Non-alcoholic fatty liver disease (NAFLD) is currently the most prevalent chronic liver disease in Western countries, affecting approximately 25% of the adult population. This condition encompasses a spectrum of liver diseases characterized by abnormal accumulation of fat in liver tissue (non-alcoholic fatty liver, NAFL) that can progress to non-alcoholic steatohepatitis (NASH), characterized by the presence of liver inflammation and damage. The latter form often coexists with liver fibrosis which, in turn, may progress to a state of cirrhosis and, potentially, hepatocarcinoma, both irreversible processes that often lead to the patient’s death and/or the need for liver transplantation. Along with the high associated economic burden, the high mortality rate among NAFLD patients raises interest, not only in the search for novel therapeutic approaches, but also in early diagnosis and prevention to reduce the incidence of NAFLD-related complications. In this line, an exhaustive characterization of the immune status of patients with NAFLD is mandatory. Herein, we attempted to gather and compare the current and relevant scientific evidence on this matter, mainly on human reports. We addressed the current knowledge related to circulating cellular and soluble mediators, particularly platelets, different leukocyte subsets and relevant inflammatory soluble mediators.

Background and Aims: Metabolic dysfunction‐associated steatotic liver disease (MASLD) recurrence after liver transplantation (LT) seems unavoidable and gradual. We aimed to evaluate the diagnostic accuracy in the post‐LT setting of patients transplanted for metabolic dysfunction‐associated steatohepatitis (MASH) of recurrent hepatic steatosis and fibrosis identified with FibroScan, compared to biopsy findings.Methods: This prospective cohort study included adults transplanted for MASH between 2010 and 2022 in three LT centres in Spain who underwent FibroScan and biopsy at least 1‐year after LT.Results: In total, 44 patients transplanted for MASH after LT were included. The median time from LT to biopsy and FibroScan was 24.5 (interquartile range [IQR]:16–46) and 26.0 (IQR: 16.8–41.5) months, respectively. The median time between biopsy and FibroScan was 2.0 (IQR: 0–5) months. On FibroScan, significant steatosis was diagnosed in about half of the patients (n = 21, 47.7%), yet advanced fibrosis in only two cases (4.6%). On biopsy, a quarter of biopsied patients (n = 11, 25%) had a MASH diagnosis, two (4.6%) with significant fibrosis and one (2.3%) with cirrhosis. All patients with liver stiffness measurement (LSM) values <8 kPa (n = 35, 79.5%) had a fibrosis stage ≤F1 (negative predictive value = 100%). The combination of post‐LT hypertension (odds ratio [OR]: 12.0, 95% confidence interval [CI]: 1.8–80.4, p = .010) and post‐LT dyslipidaemia (OR: 7.9, 95% CI: 1.3–47.1, p = .024) with LSM (OR: 1.7, 95% CI: 1.1–2.8, p = .030) was independently associated with MASLD.Conclusions: Although biopsy remains the gold standard for detecting fibrosis, our results suggest that LSM values <8 kPa after LT for MASH are strongly correlated with absence of significant/advanced fibrosis.

The response of patients with chronic liver disease (CLD) to COVID-19 vaccines remains unclear. Our aim was to assess the humoral immune response and efficacy of two-dose COVID-19 vaccines among patients with CLD of different aetiologies and disease stages. A total of 357 patients were recruited in clinical centres from six European countries, and 132 healthy volunteers served as controls. Serum IgG (nM), IgM (nM), and neutralising antibodies (%) against the Wuhan-Hu-1, B.1.617, and B.1.1.529 SARS-CoV-2 spike proteins were determined before vaccination (T0) and 14 days (T2) and 6 months (T3) after the second-dose vaccination. Patients fulfilling inclusion criteria at T2 (n = 212) were stratified into 'low' or 'high' responders according to IgG levels. Infection rates and severity were collected throughout the study. Wuhan-Hu-1 IgG, IgM, and neutralisation levels significantly increased from T0 to T2 in patients vaccinated with BNT162b2 (70.3%), mRNA-1273 (18.9%), or ChAdOx1 (10.8%). In multivariate analysis, age, cirrhosis, and type of vaccine (ChAdOx1 > BNT162b2 > mRNA-1273) predicted 'low' humoral response, whereas viral hepatitis and antiviral therapy predicted 'high' humoral response. Compared with Wuhan-Hu-1, B.1.617 and, further, B.1.1.529 IgG levels were significantly lower at both T2 and T3. Compared with healthy individuals, patients with CLD presented with lower B.1.1.529 IgGs at T2 with no additional key differences. No major clinical or immune IgG parameters associated with SARS-CoV-2 infection rates or vaccine efficacy. Patients with CLD and cirrhosis exhibit lower immune responses to COVID-19 vaccination, irrespective of disease aetiology. The type of vaccine leads to different antibody responses that appear not to associate with distinct efficacy, although this needs validation in larger cohorts with a more balanced representation of all vaccines. In patients with CLD vaccinated with two-dose vaccines, age, cirrhosis, and type of vaccine (Vaxzevria > Pfizer BioNTech > Moderna) predict a 'lower' humoral response, whereas viral hepatitis aetiology and prior antiviral therapy predict a 'higher' humoral response. This differential response appears not to associate with SARS-CoV-2 infection incidence or vaccine efficacy. However, compared with Wuhan-Hu-1, humoral immunity was lower for the Delta and Omicron variants, and all decreased after 6 months. As such, patients with CLD, particularly those older and with cirrhosis, should be prioritised for receiving booster doses and/or recently approved adapted vaccines.

