Search

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.

Hepatitis C virus (HCV) vaccines may be able to increase viral clearance in combination with antiviral therapy. We analysed viral dynamics and HCV-specific immune response during retreatment for experienced patients in a phase Ib study with E1E2MF59 vaccine. Seventy-eight genotype 1a/1b patients [relapsers (30), partial responders (16) and nonresponders (32) to interferon-(IFN)/ribavirin-(RBV)] were randomly assigned to vaccine (V:23), Peg-IFNα2a-180-ug/qw and ribavirin 1000–1200-mg/qd for 48 weeks (P/R:25), or their combination (P/R + V:30). Vaccine (100 μg/0.5 mL) was administered intramuscularly at week 0-4-8-12-24-28-32-36. Neutralizing of binding (NOB) antibodies and lymphocyte proliferation assay (LPA) for E1E2-specific-CD4 + T cells were performed at week 0-12-16-48. Viral kinetics were analysed up to week 16. The vaccine was safe, and a sustained virological response (SVR) was achieved in 4 P/R + V and 2 P/R patients. Higher SVR rates were observed in prior relapsers (P/R + V = 27.3%; P/R = 12.5%). Higher NOB titres and LPA indexes were found at week 12 and 16 in P/R + V as compared to P/R patients (P = 0.023 and 0.025, P = 0.019 and

Wait-listed (n = 226) or post-liver transplantation (n = 241) chronic hepatitis B (CHB) patients with lamivudine-resistant hepatitis B virus (HBV) were treated with adefovir dipivoxil for a median of 39 and 99 weeks, respectively. Among wait-listed patients, serum HBV DNA levels became undetectable (

The changing scenario of hepatitis B virus therapy has encouraged the organisation of a workshop, endorsed by three Italian scientific societies, aimed at defining the current recommendations for hepatitis B virus treatment. Liver histology and stage of disease remain fundamental for treatment decisions; interferon and nucleoside/nucleotide analogues-based therapy represent different strategies for different phases of the hepatitis B virus disease. The recommendations defined: new and lower cut-off of hepatitis B virus–DNA for eligibility to therapy according to disease stage, how to optimise the use of nucleoside/nucleotide analogues and to individualise the monitoring of response and what to do with treatment failures. Specific recommendations have also been given for cirrhosis patients, those immune suppressed and co-infected with HIV and other hepatitis viruses. © 2008 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Hepatitis delta virus is a human pathogen that is responsible for a severe form of hepatitis affecting hepatitis B envelope Ag carriers. We have previously identified a series of hepatitis delta Ag (HDAg) epitopes that are recognized by CD4+ T cell clones isolated from infected subjects. Herein, we show that the presentation of soluble HDAg to CD4+ T cell clones that are specific for the HDAg(106-121) epitope was exceptionally unaffected by the inhibition of the APC-processing machinery when APCs were fixed with glutaraldehyde before Ag pulsing or treated with chloroquine or brefeldin A. Interestingly, 5 h of pulsing was strictly required for the efficient presentation of the HDAg(106-21) epitope by fixed APCs, suggesting that some form of extracellular processing had occurred. Indeed, fixed APCs were able to present HDAg after only 1 h of pulsing when HDAg was preincubated with serum for 5 h. More important, presentation was completely abrogated when Ag was previously incubated in medium containing serum in the presence of a potent inhibitor of trypsin activity such as the secretory leukoprotease inhibitor. These results show that HDAg may undergo extracellular processing and suggest that the generation of immunogenic epitopes directly by serum proteases could play a role in the immune response against hepatitis delta virus during infection.

Platelet and white blood cell counts decrease in chronic viral hepatitis patients treated with alpha interferon.To analyse whether delta negative variations in platelets and white blood cells are influenced by type, dose and duration of alpha interferon treatment, we studied 340 consecutive patients (mean treatment 8 months, range 4-18 months).A total of 204 (60%) patients were treated with recombinant alpha interferons (30% alpha-2a and 30% alpha-2b), 64 (19%) with N3.leukocytic and 72 (21%) N1.lymphoblastoid natural interferons. Median age and male/female ratios were comparable in the 3 groups (41, 41 and 43 years and 2.3, 2.6 and 2.5, respectively). The lowest platelets and white blood cells counts were observed between the 2nd and the 4th month of therapy in all patients. Age, sex, aetiology and duration of interferon therapy did nor influence the platelets and white blood cells reduction rates. The decrease was lower for patients treated with N3.leukocytic interferon than for the other interferons. A significant difference was observed between interferon doses when the groups treated with 3 or 9-10 MIU were compared. However, dose or cirrhosis-related bias are ruled out by similar proportions of cirrhosis and patients treated with 3 MIU in the 3 groups of patients treated with different types of interferon.The type of interferon appears to represent a major cause of the different haemopoietic toxicity. The lowest toxicity of N3.leukocytic interferon may have clinical implications for the choice of interferon in patients with low baseline platelets and white blood cells counts. These findings prompt prospective studies on larger series of patients.

