Beneficial effects of DAAs on cardiac function and structure in hepatitis C patients with low-moderate liver fibrosis.

Hepatitis C virus (HCV)-related chronic infection has been associated with a higher incidence of cardiovascular diseases. An altered morphology and function of both left and right heart have been described in HCV patients; however, the causality of the association is still debated. Ninety-eight nonobese and nondiabetic HCV patients (59.5 ± 12.0 years; males 52%) with Fibroscan-Transient Elastography assessed low-moderate liver fibrosis that achieved sustained viral response at 12 and 24 weeks after DAAs (direct-acting antivirals) participated. 56 were matched with 52 control subjects for age, sex and cardiovascular risk factors at baseline. A trans-thoracic echocardiography was performed in each subject at baseline (T0) and repeated in all HCV patients after eradication (6 months later eligibility, T1). TNF-α and IL-10 were measured at baseline and at T1. A concentric remodelling of the left heart in HCV participants was identified, whereas tricuspidal annular plane systolic excursion, right indexed atrial volume, right basal ventricular diameter, inferior vena cava diameter and pulmonary arterial pressure were higher in HCV participants compared to matched controls. After virus eradication, left indexed atrial volume and all right cardiac chambers measures were lower than baseline. A significant reduction of TNF-α was shown at T1, while IL-10 did not change. This study shows a concentric remodelling of the left ventricle and structural modifications in the right sections in HCV patients compared to controls. Virus eradication with DAAs was associated with a reduction of the main right atrioventricular parameters indicating a direct involvement of the HCV in cardiac changes.

Newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with DAAs: A prospective population study.

BACKGROUND & AIMS: Direct-acting antiviral agents (DAAs) are safe and effective in patients with hepatitis C. Conflicting data were reported on the risk of hepatocellular carcinoma (HCC) during/after therapy with DAAs. The aim of this study was to evaluate the incidence of newly diagnosed HCC and associated risk factors in patients with advanced hepatitis C treated with DAAs. METHODS: The study is based on the NAVIGATORE platform, a prospectively recording database of all patients with hepatitis C receiving DAAs in the Veneto region of Italy. The inclusion criteria were: fibrosis stage ≥F3. The exclusion criteria were: Child-Turcotte-Pugh (CTP)-C, liver transplantation before DAAs, history or presence of HCC, follow-up <4 weeks after starting DAAs. A total of 3,917 out of 4,234 consecutive patients were included, with a mean follow-up of 536.2 ±â€¯197.6 days. RESULTS: Overall, HCC was diagnosed in 55 patients. During the first year, HCC incidence was 0.46% (95% CI 0.12-1.17) in F3, 1.49% (1.03-2.08) in CTP-A and 3.61% (1.86-6.31) in CTP-B cirrhotics; in the second year, HCC incidences were 0%, 0.2%, and 0.69%, respectively. By multivariate analysis, HCC was significantly associated with an aspartate aminotransferase to platelet ratio ≥2.5 (hazard ratio [HR] 2.03; 95% CI 1.14-3.61; p = 0.016) and hepatitis B virus infection (HR 3.99; 1.24-12.91; p = 0.021). Failure to achieve a sustained virological response was strongly associated with development of HCC (HR 9.09; 5.2-16.1; p = 0.0001). A total of 29% of patients with HCC had an aggressive tumor, often seen in the early phase of treatment. CONCLUSIONS: These data, obtained in a large, prospective, population-based study, indicate that in patients with advanced hepatitis C receiving DAAs, the risk of "de novo" hepatocarcinoma during the first year is not higher, and might be lower, than that of untreated patients. The risk further declines thereafter. Early hepatocarcinoma appearance may reflect pre-existing, microscopic, undetectable tumors. LAY SUMMARY: Hepatocellular carcinoma is one of the complications of hepatitis C related cirrhosis. Treating patients with advanced hepatitis C with the new interferon-free direct-acting antiviral agents has been associated with improvement in liver function and survival, while more conflicting data have been reported regarding the risk of hepatocellular carcinoma. We report the results of a prospective population study on the incidence of newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with direct-acting antiviral agents, clearly indicating that the residual hepatocellular carcinoma risk is reduced and declines progressively with time after a sustained virological response. Development of a liver tumor during/after therapy was associated with known risk factors and with virological failure.

Relationship between ABO blood group and von Willebrand factor levels: from biology to clinical implications.

Although a number of studies have demonstrated the influence of ABO blood group on plasma levels of von Willebrand factor (VWF), the nature of this association and its clinical importance is still largely unknown.In this review, the most recent advances in our understanding of the mechanisms by which ABO blood group determines plasma VWF levels and their clinical impact will be discussed.

[Hepatitis C in hemophiliacs]. / L'epatite C negli emofilici.

Hepatitis C virus (HCV) infection is an important cause of morbidity and mortality in patients with hereditary bleeding disorders treated with non virus inactivated clotting factor concentrates during the 1970s. In this article, we briefly report the actual knowledge about HCV infection in hemophiliacs, by analyzing the prevalence of HCV infection, the genotype distribution, the natural history of the infection and the most important factors involved in the progression of chronic hepatitis into liver cirrhosis, hepatic decompensation and hepatocellular carcinoma. Finally, we describe the main advances in the treatment of HCV infection.

