Goble SR et al. · Jul 1, 2026
An ICD-10 code specific for hepatic encephalopathy (HE), K76.82, was introduced in October of 2022. We aimed to assess changes in HE documentation following the introduction of this code. Using the National Inpatient Sample, we compared utilization of ICD-10 codes historically used to identify HE before and after K76.82. From 2016 to 2021, 20.0% of cirrhosis hospitalizations included a non-specific HE code, decreasing to 4.7% in 2023. K76.82 was used in 20.3% of hospitalizations in 2023. The introduction of K76.82 has dramatically changed the documentation of HE, and future studies assessing HE trends and outcomes need to account for these changes.
Medicine
Hintersteininger M et al. · Jul 1, 2026
Background & aims Transjugular intrahepatic portosystemic shunt (TIPS) placement is used to treat complications of portal hypertension. This study aimed to evaluate the prognostic value of von Willebrand factor antigen (VWF) dynamics following TIPS placement. Methods Patients with TIPS placement at the Medical University of Vienna (2018-2025) and University Medical Center Mainz (2022-2025) with available VWF at baseline (BL) were included. Patients from both cohorts with available VWF after 3 months (M3) were included in the combined longitudinal cohort (CLC). Meaningful VWF decrease (VWF-Response) was defined as a relative VWF change (ΔVWF) of at least -5% at M3. Patients were stratified by presence of VWF-Response and interleukin-6 decrease (IL6-Response) into three groups: both (R2), either/or (R1), and neither (R0). Results Overall, 113 and 86 patients were included in the Vienna and Mainz cohorts, respectively. BL VWF was not associated with mortality in both cohorts. 118 patients constituted the CLC, which showed median BL VWF of 313.0% that decreased to 262.0% at M3 (p = 0.007). Fifty-three patients (44.9%) achieved VWF-Response. Both, VWF change (ΔVWF; asHR: 2.75; 95% CI: 1.07-7.11; p = 0.037) and VWF-Response (asHR: 0.24; 95% CI: 0.09-0.61; p = 0.003) were independently associated with survival. According to VWF and IL6 responses, patients were stratified as low-risk (R2), versus intermediate-risk (R1) versus high-risk (R0) with a cumulative incidence of death at 2 years of follow-up of R2: 10.6% versus R1: 23.1% versus R0: 46.7%, respectively. Conclusion After TIPS placement, VWF-Response identifies patients with a favourable prognosis and can be combined with IL6-Response for risk stratification regarding mortality.
Medicine
Bedoya JU et al. · Jul 1, 2026
Background & aims Transjugular intrahepatic portosystemic shunt (TIPS) improves survival in refractory ascites. A careful patient's selection is mandatory as TIPS can lead to complications. Liver volumetry is predictive of outcomes before hepatic surgery, but data on its role before TIPS placement are scarce. We aimed to evaluate whether liver and spleen volume measurements are associated with prognosis after TIPS placement in patients with ascites. Methods We analysed data from three French centers, treated with TIPS between 2017 and February 2022. Inclusion criteria encompassed a TIPS placement for refractory or recurrent ascites and availability of cross-sectional imaging. Exclusion criteria included non-cirrhotic portal hypertension, other indications for TIPS, hepatocellular carcinoma beyond Milan criteria, and extrahepatic malignancy. Liver and spleen volumes were measured using pre-TIPS CT or MRI scans. The primary endpoint was 1-year transplant-free survival (TFS). Secondary endpoints were overt hepatic encephalopathy (HE), recurrence of ascites, acute variceal bleeding, and jaundice. Results The 160 patients were included (median age 60 years, male gender 83.8%, alcohol-related cirrhosis 58.8%, with active alcohol consumption in 25.6%, Child-Pugh B cirrhosis in 81.2%, median MELD score was 12). The 1-year TFS was 60.1%. Multivariate analysis identified serum creatinine (HR = 1.01 95% CI [1.00-1.01], p = 0.04), total bilirubin (HR = 1.02 95% CI [1.02-1.04], p = 0.004), and portal pressure gradient (HR = 1.09 95% CI [1.01-1.18], p = 0.03) as independent factors associated with TFS. Neither liver-to-spleen volume ratios (LSVR) (p = 0.36) nor liver volume index (p = 0.92) were significantly associated with death or LT. Overall, 38.1% of patients developed overt HE after TIPS, with lower platelet count (HR = 1.01 95% CI [1.00-1.01], p = 0.04) emerging as an independent predictor. No radiological characteristics were associated with the recurrence of ascites. Conclusions In this multicenter study, liver and spleen volumes were not associated with transplant-free survival or liver-related outcomes in patients undergoing TIPS for ascites. These findings suggest that liver volumetry should not be a determining factor in patient selection for TIPS placement.
