Telomere biology disorders (TBDs) are rare inherited conditions caused by defects in telomere maintenance genes, leading to premature cellular aging and multisystem disease. The liver is the third most affected organ after the bone marrow and the lungs. Liver involvement ranges from asymptomatic biochemical abnormalities to porto-sinusoidal vascular disease, early-onset cirrhosis, and hepatopulmonary syndrome, often presenting without classic extrahepatic features of TBDs and posing significant diagnostic challenges. Disease severity and age of onset are strongly influenced by telomere length and genetic inheritance patterns. Autosomal recessive, X-linked recessive, and de novo TINF2-associated inheritance patterns are associated with severe childhood liver disease, while autosomal dominant inheritance patterns present in adulthood with isolated liver pathology. Acquired liver disease may also independently lead to telomere attrition and accelerate cellular senescence and fibrosis progression. Currently, management of TBD-related liver disease is largely supportive, with limited evidence suggesting potential benefit from androgen therapy, and there is growing experience supporting liver transplantation, particularly for advanced disease or hepatopulmonary syndrome. Early recognition, multidisciplinary care, and genetic counseling are essential to optimize outcomes. Future clinical trials studying telomere-targeted therapies warrant focus on hepatic endpoints.

The epidemiological landscape of paired hepatitis B virus (HBV)/hepatitis delta virus (HDV) genotype (GT) among patients with HDV in the US remains unknown. HBV/HDV genotypes were assessed in two independent US cohorts: Cohort 1 included 5222 HBV-positive patients from Quest Diagnostics, including 114 anti-HDV+ patients; Cohort 2 included 178 anti-HDV+ samples from highly phenotyped patients managed at the National Institutes of Health (NIH). HBV/HDV sequencing and genotyping were analysed using phylogenetic analyses. In the overall cohort, HBV and HDV genotypes were determined for 197 (67%) and 139 (48%) patients, respectively, with HDV GT1 and GT5 and paired HBV/HDV genotypes D/1 and A/1 being the most prevalent. The most frequent HBV genotypes were GTD (40%) and GTA (35%), and the most frequent HDV genotypes were GT1 (84%) and GT5 (13%). Among 111 paired HBV/HDV genotypes, D/1 (50%) and A/1 (26%) were most common. In Cohort 2, 77 (79%) patients with HDV GT1 were foreign-born, most commonly Mongolian-born (47/77, 61%), while 21% (20/77) were US-born. Among patients with HDV GT5, GT6, or GT7, 93% (14/15) were of African origin. Overall, these findings provide the first comprehensive US analysis of HBV/HDV paired genotypes among patients with HDV and indicate that HBV genotype distributions differ between HBV/HDV coinfection and HBV monoinfection.

Background and Aims: Insulin resistance is a common extrahepatic manifestation of hepatitis C virus (HCV) infection (HCVi), but its mechanism is poorly understood. While systemic insulin resistance is documented, portal insulin dynamics, a key regulator of hepatic metabolism, remain unexplored. This study aimed to investigate the relationship between insulin, the gut-liver axis, and immunometabolic changes in patients with HCV. Methods: HCV patients were evaluated before (HCVi; n = 29) and after sustained virologic response (SVR) achieved with sofosbuvir/velpatasvir treatment (SVR, n = 23) (NCT02400216). Liver biopsies, portal blood, and peripheral blood were collected at both phases. Statistical analyses were conducted using Wilcoxon rank-sum tests, Mann-Whitney tests, and Pearson's correlation coefficients to assess differences and associations across insulin, glucose, cytokines, metabolites, immune cells, and hepatic liver transcriptomics to elucidate impaired insulin homeostasis in HCVi. Results: HCV patients had significantly reduced portal insulin compared to SVR (p = 0.02), while peripheral insulin, portal glucose, and peripheral glucose remained unchanged. Portal insulin correlated positively with proinflammatory cytokines and vascular injury markers and negatively with CD8/CD62L/CD45RA/CD3 cells (naive cytotoxic T-cells) and non-standard nucleotides. Hepatic transcriptomic analysis revealed portal insulin correlated positively with immune and negatively with amino acid pathways, reflecting insulin's role in the perturbations of immunometabolism during HCVi. Conclusions: Lower por tal insulin during HCVi is associated with changes consistent with altered pancreatic insulin secretion and decreased hepatic insulin extraction. The observed correlations support a potential relationship between the immune response and insulin dynamics, indicating an interplay between the immune system, metabolism, and insulin in HCVi, with clinical implications for the management of dysglycemia.

