Multi-omics study unravels gut microbiota and metabolites alteration in patients with Wilson's disease.

Hepatolenticular degeneration (HLD), also known as Wilson's disease (WD), is a rare autosomal recessive disorder regarding copper metabolism. Whether gut microbiota imbalance is involved in developing HLD remains unknown. A comprehensive 16S rRNA amplicon sequencing, metagenomic sequencing, and metabonomic analysis were undertaken in patients with WD to analyze the composition and function profiles of gut microbiota in patients with WD. The data demonstrated differences in gut microbiota and metabolic pathways between WD patients and normal individuals, significantly decreasing bacterial richness and diversity. The levels of Selenomonaceae and Megamonas in WD patients are significantly higher than those in healthy individuals. The relative abundances of Roseburia inulinivorans in patients with WD are lower than in healthy individuals. Compared with healthy people, the level of metabolites in patients with WD is abnormal. Leucylproline, 5-Phenylvaleric Acid and N-Desmethylclobazam, which have nutritional and protective effects, are significantly reduced fecal metabolites in patients with WD. D-Gluconic acid, which can chelate metal ions, may be a potential treatment for WD. The positive correlation it demonstrates with Alistipes indistinctus and Prevotella stercora indicates potential bacteria able to treat WD. These metabolites are mainly related to the biosynthesis of antibiotics, alpha-linolenic acid metabolism, one carbon pool by folate, nicotinate and nicotinamide metabolism. In conclusion, the data from this study elucidate novel mechanisms describing how abnormal gut miccrobiota contribute to the pathogenesis of WD and outlines new molecules for the treatment of WD.

Clinical and laboratory profile and outcome in children with Wilson disease: an observational study in South India.

BACKGROUND: Wilson disease is an autosomal recessive disorder owing to defective copper metabolism which causes abnormal accumulation of copper and damage to the liver, brain, kidneys and other organs. AIM: To describe the clinical features, laboratory investigations and outcome of Wilson disease in children. METHODS: A retrospective observational study was conducted in the paediatric department of a tertiary- care hospital in South India by reviewing medical records between January 2018 and March 2023. The diagnosis of Wilson disease was confirmed by the presence of low serum ceruloplasmin and/or high urine copper excretion in combination with clinical and ophthalmological features. RESULTS: A total of 32 cases were analysed. The mean (SD) age at presentation was 110 (36) months with a M:F ratio of 1.6:1. Isolated hepatic involvement was seen in 19 (60%) patients while 13 (40%) patients had a neurological presentation, either as an isolated entity or in combination with hepatic manifestations. Low serum ceruloplasmin levels were detected in 31 (96%) patients. Urine copper levels were elevated in all patients. Twenty-one patients were commenced on D penicillamine while 11 patients were treated with a combination chelation therapy with zinc. Eighteen patients (56%) were on regular follow-up. CONCLUSION: The clinical presentation of Wilson disease in children is diverse, varying from the more common hepatic or neurological manifestations to the less common atypical forms of the disease. Diagnosis is based on clinical and ophthalmological features in combination with biochemical abnormalities in the form of low ceruloplasmin and high urinary copper. The majority of patients can be medically managed with chelation therapy.

Adverse pregnancy outcomes and effect of treatment in Wilson disease during pregnancy: Systematic review and meta-analysis.

BACKGROUND AND AIMS: Wilson disease (WD) is a rare disorder of copper metabolism, leading to liver and neurological disease. Existing literature on WD in pregnancy is scarce, limiting preconception and obstetrical counselling. In this systematic review with meta-analysis, we determine the prevalence of various adverse pregnancy and neonatal outcomes in WD, as well as evaluate the impact of WD treatment on these outcomes. METHODS: Scopus, MEDLINE and EMBASE were searched until 12 May 2023, for studies of pregnant individuals with WD and at least one pregnancy or neonatal outcome of interest. Meta-analysis of single proportions was conducted to pool prevalence data for each outcome. Outcome rates were compared between treated and untreated groups in a meta-analysis of dichotomous events. RESULTS: Sixteen studies, published from 1975 to 2022, were included in the systematic review. Thirty-seven percent of pregnancies reported at least one adverse pregnancy outcome. Spontaneous abortions (20%), liver diseases of pregnancy (4.5%) and preterm births (2%) were the most frequent adverse pregnancy outcomes in patients with WD. The prevalence of spontaneous abortions was significantly lower in pregnant individuals with WD who received treatment during pregnancy (OR: .47, 95% CI: 35%-63%). The prevalence of any adverse pregnancy outcome was also significantly lower with treatment (OR: .53, 95% CI: .37-.76), which appears to be mostly driven by the reduction of spontaneous abortions. CONCLUSIONS: There is low to moderate quality evidence to suggest that preconception and obstetrical counselling for patients with WD should include a discussion on the potentially high frequency of adverse pregnancy outcomes in this population, as well as the importance of continuing WD treatment during pregnancy to ensure satisfactory pregnancy course and potentially minimize the risk of spontaneous abortions.

