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The incidence of chronic hepatitis B (CHB) is declining due to successful implementation of vaccination programs and widespread use of antiviral therapy. We aimed to study time-trends in disease characteristics and comorbidities in newly referred CHB patients.We collected information on hepatitis B virus (HBV) related disease characteristics (including hepatitis B e-antigen (HBeAg) status, viremia, stage of liver fibrosis and indication for treatment and/or hepatocellular carcinoma (HCC) surveillance) and presence of comorbidities in all CHB patients referred to our center from 1980 through 2020. Patient characteristics were compared according to referral date (before 2000, between 2000 and 2010 and after 2010).We identified 1515 eligible patients. Patients referred after 2010 were older (36 versus 34 years, p 0.001), more often non-Caucasian (82.3% versus 55.0%, p 0.001) and more frequently HBeAg negative (81.5% versus 49.8%, p 0.001) when compared to patients referred before 2000. Adjusted for ethnicity, sex and age, patients referred after 2010 were less likely to have significant fibrosis (adjusted odds ratio [aOR]:0.178, p 0.001) or indication for antiviral therapy (aOR:0.342, p 0.001) but were more likely to be affected by the metabolic syndrome (aOR:1.985, p = 0.013), hepatic steatosis (aOR:1.727, p 0.001) and metabolic dysfunction associated fatty liver disease (MAFLD) (aOR:1.438, p = 0.013).The characteristics of the CHB populations are changing. Newly referred patients are older, have less active HBV related liver disease but are more likely to be co-affected by MAFLD. These findings provide guidance for adequate allocation of resources to cope with the changing characteristics of the CHB population.Foundation for Liver and Gastrointestinal Research Rotterdam, the Netherlands and Gilead Sciences.

Background Serum hepatitis B surface antigen (HBsAg) levels correlate with the duration of chronic hepatitis B virus (HBV) infection and may predict the extent of hepatic fibrosis. Methods We analyzed data from the SONIC-B database, which contains data from 8 global randomized trials and 2 large hepatology centers. Relationship between HBsAg levels and presence of significant fibrosis (Ishak 3–4) or cirrhosis (Ishak 5–6) were explored, and clinically relevant cutoffs were identified to rule out cirrhosis. Results The dataset included 2779 patients: 1866 hepatitis B e antigen (HBeAg)-positive; 322 with cirrhosis. Among HBeAg-positive patients, lower HBsAg levels were associated with higher rates of significant fibrosis (odds ratio [OR], 0.419; P < .001) and cirrhosis (OR, 0.435; P < .001). No relationship was observed among HBeAg-negative patients. Among HBeAg-positive patients, genotype-specific HBsAg cutoffs had excellent negative predictive values (>97%) and low misclassification rates (≤7.1%) and may therefore have utility in ruling out cirrhosis. Diagnostic performance of the HBsAg cutoffs was comparable among patients in whom cirrhosis could not be ruled out with fibrosis 4 (FIB-4). Conclusions Hepatitis B virus genotype-specific HBsAg cutoffs may have utility in ruling out presence of cirrhosis in HBeAg-positive patients with genotypes B, C, and D and can be an adjunct to FIB-4 to reduce the need for further testing.

Contains fulltext : 290866.pdf (Publisher’s version ) (Open Access) BACKGROUND: Management of focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA), is multidisciplinary and subject to practice variation. We aimed to evaluate variation in clinical management of FNH and HCA in Europe. METHODS: We distributed an online survey (November 2021-March 2022) among 294 European experts. The survey included questions on local practice and included eight clinical vignettes. The clinical vignettes focused on FNH or HCA management in the setting of sex, lifestyle modification, and pregnancy. RESULTS: The response rate was 32% and respondents included surgeons (38%), gastroenterologists/hepatologists (25%), radiologists (32%), and pathologists (1.6%) from ten European countries. We observed practice variation with regard to lifestyle modification and imaging follow-up in patients with FNH, and with regard to the management of HCA >5 cm before and during pregnancy. Finally, the management of HCA >5 cm after lifestyle modification deviated from EASL guideline recommendations. CONCLUSION: Our survey illustrates variability in FNH and HCA management in Europe. Several areas were identified for future research and guideline recommendations, including FNH follow-up and the management of HCA >5 cm. We propose the organization of Delphi consensus meetings to prioritize areas of research and update current guidelines to optimize management for all patients with benign liver tumors.

We present a 49 year old female patient with Crohn's disease (CD) in remission on vedolizumab therapy who experienced a symptomatic, though benign, course of acute hepatitis E. Routine blood tests showed substantial elevation of liver enzymes and polymerase chain reaction (PCR) testing confirmed hepatitis E virus (HEV) infection. Vedolizumab therapy was paused, liver enzymes improved three weeks after infection and normalized after six months. The patient recovered completely from mild symptoms. This case shows that hepatitis E is a potential cause of acute hepatitis during vedolizumab therapy, and in this case the infection has run a benign course.

Purpose To establish optimal management of patients with an umbilical hernia complicated by liver cirrhosis and ascites. Methods Patients with an umbilical hernia and liver cirrhosis and ascites were randomly assigned to receive either elective repair or conservative treatment. The primary endpoint was overall morbidity related to the umbilical hernia or its treatment after 24 months of follow-up. Secondary endpoints included the severity of these hernia-related complications, quality of life, and cumulative hernia recurrence rate. Results Thirty-four patients were included in the study. Sixteen patients were randomly assigned to elective repair and 18 to conservative treatment. After 24 months, 8 patients (50%) assigned to elective repair compared to 14 patients (77.8%) assigned to conservative treatment had a complication related to the umbilical hernia or its repair. A recurrent hernia was reported in 16.7% of patients who underwent repair. For the secondary endpoint, quality of life through the physical (PCS) and mental component score (MCS) showed no significant differences between groups at 12 months of follow-up (mean difference PCS 11.95, 95% CI − 0.87 to 24.77; MCS 10.04, 95% CI − 2.78 to 22.86). Conclusion This trial could not show a relevant difference in overall morbidity after 24 months of follow-up in favor of elective umbilical hernia repair, because of the limited number of patients included. However, elective repair of umbilical hernia in patients with liver cirrhosis and ascites appears feasible, nudging its implementation into daily practice further, particularly for patients experiencing complaints. Trial registration Clinicaltrials.gov, NCT01421550, on 23 August 2011.

