Cross-species transmission and histopathological variation in specific-pathogen-free minipigs infected with different hepatitis E virus strains.

Hepatitis E virus (HEV) is a major cause of viral hepatitis worldwide. Pigs are the natural host of HEV genotype 3 and the main reservoir of HEV. As the host range of HEV genotype 3 expands, the possibility that HEV from various species can be transmitted to humans via pigs is increasing. We investigated the potential cross-species transmission of HEV by infecting minipigs with swine HEV (swHEV), rabbit HEV (rbHEV), and human HEV (huHEV) and examining their histopathological characteristics and distribution in various organs. Fifteen specific-pathogen-free Yucatan minipigs were infected with swHEV, rbHEV, huHEV, or a mock control. In the present study, we analysed faecal shedding, viremia, and serological parameters over a seven-week period. Our results indicated that swHEV exhibited more robust shedding and viremia than non-swHEVs. Only swHEV affected the serological parameters, suggesting strain-specific differences. Histopathological examination revealed distinct patterns in the liver, pancreas, intestine, and lymphoid tissues after infection with each HEV strain. Notably, all three HEVs induced histopathological changes in the pancreas, supporting the association of HEVs with acute pancreatitis. Our results also identified skeletal muscle as a site of HEV antigen presence, suggesting a potential link to myositis. In conclusion, this study provides valuable insights into the infection dynamics of different HEV strains in minipigs, emphasizing the strain-specific variations in virological, serological, and histological parameters. The observed differences in infection kinetics and tissue tropism will contribute to our understanding of HEV pathogenesis and the potential for cross-species transmission.

Realm of hepatitis E: Challenges and opportunities.

Hepatitis E virus (HEV), responsible for widespread viral hepatitis, infects approximately 2.3 billion individuals globally, with a significant mortality burden in Asia. The virus, primarily transmitted through contaminated water and undercooked meat, is often underdiagnosed, particularly in immunocompromised patients. Current HEV treatments, while effective, are limited by adverse effects, necessitating research into safer alternatives. Moreover, HEV's extrahepatic manifestations, impacting the nervous and renal systems, remain poorly understood. This study underscores the imperative for enhanced HEV research, improved diagnostic methods, and more effective treatments, coupled with increased public health awareness and preventive strategies.

Extrahepatic Manifestations of Chronic Hepatitis C Virus (HCV) Infection.

Hepatitis C virus (HCV) is a well-recognized, major cause of various liver-related conditions such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Apart from liver disease, chronic HCV infection is also associated with several extrahepatic manifestations that can lead to significant morbidity and mortality. These extrahepatic manifestations include essential mixed cryoglobulinemia (EMC), lymphomas, porphyria cutanea tarda, lichen planus, necrolytic acral erythema, glomerulonephritis, subclinical autoantibody formation, immune thrombocytopenia, thyroid disease, Sjögren's disease/sicca symptoms, diabetes mellitus, ocular diseases, musculoskeletal disorders, cardiovascular diseases, neurocognitive dysfunction, and leukocytoclastic vasculitis. We are presenting a case of chronic HCV infection linked to the extrahepatic manifestations of the disease which can be directly related to HCV or indirectly related to EMC from HCV. An awareness and knowledge of these extrahepatic manifestations will highlight the importance of recognizing the symptoms for an early diagnosis and effective anti-viral treatment in order to improve or resolve the long-term complications of chronic HCV infection.

Demyelinating neuropathy in patients with hepatitis B virus: A case report.

BACKGROUND: Hepatitis B rarely leads to demyelinating neuropathy, despite peripheral neuropathy being the first symptom of hepatitis B infection. CASE SUMMARY: A 64-year-old man presented with sensorimotor symptoms in multiple peripheral nerves. Serological testing showed that these symptoms were due to hepatitis B. After undergoing treatment involving intravenous immunoglobulin and an antiviral agent, there was a notable improvement in his symptoms. CONCLUSION: Although hepatitis B virus (HBV) infection is known to affect hepatocytes, it is crucial to recognize the range of additional manifestations linked to this infection. The connection between long-term HBV infection and demyelinating neuropathy has seldom been documented; hence, prompt diagnostic and treatment are essential. The patient's positive reaction to immunoglobulin seems to be associated with production of the antigen-antibody immune complex.

Extrahepatic manifestations of HCV where do we stand? / Manifestaciones extrahepáticas del VHC. ¿Dónde nos encontramos?

