This letter reports long-term (6-11 years) follow-up of a series with acute Hepatitis E virus (HEV) infection, highlighting its neurotropic potential in immunocompetent individuals. Among 20 individuals with documented viremia, 15% developed delayed meningo-encephalomyelitis, despite no acute neurological signs. HEV RNA detection in cerebrospinal fluid supports the role of active viral replication in central nervous system invasion. Both genotype 3 and genotype 1 were implicated. Two patients later developed neoplastic diseases in lung and pancreas. Although limited by small sample size, findings suggest neurological complications of HEV may be underrecognized and warrant broader diagnostic screening beyond acute hepatitis.

Interstitial lung diseases (ILDs) comprise a heterogeneous group of lung disorders marked by progressive fibrosis and increased vulnerability to respiratory infections, which can trigger sudden outbreaks and worsen outcomes. Vaccination is a key preventive strategy in ILD patients to reduce infection-related morbidity and mortality. This review examines the importance of immunisation in individuals with ILDs, with particular emphasis on influenza, pneumococcal and severe acute respiratory syndrome coronavirus 2 vaccines endorsed by major health organisations. Despite evidence of their effectiveness, vaccination rates among patients with ILD remain low. Tailored vaccine strategies may enhance protection in this group. Additionally, although data are limited, immunisations against respiratory syncytial virus, Haemophilus influenzae, varicella-zoster virus, and pertussis may provide additional protection, particularly in older adults and those receiving immunosuppressive therapy. Hepatitis B vaccination should also be considered for patients on immunosuppressive therapies to prevent infection. Healthcare providers should actively encourage vaccination and address obstacles to immunisation in ILD patients. More research is necessary to assess the safety, effectiveness and optimal vaccination approaches for this vulnerable group. Ultimately, implementing systematic vaccination programmes and clear clinical guidelines is essential to improve preventive care and health outcomes for those with ILDs.

Hepatitis E virus (HEV) infection is a major cause of acute viral hepatitis worldwide. HEV is a positive-strand RNA virus encoding three open reading frames (ORFs). The ORF3 protein is a small membrane-associated protein essential for viral particle secretion; however, its precise role in the viral life cycle remains incompletely understood. Here, we performed immunoprecipitation followed by mass spectrometry to identify host proteins interacting with the HEV ORF3 protein. Candidate interactors were validated by co-immunoprecipitation, confirming physical interactions between ORF3 and cysteine-rich and transmembrane domain-containing protein 1 (CYSTM1), Ras-related protein Rab24, and transferrin receptor 1 (TfR1). Confocal microscopy demonstrated colocalization of all three host factors with ORF3 protein. Gene silencing and knockout revealed that each protein contributes to virus production, with TfR1 depletion producing the most pronounced effect. In cells harboring replicating HEV, TfR1 colocalized with the ORF2 (capsid) and ORF3 proteins at Rab11A-positive recycling endosomes. Silencing of TfR1 in primary human hepatocytes, followed by HEV RNA transfection or infection, confirmed its role in virus production, particularly in the assembly of infectious particles, consistent with its colocalization with the HEV ORF2 protein. Collectively, our proteomics-based analysis identifies TfR1, along with CYSTM1 and Rab24, as novel ORF3-interacting host factors required for efficient production of infectious HEV. These findings provide new insights into the role of ORF3 protein in viral assembly and highlight TfR1 as a key host factor in the HEV life cycle.

Despite curative hepatitis C virus (HCV) treatments, only one-third of cases receive treatment nationally. To evaluate how demographic and clinical characteristics were associated with HCV test result awareness and treatment completion, we analyzed programmatic data of a linkage-to-care program in Los Angeles County. Among 512 respondents, 433 (85%) were aware of their positive test result; of those, 138 (32%) received treatment. Black or African American people were less likely (adjusted prevalence odds ratio [APOR] = 0.43; 95% CI, 0.20-0.92) to be aware of their positive test result than White people. Among those aware of their test results, treatment completion was more likely when a specialist physician ordered the HCV test (APOR = 2.13; 95% CI, 1.03-4.41) than when a primary care provider ordered it, and people with symptoms of liver disease were less likely to complete treatment (APOR = 0.16; 95% CI, 0.08-0.35) than people without symptoms. Clinical and community notification and linkage programs, with a focus on racial and ethnic minority populations, will be necessary to bridge the gap between awareness and treatment initiation among Los Angeles County residents.