Aims: Electronic prescribing systems may improve medication safety, but only when used appropriately. The effects of task analysis-based training on clinical, learning and behavioural outcomes were evaluated in the outpatient setting, compared with the usual educational approach. Methods: This was a multicentre, cluster randomized trial [EDUCATional intervention for IT-mediated MEDication management (MEDUCATE trial)], with physicians as the unit of analysis. It took place in the outpatient clinics of two academic hospitals. Participants comprised specialists and residents (specialty trainees, in the UK) and their patients. Training took the form of a small-group session and an e-learning. The primary outcome was the proportion of medication discrepancies per physician, measured as discrepancies between medications registered by physicians in the electronic prescribing system and those reported by patients. Clinical consequences were estimated by the proportion of patients per physician with at least one missed drug–drug interaction with the potential for causing adverse drug events. A questionnaire assessed physicians' knowledge and skills. Results: Among 124 participating physicians, primary outcome data for 115 (93%) were available. A total of 1094 patients were included. A mean of 48% of registered medications per physician were discrepant with the medications that their patients reported in both groups (P = 0.14). Due to registration omissions, a mean of 4% of patients per physician had one or more missed drug–drug interactions with the potential to cause a clinically relevant adverse drug event in the intervention group, and 7% in controls (P = 0.11). The percentages of correct answers on the knowledge and skills test were higher in the intervention group (57%) compared with controls (51%; P = 0.01). Conclusion: The training equipped outpatient physicians with the knowledge and skills for appropriate use of electronic prescribing systems, but had no effect on medication discrepancies.

An abundance of noninvasive scores have been associated with fibrosis and hepatocellular carcinoma (HCC) development. We aimed to compare the prognostic ability of these scores in relation to liver histology in chronic hepatitis B (CHB) patients. Liver biopsies from treatment-naïve CHB patients at one tertiary care centre were scored by a single hepato-pathologist. Laboratory values at liver biopsy were used to calculate the PAGE-B, REACH-B, GAG-HCC, CU-HCC and FIB-4 scores. Any clinical event was defined as HCC development, liver failure, transplantation and mortality. HCC and mortality data were obtained from national database registries. Of 557 patients, 40 developed a clinical event within a median follow-up of 10.1 (IQR 5.7-15.9) years. The PAGE-B score predicted any clinical event (C-statistic.86, 95% CI: 0.80-0.92), HCC development (C-statistic .91) and reduced transplant-free survival (C-statistic .83) with good accuracy, also when stratified by ethnicity, antiviral therapy after biopsy or advanced fibrosis. The C-statistics (95% CI) of the REACH-B, GAG-HCC, CU-HCC and FIB-4 scores for any event were .70 (0.59-0.81), .82 (0.75-0.89), .73 (0.63-0.84) and.79 (0.69-0.89), respectively. The PAGE-B event risk assessment improved modestly when combined with the Ishak fibrosis stage (C-statistic .87, 95% CI: 0.82-0.93). The PAGE-B score showed the best performance in assessing the likelihood of developing a clinical event among a diverse CHB population over 15 years of follow-up. Additional liver histological characteristics did not appear to provide a clinically significant improvement.

Tocilizumab is a humanized monoclonal antibody targeting the interleukin-6 receptor that is frequently used for the treatment of refractory rheumatoid arthritis. Since patients with hepatitis B virus (HBV) infection were excluded from pivotal trials, the risk of HBV reactivation with this novel drug class remains uncertain. We present the first case of tocilizumab-associated HBV reactivation resulting in fulminant hepatic failure and a need for liver transplant. Our findings underscore the need for prophylactic antiviral therapy in patients being treated with novel immunosuppressive agents.

Background Although benign in itself, hepatocellular adenoma (HCA) can be complicated by hormone-induced growth, and subsequent haemorrhage and rupture. The exact risk of haemorrhage and rupture is not known. This systematic review of the literature was carried out with the aim of estimating the risk of haemorrhage and rupture in HCA. Methods A systematic literature search of the PubMed and Embase databases was performed for all articles relevant to haemorrhage and/or rupture of HCA, published between 1969 and March 2011. Results Twenty-eight articles met the selection criteria, containing a total of 1176 patients. Haemorrhage was reported with an overall frequency of 27·2 per cent among patients, and in 15·8 per cent of all HCA lesions. Rupture and intraperitoneal bleeding were reported in 17·5 per cent of patients. Bleeding was the first symptom in 68·5 per cent of patients with a bleeding HCA. Six of 13 articles reporting the size of HCA lesions in which bleeding occurred mentioned haemorrhage in HCAs smaller than 5 cm. Conclusion Haemorrhage and rupture are common in patients with HCA.

