BACKGROUND: The occurrence of portal vein system thrombosis (PVST) after splenectomy in patients with Wilson disease (WD) can lead to serious complications. The early identification of high-risk patients can help improve patient prognosis. This study aimed to establish and validate a personalized nomogram for assessing the risk of PVST after splenectomy in patients with WD and hypersplenism.
METHODS: We retrospectively collected the data from 81 patients with WD and hypersplenism who underwent splenectomy. Based on whether PVST occurred within a month after the operation, they were divided into the PVST group and the non-PVST group. The clinical data of the 2 groups were compared, and univariate analysis was used to select the statistically significant features and incorporated into the least absolute shrinkage and selection operator (LASSO) regression model for optimization. Multivariate logistic regression analysis was used to determine the independent risk factors for PVST after splenectomy, which were then applied to establish a personalized nomogram. We calculated the concordance (C)-index and drew the receiver operating characteristic (ROC) curve, the model calibration curve, and the clinical decision analysis (DCA) curve to evaluate the accuracy, calibration, and clinical applicability of the model, respectively. We used bootstrapping for internal validation of the model.
RESULTS: Univariate analysis showed that the differences in preoperative portal vein diameter and velocity of portal blood flow, postoperative mean platelet volume (MPV), mean platelet distribution width (PDW), D-dimer, prothrombin time (PT), and the increase of platelet count (PLT) were of statistical significance (P<0.05). According to the results of the LASSO and multivariate logistic regression analyses, a model including preoperative portal vein diameter, preoperative portal blood flow velocity, postoperative D-dimer, and the increase of PLT was established to predict the risk of PVST after splenectomy. The model showed good accuracy with a C-index of 0.838 (95% CI: 0.750-0.926) and had a well-fitted calibration curve. Furthermore, internal validation showed it achieved a moderate C-index of 0.805. The DCA curve indicated that the model has clinical applicability when patients are treated at thresholds of 2-100%.
CONCLUSIONS: Establishing a predictive model for the risk of PVST in patients with WD and hypersplenism after splenectomy can help clinicians identify patients at high risk of PVST who require intervention measures.

In this paper, we describe the multimodal MRI findings in a patient with Wilson disease and a seizure disorder, characterized by an electroclinical picture resembling juvenile myoclonic epilepsy. The brain structural MRI showed a deposition of ferromagnetic materials in the basal ganglia, with marked hypointensities in T2-weighted images of globus pallidus internus bilaterally. A resting-state fMRI study revealed increased functional connectivity in the patient, compared to control subjects, in the following networks: (1) between the primary motor cortex and several cortical regions, including the secondary somatosensory cortex and (2) between the globus pallidus and the thalamo-frontal network. These findings suggest that globus pallidus alterations, due to metal accumulation, can lead to a reduction in the normal globus pallidus inhibitory tone on the thalamo-(motor)-cortical pathway. This, in turn, can result in hyperconnectivity in the motor cortex circuitry, leading to myoclonus and tonic-clonic seizures. We suppose that, in this patient, Wilson disease generated a \'lesion model\' of myoclonic epilepsy.

UNASSIGNED: The goal of the present work is to provide an overview of the differential diagnosis of Wilson disease.
UNASSIGNED: Wilson disease is a rare condition due to copper accumulation primarily in the liver and brain. Although there is no definitive cure, current anti-copper treatments are associated with better outcomes if initiated early and if the diagnosis is made promptly. However, diagnostic delays are frequent and often Wilson disease represents a diagnostic challenge. The diagnosis ultimately relies on a combination of clinical, laboratory and genetic findings, and it is crucial that clinicians list Wilson disease in their differential diagnosis, especially in patients presenting with a hepatocellular pattern of liver injury. Some biochemical and liver histological features of Wilson disease overlap with those of more common conditions including nonalcoholic fatty liver disease, alcohol-associated liver disease, and autoimmune hepatitis. In particular, hepatic steatosis, hepatocyte glycogenated nuclei, ballooning degeneration, and Mallory-Denk bodies are often identified in Wilson disease as well as more common liver diseases. In addition, the natural history of liver damage in Wilson disease and the risk of developing liver cancer are largely understudied.
UNASSIGNED: We conducted an enlarged review of published papers on Wilson disease focusing on its diagnosis and distinctive clinical and liver pathology features in relation to common non-cholestatic liver diseases with the final goal in aiding clinicians in the diagnostic process of this rare but treatable condition.
UNASSIGNED: Aside from markedly altered copper metabolism, Wilson disease has essentially no pathognomonic features that can distinguish it from more common liver diseases. Clinicians should be aware of this challenge and consider Wilson disease in patients presenting with a hepatocellular pattern of liver injury.