Hepatitis C virus (HCV) infection has been associated as up 40–70% of patients with extrahepatic manifestations (EHM) and 36 different syndromes. These could be attributed to the fact that HCV is lymphotropic, particularly B lymphotropic, and not merely hepatotropic, and could trigger immunological alterations indirectly by exerting a chronic stimulus on the immune system with production of immunoglobulins having rheumatoid activity forming immune complexes and production of cryoglobulins. Cryoglobulinemoa plays a pivotal role in producing most EHM of HCV such as vasculitis, glomerulonephritis, arthritis and neuropathies. Less frequently; while less frequently, the direct viral cytopathic effect could lead to EHMs independent of cryoglobulinemia. The mainstay of treatment of EMH has been antivirals, since interferon era to direct-acting drugs era, with no differences between the two eras, despite the better virological response. Longer evaluation of virological response and clinical investigation with longer follow-ups are necessary.(AU)

La infección por el virus hepatitis C (VHC) se ha asociado a 40-70% de los pacientes con alguna manifestación extrahepática (MEH) y 36 síndromes diferentes, atribuibles a que el VHC es linfotrópico, particularmente linfotrópico B, y no simplemente hepatotrópico. El VHC podría desencadenar alteraciones inmunológicas al ejercer un estímulo crónico del sistema inmunológico con producción de inmunoglobulinas con actividad reumatoide y formación de complejos inmunes y crioglobulinas. Estas desempeñan un papel fundamental en la mayoría de las MEH como vasculitis, glomerulonefritis, artritis y neuropatías, mientras, menos frecuentemente, el efecto citopático viral directo podría conducir a MEH independientes de crioglobulinas. El principal tratamiento de las MEH ha sido el antiviral, desde la era del interferón hasta la de los fármacos de acción directa, sin diferencias entre las dos épocas, a pesar de la mejor respuesta virológica. Son necesarias evaluaciones más prolongadas de la respuesta virológica e investigación clínica con seguimientos más largos.(AU)

Treatment of HCV with direct-acting antivirals on reducing mortality related to extrahepatic manifestations: a large population-based study in British Columbia, Canada.

Background: HCV infection is associated with mortality due to extrahepatic manifestations (EHM). Sustained virologic response (SVR) following direct-acting antiviral (DAA) therapy has been linked to decreased all-cause and liver-related mortality. However, evidence regarding the impact of DAA on EHM-related deaths is lacking. This study aimed to assess the impact of DAA and SVR on EHM-related mortality. Methods: The British Columbia Hepatitis Testers Cohort comprises ∼1.7 million people tested for HCV between 1990 and 2015 and is linked with administrative health data. Among individuals diagnosed with HCV by 12/31/2020, those who received at least one DAA treatment were matched to those who never received treatment by the year of their first HCV RNA positive date. We compared three groups: treated & SVR, treated & no-SVR, and untreated; and generated EHM mortality rates and incidence curves. To account for differences in baseline characteristics, we used inverse probability of treatment weights (IPTW). IPTW-weighted multivariable cause-specific Cox regression models were adjusted for competing risk and confounders. Findings: Study population included 12,815 treated (12,287 SVR, 528 no-SVR) and 12,815 untreated individuals (median follow-up 3.4 years, IQR 2.9). The untreated group had the highest EHM mortality rate (30.9 per 1000 person-years [PY], 95% CI 29.2-32.8), followed by the treated & no-SVR group (21.2 per 1000 PY, 95% CI 14.9-30.1), while the treated & SVR group had the lowest EHM mortality rate (7.9 per 1000 PY, 95% CI 7.1-8.7). In the multivariable model, EHM mortality in the treated & SVR group was significantly decreased (adjusted cause-specific hazard ratio [acsHR] 0.20, 95% CI 0.18-0.23). The treated & SVR group had significant reductions in mortality related to each of the EHMs (78-84%). Interpretation: Treatment of HCV with DAA was associated with significant reductions in EHM-related mortality. These findings emphasize the critical importance of timely diagnosis and treatment of HCV to prevent deaths associated with EHM, and have important implications for clinical practice and public health. Funding: This work was supported by the BC Centre for Disease Control and the Canadian Institutes of Health Research (CIHR) [Grant # NHC-348216, PJT-156066, and PHE-337680]. DJ has received Doctoral Research Award (#201910DF1-435705-64343) from the Canadian Institutes of Health Research (CIHR) and Doctoral fellowship from the Canadian Network on Hepatitis C (CanHepC). CanHepC is funded by a joint initiative of the Canadian Institutes of Health Research (CIHR) (NHC-142832) and the Public Health Agency of Canada (PHAC).

Extrahepatic manifestations of HCV where do we stand?

