Rare liver diseases are associated with diagnostic delay, fragmented care, inconsistent management, and limited patient support. Patient pathways may help address these challenges by translating clinical guidance and patient priorities into practical, coordinated care processes. This manuscript presents a European template for developing patient-centred pathways for rare liver diseases within ERN RARE-LIVER. The template was developed through multidisciplinary collaboration involving hepatologists, specialist nurses, patient representatives, patient organisations, and EURORDIS, and was informed by clinical guidance, patient-journey principles, and iterative expert and patient review. The proposed framework follows four phases of the patient journey: pre-diagnosis, diagnosis, management, and long-term follow-up. It includes disease-specific sections, educational resources, frequently asked questions, and “10 key questions” to support shared decision-making. Pathways for non-cirrhotic portal vein thrombosis, polycystic liver disease, and portosinusoidal vascular disorder illustrate the practical application of the template. This European template provides a practical, adaptable framework aimed at supporting harmonised, multidisciplinary, and patient-centred care for rare liver diseases across European healthcare settings. Future work should evaluate implementation, usability, and impact on care coordination and patient experience.

BACKGROUND & AIMS:Sinusoidal obstruction syndrome (SOS) is a potentially severe complication of conditioning regimens in hematopoietic stem cell transplantation (HSCT). Its long-term outcome is unknown. The aim of this study was to investigate the long-term liver outcome of patients with SOS. METHODS:We retrospectively analyzed the outcome of all patients with histologically proven SOS related to HSCT conditioning who survived 6 months or more after HSCT. 22 patients with SOS were included. RESULTS:Median follow-up after SOS was 6.1 years. During this period, 10 patients (45%) developed signs of portal hypertension and 8 (36%) of them liver-related complications (ascites, n=8; spontaneous bacterial peritonitis, n=1; hepatic encephalopathy, n=3; variceal bleeding, n=3). Cumulative incidence of signs of portal hypertension was 27% at 3 years. Patients who developed signs of portal hypertension were less likely to have received defibrotide (hazard ratio:0.096; p<0.001) and had lower mean arterial pressure than those who did not. Of the 10 patients who developed signs of portal hypertension during follow-up, 3 underwent a second liver biopsy; all biopsies showed features of porto-sinusoidal vascular disorder. Cumulative incidence of death, considering non-liver-related death as a competing event, was significantly higher in patients who developed signs of portal hypertension than in those who did not [hazard ratio: 10.7 (1.27-89.9)]. CONCLUSION:Development of signs of portal hypertension and liver-related complications are common in the long-term after SOS following HSCT, especially when patients did not receive defibrotide, and this affects patients' survival. Features consistent with a porto-sinusoidal vascular disorder may be seen in liver histology in a subset of patients at the long-term follow-up after SOS. IMPACT AND IMPLICATIONS:Long-term liver outcome of sinusoidal obstruction syndrome (SOS) following conditioning regimens in haematopoietic stem cell transplantation (HSCT) is unknown.This study demonstrates that signs of portal hypertension and liver-related complications are common during long-term follow-up after SOS following HSCT. Treatment of SOS with defibrotide seems to be associated with a lower risk of developing portal hypertension. Liver histology at the long-term follow-up after SOS may show features consistent with PSVD.SOS following HSCT might thus be removed from the PSVD exclusion criteria.

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.

BACKGROUND & AIMS:Vascular liver diseases (VLDs) are rare conditions affecting adults of working age, yet there are no real-world data on their impact on employment. METHODS:A multicenter cross-sectional study was conducted in France and Spain, using clinical records and self-administered questionnaires. Employment outcomes in patients with a VLD and controls were compared using indirect standardisation with age- and sex-adjusted population norms. Multivariable logistic regression assessed factors associated with health-related inactivity (unable to work due to illness/disability) and health-related absenteeism from work. RESULTS:Of 1136 eligible patients, 595 (52.4%) responded and the data of 432 participants aged 25-64 were analysed. Health-related inactivity (13.0% of patients) and health-related absenteeism over the last year (48.5%) were higher in patients with a VLD than in the general population (Standardised Ratio (SR) = 2.61, 95%CI:1.95-3.42; SR = 1.57, 95%CI:1.33-1.87 respectively). History of gastrointestinal bleeding (adjusted Odds Ratio (aOR) = 2.64, 95%CI:1.17-5.98) and prior interventional procedures (aOR = 2.49, 95%CI:1.06-5.88) were significantly associated with inactivity. Older patients (versus 25-44 years old) and those with a low/moderate educational level (versus high) were more likely to experience inactivity (aOR = 2.23, 95%CI:1.07-4.65; aOR = 3.11, 95%CI:1.53-6.35 respectively). Absenteeism was associated with moderate/severe pain (aOR = 2.45,95%CI:1.10-5.44) and unmet needs for special illness-related leave (aOR = 2.97,95%CI:1.33-6.63). CONCLUSIONS:Patients with VLD face disadvantages in employment participation and absenteeism, driven by disease severity and symptom burden. These effects are most pronounced among low-educated individuals, highlighting socioeconomic disparities in work retention. This underscores the need for targeted workplace accommodations, supportive employment policies, and social care support.