Background: Gan-Dou-Fu-Mu decoction (GDFMD) improves liver fibrosis in experimental and clinical studies including those on toxic mouse model of Wilson disease (Model). However, the mechanisms underlying the effect of GDFMD have not been characterized. Herein, we deciphered the potential therapeutic targets of GDFMD using transcriptome analysis. Methods: We constructed a tx-j Wilson disease (WD) mouse model, and assessed the effect of GDFMD on the liver of model mice by hematoxylin and eosin, Masson, and immunohistochemical staining. Subsequently, we identified differentially expressed genes (DEGs) that were upregulated in the Model (Model vs. control) and those that were downregulated upon GDFMD treatment (compared to the Model) using RNA-sequencing (RNA-Seq). Biological functions and signaling pathways in which the DEGs were involved were determined by gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway analyses. A protein-protein interaction (PPI) network was constructed using the STRING database, and the modules were identified using MCODE plugin with the Cytoscape software. Several genes identified in the RNA-Seq analysis were validated by real-time quantitative PCR. Results: Total of 2124 DEGs were screened through the Model vs. control and Model vs. GDFMD comparisons, and dozens of GO and KEGG pathway terms modulated by GDFMD were identified. Dozens of pathways involved in metabolism (including metabolic processes for organic acids, carboxylic acids, monocarboxylic acids, lipids, fatty acids, cellular lipids, steroids, alcohols, eicosanoids, long-chain fatty acids), immune and inflammatory response (such as complement and coagulation cascades, cytokine-cytokine receptor interaction, inflammatory mediator regulation of TRP channels, antigen processing and presentation, T-cell receptor signaling pathway), liver fibrosis (such as ECM-receptor interactions), and cell death (PI3K-Akt signaling pathway, apoptosis, TGF-beta signaling pathway, etc.) were identified as potential targets of GDFMD in the Model. Some hub genes and four modules were identified in the PPI network. The results of real-time quantitative PCR analysis were consistent with those of RNA-Seq analysis. Conclusions: We performed gene expression profiling of GDFMD-treated WD model mice using RNA-Seq analysis and found the genes, pathways, and processes effected by the treatment. Our study provides a theoretical basis to prevent liver fibrosis resulting from WD using GDFMD.

Wilson disease (WD) is rare genetic disorder that presents with varied phenotype that can at times make the diagnosis challenging. Medical treatments are available, but there are still unmet needs for patients. Since life-long therapy is necessary, adherence to medical therapy and best practices for monitoring and individualizing therapy continue to evolve. Studies are ongoing that address some of these issues. In the current review we focused our attention to recent advances in the diagnosis of WD, current medical treatments, future potential therapies and treatment monitoring. We include discussion of new methodology for detection and quantitation of ophthalmologic signs of WD, new brain imaging modalities for early detection of neurologic involvement in patients and potential new diagnostic methodology using blood samples that may be applicable to newborn screening and adult disease diagnosis. In addition, there are new strategies aimed at improving adherence and outcomes with currently available therapies, including once daily chelation dosing and discussion of the efficacy of different zinc salt compounds. With respect to new therapies with different mechanisms of action, we discuss studies on Bis-choline tetrathiomolybdate (TTM) in patients, pre-clinical studies of a novel chelator methanobactin and other animal studies exploring cures for WD with gene therapy using adeno-associated vectors (AAVs) that introduce ATP7B into liver cells. There are also promising advances in the more accurate measurement of non-ceruloplasmin bound copper and exchangeable copper in the circulation which would potentially help with monitoring and individualization of treatment and possibly play a role in future disease diagnosis.