[Analysis of clinical and genetic characteristics of the severe liver disease phenotype in patients with hepatolenticular degeneration].

Objective: To investigate the clinical and genetic characteristics and predictive role of the severe liver disease phenotype in patients with hepatolenticular degeneration (HLD). Methods: Inpatients with HLD confirmed at Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine from January 1989 to December 2022 were selected as the research subjects. Clinical classification was performed according to the affected organs. Patients with liver disease phenotypes were classified into the liver disease group and further divided into the severe liver disease group and the ordinary liver disease group. The clinical characteristics and genetic variations were compared in each group of patients. The predictive indicators of patients with severe liver disease were analyzed by multiple regression. Statistical analysis was performed using the t-test, Mann-Whitney U test, or χ(2) test according to different data. Results: Of the 159 HLD cases, 142 were in the liver disease group (34 in the severe liver disease group and 108 in the ordinary liver disease group), and 17 were in the encephalopathy group. The median age of onset was statistically significantly different between the liver disease group and the encephalopathy group [12.6 (7.0, 13.3) years versus 16.9 (11.0, 21.5) years, P<0.01]. 156 ATP7B gene mutation sites were found in 83 cases with genetic testing results, of which 54 cases carried the p.Arg778Leu gene mutation (allele frequency 46.2%). Compared with patients with other types of gene mutations (n=65), patients with homozygous p.Arg778Leu mutations (n=18) had lower blood ceruloplasmin and albumin levels, a higher prognostic index, Child-Pugh score, an international normalized ratio, and prothrombin time (P<0.05). Hemolytic anemia, corneal K-F ring, homozygous p.Arg778Leu mutation, and multiple laboratory indexes in the severe liver disease group were statistically significantly different from those in the ordinary liver disease group (P<0.05). Multivariate logistic regression analysis showed that the predictive factors for severe liver disease were homozygous p.Arg778Leu mutation, total bilirubin, and bile acids (ORs=16.512, 1.022, 1.021, 95% CI: 1.204-226.425, 1.005-1.039, and 1.006-1.037, respectively, P<0.05). The drawn ROC curve demonstrated a cutoff value of 0.215 3, an AUC of 0.953 2, and sensitivity and specificity of 90.91% and 92.42%, respectively. Conclusion: Liver disease phenotypes are common in HLD patients and have an early onset. Total bilirubin, bile acids, and the homozygous p.Arg778Leu mutation of ATP7B is related to the severity of liver disease in HLD patients, which aids in predicting the occurrence and risk of severe liver disease.

[Genotype-phenotype relationship and genetics study of 115 cases with Wilson's disease].

