Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific disorder characterized by elevated maternal serum total bile acid (TBA) and increased risk of adverse fetal outcomes, yet current therapies and preventive strategies remain suboptimal. Here, we present a preclinical investigation of nanocellulose as a gut microbiota-targeted dietary intervention to restore bile acid homeostasis. We demonstrate that nanocellulose, particularly cellulose nanofibers (CNF), administered prophylactically, attenuated maternal TBA and improved offspring survival in a rat ICP model by enriching probiotic microbial taxa while suppressing bile acid-transforming bacteria. These microbial shifts promoted the accumulation of fecal primary bile acids and activation of gut-liver farnesoid X receptor (FXR) signaling. This cascade reduced intestinal reabsorption and hepatic synthesis of bile acids while promoting their excretion in feces. Collectively, pre-gestational CNF effectively lowered systemic bile acid burden and mitigated the ICP phenotype. Our findings identify CNF as a biosafe, microbiota-responsive dietary fiber with translational potential for early preventive management of bile acid-related disorders during pregnancy.

Edema formation and ascites are common features in liver disease. The excessive accumulation of body water is caused by increased kidney water retention; yet the mechanisms linking liver and kidney function remain incompletely understood. This review explores the emerging concept of a liver-kidney axis, with bile acids (BAs) as potential mediators for kidney water handling. In cholestatic liver disease, as seen in liver cirrhosis, impaired hepatic BA flow to the duodenum elevates systemic BA concentrations, which can modulate signaling pathways through the BA receptors Farnesoid X Receptor (FXR, NR1H4) and G-protein-coupled bile acid receptor 1 (TGR5, GPBAR1), thereby increasing kidney Na[+] and water retention in experimental models. Moreover, BAs can directly activate the sodium channel ENaC in isolated mouse collecting ducts and in mouse distal colon epithelial cells. Thus, BAs can promote sodium and water retention in parallel with the classical sodium- and water-retaining systems, such as the renin-angiotensin-aldosterone system. This effect may potentially contribute to water retention in pregnancy-associated conditions and in proteinuric kidney diseases, where liver function is affected, e.g., by loss of plasma proteins, altering hepatic BA metabolism. In this review, we will describe the synthesis of BAs, their modifications, and kidney BA metabolism in health and disease, and highlight a potential dynamic interplay between liver and kidney function, mediated in part by BAs, with implications for understanding and treating water retention disorders.

Drug-induced liver injury (DILI) in children remains a diagnostic challenge due to its broad clinical and histologic spectrum. Based on pathogenesis, DILI is classified as idiosyncratic, intrinsic (direct), or indirect. In the United States, antimicrobials and antiepileptic medications are the most commonly implicated agents. Because histologic features are often nonspecific, diagnosis and assessment of causality rely on clinicopathologic correlation. Although not always required, liver biopsy can aid in characterizing injury patterns, assessing severity, and excluding mimickers. This review highlights the major morphologic patterns of pediatric DILI, associated agents, and practical considerations for biopsy interpretation in routine practice.

Microcystins (MCs) are cyanobacterial toxins found in water and food and are suspected to pose significant health risks, particularly to the liver. To gain insight into the mechanisms of hepatotoxicity and the potential carcinogenicity of MCs, this study investigated the effects of MC-LR, -LA, and -RR (congeners differing in cellular uptake and detoxification efficiency) on PP2A activity, cell proliferation, and gene expression profiling focused on toxicity pathways and carcinogenesis in HepaRG cells. The three MCs similarly inhibited PP2A activity; however, only MC-LR and -LA significantly increased cell proliferation. Gene expression profiles (mRNA) revealed strong, similar treatment effects induced by MC-LR and -LA (R2 = 0.66), whereas -RR affected fewer genes, showing weak correlations with the other two congeners (-LRx-RR - R[2] = 0.31; -LAx-RR - R[2] = 0.06). Moreover, MC-LR and -LA, but not -RR, affected several liver-enriched toxicity pathways, which correlate most closely to hepatocellular/liver carcinoma, cholestasis, and fibrosis. All congeners altered carcinogenesis-related miRNA expression, but no consistent pattern was observed among them. Overall, the present findings reinforce the congener-specific toxicity of MCs, likely driven by differences in toxicokinetics among congeners. Furthermore, the findings indicate that MC-induced liver effects also involve PP2A-independent mechanisms, as MC-LR/-LA and -RR elicited markedly different biological responses despite comparable PP2A inhibition. Finally, the study demonstrates the applicability of the NAM-based approach for evaluating liver effects (hepatocytes) in the MC family and, as structurally different congeners were investigated, provides data that could be used for read-across and grouping.