The development of anti-interferon (anti-IFN) antibodies in the serum of patients undergoing antiviral therapy has been postulated as one possible cause of interpatient variability in response to therapy. We analyzed the relationship between the appearance of anti-IFN antibodies and the loss of response to interferon-alpha (IFN-alpha), as characterized by a breakthrough of serum aminotransferase after a period of complete biochemical remission. The analysis involved clinical trials where neutralizing anti-IFN antibodies were detected by standardized and comparable methods. The results show that a time relationship between breakthrough and anti-IFN antibodies is observed in only a few cases and is independent of the type of IFN-alpha preparation used. Thus, causes of IFN resistance other than anti-IFN antibodies must also be implicated in most breakthrough cases. Another potential is the selection of drug-resistant viral strains. Current ration behavior following the appearance of breakthrough (from whatever cause) in clinical practice advocates changing treatment to a different type of IFN-alpha. The detection of anti-IFN enzyme-linked immunosorbent assay (ELISA) antibodies or IFN neutralizing antibodies does not appear to provide any additional information for decision making.

Two hundred and twenty-eight patients who underwent orthotopic liver transplantation for hepatitis B-related cirrhosis in 11 European Liver Transplant Centers were collected. The male/female ratio was 184/44, with a median age of 41 years (13-66). In 55 patients (24%) hepatocellular carcinoma was associated with liver disease. All cases were stratified for pre-orthotopic liver transplantation viral characteristics: HBV-DNA neg/HBeAg neg: 106 patients (47%), HBV-DNA neg/Delta pos: 80 (35.5%), HBV-DNA pos/HBeAg pos: 28 (12.5%), other 14 (5%). In 49 patients (21.4%) post-orthotopic liver transplantation passive prophylaxis with anti-HBs immunoglobulins was not followed, while in 179 patients the anti-HBs serum titer was kept above 100-200 mU/ml. Overall 5-year actuarial survival of the series was 54%. One hundred and eighty-five patients were evaluable for HBsAg reappearance in the serum at various intervals after orthotopic liver transplantation. Overall 3-year HBV-free survival of these patients was 55%. There was a significant difference in 3-year HBV-free survival between HBV-DNA neg (52%), HBV-DNA pos (13%) and Delta pos (73%) patients (p: 0.03). Sixty-three percent of patients in the prophylaxis group were HBV-free, compared to only 25% of untreated patients (p0.001). Three-year HBV-free survival in patients with or without HCC was 44% and 59%, respectively. Cox-multivariate analysis revealed that only post-transplantation prophylaxis (p: 0.003) and pre-transplantation viral activity (p: 0.004) can be considered as independent factors affecting HBV recurrence. Candidates with hepatocellular carcinoma in HBV-cirrhosis should not be excluded from orthotopic liver transplantation, supporting the idea of a higher risk of post-transplantation viral reactivation.

Hepatitis C Virus (HCV) is a RNA virus that lacks the retroviral properties of surviving in infected hosts by integration into cellular DNA, nevertheless it is capable to cause chronic infection and disease in a considerable number of infected individuals (30-70% of cases). This results in a worldwide prevalence of chronic HCV carriers similar to those of hepatitis B virus carriers. We review and discuss here some of the peculiar aspects of chronic HCV infection and associated disease.

We investigated by molecular biology the possibility that the HC virus passes by the dialysis membranes into the ultrafiltrate, making the HD monitor a way of HCV transmission. HCV-RNA was tested in blood and in UF samples during 2 HD sessions at T-0, 30, 60, 120 min and at HD end. HCV-RNA was measured by RT-PCR. Viraemia in patients was10(-4) gen Eq/ml and remained unchanged along HD, HCV-RNA was not found in whole UF and its x100 concentrates during the HD. We failed to prove the passage of the HCV into the UF, at least in standard conditions.