BACKGROUND AND AIMS:Screening endoscopy can be spared in patients with compensated cirrhosis when spleen stiffness measurement (SSM) by vibration-controlled transient elastography (VCTE) is ≤40 kPa, as they have a low probability of high-risk varices (HRV). Conversely, endoscopy is required in all patients with chronic portal vein thrombosis (PVT) without cirrhosis. The objective was to evaluate the performance of SSM-VCTE to exclude HRV in patients with chronic PVT. METHODS:We retrospectively included patients with chronic PVT without cirrhosis, who underwent an upper endoscopy within 2 years before or after SSM-VCTE in 16 VALDIG centers, divided into a derivation and a validation cohort. RESULTS:159 patients were included in the derivation cohort; 43% had HRV. 187 patients were included in the validation cohort; 32% had HRV. By univariable analysis, myeloproliferative neoplasm, ascites, hemoglobin, bilirubin, albumin, splenomegaly, portosystemic collaterals, liver stiffness - spleen diameter to platelet ratio score, liver stiffness measurement and SSM-VCTE were associated with HRV in both cohorts. By multivariable binary logistic regression analysis, only SSM-VCTE (p <0.005) remained associated with HRV in both cohorts. In the derivation cohort, SSM-VCTE ≤ 40 kPa had a sensitivity of 97% to rule out HRV, and could spare 41% of endoscopies, with 3% of HRV missed, and a 97% negative predictive value (NPV). In the validation cohort, SSM-VCTE ≤ 40 kPa could spare 43% of endoscopies, with 5% of HRV missed, and a 96% NPV. CONCLUSIONS:This study gathering a total of 346 patients with chronic PVT without cirrhosis showed that SSM-VCTE ≤ 40 kPa can be used to identify patients with a probability of HRV ≤5%, in whom endoscopy can be spared. IMPACT AND IMPLICATIONS:Patients with chronic portal vein thrombosis who do not have cirrhosis usually have low liver stiffness measurement values; the liver stiffness cut-offs used to rule out high-risk varices in patients with cirrhosis cannot therefore be used in this population. We show here that spleen stiffness measurement by vibration-controlled transient elastography ≤40 kPa is able to identify patients with chronic portal vein thrombosis with a very low probability of high-risk varices, in whom screening endoscopy can be spared. Annual surveillance of spleen stiffness measurement could reduce the need for repeated screening endoscopies throughout a person's lifetime. This approach could enhance quality of life while also reducing risks associated with endoscopic procedures, particularly those related to anesthesia.

Obstruction of the hepatic veins and therefore of hepatic venous drainage, located between the small hepatic venules and the junction of the inferior vena cava (IVC) with the right atrium, in the absence of sinusoidal obstruction syndrome, heart failure, or pericardial disease, is called Budd-Chiari syndrome (BCS). Primary BCS, which is the only form discussed here, corresponds to endoluminal obstruction due to thrombosis. BCS is a rare disease, with an annual incidence of approximately 1 case per million. Its clinical presentation is very heterogeneous, ranging from asymptomatic forms (≈15%) to acute liver failure (ALF). The most common symptoms are ascites (83%), hepatomegaly (67%), and abdominal pain (61%). Diagnosis: BCS should be systematically considered in all cases of acute or chronic liver disease. Doppler ultrasound: first-line examination. CT-scan or MRI with contrast: diagnostic confirmation, assessment of portal hypertension and treatment options. Liver biopsy: exceptionally indicated only if the hepatic veins are patent and small vein BCS is suspected. Management: the strategy is based on a stepwise approach: emergency investigation and treatment of the cause(s). Lifelong anticoagulation, started urgently (LMWH then VKA; DOAC possible to be evaluated in a specialist center). Treatment of complications (ascites, encephalopathy, varices). Percutaneous angioplasty if short stenosis is accessible. TIPS if medical treatment or angioplasty fails. Liver transplantation (LT) in case of treatment failure or BCS with fulminant hepatitis that does not respond to anticoagulant treatment. This strategy results in a 5-year survival rate of 74–89%. LT is necessary in 13–18% of patients, with excellent long-term results comparable to or even superior to those for other indications. Monitoring and complications: hepatocellular carcinoma (HCC). Lifelong monitoring of patients with SBC by a multidisciplinary team is essential due to the risks of complications from the underlying disease or liver disease and the risk of malignant transformation. As soon as the diagnosis is announced, it is also useful to inform patients of the existence of patient associations, such as AMVF, Accueil – AMVF Asso, helping to limit the isolation associated with this rare disease. Pregnancy: a preconception consultation is strongly recommended for any patient planning to become pregnant, in order to anticipate therapeutic adjustments and assess maternal-fetal risk.