Cytomegalovirus (CMV) viral load after liver transplantation (LT) is controlled by cell mediated immune responses (CMI). Quantification of CMV-specific T-cells may identify patients who control CMV spontaneously and avoid expensive and potentially toxic antiviral therapies. Prospective post-LT clinical, virological and immunological monitoring was carried out up to 1-year post-LT in a cohort of adult recipients. The CMV-specific T-cell response was characterized using flow cytometry intracellular cytokine staining in 49 LT recipients-R (79.6% R+, 20.4% R-). CMV infection occurred in 24 patients (18 D+/R+ and 6 D+/R-). Only patients with undetectable polyfunctional CMV-specific CD4+ T-cells developed CMV infection. Predictive models showed that polyfunctional CMV-specific CD4+ T-cells pre-existing before LT are protective for CMV reactivation posttransplantation. Quantitation of CD4+ T-cell responses to CMV may be a useful marker for spontaneous control of viral replication to tailor antiviral prophylaxis after LT.

Background and Aims: Changes in hepatitis delta virus (HDV) epidemiology have been highlighted recently in the context of increasing worldwide migrations. The lack of comprehensive real-world data on HDV in the Valencia region highlights the need for a structured registry to accurately estimate disease prevalence and burden and to generate robust real-world evidence on clinical outcomes and therapeutic effectiveness. We aimed to better understand the barriers for successful HDV patient care in our region by establishing a registry as well as linking previously under-recognized or lost to follow-up (FU)cases to care. Methods: After a search of all possible HDV cases in a Spanish region, attempts were made (through letters and phone calls) to relink to care those lost to FU. Two approaches were undertaken: (i) search of the Microbiology Labs Database, and (ii) clinical chart review from adult patients attending the Hepatology or Infectious Disease (ID) Units outpatient clinics of the three participant hospitals between January 2011 and June 2021. Results: Only one third of anti-HDV positive patients without adequate clinical management could be successfully linked or re-linked to care, highlighting a substantial gap in follow-up. Among 243 HDV cases detected (7.5% of HBsAg-positive patients), 111 belonged to the hospitals’ health department, and after excluding deceased or transplanted individuals, the final study cohort consisted of 84 patients. Of these, 27.4% were adequately followed in Hepatology or Infectious Disease Clinics, 11.9% had been inadequately followed recently, 45.2% had been lost to follow-up for several years, and 15.5% had never been evaluated in outpatient clinics. Overall, only a third of the patients without adequate clinical management could be successfully linked/relinked to care. Conclusions: In our setting, only a minority of anti-HDV positive patients are adequately managed in specialized outpatient clinics, with unsuccessful attempts to link many patients to care, particularly among young migrant men. These findings underscore the need for alternative strategies, such as decentralized testing, reflex testing, and the involvement of patient navigators or social workers, to strengthen linkage to care and improve retention.

Wilson disease is a rare autosomal recessive disorder caused by copper accumulation, primarily affecting the liver and brain. While genetic estimates suggest a global prevalence of 13.9-15.4 per 100,000 individuals, clinical diagnoses are significantly lower, raising concerns of underdiagnosis. We aimed to investigate the presence of undiagnosed Wilson Disease in patients who underwent liver transplantation for cryptogenic liver disease at a large transplantation center. This observational study analyzed adult patients transplanted for cryptogenic liver disease at La Fe University Hospital (1991-2023). Comprehensive clinical, biochemical, and imaging assessments were used to exclude known liver diseases. ATP7B gene sequencing-including all exons, flanking introns, and the promoter region-was performed using Sanger sequencing. Variant interpretation was conducted using ClinVar, HGMD, GERP, CADD, REVEL, PolyPhen-2, and gnomAD. Among 2708 patients, 17 fulfilled the criteria for cryptogenic liver disease. Twenty-two distinct ATP7B single nucleotide variants were identified. None were classified as pathogenic. One novel variant (c.256A>C) was detected, but its pathogenicity could not be confirmed. No conclusive evidence of undiagnosed Wilson Disease was found in the cohort. Despite higher genetic prevalence estimates, this study did not identify undiagnosed Wilson Disease cases among liver transplant recipients with cryptogenic liver disease, suggesting a low prevalence of missed diagnoses in this clinical setting. Larger, multicenter studies are warranted to explore the potential underdiagnosis of Wilson Disease in broader populations.