Hepatic encephalopathy in Wilson's disease.
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ABSTRACT:
SUBMITTER: Pawaskar RS
PROVIDER: S-EPMC8257181 | biostudies-literature | 2020 Nov
REPOSITORIES: biostudies-literature
Publications
Hepatic encephalopathy in Wilson's disease.
Pawaskar Rachhanaa Satish RS Velhal Gajanan Dattatray GD
The Indian journal of medical research 20201101 Suppl 1
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Project description:Clinical presentation of Wilson disease (WD) includes hepatic and neurologic manifestations. This study compares subcortical brain regions by magnetic resonance imaging in patients with WD and without neurological symptoms. Distinct atrophy affecting the basal ganglia, accumbens, and hippocampus was present in neurological WD. Cerebellar atrophy was observed in hepatic WD without neurological symptoms.
| S-EPMC8453945 | biostudies-literature
Project description:Wilson disease is an autosomal recessive disorder affecting the ATP7B gene located on chromosome 13q. This leads to copper deposition in various organs, most importantly in the liver and brain. The genetic mutations are vast, well reported in the West but poorly documented in developing countries. Hence the diagnosis is made with a constellation of clinico-laboratory parameters which have significant overlap with other liver diseases and often pose a significant dilemma for clinicians. Diagnostic scoring systems are not fool-proof. The availability and affordability of chelators in developing countries impact the drug compliance of patients. While D-penicillamine is a potent drug, its side effects lead to drug discontinuation. Trientine is cost-prohibitive in developing countries. There is no single test to assess the adequacy of chelation. Exchangeable urinary copper is an essential upcoming diagnostic and prognostic tool. In the presence of cirrhosis, hypersplenism clouds the assessment of myelosuppression of drugs. Similarly, it may be difficult to distinguish disease tubulopathy from drug-induced glomerulonephritis. Neurological worsening due to chelators may appear similar to disease progression. Presentation as fulminant hepatic failure requires rapid workup. There is a limited window of opportunity to salvage these patients with the help of plasmapheresis and other liver-assisted devices. This review addresses the challenges and clinical dilemmas faced at beside in developing countries.
| S-EPMC10642431 | biostudies-literature
Project description:Wilson's disease (WD) is an autosomal recessive disorder that results in accumulation of copper in the liver as a consequence of mutations in the gene encoding the copper-transporting P-type ATPase (ATP7B). WD is a chronic liver disorder, and individuals with the disease present with a variety of complications, including steatosis, cholestasis, cirrhosis, and liver failure. Similar to patients with WD, Atp7b⁻/⁻ mice have markedly elevated levels of hepatic copper and liver pathology. Previous studies have demonstrated that replacement of zinc in the DNA-binding domain of the estrogen receptor (ER) with copper disrupts specific binding to DNA response elements. Here, we found decreased binding of the nuclear receptors FXR, RXR, HNF4α, and LRH-1 to promoter response elements and decreased mRNA expression of nuclear receptor target genes in Atp7b⁻/⁻ mice, as well as in adult and pediatric WD patients. Excessive hepatic copper has been described in progressive familial cholestasis (PFIC), and we found that similar to individuals with WD, patients with PFIC2 or PFIC3 who have clinically elevated hepatic copper levels exhibit impaired nuclear receptor activity. Together, these data demonstrate that copper-mediated nuclear receptor dysfunction disrupts liver function in WD and potentially in other disorders associated with increased hepatic copper levels.
| S-EPMC4588285 | biostudies-literature
Project description:HSD17B13 encodes hydroxysteroid 17-β dehydrogenase 13, a novel liver lipid-droplet associated protein that is involved in the regulation of lipid biosynthetic processes. A protein-truncating HSD17B13 variant (rs72613567) was shown to protect individuals from alcoholic and non-alcoholic liver disease. Since steatosis is a common feature in Wilson's disease (WD), we aimed to assess whether the HSD17B13 variant modulates the phenotypic presentation and progression of WD.MethodsThe HSD17B13:TA (rs72613567) variant was determined by allelic discrimination real-time PCR in 586 patients. The HSD17B13 genotype was correlated with the phenotypic presentation. The age of onset and the type of symptoms at presentation were used as markers of the WD phenotype.ResultsThe overall HSD17B13:TA allele frequency in patients with WD was 23.3% (273/1,172), not significantly different from the reported minor allele frequency. There was a significantly lower HSD17B13:TA allele frequency in patients with fulminant WD compared to all other phenotypic WD groups (11.0% vs. 24.0%, p < 0.01). Among the patients with fulminant WD there was a trend for a gender effect; none of the male patients carried the HSD17B13:TA allele. HSD17B13:TA allele frequency was more common in patients with minimal or no fibrosis (49 [31.1%] had simple steatosis and 20 minimal changes at biopsy) than in patients with cirrhosis or advanced fibrosis (22.3%, p = 0.025).ConclusionsThe HSD17B13:TA allele modulates the phenotype and outcome of WD. This allele likely ameliorates hepatic fibrosis and reduces the transition from copper induced hemolysis to fulminant disease in patients with WD.Lay summaryWilson's disease is a hereditary disease caused by accumulation of copper in the liver and other tissues. It presents with a variety of clinical symptoms. In this study we explored the role of a recently described gene mutation (HSD17B13:TA) which apparently protects the liver against toxins like alcohol. The results indicate that this mutation plays a role in the evolution of liver disease. Patients with Wilson's disease who carry this mutation are more likely to have mild disease, while the absence of the mutation is associated with the most severe form - fulminant Wilson's disease.
