Progressive familial intrahepatic cholestasis (PFIC) is a group of disorders characterized by inappropriate bile formation, causing hepatic accumulation of bile acids and, subsequently, liver injury. Until recently, no approved treatments were available for these patients. Recent clinical trials for PFIC treatment have focused on intestine-restricted ileal bile acid transporter (IBAT) inhibitors. These compounds aim to reduce the pool size of bile acids by interrupting their enterohepatic circulation. Other emerging treatments in the pipeline include systemic IBAT inhibitors, synthetic bile acid derivatives, compounds targeting bile acid synthesis via the FXR/FGF axis, and chaperones/potentiators that aim to enhance the residual activity of the mutated transporters. Substantial progress has been made in drug development for PFIC patients during the last couple of years. Although data concerning long-term efficacy are as yet only scarcely available, new therapies have demonstrated robust efficacy in a considerable fraction of patients at least on the shorter term. However, a substantial fraction of PFIC patients does not respond to these novel therapies and thus still requires surgical treatment, including liver transplantation before adulthood. Hence, there is still an unmet medical for long-term effective medical, preferably non-surgical, treatment for all PFIC patients.

Introduction: Amanita phalloides poisoning is a serious health problem with a mortality rate of 10–40%. Poisonings are characterized by severe liver and kidney toxicity. The effect of Amanita phalloides poisonings on hematological parameters has not been systematically evaluated thus far. Methods: Patients with suspected Amanita phalloides poisonings were retrospectively selected from the hospital database of the University Medical Center Groningen (UMCG). Medical data—including demographics; liver, kidney, and blood parameters; treatment; and outcomes—were collected. The severity of the poisoning was scored using the poison severity score. Results: Twenty-eight patients were identified who were admitted to the UMCG with suspected Amanita phalloides poisoning between 1994 and 2022. A time-dependent decrease was observed for hemoglobin and hematocrit concentrations, leukocytes, and platelets. Six out of twenty-eight patients developed acute liver failure (ALF). Patients with ALF showed a higher increase in liver enzymes, international normalized ratios, and PSS compared to patients without ALF. Conversely, hemoglobin and platelet numbers were decreased even further in these patients. Three out of six patients with ALF died and one patient received a liver transplant. Conclusion: Our study shows that Amanita phalloides poisonings may be associated with hematotoxicity in patients. The quantification of hematological parameters is of relevance in intoxicated patients, especially in those with ALF.

Amanita phalloides poisonings account for the majority of fatal mushroom poisonings. Recently, we identified hematotoxicity as a relevant aspect of Amanita poisonings. In this study, we investigated the effects of the main toxins of Amanita phalloides, α- and β-amanitin, on hematopoietic cell viability in vitro. Hematopoietic cell lines were exposed to α-amanitin or β-amanitin for up to 72 h with or without the pan-caspase inhibitor Z-VAD(OH)-FMK, antidotes N-acetylcysteine, silibinin, and benzylpenicillin, and organic anion-transporting polypeptide 1B3 (OATP1B3) inhibitors rifampicin and cyclosporin. Cell viability was established by trypan blue exclusion, annexin V staining, and a MTS assay. Caspase-3/7 activity was determined with Caspase-Glo assay, and cleaved caspase-3 was quantified by Western analysis. Cell number and colony-forming units were quantified after exposure to α-amanitin in primary CD34+ hematopoietic stem cells. In all cell lines, α-amanitin concentration-dependently decreased viability and mitochondrial activity. β-Amanitin was less toxic, but still significantly reduced viability. α-Amanitin increased caspase-3/7 activity by 2.8-fold and cleaved caspase-3 by 2.3-fold. Z-VAD(OH)-FMK significantly reduced α-amanitin-induced toxicity. In CD34+ stem cells, α-amanitin decreased the number of colonies and cells. The antidotes and OATP1B3 inhibitors did not reverse α-amanitin-induced toxicity. In conclusion, α-amanitin induces apoptosis in hematopoietic cells via a caspase-dependent mechanism.

Aim: Non‐surgical treatment of acute liver failure (ALF) is primarily supportive and depends on the underlying cause. While N‐acetylcysteine (NAC) is proven effective in paracetamol‐induced ALF, its potential benefits in non‐paracetamol ALF for paediatric patients remain unclear. This systematic review aimed to evaluate the efficacy of NAC in paediatric patients with non‐paracetamol‐induced ALF. Methods: PubMed and Embase were searched for studies published before 20 August 2025. The review was registered on PROSPERO (CRD420251146345). Eligible studies included paediatric patients receiving NAC for non‐paracetamol‐induced ALF. Primary outcomes were overall survival and transplant‐free survival. Results: Statistical analyses were performed with Review Manager version 7.2.0 with a random‐effect model, and heterogeneity was assessed with I ² . Risk of bias 2 and risk of bias in non‐randomized studies of interventions were used for bias assessment. The meta‐analysis included 310 patients receiving NAC and 242 controls. Overall survival was 77.7% in the NAC group and 73.5% in controls (OR 1.34, 95% CI: 0.90–1.99, p = .15). Transplant‐free survival was 60.1% for NAC and 61.6% for controls (OR 0.81, 95% CI 0.26–2.46, p = .71). Conclusions: Current evidence indicates that NAC does not significantly impact overall survival and transplant‐free survival in paediatric patients with non‐paracetamol‐induced ALF. Given the limited availability of randomized controlled trials, future research should preferably include such study designs, although ethical challenges may limit feasibility. Systematic collection of clinical data remains essential to better assess potential therapeutic effects. Current literature does not support the use of NAC in non‐paracetamol‐induced ALF in children.