Objective: To explore the genotype-phenotype relationship of Wilson's disease (WD) and further study the mutation spectrum in the ATP7B gene. Methods: The clinical data and genetic test results of 115 cases with WD diagnosed in the First Affiliated Hospital of Zhengzhou University from 2015 to 2022 were retrospectively analyzed. The rank sum test was used for quantitative data comparison, and χ(2) test was used for count data comparison. Multivariate logistic regression was used to analyze the relationship between patients' genotype and phenotype. Results: The onset of liver manifestations (hepatic type) accounted for 60.9%, neurological symptoms (cerebral type) for 13.0%, and mixed hepato-cerebral symptoms for 26.1%. Presymptomatic individuals (hepatic types) accounted for 62.9%. Next-generation sequencing- diagnosed WD cases accounted for 87.8%. Combined multiplex ligation-dependent probe amplification assay-diagnosed WD cases accounted for 89.6%. A single case with a detected pathogenic locus accounted for 10.4%. The diagnostic rate of WD by genetic testing combined with clinical data was 100%. A total of 76 ATP7B mutations were detected, and the top three mutation frequencies were c.2333G>T (p.Arg778Leu) (30.7%), c.2975C>T (p.Pro992Leu) (7.3%), and c.2621C>T (p.Ala874Val) (6.4%). The mutations were mainly distributed in exons 8, 11-13, and 15-18, accounting for more than 90% of the total mutations. Eight new mutations were found, including c.3724G>A (p.Glu1242Lys), c.3703G>C (p.Gly1235Arg), c.3593T>C (p.Val1198Ala), c.2494A>C (p.Lys832Gln), c.1517T>A (p.Ile506Lys), c.484G>T (p.Glu162Ter), c.1870-49A>G, and the missing of exons 10-21. Liver histopathology showed cellular edema, degeneration, inflammation, and necrosis, as well as a 42.8% copper staining positive rate. Genotype-phenotype analysis showed that the p.Arg778Leu mutation had higher alanine aminotransferase (ALT) levels than those carrying other mutations (P=0.024), while the homozygous mutation of p.Arg778Leu was associated with cerebral-type patients (P=0.027). Conclusion: Genetic testing plays an important role in the diagnosis of WD. p.Arg778Leu is the first high-frequency mutation in the Chinese population, and patients carrying it have higher ALT levels. The p.Arg778Leu homozygous mutation is prone to causing cerebral-type WD. This study expands the ATP7B gene mutation spectrum.

Exploring the impact of gut microbiota on liver health in mice and patients with Wilson disease.

BACKGROUND AND AIMS: Distinctive gut microbial profiles have been observed between patients with Wilson disease (WD) and healthy individuals. Despite this, the exact relationship and influence of gut microbiota on the advancement of WD-related liver damage remain ambiguous. This research seeks to clarify the gut microbiota characteristics in both human patients and mouse models of WD, as well as their impact on liver injury. METHODS: Gut microbial features in healthy individuals, patients with WD, healthy mice and mice with early- and late-stage WD were analysed using 16S rRNA gene sequencing. Additionally, WD-afflicted mice underwent treatment with either an antibiotic cocktail (with normal saline as a control) or healthy microbiota (using disease microbiota as a control). The study assessed gut microbiota composition, hepatic transcriptome profiles, liver copper concentrations and hepatic pathological injuries. RESULTS: Patients with hepatic WD and mice with WD-related liver injury displayed altered gut microbiota composition, notably with a significant reduction in Lactobacillus abundance. Additionally, the abundances of several gut genera, including Lactobacillus, Veillonella and Eubacterium coprostanoligenes, showed significant correlations with the severity of liver injury in patients with WD. In WD mice, antibiotic treatment or transplantation of healthy microbiota altered the gut microbial structure, increased Lactobacillus abundance and modified the hepatic transcriptional profile. These interventions resulted in reduced hepatic copper concentration and alleviation of WD-related liver injury. CONCLUSIONS: Individuals and mice with pronounced WD-related liver injury exhibited shifts in gut microbial composition. Regulating gut microbiota through healthy microbiota transplantation emerges as a promising therapeutic approach for treating WD-related liver injury.

Berberine alleviates ovarian tissue damage in mice with hepatolenticular degeneration by suppressing ferroptosis and endoplasmic reticulum stress.

OBJECTIVE: Hepatolenticular degeneration (HLD) is an autosomal recessive disorder that manifests as multiorgan damage due to impaired copper (Cu) metabolism. Female patients with HLD often experience reproductive impairments. This study investigated the protective effect of berberine against ovarian damage in toxic-milk (TX) mice, a murine model for HLD. METHODS: Mice were categorized into control group, HLD TX group (HLD group), penicillamine (Cu chelator)-treated TX group and berberine-treated TX group. Body weight, ovary weight and the number of ovulated eggs were recorded. Follicular morphology and cellular ultrastructure were examined. Total iron, ferrous iron (Fe2+) and trivalent iron (Fe3+) levels, as well as malondialdehyde (MDA), glutathione (GSH) and oxidized glutathione (GSSG), were measured in the ovaries. Western blot analysis was used to analyze the expression of proteins related to ferroptosis and endoplasmic reticulum (ER) stress. RESULTS: Ovarian tissue damage was evident in the HLD group, with a significant increase in ferroptosis and ER stress compared to the control group. This damage was inhibited by treatment with penicillamine, a Cu chelator. Compared with the HLD group, berberine increased the number of ovulations, and improved ovarian morphology and ultrastructure. Further, we found that berberine reduced total iron, Fe2+, MDA and GSSG levels, elevated GSH levels, decreased the expression of the ferroptosis marker protein prostaglandin-endoperoxide synthase 2 (PTGS2), and increased glutathione peroxidase 4 (GPX4) expression. Furthermore, berberine inhibited the expression of ER stress-associated proteins mediated by the protein kinase RNA-like ER kinase (PERK) pathway. CONCLUSION: Ferroptosis and ER stress are involved in Cu-induced ovarian damage in TX mice. Berberine ameliorates ovarian damage in HLD TX mice by inhibiting ferroptosis and ER stress. Please cite this article as: Liu QZ, Han H, Fang XR, Wang LY, Zhao D, Yin MZ, Zhang N, Jiang PY, Ji ZH, Wu LM. Berberine alleviates ovarian tissue damage in mice with hepatolenticular degeneration by suppressing ferroptosis and endoplasmic reticulum stress. J Integr Med. 2024; 22(4): 494-503.