Medicine
Nelson SE et al. · Jul 1, 2026
Proteases are powerful therapeutic agents, offering unique advantages over conventional small molecules and biologics through their ability to directly and precisely cleave and (de)activate their protein targets. Since the early 1990s, FDA-approved protease therapeutics have served as replacement therapies for hematological disorders, as enzyme supplements for digestive disorders, and as treatments for neuromuscular disorders. Recent developments have expanded the use of native proteases to modulate antibody responses, improve transplant outcomes, and treat rare conditions with high unmet needs. Despite challenges such as immunogenicity and substrate specificity, the therapeutic landscape of proteases is being redefined by innovations in enzyme engineering and discovery. These advances, combined with targeted delivery strategies and improved stability, are reshaping proteases into precise and adaptable therapeutic agents. Rather than being limited to traditional uses, proteases are increasingly recognized for their potential to address complex conditions such as viral infections, neurodegeneration, and fibrosis, among others. With continued development, proteases are positioned to become a versatile and robust class of biologics with expanding clinical relevance. The present review explores the evolving landscape of protease therapeutics, focusing on their clinical applications, immune-modulatory capabilities, and future potential in precision medicine. This review provides a timely update to the comprehensive article "Proteases as Therapeutics" by Craik, Page, and Madison, published in the Biochemical Journal in 2011.
Medicine
Mondelli MU et al. · Jul 1, 2026
Background and aims Herpes simplex virus (HSV) infection is common worldwide, but hepatic involvement is rare. HSV hepatitis is an uncommon yet frequently catastrophic cause of acute hepatitis and acute liver failure (ALF), accounting for Methods We describe three cases of HSV hepatitis presenting with distinct risk profiles and clinical manifestations and review the diagnostic and therapeutic challenges associated with this condition. Results Clinical presentation was nonspecific in all cases, and mucocutaneous lesions were absent or delayed, contributing to diagnostic uncertainty. All patients exhibited marked aminotransferase elevation with relatively modest hyperbilirubinemia ("anicteric hepatitis"), frequently accompanied by cytopenias and coagulopathy. Delayed recognition was associated with rapid clinical deterioration, whereas earlier initiation of intravenous acyclovir was associated with biochemical and clinical improvement. Diagnosis was established using polymerase chain reaction-based detection of HSV DNA in blood and tissue samples. Conclusions HSV hepatitis remains an under-recognized cause of ALF across a broad spectrum of immunocompromised and seemingly immunocompetent patients. Given the narrow therapeutic window and favourable safety profile of acyclovir, empiric intravenous antiviral therapy should be considered in patients with ALF of indeterminate aetiology while diagnostic testing is pending, particularly in high-risk clinical settings. Increased awareness of this overlooked diagnosis may improve outcomes and prevent avoidable mortality.