Altered intestinal function precedes the appearance of bacterial DNA in serum and ascites in patients with cirrhosis: a pilot study.

OBJECTIVES: Bacterial translocation seems to precede the occurrence of overt bacterial infection in patients with cirrhosis. The presence of bacterial DNA in blood and ascites correlates with bacterial translocation and is frequent in patients with advanced cirrhosis without overt infection. Our aim was to search for bacterial DNA in patients with cirrhosis both with and without ascites, and to study its correlation with abnormal intestinal motility or permeability and the presence of bacterial overgrowth. METHODS: Blood and ascites samples were obtained on day 1, and blood samples were taken twice a day for the following 3 days. Bacterial DNA was assayed by polymerase chain reaction using universal primers for rRNA 16 s. Oro-caecal transit time and bacterial overgrowth were assessed with Lactulose H(2) breath testing. Intestinal permeability was assessed by determining urinary lactulose and mannitol excretion with high performance liquid chromatography. RESULTS: We studied seven patients (six were male, age range was 42-78 years). Aetiology was alcohol in four, HCV in two, HBV in one; ascites was present in four and Child-Pugh grade was A in four and B in three. All patients had increased intestinal permeability, six had decreased transit time and one had bacterial overgrowth. In only one patient (with ascites), polymerase chain reaction was positive for bacterial DNA both in ascites and serum for all 4 days on which samples were taken. CONCLUSION: Increased intestinal permeability and abnormal motility were frequent without evidence of bacterial translocation in cirrhosis even without ascites. They are likely to be facilitators for bacterial translocation and thus precede it.

Is liver resection justified in advanced hepatocellular carcinoma? Results of an observational study in 464 patients.

BACKGROUND AND OBJECTIVE: The role of liver resection in advanced hepatocellular carcinoma (multinodular or with macroscopic vascular involvement) is still controversial. The aim of this study is to evaluate the role of surgical resection compared to other therapeutic modalities in patients with advanced hepatocellular carcinoma (HCC). METHODS: Four hundred sixty four patients with HCC observed from 1991 to 2007 were included in the study. All the patients were evaluated for the treatment of HCC in relation to the severity of liver impairment and tumor stage. All the patients included in the study had no evidence of distant metastases. RESULTS: Median follow up time for surviving patients was 25 months (range 1-155). Two-hundred and eighty-three patients were in Child-Pugh class A, 161 in class B, and 20 in class C. Two-hundred and seventy-one patients had single HCC, 121 patients had two or three HCCs, and 72 more than three HCCs. One-hundred and thirty-six patients (29.3%) were submitted to liver resection (LR), 232 (50.0%) to local ablative therapies (LAT) (ethanol injection, radiofrequency ablation, chemoembolization), eight (1.7%) to liver transplantation (LT), and 88 (19%) to supportive therapy (ST). Median survival time for all patients was 36 months (95% CI 24-36). Median survival time was 57 months for LR, 30 months for LAT, and 8 months for ST, with a 5-year survival of 47%, 20%, and 2.5%, respectively (p = 0.001). Actuarial 5-year survival for patients submitted to LT was 75%. Overall survival was significantly shorter in patients with multiple HCCs compared to single HCC, with median survival times of 39, 16, and 11 months for patients with a single HCC, with two to three HCCs, and with more than three HCCs, respectively (p = 0.01). Survival for patients with single HCC was significantly longer in patients submitted to LR compared to LAT and ST with median survival times of 57, 37, and 14 months, respectively (p = 0.02). Also, in patients with multinodular HCCs (2-3 HCCs) LR showed the best results with a median survival time of 58 months compared to 22 and 8 months for LAT and ST (p = 0.01). In patients with more than three HCCs, LR did not show different results compared to LAT and ST. Seventy-three patients had evidence of macroscopic vascular involvement; median survival in this subgroup of patients was significantly shorter compared to patients without vascular involvement, 10 and 36 months, respectively. Survival for patients with macroscopic vascular involvement submitted to LR or LAT was significant longer compared to ST, with mean survivals of 27, 30, and 12 months, respectively (p = 0.01). CONCLUSIONS: The present study shows that the surgery can achieve good results in patients with single HCC and good liver function. Also, patients with multinodular HCCs (two to three nodules) could benefit from LR where survival is longer than after LAT or ST. In patients with more than three HCCs, LR have similar results of LAT. Macroscopic vascular invasion is a major prognostic factor, and the LR is justified in selected patients, where it can allow good long-term results compared to ST.

The effect of iron depletion on chronic hepatitis C virus infection.

Increasing evidence exists that iron overload, a common finding in chronic hepatitis C virus (HCV) infection, plays an important role in the pathophysiology of this disease. The mechanisms by which iron excess induces liver damage along with the benefit of iron depletion via phlebotomy on biochemical and histological outcomes in patients with chronic HCV infection have been discussed in this review. Finally, we focus on the effect of iron reduction on the rate of response to interferon antiviral therapy.