We studied the prevalence of long-term responders to interferon-alpha (IFN-alpha) treatment (undetectable levels of serum IgM anti-HBc, HBV-DNA and normal ALT values for 3 years) in 53 anti-HBe-positive chronic hepatitis B patients. Forty-two of them were treated with (6-18 MU) alpha-2a-recombinant-IFN t.w. for 4-6 months, and the remaining 11 with 10 MU of lymphoblastoid-IFN thrice weekly for 6 months. At the end of treatment, HBV-DNA levels were undetectable and ALT values within the normal range in 34 of 53 patients (60%); IgM anti-HBc levels decreased in all the 34 patients, falling below 10 PEI U in 2/34 (6%). Response to treatment was maintained throughout the follow-up (mean 3 years, range 2-7 years) in five patients (9.4%). The remaining 29 patients experienced HBV reactivation within median follow-up of 6 months (range 1-22 months; 90% of cases within 12 months). Overall 4/9 long-term responders (44.4%) cleared serum HBsAg. In conclusion, chronic anti-HBe-positive hepatitis B has a lower IFN treatment response rate than the HBeAg-positive form; however, among long-term responders, the incidence of serum HBsAg clearance is comparable in the two forms. Because of the high rate of relapses, stringent monitoring criteria (HBV-DNA, IgM anti-HBc and ALT monthly tested for at least 12 months) are mandatory.

Patients with chronic but not acute hepatitis delta virus infection undergo a strong accumulation of a protein of cellular origin which specifically reacts with a panel of anti-c-myc antibodies and which is expressed in the same nuclei that express the delta antigen. In this paper we report on the in vitro characterization of this phenomenon. The delta antigen induced c-myc antigen accumulation can occur in vitro upon transfection of HBsAg positive and negative cell lines with HDAg expression vectors. Using recombinant vaccinia viruses expressing only p24 or p27 we demonstrate that structures common to the two isoforms of HDAg are responsible for the phenomenon, which is not restricted to cells of hepatic origin.

The aim of the study was to evaluate the direct influence of lipid parameters (total and HDL-cholesterol, triglycerides and total lipids) on the rheologic-coagulative pattern. We studied blood rheological properties--blood (BV), plasmatic (PV), and seric (SV) viscosity, whole blood (WBF) and red cell (RCF) filterability--and some coagulative factors--fibrinogen (Fib), levels of clotting factor VII (fVIIc) and VIII (fVIIIc) activity--in 156 men aged 40-54 years; 87 patients had type II hyperlipoproteinemia (46 type IIa and 41 type IIb) and 69 were normolipemic controls. Smokers, patients with arterial hypertension, diabetes mellitus or cardiovascular clinical manifestations were excluded. Type IIb hyperlipoproteinemic patients had increased blood viscosity (shear rate 225 sec-1, p. less than 0.01), which was positively correlated with triglycerides and fibrinogen concentration. Levels of fibrinogen, fVIIc and fVIIIc activity did not differ significantly in hyperlipemic patients and controls, although fVIIc activity and fibrinogen were both positively related with lipid parameters. These data suggest that, in absence of other major risk factors, the alterations of the rheologic-coagulative pattern are mainly dependent on the severity of the lipid disorder.

Computed tomography and real-time ultrasonography may not be conclusive for the diagnosis of the Budd-Chiari syndrome; in many cases more information may be needed, especially on vascular alterations. Doppler ultrasonography provides qualitative data on flow direction and pattern, thereby contributing significantly to diagnosis. Eight cases in which hepatic vein patency was unclear and presence of intrahepatic vessels resembling hepatic veins raised problems of interpretation in real-time ultrasonography are described. In some cases, patency or occlusion of the upper portion of the inferior vena cava were difficult to identify with real-time ultrasonography. Doppler ultrasonographic investigation showed flow in the hepatic veins to be completely absent in two cases and reversed in another two. In the remaining four cases, a flat waveform was evident. Flow in the inferior vena cava was reversed in four cases and showed a flat waveform in three other cases. Portal vein thrombosis was detected in only one case, whereas the remaining seven patients showed slow hepatopetal flow. These findings demonstrate that absent or reversed flow in the hepatic veins and/or flat flow in the hepatic veins associated with reversed flow in the inferior vena cava may be considered diagnostic for the Budd-Chiari syndrome. For this series the sensitivity of Doppler ultrasonography was 87.5%.

