F. Donato

Y chromosome loss in male patients with primary biliary cirrhosis.

Sex chromosome abnormalities have been advocated to be involved in the striking female prevalence of primary biliary cirrhosis (PBC) and women with PBC manifest an increased X chromosome loss in peripheral blood mononuclear cells compared to age-matched healthy women. Our knowledge of the etiopathogenesis of autoimmunity in male patients remains, however, limited. Next to the possible role of androgens and their imbalances, the Y chromosome appears as a potential candidate for influence of the immune function in men. Herein we analyzed a population of male patients with primary biliary cirrhosis (n = 26) and healthy controls (n = 88) to define a potential association of disease and the loss of the Y chromosome. We demonstrate that Y chromosome loss indeed is higher in PBC males compared to healthy controls, and this phenomenon increases with aging. We were, thus, able to confirm the existence of an analogous mechanism in the male population to previously identified X haploinsufficiency in female patients with organ-specific autoimmune disease. We propose that this commonality might represent a relevant feature in the etiopathogenesis of autoimmune diseases that should be further investigated.

Practice guidelines for the treatment of hepatitis C: Recommendations from an AISF/SIMIT/SIMAST expert opinion meeting

It is increasingly clear that a tailored therapeutic approach to patients with hepatitis C virus infection is needed. Success rates in difficult to treat and low-responsive hepatitis C virus patients are not completely satisfactory, and there is the need to optimise treatment duration and intensity in patients with the highest likelihood of response. In addition, the management of special patient categories originally excluded from phase III registration trials needs to be critically re-evaluated. This article reports the recommendations for the treatment of hepatitis C virus infection on an individual basis, drafted by experts of three scientific societies.

Reappraisal of surgical treatment of small hepatocellular carcinomas in cirrhosis: clinicopathological study of resection or transplantation.

Thirty-two patients with hepatocellular carcinoma (HCC) occurring in individuals with cirrhosis had a potentially curative surgical procedure. Twenty-two had segmental hepatic resections (HR), and 10 underwent orthotopic liver transplantation (OLTx). The diagnosis of hepatic malignancy was established in each case preoperatively, and each case was studied intraoperatively by means of sonography. Postoperatively each surgical specimen was examined pathologically with attention to the possibility of intrahepatic tumor spread. Twenty-three of the 32 patients had single small HCC lesion (<5 cm diameter) identified preoperatively. Sixteen of these underwent HR and seven underwent OLTx. Multiple additional neoplastic lesions were found in 19% of the 16 HR cases and in 14% of those undergoing OLTx when the resection specimens were examined pathologically. Vascular invasion was present in 43% of the OLTx patients and in 25% of the HR patients. Subtotal hepatic resection for small HCC occurring in cirrhosis has produced few long-term survivals. Both pre- and intraoperative sonography have been shown to underestimate the extent and distribution of these tumors. Based upon this experience that (1) vascular spread occurs often in HCC and (2) a high risk of postoperative hepatic failure can be expected after HR in cirrhotic individuals, OLTx is the most rational surgical procedure for such cases as it has the potential to cure.

Treatment of hepatitis C-related kidney disease

Introduction: Hepatitis C virus (HCV) infection has been associated with a large spectrum of glomerular lesions in both native and transplanted kidneys. The most common HCV-associated renal disease is type I membranoproliferative glomerulonephritis usually, but not invariably, in the context of type II mixed cryoglobulinemia (MC). HCV infection is also the major cause of MC, a systemic vasculitis characterized by involvement of small and, less frequently, medium-sized vessels. Conflicting data exist on the treatment of HCV-associated glomerular disease. Areas covered: This review examines the drugs used for management of HCV-related kidney disease and discusses current and new strategies. All literature concerning treatment of HCV-associated kidney disease has been retrieved by electronic (Medline) and manual searches. Expert opinion: Various approaches have been recommended for the treatment of HCV-related glomerular disease, including immunosuppressive therapy (corticosteroids, cytotoxic agents and mAbs) and antiviral therapy. These regimens should be considered according to the level or proteinuria and kidney failure. Immunosuppressive agents are recommended in patients with nephrotic syndrome and/or rapidly progressive kidney failure. Antiviral treatment based on IFN and/or ribavirin or triple antiviral therapy (PEGylated-IFN/ribavirin/telaprevir or boceprevir) has been adopted in patients with moderate proteinuria and slow loss of kidney failure; however, the number of patients enrolled was small. Some patients with HCV-related cryoglobulinemic glomerulonephritis have been treated with rituximab but some issues about its role remain to be clarified. The antiviral treatment of HCV-related glomerular disease is expected to improve in the near future with new agents provided with greater efficacy and safety. However, the affordability of these drugs remains a pivotal issue, particularly in low-income countries.