Wilson's Disease in an Early Adolescent: Classic Magnetic Resonance Imaging Findings.

Wilson's disease (WD), alternatively termed hepatolenticular degeneration, represents a rare autosomal recessive disorder typified by disrupted copper metabolism, culminating in copper accumulation across various organs. WD commonly manifests with early-onset liver cirrhosis, with notable involvement of the central nervous system, particularly impacting the midbrain and basal ganglia. This case report delineates the clinical presentation of an early adolescent female with WD, accentuating classical magnetic resonance imaging (MRI) findings. These MRI findings, which include the "face of a giant panda sign" and the "Face of a miniature panda sign," are pivotal for expeditious diagnosis. Recognition of these classical signs underscores the indispensable role of MRI in elucidating the neurological dimensions of WD.

Subnormal Serum Liver Enzyme Levels: A Review of Pathophysiology and Clinical Significance.

Subnormal levels of liver enzymes, below the lower limit of normal on local laboratory reports, can be useful diagnostically. For instance, subnormal levels of aminotransferases can be observed in vitamin B6 deficiency and chronic kidney disease. Subnormal alkaline phosphatase levels may indicate the presence of hypophosphatasia, Wilson's disease, deficiencies of divalent ions, or malnutrition. Subnormal levels of gamma glutamyl transferase may be seen in cases of acute intrahepatic cholestasis, the use of certain medications, and in bone disease. Finally, subnormal levels of 5'-nucleotidase have been reported in lead poisoning and nonspherocytic hemolytic anemia. The aim of this review is to bring attention to the fact that subnormal levels of these enzymes should not be ignored as they may indicate pathological conditions and provide a means of early diagnosis.

Kayser-Fleischer rings: The pathognomonic for Wilson's disease.

Wilson's disease is a genetic disorder of copper metabolism that primarily manifests with hepatic and neurological features. Kayser-Fleischer rings (KF rings) are pathognomonic of Wilson's disease and helps in establishing its diagnosis.

Atypical Presentation of Wilson Disease: Unravelling a Clinical and Radiological Complexity in a Rare Case.

Wilson disease (WD) is an autosomal recessive disorder marked by aberrations in copper metabolism, leading to its accumulation in vital organs such as the liver, brain, cornea, kidneys, and heart. While WD typically presents with hepatic symptoms in early childhood, neuropsychiatric manifestations are more prevalent during adolescence. This case report highlights an extraordinary instance of WD in an eight-year-old girl, characterized by intricate clinical and radiological features. The patient exhibited atypical symptoms, emphasizing the importance of recognizing diverse presentations of WD. Delayed diagnosis and treatment initiation can prove fatal in WD cases, underscoring the significance of awareness regarding these unusual clinical and radiological features to facilitate prompt intervention and prevent adverse outcomes.

Resolution of Wing-Beating Tremor and Magnetic Resonance Imaging Lesions in Wilson's Disease Following Penicillamine.

Background: The wing-beating tremor, characteristic of Wilson's disease (WD), is a disabling symptom that can be resistant to anti-copper and anti-tremor medications. Phenomenology Shown: This video illustrates severe bilateral wing-beating tremor, moderate head and lower limb tremors, mild cervical dystonia, and subtle cerebellar ataxia, with nearly resolution after penicillamine treatment. Educational Value: This case highlights a typical aspect of WD, emphasizing the importance of early detection and treatment, and its correlation with MRI findings. Highlights: This case highlights the typical wing-beating tremor in Wilson's disease and its correlation with the involvement of the dentato-rubro-thalamic pathway. The early diagnosis and initiation of treatment with penicillamine resulted in an excellent clinical and radiological response.