Hepatitis C virus (HCV) infection has been associated as up 40-70% of patients with extrahepatic manifestations (EHM) and 36 different syndromes. These could be attributed to the fact that HCV is lymphotropic, particularly B lymphotropic, and not merely hepatotropic, and could trigger immunological alterations indirectly by exerting a chronic stimulus on the immune system with production of immunoglobulins having rheumatoid activity forming immune complexes and production of cryoglobulins. Cryoglobulinemoa plays a pivotal role in producing most EHM of HCV such as vasculitis, glomerulonephritis, arthritis and neuropathies. Less frequently; while less frequently, the direct viral cytopathic effect could lead to EHMs independent of cryoglobulinemia. The mainstay of treatment of EMH has been antivirals, since interferon era to direct-acting drugs era, with no differences between the two eras, despite the better virological response. Longer evaluation of virological response and clinical investigation with longer follow-ups are necessary.

Effect of treatment with direct-acting antiviral agents on the prognosis of extrahepatic diseases in patients with hepatitis C / 临床肝胆病杂志

The prognosis of patients with hepatitis C virus infection depends not only on liver lesions， but also on extrahepatic sequelae. Direct-acting antiviral agents （DAAs）， as the first-line drugs in the treatment of hepatitis C， have helped more and more patients achieve sustained virologic response and clinical cure， but its effect on the prognosis of extrahepatic diseases remains unclear. This article reviews the effect of DAAs treatment on the prognosis of extrahepatic diseases in patients with hepatitis C and points out that long-term follow-up monitoring is still required for patients with hepatitis C after cure.

Viral Biology and Immune Privilege in the Development of Extrahepatic Manifestations During Hepatitis E Virus Infection.

Hepatitis E virus (HEV) exhibits tropism toward hepatocytes and thus affects the liver; however, HEV may also affect other tissues, including the heart, kidneys, intestines, testicles, and central nervous system. To date, the pathophysiological links between HEV infection and extrahepatic manifestations have not yet been established. Considering that HEV infects multiple types of cells, the direct effects of virus replication in peripheral tissues represent a plausible explanation for extrahepatic manifestations. In addition, since the immune response is crucial in the development of the disease, the immune characteristics of affected tissues should be revisited to identify commonalities explaining the effects of the virus. This review summarizes the most recent advances in understanding the virus biology and immune-privileged status of specific tissues as major elements for HEV replication in diverse organs. These discoveries may open avenues to explain the multiple extrahepatic manifestations associated with HEV infection and ultimately to design effective strategies for infection control.

Acute Hepatitis E Induced the First Episode of Immune-Mediated Thrombotic Thrombocytopenic Purpura: The First Case Report.

Purpose: Hepatitis E virus infection mainly presents with liver-related symptoms, and multiple studies have shown that hepatitis E virus infection can also induce extrahepatic-related symptoms. Thrombotic thrombocytopenic purpura is an uncommon and fatal thrombotic microangiopathy characterized by severe thrombocytopenia, organ damage, and microangiopathic haemolytic anaemia. We report the first case in which acute hepatitis E induced the first episode of immune-mediated thrombotic thrombocytopenic purpura. Patients and Methods: A 53-year-old male was admitted to our emergency department with fever, thrombocytopenia, and abnormal liver function. Laboratory tests revealed significant bilirubin, AST, and ALT elevations, renal impairment, positive anti-HEV IgM and IgG antibody results, schistocytes on the blood smear, 0% ADAMTS-13 activity, and positive ADAMTS13 inhibitor results. He was diagnosed with acute hepatitis E, which induced the first episode of immune-mediated thrombotic thrombocytopenic purpura. Results: After receiving treatment with plasmapheresis, glucocorticoid medication, rituximab, and other supportive medicines, the patient's physiological circumstances and laboratory indicators improved, and a 4-month follow-up revealed no abnormalities. Conclusion: This is a unique case report of an acute hepatitis E-induced immune-mediated thrombotic thrombocytopenic purpura initial episode. This case report offers evidence that hepatitis E virus infection can cause thrombotic thrombocytopenic purpura. In patients with abnormal liver function and thrombocytopenia, we advise screening for hepatitis E or thrombotic thrombocytopenic purpura.

Prevalence of hepatitis C virus among patients with arthralgia: is it logic for screening?

