Addressing barriers to the prevention, diagnosis and treatment of hepatitis B and C in the face of persisting fiscal constraints in Europe: report from a high level conference.

In the WHO-EURO region, around 28 million people are currently living with chronic viral hepatitis, and 120,000 people die every year because of it. Lack of awareness and understanding combined with the social stigma and discrimination exacerbate barriers related to access to prevention, diagnosis and treatment services for those most in need. In addition, the persisting economic crisis has impacted on public health spending, thus posing challenges on the sustainable investment in promotion, primary and secondary prevention, diagnosis and treatment of viral hepatitis across European countries. The Hepatitis B and C Public Policy Association in cooperation with the Hellenic Center for Disease Prevention and Control together with 10 partner organizations discussed at the Athens High Level Meeting held in June 2014 recent policy developments, persisting and emerging challenges related to the prevention and management of viral hepatitis and the need for a de minimis framework of urgent priorities for action, reflected in a Call to Action (Appendix S1). The discussion confirmed that persisting barriers do not allow the full realisation of the public health potential of diagnosing and preventing hepatitis B and C, treating hepatitis B and curing hepatitis C. Such barriers are related to (a) lack of evidence-based knowledge of hepatitis B and C, (b) limited access to prevention, diagnosis and treatment services with poor patient pathways, (c) declining resources and (d) the presence of social stigma and discrimination. The discussion also confirmed the emerging importance of fiscal constraints on the ability of policymakers to adequately address viral hepatitis challenges, particularly through increasing coverage of newer therapies. In Europe, it is critical that public policy bodies urgently agree on a conceptual framework for addressing the existing and emerging barriers to managing viral hepatitis. Such a framework would ensure all health systems share a common understanding of definitions and indicators and look to integrate their responses to manage policy spillovers in the most cost-effective manner, while forging wide partnerships to sustainably and successfully address viral hepatitis.

The state of hepatitis B and C in the Mediterranean and Balkan countries: report from a summit conference.

The burden of disease due to chronic viral hepatitis constitutes a global threat. In many Balkan and Mediterranean countries, the disease burden due to viral hepatitis remains largely unrecognized, including in high-risk groups and migrants, because of a lack of reliable epidemiological data, suggesting the need for better and targeted surveillance for public health gains. In many countries, the burden of chronic liver disease due to hepatitis B and C is increasing due to ageing of unvaccinated populations and migration, and a probable increase in drug injecting. Targeted vaccination strategies for hepatitis B virus (HBV) among risk groups and harm reduction interventions at adequate scale and coverage for injecting drug users are needed. Transmission of HBV and hepatitis C virus (HCV) in healthcare settings and a higher prevalence of HBV and HCV among recipients of blood and blood products in the Balkan and North African countries highlight the need to implement and monitor universal precautions in these settings and use voluntary, nonremunerated, repeat donors. Progress in drug discovery has improved outcomes of treatment for both HBV and HCV, although access is limited by the high costs of these drugs and resources available for health care. Egypt, with the highest burden of hepatitis C in the world, provides treatment through its National Control Strategy. Addressing the burden of viral hepatitis in the Balkan and Mediterranean regions will require national commitments in the form of strategic plans, financial and human resources, normative guidance and technical support from regional agencies and research.

Salivary proteomic profile of young healthy subjects.

Background: The incidence of noncommunicable diseases (NCDs) has been rapidly ramped up worldwide. Hence, there is an urgent need to non-invasively detect NCDs possibly by exploiting saliva as a 'liquid biopsy' to identify biomarkers of the health status. Since, the absence of standardized procedures of collection/analysis and the lack of normal ranges makes the use of saliva still tricky, our purpose was to outline a salivary proteomic profile which features healthy individuals. Methods: We collected saliva samples from 19 young blood donors as reference population and the proteomic profile was investigated through mass-spectrometry. Results: We identified 1,004 proteins of whose 243 proteins were shared by all subjects. By applying a data clustering approach, we found a set of six most representative proteins across all subjects including Coronin-1A, F-actin-capping protein subunit alpha, Immunoglobulin J chain, Prosaposin, 78 kDa glucose-regulated protein and Heat shock 70 kDa protein 1A and 1B. Conclusion: All of these proteins are involved in immune system activation, cellular stress responses, proliferation, and invasion thus suggesting their use as biomarkers in patients with NCDs.