Drug-induced anti-factor VIII antibodies: a systematic review.

Acquired hemophilia A is an uncommon but potentially life-threatening hemorrhagic disorder caused by the onset of autoantibodies against coagulation factor VIII. Acquired hemophilia A is most frequently associated with autoimmune diseases, solid tumors, lymphoproliferative diseases, pregnancy, and drug reactions. However, in approximately 50 percent of the patients no underlying disorder can be identified. Prompt diagnosis of this acquired bleeding disorder is essential for appropriate management aimed to control hemorrhage and suppress the inhibitor. Based on electronic and manual searches of the published literature, this review examines the current knowledge on drug-induced factor VIII autoantibodies. A total of 34 cases were identified, mostly related to a variety of agents, including antibiotics and psychiatric and immunomodulatory drugs. In particular there is increased evidence for an association between acquired hemophilia A and interferon given as treatment for hepatitis C virus infection. Although most inhibitors reported in the literature were at high titers (mean: 67.7 Bethesda Units/ml), their prognosis was good, as they disappeared in most cases after suspension of the involved drug or after immunosuppressive therapy (complete remission rate: 83.3%). However, further studies are needed to better elucidate the epidemiology, natural history, clinical relevance, and optimal treatment of drug-associated factor VIII autoantibodies.

Treatment of hepatitis C in hemophiliacs.

Hepatitis C virus (HCV) infection is a major cause of morbidity and mortality in hemophiliacs who received nonvirucidally treated large-pool clotting factor concentrates before 1986. In fact, although many hemophiliacs infected with HCV have a slow progression of liver disease, in a minority of them hepatitis evolves toward end-stage liver disease and hepatocarcinoma. Moreover, a significant percentage of HCV-infected hemophiliacs were also coinfected with human immunodeficiency virus (HIV), which can accelerate the progression of liver disease. Thus, the aim of anti-HCV therapy is to interrupt the chronic infection in order to prevent the progression of hepatitis to cirrhosis, liver decompensation, cancer and, ultimately, death. In this review we present the literature data on anti-HCV treatment in hemophiliacs. Combination therapy with interferon (IFN) and ribavirin has improved the poor results obtained with IFN monotherapy and has become the standard treatment of chronic hepatitis C. Given the positive results obtained with pegylated interferon plus ribavirin in nonhemophiliacs, ongoing trials are evaluating this promising therapy in HCV-chronically infected hemophilic patients; preliminary results show a sustained response rate similar to that in patients without coagulopathy. Finally, based on the encouraging results in coinfected nonhemophiliacs, anti-HCV treatment should also be considered for those HIV-positive hemophiliacs in whom anti-retroviral treatment has stabilized the HIV infection.

Liver transplantation: making the best out of what we have.

Since the first human liver transplantation, carried out in 1963, the procedure has become routine with an excellent outcome in terms of both quality and length of survival. One of the major challenges facing the transplant community is the shortage of donor organs. Possible approaches to overcoming this problem include changes in legislation, setting up of organizational structures, more effective use of marginal donor livers, splitting livers, and the development of living related transplants. Alternative treatments to liver transplantation have been sought, including hepatocyte transplantation, xenotransplantation, liver-directed gene therapy, extracorporeal liver support systems, tissue-engineered organs, and auxiliary partial orthotopic liver transplantation.

Nonresponse to interferon monotherapy in HCV-related chronic hepatitis: results of retreatment and prognostic factors.

At present two of the most relevant problems of the therapy of HCV-related chronic active hepatitis are the retreatment of nonresponders to interferon-alpha (IFN-alpha) and the definition of a prognostic index of response. We treated 44 patients who previously were nonresponders to IFN-alpha alone with IFN-alpha plus ribavirin for 12 months. Among the tests performed, we included the serum level of soluble intercellular adhesion molecule-1 (sICAM-1) at the beginning of the trial and at 3 months thereafter. We obtained 56.81% end of treatment responses and 47.72% sustained responses. A decrease of at least 10% of the sICAM-1 serum level during the first 3 months of treatment strongly correlated to the results of therapy while the usual important prognostic factors (HCV genotype and viral load) did not show this relation.

Update on chronic hepatitis C in hemophiliacs.

BACKGROUND AND OBJECTIVES: Hepatitis C virus (HCV) infection is an important cause of morbidity and mortality in patients affected by hereditary bleeding disorders and treated with non-virus inactivated clotting factor concentrates during the 1970s. INFORMATION SOURCES: In this review, we briefly report the present knowledge about HCV infection in hemophilic patients. The natural course of hepatitis C virus infection in hemophiliacs is described, by analyzing the prevalence of HCV infection, the genotype distribution and the risk factors involved in the progression of chronic hepatitis into severe liver disease such as cirrhosis, liver decompensation and hepatocellular carcinoma. STATE OF THE ART AND PERSPECTIVES: We focus on the most important advances in the treatment of hepatitis C in hemophiliacs.