BACKGROUND AND AIMS:The tryptophan pathway is an integral component of the gut-liver axis; however, the role in hepatitis C virus infection (HCV) and liver disease progression remains poorly understood. This study investigated tryptophan metabolites in portal and peripheral serum during and after HCV, and their relationship to inflammatory and clinical markers. METHODS:HCV infected patients were evaluated during infection (HCVi, n = 24) and 6 months after sofosbuvir/velpatasvir mediated sustained virologic response (SVR, n = 19) (NCT02400216). Liver biopsies, portal and peripheral blood collection, and stool sampling were performed at both time points. Statistical analyses assessed metabolite abundance during infection and recovery, and their associations with cytokines, clinical parameters, and the microbiome. RESULTS:During infection, peripheral tryptophan and kynurenine were elevated while indolelactate and xanthurenate were reduced (p < 0.05). In the portal blood, kynurenine/tryptophan ratio and kynurenine were increased, whereas indoleacetate and xanthurenate were decreased (p < 0.05). Tryptophan metabolites positively correlated with hepatic activity index, gamma-glutamyl transferase, total bilirubin, spleen volume/height ratio, and pro-inflammatory cytokines including CXCL9, CXCL10, TNFα, IL6, and IL-12p40. Negatively, correlations were observed with gut microbes Dorea longicatena and Qiania dongpingenesis. CONCLUSIONS:Elevated kynurenine in portal blood suggests upregulation of gut-mediated pro-inflammatory pathways during HCV infection. Integration of multi-omics data from the gut-liver axis highlights the contribution of the tryptophan pathway to inflammatory responses in HCV. However, small sample size, absence of quantitative values for all pathway metabolites, and reliance on correlative rather than causative associations limit mechanistic interpretation. Future studies with larger cohorts and functional analyses are needed to clarify causal mechanisms and evaluate therapeutic potential of targeting the tryptophan pathway. TRIAL REGISTRATION:NCT02400216.

INTRODUCTION:Noncirrhotic portal hypertension (NCPH) refers to a diverse group of disorders that affects the hepatic portosinusoidal vascular system resulting in portal hypertension (PH). Unlike cirrhosis, there are no noninvasive criteria to diagnose PH and varices in NCPH. METHODS:A prospective cohort of patients with NCPH who had transjugular liver biopsy, liver stiffness (LSM) measured using transient elastography, and laboratory and imaging data were included. PH was defined by the presence of one among the following-varices on endoscopy, portosystemic collaterals, or ascites on imaging. Logistic regression was used to identify predictors. The classification tree approach was used to identify cutoff values for the stepwise decision model. RESULTS:Of the 59 patients, 41 (69%) had PH and 36 (62%) had varices. LSM was higher in patients with PH (11.5 kPa vs 5.7 kPa, P < 0.01) and varices (12 kPa vs 5.9 kPa, P < 0.01). Platelet count was lower in patients with PH (79 vs 218 × 10 9 /L, P < 0.01) and varices (75 vs 209 × 10 9 /L, P < 0.01). Multivariate analysis combining LSM and platelet count predicts PH (area under receiver operating characteristic 96% [91%-99%]) and varices (area under receiver operating characteristic 92% [85%-99%]). A stepwise model combining platelet 140 × 10 9 /L and LSM 7 kPa performed with a sensitivity of 100%, negative predictive value of 100%, and accuracy of 90% to detect PH. The same model performed with sensitivity of 100%, negative predictive value of 100%, and accuracy of 81% to detect varices. DISCUSSION:Noninvasive model combining LSM with platelet count can aid in identifying NCPH patients with PH and varices. However, this model requires validation in an independent cohort.