Aliment Pharmacol Ther 2012; 35: 266–274 Summary Background Polycystic liver disease (PLD) is a phenotypical expression of autosomal dominant polycystic kidney disease and isolated polycystic liver disease. Somatostatin analogues, such as lanreotide, reduce polycystic liver volume. Aim To establish long-term outcome and safety of lanreotide. Methods This was an open-label, observational extension study of a 6-month, randomised, placebo-controlled trial with lanreotide (120 mg/month) in PLD. The length of total treatment was 12 months. Primary endpoint was relative change in liver volume, as determined by CT-volumetry after 12 months of treatment. We offered patients a CT scan 6 months after stopping lanreotide. Results A total of 41/54 (76%) patients participated in the extension study. Liver volume decreased by 4% (IQR −8% to −1%) after 12 months of treatment. The greatest effect was observed during the first 6 months of treatment (decrease of 4% (IQR −6% to −1%)). Liver volume remained unchanged during the following 6 months. We found that liver volume increased by 4% (IQR 0–6%) 6 months after end of treatment (n = 22). Conclusions Lanreotide reduces liver volume within the first 6 months of treatment and the beneficial effect is maintained in the following 6 months. Stopping results in recurrence of polycystic liver growth. This suggests that continuous use of lanreotide is needed to maintain its effect.

In November 2002, the Netherlands adopted a vaccination program targeted at behavioural risk groups. Between January 2003 and December 2007, 1386 patients acutely infected with HBV were reported. Reported cases declined from 326 in 2003 to 220 in 2007. Sexual intercourse was the most frequently reported mode of transmission (65%), especially among men having sex with men. Genotypes A and D remained predominant. In total, 40,600 participants were fully vaccinated, the overall compliance was 62%, and the estimated overall program coverage was 12% of the at-risk population. With more effort, more susceptibles may be reached, but the program will not be sufficient to substantially reduce HBV in the Netherlands. Therefore, universal vaccination should be considered. (C) 2009 Elsevier Ltd. All rights reserved.

Background/Aim: The evidence on the efficacy of somatostatin analogues in the treatment of hepatocellular carcinoma (HCC) in humans is conflicting. A variety of human tumors demonstrate somatostatin receptors. All subtypes bind human somatostatin with high affinity, while somatostatin analogues bind with high affinity to somatostatin receptor subtype 2 (sst2). We investigated the sst2 expression in HCC and examined whether HCCs expressing sst2 are a distinct subgroup. Patients and Methods: Forty-five human HCCs were tested for sst2 expression and biological alterations. The proliferative capacity was determined with Ki67 immunostaining and the DNA ploidy status was measured by fluorescent in situ hybridization with a chromosome 1-specific repetitive DNA probe. Expression of tumor suppressor genes (p16, p53 and Rb1) was measured by immunohistochemistry. Results: sst2 expression was detected in 30 tumors (67%). No correlation existed between sst2 expression and the immunoprofiles of the tumor suppressor genes, aneuploidy, proliferation, age, gender, α-fetoprotein levels, tumor size, tumor grade and underlying liver disease. Conclusion: In 67% of the patients with HCC, sst2 could be detected in the tumor. No clinical, pathological or biological characteristics were specific for sst2-positive tumors.

SUMMARY Background Ascites is the most common complication of cirrhosis, associated with an expected survival below 50% after 5 years. Prognosis is particularly poor for patients with refractory ascites and for those developing complications, including spontaneous bacterial peritonitis (SBP) and hepatorenal syndrome (HRS). Aim To provide an evidence-based overview of the pathophysiology, diagnosis and clinical management of ascites secondary to liver cirrhosis. Methods Review based on relevant medical literature. Results Portal hypertension, splanchnic vasodilatation and renal sodium retention are fundamental in the pathophysiology of ascites formation. The SAAG (serum-ascites albumin gradient) allows reliable assessment of the cause of ascites. The majority of cirrhotic patients with ascites can be managed with dietary sodium restriction in combination with diuretic agents. Large volume paracentesis with albumin suppletion and TIPS are therapeutic options in patients with refractory ascites. Prophylactic antibiotics for SBP should be given in certain patient populations. Conclusions Recent advances in the diagnosis and treatment of ascites and associated complications have improved the medical management and poor prognosis of patients with these manifestations of advanced liver disease. Early diagnosis, adequate treatment and focus on prevention of complications remain essential as well as timely referral for liver transplantation.

Background Strong suppression of viral replication and normalization of alanine aminotransferase is feasible with nucleos(t)ide analogues. It is estimated viral replication and liver inflammation can be controlled in 90\% of patients with chronic hepatitis B with the current available treatments. Aim To review the studies currently available on the management of chronic hepatitis B with nucleos(t)ide analogues. Results Although very potent, nucleos(t)ide analogues are not effective in every patient. Some factors are known to influence treatment outcome, but many host and viral factors are still unknown. Stopping rules have to be defined to assess treatment efficacy in an early stage and change the regimen. Discontinuation of nucleos(t)ide analogues is often followed by reactivation of HBV. Data on the risk factors for relapse are necessary in order to decide if treatment can be safely discontinued. Another major drawback of nucleos(t)ide analogues is the emergence of resistance. The efficacy of compounds for the treatment of mutant virus and the impact of cross-resistance is largely unknown. The use of combination therapy to prevent resistance looks promising, but has to be proven. Conclusions HBV has become a treatable disease, however much research is needed to optimize treatment for individual patients and treatment failures.