Treating the Neurologic Manifestations of Wilson's Disease With Liver Transplantation.

Wilson's Disease (WD) manifests with systemic and neuropsychiatric symptoms, caused by an ATP7B genetic mutation, leading to an accumulation of copper. Presentations are diverse and the diagnosis should be considered in anyone under 50 with a new onset movement disorder. Early recognition and treatment can limit morbidity. While liver transplantation (LT) is recommended in WD patients with hepatic failure, its use for pure neurologic indication remains controversial. We present a patient who failed medical management and underwent LT for pure neurologic indications. Subsequent neurologic symptom improvement supports the use of LT for patients with pure neurologic manifestations of WD.

Identification of lncRNA-miRNA-mRNA Networks in the Lenticular Nucleus Region of the Brain Contributes to Hepatolenticular Degeneration Pathogenesis and Therapy.

Long non-coding RNAs (lncRNAs) are a recently discovered group of non-coding RNAs that play a crucial role in the regulation of various human diseases, especially in the study of nervous system diseases which has garnered significant attention. However, there is limited knowledge on the identification and function of lncRNAs in hepatolenticular degeneration (HLD). The objective of this study was to identify novel lncRNAs and determine their involvement in the networks associated with HLD. We conducted a comprehensive analysis of RNA sequencing (RNA-seq) data, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and computational biology to identify novel lncRNAs and explore their potential mechanisms in HLD. We identified 212 differently expressed lncRNAs, with 98 upregulated and 114 downregulated. Additionally, 32 differently expressed mRNAs were found, with 15 upregulated and 17 downregulated. We obtained a total of 1131 pairs of co-expressed lncRNAs and mRNAs by Pearson correlation test and prediction and annotation of the lncRNA-targeted miRNA-mRNA network. The differential lncRNAs identified in this study were found to be involved in various biological functions and signaling pathways. These include translational initiation, motor learning, locomotors behavior, dioxygenase activity, integral component of postsynaptic membrane, neuroactive ligand-receptor interaction, nuclear factor-kappa B (NF-κB) signaling pathway, cholinergic synapse, sphingolipid signaling pathway, and Parkinson's disease signaling pathway, as revealed by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Six lncRNAs, including XR_001782921.1 (P < 0.01), XR_ 001780581.1 (P < 0.01), ENSMUST_00000207119 (P < 0.01), XR_865512.2 (P < 0.01), TCONS_00005916 (P < 0.01), and TCONS_00020683 (P < 0.01), showed significant differences in expression levels between the model group and normal group by RT-qPCR. Among these, four lncRNAs (TCONS_00020683, XR_865512.2, XR_001780581.1, and ENSMUST00000207119) displayed a high degree of conservation. This study provides a unique perspective for the pathogenesis and therapy of HLD by constructing the lncRNA-miRNA-mRNA network. This insight provides a foundation for future exploration in this field.

Clinical features of patients with hepatolenticular degeneration aged above 35 years / 临床肝胆病杂志

ObjectiveTo investigate the clinical features of patients with hepatolenticular degeneration （HLD） aged above 35 years. MethodsA retrospective analysis was performed for the clinical data of the patients with HLD， aged above 35 years， who attended West China School of Public Health， Sichuan University， from April 2018 to April 2023， and according to their clinical symptoms， they were divided into mixed type group with 13 patients， liver type group with 12 patients， and brain type group with 5 patients. Related data were collected， including general information （sex， clinical manifestation， age at confirmed diagnosis， time from initial symptoms to confirmed diagnosis， and family history）， laboratory examination （routine blood test， liver and renal function， serum copper， serum ceruloplasmin， urinary copper， and coagulation function）， and radiological examination. A one-way analysis of variance was used for comparison of normally distributed continuous data between multiple groups， and the Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between multiple groups； the Fisher’s exact test was used for comparison of categorical data between groups. ResultsFor the 30 patients with HLD， the male/female ratio was 3∶1， and the mean age was 46.13±5.88 years； the patients with positive Kayser-Fleischer ring of the cornea accounted for 43.33%， and the patients with liver cirrhosis accounted for 66.67%. There were significant differences between the three groups in globulin， albumin/globulin ratio， alanine aminotransferase， prothrombin time， international normalized ratio， and activated partial thromboplastin time （F=5.893， 4.513， 4.424， 5.029， 5.248， and 4.942， all P<0.05）. ConclusionMost patients are male among the patients diagnosed with HLD after 35 years of age， with the main clinical types of mixed type and liver type， and such patients tend to have poor liver and coagulation functions. For unexplained liver function abnormalities and liver cirrhosis in this age group， the indicators such as serum ceruloplasmin and urinary copper should be screened as early as possible， and liver and kidney function and coagulation function should be monitored.

