[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.

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; Epub ahead of print.

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.

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.

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.

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.

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.

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.

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.

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.

Magnetic resonance imaging pontine signal abnormality in neurological Wilson disease: A case report.

Key Clinical Message: WD is diagnosed with the help of a brain MRI, which frequently reveals hyperintensities in the lentiform nucleus. But occasionally, high signals can be seen in the pons, thalamus, and midbrain. Abstract: Wilson disease is a rare inherited disorder due to impaired copper excretion. The brain MRI mainly shows hyperintensities in the lentiform nucleus. We report the case of an 18 years old female diagnosed with neurological Wilson disease, presenting with uncommon brain MRI hyperintensities, predominantly in the pons, thalamus, and midbrain.

Identification of Lncrna-Mrna Networks in Hepg2 Cells upon ATP7B Knockout and Copper Accumulation.

Background: Hepatolenticular degeneration (HLD) is an inherited disorder caused by the mutation in the adenosine triphosphatase copper transporting ß gene (ATP7B). W aimed to explore the genetic changes in HLD using bioinformatics analysis. Methods: The study was conducted in Nepal, in 2019. The GSE107323 dataset was downloaded and the differentially expressed lncRNAs (DElncRNAs) as well as differentially expressed genes (DEGs) induced by ATP7B knockout (KO) and copper toxicity were clustered using Mfuzz clustering analysis. LncRNAs and genes with high coexpression (correlation coefficient > 0.9) and pathways involving the DEGs were used to construct the lncRNA-gene-pathway network. Results: ATP7B KO and ATP7B KO + copper induced 51 overlapping DEGs and 687 overlapping DElncRNAs, respectively. Mfuzz analysis identified four clusters, including two clusters of consistently upregulated and downregulated DEGs/DElncRNAs. The lncRNA-gene-pathway network consisted of 13 DElncRNAs, 10 DEGs, and two pathways, including "hsa04630: Jak-STAT signaling pathway" and "hsa04920: Adipocytokine signaling pathway". Eight downregulated genes, including erythropoietin (EPO), insulin receptor substrate 1 (IRS1), and PPARG coactivator 1 alpha (PPARGC1A), and two upregulated genes (cardiotrophin-like cytokine factor 1 and cyclin D3) were involved in the two pathways. These genes were targeted by multiple lncRNAs, including PCAT6 and MALAT1. Conclusion: Collectively, the differentially expressed lncRNA-mRNA axes play crucial roles in HLD pathogenesis through mediating cell proliferation and inflammation. Moreover, the EPO, IRS1, or PPARGC1A genes were potent therapeutic targets for HLD.

[Application of a low copper diet guidance based on food exchange portions in children with hepatolenticular degeneration]. / åŸºäºŽé£Ÿç‰©äº¤æ¢ä»½æ³•çš„ä½Žé“œé¥®é£ŸæŒ‡å¯¼åœ¨è‚è±†çŠ¶æ ¸å˜æ€§æ‚£å„¿ä¸­çš„åº”ç”¨æ•ˆæžœ.

OBJECTIVES: To study the efficacy of a low-copper diet guidance based on food exchange portions in children with hepatolenticular degeneration. METHODS: A self-controlled study was conducted from July 2021 to June 2022, including 30 children under the age of 18 who were diagnosed with hepatolenticular degeneration and poorly controlled with a low-copper diet. During the medical visit, personalized low-copper diet guidance was provided to the children and their parents using a copper-containing food exchange table and a copper food exchange chart. During home care, compliance with the low-copper diet of the children was improved by recording dietary diaries and conducting regular follow-ups. The changes in 24-hour urine copper level, liver function indicators, and the low-copper diet knowledge of the children's parents were observed before and after the intervention, with no change in the original drug treatment. RESULTS: After 8, 16, and 24 weeks of intervention, the 24-hour urine copper level decreased significantly compared to before intervention (P<0.05). When compared to 8-week intervention, the urine copper level decreased significantly after 16 and 24 weeks of intervention. The 24-hour urine copper level after 24 weeks of intervention decreased significantly compared to 16 weeks of intervention (P<0.05).After 24 weeks of intervention, the alanine aminotransferase and aspartate aminotransferase levels decreased significantly compared to before intervention (P<0.05). Additionally, in 16 of the cases (53%), alanine aminotransferase and aspartate aminotransferase returned to normal levels. Following 8 weeks of intervention, the low-copper diet knowledge of the children's parents increased significantly (P<0.05). CONCLUSIONS: A low-copper diet guidance based on food exchange portions can effectively decrease the urine copper level and improve liver function in children with hepatolenticular degeneration. Furthermore, it can increase the low-copper diet knowledge of the children's parents.

Changes in Hepatic Function After Splenectomy for Hepatolenticular Degeneration, Cirrhosis, and Hypersplenism.