BACKGROUND: Gandou decoction (GDD) has been widely used in the treatment of Wilson disease (WD) for decades. It is optimized from the Dahuanghuanglianxiexin decoction, Yinchenhao decoction, and Huanglianjiedu decoction. It was first reported in the Treatise on Febrile and Miscellaneous Diseases and A Handbook of Prescriptions for Emergencies published in the Eastern Han Dynasty and the Eastern Jin Dynasty respectively. Hepatic injury is one of the most severe complications of WD. The current study aimed to explore the hepatic-protection effects of GDD and its exact therapeutic target, with a particular focus on the expression of oxidative stress and the Wnt/β-catenin pathway.
METHODS: Hepatic injury was induced in a copper-loaded rat model using the intragastric administration of copper(II) sulfate pentahydrate (CuSO4·5H2O). The water extract of GDD (0.4 g/kg/d) was administered twice a day for 4 weeks. Copper content and alanine aminotransferase (ALT) level, structural observation under the microscope, and immunohistochemical analysis of liver tissue were performed after the final administration. Moreover, the expression of β-catenin, GSK3β, Dishevelled-3, c-Myc, and p-GSK3β of liver tissue were detected to explore the relationship between the hepatic protection of GDD and the Wnt/ β-catenin signal pathway of GDD. We also stimulated the rat hepatic cell line BRL-3A with CuSO4·5H2O to establish a hepatic injury cytomodel. GDD serum at a concentration of 20% was administered into the model cell for 24 h. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and flow cytometry were performed to detect cell viability, mitochondrial membrane potential (MMP), and the expression of reactive oxygen species (ROS). Meanwhile, the expression of the Wnt/β-catenin signal pathway-related proteins was evaluated.
RESULTS: GDD reduced copper and ALT while inhibiting oxidative stress and the degeneration and necrosis of liver tissue and hepatocytes. Treatment with GDD improved cell viability and MMP while suppressing the ROS level. Furthermore, GDD rectified the expression of Wnt/β-catenin signal pathway-related proteins in both livers of the copper-loaded and copper-stimulated BRL-3A cell lines.
CONCLUSIONS: GDD had apparent therapeutic effects on the hepatic injury of copper-loaded rats and copper-stimulated BRL-3A cells. Its mechanism is related to its regulatory effect on the Wnt/β-catenin pathway rectification and oxidative stress antagonism.

Acute liver failure (ALF) is an infrequent, unpredictable, potentially fatal complication of acute liver injury (ALI) consequent to varied etiologies. Etiologies of ALF as reported in the literature have regional differences, which affects the clinical presentation and natural course. In this part of the consensus article designed to reflect the clinical practices in India, disease burden, epidemiology, clinical presentation, monitoring, and prognostication have been discussed. In India, viral hepatitis is the most frequent cause of ALF, with drug-induced hepatitis due to antituberculosis drugs being the second most frequent cause. The clinical presentation of ALF is characterized by jaundice, coagulopathy, and encephalopathy. It is important to differentiate ALF from other causes of liver failure, including acute on chronic liver failure, subacute liver failure, as well as certain tropical infections which can mimic this presentation. The disease often has a fulminant clinical course with high short-term mortality. Death is usually attributable to cerebral complications, infections, and resultant multiorgan failure. Timely liver transplantation (LT) can change the outcome, and hence, it is vital to provide intensive care to patients until LT can be arranged. It is equally important to assess prognosis to select patients who are suitable for LT. Several prognostic scores have been proposed, and their comparisons show that indigenously developed dynamic scores have an edge over scores described from the Western world. Management of ALF will be described in part 2 of this document.

