Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED/APS-1) is a monogenic disorder of failed central tolerance caused by deleterious variants in the autoimmune regulator (AIRE) gene. Interferon-γ-driven inflammation in APECED underlies multiorgan autoimmunity and chronic mucocutaneous candidiasis and is targetable with JAK1/2 inhibition. Yet, whether early cytokine blockade can avert irreversible endocrine failure is currently unknown. Here, we describe two individuals with APECED who developed early autoimmune hypoparathyroidism and hypergonadotropic hypogonadism and in whom JAK1/2 inhibition halted progression and reversed biochemical and clinical abnormalities, preserving parathyroid and gonadal function. Specifically, patient 1 at the age of 2 years developed progressively declining intact parathyroid hormone (iPTH) levels that became undetectable within four months, while calcium and phosphorus levels remained normal, consistent with early, subclinical hypoparathyroidism. Ruxolitinib normalized iPTH levels and preserved calcium levels (Figure 1 A and B). Serum CXCL9 levels dropped and then increased, associated with a transient decline in iPTH levels; when the ruxolitinib dose was increased, iPTH increased, and CXCL9 dropped again and has remained normal after 18 months of treatment (Figure 1 C), suggesting that CXCL9 may be a potential biomarker of ruxolitinib efficacy in APECED. Ruxolitinib also remitted mycophenolate-refractory autoimmune hepatitis and recurrent oral candidiasis, which had occurred despite the absence of autoantibodies against IL-17A or IL-17F. Patient 2, at the age of 18 years, developed clinical and biochemical features of early hypergonadotropic hypogonadism. Screening labs showed declining anti-Müllerian hormone (AMH) and elevated follicle-stimulating hormone (FSH) and luteinizing hormone (LH). She reported severe hot flashes and oligomenorrhea with only three menses over five months, a reduction from her prior regular 28-day cycles. After initiation of ruxolitinib, hot flashes resolved while FSH, LH, and AMH normalized, and regular 28-day menstrual cycles were restored (Figure 2 A–C). Ruxolitinib caused no hematopoietic, hepatic, or renal toxicity in either patient. These findings provide, to our knowledge, the first clinical evidence that timely JAK–STAT pathway inhibition can intercept endocrine autoimmunity in APECED. More broadly, they advance a disease-interception paradigm in which early, pathway-directed cytokine blockade may alter the natural history of autoimmune endocrinopathies.Figure 1.Ruxolitinib reverses early hypoparathyroidism in patient 1. Data points in black represent time points before ruxolitinib initiation, while those in green and blue represent time points while receiving ruxolitinib at the indicated dose. A) Serum iPTH over time relative to ruxolitinib initiation. The dashed horizontal line represents the lower limit of normal for this assay. B) Total calcium levels over time relative to ruxolitinib initiation. C) Serum CXCL9 levels over time relative to ruxolitinib initiation. The dashed horizontal line marks the upper limit of normal for this assay.Figure 2.Ruxolitinib reverses premature ovarian failure in patient 2. Data points in black represent time points before ruxolitinib initiation, while those in green and blue represent time points while receiving ruxolitinib at the indicated dose. Serum AMH (A), FSH (B), and LH (C) levels over time relative to ruxolitinib initiation. The dashed lines represent the lower (A) or upper (B and C) limits of normal for these assays.

Abstract Purpose: Develop an automated hepatocellular carcinoma (HCC) detection model on multi-phasic contrast-enhanced T1 MRI images. Methods: Multi-phase (pre-contrast, arterial, venous, and delayed phases) contrast-enhanced T1 MRIs were obtained from two institutions (Center 1: n=106; Center 2: n=87) and acquired between 2007 and 2023. An expert radiologist manually contoured 1794 focal liver lesions across 586 scans and assigned each lesion a score using the Liver Imaging Reporting and Data System (LI-RADS). Six 3D full-resolution nnU-Net models were trained on multi-phase (pre-contrast, arterial, venous, and delayed) or only arterial-phase contrast-enhanced T1 images. Lesion size (maximum lesion diameter ≥ 1 cm) and lesion score (LI-RADS ≥ 3) criteria were applied to assess the impact on the training of these nnU-Net models. Model performance was evaluated at a scan and lesion level. Performance metrics included dice similarity coefficient (DSC), sensitivity, specificity, accuracy, and positive predictive value (PPV). Results: The arterial phase without lesion criteria was determined to have the best overall performance among the models developed. At the scan level, the arterial phase model achieved 93% (40/43) sensitivity, 46.6% (7/15) specificity, and 81% (47/58) accuracy. At a lesion level for the arterial phase model, the performance dropped slightly, with 65.9% (126/191) sensitivity, 68.1% (126/185) PPV, and 51.8% (133/257) accuracy. In a failure analysis, it was observed that 45.2% (57/126) of true-positive lesions had a LIRADS score ≥ 4, while 9.2% (6/65) of false-negative lesions had a LIRADS score ≥ 4. Conclusion: An arterial phase contrast-enhanced MRI nnU-Net model was developed on multi-institutional data to detect HCC in patients with cirrhosis, producing promising results. This study indicates that AI models can improve detection in high-risk patients. Citation Format: Emma J. Stevenson, Nathan Lay, Stephanie A. Harmon, Haoyue Zhang, Fahmida Haque, Peter Choyke, Theo Heller, Ross Filice, Baris Turkbey, Christine Hsu. Automated segmentation of hepatocellular carcinoma lesions on contrast-enhanced MRI using an AI model in patients with cirrhosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2782.