Association between hepatitis B virus and chronic kidney disease: A systematic review and meta-analysis

BACKGROUND Hepatitis B virus infection and chronic kidney disease are prevalent and remain a major public health problem worldwide. It remains unclear how infection with hepatitis B virus impacts on the development and progression of chronic kidney disease. AIM To evaluate the effect of infection with HBV on the risk of chronic kidney disease in the general population. MATERIAL AND METHODS We conducted a systematic review of the published medical literature to determine if hepatitis B infection is associated with increased likelihood of chronic kidney disease. We used the random effects model of DerSimonian and Laird to generate a summary estimate of the relative risk for chronic kidney disease (defined by reduced glomerular filtration rate and/or detectable proteinu-ria) with hepatitis B virus across the published studies. Meta-regression and stratified analysis were also conducted. RESULTS We identified 16 studies (n = 394,664 patients) and separate meta-analyses were performed according to the outcome. The subset of longitudinal studies addressing ESRD (n = 2; n = 91,656) gave a pooled aHR 3.87 (95% CI, 1.48; 6.25, P 0 0.0001) among HBV-in-fected patients and no heterogeneity was recorded. In meta-regression, we noted the impact of male (P = 0.006) and duration of follow-up (P = 0.007) upon the adjusted hazard ratio of incidence of chronic kidney disease (including end-stage renal disease). No relationship occurred between HBV positive status and prevalent chronic disease (n = 7, n = 109,889 unique patients); adjusted odds ratio, were 1.07 (95% CI, 0.89; 1.25) and 0.93 (95% CI, 0.76; 1.10), respectively. CONCLUSIONS HBV infection is possibly associated with a risk of developing reduced glomerular filtration rate in the general population; no link between HBV sero-positive status and frequency of chronic kidney disease or proteinuria was noted in cross-sectional surveys.

Recipient female gender is a risk factor for graft loss after liver transplantation for chronic hepatitis C: Evidence from the prospective Liver Match cohort.

BACKGROUND Female gender has been reported to be a risk factor for graft loss after liver transplantation for hepatitis C virus (HCV)-related cirrhosis but evidence is limited to retrospective studies. AIMS To investigate the impact of recipient gender and donor/recipient gender mismatch on graft outcome. METHODS We performed a survival analysis of a cohort of 1530 first adult transplants enrolled consecutively in Italy between 2007 and 2009 and followed prospectively. After excluding possible confounding factors (fulminant hepatitis, human immunodeficiency virus co-infection, non-viremic anti-HCV positive subjects), a total of 1394 transplant recipients (604 HCV-positive and 790 HCV-negative) were included. RESULTS Five-year graft survival was significantly reduced in HCV-positive patients (64% vs 76%, p=0.0002); Cox analysis identified recipient female gender (HR=1.44, 95% CI 1.03-2.00, p=0.0319), Mayo clinic End stage Liver Disease score (every 10 units, HR=1.25, 95% CI 1.03-1.50; p=0.022), portal thrombosis (HR=2.40, 95% CI 1.20-4.79, p=0.0134) and donor age (every 10 years, HR=1.14, 95% CI 1.05-1.24, p=0.0024) as independent determinants of graft loss. All additional mortality observed among female recipients was attributable to severe HCV recurrence. CONCLUSIONS This study unequivocally shows that recipient female gender unfavourably affects the outcome of HCV-infected liver grafts.

Cost-effectiveness of pretransplant sofosbuvir for preventing recurrent hepatitis C virus infection after liver transplantation.