Medicine
Lim JZM et al. · Jul 1, 2026
Background Diabetic foot ulceration (DFU) and lower limb complications are highly prevalent in people with end-stage kidney disease (ESKD), particularly those receiving dialysis; however, the overall burden and outcomes remain incompletely characterised. This systematic review with narrative synthesis aimed to summarise study characteristics and evidence on the epidemiology of DFU in ESKD, including incidence, prevalence, wound healing outcomes, and associations with lower-extremity amputation (LEA) and mortality. Methods MEDLINE (via PubMed), EMBASE and the Cochrane Database of Systematic Reviews were searched from inception to 31 January 2026 for longitudinal and cross-sectional studies, including registry data, in adults with ESKD or on dialysis. Outcomes included DFU epidemiology, wound healing, revascularisation, LEA and mortality. Results The review included 64 observational studies. In dialysis-dependent populations, DFU incidence is high and increases with advancing renal impairment, often preceding dialysis initiation. Evidence on whether dialysis initiation itself increases DFU risk is limited and heterogeneous, although observational cohorts suggest a temporal association with haemodialysis initiation, particularly within the first 2 years. Data comparing haemodialysis and peritoneal dialysis are scarce. Wound healing outcomes were variable, with earlier recurrence observed, although multidisciplinary care improved healing, largely driven by perfusion and ulcer severity rather than renal function alone. Although based on observational and heterogeneous data, dialysis-dependent ESKD was frequently identified as an independent predictor of LEA after adjustment for confounders, with coexisting peripheral arterial disease, a key determinant of adverse limb outcomes. Mortality risk appeared to compound following amputation, with observational data suggesting high post-amputation mortality (approaching 50% at 2 years and 70% at 5 years), consistent with a shift towards limb loss rather than increased DFU occurrence. Interpretation is limited by study heterogeneity, observational design, limited long-term data on healing and recurrence, and inadequate stratification by dialysis modality. Conclusions Current evidence underscores substantial gaps in understanding the natural history and optimal management of diabetic foot disease in dialysis-dependent ESKD. Future research should prioritise well-designed prospective studies to delineate dialysis-specific risk pathways, incorporate robust stratification by dialysis modality, and evaluate interventions targeting ischaemia and limb preservation. Standardisation of outcome reporting, particularly for healing durability and recurrence, will be essential to enable meaningful comparisons and guide the development of tailored multidisciplinary care models for this high-risk population.
Medicine
Kaye LK et al. · Jul 1, 2026
Early detection of deterioration in children in hospital is essential for improving patient outcomes, prompting NHS England to introduce a digital National Paediatric Early Warning System (PEWS) in November 2023. Our service evaluation examined a locally delivered digital version of the PEWS system, introduced in July 2025 to explore paediatric staffs' acceptance before and after implementation, measured by the Technology Integration Evaluation Resource (TIER), based on the Technology Integration Model. Online surveys were completed pre- and post-implementation. Acceptance did not significantly change over time. However, user motivation, agency and perceived cost-benefit as well as perceptions of PEWS as an extension of self, were positively associated with acceptance, highlighting key psychological factors influencing digital health adoption.
Medicine
Dinkelborg K et al. · Jul 1, 2026
Background and aims Hepatitis E virus (HEV) infection is very frequent in Europe with more than 2 million annual infections. Patients with liver cirrhosis may face an increased risk of suffering from acute-on-chronic liver failure (ACLF) due to HEV infection. We explored the consequences and prevalence of HEV infection in individuals with liver cirrhosis. Methods We retrospectively analysed the clinical outcome of all consecutive patients who were hospitalized at our center due to acute HEV infection and analysed their outcome between 2014 and 2024. Next, we tested 249 sera from 184 cirrhotic patients during individual episodes of acute hepatic decompensation for anti-HEV IgM and HEV-RNA to analyse the relevance of acute HEV infection as a triggering event. Finally, we established a single center cohort of patients with advanced liver cirrhosis, and assessed the anti-HEV IgG seroprevalence (n = 332). Results Over the past decade, 32 patients with liver cirrhosis who were hospitalized due to acute HEV infection were identified. Among these patients, 16 (50%) developed ACLF, resulting in five fatalities (31.3%) and three individuals (18.8%) requiring liver transplantation for survival. Of 249 sera obtained during acute hepatic decompensation, 11 (4.4%) were either HEV-RNA positive (n = 2) and/or anti-HEV IgM positive (n = 10), linking HEV infection to these acute decompensations. Screening of patients with liver cirrhosis for anti-HEV IgG showed that 67.2% of patients (223/332) were anti-HEV negative and thus at potential risk for future HEV infection. Conclusions Patients with advanced liver cirrhosis are at risk of acute HEV infection, which is a relevant cause of hepatic decompensation and ACLF with high mortality in these patients. Trial registration DRKS00010664; NCT04801290.