Preprocedural prophylaxis with blood products in patients with cirrhosis: Results from a survey of the Italian Association for the Study of the Liver (AISF).

INTRODUCTION: The concept of rebalanced hemostasis in cirrhosis challenges the policy of transfusing plasma or platelets before invasive procedures in patients with prolonged PT or severe thrombocytopenia. Recent guidelines recommend against plasma transfusion and suggest avoiding/minimizing platelet transfusions. AIM: We assessed how hepato-gastroenterologists manage prolonged PT/INR or severe thrombocytopenia before invasive procedures. METHODS: On May 2021, AISF members were sent a questionnaire addressing the PT/INR and platelet thresholds required before invasive procedures, the use of other markers of bleeding risk or other hemostatic treatments and the burden of pre-emptive plasma and platelet transfusions. RESULTS: Of 62 respondents, 94% and 100% use PT/INR and platelet count to assess bleeding risk, respectively. Only 37% and 32% require less conservative PT/INR or platelet counts thresholds for low-risk procedures, respectively. As for those applying single thresholds, 68% require PT/INR <1,5 and 86% require platelet counts ≥50 × 109/L. Half respondents use additional indicators of bleeding risk and 63% other hemostatic treatments. Low-risk procedures account for 70% of procedures, and for 50% and 59% of plasma and platelets units transfused, respectively. CONCLUSIONS: the survey indicates lack of compliance with guidelines that advise against plasma and platelet transfusions before invasive procedures and the need for prospective studies and inter-society consensus workshops.

Reduced circulating FABP2 in patients with moderate to severe COVID-19 may indicate enterocyte functional change rather than cell death.

The gut is of importance in the pathology of COVID-19 both as a route of infection, and gut dysfunction influencing the severity of disease. Systemic changes caused by SARS-CoV-2 gut infection include alterations in circulating levels of metabolites, nutrients and microbial products which alter immune and inflammatory responses. Circulating plasma markers for gut inflammation and damage such as zonulin, lipopolysaccharide and ß-glycan increase in plasma along with severity of disease. However, Intestinal Fatty Acid Binding Protein / Fatty Acid Binding Protein 2 (I-FABP/FABP2), a widely used biomarker for gut cell death, has paradoxically been shown to be reduced in moderate to severe COVID-19. We also found this pattern in a pilot cohort of mild (n = 18) and moderately severe (n = 19) COVID-19 patients in Milan from March to June 2020. These patients were part of the first phase of COVID-19 in Europe and were therefore all unvaccinated. After exclusion of outliers, patients with more severe vs milder disease showed reduced FABP2 levels (median [IQR]) (124 [368] vs. 274 [558] pg/mL, P < 0.01). A reduction in NMR measured plasma relative lipid-CH3 levels approached significance (median [IQR]) (0.081 [0.011] vs. 0.073 [0.024], P = 0.06). Changes in circulating lipid levels are another feature commonly observed in severe COVID-19 and a weak positive correlation was observed in the more severe group between reduced FABP2 and reduced relative lipid-CH3 and lipid-CH2 levels. FABP2 is a key regulator of enterocyte lipid import, a process which is inhibited by gut SARS-CoV-2 infection. We propose that the reduced circulating FABP2 in moderate to severe COVID-19 is a marker of infected enterocyte functional change rather than gut damage, which could also contribute to the development of hypolipidemia in patients with more severe disease.

Diversity of hepatitis B virus infecting Malaysian candidate blood donors is driven by viral and host factors.