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.

Introduction Hepatopathy affects approximately 10% of patients with sickle cell disease (SCD), related to ischemia, iron overload, pigment stones, and sequestration. Sickle hepatopathy is linked to increased mortality, yet its impact on hematopoietic cell transplant (HCT) outcomes remains poorly understood as HCT can reverse the SCD phenotype but also carries potential liver-related toxicity. This study aims to evaluate the effect of underlying hepatopathy on HCT outcomes and, conversely, the effect of HCT on sickle cell–associated liver disease. Objectives 1. Recognize the gap in knowledge about the impact of pre-transplant sickle cell-related hepatopathy on transplant outcomes.2. Understand if there is an increased risk of vaso-occlusive disease (VOD) and other serious adverse transplant outcomes in patients with hepatopathy.3. Evaluate the impact of stem cell transplantation on hepatopathy in patients with sickle cell disease. Methods We conducted a retrospective chart review of 19 patients with SCD who received a nonmyeloablative HCT and had pre- and post-HCT liver biopsies. We evaluated HCT outcomes, peri-transplant toxicity, and liver pathology. We defined sickle hepatopathy as an elevated ferritin greater than 1000 mcg/L and/or a direct bilirubin greater than 0.4 mg/dL. A clinical pathologist evaluated biopsy samples for inflammation and fibrosis using the Histologic Activity Index and the Deugnier iron scoring system. Results Pre-HCT histopathology showed nodular regenerative hyperplasia in 15.8% of patients, while 10.5% had cirrhosis, and 10.5% had bridging fibrosis. Pre-HCT, 47.4% patients had a ferritin level >1000 mcg/L which persistent in only 44.4% of these patients post-HCT; 68.4% patients had a direct bilirubin >0.4 mg/dL pre-HCT which persistent in only 38.5% of these patients post-HCT. No patients experienced veno-occlusive disease. 31.5% of patients received ursodiol prophylaxis, and no patients received defibrotide prophylaxis or treatment. Conclusion Among 12 patients with available pre- and post-HCT HAI inflammation scores, 91.7% showed improvement or stability and of the 6 patients with elevated pre-HCT HAI fibrosis scores and post-HCT data, 66.6% demonstrated improvement or stability. Deugnier scores improved or remained stable in 55.5% of 9 patients. Our data suggest that non-myeloablative HCT can result in stable to improved liver disease with HCT outcomes comparable to patients who undergo HCT for SCD without pre-existing sickle cell hepatopathy.

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:Severe intestinal or hepatobiliary cryptosporidiosis affects patients with inborn errors of immunity (IEI), particularly those with CD40 ligand or CD40 deficiency, major histocompatibility complex class II deficiency, interleukin-21 receptor deficiency, and DOCK8 deficiency. Susceptibility to Cryptosporidium reflects defects in lymphocyte development, activation, and effector function. METHODS:We conducted a retrospective chart review of IEI patients with cryptosporidiosis, focusing on 17 individuals with chronic infection who underwent hematopoietic cell transplant (HCT), to characterize their clinical course, diagnostic evaluation, management, and outcomes. A literature review was also performed to summarize current knowledge of cryptosporidiosis in IEI patients. RESULTS:Patients frequently presented with secondary sclerosing cholangitis, posing significant diagnostic and therapeutic challenges. Molecular diagnostic assays offered higher sensitivity than conventional microscopy. Antiparasitic agents had limited efficacy against hepatobiliary disease. Durable immune reconstitution through HCT remained the mainstay of management, though it carries risk, especially in patients with established liver disease. Prophylactic strategies for at-risk individuals remain underexplored but should include exposure avoidance and consideration of antiparasitic prophylaxis. CONCLUSIONS:Cryptosporidium-related sclerosing cholangitis imposes a substantial disease burden in susceptible IEI patients, underscoring the importance of early recognition and proactive management, particularly timely immune reconstitution in this population.