BACKGROUND: Hepatitis C virus (HCV) is well-known to be associated with multiple extrahepatic manifestations such as arthralgia, myalgia, arthritis, and vasculitis. Many studies reported frequent rheumatologic manifestations among patients infected by HCV. The purpose of this study was to determine the prevalence of HCV among chronic unexplained arthralgia patients in order to aid in the early detection and treatment of silent HCV infection. METHODS: This study was a cross-sectional observational study conducted from July 2020 to May 2022. It included 145 individuals suffering from chronic unexplained arthralgia, with vast majority having oligoarticular joint pain (110, 75.9%). They were 103 (71%) females and 42 (29%) males. Serum samples from all patients were examined for the presence of anti-HCV antibodies using a rapid immunochromatographic assay. Seropositive samples were further examined using polymerase chain reaction (PCR) for detection of HCV RNA to confirm HCV infection. RESULTS: Out of 145 patients who complained of arthralgia, seven patients tested positive for anti-HCV with a seroprevalence of 4.8% while five patients tested positive for HCV-RNA with a molecular prevalence of 3.4%. All positive patients were males (11.9%) with high statistical significance (χ2 = 12.7 and p = 0.002). No association was found between HCV infection and age, blood transfusion, surgery, using personal shaving tools, or being a health-care worker. CONCLUSIONS: The prevalence of HCV was high among males who complained of arthralgia. Patients with arthralgia, especially male patients, are recommended to perform HCV screening test.

Genotype 4 HEV infection triggers the initiation and development of acute pancreatitis.

The role of HEV infection in AP remains unclear. 1000 patients with AP and 1000 HCs were enrolled, and pancreatitis was evaluated in HEV-infected rhesus macaques. The positive rates of anti-HEV IgG, IgM, and HEV RNA in the AP patients were significantly higher than HCs. With the increase in the severity of AP, the percentage of HEV infection increased. AP patients were divided into AP- and AP + AHE groups. The percentage of severe AP in the AP + AHE group was significantly higher than in the AP- group. HEV infection was one of the main independent risk factors and had high predictive power for AP outcomes. A high level of HEV titer would prolong the recovery time and increase the risk of recurrent AP. Moreover, AP + AHE patients receiving conservative treatment showed a better prognosis. Furthermore, HEV can replicate in the pancreas of rhesus macaques. The pancreatic islet structure was damaged, the tissue was loose after 272 dpi, and a large amount of hyperemia appeared after 770 dpi. HEV infection also caused a large number of inflammatory cells in the pancreas. The pancreas and liver had a comparable viral load. HEV infection affects AP's occurrence, development, and prognosis.

Clinical Manifestations of Hepatitis E.

The clinical manifestations of hepatitis E are similar to those of other types of viral hepatitis. While acute hepatitis E is usually self-limited, pregnant women and chronic liver disease patients suffering from acute hepatitis E usually present with severe clinical manifestations that may develop into fulminant hepatic failure. Chronic HEV infection is typically seen in organ transplant patients; most HEV cases are asymptomatic and rarely display jaundice, fatigue, abdominal pain, fever, fatigue, or ascites. The clinical manifestations of HEV infection in neonates are diverse and have varied clinical signs, biochemistry, and virus-biomarkers. Lastly, the extrahepatic manifestations and complications of hepatitis E are in need of further study.

A personal journey through Oral medicine: The tale of hepatitis C virus and oral lichen planus.

Around 30 years ago, the hepatitis C virus (HCV) was identified and soon it was shown that this virus, further to the liver, could affect a variety of organ systems. This article summarizes how an association between HCV and a relatively common oral disorder, oral lichen planus (OLP), was revealed. Through key publications, many of them published in Journal of Oral Pathology and Medicine, it is shown the building of strong epidemiologic evidence supporting the association and how a plausible pathogenic link between HCV and OLP was discovered. As HCV infection is now potentially curable, modern direct antiviral agents can be used to effectively cure also OLP in HCV-infected patients.

Impact of direct-acting antiviral treatment for hepatitis C on cardiovascular diseases and extrahepatic cancers.

PURPOSE: The impact of direct-acting antivirals (DAAs) on extrahepatic complications in chronic hepatitis C (CHC) patients remains poorly described. We estimated the association of DAAs with cardiovascular events and extrahepatic cancers. METHODS: The prospective ANRS CO22 HEPATHER cohort was enriched with individual data until December 2018 from the French Health Insurance Database (SNDS). CHC patients were enrolled between August 2012 and December 2015 in 32 French hepatology centers. A total of 8148 CHC adults were selected. Cardiovascular events (stroke, acute coronary syndrome, pulmonary embolism, heart failure, arrhythmias and conduction disorders [ACD], peripheral arterial disease [PAD]) and extrahepatic solid cancers were derived from the SNDS. Associations between DAAs and extrahepatic events were estimated using marginal structural models, with adjustments for clinical confounders. RESULTS: Analyses of 12 905 person-years of no DAA exposure and 22 326 person-years following DAA exposure showed a decreased risk of PAD after DAA exposure (hazard ratio [HR], 0.54; 95% CI, 0.33-0.89), a beneficial effect of DAAs on overall cardiovascular outcomes in patients with advanced fibrosis (aHR, 0.58; 95% CI, 0.42-0.79), and an increased risk of ACD (hazard ratio [HR], 1.46; 95% CI, 1.04-2.04), predominant after the first year following DAA initiation. There was no association between DAAs and extrahepatic cancer risk (HR, 1.23; 95% CI, 0.50-3.03). CONCLUSIONS: DAAs were not associated with extrahepatic cancer development or reduction. They were associated with a decreased risk of PAD and an increased risk of ACD, supporting long-term cardiac monitoring after DAA therapy.