Malaysia is a medium endemic country for hepatitis B virus (HBV) infection but little is known about HBV strains circulating in Malaysian blood donors. Viral load, HBsAg concentrations and nested PCR products from 84 HBV surface antigen (HBsAg) positive samples were analysed in detail. Median viral load was 3050 IU/mL and median HBsAg 1150 IU/mL. Fifty-six full genome, 20 pre-S/S, 1 S gene and six basic core promoter/precore-only sequences were obtained. Genotypes B and C were present at a ratio of 2:1, and two genotype D samples were obtained, both from donors of Indian background. Phylogenetically, genotype B was more diverse with subgenotypes B2-5, B7 and B8 present, while most genotype C strains were from subgenotype C1. Genotypes B and C were equally frequent in ethnic Malays, but 80% of strains from Chinese were genotype B. HBsAg concentrations were higher in genotype C than in genotype B, in Chinese than Malays and in donors under the age of 30. HBV vaccine escape substitutions (P120S/T, I126N and G145G) were present in six strains. In the large surface protein, immuno-inactive regions were more mutated than CD8 epitopes and the major hydrophilic region. Strains of genotype B or from ethnic Malays had higher genetic diversity than strains of genotype C or from Chinese donors. Hence HBV strains circulating in Malaysia are phylogenetically diverse reflecting the ethnic mix of its population. Ethnic Malays carry lower HBsAg levels and higher genetic diversity of the surface antigen, possibly resulting in more effective immune control of the infection.

The state of hepatitis B and C in Europe: report from the hepatitis B and C summit conference*.

Worldwide, the hepatitis B virus (HBV) and the hepatitis C virus (HCV) cause, respectively, 600,000 and 350,000 deaths each year. Viral hepatitis is the leading cause of cirrhosis and liver cancer, which in turn ranks as the third cause of cancer death worldwide. Within the WHO European region, approximately 14 million people are chronically infected with HBV, and nine million people are chronically infected with HCV. Lack of reliable epidemiological data on HBV and HCV is one of the biggest hurdles to advancing policy. Risk groups such as migrants and injecting drug users (IDU) tend to be under-represented in existing prevalence studies; thus, targeted surveillance is urgently needed to correctly estimate the burden of HBV and HCV. The most effective means of prevention against HBV is vaccination, and most European Union (EU) countries have universal vaccination programmes. For both HBV and HCV, screening of individuals who present a high risk of contracting the virus is critical given the asymptomatic, and thereby silent, nature of disease. Screening of migrants and IDUs has been shown to be effective and potentially cost-effective. There have been significant advances in the treatment of HCV and HBV in recent years, but health care professionals remain poorly aware of treatment options. Greater professional training is needed on the management of hepatitis including the treatment of liver cancer to encourage adherence to guidelines and offer patients the best possible outcomes. Viral hepatitis knows no borders. EU Member States, guided by the EU, need to work in a concerted manner to implement lasting, effective policies and programmes and make tackling viral hepatitis a public health priority.

Thrombolytic treatment of acute myocardial infarction in the presence of ventricular paced rhythm.

Usually, therapeutic decisions in patients with acute chest pain are based on the 12-lead electrocardiogram because ST-segment elevation is highly specific for myocardial infarction, but the presence of pacing-induced repolarization changes makes electrocardiogram interpretation difficult. The authors report an acute myocardial infarction patient with ventricular paced rhythm successfully treated by thrombolytic therapy. The aim of this work aims to highlight the difficulty with electrocardiographic diagnosis and timely treatment of myocardial infarction in the presence of ventricular pacing.

Review article: management of patients with chronic hepatitis C virus infection and "normal" alanine aminotransferase activity.