There are reports of pretransplant sofosbuvir (SOF) plus ribavirin being effective in preventing recurrent hepatitis C virus (HCV) infection after liver transplantation (LT). The aim of this study was to assess the cost‐effectiveness of this strategy in the area served by the North Italy Transplant program. We retrospectively assessed the impact of HCV infection on post‐LT survival in 2376 consecutive adult patients (MELD ≤ 25, unknown genotype, period 2004–2009) and the prevalence costs of conventional standard of care (SOC) antiviral therapy (pegylated interferon plus ribavirin) after LT. A Markov model was developed to compare two strategies: 12–24 weeks of SOF+ ribavirin for pre‐LT anti‐HCV treatment versus on‐demand post‐LT SOC antiviral therapy. Among the 1794 patients undergoing LT, 860 (48%) were HCV+ and 50% of them were given SOC therapy after LT (mean cost of drugs and adverse effect management = 14 421€ per patient). HCV etiology had a strong impact on post‐LT survival (hazard ratio = 1.59, 95% CI = 1.22–2.09, P = 0.0007). After Monte Carlo simulation, pre‐LT SOF therapy showed a median survival benefit of 1.5 quality‐adjusted life years and an Incremental cost‐effectiveness ratio (ICER) of 30 663€/QALY, proving cost‐effective in our particular Italian scenario. The costs of SOF therapy, sustained viral response rate 12 weeks after LT, and recipients age were the main ICER predictors at multivariate analysis. This study proposes a dynamic model based on real‐life data from northern Italy for adjusting the costs of pre‐LT direct‐acting antiviral therapies to the actual sustained virological response reached after LT.

Early and late de novo tumors after liver transplantation in adults: the late onset of bladder tumors in men.

Background De novo tumors (DNT) after liver transplantation (LT) represent a growing concern. Patients and Methods We analyzed the incidence of DNT, type, time of onset, risk factors and mortality (as of 2010) in 494 adult patients transplanted in the last 26 years (1983–2009). Results DNT occurred in 41 (8.3%) of the patients. The Standardized Incidence Ratio (SIR) compared with the Italian population was 1.8. There was a higher incidence in males (SIR 2.0), an expected extremely high rate of Kaposi’s sarcoma (SIR 127.95) and unexpected higher rates of tumors of the bladder in males (SIR 3.3). The incidence of DNT was higher within the first two years of LT (SIR 2.7) for Kaposi’s sarcoma (SIR 393.3) and after 10 years (SIR 1.7) for bladder tumors (SIR 10.6). Multivariate analysis identified alcoholic cirrhosis (HR = 3.0, 95% CI = 1.2–7.8) and sclerosing cholangitis (HR = 3.5, 95% CI = 1.1–11.3) in the recipient as main risk factors for the occurrence of DNT. Conclusions Surveillance protocols for DNT must be specifically oriented to patients transplanted for alcoholic cirrhosis and sclerosing cholangitis. They should focus on early detection of Kaposi’s sarcomas, and more remarkably, on late development bladder tumors in men after LT.

Direct-acting antivirals for hepatitis C virus in patients on maintenance dialysis

The frequency of hepatitis C virus (HCV) infection remains high in patients with chronic kidney disease (CKD) and plays a detrimental role in mortality in this population. According to the latest survey, the adjusted hazard ratio for HCV-positive versus HCV-negative patients on long-term dialysis was 1.12 (95% CI, 1.05 to 1.20) and 1.10 (95% CI, 0.98 to 1.22) for all-cause and cardiovascular mortality, respectively. An impairment on quality of life has also been documented in HCV-infected patients undergoing regular dialysis. Most clinicians have been so far reluctant to treat hepatitis C in patients with advanced CKD, due to concerns regarding low efficacy and safety of interferon-based regimens. The advent of all-oral, direct-acting antivirals (DAAs) has revolutionized treatment paradigms for HCV, including patients with other comorbidities such as CKD. Two combinations of DAAs have been recently approved for the treatment of HCV in advanced CKD: elbasvir/grazoprevir (evaluated in 1 randomized controlled trial) and ombitasvir/paritaprevir/ritonavir/dasabuvir with or without ribavirin (examined in some observational, single-arm studies). These antiviral combinations have provided high safety and efficacy (SVR12 rates >90%) in HCV-infected patients with stage 4–5 CKD. Sofosbuvir, a nucleotide analogue inhibitor of the HCV NS5B polymerase, is the cornerstone of most anti-HCV current regimens but is not currently recommended for patients with severe renal insufficiency (eGFR <30 mL/min per 1.73 m2). However, several small-sized studies have been published on the safety and efficacy of sofosbuvir-based regimens for patients with hepatitis C on maintenance dialysis>; overall, the viral response was satisfactory (SVR12 rates ranging between 58% and 100%) with a few drug-related drop-outs. Studies are in progress to assess whether ribavirin-free antiviral combinations with novel DAAs are a viable option for patients with severe renal impairment and chronic HCV infection.

