INTRODUCTION: The diagnosis of Wilson disease (WD) is plagued by biochemical and clinical uncertainties. Thus, calculated parameters have been proposed. This study aimed to: (a) compare the diagnostic values of non-caeruloplasmin copper (NCC), NCC percentage (NCC%), copper-caeruloplasmin ratio (CCR) and adjusted copper in WD; and (b) derive and evaluate a discriminant function in diagnosing WD. METHODS: A total of 213 subjects across all ages who were investigated for WD were recruited. WD was confirmed in 55 patients, and the rest were WD free. Based on serum copper and caeruloplasmin values, NCC, NCC%, CCR and adjusted copper were calculated for each subject. A function was derived using discriminant analysis, and the cut-off value was determined through receiver operating characteristic analysis. Classification accuracy was found by cross-tabulation. RESULTS: Caeruloplasmin, total copper, NCC, NCC%, CCR, adjusted copper and discriminant function were significantly lower in WD compared to non-WD. Discriminant function showed the best diagnostic specificity (99.4%), sensitivity (98.2%) and classification accuracy (99.1%). Caeruloplasmin levels <0.14 g/L showed higher accuracy than the recommended 0.20 g/L cut-off value (97.7% vs. 87.8%). Similarly, molar NCC below the European cut-off of 1.6 umol/L showed higher accuracy than the American cut-off of 3.9 umol/L (80.3% vs. 59.6%) (P < 0.001). NCC%, mass NCC, CCR and adjusted copper showed poorer performances. CONCLUSION Discriminant function differentiates WD from non-WD with excellent specificity, sensitivity and accuracy. Performance of serum caeruloplasmin <0.14 g/L was better than that of <0.20 g/L. NCC, NCC%, CCR and adjusted copper are not helpful in diagnosing WD.
Humans ; Hepatolenticular Degeneration/diagnosis* ; Copper/analysis* ; Ceruloplasmin/metabolism* ; Repressor Proteins

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.
Humans ; Child ; Hepatolenticular Degeneration/therapy* ; Alanine Transaminase ; Copper ; Food ; Aspartate Aminotransferases

OBJECTIVE: To analyze the clinical phenotypes and ATP7B gene variants among children patients with Wilson' s disease from Northwestern China. METHODS: The clinical features and variants of the ATP7B gene among 75 children with hepatic Wilson' s disease were retrospectively analyzed. RESULTS: Among the 75 cases, 4 were presymptomatic, 59 had isolated transaminase elevation, 12 had acute and/or chronic liver diseases. Nine children were found to harbor homozygous variants, 64 harbored compound heterozygous variants, and two only had heterozygous variants of the ATP7B gene. In total 49 variants were detected, with common variants including c.2333G>T (p.Arg778Leu), c.2621C>T (p.Ala874Val) and c.2975C>T (Pro992Leu), which yielded allelic frequencies of 28.7%, 12.7% and 9.3%, respectively. Six novel variants were detected, which included c.1908dupC (p.Asn637Glnfs*118), c.4179_4180insC (p.Pro1394Profs*15), c.1604A>G (p.Glu535Gly), c.2278C>T (p.Pro760Ser), c.3008C>A (p.Ala1003Glu) and c.3532A>C (p.Thr1178Pro). Except for c.1604A>G (p.Glu535Gly), the remainder five were all predicted to be likely pathogenic. No significant correlation was found between genotype and phenotype among the patients. CONCLUSION The common mutation types of the ATP7B gene among patients with hepatic Wilson disease in Northwestern China are c.2333G>T (p.Arg778Leu), c.2621C>T (p.Ala874Val) and c.2975C>T (p.Pro992Leu), there is no significant correlation between their genotypes and phenotypes.
Copper-Transporting ATPases/genetics* ; Genotype ; Hepatolenticular Degeneration/genetics* ; Humans ; Mutation ; Phenotype ; Retrospective Studies

In order to help liver disease-related clinicians make reasonable decisions for the diagnosis and treatment of hepatolenticular degeneration, the Inherited and Metabolic Liver Disease Cooperative Group of Hepatology Branch of Chinese Medical Association organized relevant field domestic experts in 2021 to jointly compile this guideline based on the clinical and basic research progress.
Gastroenterology ; Hepatolenticular Degeneration/therapy* ; Humans