BACKGROUND: Hepatitis C virus infection, a major cause of chronic liver disease, occurs with normal serum alanine aminotransferase activity in approximately 25% of patients. These patients have historically remained untreated but substantial evidence indicates liver damage, progression of disease and impaired quality of life in some individuals. AIM: To review the current management of patients with chronic hepatitis C and normal alanine aminotransferase activity. METHODS: This review represents the summary of discussions at a Clinical Workshop with a comprehensive literature searching of available databases (PubMed and Embase). RESULTS: Current limits defining normal serum alanine aminotransferase activity are not representative of a "healthy" status. Most patients with hepatitis C and normal alanine aminotransferase levels have histologically proven liver damage that, although generally mild, may be significant (> or =F2) in up to 20% of patients and progresses at approximately 50% of the rate in patients with elevated alanine aminotransferase levels. Some patients have persistently normal alanine aminotransferase activity and may have a more benign outcome, but a significant proportion (> or =20%) experience periods of increased serum alanine aminotransferase activity which may be associated with enhanced disease progression. CONCLUSIONS: A treatment approach that considers host and virus-related variables and optimizes patient and cost benefits may therefore provide more effective management of patients with chronic hepatitis C and normal alanine aminotransferase activity.

Animal model for liver cell banking from non-heart beating donors after prolonged ischaemia time.

BACKGROUND AND AIM: Although there is a growing interest on the use of non-heart beating donors to enlarge the liver donor pool, livers with prolonged warm ischaemia time are not currently considered for organ transplantation. We hypothesised that these organs may represent a source of hepatocytes for cell transplantation and/or use in bioartificial liver devices. Thus, we investigated if prolonged ischaemia could influence the recovery and viability of functional hepatocytes dissociated from rat livers. METHODS: Hepatocytes were isolated from the liver within 15 min after death (t=15 min) and after 4, 8 and 12h of ischaemia. Cells were either maintained in culture or cryopreserved. In all products, we evaluated cell recovery and viability, hepatocyte markers and cellular functions, including albumin and urea production. RESULTS: The number of cells per gram of tissue was similar at 15 min, 4 and 8h, while it was significantly decreased at 12h. About 0.2 x 10(6) viable cells expressing hepatocyte markers and producing albumin and urea were isolated up to 8h of ischaemia per gram of tissue. CONCLUSIONS: Recovery of viable and functional hepatocytes seems possible after prolonged ischaemia time. These data warrant the evaluation of hepatocyte isolation from human livers of non-heart beating donors.

The current risk of retroviral infections transmitted by transfusion in patients who have undergone multiple transfusions. Cooleycare Cooperative Group.

BACKGROUND: To conduct a multicenter, prospective survey within the program of the Cooleycare Cooperative Group to evaluate the rate of transfusion-transmitted infections with human immunodeficiency virus (HIV) and human T-lymphotropic virus (HTLV) in a cohort of patients who were homozygous for beta thalassemia and underwent multiple transfusions during the 6-year follow-up. PATIENTS AND METHODS: One thousand three hundred eighty-four patients with beta thalassemia from 36 centers were enrolled from December 1989 to March 1990. Serum samples were tested at regular intervals during the period from December 1989 to March 1996 for anti-HIV and anti-HTLV antibodies in 1 laboratory. Samples from 1073 and 1001 of the 1384 patients were available for evaluation also during the periods from December 1992 to March 1993 and December 1995 to March 1996, respectively. The risk of acquiring infection was calculated by the ratio between the number of patients who experienced seroconversion and the number of red blood cell units administered to the patients during the study period. RESULTS: The prevalence of HIV infection found in the period from December 1989 to March 1990 was 2.9% (40 of 1384 patients). During follow-up, 1 of 1001 patients showed anti-HIV seroconversion. The incidence of HIV infection was 1.7 per 10,000 person-years (upper boundary of the 95% confidence interval, 5 per 10,000). The risk of HIV infection was 1 in 190,000 U (upper boundary of the 95% confidence interval, 1 in 67,000). At baseline, 4 patients were infected with HTLV (3 with HTLV-1 and 1 with HTLV-2). No seroconversions were observed during follow-up; the risk of HTLV infection was less than 1 in 190,000 U. CONCLUSION: The application of reliable screening procedures for donor selection reduced the transmission of transfusion-associated HIV infection in 1989-1995 to fewer than 2 cases in 10,000 person-years or 1 case per 190,000 units of red blood cells.