Only in a minority of patients with chronic hepatitis B (CHB) will treatment with interferon (IFN)-alpha or nucleoside analogues lead to sustained virological response. In vivo immunization (IVI) following virus suppression aims to optimize conditions for an effective immune response: following rapid and profound virus suppression by interferon-lamivudine combination therapy, lamivudine is withdrawn intermittently during continued interferon therapy. It is thought that withdrawal of lamivudine will lead to increased viral replication and increased antigen expression with subsequent immune stimulation. The aim of this prospective pilot study was to evaluate IVI as a therapeutic approach for CHB. Fourteen HBeAg-positive CHB patients were treated for 42 weeks with a combination of pegylated interferon-alpha 2b and lamivudine. After 12 weeks of combination therapy lamivudine was withdrawn intermittently for three consecutive periods of 4 weeks until it was permanently stopped on week 36. At the end of follow-up (week 52) all patients had remained HBeAg positive and the median viral load was similar to baseline. During the initial 12 weeks of treatment, there was a reduction of both the hepatitis B virus (HBV)-specific proliferation capacity of Th-cells and the frequencies of IFNgamma-producing cells. During the lamivudine interruption-cycle there was an inverse relation between the increase of HBV-DNA, and the decrease in proliferation capacity and frequency of IFN-gamma-producing cells. The intrahepatic fraction of CD8(+) T-cells increased during lamivudine withdrawal. In conclusion, IVI was able to transiently stimulate the HBV-specific immune responsiveness of T-cells, but the magnitude of the response was insufficient to cause a beneficial virological effect.

To gain insight into hepatitis B virus (HBV) transmission in the Netherlands, epidemiological data and sera were collected from reported cases of acute HBV infections in the Netherlands in 2004. Cases were classified according to mode of transmission. A fragment of the S-gene of HBV (648 bp) was amplified, sequenced, and subjected to phylogenetic analysis. Of the 291 acute HBV cases reported in 2004, 158 (54%) were available for genotyping. Phylogenetic analysis identified 6 genotypes: A (64%), B (3%), C (3%), D (21%), E (5%) and F (5%). Of HBV infected men having sex with men, 86% were infected with genotype A, accounting for 43% of all patients infected with this genotype. There were only three reported cases of injecting drug use of which one was available for sequencing (genotype A). Unlike the genotype A cluster, sequences within the genotype B-E clusters were heterogenic. Within genotype F, several isolates had identical sequences, but patients could not be epidemiologically linked. Sexual transmission, particularly by men having sex with men was the most important transmission route for HBV. Injecting drug use plays a minor role. Genotype A is predominant in the Netherlands, especially among men having sex with men. In addition to imported strains, there seems to be a pool of related but non-identical strains circulating among chronic carriers in the migrant population, from which occasionally new patients are infected, primarily by heterosexual transmission.

A 65-year-old man was referred for assessment of advanced liver disease. Seventeen years previously he had been diagnosed with ulcerative colitis, and 7 years later with primary sclerosing cholangitis (PSC). After several episodes with variceal bleeding caused by secondary biliary cirrhosis, a transjugular intrahepatic portosystemic shunt (TIPS) was created. Because of recurrent bacterial cholangitis, endoscopic retrograde cholangiography was performed, showing irregular narrowing of the intrahepatic bile ducts with saccular dilatations, findings considered compatible with PSC (figure 1). Also, a round filling defect in the common bile duct (CBD) was noted. After biliary sphincterotomy, a 6 mm polyp was removed. Histopathology review revealed a papillary adenoma with low-grade dysplasia. Figure 1 Cholangiography showing irregular intrahepatic bile ducts, saccular dilatations …

Background: Identification of tumour antigens is crucial for the development of vaccination strategies against hepatocellular carcinoma (HCC). Most studies come from eastern-Asia, where hepatitis-B is the main cause of HCC. However, tumour antigen expression is poorly studied in low-endemic, western areas where the aetiology of HCC differs. Methods: We constructed tissue microarrays from resected HCC tissue of 133 patients. Expression of a comprehensive panel of cancer-testis (MAGE-A1, MAGE-A3/4, MAGE-A10, MAGE-C1, MAGE-C2, NY-ESO-1, SSX-2, sperm protein 17), onco-fetal (AFP, Glypican-3) and overexpressed tumour antigens (Annexin-A2, Wilms tumor-1, Survivin, Midkine, MUC-1) was determined by immunohistochemistry. Results: A higher prevalence of MAGE antigens was observed in patients with hepatitis-B. Patients with expression of more tumour antigens in general had better HCC-specific survival (P = 0.022). The four tumour antigens with high expression in HCC and no, or weak, expression in surrounding tumour-free-liver tissue, were Annexin-A2, GPC-3, MAGE-C1 and MAGE-C2, expressed in 90, 39, 17 and 20% of HCCs, respectively. Ninety-five percent of HCCs expressed at least one of these four tumour antigens. Interestingly, GPC-3 was associated with SALL-4 expression (P = 0.001), an oncofetal transcription factor highly expressed in embryonal stem cells. SALL-4 and GPC-3 expression levels were correlated with vascular invasion, poor differentiation and higher AFP levels before surgery. Moreover, patients who co-expressed higher levels of both GPC-3 and SALL-4 had worse HCC-specific survival (P = 0.018). Conclusions: We describe a panel of four tumour antigens with excellent coverage and good tumour specificity in a western area, low-endemic for hepatitis-B. The association between GPC-3 and SALL-4 is a novel finding and suggests that GPC-3 targeting may specifically attack the tumour stem-cell compartment.

The efficacy of anti-viral intravenous immunogobulins (anti-HBs Ig and anti-CMV Ig) in preventing acute rejection after liver transplantation was assessed in a retrospective analysis, and correlated to their effects on immune cells in vitro. HBs Ag-positive liver graft recipients (n = 40) treated prophylactically with anti-HBs Ig had a significantly lower incidence of acute rejection compared with recipients without viral hepatitis (n = 147) (12% vs. 34%; p = 0.012), while the incidence of rejection in HCV-positive recipients (n = 29) was similar to that in the control group. Treatment with anti-CMV Ig (n = 18) did not protect against rejection. In vitro, anti-HBs Ig suppressed functional maturation of and cytokine production by human blood-derived dendritic cells (DC) at concentrations similar to the serum concentrations reached during anti-HBs Ig treatment of liver graft recipients. In addition, anti-HBs Ig inhibited allo-antigen- and lectin-stimulated proliferation of peripheral T cells. Anti-CMV Ig suppressed functional DC-maturation and alloantigen-stimulated T-cell proliferation, but not lectin-driven T-cell proliferation. In conclusion, anti-HBs Ig protects against acute rejection after liver transplantation, probably by functional inhibition of the two principal immune cells involved in allograft rejection, DC and T cells.