BACKGROUND AND AIMS:Deficiency of adenosine deaminase 2 (DADA2) is caused by mutations in the ADA2 gene and results in an auto-inflammatory state. Hepatosplenomegaly, with or without abnormalities in liver enzymes, has been reported in DADA2. Anti-tumour necrosis factor (anti-TNF) therapy is the standard of care for the prevention of recurrent ischemic strokes and reduction of inflammatory burden. However, little is known about the extent of hepatic involvement and the utility of non-invasive tools for identifying liver disease and monitoring treatment response. METHODS:Retrospective analysis was performed on a prospective cohort of 70 patients with DADA2. Patients underwent baseline and annual laboratory testing, abdominal imaging and transient elastography. Hepatomegaly and splenomegaly were assessed on imaging, with splenomegaly defined using the spleen-to-height (SH) ratio. Liver biopsy and esophagogastroduodenoscopy were performed when indicated. RESULTS:At baseline, elevated ALT was uncommon (29%). Hepatomegaly and splenomegaly were present in 36% and 58%, respectively. Liver biopsies were performed in 12 patients, 8 of whom showed porto-sinusoidal vascular disease (PSVD). Over a median follow-up of 4.5 years, 40% demonstrated persistently elevated ALT levels. Clinically evident portal hypertension was present in 14%, and decompensation events, such as ascites and variceal bleeding, occurred in 5%. Anti-TNF therapy resulted in resolution of splenomegaly in 28% and a reduction in mean SH ratio across the entire cohort. Patients who underwent haematopoietic cell transplantation (HCT) appeared to be at risk for complications such as hepatic graft versus host disease and veno-occlusive disease. CONCLUSIONS:DADA2 vasculopathy appears to affect intrahepatic portal veins and result in PSVD. SH ratio shows significant promise in identifying liver involvement and monitoring treatment response. The improvement in SH suggests that PSVD may be reversible with treatment in this setting. Hepatic evaluation at baseline is encouraged for all patients, and pre-HCT liver biopsy should be considered, as there can be clinically silent liver disease that could potentially cause transplant-related complications.

Purpose To develop a deep learning model that automatically delineates the eight liver Couinaud segments and the spleen at CT for future liver remnant (FLR) volumetry. Materials and Methods In this retrospective study (January 2001-October 2025), eight liver Couinaud segments and the spleen were manually labeled on CT scans of patients from institution A and the public Medical Segmentation Decathlon dataset. A three-dimensional nnU-Net segmentation model was trained on this dataset and evaluated on three datasets (one internal and two external). Results The training dataset included 498 patients (442 from the public Medical Segmentation Decathlon dataset and 56 from institution A, mean age ± SD, 55 years ± 7; 38 men), and the testing dataset included 64 patients from institution A (50 had liver fibrosis and eight underwent portal vein embolization; PVE), 197 patients from the publicly available colorectal liver metastases (CRLM) dataset (mean age, 59 years ± 12; 117 men), and 50 patients (25 were healthy and 25 had cirrhosis) from an external site (institution B; mean age, 49 years ± 9; 29 men). For the whole liver in institution A and institution B, Dice scores of 0.98 ± 0.02 (95% CI: 0.97, 0.99) and 0.98 ± 0.03 (95% CI: 0.97, 0.99), and 95% percentile Hausdorff distance (HD) errors of 2.5 mm ± 3.8 (95% CI: 1.6, 3.3) and 3.3 mm ± 6.6 (95% CI: 1.4, 5.2) were obtained, respectively. The pre-PVE FLR% and post-PVE FLR% volume differences (manual vs automated, eight patients) were 0.03 ± 2.4 and -0.39 ± 3.0, respectively. For the FLR in the CRLM dataset, a Dice score of 0.99 ± 0.01 (95% CI: 0.99, 0.993) and an HD error of 0.9 mm ± 1.8 (95% CI: 0.6, 1.1) were achieved. Conclusion The model accurately estimated preoperative FLR volumetry and generalized well to patients with colorectal liver metastases, fibrosis, and cirrhosis and healthy controls. Keywords: CT, Deep Learning, Couinaud, Spleen, Future Liver Remnant, Portal Vein Embolization, Cirrhosis, Fibrosis Supplemental material is available for this article. © RSNA, 2026.