While shrinkage and preliminary test estimation have long been studied in linear and static Cox models, their theoretical integration within models featuring time-dependent covariates has remained unresolved due to the evolving risk set and nonhomogeneous information accumulation inherent in such data. In this study, we develop a unified framework for shrinkage estimation in the time-dependent Cox proportional hazards model, by extending the classical Stein-type theory to a dynamic semiparametric survival setting. Our theoretical analyses reveal that the positive-rule Stein estimator preserves unbiasedness under valid restrictions while adaptively attenuating variance inflation when the restriction is approximately correct, striking a principled balance between efficiency and robustness. A comprehensive Monte Carlo simulation study and an empirical application to the Mayo Clinic primary biliary cirrhosis dataset substantiate the theoretical advantages, demonstrating that the superior estimation strategy achieves substantial efficiency gains relative to both unrestricted and penalized estimators such as adaptive LASSO.

Drug-induced liver injury (DILI) is liver damage caused by drugs, their metabolites, or other exogenous substances. In severe cases, it may progress to acute liver failure (ALF), posing a significant threat to patient survival. The pathogenesis of DILI involves multiple mechanisms, including oxidative stress, mitochondrial dysfunction, inflammatory and immune responses, cholestasis, and dysfunction of transport proteins. The mechanisms underlying DILI induced by traditional Chinese medicines (TCM) and Western medicines share certain similarities but also exhibit notable differences. Currently, the clinical diagnosis of DILI still relies on conventional biochemical indicators of liver injury. However, with the exploration of novel biomarkers, particularly through the integration of multi-omics approaches and gut microbiota research, diagnostic strategies are continuously evolving. In terms of treatment, DILI caused by Western medicines is generally managed through drug withdrawal, hepatoprotective therapy, and liver transplantation when necessary. In contrast, TCM-induced DILI presents greater therapeutic challenges due to the complex of its components and diverse mechanisms. Emerging diagnostic and therapeutic approaches, such as probiotics, antioxidants, compound herbal formulas, and genetic susceptibility analysis, have attracted increasing attention and are expected to become more effective strategies for the predicting and managing DILI. A comprehensive understanding of the mechanisms, diagnostic advances, and therapeutic strategies of DILI, along with a comparative analysis of DILI induced by TCMs and Western medicines, may provide new insights for its prevention and treatment. Future research should focus on individualized medication, genetic susceptibility, and emerging intervention strategies to improve drug safety awareness and promote rational drug use in clinical practice.

Cholestasis secondary to protein serine kinase H1 (PSKH1) is a recently described entity, which leads to chronic liver disease in childhood or early teenage years with or without renal insufficiency. Mutations in the PSKH1 gene reduce PSKH1's kinase activity, leading to abnormally long and convoluted cilia in renal tubules and bile ducts, disrupting normal function. There are very few reports highlighting the outcomes of liver transplantation (LT) for PSKH1-related liver disease. There have been no reports of PSKH1-induced cholestasis reported from India till date. We describe the first report of Living donor liver transplantation (LDLT) for PSKH1-related chronic liver disease from India and also discuss the clinical presentation, management challenges and the safety of utilizing heterozygous donors in this situation.

Employing a narrative review approach, this article examines the value of combining homocysteine (Hcy) with multiple indicators for screening pregnancy complications. Hcy serves as a key biomarker in one-carbon metabolism and vascular endothelial function. Elevated Hcy levels are significantly correlated with adverse pregnancy outcomes, including preeclampsia (PE), fetal growth restriction (FGR), gestational diabetes mellitus (GDM), and intrahepatic cholestasis of pregnancy (ICP). Hcy levels are influenced by nutritional factors (folate, vitamin B12) and genetic factors (MTHFR polymorphisms). However, the predictive power of Hcy alone is limited due to variations in gestational age, ethnicity, nutritional status and genetic background. Recent studies have therefore explored combined screening strategies: Hcy together with platelet parameters helps differentiate the risk of ICP from that of GDM; adding uterine artery (UtA) Doppler ultrasonography improves the diagnostic sensitivity for detecting PE and FGR; integrating glycolipid metabolic markers (Glycosylated Serum Protein, Cystatin-C, apoB/apoA1) provides additional predictive value for adverse outcomes in GDM. Positioning Hcy as a functional endpoint of gene-nutrient interactions and combining it with nutritional and genetic assessments may facilitate early warning of pregnancy complications and enable individualized intervention.

Liver disease in horses is primarily evaluated using the routine serum biochemical profile with a few additional specialty tests of liver function that are performed when indicated. Serum enzyme activities are evaluated to indicate hepatocellular damage and cholestasis. Liver function is evaluated using synthetic markers like BUN, albumin, bilirubin, and clotting times, while clearance function tests such as serum bile acids and ammonia are performed separately. Most equine liver disease is characterized by some degree of hepatocellular damage and cholestasis, while decreased liver function is less common because of the large reserve capacity of the organ.