Despite the advent of well-tolerated and curative direct-acting antivirals (DAAs) for hepatitis C virus (HCV), rates of acute HCV infections have increased in the past decade, persistently falling short of national eradication goals. HCV elimination strategies have adopted the care cascade, a framework originating in HIV care, to assess where patients are lost at each step of diagnosis, linkage to care, receipt of DAAs, and achievement of sustained virologic response. Interventions aimed at strengthening the HIV care cascade, including community-based testing, rapid initiation of treatment, and federal funding for treatment and housing, have been instrumental in increasing the number of people living with HIV who achieve viral suppression. Widescale uptake of HCV treatment, meanwhile, continues to face barriers, from payor restrictions to provider hesitance to treat patients who use drugs, despite evidence demonstrating high rates of treatment completion among this population. HIV care has critically reframed treatment nonadherence as a need for more support, rather than as a value judgment and as a reflection of the patient's ability to receive treatment. We advocate for this approach to be applied to HCV care to provide broader and more equitable access to HCV treatment, and ultimately cure, particularly for marginalized populations such as people who use drugs (PWUD). We propose solutions for increasing HCV treatment uptake using lessons from HIV care, including using a test and treat approach to initiate DAAs during hospital admission.

Liver sinusoidal endothelial cells (LSECs) form a specialized discontinuous microvascular interface between sinusoidal blood and the hepatic parenchyma. Functioning as a central regulator of hepatic homeostasis, LSECs integrate metabolic, inflammatory, and hemodynamic signals to maintain sinusoidal permeability, immune tolerance, vascular tone, and lipid exchange. During acute injury or sustained hepatic stress, LSECs may lose their differentiated sinusoidal phenotype and acquire features of capillarization, including fenestrae loss, subendothelial matrix accumulation, impaired scavenging activity, and attenuation of KLF2-eNOS-NO signaling. Capillarized LSECs are not merely a byproduct of hepatic damage; instead, they may function as early endothelial sentinels and important contributors to the amplification of parenchymal injury, inflammation, fibrogenesis, and tumor immune evasion. This review summarizes the physiological functions of LSECs and examines mechanisms through which LSEC dysfunction contributes to acute liver injury, metabolic dysfunction-associated steatotic liver disease, viral hepatitis, cirrhosis, and hepatocellular carcinoma. By comparing conserved mechanisms with disease-specific spatial and molecular triggers, this review highlights how LSEC phenotypic switching disrupts the angiocrine-immune-fibrotic axis and contributes to disease progression. Recent advances in single-cell and spatial omics, LSEC subpopulation heterogeneity, and capillarization-aware therapeutic delivery are further discussed. Finally, therapeutic reprogramming of dysfunctional LSECs toward a quiescent, fenestrated, and tolerogenic phenotype is proposed as a strategy to restore sinusoidal homeostasis and improve treatment of liver diseases.

More than 300 million people globally have viral hepatitis. Predominantly caused by hepatitis A, B, and C viruses, viral hepatitis continues to confer high levels of morbidity and mortality despite the availability of vaccines and advances in therapies. Symptom severity varies during acute infection, with management focused on stabilization and serial monitoring to ensure resolution of liver injury. Infection with hepatitis A virus is generally self-limited, with low but increasing rates of mortality and hospitalization due to factors such as poorer baseline health status, older age, and coexisting liver disease. About 95% of acute hepatitis B cases in adults resolve spontaneously; treatment is rarely needed in acute infection. In contrast, only about 25% of acute hepatitis C cases resolve spontaneously, and immediate initiation of treatment at diagnosis is recommended. Screening for hepatitis B and C is recommended for all adults. Hepatocellular carcinoma screening is recommended for those with hepatitis B and cirrhosis or specific risk factors, and for those with hepatitis C and advanced liver fibrosis or cirrhosis. Treatment of hepatitis B involves assessment of specific factors to determine antiviral need; the goal of treatment is suppression of viral replication, thereby reducing risks of liver disease progression and hepatocellular carcinoma. Curative medications are available for hepatitis C.