Hepatitis C and its metabolic complications in kidney disease

INTRODUCTION Evidence has been accumulated during the last decade showing that HCV infection plays an important activity at hepatic and extra-hepatic level. Chronic HCV is associated with a large spectrum of extra-hepatic manifestations including lympho-proliferative diseases and metabolic abnormalities (such as insulin resistance and fatty liver disease). MATERIAL AND METHODS We have performed an extensive review of the medical literature regarding the increased risk of cardiovascular and kidney disease that has been observed in various groups of HCV-infected patients. The potential link between such increased risk and the metabolic consequences of chronic HCV infection has been explored. RESULTS According to a systematic review with a meta-analysis of longitudinal studies (n = 9 clinical observational studies; n = 1,947,034 unique patients), we found a strong relationship between positive anti-HCV serologic status and increased incidence of chronic kidney disease in the adult general population, the summary estimate for adjusted hazard ratio was 1.43 (95% confidence intervals, 1.23; 1.63, P = 0.0001) (random-effects model) in anti-HCV positive patients. In another meta-analysis of clinical observational studies (n = 145,608 unique patients on long term dialysis; n = 14 observational studies), anti-HCV sero-positive status was an independent and significant risk factor for death in patients on maintenance dialysis. The summary estimate for adjusted relative risk (all-cause mortality) was 1.35 with a 95% confidence interval (CI) of 1.25; 1.47 (P < 0.01) in anti-HCV positive patients on maintenance dialysis. An updated and stratified analysis (n = 4 studies, n = 91,916 patients on maintenance dialysis) resulted in an adjusted HR for cardiovascular mortality among anti-HCV positive patients of 1.21 (95% CI, 1.06; 1.39) (P < 0.01); the homogeneity assumption was not rejected. The mechanisms underlying such relationships remain unclear; it has been suggested that HCV promotes atherogenesis through direct and indirect mechanisms. CONCLUSIONS Clinical trials are under way to assess whether the clearance of HCV RNA from serum by direct-acting antiviral drugs reduces all cause or disease-specific (cardiovascular) mortality among patients on maintenance dialysis.INTRODUCTION Evidence has been accumulated during the last decade showing that HCV infection plays an important activity at hepatic and extra-hepatic level. Chronic HCV is associated with a large spectrum of extra-hepatic manifestations including lympho-pro-liferative diseases and metabolic abnormalities (such as insulin resistance and fatty liver disease). MATERIAL AND METHODS We have performed an extensive review of the medical literature regarding the increased risk of cardiovascular and kidney disease that has been observed in various groups of HCV-infected patients. The potential link between such increased risk and the metabolic consequences of chronic HCV infection has been explored. RESULTS According to a systematic review with a meta-analysis of longitudinal studies (n = 9 clinical observational studies; n = 1,947,034 unique patients), we found a strong relationship between positive anti-HCV serologic status and increased incidence of chronic kidney disease in the adult general population, the summary estimate for adjusted hazard ratio was 1.43 (95% confidence intervals, 1.23; 1.63, P = 0.0001) (random-effects model) in anti-HCV positive patients. In another meta-analysis of clinical observational studies (n = 145,608 unique patients on long term dialysis; n = 14 observational studies), anti-HCV sero-positive status was an independent and significant risk factor for death in patients on maintenance dialysis. The summary estimate for adjusted relative risk (all-cause mortality) was 1.35 with a 95% confidence interval (CI) of 1.25; 1.47 (P < 0.01) in anti-HCV positive patients on maintenance dialysis. An updated and stratified analysis (n = 4 studies, n = 91,916 patients on maintenance dialysis) resulted in an adjusted HR for cardiovascular mortality among anti-HCV positive patients of 1.21 (95% CI, 1.06; 1.39) (P < 0.01); the homogeneity assumption was not rejected. The mechanisms underlying such relationships remain unclear; it has been suggested that HCV promotes atherogenesis through direct and indirect mechanisms. CONCLUSIONS Clinical trials are under way to assess whether the clearance of HCV RNA from serum by direct-acting antiviral drugs reduces all-cause or disease-specific (cardiovascular) mortality among patients on maintenance dialysis.