Transmission of viral hepatitis by blood and blood derivatives: current risks, past heritage.

For more than 40 years in the history of transfusion medicine, transmission of viral hepatitis from infected donors to recipients has been a frequent and serious adverse effect of the administration of blood components and plasma derivatives. This epidemic is now over, at least in developed and resource-rich countries. Hence, the attention of clinicians and investigators now focuses mainly on the measures to reduce the residual risk, on the possible emergence of novel or undiscovered agents causing post-transfusion hepatitis, and on the long-term outcome of patients who became infected more than ten years ago. The present article reviews these issues.

Clinical management of HCV carriers with normal aminotransferase levels.

An ad hoc committee appointed by the Italian Association for the Study of the Liver (AISF) proposed these Practice Guidelines for the management of HCV carriers with persistently normal aminotransferase levels. Only stringent ALT determinations will make it possible to distinguish these subjects from those in temporary biochemical remission. The overall prevalence in Italy has been estimated between 1.5 and 10.6%. HCV RNA quantitation and genotype determination are not predictors of the presence and severity of liver damage nor correlate with the outcome of the disease, and should not be used in clinical practice for the management and surveillance of HCV carriers with normal ALT. Only a minority of HCV carriers with normal ALT levels show a normal morphological picture (true 'healthy carriers'). Disease activity is mild in most cases; fibrosis is generally mild and cirrhosis is very rare. Histological activity, as monitored by sequential liver biopsies, seems to have very slow evolution. HCV carriers should not undergo liver biopsy on a routine basis. Liver biopsy can be reasonably proposed only in selected cases. Until the results of studies with PEG interferon plus ribavirin are available, HCV carriers should not receive antiviral treatment outside controlled experimental studies.

Clinical course of pregnant women with chronic hepatitis C virus infection and risk of mother-to-child hepatitis C virus transmission.

As far as concerns chronic hepatitis C virus infection in pregnant women, different points remain to be elucidated, such as the clinical course, the rate of mother-to-child hepatitis C virus transmission and, in particular, its route and the possible risk factors. This review aimed to analyse current data on the prevalence of chronic hepatitis C virus infection in pregnant women and its relationship with risk factors, the rate of mother-to-child hepatitis C virus transmission and the factors possibly involved, particularly the maternal hepatitis C virus viral load and the human immunodeficiency virus coinfection, and the type of delivery and feeding. Finally, the appropriate timing for HCV-RNA testing in newborns has been reviewed.

Quality-related variables at hepatological websites.

BACKGROUND: The amount of hepatology-related information available on the Internet has substantially increased, but little is known about the characteristics and quality of the websites. AIM: The aim of this study was to describe analytically and evaluate critically the information concerning three diseases of hepatological interest: chronic hepatitis, hemochromatosis and Caroli's disease. METHODS: In accordance with a validated method, the three search terms were entered into four English language search engines and the first five links of each were considered (a total of 60 sites). The characteristics of the websites were described and their quality was evaluated by three independent reviewers who assigned scores of 1-5 for accuracy, reliability and depth. The relationships between the site characteristics and quality scores were analysed by means of multiple logistic regression. RESULTS: The overall rating score was sufficient (>3) in 51% (95% confidence interval: 38-65%) of cases. The majority of the sites (73%) were aimed at patients rather than at physicians. Commercial sponsorship was significantly more frequent among the chronic hepatitis sites (45%) than among the hemochromatosis (15%) or Caroli's disease sites (0%) (P = 0.002); 61% of the commercial sites did not include a financial disclosure. The only variable that independently related to poor quality was the presence of commercial sponsorship (odds ratio 18.1; 95% confidence interval: 1.7-192.5). CONCLUSIONS: Hepatological websites are characterised by poor quality and are mainly aimed at patients. Quality is negatively affected by commercial interests, which are often undeclared. Guidelines for the certification and surveillance of websites relating to liver diseases are highly advisable.