[Extra hepatic manifestations of hepatitis A]. / Les manifestations extra-hépatiques de l'hépatite A.

Viral hepatitis A is characterized by a wide range of clinical pictures ranging from a completely unapparent infection to a fulminant, potentially fatal hepatitis or the classical icteric form. Hepatitis A can develop in an unusual way and extrahepatic manifestations (neurological, renal, haematological, cholecystitis, acute pancreatitis, vasculitis, etc.) can occasionally complicate the course of the disease. Although hepatitis A infection was identified in the early 1970s, there are few or no studies assessing the actual frequency of these complications. They have been studied mainly through clinical case reports. Currently, since the disease has become more common in adults, these complications are being increasingly observed. We present an update on extrahepatic complications during hepatitis A, which should be known by both specialist doctors (infectiologists internists, hepatologists and others) and general practitioners.

[Case of multiple systemic (extrahepatic) manifestations of chronic HCV infection (analysis of the literature and own observations). Case report].

The article presents a description of a patient with chronic HCV infection and multiple extrahepatic manifestations, which manifested in dynamics and were recorded with a different sequence during 15 years of follow-up. In the patient we observed, the most frequently recorded extrahepatic manifestations were verified: porphyria cutanea tarda, mixed cryoglobulenemia, and utoimmune thyroiditis. Chronic HCV infection is often diagnosed in the presence of psoriasis was assessed as a paraneoplastic disease.

Acute Kidney Injury as a Rare Complication of Acute Hepatitis E in a Child; A Case Report.

Hepatitis E virus (HEV) infection is a significant public health problem, which infects 20 million individuals every year. The clinical presentation of acute HEV infection is similar to hepatitis A virus (HAV) infection, and few affected children may progress to develop acute liver failure. Extrahepatic manifestations involving other systems have been reported with acute and chronic HEV genotype 3 infections both in adults and children. Herein we report acute kidney injury as a rare complication of acute hepatitis E in a child who recovered with a medical line of management.

Prevalence of HEV infection in acute non-ABC hepatitis and prognostic role of extrahepatic manifestations.

Background: HEV-3 and HEV-4 are emerging cause of zoonotic acute hepatitis in high-income countries. In Europe the disease is underdiagnosed but hyperendemic areas have been identified. We describe a population with acute non-ABC (n-ABC) hepatitis in Abruzzo, the Italian region with the highest seroprevalence reported. The study was included in the surveillance of acute hepatitis E by the Italian Institute of Public Health started in 2004 and implemented in 2015. Methods: Patients with n-ABC hepatitis during 2004-2018 in all Abruzzo Infectious Disease Departments were tested for HEV-IgM (Wantai®) and HEV-RNA (ORF3). Positive samples were sequenced (Beckman Coulter®) and phylogenetic tree (MEGA 6.06 software) obtained. Clinical data were retrospectively collected and an alimentary risk factors-questionnaire was administered. Categorical and quantitative variables were compared (Chi square test or Fisher test and Wilcoxon test). Results: 97 hospitalized patients were tested, most cases (91.7%) after 2015. Overall, HEV-IgM resulted positive in 36% and HEV-RNA detectable in 33.3%. All 24 sequences obtained were HEV-3, with two small groups of closely related strands. L'Aquila was the Province with higher positivity rate (44%). Retrospective clinical data were acquired in 86.5% of patients, no one having liver failure. Higher ALT-levels (1282.34 vs 893.25, p=0.0139) and extrahepatic symptoms (OR 16.69, p=0.0018) were strongly associated with HEV-IgM presence. Two small outbreaks are described. Conclusions: More than one third of n-ABC hepatitis in all Abruzzo are HEV-related. Extrahepatic symptoms correlate with HEV aetiology. Implementing surveillance is mandatory to really understand the extent of the disease.