Hepatitis D virus and hepatitis B virus nucleic acids were detected by Northern and Southern blot hybridization in the sera and livers of 85 chronic carriers of HBsAg and anti-hepatitis D followed up for a mean of 10 yr. We identified three subsets of patients: 13 with hepatitis D virus and hepatitis B virus viremia, 53 with serum hepatitis D virus RNA, but without hepatitis B virus DNA and 19 negative for both nucleic acids. Genomic and subgenomic forms of hepatitis D virus RNA were detected only in patients with hepatitis D virus and hepatitis B virus viremia. Histological findings and disease activity at admission were comparable in the three groups of patients, but the outcome was significantly worse in patients with active replication of both viruses; two of them died of terminal liver failure and hepatocellular carcinoma developed in two; the remaining patients had an uneventful course. These results suggest that active hepatitis B virus replication represents an important previously unrecognized determinant of severe liver damage in patients with chronic hepatitis D virus infection. Since hepatitis B virus provides the means for hepatitis D virus secretion and release from infected cells, active hepatitis B virus multiplication favoring the spread of hepatitis D virus from cell to cell may increase the pathogenetic potential of the defective agent.

Serum or liver markers of hepatitis delta virus (HDV) infection were found in 20 of 22 (90%) Italian patients presenting with an ostensible type B hepatitis that ran an accelerated course to cirrhosis. The features of the illness conformed to a syndrome of HDV infection in young males carrying the hepatitis B surface antigen (HBsAg); a latent HBsAg state was documented in many patients by a history of prior exposure to the hepatitis B virus (HBV) or by the absence of IgM antibodies to the HB core antigen. Characteristic of the disease were the clinical overture as a severe hepatitis, the lobular involvement by an extensive necroinflammatory reaction, the exuberant expression of intrahepatic hepatitis delta antigen and an atypical HBV profile of inactive infection or accelerated seroconversion from HBeAg to anti-HBe. Superimposed upon HBV infection, HDV may create a rapidly progressive course which resembles very aggressive hepatitis B but is infrequently observed in hepatitis B alone.

Cirrhotic liver hepatocellular carcinoma (HCC) was evaluated with both US and CT. In a group of 600 cirrhotic patients 64 had HCC, which was confirmed at histology in 24 cases, and by disease evolution in the other 40; single focal degeneration was proven in 40 patients, multiple (2, 3 focal lesions), or diffuse degeneration (more than 3 focal lesions) in the remaining 24. Sixteen patients had associated portal thrombosis. US recognized 38/40 single HCC, 22/24 multiple or diffuse lesions, and 11/16 portal vein thromboses. Degeneration was most frequently hypo/isoechoic in small tumors, hyperechoic and mixed in large lesions. When small lesions are hyperechoic their differentiation from both hemangiomas and regeneration noduli is extremely difficult. In such cases CT is mandatory. US diagnostic accuracy is by far superior to that of CT: 95% vs 85% in single lesions and 91.6% vs 87.5% in diffuse forms. Overall accuracy is 93.7% for US and 85.9% for CT. The authors believe that US should be performed every 6 months on cirrhotic patients, so as to allow HCC to be detected in time for radical surgery, while CT should be performed only when doubts persist.