BACKGROUND & AIMS:Autoreactive CD4 T cells, which recognize liver self-antigens such as SepSecS, are potentially main drivers of the chronic inflammatory response during autoimmune hepatitis (AIH). Previous studies have revealed SepSecS epitopes often associated with HLA-DRB1∗03 or HLA-DRB1∗04 restriction, two alleles enriched in AIH population. However, human leukocyte antigen (HLA) restriction of numerous SepSecS epitopes remains incomplete, and whether they could be presented by non-HLA-DR molecules remains unclear. Here, we investigated epitope recognition and HLA restriction of SepSecS-specific CD4 T cells from AIH patients. METHODS:We cloned 17 T-cell receptor αβ (TCRαβ) from the most expanded SepSecS-specific CD4 T cells of five AIH patients from our previous studies into a murine hybridoma T-cell line. The epitope reactivity of each TCR cell line was identified via IL-2 secretion following culture with 20-mer overlapping peptides of the SepSecS protein and immortalized B-cell lines. HLA restriction was defined using HLA blocking antibodies. We analyzed 484 SepSecS-specific TCRs from nine AIH patients using GLIPH2 algorithm. CD154 activation-induced marker assay was used to evaluate the SepSecS epitope reactivity in AIH patients (n = 11). RESULTS:Autoreactive TCRs recognized six SepSecS amino acid regions in vitro, with four distinct class II HLA restrictions, including non-HLA-DR restrictions. The GLIPH2 algorithm clustered SepSecS-specific TCRs into six groups. Notably, 6% of the total SepSecS-specific TCR clonotypes shared common CDR3β motifs linked to the recognition of HLA-DPA1∗02:01/HLA-DPB1∗01:01-restricted SepSecS152-179 epitope. Ex vivo peptide stimulation assay revealed that SepSecS152-179 epitope represents 15% to 67% of total SepSecS CD4 T-cell reactivity in HLA-DPA1∗02:01∼HLA-DPB1∗01:01 AIH patients (n = 5). CONCLUSIONS:We highlighted that SepSecS epitopes could be presented by HLA-DR and non-HLA-DR molecules to autoreactive CD4 TCRs with potentially conserved CDR3 motifs for common epitope recognition. IMPACT AND IMPLICATIONS:In AIH, SepSecS is a key autoantigen targeted by the adaptive immune system, but only few T-cell epitopes are defined and associated with a precise HLA restriction. By reconstructing TCRs from the most expanded SepSecS-specific CD4 T cells of AIH patients, we identified new T-cell epitopes and their specific class II HLA restriction, including peptides presented by non-HLA-DR molecules. From a clinical perspective, these findings could be used to develop tools to track the frequency of autoreactive T cells in patients. This work could also pave the way for self-antigen-specific immunotherapies, such as peptide-based desensitization or the development of HLA-multimer technologies to selectively deplete or reprogram pathogenic T cells without inducing systemic immunosuppression.

Telomere-related gene (TRG) pathogenic variants are detected in ∼30% of familial pulmonary fibrosis (PF) cases. Danazol, a synthetic sex hormone with androgenic properties, has been found associated with telomere elongation and hematologic response in patients with short telomeres. The objective of the ANDROTELO multicenter, prospective, open-label single-arm phase II clinical trial ( NCT03710356 ) was to evaluate the efficacy and safety of danazol in carriers of TRG mutations with PF or bone-marrow failure (BMF).Included patients were carriers of a pathogenic or likely pathogenic TRG variant and presented a PF lung involving ≥10% parenchymal involvement on chest CT (PF group) and/or severe BMF (BMF group). Treatment was danazol 400 mg twice a day for 12 months. We included 25 patients with PF (16 males) and 5 with BMF (2 males). One PF patient withdrew consent. At inclusion, the median age in the PF group was 62.5 years, FVC 69% (interquartile range 40;120) and DLCO 44% (29;84). Ten of 24 PF patients (42%) completed the 12-month treatment. Causes of premature treatment discontinuation were side effects (n=9), death (n=3), lung transplantation (n=1), and disease progression (n=1). Fourteen PF patients were evaluated at month 12: 8 showed a relative decline of FVC of <5%. The median relative decrease in FVC and DLCO was −10% (interquartile range −14;−2) and −10.3% (−22.7;4.2). The 5 patients in the BMF group completed the 12-month treatment and exhibited at least partial response. Danazol was poorly tolerated in patients with TRG-related PF in this study, thus precluding efficacy assessment.

We aimed to describe porto-sinusoidal vascular disease (PSVD) in a large cohort of predominantly antibody deficiency (PAD) patients and sought to identify contributing factors for PSVD development by comparing CVID patients with and without PSVD. Patients were retrospectively identified from a national database. Sixty-eight of 386 PAD patients, including 63 of 267 CVID patients were diagnosed with PSVD. Median time from PAD to PSVD diagnosis was 9.2 years (interquartile range, 4.6–14.5). CVID patients with late onset combined immunodeficiency and non-infectious complications were overrepresented among PSVD patients (37.5