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Open research questions in Liver Diseases and Immunity

25 unresolved questions extracted from the limitations and future-work sections of 184 Liver Diseases and Immunity papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • IL-21R blockade ameliorated disease in a murine BA model, identifying the IL-21/IL-21R axis as a potential therapeutic target warranting further investigation.

    IL-21-producing peripheral helper T cells associate with autoimmune bile duct injury in biliary atresia · 2026 · DOI

  • ObjectiveAlthough immune dysregulation is implicated in the pathogenesis of BA, the specific mechanisms driving bile duct injury remain incompletely understood.

    IL-21-producing peripheral helper T cells associate with autoimmune bile duct injury in biliary atresia · 2026 · DOI

  • However, the cellular mechanisms linking local immune activation to bile duct injury are unclear, and the roles of organized lymphoid structures and specific CD4 T cell subsets in orchestrating local humoral responses have not been characterized.

    IL-21-producing peripheral helper T cells associate with autoimmune bile duct injury in biliary atresia · 2026 · DOI

  • While MMP-7 has emerged as a promising biomarker for fibrosis in hepatocyte-centric diseases like NAFLD, its role in PBC—a disease centered on biliary injury—remains poorly defined (22, 23).

    Serum matrix metalloproteinase-7 as a diagnostic and prognostic biomarker in primary biliary cholangitis · 2026 · DOI

  • Inflammatory and fibrogenic stimuli, such as transforming growth factor-{beta} (TGF{beta}) and lipopolysaccharide (LPS) signaling, drive these processes, but their underlying transcriptional mechanisms in cholangiocytes remain incompletely defined.

    Cholangiocyte RUNX1 Orchestrates Fibrogenic and Inflammatory Signaling to Drive Biliary Fibrosis · 2026 · DOI

  • Discussion: The mechanisms underlying liver injuries following COVID-19 vaccination remain incompletely understood, and a causal relationship has not been definitively established.

    COVID-19 vaccine-associated liver injury and autoimmune hepatitis: a case series · 2026 · DOI

  • The close association between immune cell infiltration around the intrahepatic bile ducts and bile duct damage, and the causal and potential relationships of immune cells in the pathogenesis of PBC, remain unclear.

    Genetic mechanisms of primary biliary cholangitis and its association with immune cells using mendelian randomization and biological annotation · 2026 · DOI

  • Observational research is inherently subject to bias, such as heterogeneity of included cases, referral bias, missing data, overlooked confounders, etc. Here, all cases have under- gone case-ascertainment at the source by three experienced investigators (CYP, KB and KvM). We have corrected for transplantation-center bias in our analysis. Furthermore, we have tried to take as many potential confounders into account including well-known such as sex, PSC type, age at diagno- sis, concurrent IBD and type of, but—importantly—also immortality bias by incorporating UDCA as time-dependent variable. A putative different effect of UDCA in patients who used the drug earlier in their disease course versus later was made less likely by a sensitivity analysis comparing par- tial users who predominantly were prescribed UDCA during the first half of their disease course versus second half. This did not reveal a difference in effect size (data not shown). Because we could mine four different sources of medication use and applied two different decision rules for estimating the duration of medication use, and discarded in the end patients with uncertain use, we think that user classifica- tion was as optimal as attainable. To counter selection bias, calendar year of PSC diagnosis was considered as covari- ate. As UDCA became common practice as prescription for PSC patients in the late nineties, patients who had an earlier calendar year of PSC diagnosis could potentially represent a selection of patients with a more favorable prognosis as they have lived long enough to participate in the study and receive the treatment when it became available. This poten- tial bias was not apparent as calendar year did not signifi- cantly contribute to the multivariable models. Since ALP levels at diagnosis were comparable for all groups, there was no indication that prescription bias played a substantial role. In the Netherlands, commonly, every patient with a diagno- sis of PSC gets UDCA prescribed irrespective of the severity of cholestasis. Nevertheless, prescription bias cannot fully be ruled out, and would perhaps offer an alternative explana- tion for the observed trend benefiting the always-user group over the never-user group, suggesting that physicians were possibly less inclined to prescribe UDCA to patients with a less favorable prognosis. For instance, the occurrence of HB carcinoma in never users was 18% versus 6% in always users. It may be that physicians refrained from prescribing a drug like UDCA aimed at impacting long-term prognosis in these patients. Excluded patients categorized as uncertain use, which we deliberately left out of the analysis to avoid the inherent bias of retrospective data, were more frequently included in district general hospitals, which could lead to underrepresentation of these patients. Data on dosing were reliably available for all prospectively followed patients. However, because a putative modifying effect on outcome was presumed upon long-term use only, we chose to involve all patients from whom we had reasonable or affirmative medication use available with the longest follow-up attain- able. Indeed, our study presents the longest FU data regard- ing UDCA use so far. A drawback was that reliable granular information on dosing was available in half of the cohort only. However, UDCA dosing in the Netherlands since its introduction has been commonly 10–20 mg/kg, which is according to most guidelines on PSC, despite the fact that there is no evidence on the optimal dose of UDCA in PSC. In conclusion, this population-based long-term observa- tional study failed to demonstrate that use of UDCA affects long-term outcomes in PSC patients, and consequently does not support current suggestions in recent clinical practice guidelines. Acknowledgements The authors would like to thank Prof. Dr. U. H. Beuers for his expert advice. Funding This study was funded by Dutch Organization for Health Research and Development ZonMW (Grant No. 836041010) (Cyriel Y. Ponsioen). The funding source was involved in the study design, but had no role in the collection, analysis, or interpretation of the data. The funding source did not participate in writing or the decision to submit the article for publication.

    The longstanding issue of the benefit of ursodeoxycholic acid in primary sclerosing cholangitis: a long-term population-based study · 2026 · DOI

  • Research aimed at studying the clinical course of PSC in children and improving early diagnosis is relevant, especially given the limited access to modern diagnostic methods, such as magnetic resonance cholangiopancreatography, the need for invasive studies, and the lack of standardized diagnostic criteria adapted to childhood, which complicates the diagnosis and treatment of these patients.

    Phenotypes of primary sclerosing cholangitis in children · 2024 · DOI

  • Whether the broader cellular composition of the liver might enable improved specificity of diagnosis has not been systematically tested.

    Hepatic CD8+TOX+ T-cells are a hallmark of autoimmune hepatitis · 2026 · DOI

  • The pathophys- iology linking PBC and dRTA is not fully defined; Figure 2.

    A rare renal manifestation of primary biliary cholangitis: case report and brief review · 2026 · DOI

  • Progressive splenic infarction and acute cholestatic liver injury are uncommon complications, and their concurrent presentation has not been previously reported.

    Splenic Marginal Zone Lymphoma Presenting with Progressive Splenic Infarction and Acute Cholestatic Liver Injury- a Case Report · 2026 · DOI

  • Future research should focus on integrating redox biology into therapeutic design, with emphasis on identifying patient subgroups most likely to benefit from targeted antioxidant modulation.

    Cholestatic and autoimmune liver diseases, bile duct injury, oxidative stress, and therapeutic strategies · 2026 · DOI

  • Although a clear correlation between elevated levels of maternal serum bile acids and deficient fetal outcome has been established in clinical practice, the underlying mechanisms remain elusive.

    Intrahepatic cholestasis of pregnancy and fetal outcomes. Mini review · 2017 · DOI

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25 open questions have been extracted from the limitations and future-work passages of 184 Liver Diseases and Immunity papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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