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.

Abstract Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED/APS-1) is a monogenic disorder of failed central tolerance. Interferon-γ-driven inflammation in APECED underlies multiorgan autoimmunity and chronic mucocutaneous candidiasis and is targetable with JAK1/2 inhibition. Whether early cytokine blockade can avert irreversible endocrine failure is currently unknown. Here, we describe two individuals with APECED who developed evolving autoimmune hypoparathyroidism and hypergonadotropic hypogonadism. Treatment with the JAK1/2 inhibitor ruxolitinib halted progression and reversed biochemical and clinical abnormalities, preserving parathyroid and gonadal function. These findings provide clinical evidence that timely JAK-STAT pathway inhibition can intercept evolving endocrine autoimmunity in APECED. More broadly, they advance a disease-interception paradigm in which early, pathway-directed cytokine blockade may alter the natural history of autoimmune endocrinopathies.

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.

Primary immune regulatory disorders (PIRDs) are inborn errors of immunity characterized by immune dysregulation and multisystem involvement, whose hepatic manifestations can mimic autoimmune, cholestatic, or microvascular liver disease. Among these, heterozygous signal transducer and activator of transcription 1 gain-of-function pathogenic variants are predominantly associated with autoimmune hepatitis-like liver injury whereas vascular and portal hypertensive phenotypes are rarely reported and likely underrecognized. We describe a young adult with recurrent infections and progressive liver disease who ultimately received the diagnosis of a signal transducer and activator of transcription 1 gain-of-function mutation. The case illustrates the spectrum of hepato-gastrointestinal involvement in PIRDs, emphasizing diagnostic considerations, imaging and histopathologic features, and management strategies including conventional immunosuppression, targeted Janus kinase inhibition, and hematopoietic stem cell transplantation. We also outline infectious complications of Janus kinase inhibition, including progressive multifocal leukoencephalopathy.

We performed a single-center retrospective analysis of chronic granulomatous disease (CGD) autopsy reports to better understand causes of death, end-organ damage, and disease pathophysiology. Forty-four autopsies of CGD patients, including one X-linked female carrier, were performed from February 1990 to June 2025. These cases represent approximately 60% of the CGD deaths over 35 years. There was an increase in age at death over this time, despite a heavy burden of infections. The immediate cause of death was infection n = 30 (68%); Aspergillus species (33%) was the most frequent pathogen. One death was associated with SARS-CoV-2. An aggressive new Aspergillus species, Aspergillus tanneri, and an unidentified Burkholderia species were identified in this cohort.Noninfectious causes of death in 14 patients were associated to accident (1), respiratory failure (2), renal failure (2), surgical complications (1), post-transplant complications (2), cardiovascular complications (2), cerebral infarction (1), Transfusion-Related Acute Lung Injury (TRALI), a serious complication of blood transfusions where the recipient experiences acute lung injury in one case, and one death attributed to metastatic pancreatic ductal adenocarcinoma.A substantial portion had characteristic pigmented-laden macrophages in multiple organs, with a high concentration in the brain parenchyma. Atherosclerotic manifestations were present in a third of the cases. One patient, p22phox, had minimal atherosclerosis manifestations early in life (19 yrs). Lungs and hearts were significantly heavier when compared to norms. Livers were not significantly larger, although there was evidence of underlying inflammatory disease. Periportal inflammation was noted in 19 patients (46%), and nodular regenerative hyperplasia (NRH) was found in 7 (16%). Kidneys were small overall (atrophic), which may be related to drug exposure, specifically amphotericin B. Glomerulosclerosis or chronic renal compromise was found in 17 patients (41%), two of whom were children. Among those with glomerulosclerosis, one had never received amphotericin B. This pathology review shows pigment-laden macrophages across multiple organs not previously recognized, including the brain parenchyma. This is the largest autopsy series known in this population, underscoring the increased survival over time. With fungal infections being the most common cause of death, this emphasizes the importance of antifungal development and definitive cure in this disease.