Observation on the Therapeutic Effect of Yiqi Huoxue Huazhuo Therapy on Hepatic Fibrosis in Wilson's Disease / 广州中医药大学学报

Objective To assess the clinical effect of the Yiqi Huoxue Huazhuo therapy(the therapy for replenishing qi,activating blood and resolving turbidity)for the treatment of hepatic fibrosis in Wilson's disease(WD,also known as hepatolenticular degeneration).Methods Using retrospective research method,52 patients with liver fibrosis in WD of qi deficiency and blood stasis type were divided into 24 cases in the control group and 28 cases in the treatment group according to the treatment method.The control group was treated with conventional decopper therapy with western medicines,and the treatment group was treated with Chinese herbal decoction based on Yiqi Huoxue Huazhuo therapy together with conventional decopper therapy.Both groups were treated for a total of 4 weeks.Before and after the treatment,the two groups were observed in the changes of traditional Chinese medicine(TCM)syndrome scores,Unified Wilson's Disease Rating Scale(UWDRS)hepatic symptom scores,serum levels of liver fibrosis indicators of pre-collagen typeⅢ(PCⅢ),hyaluronic acid(HA),collagenⅣ(CⅣ),and laminin(LN),C-X-C motif chemokine ligand 10(CXCL10)level,and the point shear-wave elastography(pSWE)values of hepatic ultrasound based on acoustic radiation force impulse imaging(ARFI).After treatment,the clinical efficacy of the two groups was evaluated.Results(1)After 4 weeks of treatment,the total effective rate of the treatment group was 85.71%(24/28),while that of the control group was 54.17%(13/24),and the intergroup comparison(tested by chi-square test)showed that the therapeutic efficacy of the treatment group was significantly superior to that of the control group(P＜0.05).(2)After treatment,the TCM syndrome scores in both groups were decreased compared with those before treatment(P＜0.01),and the decrease of TCM syndrome scores in the treatment group was significantly superior to that in the control group(P＜0.05).(3)After treatment,the UWDRS liver symptom scores in the two groups were decreased compared with those before treatment(P＜0.01),but the difference was not statistically significant when comparing between the two groups after treatment(P＞0.05).(4)After treatment,serum levels of liver fibrosis indicators of HA,LN,CⅣ and PCⅢ in the treatment group were all decreased compared with those before treatment(P＜0.01),while in the control group only serum LN and PCⅢlevels were decreased(P＜0.05).The intergroup comparison showed that the decrease of serum HA,LN,and PCⅢlevels in the treatment group was superior to that in the control group(P＜0.05 or P＜0.01),while the decrease of serum CⅣlevel tended to be superior to that in the control group,but the difference was not statistically significant(P＞0.05).(5)After treatment,the serum chemokine CXCL10 level in the treatment group was significantly decreased compared with that before treatment(P＜0.01),while the level tended to decrease in the control group,but the difference was not statistically significant(P＞0.05).The intergroup comparison showed that the reduction of serum CXCL10 level in the treatment group was significantly superior to that in the control group(P＜0.05).(6)After treatment,the pSWE values of hepatic ultrasound in the two groups were lower than those before treatment(P＜0.01),and the reduction of pSWE values in treatment group was significantly superior to that of the control group(P＜0.01).Conclusion Yiqi Huoxue Huazhuo therapy can effectively reduce the TCM syndrome scores of WD patients,improve the UWDRS hepatic symptom scores,down-regulate the liver fibrosis indicator level and serum CXCL10 expression level,reduce the pSWE values of hepatic ultrasound,and enhance the clinical efficacy.