The relationship between the professional background of the physician requesting the biopsy procedure (whether non-specialist or specialist in hepatology/gastroenterology) and the subsequent decision of treatment of the patients was analyzed. Treatment was divided into two categories named arbitrarily "no therapy" (general supportive measures) or "therapy" (causal treatment based on active drugs or measures aimed at affecting the cause of the disease). Of the 204 cases of outpatient needle biopsies available for study, 157 were made by specialist request and 47 were made by a non-specialist request. Sixty-eight (43%) of the former, but only 3 (2%) of the latter had "therapy" (p = 0.0001). Also, patients in which histology showed chronic active liver disease had "therapy" more frequently (49 of 109, 44.9%) than those without chronic active liver disease (22 of 95, 23%) with p less than 0.01. However, patients with histological active chronic disease were not more frequent among specialist requests (56.6%) than among the non-specialist requests (42.5%). But among patients attended by the specialist, there were more patients (31.8%) with positive serum markers of Hepatitis B virus infection than among those sent by others (12.7%) with p less than 0.01. We conclude that at least in the premises in which this study was carried out, blind liver biopsies will lead to active treatment more often in patients treated by a specialized physician, because these patients are more likely to have a virus identified as the cause of their liver disease and consequently will receive antiviral treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatitis B virus (HBV) plays a major role in liver carcinogenesis. HBV-DNA integration into cellular DNA provides some molecular basis for understanding the mechanisms of neoplastic transformation of the liver cell. Persistence of HBV-DNA episomic forms, necro-inflammation in the liver, and cirrhosis appear to be additional promoting factors. We studied the possible association between hepatocellular carcinoma (HCC) and the defective hepatitis D virus (HDV), a virus that requires the helper function of HBV. Patients infected with HDV and HBV develop HCC about 10 years earlier than those infected with HBV alone. Persistence of active HDV disease and low levels of "wild-type" HBV (i.e., secreting the hepatitis B surface antigen [HBsAg]) are associated with progressive liver disease and HCC. Therefore, HBV replication, in spite of being inhibited by HDV, appears to play a major role sustaining HDV pathogenicity. Detection of antibody to the hepatitis C virus (HCV) in many HCC patients raises the important question whether HCV has oncogenic potential. Clinico-epidemiological data show that the most severe forms of liver disease in patients with multifactorial liver damage occur in those infected with HCV. The prevalence of HBV markers in patients with cirrhosis, HCC, and HCV infection is higher than in individuals with comparable age and other diseases. HBV-DNA integration occurring early during HBV infection can persist in those with and without detectable HBsAg in their serum. Therefore, one can speculate that in patients with integrated HBV-DNA and concurrent HCV infection, cirrhosis and HCC may develop more easily than in patients without HBV-DNA integration. HCV hampering the immune system also might play a role in the genesis of HCC. The evidence that multiple hepatitis viruses are more frequently associated with HCC than infections of one virus alone has important practical consequences. It warrants the identification of high risk patients so that they can be monitored frequently for early diagnosis and treatment.

Hepatitis viruses may cause liver cancer (HCC) through an indirect mechanism inducing inflammation and cirrhosis. Only hepatitis B virus (HBV) was shown to have a direct oncogenetic potential. Hepatitis D virus (HDV) infection, superimposed on the oncogenetic background provided by chronic HBV infection, appears to provide an additional risk for HCC. Patients with florid infections from both HBV and HDV and active liver inflammation develop HCC at a significantly younger age than those infected by HBV alone or infected by hepatitis C virus (about 10 years earlier). In patients positive for serum HBV-DNA/HDV-RNA and/or IgM anti-HBc/IgM anti-HD it is mandatory to program a more frequent (thrice a year) schedule of screenings (ultrasound scan, alpha-1-phetoprotein, etc.) for prophylaxis of HCC.

This review summarizes our current understanding of nonalcoholic fatty liver disease (NAFLD), a multi-factorial systemic disease resulting from a complex interaction between a specific genetic background and multiple environmental/metabolic “hits”. The role of gut microbiota, lipotoxicity, inflammation and their molecular pathways is reviewed in-depth. We also discuss the epidemiology and natural history of NAFLD by pinpointing the remarkably high prevalence of NAFLD worldwide and its inherent systemic complications: hepatic (steatohepatitis, advanced fibrosis and cirrhosis), cardio-metabolic (cardiovascular disease, cardiomyopathy, arrhythmias and type 2 diabetes) and neoplastic (primary liver cancers and extra-hepatic cancers). Moreover, we critically report on the diagnostic role of non-invasive biomarkers, imaging techniques and liver biopsy, which remains the reference standard for diagnosing the disease, but cannot be proposed to all patients with suspected NAFLD. Finally, the management of NAFLD is also reviewed, by highlighting the lifestyle changes and the pharmacological options, with a focus on the innovative drugs. We conclude that the results of ongoing studies are eagerly expected to lead to introduce into the clinical arena new diagnostic and prognostic biomarkers, prevention and surveillance strategies as well as to new drugs for a tailored approach to the management of NAFLD in the individual patient.

a b s t r a c t The prevalence of fatty liver (steatosis) in the general population is rapidly increasing worldwide. The progress of knowledge in the physiopathology of fatty liver is based on the systems biology approach to studying the complex interactions among different physiological systems. Similarly, translational and clinical research should address the complex interplay between these systems impacting on fatty liver. The clinical needs drive the applications of systems medicine to re-define clinical phenotypes, assessing the multiple nature of disease susceptibility and progression (e.g. the definition of risk, prognosis, diag- nosis criteria, and new endpoints of clinical trials). Based on this premise and in light of recent findings, the complex mechanisms involved in the pathology of fatty liver and their impact on the short- and long- term clinical outcomes of cardiovascular, metabolic liver diseases associated with steatosis are presented in this review using a new "systems medicine" approach. A new data set is proposed for studying the impairments of different physiological systems that have an impact on fatty liver in different subsets of subjects and patients.