Objectives: To summarize the clinical phenotypes and the variation spectrum of ATP7B gene in Chinese children with Wilson's disease (WD) and to investigate their significance for early diagnosis. Methods: Retrospective analysis was performed on the clinical data of 316 children diagnosed as WD in Guangzhou Women and Children's Medical Center during the period from January 2010 to June 2021. The general situations, clinical manifestations, lab test results, imaging examinations, and ATP7B gene variant characteristics were collected. The patients were divided into asymptomatic WD group and symptomatic WD group based on the presence or absence of clinical symptoms at the time that WD diagnosis was made. The χ² test, t test or Mann-Whitney U test were used to compare the differences between groups. Results: Among the 316 children with WD, 199 were males and 117 were females, with the age of 5.4 (4.0, 7.6) years at diagnosis; 261 cases (82.6%) were asymptomatic with the age of 4.9 (3.9, 6.4) years; whereas 55 cases (17.4%) were symptomatic with the age of 9.6 (7.3, 12.0) years. The main symptoms invloved liver, kidney, nervous system, or skin damage. Of all the patients, 95.9% (303/316) had abnormal liver function at diagnosis; 98.1% (310/316) had the serum ceruloplasmin lever lower than 200 mg/L; 97.7% (302/309) had 24-hour urine copper content exceeding 40 μg; only 7.4% (23/310) had positive corneal K-F rings, 8.2% (23/281) had abnormal MRI signals in the lenticular nucleus, and all of them had symptoms of damage in liver, kidney or nervous system. Compared with the group of symptomatic WD, asymptomatic group had higher levels of serum alanine aminotransferase and lower levels ceruloplasmin and 24-hour urine copper [(208±137) vs. (72±78) U/L, (55±47) vs. (69±48) mg/L, 103 (72, 153) vs. 492 (230, 1 432) μg; t=9.98, -1.98, Z=-4.89, all P<0.001]. Among the 314 patients completing genetic sequencing, a total of 107 mutations in ATP7B gene were detected, of which 10 are novel variants, and 3 cases (1.0%) had large heterozygous deletion (exons 10 to exon 11) in ATP7B gene. The percentage of missense mutation in asymptomatic WD children was significantly higher than that in symptomatic WD (81.5% (422/518) vs. 69.1% (76/110), χ²=8.47, P<0.05). WD patients carrying homozygous variant of c.2 333G>T had significantly low levels of ceruloplasmin than those not carrying this variant ((23±5) vs. (61±48) mg/L, t=-2.34, P<0.001). Conclusions: The elevation of serum ALT is an important clue for early diagnosis of WD in children, while serum ceruloplasmin and 24-hour urine copper content are specific markers for early diagnosis of WD. In order to confirm the diagnosis of WD, it is necessary to combine the Sanger sequencing with multiplex ligation-dependent probe amplification or other testing technologies.
Ceruloplasmin/metabolism* ; Child ; Child, Preschool ; Copper/metabolism* ; Copper-Transporting ATPases/genetics* ; Female ; Hepatolenticular Degeneration/genetics* ; Humans ; Male ; Mutation ; Phenotype ; Retrospective Studies

OBJECTIVE: To establish and validate predictive nomogram for liver fibrosis in patients with Wilson disease (WD) showing abnormal lipid metabolism. METHODS: We retrospectively collected the clinical data of 500 patients with WD showing abnormalities in lipid metabolism, who were treated in the Department of Encephalopathy of the First Affiliated Hospital of Anhui University of Chinese Medicine from December, 2018 to December, 2021 and divided into modeling group and validation group. The independent risk factors of liver fibrosis in these patients were screened using LASSO regression and multivariate logistic regression analysis for establishment of the predictive nomogram. The area under the curve (AUC), calibration curve and decision curve of the receiver-operating characteristic curve (ROC) were used for internal and external verification of the nomogram in the modeling and validation group and evaluating the differentiation, calibration and clinical practicability of the model. RESULTS: Triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (Apo-B) were independent risk factors for the development of liver fibrosis in patients with WD and abnormal lipid metabolism (P < 0.05). The predictive nomogram showed good discrimination, calibration and clinical utility in both the modeling and validation groups. CONCLUSION The established predictive nomogram in this study has a high accuracy for early identification and risk prediction of liver fibrosis in patients with WD having abnormal lipid metabolism.
Humans ; Hepatolenticular Degeneration ; Lipid Metabolism ; Retrospective Studies ; Liver Cirrhosis ; Cholesterol, LDL

A transcriptional regulatory network for wild-type and ATP7B-knockout HepG2 cells exposed to copper was constructed by bioinformatics methods to explore the potential mechanism of key transcription factors in the pathogenesis of hepatolenticular degeneration. The differentially expressed genes (DEGs) for wild-type and ATP7B-knockout HepG2 cell lines without copper and exposed to copper were collected from the gene expression omnibus (GEO) database. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis were performed for DEGs induced by copper. The key functional modules and genes were identified based on the protein-protein interaction (PPI) network. Moreover, the enrichment analysis of genes in functional modules was performed. Finally, a transcriptional regulatory network was constructed to screen the core transcription factors. A total of 1 034 genes, including 509 down-regulated genes and 525 up-regulated genes, were selected as DEGs. The up-regulated and down-regulated functional modules based on PPI network included 3 785 and 3 931 genes, respectively. Genes in key functional modules were enriched in cell-substrate junction, chromosomal region, spliceosomal complex and ribosome. They were involved in mRNA processing, histone modification, RNA splicing, regulation of DNA metabolic process, protein phosphorylation and other biological processes. Moreover, they were correlated to transcriptional coregulator activity, DNA-binding transcription factor binding, ubiquitin-like protein ligase binding and other molecular functions. KEGG analysis showed that genes in key functional modules were significantly enriched in hepatitis B, MAPK signaling pathway, cellular senescence and apoptosis, neurotrophin signaling pathway and pathways of neurodegeneration-multiple diseases. The transcriptional regulatory network contained 11 differentially expressed transcription factors and 96 DEGs. Among them, U2AF1, NFRKB, FUS, MAX, SRSF1, CEBPA and RXRA were the core transcription factors, which may facilitate the study of the biological function of relevant molecules in transcriptional regulation of hepatolenticular degeneration.
Humans ; Transcriptome ; Gene Expression Profiling/methods* ; Hepatolenticular Degeneration/genetics* ; Copper ; Gene Regulatory Networks ; Computational Biology/methods* ; Transcription Factors/genetics* ; DNA ; DNA-Binding Proteins/genetics* ; Serine-Arginine Splicing Factors/genetics*