Proliferating cell nuclear antigen assessed by a computer-assisted image analysis system in patients with chronic viral hepatitis and cirrhosis.

BACKGROUND: Assessment of liver cell proliferation by immunodetection of proliferating cell nuclear antigen may predict regenerative potential and survival of liver and hepatocellular carcinoma risk in patients with chronic viral hepatitis. AIM: To evaluate proliferating cell nuclear antigen status and its clinical significance in a large cohort of patients with chronic viral hepatitis and different degree of liver damage by a computer assisted imaging analysis system. MATERIALS: Liver biopsies from 358 patients with chronic hepatitis (259 males, 49 years, 63% with hepatitis C infection, 27% with hepatitis B virus, 10% with multiple infections) were studied. METHODS: Proliferating cell nuclear antigen was localised by immunoperoxidase on microwave oven pre-treated formalin-fixed, paraffin embedded sections using PC10 monoclonal antibody. Proliferating cell nuclear antigen labelling index was calculated by an automated imaging system (Immagini e Computers, Milan, Italy). RESULTS: Mean proliferating cell nuclear antigen labelling index ranged from 0.1% for patients with minimal changes to 3.6% for those with cirrhosis and hepatocellular carcinoma. Overall, proliferating cell nuclear antigen labelling index was higher in males, in older patients, in multiple infections and in hepatitis C virus compared to hepatitis B virus related cases. By linear regression analysis, proliferating cell nuclear antigen labelling index correlated with older age, male gender; higher transaminase levels, hepatitis C virus, higher histological gradIng and staging: by multivariate analysis male gender, hepatitis C virus, higher grading and staging resulted as independent variables. Both hepatitis C virus or hepatitis B virus cirrhotics had similar liver cell proliferation rate but those with hepatitis B virus had higher prevalence of liver cell dysplasia with respect to those with hepatitis C virus. CONCLUSIONS: Proliferating cell nuclear antigen labelling index was a reliable assay for assessing liver cell proliferation rate in patients with chronic viral hepatitis and correlated with liver disease severity

High frequency of anti-endomysial reactivity in candidates to heart transplant.

BACKGROUND: A possible link between coeliac disease and dilated cardiomyopathy has recently been suggested. AIMS: . To assess the frequency of anti-endomysial antibodies, the marker for coeliac disease, in patients with different forms of heart failure, and to establish the clinical features of those endomysial antibody positive. SUBJECTS AND METHODS: . A total of 642 consecutive patients entering the waiting list for heart transplantation from 1995 through 1997 were studied. The prevalence of endomysial IgA antibodies, determined by indirect immunofluorescence, was compared to that observed in three surveys conducted in the Italian general population. RESULTS: Of the 642 patients, 12 (1.9%; 95% confidence interval 0.97-3.2) resulted endomysial antibody positive, versus 34/9,720 healthy controls (0.35%; 95% confidence interval, 0.23-0.47), accounting for a relative risk of 5.3 (95% confidence interval, 2.8-10.3). Anti-endomysial antibodies were found in 6/275 patients with dilated cardiomyopathy and 6/367 with other forms of heart failure (2.2% versus 1.6%; 95% confidence interval 0.8-4.7 and 0.6-3.5), with no statistical difference. The 12 endomysial antibody positive patients were leaner (body mass index, 22.0 +/- 1.9 vs 24.2 +/- 3. 1, p<0. 05) than 36 seronegative patients matched for baseline demographics and aetiology of cardiomyopathy No differences were observed as regards clinical, biochemical and echocardiographic features, mortality in waiting list and 2-year post-transplant survival. CONCLUSIONS: Patients with end-stage heart failure are at increased risk for coeliac disease as compared to the general population.