BACKGROUND & AIMS:Fibroblast growth factor 21 (FGF21) analogs are in development for metabolic dysfunction-associated steatotic liver disease (MASLD), but their impact on problematic alcohol use (PAU), alcohol use disorder, binge drinking, and alcohol-related liver disease (ALD) is unknown. METHODS:We leveraged genome-wide association study data from the UK Biobank, FinnGen, Million Veterans Program, and GenomALC for PAU, alcohol use disorder, binge drinking, weekly drinks, and ALD. Our four-tier evaluation included: (1) multivariable Mendelian randomization (MR) and mediation with circulating FGF21 levels; (2) comparative MR of MASLD and ALD targets (PNPLA3, TM6SF2, HSD17B13) using liver fat and expression instruments; (3) receptor-focused MR of β-Klotho (KLB) and FGFR1/2/3 incorporating brain-region expression; and (4) a phenome-wide MR across 1,022 traits to assess safety. RESULTS:Genetically higher FGF21 protein levels were associated with lower PAU (β = -0.097, 95% CI -0.135 to -0.059, p = 6.13 × 10-7), fewer binge episodes, reduced drinking, and lower ALD risk (odds ratio [OR] = 0.79, 95% CI 0.638-0.987, p = 0.038). Multivariable MR and mediation attributed these effects entirely to behavioral pathways (reduced drinking, improved diet) and increased basal metabolic rate. In comparative MR, FGF21 - unlike PNPLA3, or HSD17B13 - reduced alcohol outcomes: a 1-SD rise in hepatic FGF21 expression reduced PAU (β = -0.245, 95% CI -0.409 to -0.082, p = 0.003) and ALD (OR = 0.54, 95% CI 0.417-0.697, p = 2.44×10-6) risk. Receptor analyses implicated hippocampal FGFR3 (OR = 0.909, 95% CI 0.876-0.943, p = 4.28 × 10-7) and basal ganglia KLB expression, supporting a liver-brain axis. Phenome-wide MR uncovered 28 Bonferroni-significant protective associations with higher FGF21 (e.g. gout). Hepatic FGF21 expression showed fewer on-target liabilities than HSD17B13 or PNPLA3. CONCLUSIONS:Human genetic evidence indicates that FGF21 analogs mitigate hazardous drinking and ALD via both behavioral and metabolic pathways. These findings distinguish FGF21 from other MASLD targets and highlight its potential for precision treatment of alcohol-related disorders. IMPACT AND IMPLICATIONS:This study leverages human genetic evidence to validate FGF21 - a liver-derived hormone currently in clinical trials for fatty liver disease - as a dual-action therapeutic that both curbs harmful drinking behaviors and protects against alcohol-related liver injury, addressing a critical therapeutic gap with limited existing pharmacotherapies. The results are important for clinicians and researchers seeking precision medicine strategies for alcohol use disorder and liver disease, as well as for patients who currently face limited treatment options. By pinpointing FGF21's behavioral and metabolic pathways and demonstrating a favorable safety profile, our findings support the repurposing of FGF21 analogs in clinical trials of alcohol use disorder and alcohol-related liver disease and suggest that genetic stratification could optimize patient selection for therapy. While these conclusions rely on European-ancestry genetic data and Mendelian randomization assumptions, they help inform future clinical studies, biomarker development, and policy efforts aimed at expanding treatment options for alcohol-related conditions.