BACKGROUND: Patients with hepatic reticulum degeneration (HLD) may eventually develop complications of cirrhosis with splenomegaly and hypersplenism, requiring splenectomy to alleviate hypersplenism and complete lifelong copper therapy. The purpose of this study is to investigate the effect of splenectomy on liver function in patients with hypersplenism. METHODS: A retrospective systematic analysis was conducted on the liver function indicators of 220 HLD patients who underwent splenectomy from January 2015 to January 2018 before surgery and on days 1, 3, 5, 7, and 14 after surgery. Among them, 30 patients were followed up for 6 months. RESULTS: The Child score increased on the 1st day after surgery and gradually decreased after the 1st day. The level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TB) increased 5 days after surgery (P < .01) and decreased on the 14th day after surgery (P < .01); the level of albumin (ALB) decreased on the 1st, 3rd, and 5th day after surgery (P < .01) and increased on the 14th day (P < .01). The follow-up results of the patient for 6 months showed that the levels of ALT and AST decreased, while the levels of ALB increased 6 months after surgery. CONCLUSION: Splenectomy is proved to be beneficial for the improvement of liver function in HLD patients combined with hypersplenism, which realize a lifelong anti-copper treatment.

Treatment of liver fibrosis in hepatolenticular degeneration with traditional Chinese medicine: systematic review of meta-analysis, network pharmacology and molecular dynamics simulation.

Background: Traditional Chinese medicine (TCM) is widely used in the clinical treatment of hepatolenticular degeneration (HLD) and liver fibrosis (LF). In the present study, the curative effect was assessed using meta-analysis. The possible mechanism of TCM against LF in HLD was investigated using network pharmacology and molecular dynamics simulation. Methods: For literature collection, we searched several databases, including PubMed, Embase, Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure (CNKI), VIP Database for Chinese Technical Periodicals (VIP) and Wan Fang database until February 2023, and the Review Manager 5.3 was used to analyze the data. Network pharmacology and molecular dynamics simulation were used to explore the mechanism of TCM in treating LF in HLD. Results: The results of the meta-analysis revealed that the addition of Chinese herbal medicine (CHM) in treating HLD resulted in a higher total clinical effective rate than western medicine alone [RR 1.25, 95% CI (1.09, 1.44), p = 0.002]. It not only has a better effect on liver protection [Alanine aminotransferase: SMD = -1.20, 95% CI (-1.70, -0.70), p < 0.00001; Aspartate aminotransferase: SMD = -1.41, 95% CI (-2.34, -0.49), p = 0.003; Total bilirubin: SMD = -1.70, 95% CI (-3.36, -0.03), p = 0.05] but also had an excellent therapeutic effect on LF through four indexes [Hyaluronic acid: SMD = -1.15, 95% CI (-1.76, -0.53), p = 0.0003; Procollagen peptide III: SMD = -0.72, 95% CI (-1.29, -0.15), p = 0.01; Collagen IV: SMD = -0.69, 95% CI (-1.21, -0.18), p = 0.008; Laminin: SMD = -0.47, 95% CI (-0.95, 0.01), p = 0.06]. Concurrently, the liver stiffness measurement decreased significantly [SMD = -1.06, 95% CI (-1.77, -0.36), p = 0.003]. The results of network pharmacological experiments and molecular dynamics simulation indicate that the three high-frequency TCMs (Rhei Radix Et Rhizoma-Coptidis Rhizoma-Curcumae Longae Rhizoma, DH-HL-JH) primarily act on the core targets (AKT1, SRC, and JUN) via the core components (rhein, quercetin, stigmasterol, and curcumin), regulate the signal pathway (PI3K-Akt, MAPK, EGFR, and VEGF signaling pathways), and play a role of anti-LF. Conclusion: Meta-analysis indicates that TCM is beneficial in treating HLD patients and improving LF. The present study successfully predicts the effective components and potential targets and pathways involved in treating LF for the three high-frequency CHMs of DH-HL-JH. The findings of the present study are hoped to provide some evidence support for clinical treatment. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO, identifier: CRD42022302374.

[Factors influencing the clinical phenotype of hepatolenticular degeneration].

Hepatolenticular degeneration is an autosomal recessive genetic disease caused by mutations in the ATP7B gene. More than 800 mutations have been identified in the ATP7B gene so far, with significant differences in clinical phenotypes among different mutation sites. Totally different clinical phenotypic mutations can even exist in the same gene. Although copper accumulation due to gene mutation is the basis of the pathogenesis of hepatolenticular degeneration, more and more evidence demonstrates that it is difficult to explain the diversity of clinical manifestations solely from the perspective of gene mutation. Therefore, this article reviews the research progress on the factors influencing genotype, modifier genes, epigenetics, age, gender, diet, and other factors on the phenotype of patients with hepatolenticular degeneration.