Medicine
Zhang X et al. · Jul 1, 2026
Metabolic dysfunction-associated steatotic liver disease (MASLD) is primarily driven by a Western-style diet and exacerbated with aging, yet underlying mechanisms remain unclear. Given the essential role of thyroid hormone (TH) in MASLD progression, we hypothesized that impaired intrahepatic TH action during aging promotes MASLD progression and severity of MASH with fibrosis. We evaluated hepatic TH metabolism in young (18-24 weeks) and old (108-120 weeks) C57BL/6J mice fed either a normal chow diet (NCD) or a Western diet with fructose (WDF) for 8 weeks. Liver histology, metabolic parameters, inflammatory and fibrotic markers, intrahepatic thyroxine (T4) and triiodothyronine (T3) concentrations, and activities of deiodinase enzymes (Dio1 and Dio3) were measured. Additionally, an in vitro hepatocyte senescence model using AML12 cells was employed to assess age-related alterations in deiodinase expression and the therapeutic efficacy of resmetirom (an FDA-approved thyromimetic). Aging and WDF synergistically exacerbated hepatic inflammation and fibrosis, accompanied by significant reductions in intrahepatic T4 and T3. Aging markedly decreased Dio1 activity, which converts T4 to active T3, whereas WDF partially restored Dio1 in old mice. Conversely, Dio3 activity, responsible for TH inactivation, increased with age but exhibited age-dependent differential responses to WDF, findings mirrored in senescent hepatocytes. Notably, resmetirom significantly reduced senescence markers, inhibited senescence-associated secretory phenotype (SASP) genes, inflammasome activation, endoplasmic reticulum (ER) stress, and activated autophagy. Collectively, our findings demonstrate that aging and stress by a Western-style diet synergistically impair hepatic TH signaling, accelerating MASLD progression. Furthermore, resmetirom improved hepatic senescence, highlighting its potential therapeutic repurposing for aging-associated hepatic pathologies, including MASLD.
Medicine
Park WD. · Jul 1, 2026
Haemangiosarcoma (HSA) is a highly aggressive vascular tumour in dogs, characterised by rapid growth, early metastasis, and poor prognosis despite conventional treatment with surgery and doxorubicin-based chemotherapy. A 14-year-old spayed female Maltese (4.14 kg) was presented with progressive abdominal distension and anorexia. Imaging revealed a large retroperitoneal mass, and computed tomography identified a 12.1 × 8.0 × 8.5 cm heterogeneous tumour. Exploratory laparotomy confirmed the lesion was unresectable, and biopsy findings were most consistent with presumptive haemangiosarcoma (HSA) due to the small, cautery-affected specimen. Medical therapy was initiated with toceranib phosphate (10 mg every other day), followed one week later by propranolol (0.3 mg/kg twice daily) and piroxicam (0.3 mg/kg once daily). The patient was monitored every 2-4 weeks with physical examination and serial haematology and serum biochemistry. Two months after initiating therapy, the abdominal ultrasonography demonstrated tumour reduction to 4.9 × 2.7 cm, and after 7 months the mass was no longer detectable on radiographic follow-up imaging (radiography and ultrasonography). Throughout treatment, haematologic and biochemical values remained within reference intervals, no clinically significant adverse effects were observed, and the owner reported resolution of abdominal distension with improved activity. This case demonstrates that combined therapy with toceranib, propranolol, and piroxicam achieved radiographic and clinically sustained remission of unresectable canine presumptive HSA while preserving quality of life. These findings suggest that multimodal therapy targeting angiogenesis and tumour growth pathways may represent a promising alternative strategy for managing this malignancy and warrant further clinical evaluation.
Medicine