BackgroundThe microbiome of patients with hepatitis D virus (HDV) has yet to be characterized. This study aims to (1) characterize gut microbial composition in HDV, (2) determine its functional profile, (3) identify microbial species that contribute to changes in pathway expression, and (4) correlate the changes in the gut microbiome with clinical markers of disease severity.MethodsCross-sectional analyses of 35 HDV-infected patients and 32 healthy controls (HCs) were performed. DNA and RNA were isolated from stool and sequenced by shotgun-sequencing. Microbial and functional profiles were compared between the HDV-cohort and HCs to identify disease-specific alterations to the gut microbiome. Clinical metadata were used to identify correlations with disease severity.ResultsThere were significant changes in the composition of the gut microbiome in HDV-infected patients as compared with HCs, spanning multiple bacterial phyla. Expression of 194 pathways was significantly increased in the HDV group. Pathways that were upregulated in the HDV cohort were related to amino acid and carbohydrate biosynthesis or involved important metabolic cofactors and carriers. Several microbial species, including Bacteroides fragilis, Cateibacterium mitsuokai, and Faecalibacterium prausnitzii, were identified as contributing to the differentially expressed pathways. Four genera correlated with hepatic venous pressure gradient (HVPG).ConclusionThere are significant differences in microbial composition between HDV and HCs, several of which are found to be altered in other liver diseases. Upregulated pathways suggest a broader dysregulation of energy metabolism, even in early disease. These findings provide insight into pathways that may lead to liver disease progression in HDV.

BACKGROUND Cardiopulmonary changes in noncirrhotic portal hypertension (NCPH) are poorly understood. AIM To investigate cardiopulmonary changes using transthoracic echocardiography (TTE) in NCPH and their correlation with clinical features. METHODS Prospective cohort including 10 preclinical NCPH [without portal hypertension (PH)] and 32 NCPH subjects who underwent TTE with agitated saline injection and comprehensive clinical evaluation were assessed. PH was defined by presence of either varices, ascites or portosystemic shunting. Intrapulmonary vascular dilatation (IPVD) is defined as appearance of microbubbles in the left atrium after three heartbeats. Right ventricular systolic pressure (RVSP) > 38 mmHg was used to identify possible porto-pulmonary hypertension. Cardiomyopathy is defined using cirrhotic cardiomyopathy consortium criteria. RESULTS Among 42 subjects, 17 (40%) had IPVD, 4 (9.5%) had RVSP > 38 mmHg, and 6 (14%) had cardiomyopathy. Aspartate aminotransferase to alanine aminotransferase (AST/ALT) (1.3 vs 1, P = 0.04) and liver stiffness measurement (LSM) (12.4 kPa vs 7.1 kPa, P = 0.03) were higher in those with IPVD. Presence of either LSM > 10 or AST/ALT > 1.2 aided in identifying subjects with IPVD-sensitivity, specificity, and accuracy of 76%. RVSP correlated with oxygen saturation (r = -0.33), and free right hepatic vein pressure (r = 0.43). Those with PH had higher left atrial volume (LAV) (62 mL vs 48 mL, P < 0.01), and LAV index (LAVI) (35 m2 vs 23 m2, P < 0.01) compared to those without PH. Total bile acids, especially primary bile acids positively correlated with LAV (r = 0.36), and LAVI (r = 0.41). CONCLUSION Similar to cirrhotic patients, cardiopulmonary changes are prevalent in NCPH, especially among those with PH. In NCPH, cardiopulmonary changes occur despite preserved synthetic function, suggesting the NCPH model's value in understanding cardiopulmonary dysfunction in liver disease.