Background Depression is considered the most frequent interferon (IFN)-α-induced psychiatric disorder. However, other neuropsychiatric side effects of IFN treatment, such as irritability, anxiety, and manic episodes, are reported as well. We analyzed the impact of lifetime manic–hypomanic symptoms and anxiety on the development of depression in hepatitis-C-virus-infected subjects treated with two different types of IFN-α. Methods At baseline, subjects received thorough diagnostic assessment to exclude lifetime or current psychiatric symptoms. During treatment, subjects were administered interviewer-based and self-report instruments. Results Six (12%) of 49 individuals with a negative history of psychiatric disorders developed major depression during treatment with IFN. The onset of depression was significantly associated with the presence of lifetime subthreshold manic–hypomanic symptoms. Subjects exceeding manic threshold were more likely to develop depression than those below threshold (33.3% vs. 7.5%, P =.033). Conclusions Our data suggest that individuals treated with IFN with no past history of psychiatric disorders are more likely to develop depression if they experienced subthreshold manic–hypomanic symptoms in their lifetime. These findings derive from an exploratory study and may have important implications for the prevention of IFN-induced depression if replicated in larger studies.

The integration of human and artificial intelligence (AI) in medicine has only recently begun but it has already become obvious that intelligent systems can dramatically improve the management of liver diseases. Big data made it possible to envisage transformative developments of the use of AI for diagnosing, predicting prognosis and treating liver diseases, but there is still a lot of work to do. If we want to achieve the 21st century digital revolution, there is an urgent need for specific national and international rules, and to adhere to bioethical parameters when collecting data. Avoiding misleading results is essential for the effective use of AI. A crucial question is whether it is possible to sustain, technically and morally, the process of integration between man and machine. We present a systematic review on the applications of AI to hepatology, highlighting the current challenges and crucial issues related to the use of such technologies.

The 69th World Health Assembly endorsed the Global Health Sector Strategy for Viral Hepatitis, embracing a goal to eliminate hepatitis infection as a public health threat by 2030. This was followed by the World Health Organization's (WHO) global targets for the care and management of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. These announcements and targets were important in raising awareness and calling for action; however, tracking countries’ progress towards these elimination goals has provided insights to the limitations of these targets. The existing targets compare a country's progress relative to its 2015 values, penalizing countries who started their programmes prior to 2015, countries with a young population, or countries with a low prevalence. We recommend that (1) WHO simplify the hepatitis elimination targets, (2) change to absolute targets and (3) allow countries to achieve these disease targets with their own service coverage initiatives that will have the maximum impact. The recommended targets are as follows: reduce HCV new chronic cases to ≤5 per 100000, reduce HBV prevalence among 1-year-olds to ≤0.1%, reduce HBV and HCV mortality to ≤5 per 100000, and demonstrate HBV and HCV year-to-year decrease in new HCV- and HBV-related HCC cases. The objective of our recommendations is not to lower expectations or diminish the hepatitis elimination standards, but to provide clearer targets that recognize the past and current elimination efforts by countries, help measure progress towards true elimination, and motivate other countries to follow suit.