Wilson disease (WD) may present symptomatically at any age. There is great variability in the neurological symptoms present, in the clinical state of WD patients, and in the response to decoppering therapy. Early diagnosis and compliance with anti-copper therapy are essential. Here we present five different WD cases to illustrate different problems encountered during diagnosis and treatment. The first case demonstrates that decoppering therapy may be very effective even with severe neurological symptoms. In addition, we see the importance of family screening, especially among the proband\'s siblings. Case 2 shows that we must be very careful during diagnosis. In the reported family, WD was diagnosed in the father of the proband although her brother had liver pathology but not caused by WD. Other cases teach us that decoppering therapy with d-penicillamine must be introduced slowly because of the high risk of neurological deterioration, especially in patients with typical WD brain changes even without neurological signs. We also have to consider concomitant therapies in WD patients. Neuroleptics may cause exacerbation and should be used at a low dose and for the shortest period possible. A full consideration for the issues surrounding the diagnosis and treatment of WD can lead to optimised care with reduced risk of progression and disability.

Wilson disease (WD) is a genetic disorder caused by pathological tissue copper accumulation with secondary damage of affected organs (mainly, but not limited to, the liver and brain). The main clinical symptoms of WD are, in concordance with the pathogenesis, hepatic and/or neuropsychiatric. Current treatment options for WD, based on drugs leading to negative copper body balance like chelators or zinc salts, were introduced more than 40 years ago and are generally effective in the majority of WD cases if used lifelong. However, especially in neurological patients, treatment may lead to neurological deterioration, which is often irreversible. Further, almost 50% of neurologically affected WD patients present with persistent neurological deficits despite the use of anti-copper treatment. In addition, up to 30% of patients treated with the widely used drug, d-penicillamine, present with adverse events related to treatment, which often leads to treatment discontinuation. Finally, almost 25% of WD patients do not adhere with anti-copper treatment, partially due to drug-related adverse events and complex treatment regimens (3 times daily, before meals, etc.). These limitations with current treatments have led to the search for other WD treatment possibilities. Currently, research is mainly focused on: (I) new agents with better safety profiles and less neurological deterioration properties compared with traditional chelators, e.g., tetrathiomolybdate salts or central nervous system-penetrable trientine, with the aim to provide more effective copper removal from brain tissue; (II) other non-chelating drugs that lead to removal of copper from cells [e.g., methanobactin (currently in preclinical studies)]; (III) cell and gene therapy. In this article, current research on future treatments for WD is reviewed.

The understanding and management of Wilson disease (WD) have dramatically improved since the first description of the disease by K. Wilson more than a century ago. However, the persistent long delay between the first symptoms and diagnosis emphasizes challenges in diagnosing earlier this copper overload disorder. As a treatable disease, WD should be detected early in the course of the disease by any health professionals at any care level, but the rare prevalence of the disease explains the lack of awareness of referring physicians. The most important challenge is to train physicians to recognize atypical or rare symptoms of WD that will lead to discuss the diagnosis more systematically. Atypia can come from the age of onset, the liver [non-alcoholic steatohepatitis (NASH) presentation], the central or peripheral nervous system (neuropathy, epilepsy, sleep disorders…) or may be due to lesions of other organs (renal manifestations, osteo-articular disorders or endocrine disturbances). Isolated biological anomalies, rare radiological findings or inadequate interpretation of copper test may also lead to misdiagnosis. The second challenge is to confirm the diagnosis faster and more effectively so as not to delay the initiation of treatment, and expand family screening as the genetic prevalence is higher than previously expected. Generalization of the exchangeable copper assay and the next generation sequencing (NGS) are two promising ways to overcome this ultimate challenge. By drawing attention to the earliest and rare symptoms and to new biomarkers and diagnostic tools, we hope that this article will increase diagnostic awareness and reduce delays so that patients can start their treatment earlier in the course of the illness and thus have a better disease prognosis.