| S-EPMC7001574 | biostudies-literature
Project description:BackgroundWilson's disease (WD) is a genetic disorder that impairs the excretion of copper in hepatocytes and results in excessive copper deposition in multiple organs. The replacement of disordered hepatocytes with functional hepatocytes can serve as a lifelong therapeutic strategy for the treatment of WD. The aim of this study was to determine the hepatocyte repopulation effects of fibroblast-derived hepatic progenitor cells in the treatment of WD.MethodsInduced hepatic progenitor cells (iHPCs) were generated through direct reprogramming of adult mouse fibroblasts infected with lentivirus carrying both the Foxa3 and Hnf4α genes. These iHPCs were subsequently identified and transplanted into copper-overload WD mice with the Atp7b (H1071Q) mutation via caudal vein injection.ResultsAfter lentivirus infection, the fibroblasts transformed into Foxa3- and Hnf4α-overexpressing cobblestone-like cells with reduced expression of fibroblast markers and increased expression of epithelial cell and hepatic progenitor cell markers, i.e., iHPCs. Sixteen weeks after transplantation into WD mice, approximately 2% of hepatocytes were derived from iHPCs, and these iHPC-derived hepatocytes expressed a tight junction-associated protein of the bile canal, tight junction protein 1 (Zo1). There was a decrease in the serum copper concentration and relative activity of serum ceruloplasmin at weeks 4 and 8 after iHPCs transplantation compared with those of WD fed mice administered saline or fibroblasts. Furthermore, iHPC transplantation markedly reduced the proportion of CD8+ T lymphocytes and natural killer cells compared with those in fibroblast-transplanted WD mice and downregulated the transcription of the inflammatory cytokines, including tumor necrosis factor α (Tnfα), interleukin 1β (IL-1β), and IL-6, compared with those in WD mice and in fibroblast-transplanted WD mice.ConclusioniHPCs reprogrammed from adult fibroblasts can repopulate hepatocytes and exert therapeutic effects in WD mice, representing a potential replacement therapy for clinical application.
| S-EPMC11899129 | biostudies-literature
Project description:Copper is essential to mammalian physiology, and its homeostasis is tightly regulated. In humans, genetic defects in copper excretion result in copper overload and Wilson's disease (WD). Previous studies on the mouse model for WD (Atp7b(-)(/-)) revealed copper accumulation in hepatic nuclei and specific changes in mRNA profile prior to the onset of pathology. To find a molecular link between nuclear copper elevation and changes in hepatic transcriptome, we utilized quantitative ionomic and proteomic approaches. X-ray fluorescence and inductively coupled plasma mass spectrometry analysis indicate that copper in the Atp7b(-/-) nucleus, while highly elevated, does not markedly alter nuclear ion content. Widespread protein oxidation is also not observed, although the glutathione reductase SelH is upregulated, likely to maintain redox balance. We further demonstrate that accumulating copper affects the abundance and/or modification of a distinct subset of nuclear proteins. These proteins populate pathways that are most significantly associated with RNA processing. An alteration in splicing pattern was observed for hnRNP A2/B1, itself the RNA shuttling factor and spliceosome component. Analysis of hnRNP A2/B1 mRNA and protein revealed an increased retention of exon 2 and a selective 2-fold upregulation of a corresponding protein splice variant. Mass spectrometry measurements suggest that the nucleocytoplasmic distribution of RNA binding proteins, including hnRNP A2/B1, is altered in the Atp7b(-/-) liver. We conclude that remodeling of the RNA processing machinery is an important component of cell response to elevated copper that may guide pathology development in the early stages of WD.