Background and aims: Flares are a well known phenomenon during antiviral treatment for chronic hepatitis B. Little is known about the effect of flares on response. We investigated the timing and characteristics of flares, in relation to treatment response (hepatitis B e antigen loss). Patients: A total of 266 patients, participating in a global randomised controlled study, were assigned to 52 weeks of 100 μg pegylated (Peg)-interferon α-2b weekly, combined with either daily lamivudine 100 mg or placebo. Results: Sixty seven patients (25%) exhibited 75 flares, with 38 (51%) flares in the combination therapy and 37 (49%) in the monotherapy groups. Overall, 30% of patients with and 38% of patients without a flare responded to therapy (p = 0.25). In 24 patients (36%) the flare was followed by a decrease in hepatitis B virus (HBV) DNA (host induced flare). In 25 (38%) patients the flare was preceded by an increase in HBV DNA (virus induced flare). In 17 (26%) patients the flare did not meet one of these criteria (indeterminate flare). Of patients with host induced flare, 58% responded whereas only 20% of patients with virus induced flares responded (p = 0.008). Hepatitis B surface antigen loss (n = 8) was exclusively seen in patients experiencing a host induced flare. Multivariate logistic analysis showed that host induced flares was an independent predictor of response (p = 0.043). Conclusion: Flares are not more common in responders than in non-responders to Peg-interferon α-2b therapy. Virus induced flares, which occur after an increase in HBV DNA level, and most probably are indicative for increased expression of viral antigens, did not lead to treatment response. In contrast, host induced flares which were followed by a HBV DNA decrease were highly associated with treatment response.

Hepatocellular carcinoma (HCC) is one of the most common primary cancers in the world and the third most common cause of cancer mortality world-wide. Surgery is the gold standard in the treatment of patients with HCC. The prognosis is mainly determined by the underlying liver disease and recurrent rates. In the Western World, up to 30% of the patients with HCC have a non-cirrhotic liver. The main prognostic factor in this special group of patients are the recurrences. Most recurrences are intrahepatic; however, 30% of the recurrences are extrahepatic. The role of resection in case of intrahepatic recurrences is widely accepted, particularly in the non-cirrhotic liver. The role of resection in extrahepatic HCC recurrences is not well established and unknown among many physicians. We present two patients with HCC in a non-cirrhotic liver with extrahepatic recurrences and long-term survival after resection. The corresponding literature support an aggressive approach in case of extrahepatic HCC recurrence in selected cases: resectable metastasis, preserved liver function, absence of intracranial metastasis and control of the primary tumour. Further research is warranted because of the limited number of reports and the absence of randomized trials.

Cytotoxic T lymphocytes (CTL) and Kupffer cells play an important role in the immune control of hepatitis B virus (HBV), but may also induce liver injury during infection. We investigated the intrahepatic immune response in liver biopsies of chronic HBV patients in relation to inflammatory liver injury and viral control. Forty-seven liver biopsies from patients with chronic HBV with varying degrees of inflammation (ALT values) were selected. Acute hepatitis and normal liver specimens served as controls. Immune effector cells, cytotoxic effector molecules and cytokine producing cells were quantified after immunohistochemical staining in lobular and portal areas of the biopsies. The intralobular number of CD8+ T-lymphocytes was significantly decreased in biopsies of patients with high ALT (r = -0.54; P < 0.001). Higher ALT-values were correlated with increased numbers of granzyme+ cells in portal areas (r = 0.65; P < 0.001) and higher numbers of intralobular Fas-L+ cells (r = 0.32; P = 0.05). Fas-L was expressed on Kupffer and lymphoid cells. More intralobular CD8+ T-lymphocytes were found in HBeAg- than in HBeAg+ patients (P = 0.002). But IFN-gamma and TNF-alpha producing cells were observed sporadically in chronic HBV patients. Hence, in chronic HBV infection, low viral replication and HBeAg negativity is related to increased presence of intralobular CD8+ T-lymphocytes. Persistence of the virus may be caused by the absence of cells producing anti-viral cytokines in the liver. Inflammatory liver injury during chronic HBV infection is probably not the result of increased numbers of infiltrating CD8+ T-lymphocytes, but of Fas-L expression by Kupffer cells and increased cytolytic activity of cells in portal areas.

Background The aim was to determine the degree of local control of hepatocellular carcinoma (HCC) in patients with cirrhotic liver disease when treated with ultrasonographically guided interstitial laser coagulation (ILC) with temporary hepatic artery occlusion. Methods Sixteen patients with 24 HCC tumours were treated. Follow-up was by computed tomography or magnetic resonance imaging every 3 months. Results Nineteen of 24 tumours showed complete necrosis immediately after treatment, and there was no tumour recurrence during follow-up (mean 14 months, median 12 months). No effect on liver function was observed after 1 week and there was no death. In 13 of the 16 patients, new HCC foci developed at other sites. Conclusion Percutaneous ILC combined with temporary hepatic artery occlusion during a single session is an effective local treatment for HCC nodules smaller than 5 cm. However, new HCC lesions develop in the majority of patients, which underscores the need for adjuvant therapy or repeated treatment in these patients.