Liver transplantation for inherited metabolic liver diseases / 器官移植

Inherited metabolic liver disease (IMLD) is a category of liver metabolic diseases caused by genetic disorders. The pathogenesis of IMLD is complex, which primarily comprises the accumulation of harmful metabolic substrates or products caused by specific enzyme defects and energy defects or abnormal deposition caused by abnormal metabolism of glucose, fat and other substances. In recent years, liver transplantation has played an increasingly critical role in the treatment of IMLD with the development of liver transplantation. At present, IMLD has become the second most important indication after biliary atresia in pediatric liver transplantation. Currently, IMLD patients receiving liver transplantation can be divided into two categories: the first category is IMLD complicated with liver disease; Category 2 patients have a normal liver structure but are deficient in related metabolic enzymes. It can not only replace the liver with abnormal structure and function, but also provide normal enzymes required for patients' metabolism, which may improve their quality of life and even save their lives. In this article, common feasible liver transplantation for IMLD, clinical prognosis and surgical procedures of liver transplantation for IMLD were reviewed, aiming to provide reference for liver transplantation for IMLD.

Hepatolenticular degeneration with depressive episodes of bipolar disorder： a case report / 四川精神卫生

This case reported a 17-year-old female patient who presented to the hospital with "poor mood and irritability for more than 5 months". The patient was diagnosed with hepatolenticular degeneration at the age of five. According to the International Classification of Diseases， tenth edition （ICD-10）， she was diagnosed with hepatolenticular and depressive episodes of bipolar disorder. The condition improved after administration of a combination of a mood stabilizer and an antidepressant. There are few reports of hepatolenticular degeneration combined with depressive episodes of bipolar disorder， and it is controversial whether the diagnosis should be considered a psychiatric disorder due to a physical illness or a co-morbidity. In addition， somatic conditions are often overlooked in the treatment of patients with psychiatric disorders. This case analyzed the diagnosis and medication by integrating the patient's psychiatric symptoms and somatic conditions， suggesting that psychiatrists should pay attention to both psychiatric symptoms and the patient's previous history of somatic diseases in their clinical work for rational diagnosis and treatment.

Wilson disease: the diagnostic challenge and treatment outcomes in a series of 262 cases / Doença de Wilson: o desafio diagnóstico e resultados do tratamento em uma série de 262 casos

Abstract Background Wilson disease (WD) is an autosomal recessive disorder that leads to organ toxicity due to copper overload. Early diagnosis is complicated by the rarity and diversity of manifestations. Objective To describe the diagnostic features and response to treatment in our cohort of WD patients. Methods This was a retrospective analysis of 262 WD patients stratified by clinical presentation, complementary exams, ATP7B genotyping, and response to treatment. Results Symptoms occurred at an average age of 17.4 (7-49) years, and patients were followed up for an average of 9.6 (0-45) years. Patients presented mainly with hepatic (36.3%), neurologic (34.7%), and neuropsychiatric (8.3%) forms. Other presentations were hematologic, renal, or musculoskeletal, and 16.8% of the patients were asymptomatic. Kayser-Fleischer rings occurred in 78.3% of the patients, hypoceruloplasminemia in 98.3%, and elevated cupruria/24h in 73.0%, with an increase after D-penicillamine in 54.0%. Mutations of the ATP7B gene were detected in 84.4% of alleles. Brain magnetic resonance imaging showed abnormalities in the basal ganglia in 77.7% of patients. D-penicillamine was the first choice in 93.6% of the 245 patients, and 21.1% of these patients were switched due to adverse effects. The second-line therapies were zinc and trientine. The therapeutic response did not differ significantly between the drugs (p= 0.2). Nine patients underwent liver transplantation and 82 died. Conclusion Wilson disease is diagnosed at a late stage, and therapeutic options are limited. In people under 40 years of age with compatible manifestations, WD could be considered earlier in the differential diagnosis. There is a need to include ATP7B genotyping and therapeutic alternatives in clinical practice.