Objective: To analyze the clinical characteristics of Wilson's disease (WD) with onset of acute liver failure (ALF) in children. Methods: Clinical data of 19 children diagnosed with WD presented with ALF in Xi'an Children's Hospital from January 2016 to April 2021 were retrospectively analyzed, including general condition, clinical manifestation, laboratory examination, and gene detection. The children were divided into the death group and survival group according to the clinical outcome. The children who had hepatic WD with non-ALF onset during the same period were selected as the control. The general conditions and laboratory indexes were compared between death group and survival group, ALF group and non-ALF group. T-test, Mann Whitney U test or χ² test were used to compare the differences between the two groups. Results: Of the 19 WD children with ALF onset, 10 were females and 9 were males. The age of admission was (10.1±2.6) years and time to onset of first visit was 9 (4, 15) days. Among the WD children with ALF onset, 4 children were lost to follow-up, 5 cases death (death group) and 10 cases survived (survival group). The ceruloplasmin in the death group was higher than that in the survival group (0.078 (0.055, 0.105) vs. 0.033 (0.027, 0.058) g/L, Z=-2.33, P=0.020). There were 95 children who had hepatic WD with non-ALF onset. The WD patients with ALF onset were older at admission (9.9 (8.0, 11.1) vs. 5.4 (3.7, 6.9) years, Z=-5.25, P<0.001), had higher ceruloplasmin (0.060 (0.030, 0.078) vs. 0.024 (0.006, 0.060) g/L, Z=-3.11, P=0.002), 24 h urinary copper (674 (205, 1 803) vs. 149 (108, 206) μg, Z=-4.25, P<0.001), and positive rate of K-F ring [17/19 vs. 7%(7/95), χ²=50.17, P<0.001] while shorter onset time at initial visit (0.3 (0.1, 0.5) vs. 1.0 (0.7, 6.0) months, Z=-4.28, P<0.001). There was no gender difference between the two groups [9/19 vs. 61%(58/95), χ²=1.22, P=0.269]. Of the 19 WD children with ALF onset, 13 had the ATP7B gene tested, and 15 reported variants were detected. The main variations were c.2333G>T (p. Arg778Leu), c.2621C>T (p. Ala874Val) and c.2975C>T (p. Pro992Leu). The allele frequencies were 6/26(23%), 4/26(15%) and 3/26(12%), respectively. Conclusions: Children of WD onset with ALF are school-aged and above. They have an acute onset, a short course of the disease, and poor prognosis. The positive rate of K-F ring, ceruloplasmin and urinary copper are higher than those of the hepatic WD children with non-ALF onset.
Ceruloplasmin/metabolism* ; Child ; Copper/metabolism* ; Female ; Hepatolenticular Degeneration/genetics* ; Humans ; Liver Failure, Acute/therapy* ; Male ; Retrospective Studies

Hepatolenticular degeneration (Wilson's disease, WD) is a kind of autosomal recessive genetic disease characterized by disorders of copper metabolism. It is caused by mutations in the ATP7B gene, resulting in impaired excretion of copper into the bile, and then pathological deposition in the liver, brain, and other organs. Early diagnosis and treatment can significantly improve the prognosis of patients with WD. However, there is still no clear consensus on the treatment and management of WD during pregnancy. Herein, the clinical management of WD during pregnancy is summarized for clinicians' reference.
Copper ; Copper-Transporting ATPases/genetics* ; Female ; Hepatolenticular Degeneration/therapy* ; Humans ; Mutation ; Pregnancy

In order to help liver disease-related clinicians make rational decisions, the Inherited and Metabolic Liver Disease Cooperative Group of Hepatology Branch of Chinese Medical Association released the 2022 edition guidelines for hepatolenticular degeneration diagnosis and treatment. This article introduces the ten highlights of this guideline from the aspects of epidemiology, pathogenesis, clinical characteristics, laboratory tests, diagnosis, treatment, monitoring, and so forth, with practicality and operability as prominent features.
Gastroenterology ; Hepatolenticular Degeneration/therapy* ; Humans