Introduction: With the introduction of HAART, the HIV-1 has turned from a lethal into a chronic infection in the majority of patients. In homosexual populations, 20% of HIV-1 infected patients suffer from a chronic HBV infection, which may eventually lead to complications of the liver disease because of prolonged survival. Lamivudine is effective in reducing both HIV-1 and HBV viral replication. However, resistance for lamivudine may complicate the course of the HBV disease in HIV-1-infected patients. We, therefore, conducted a retrospective study in HIV-1-HBV co-infected patients on lamivudine therapy. Patients and methods: All HIV-1-HBV co-infected patients who were treated with lamivudine for over 6 months in five major referral clinics in The Netherlands with HBV DNA above 2.0×10 5 geq ml −1 at baseline, were evaluated. Retrospectively, the course of HBV DNA in available serum samples was established. If HBV DNA was detectable with the sensitive PCR-assay, YMDD-analyses of the polymerase gene of the hepatitis B virus was executed with the INNO-LiPA-DR-strip. Results: Forty-six patients were evaluated. The median level of HBV DNA at start of lamivudine therapy was 1.31×10 9 geq ml −1 (range 3.5×10 5 –2.0×10 10 , n =43). Of three patients no baseline sample was available, but since HBV DNA was still above 2.0×10 5 geq ml −1 at week 3, 7 and 11, these patients were included. Median duration of lamivudine therapy was 97 weeks (range 27–263). The percentage of detected mutations was 25 and 52% at 1 and 2 years, respectively. Twenty-two patients ultimately developed a mutation. Both baseline Body Mass Index (BMI) and the decrease in CD4 cell count as a time dependent factor were significantly related to the emergence of mutations. In 10 out of 12 evaluated patients, HBV DNA levels returned to baseline level or even above baseline level after the development of mutant virus. One patient (5%) developed a flare of serum transaminases (ALT>10×ULN) 24 weeks after first detection of variant virus. Conclusion: There is a linear time-dependent appearance of HBV mutations for lamivudine in our population. In a minority of patients (5%), development of a mutation was followed by a significant elevation of serum transaminases. A decline in CD4 cell count, which may indicate less response to HAART, induces a faster emergence of mutations and close surveillance of HBV co-infected patients on therapy may be indicated due to the prolonged survival of HIV-1 patients.

End-stage liver disease caused by chronic hepatitis C viral infection is one of the major indications for liver transplantation. However, evidence for ongoing viral replication can already be found days after surgery and may lead sequentially to lobular hepatitis, chronic active hepatitis, fibrosis and liver cirrhosis. In some patients, this evolution is remarkably fast, most probably enhanced by the immunosuppressive therapy. A minority of patients develop a clinical picture of progressive cholestatic liver disease with histological signs of chronic rejection, which may necessitate retransplantation. While the 1- and 5-year survival rates for all patients transplanted because of hepatitis C virus (HCV)-induced liver cirrhosis are satisfactory, severe complications of disease recurrence are nonetheless expected during the first and second decade after liver transplantation. Larger and preferably randomized studies are needed to investigate whether combination therapy with interferon and ribavirin, preferably initiated as soon as possible after liver transplantation, prevents the fast evolution to cirrhosis without the appearance of chronic rejection and the expected complications of recurrent end-stage HCV-induced liver disease. The final goal should be the inhibition of viral replication even before liver transplantation, but other antiviral strategies should probably be used to attain this goal in patients with decompensated cirrhosis. Although the recurrence of a hepatitis C infection and concomitant disease in the liver graft may cause substantial morbidity, end-stage liver disease and liver failure caused by a chronic hepatitis C infection remain good indications for liver transplantation.

Further understanding of the molecular biology and pathogenesis of hepatocellular carcinoma (HCC) is crucial for future therapeutic development. SMAD4, recognized as an important tumor suppressor, is a central mediator of transforming growth factor beta (TGFB) and bone morphogenetic protein (BMP) signaling. This study investigated the role of SMAD4 in HCC. Nuclear localization of SMAD4 was observed in a cohort of 140 HCC patients using tissue microarray. HCC cell lines were used for functional assay in vitro and in immune-deficient mice. Nuclear SMAD4 levels were significantly increased in patient HCC tumors as compared with adjacent tissues. Knockdown of SMAD4 significantly reduced the efficiency of colony formation and migratory capacity of HCC cells in vitro and was incompatible with HCC tumor initiation and growth in mice. Knockdown of SMAD4 partially conferred resistance to the anti-growth effects of BMP ligand in HCC cells. Importantly, simultaneous elevation of SMAD4 and phosphorylated SMAD2/3 is significantly associated with poor patient outcome after surgery. Although high levels of SMAD4 can also mediate an antitumor function by coupling with phosphorylated SMAD1/5/8, this signaling, however, is absent in majority of our HCC patients. In conclusion, this study revealed a highly non-canonical tumor-promoting function of SMAD4 in HCC. The drastic elevation of nuclear SMAD4 in sub-population of HCC tumors highlights its potential as an outcome predictor for patient stratification and a target for personalized therapeutic development.

Background: In recent years chronic hepatitis E virus (HEV) infections have been reported in immunosuppressed patients, including HIV-positive patients with low CD4 cell counts. Because of delayed anti-HEV seroconversion in patients with CD4 cell count

A human monoclonal anti-hepatitis B antibody preparation (TUVIRUMAB) was administered 6 times over a 2-week period in a dose-escalating scheme to chronic hepatitis B patients pre-treated with lamivudine. The capacity of the TUVIRUMAB antibody to "neutralize" hepatitis B surface antigen in the circulation was investigated by means of experimental enzyme-immunoassays. Monoclonal antibody conjugates enabled the detection of HBsAg, TUVIRUMAB, and HBsAg/TUVIRUMAB complexes. The results showed that (1) TUVIRUMAB was able partially to "neutralize" in vitro and in vivo, (2) HBsAg/TUVIRUMAB complexes can be traced by assays that capture the complex at either its HBsAg or its TUVIRUMAB component, (3) the final concentration of TUVIRUMAB at the end of therapy varied greatly but seemed to be related to HBsAg production at the start of therapy, (4) for at least 14 days after discontinuation of therapy, a minimal HBsAg level could be maintained in the presence of a declining TUVIRUMAB titer in patients with less than 3 microg/ml HBsAg before the start of therapy, (5) three months after therapy, all HBsAg levels had returned to pre-treatment levels and TUVIRUMAB had disappeared.