BACKGROUND: The time-related variability of HCC biomarkers has not been investigated so far. OBJECTIVE: To assess the changes of alpha-fetoprotein (AFP) and protein induced by vitamin-K absence/antagonist-II (PIVKA-II) in patients with HCC (HCC+) as compared to patients without HCC (HCC-). METHODS: AFP and PIVKA-II were measured by a single laboratory using an automated chemiluminescent-enzyme-immunoassay (Fujirebio Inc., Tokyo, Japan) in 1163 sera of 418 cirrhotics (31.1% HBV, 58.6% HCV, 10.3% non-viral etiology) undergoing ultrasound HCC surveillance. The mean (range) number of effective time-points available for analysis was 2.8 (2.0 to 3.0); 124 patients with HCC were matched with 294 who remained HCC free for at least 12 months after the last specimen. AFP and PIVKA-II changes were estimated over time by means of a random-effect generalized least squares (RE-GLS) regression model under the missingness at random assumption. RESULTS: Patients with and without HCC had comparable chronic liver disease etiology and staging. AFP/PIVKA-II median (25th; 75th percentile) values at the latest time-point were 4.2 (2.6; 8.6) ng/mL/32 (25; 42) mAU/mL in HCC- and 8.4 (4.4; 32.1) ng/mL/66 (32; 192) mAU/mL in HCC+ (p< 0.001). Log10AFP and log10PIVKA-II time-changes differed in HCC+ and HCC- patients. In HCC+ patients, both log10AFP and log10PIVKA-II showed an increasing trend over time. In HCC- patients, log10PIVKA-II variations were minimal as compared to log10AFP variations. The percent increase of log10AFP at 6 months vs. baseline was 11% (95%CI 5 to 17%) and 5% (95%CI 1 to 8%) for log10PIVKA-II in HCC+vs. HCC- patients. CONCLUSIONS: The present retrospective study of the biological variability of AFP and PIVKA-II suggests that their time-related changes may serve as potential predictors of HCC. This topic needs to be addressed by longitudinal studies.

The physiopathology of fatty liver and metabolic syndrome are influenced by diet, life style and inflammation, which have a major impact on the severity of the clinicopathologic outcome of non-alcoholic fatty liver disease. A short comprehensive review is provided on current knowledge of the pathophysiological interplay among major circulating effectors/mediators of fatty liver, such as circulating lipids, mediators released by adipose, muscle and liver tissues and pancreatic and gut hormones in relation to diet, exercise and inflammation.

Autoimmune hepatitis (AIH) is an unresolving inflammation of the liver of unknown cause. Diagnosis requires the exclusion of other conditions and the presence of characteristic features such as specific autoantibodies. Presently, these autoantibodies have relatively low sensitivity and specificity and are identified via immunostaining of cells or tissues; therefore, there is a diagnostic need for better and easy-to-assess markers. To identify new AIH-specific autoantigens, we developed a protein microarray comprising 1626 human recombinant proteins, selected in silico for being secreted or membrane associated. We screened sera from AIH patients on this microarray and compared the reactivity with that of sera from healthy donors and patients with chronic viral hepatitis C. We identified six human proteins that are specifically recognized by AIH sera. Serum reactivity to a combination of four of these autoantigens allows identification of AIH patients with high sensitivity (82%) and specificity (92%). Of the six autoantigens, the interleukin-4 (IL4) receptor fibronectin type III domain of the IL4 receptor (CD124), which is expressed on the surface of both lymphocytes and hepatocytes, showed the highest individual sensitivity and specificity for AIH. Remarkably, patients' sera inhibited STAT6 phosphorylation induced by IL4 binding to CD124, demonstrating that these autoantibodies are functional and suggesting that IL4 neutralization has a pathogenetic role in AIH.

BACKGROUND/AIMS: Dendritic cells (DCs) play a key role in immune responses through antigen presentation and cytokine secretion. Hepatitis C virus (HCV) is able to escape elimination by the immune system and often establishes a chronic infection. To investigate whether DC dysfunction is involved in this process, we have studied monoycte-derived DCs (Mo-DCs) and plasmacytoid DCs (pDCs), which produce large amounts of IFN-alpha, from chronic HCV patients and healthy donors. METHODS: We have assessed TNF-alpha and IFN-alpha production by pDCs using intracellular staining after total PBMCs stimulation with unmethylated CG dinucleotides (CpGs). The induction of allogeneic T cell proliferation by immature Mo-DCs was measured using the MLR assay. The up-regulation of maturation markers and the production of TNF-alpha in response to LPS were analyzed using flow cytometry and ELISA, respectively. RESULTS: We have detected comparable frequencies of pDCs producing TNF-alpha and IFN-alpha in both chronic HCV patients and healthy donors and we have found that immature Mo-DCs from both patients and donors similarly induce allogeneic T cell proliferation and mature and secrete TNF-alpha in response to LPS. CONCLUSIONS: Our results demonstrate that both pDC and Mo-DCs are not impaired in HCV infected patients.

