being to evaluate the natural history of the diseases and the effect of interferon (IFN) treatment. Patients were followed up for a median period of 13 years (range, 8 to 20); 46 were infected by HBV, 11 by HCV, and 32 coinfected by HBV and HCV. A spontaneous clearance of hepatitis B surface antigen (HBsAg) occurred more frequently in coinfected patients (19%) than in the HBV-infected (2%; P = .004), with an annual seroconversion rate of 2.1% and 0.2%, respectively (P= .008). Loss of hepatitis Be antigen (HBeAg) occurred in 44% of coinfected and in 28% of HBV-infected patients. Clearance of serum HCV-RNA was observed in 34% and 9%, respectively, of coinfected and HCV-infected patients. Seventeen HBV-infected, 4 HCV-infected, and 16 coinfected patients received -IFN treatment. In the HBV group, 6 patients (35%) cleared serum HBV DNA and seroconverted to anti-HBe; in the HCV-group, none cleared HCV-RNA. In the coinfected group, 1 patient cleared both HBV DNA and HCV-RNA, 6 patients cleared serum HCV-RNA alone, and 1 only HBV DNA and HBeAg. Overall, the diseases showed a mild histological course with no evidence of liver cirrhosis. A reciprocal interference on viral replication between HBV and HCV may occur in coinfected patients. Treatment seems to be effective for selected cases and is justified in view of the uncertain prognosis of the disease in these patients.

OBJECTIVE To evaluate the efficacy of a long-term course of alpha-interferon (alpha-IFN) in the treatment of HCV-related mixed cryoglobulinaemia and to determine the impact of cryoglobulinaemia on therapeutic response to IFN in chronic hepatitis C (CHC) patients. DESIGN Prospective controlled study. SETTING University Medical Centre. PARTICIPANTS Ninety consecutive CHC patients, 50 with cryoglobulinaemia (25 symptomatic and 25 asymptomatic; median cryocrit, 8%; chronic persistent hepatitis (CPH) 7, chronic active hepatitis (CAH) 27, cirrhosis 16) and 40 without cryoglobulinaemia (CPH 6, CAH 20, cirrhosis 14). HCV genotypes in the cryoglobulinaemic and non-cryoglobulinaemic groups were: 1b 40% and 45%; 2a 40% and 30%; others 20% and 25%, respectively. INTERVENTIONS Twelve-month course of alpha-IFN 2a, 3 MU, three times weekly. MAIN OUTCOME MEASURES Disappearance of cryoglobulinaemia and related syndrome, clearance of serum HCV RNA and normalization serum transaminase levels at the end of treatment (response) and after 12 months follow-up (sustained response). RESULTS Overall, cryoglobulinaemic patients showed a similar response to IFN to those without cryoglobulinaemia (44% vs. 42.5%, respectively). In the cryoglobulinaemic group, symptomatic patients showed a lower response rate than asymptomatic patients (28% vs. 60%, respectively; P

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.

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.