A highly reproducible and sensitive real-time detection assay based on TaqMan technology was developed for the detection of hepatitis B virus (HBV) DNA and compared with two commercially available assays. The assay was validated with the Viral Quality Control panel, which also includes EUROHEP HBV DNA standards. This real-time PCR detection system had a dynamic range of 373 to 10 10 genome copies per ml and showed an excellent correlation with both the commercial HBV Digene Hybrid Capture II microplate assay (Digene Diagnostics) and the HBV MONITOR assay (Roche Diagnostics). To demonstrate its clinical utility, four chronically HBV-infected patients treated with lamuvidine were monitored using the three different assays. From the results we concluded that this assay is an excellent alternative for monitoring of HBV-infected patients in routine diagnostics and clinical practice, enabling the analysis of a large dynamic range of HBV DNA in a single, undiluted sample.

To assess the efficacy of influenza vaccination in immunocompromised adult liver transplant (LTx) recipients, the serum antibody responses of 61 of these patients and 35 liver cirrhosis patients with those of 45 of their healthy spouses were compared, after one and two vaccinations with a commercial trivalent subunit influenza vaccine. In addition, virus-specific proliferative T-cell responses were measured in LTx recipients and their healthy spouses. In all three study groups, significant rises in geometric mean antibody titers were observed for all three antigens after one vaccination. These titers did not continue to increase significantly after the second vaccination in patients with cirrhosis and control subjects but did rise for LTx recipients. The overall antibody response to all three influenza virus strains proved to be significantly lower in the LTx recipients than in the group of healthy subjects after both one and two vaccinations. More than 68% of the LTx recipients developed hemagglutination-inhibiting serum antibody titers >/=40 against all three vaccine strains after the first vaccination and more than 80% after the second vaccination. These findings correlated with the T-cell responses determined for the group of LTx recipients and healthy control individuals. Testing of the respective serum samples against influenza virus A/Sydney/5/97, which circulated in the 1997-1998 influenza season and showed a considerable mismatch with the vaccine strain A/Nanchang/933/95, indicated that such a mismatch may have significant consequences for vaccine efficacy, especially for LTx recipients. Collectively the data show that LTx recipients can be vaccinated effectively against influenza despite immunosuppressive therapy. A two-dose vaccination regimen improved vaccination efficacy in LTx recipients. Whether transplant patients generally benefit from a two-dose vaccination regimen should be evaluated further.

Currently, the best option for patients with hepatitis delta is interferon alpha therapy for at least one year. To evaluate the effect of the combination lamivudine-high-dose interferon alpha therapy, we first treated eight patients with chronic hepatitis delta infection with lamivudine for at least 24 weeks; then lamivudine was combined with a high dose of interferon alpha followed by a regular dose (9 MU tiw). Follow-up was 12 weeks. Virological, biochemical and histological features were evaluated for response to therapy. At baseline, all patients were HBsAg positive in serum and HDV RNA-(PCR)positive in plasma; HBV DNA was undetectable with the Digene Hybrid Capture assay (limit of detection 1.5 x 10(6) geq ml-(1)) in all cases. Transaminases were elevated in all patients; median ALT 68 (range 48-143) IU l(1). Seven of eight patients completed the course; one patient with a pre-existing sickle cell trait was withdrawn from the trial due to the development of a nephrotic syndrome. The HBsAg-concentration in serum decreased in two out of seven patients (29%). However, there was no significant decrease in the HBsAg-concentration in serum during treatment (median 3654 PEU l(-1) (range 548-7,684) to 5300 PEU l(-1) (range 168-19,639)). The drop of HDV RNA in plasma from baseline during treatment was not significant. Decrease of HDV RNA was observed in three out of seven patients (43%) (median 10(5) geq ml(-1); range 10(3)-10(6) to median 10(3) geq ml(-1); range 10(2)-10(7)). Serum ALT did not change as reflected by a median of 68 IU l(-1) (range 48-143) at start of therapy to 63 IU l(-1) (range 20-171) at the end of therapy. At the end of treatment transaminases had normalised in one patient and decreased in three other patients (improvement in 57%). However, three of these four patients showed a rebound after withdrawal of therapy. The Histology Activity Index (HAI) indicated a drop from a median score of 7 (range 5-9) at baseline to 5 (range 3-8) at the end of treatment, but an increase in fibrosis from a median grade of 2 (range 1-3) at baseline to 3 (range 1-4) at the end of treatment was observed. In conclusion, this study does not yield support for the combination of an HBV suppressor and 16 weeks of high-dose interferon for therapy aimed at eradicating the hepatitis delta virus.