Resumo Antecedentes A doença de Wilson (DW) é um distúrbio autossômico recessivo caracterizado por acúmulo de cobre lesivo aos órgãos. O diagnóstico precoce é dificultado pela raridade e diversidade de apresentações. Objetivo Descrever características ao diagnóstico e resposta ao tratamento em uma coorte de DW. Métodos Análise retrospectiva de 262 casos de DW quanto à apresentação clínica, exames complementares, genotipagem e resposta ao tratamento. Resultados Os sintomas surgiram em uma média aos 17,4 (7-49) anos, e os pacientes foram acompanhados por uma média de 9,6 (0-45) anos. Os pacientes apresentaram principalmente formas hepáticas (36,3%), neurológicas (34,7%) e neuropsiquiátricas (8,3%). Outras apresentações foram hematológicas, renais e musculoesqueléticas. Apenas 16,8% eram assintomáticos. Anéis de Kayser-Fleischer ocorreram em 78,3% dos pacientes, hipoceruloplasminemia em 98,3%, e cuprúria elevada/24h em 73,0%, com aumento após D-penicilamina em 54,0%. Mutações do gene ATP7B foram detectadas em 84,4% dos alelos pesquisados. A ressonância magnética cerebral mostrou alterações em gânglios da base em 77,7% dos pacientes. O tratamento com D-penicilamina foi a escolha inicial em 93,6% dos 245 casos e foi trocado em 21,1% devido a efeitos adversos. Terapias de segunda linha foram zinco e trientina. A resposta terapêutica não diferiu significativamente entre os medicamentos (p= 0,2). Nove pacientes receberam transplante hepático e 82 faleceram. Conclusão O diagnóstico da DW ainda ocorre em estágios tardios, e as opções terapêuticas são limitadas. A DW deve ser considerada precocemente no diagnóstico diferencial de pessoas com menos de 40 anos com manifestações compatíveis. É necessário incorporar na prática clínica a genotipagem do ATP7B e alternativas terapêuticas à penicilamina.

Manganese Associated with Non-Wilsonian Hepatolenticular Degeneration as a Rare Cause of Encephalopathy: Case Report

Aim: To describe the clinical picture, diagnosis, and treatment of a patient with encephalopathy as a manifestation of manganese-induced non-Wilsonian hepatolenticular degeneration (NWHD) in a high-complexity care center in a Latin American country. Case description: A 55-year-old male patient from the United States with a history of liver disease associated with alcohol consumption was admitted to the emergency department due to diarrhea, hematemesis, and psychomotor agitation. During his stay, his state of consciousness deteriorated, requiring orotracheal intubation. In his diagnostic study, cerebrospinal fluid tests were negative for infectious etiologies; the endoscopic examinations showed no marks of portal hypertension bleeding, while ammonium and tests for metabolic causes were normal. However, areas of hyperintensity in the basal ganglia were documented on brain MRI, with normal ceruloplasmin serum and urine copper levels, which ruled out Wilson's disease and determined the diagnosis of manganese-induced NWHD. Conclusion: NWHD is a rare cause of chronic encephalopathy with clinical manifestations of extrapyramidal symptoms secondary to basal ganglia dysfunction due to severe liver disease. Its diagnosis becomes a challenge, given that manganese deposits produce it, and no biomarkers can establish the level of exposure to this metal. Brain MRI is indispensable in reflecting these deposits in the basal ganglia.

Objetivo: Describir la presentación clínica, el diagnóstico y el tratamiento de un paciente con encefalopatía como manifestación de degeneración hepatolenticular no wilsoniana producida por manganeso, en un centro de alta complejidad de un país latinoamericano. Descripción del caso: Paciente masculino de 55 años, procedente de Estados Unidos, con antecedente de enfermedad hepática asociada con consumo de alcohol, quien ingresó al servicio de urgencias por un cuadro de diarrea, hematemesis y agitación psicomotora. Durante la estancia presentó deterioro en el estado de consciencia, por lo que requirió intubación orotraqueal. En su estudio diagnóstico, las pruebas de líquido cefalorraquídeo fueron negativas para etiologías infecciosas, en los estudios endoscópicos no tenía estigmas de sangrado portal hipertensivo y el amonio y los estudios para causas metabólicas fueron normales. Sin embargo, se documentaron áreas de hiperintensidad en los ganglios de la base en la resonancia magnética cerebral, con niveles de ceruloplasmina sérica y cobre urinario normales, lo que descartó enfermedad de Wilson y definió el diagnóstico de degeneración hepatolenticular no wilsoniana por depósitos de manganeso. Conclusión: La degeneración hepatolenticular no wilsoniana es una causa infrecuente de encefalopatía crónica con manifestaciones clínicas de extrapiramidalismo, secundaria a disfunción de los ganglios de la base por enfermedad hepática grave. Su diagnóstico se convierte en un reto, dado que se produce por depósitos de manganeso y no existen biomarcadores que puedan establecer el nivel de exposición a este metal. La resonancia magnética cerebral juega, por tanto, un papel indispensable al reflejar esos depósitos en los ganglios de la base.