Chronic hepatitis C (HCV) infection is considered a metabolic disease. It is associated with a specific metabolic syndrome, HCV-associated dysmetabolic syndrome (HCADS), consisting of steatosis, hypocholesterolemia and insulin resistance/diabetes. These metabolic derangements contribute to a decrease in sustained virological response (SVR) to pegylated-interferon-α-ribavirin as standard of care (SOC), and are associated with progression of liver fibrosis.The review, highlighting the impact of HCADS and metabolic syndrome components of HCV disease progression and SOC, discusses current knowledge and perspectives on metabolic therapeutic strategies aimed at improving SVR rate of SOC for chronic hepatitis C.HCV, features of HCADS and of metabolic syndrome may coexist in the same patient, thus all components of the metabolic syndrome must be assessed to individualize treatment. The results of therapeutic trials evaluating metabolic strategies combined with current SOC indicate that weight loss is a critical part of treatment which will improve both disease outcome and therapeutic response to SOC. Similarly, statins seem to improve response rate to SOC representing, once confirmed to be safe, an important therapeutic tool for HCV-infected patients. Findings from studies using insulin sensitizers combined with SOC are not conclusive and do not justify the use of this class of drugs in clinical practice.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) and chronic hepatitis C feature steatosis and insulin resistance (IR), conditions associated with the metabolic syndrome (MS).OBJECTIVES: To assess the prevalence of MS and determinants of IR in patients with NAFLD and chronic hepatitis C.METHODS: Ninety-three consecutive patients with NAFLD, 97 with chronic hepatitis C virus (HCV) genotypes 1 and 2, and 182 ‘healthy’ controls without steatosis were enrolled in the present study. The prevalence of MS was assessed by modified Adult Treatment Panel III criteria and IR by the homeostasis model assessment of insulin resistance (HOMA-IR). IR was defined as the 75th percentile of the HOMA-IR of control subjects.RESULTS: While the prevalence of IR was similar in NAFLD and HCV-infected subjects (70.0% and 78.7%, respectively), the prevalence of MS was significantly higher in NAFLD patients than in HCV-infected patients (27.9% versus 4.1%) and in controls (5.6%). With multivariate analysis, IR was predicted by body mass index (OR 1.263; 95% CI 1.078 to 1.480) and triglyceridemia (OR 1.011; 95% CI 1.002 to 1.020) in NAFLD and by sex (OR for female sex 0.297; 95% CI 0.094 to 0.940) and fibrosis stage (OR 2.751; 95% CI 1.417 to 5.340) in chronic hepatitis C.CONCLUSIONS: IR is independently associated with body mass index and triglyceridemia in NAFLD, sex and fibrosis in chronic HCV infection, and has a higher prevalence in NAFLD and chronic hepatitis C than in controls. However, the frequency of MS in HCV-infected patients, similar to that of controls, is significantly lower than that seen in NAFLD patients. The current diagnostic criteria of MS are more likely to ‘capture’ patients with NAFLD than with chronic hepatitis C, although both groups are insulin resistant.

Background. Analysis of hepatitis C virus (HCV) RNA kinetics during antiviral therapy may allow estimation of the probability of response. Methods. To assess clinical and virological correlates and the predictive value of first-phase HCV RNA kinetics during pegylated interferon and ribavirin treatment, we studied 119 patients with chronic hepatitis C who were treated with pegylated interferon and ribavirin. HCV RNA level was measured 5 min before and 2, 14, and 28 days after the start of treatment. For each patient the Delta((t0-t2)) log(10) HCV RNA value was calculated, which indicates the relative reduction in HCV RNA level from before treatment to day 2 after logarithmic transformation. Results. A Delta((t0-t2)) log(10) HCV RNA value 2.5 had a 93% positive predictive value for virological response, independent of genotype and histology. The Delta((t0-t2)) log(10) HCV RNA value was strictly related to final treatment outcome and could differentiate not only patients with a sustained virological response from nonresponders but also patients who experienced relapse from the former. The Delta((t0-t2)) log(10) HCV RNA value was highest among patients infected with genotypes 2 and 3 and was lowest among patients infected with genotype 1. It decreased with increasing grades of fibrosis and steatosis and was also inversely related to gamma-glutamyl transpeptidase (GGT) level and HOMA-IR (homeostasis model assessment for insulin resistance) score. In multivariate analysis, Delta((t0-t2)) log(10) HCV RNA value was the strongest predictor of sustained virological response and appeared to be independently related to viral genotype and GGT level. Conclusion. HCV RNA kinetics has strong predictive value. It correlates with virological and clinical parameters that are known predictors of antiviral treatment outcome, including insulin resistance. The measurement of HCV load as early as 2 days after the start of pegylated interferon and ribavirin is a useful tool for the prediction of treatment outcome in individual patients and should be used in clinical practice.