Aims—To use laboratory data and liver biopsies, prospectively obtained from hepatitis B surface antigen (HBsAg) and anti hepatitis B e antigen (anti-HBe) positive patients, for the assessment of: (1) the relation between biopsy length/number of portal tracts and sampling error; (2) the relation between the severity of piecemeal necrosis and the new grading terminology (minimal, mild, moderate, and severe chronic hepatitis); and (3) liver pathology, which has not been studied in patients with this specific serological profile. Methods—The study group (n = 174) included 104 patients with normal aminotransferase concentrations and no cases with clinically apparent cirrhosis. The specimen length and number of portal tracts were measured at light microscopy examination. Sampling error analysis was related to the discrepancies between aminotransferase concentrations versus histological grade. Detailed histological scorings were undertaken by the reference pathologist and compared with laboratory and hepatitis B virus (HBV) DNA precore sequence data. Results—Sampling error seemed to be a constant feature, even for biopsies ≥ 20 mm, but increased dramatically in biopsies < 5 mm long and/or containing less than four portal tracts. Between 25% and 30% of biopsies, graded as "mild" or "moderate" activity showed features of moderate and severe piecemeal necrosis, respectively. Ten per cent of the patients with normal aminotransferase values had stage III–IV hepatic fibrosis, and 20% had piecemeal necrosis. Only cytoplasmic, not nuclear, core antigen expression was a strong predictor of high hepatitis B viraemia. There was no association between precore stop codon mutations, grade/stage of liver disease, and hepatitis B core antigen (HBcAg) expression. Conclusions—The specimen available for light microscopical examination should be > 5 mm long and should contain more than four portal tracts. In addition, the new grading terminology might give the clinician an inappropriately mild impression of the severity of piecemeal necrosis. Furthermore, even in the presence of normal aminotransferase concentrations, considerable liver pathology can be found in 10–20% of HBsAg and anti-HBe positive individuals; such pathology is not associated with the occurrence of precore stop codon mutations. Key Words: liver pathology • chronic hepatitis B virus infection • anti-hepatitis B antigen e positive • core antigen expression • serum hepatitis B virus DNA • hepatitis grading • sampling error

A large percentage of human immunodeficiency virus (HIV) patients have serological evidence of a past or present hepatitis B virus infection (HBV). Long-term survival is increasing for HIV patients because of highly active antiretroviral therapy. Therefore, the chronic hepatitis B infection may become an important determinant of disease outcome in these co-infected patients. We describe two HIV/HBV co-infected patients who were treated with extended antiviral therapy, initially indicated for the HIV infection. Lamivudine, a suppressor of viral replication in both infections, was one of these antiviral drugs. One patient showed a severe rebound of the HBV after withdrawal of lamivudine, the other patient developed a mutant hepatitis B virus after 18 months of treatment. This mutation was exclusively induced by lamivudine. These patients show that, with improved HIV-related survival, the HBV infection should be monitored carefully, thereby enabling the physician to interfere with therapy when necessary.

Chronic hepatitis C is a slowly progressive liver disease that may evolve into cirrhosis with its potential complications of liver failure or hepatocellular carcinoma. Current therapy with α-interferon is directed at viral clearance, but sustained response is only achieved in 20–40% of patients without cirrhosis, and less than 20% in patients with cirrhosis who have the greatest need for therapy. Treatment for those who do not respond to anti-viral therapy is highly desirable. In Japan glycyrrhizin has been used for more than 20 years as treatment for chronic hepatitis. In randomized controlled trials, glycyrrhizin induced a significant reduction of serum aminotransferases and an improvement in liver histology compared to placebo. Recently, these short-term effects have been amplified by a well-conducted retrospective study suggesting that long-term usage of glycyrrhizin prevents development of hepatocellular carcinoma in chronic hepatitis C. The mechanism by which glycyrrhizin improves liver biochemistry and histology are undefined. Metabolism, pharmacokinetics, side-effects, and anti-viral and hepatoprotective effects of glycyrrhizin are discussed.

Although exacerbations of previously quiescent HBV infection, associated with chemotherapy, have been attributed to enhanced immunological responses to hepatocytes harboring reactivated HBV, the recommended treatment, prednisolone, is often unsuccessful. A young HBsAg-positive, anti-HBe-positive carrier, who received chemotherapy for choriocarcinoma, developed icteric hepatitis. The serum HBV DNA level was 34,000 x 10(6) genomic equivalents per milliliter serum. Treatment with prednisolone alone did not prevent progression to overt hepatic failure. By three days after initiating lamivudine therapy, however, there was reversal of stage III hepatic encephalopathy. With further lamivudine treatment, substantial further improvement in hepatocellular function occurred and HBV-DNA levels became undetectable. When an immunocompromised patient develops an exacerbation of hepatitis B associated with high HBV DNA levels, treatment with prednisolone seems inappropriate, as hepatocytotoxic HBV replication may be stimulated further. In this situation inhibition of HBV replication, eg, by administering lamivudine, may be life-saving.

Different guidelines exist for the management of hepatitis B virus (HBV)-infected health care workers (HCWs). Various HBV DNA levels are used as a cutoff level to determine whether an HBV-infected HCW is allowed to perform exposure-prone procedures (EPPs) or not. In this paper we discuss the factors that determine HBV DNA levels and the implications of different HBV DNA cutoff levels for EPP performing HCWs. If the level of HBV DNA in the serum of HCWs is used to determine acceptability for the conduct of EPPs, it is necessary to take into account the variability in time of HBV DNA levels in HBV carriers and the reliability and reproducibility of the molecular diagnostic test involved. The issue of standardization has to be addressed, before a universal, maximum level of viraemia for EPP performing HCWs can be introduced.

The standard treatment of an HBeAg-positive, HBV-DNA-positive chronic hepatitis B patient is a 16-week course of 10 MU alpha-interferon thrice weekly. However, the overall therapeutic effect, as measured by disappearance of the HBe-antigen, is estimated at 30%. Improvement is possible by better selection of the patient, modifications in the treatment schedule, or combination therapy. In the selection of possible candidates for combination therapy, the second generation nucleoside analogues with activity against hepatitis B are good candidates. In clinical studies, lamivudine and famciclovir are used, both of which can reduce serum HBV-DNA to levels below 1 pg/ml within weeks. The ongoing clinical studies address the efficacy and safety of these drugs after prolonged exposure, in combination with alpha-interferon and around liver transplantation in patients with decompensated liver disease.