| S-EPMC3033566 | biostudies-literature
Project description:BackgroundWilson's disease is a genetic disorder inherited in a recessive manner, caused by mutations in the copper-transporter ATP7B. Although it is a well-known disease, currently available treatments are far from satisfactory and their efficacy varies in individual patients. Due to the lack of information about drug-metabolizing enzymes and drug transporters profile in Wilson's disease livers, we aimed to evaluate the mRNA expression and protein abundance of selected enzymes and drug transporters in this liver disorder.MethodsWe analyzed gene expression (qPCR) and protein abundance (LC-MS/MS) of 14 drug-metabolizing enzymes and 16 drug transporters in hepatic tissue from Wilson's disease patients with liver failure (n = 7, Child-Pugh class B and C) and metastatic control livers (n = 20).ResultsIn presented work, we demonstrated a downregulation of majority of CYP450 and UGT enzymes. Gene expression of analyzed enzymes ranged between 18 and 65% compared to control group and significantly lower protein content of CYP1A1, CYP1A2, CYP2C8, CYP2C9, CYP3A4 and CYP3A5 enzymes was observed in Wilson's disease. Moreover, a general decrease in hepatocellular uptake carriers from SLC superfamily (significant at protein level for NTCP and OATP2B1) was observed. As for ABC transporters, the protein abundance of BSEP and MRP2 was significantly lower, while levels of P-gp and MRP4 transporters were significantly higher in Wilson's disease.ConclusionsAltered hepatic expression of drug-metabolizing enzymes and drug transporters in Wilson's disease patients with liver failure may result in changes of drug pharmacokinetics in that group of patients.
| S-EPMC8460590 | biostudies-literature
Project description:The combination of disease-specific human induced pluripotent stem cells (iPSC) and directed cell differentiation offers an ideal platform for modeling and studying many inherited human diseases. Wilson's disease (WD) is a monogenic disorder of toxic copper accumulation caused by pathologic mutations of the ATP7B gene. WD affects multiple organs with primary manifestations in the liver and central nervous system (CNS). In order to better investigate the cellular pathogenesis of WD and to develop novel therapies against various WD syndromes, we sought to establish a comprehensive platform to differentiate WD patient iPSC into both hepatic and neural lineages. Here we report the generation of patient iPSC bearing a Caucasian population hotspot mutation of ATP7B. Combining with directed cell differentiation strategies, we successfully differentiated WD iPSC into hepatocyte-like cells, neural stem cells and neurons. Gene expression analysis and cDNA sequencing confirmed the expression of the mutant ATP7B gene in all differentiated cells. Hence we established a platform for studying both hepatic and neural abnormalities of WD, which may provide a new tool for tissue-specific disease modeling and drug screening in the future.
| S-EPMC4875456 | biostudies-literature
Project description:Background & aimsHepatic encephalopathy (HE) is a frequent and severe complication in patients after transjugular intrahepatic portosystemic shunt (TIPS) insertion. However, risk factors for post-TIPS HE remain poorly defined. Minimal HE (mHE) is a well-known risk factor for overt HE in patients with cirrhosis without TIPS. We aimed to evaluate three tools frequently used for diagnosing mHE for their dynamic changes and their predictive value for overt HE after TIPS.MethodsWe prospectively recruited 84 consecutive patients before TIPS insertion and monitored them for 180 days for post-TIPS HE. Before TIPS insertion, the patients underwent the portosystemic encephalopathy (PSE) syndrome test, the animal naming test (ANT), and the critical flicker frequency (CFF). Patients were retested after TIPS insertion.ResultsThe majority of patients were male (67.9%), and the predominant indication for TIPS was refractory ascites (75%). Median age was 59 years, model for end-stage liver disease score was 12, and 66.3%, 64.6%, and 28.4% patients had evidence for mHE according to the PSE syndrome test, ANT, and CFF, respectively. Overall, 25 patients developed post-TIPS HE within 180 days after TIPS insertion. Post-TIPS incidence of overt HE was 22.2, 28.6, 45.5, and 55.6% in those with no, one, two, and three pathological tests at baseline, respectively. However, none of the three tests was significantly associated with post-TIPS HE. Of note, mean performance in all tests remained stable over time after TIPS insertion.ConclusionsPSE syndrome test, ANT and CFF, which are frequently used for diagnosing mHE have limited value for predicting HE after TIPS insertion. We could not find evidence that TIPS insertion leads to a psychometric decline in the long term.Impact and implicationsThis prospective observational study compared three diagnostic tests for mHE and showed the limited value of these tests for predicting overt HE in patients with cirrhosis undergoing TIPS insertion. In addition, the results suggest that cognitive performance generally remains stable after TIPS insertion. These results are important for physicians and researchers involved in the management of patients with cirrhosis undergoing TIPS procedures. The study's findings serve as a starting point for further investigations on the development of more effective strategies for predicting and managing post-TIPS HE.Clinical trial numberClinicalTrials.gov NCT04801290.
| S-EPMC10432804 | biostudies-literature
Project description: Not available
| S-EPMC6490514 | biostudies-literature