Background and aims. Hepatitis C virus infection is often associated with lymphoproliferative disorders such as essential mixed cryoglobulinemia and B-cell non-Hodgkin lymphoma, which show preferential expression of V H I family products. By analyzing immunoglobulin heavy chain usage, we addressed the question of whether or not clonal B-cell expansion occurrs in patients free of essential mixed cryoglobulinemia or non-Hodgkin lymphoma. Patients and methods. Four hepatitis C virus-positive patients, all undergoing liver transplantation, were studied. Peripheral blood, intra-hepatic, and lymph node lymphocytes were used as a source of B cells. A patient with hepatocellular carcinoma and fresh blood from four healthy donors were used as negative controls. V H I family sequences were cloned and analyzed by reverse transcription-polymerase chain reaction. Results. Immunoglobulin heavy chain sequences from clonally expanded B lymphocytes were identified in three out of four hepatitis C virus-infected patients. The clonally expanded B lymphocyte populations showed a broad spectra of immunoglobulin heavy chain gene usage. Conclusions. HCV infection can induce B-cell expansion with larger clonal variation. The restricted V gene usage in hepatitis C virus-associated non-Hodgkin lymphoma suggests that there may be selection mechanisms to develop non-Hodgkin lymphoma from non-malignant, clonally expanded B-cell populations in hepatitis C virus-infected patients.

Twenty-seven carriers of the hepatitis B surface antigen who underwent liver transplantation in Italy and Belgium for terminal Hepatitis delta virus (HDV) cirrhosis were investigated. In 22 of the patients, HDV infection recurred. Two patients died of coexisting HDV and hepatitis B virus (HBV) reactivation. Four patients who died of unrelated causes were found to have HDV without signs of HBV reactivation. Five patients (18%) cleared both HBV and HDV after transplantation with no evidence of hepatitis (mean follow-up, 29 months). In many surviving patients, HDV infection recurred early without signs of HBV reactivation. Disease returned in the 11 HDV-infected patients in whom HBV also recurred. Histological hepatitis did not recur during an interim of 12-33 months in the 5 HDV-infected patients in whom HBV did not return. The overall medium-term survival in patients with HDV who underwent transplantation was 77.7%. Liver transplantation offers patients with HDV a hope of cure from disease despite a high risk of reinfection. In the transplantation setting, HDV can cause subclinical infections without any apparent assistance from HBV; these infections become symptomatic only if and when HBV reactivates. Thus, HDV may not be in itself pathogenic but requires cooperation from HBV to cause the appearance of the disease.

The prevalence of hepatitis delta virus (HDV) infection was significantly higher among the relatives of 79 carriers of HBsAg with antibody to HDV (index cases) than among relatives of 111 carriers without serological evidence of HDV infection (controls). Antibody to HDV was found in 45 of the 80 (56%) carriers of HBsAg in families of index cases but only in 2 of 59 (3%) carriers in families of controls (P less than 0.0001). During follow-up new HDV infection developed in 31% of 13 susceptible carriers in families of index cases, but only in 1.2% of 162 susceptible carriers in families of controls (P less than 0.001). None of the family members previously unexposed to the hepatitis B virus had HDV markers in serum or developed this infection during the follow-up. Familial clustering shows that HDV is transmitted by personal contacts, presumably through the inapparent permucosal or percutaneous passage of virus during close or intimate contact. The family model indicates that endemic HDV is maintained and spread through the network of carriers in the community, and that HBsAg carriers in contact with HBsAg/HDV carriers are at high risk of contracting HDV.

Infection with the hepatitis B surface antigen (HBsAg)-associated delta agent (delta) was determined in a series of Italian patients with a diagnosis of acute hepatitis B (HBsAg-positive) progressive to chronicity. Twenty-two of 27 (81%) and 12 of 18 (67%) patients collected, respectively, in Naples and Cagliari, where delta is highly endemic, developed immunoglobulin M antibody to delta and/or rising titers of immunoglobulin G anti-delta during the initial acute phase of the disease. In each of them, anti-delta increased to a high-titered plateau indicative of chronic delta infection. Delta markers were found in none of the 13 patients collected in Siena, where the prevalence of delta infection is low. The great majority of the patients with anti-delta and a progressive form of HBsAg-positive hepatitis lacked the IgM antibody to hepatitis B core antigen. They were presumably unrecognized carriers of HBsAg who became infected by delta and developed hepatitis induced by this agent. In areas where delta is endemic, it may represent the true cause of seemingly type B hepatitis progressing to chronic HBsAg-positive liver disease.