Objective: Metagenomic sequencing was employed to analyze the pathogen detection profile in pediatric severe acute non-A-E hepatitis. Methods: Based on the platform of the China Childhood Severe Acute Hepatitis Collaborative Group, a case series study was conducted. This study enrolled 36 children with severe acute non-A-E hepatitis, who were admitted to 17 hospitals between April and July 2022. Clinical data, including etiological test results and liver function tests, were collected, and peripheral blood and nasopharyngeal swab specimens were obtained. Metagenomic next-generation sequencing (mNGS) was performed to detect potential infectious pathogens. Results: Among 36 children, there were 24 males and 12 females, with an onset age of 3.5 (1.1, 9.0) years. Common clinical symptoms were fever in 22 cases (61%), jaundice in 13 cases (36%), vomiting in 12 cases (33%), abdominal pain in 10 cases (28%), rash in 10 cases (28%), and diarrhea in 3 cases (8%). Serum alanine aminotransferase and aspartate aminotransferase levels were 950 (826, 1 404) and 811 (498, 1 295) U/L, respectively. Using PCR, plasma Epstein-Barr virus (EBV)-DNA was tested in 31 cases (86%) and plasma cytomegalovirus (CMV)-DNA in 25 cases (69%), and all results were below 5×10[5] copies/L. Plasma mNGS was performed on all 36 patients, detecting 11 viruses. These included EBV in 14 cases, CMV in 12 cases, human adenovirus in 2 cases, herpes simplex virus type 1 in 2 cases, adeno-associated virus type 2 (AAV2) in 1 case, and 6 other viruses. No patient tested positive for both human adenovirus and AAV2 simultaneously. Plasma mNGS results showed a viral read count of 4 (2, 10) per 1×10[8] reads. Nasopharyngeal swab mNGS was performed on 8 cases (22%), detecting 7 viruses. These included human herpesvirus 7 in 4 cases, EBV in 3 cases, and CMV in 3 cases, as well as 4 other viruses. Human adenovirus and AAV2 were not detected. Among the 4 children with human herpesvirus 7, 2 cases were also positive for human herpesvirus 6B, but neither virus was detected in their plasma mNGS. Conclusions: The detection rates of human adenovirus and AAV2 are both low among children with severe acute non-A-E hepatitis, and there are no cases of co-infection with both viruses.

Hepatitis B virus is a well-known infectious etiology of acute and chronic liver disease worldwide. Notably, 90% of children infected with hepatitis B in infancy develop chronic infection and subsequent progressive liver disease, including cirrhosis and hepatocellular carcinoma. Significant reduction in perinatal transmission in the United States (US) was seen after implementation of universal infant vaccination 30 years ago, as well as dramatic reductions in HBV incidence across Asia, coinciding with widespread hepatitis B vaccination. However, with ongoing changes to federal vaccine guidance and a steady rise in vaccine hesitancy, a comprehensive understanding of the epidemiology, transmission, screening, and prevention of hepatitis B remains important for pediatric health care providers.

We report the case of an 18-year-old female with cholestatic hepatopathy of unknown origin, presenting with therapy-resistant jaundice and pruritus following oral contraceptive use and gastrointestinal infections. In another hospital, drug-induced autoimmune hepatitis (DILI-AIH) was suspected, and corticosteroid therapy was initiated but remained unresponsive. Initiation of colestyramine led to a worsening of symptoms and increasing liver transaminases. After referral to our centre, a mini-laparoscopic liver biopsy was performed, and histopathology revealed cholestatic DILI and mild fibrosis, with no signs of AIH. After a repeated precise history from the mother, a hereditary fructose intolerance was highly suggestive, and genetic testing confirmed a homozygous mutation in the aldolase B gene (A149P). Additionally, no pathogenic mutations in genes encoding bile acid and phospholipid transporters were detected. The treatment was adjusted to sugar-free colestyramine, leading to complete resolution of symptoms. In the management of hereditary fructose intolerance, not only dietary ingredients but also the supplements and medications may contain fructose excipients that could exacerbate and aggravate liver injuries.

Emphysematous hepatitis (EH) is a rare and often fatal liver infection characterized by gas within the hepatic parenchyma without abscess formation. Diabetes mellitus and gastrointestinal malignancies are the main predisposing factors. Prompt diagnosis and aggressive treatment are essential due to its fulminant course. A 67-year-old male with uncontrolled type 2 diabetes and a long smoking history presented with abdominal pain, nausea, vomiting, dyspnea, and altered consciousness. Laboratory tests revealed elevated liver enzymes, hyperbilirubinemia, severe hyperglycemia, and increased inflammatory markers. Abdominal CT showed a gas-containing lesion in the left hepatic lobe without fluid collection. Due to rapid clinical deterioration, emergency surgical resection was performed. Despite postoperative intensive care and meropenem therapy, the patient died six hours after surgery. Cultures grew E. coli and Enterobacter hormaechei. Only 19 EH cases have been reported to date. Most patients are elderly and have diabetes. Diagnosis relies on CT imaging, which reveals intrahepatic gas without abscess. Pathogenesis may involve anaerobic bacterial fermentation and microcirculatory impairment in diabetic patients. Despite antibiotics and drainage, mortality remains high. EH should be considered in diabetic patients with sepsis and intrahepatic gas on CT. Early diagnosis and immediate intervention-including antimicrobial therapy and drainage-are critical to improving survival.