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 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 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

BACKGROUND: Menkes disease (MD) is a rare X-linked hereditary multisystemic disorder that is caused by dysfunction of copper metabolism. Patients with MD typically present with progressive neurodegeneration, some connective tissue abnormalities, and characteristic “kinky” hair. In addition, various types of urological complications are frequent in MD because of underlying connective tissue abnormalities. In this study, we studied the clinical features and outcomes of MD, focusing on urological complications. METHODS: A total of 14 unrelated Korean pediatric patients (13 boys and 1 girl) with MD were recruited, and their phenotypes and genotypes were analyzed by retrospective review of their medical records. RESULTS: All the patients had early-onset neurological deficit, including developmental delay, seizures, and hypotonia. The girl patient showed normal serum copper and ceruloplasmin levels as well as milder symptoms. Mutational analysis of the ATP7A gene revealed 11 different mutations in 12 patients. Bladder diverticula was the most frequent urological complication: 8 (57.1%) in the 14 patients or 8 (72.7%) in the 11 patients who underwent urological evaluation. Urological imaging studies were performed essentially for the evaluation of accompanying urinary tract infections. Four patients had stage II chronic kidney disease at the last follow-up. CONCLUSION: Urologic problems occurred frequently in MD, with bladder diverticula being the most common. Therefore, urological imaging studies and appropriate management of urological complications, which may prevent or reduce the development of urinary tract infections and renal parenchymal damage, are required in all patients with MD.
Ceruloplasmin ; Connective Tissue ; Copper ; Diverticulum ; Female ; Follow-Up Studies ; Genotype ; Hair ; Humans ; Medical Records ; Menkes Kinky Hair Syndrome* ; Metabolism ; Muscle Hypotonia ; Phenotype ; Renal Insufficiency, Chronic ; Retrospective Studies ; Seizures ; Urinary Bladder ; Urinary Tract Infections

Wilson's disease is a rare genetic disorder that has abnormal copper metabolism. Although the disease's main problems are found in liver and brain, some studies revealed manifestation of various musculoskeletal problems in the patients. In this report, we encountered a young patient who had fracture in the forearm bone. Initially, exception to a previous history of fracture from a motorcycle accident, the patient did not have any medical or drug use history, and laboratory work-ups were insignificant. However, with suspicion on his bone's integrity, bone densitometry was recommended and revealed osteopenic change. To disclose a cause for the change, questions were made to recall any particular history or event, and his complaint of recent vision loss led to ophthalmologic consultation where under slit-lamp test found Kayser-Fleischer ring. Further laboratory work-up found low levels of serum copper and ceruloplasmin and high copper level in 24-hr urine sample that led to the diagnosis of Wilson's disease. Although Wilson's disease has been frequently noticed with considerable musculoskeletal manifestation, it rarity makes the diagnosis illusive to a physician. Hence, despite of its rarity, it is imperative to remember the disease's bony manifestation, and it should be suspected in young patients with demineralized bone when the reason for brittle bone cannot be answered with other better known conditions.
Brain ; Ceruloplasmin ; Copper ; Densitometry ; Diagnosis* ; Forearm ; Hepatolenticular Degeneration* ; Humans ; Liver ; Male ; Metabolism ; Motorcycles

OBJECTIVETo investigate the roles of ceruloplasmin (Cp) in PI3K/PTEN cell signaling pathway change in human embryonic lung fibroblasts (HELFs) induced by silica.

METHODSHELFs transfected with pGenesil1.1 plasmid and pGenesil1.1 with PTEN shRNA (PT) plasmid were successfully established. 100 µg/ml silica and different concentrations of Cp (10, 20, 30 µg/ml) were used in this experiment and Cp were treated cells after exposed to silica for 1h. Three different cell lines (including HELFs, PT and cells were transfected with p85 dominant negative mutant plasmid (DN-p85)) were divided into control groups, silica groups and silica+different concentrations of Cp groups. MTT assay was used to detect the effects of Cp on silica-induced cell proliferation after inhibiting PTEN and p85. When suppressing the expression of PTEN and p85, western blot assay was performed to detect the levels of p85, p110, AKT308, AKT473 and ERK, JNK and their phosphorylated levels.

RESULTSAfter inhibition of PTEN, the high levels of p85 induced by 100 µg/ml silica with 30 µg/ml Cp were markedly decreased (P<0.05). When suppressing p85, the increased cell proliferation was not observed. And the high levels of AKT308, AKT473, ERK and phosphorylated JNK and ERK stimulated by 100 µg/ml silica with 30 µg/ml Cp were decrease (P < 0.05).

CONCLUSIONCp could further strengthened silica-induced cell proliferation by PI3K/AKT/MAPK cell signaling pathway, of which the level of p85 was regulated by PTEN.

Cell Proliferation ; drug effects ; Cells, Cultured ; Ceruloplasmin ; pharmacology ; Class Ia Phosphatidylinositol 3-Kinase ; metabolism ; Fibroblasts ; drug effects ; metabolism ; Humans ; PTEN Phosphohydrolase ; metabolism ; Signal Transduction ; drug effects ; Silicon Dioxide ; toxicity

Adenosine Triphosphatases ; genetics ; Alanine Transaminase ; blood ; Cation Transport Proteins ; genetics ; Ceruloplasmin ; metabolism ; Child ; Copper ; blood ; urine ; Copper-transporting ATPases ; Cornea ; pathology ; Diagnosis, Differential ; Genetic Testing ; Hepatolenticular Degeneration ; blood ; diagnosis ; genetics ; metabolism ; Humans ; Liver ; metabolism ; pathology ; Liver Function Tests ; Mutation

OBJECTIVETo explore the effect of minimally invasive Ivor-Lewis esophagectomy on acute phase responses in patients with esophageal carcinoma.

METHODSForty-eight patients with middle or low thoracic esophageal carcinoma underwent Ivor-Lewis esophagectomy. The patients were divided into small incision group (n = 25) and conventional group (n = 23) according to the patients' will. Serum levels of acute phase proteins C reactive protein (CRP), haptoglobin (HPT), α₁-acid glycoprotein (α₁-AG), ceruloplasmin (CER), transferrin (TRF), β₂-microglobulin (β₂-MG), album protein (ALB), interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) were measured and compared on 1st day before operation, at 18 hours as well as 3rd and 7th day after operation.

RESULTSThere was no significant difference in all the acute phase proteins indicators and IL-6 between the small incision and conventional groups at each time points after operation (P > 0.05). In both groups the levels of CRP, α₁-AG and HPT were significantly higher after operation than before operation (P < 0.05). The levels of ALB and TRF were significantly lower after operation than before operation (P < 0.05). The levels of CER and β₂-MG were not significantly different during perioperative period (P > 0.05). The level of TNF-α was significantly higher in the small incision group than that in the conventional group at the 18 hours postoperationally (P < 0.05), and were not significantly different on the other time points between the two groups (P > 0.05).

CONCLUSIONCompared with conventional operation, the small incision Ivor-Lewis esophagectomy do not significantly alleviate the stress of the surgical trauma in patients. Unchanging the essence of operation, if one is trying to minimize the stress caused by surgery on patients, the key factor is not the size of incision. An effective approach should be found in other operation-related factors.

Acute-Phase Proteins ; metabolism ; Aged ; C-Reactive Protein ; metabolism ; Carcinoma, Squamous Cell ; blood ; surgery ; Ceruloplasmin ; metabolism ; Esophageal Neoplasms ; blood ; surgery ; Esophagectomy ; methods ; Female ; Haptoglobins ; metabolism ; Humans ; Interleukin-6 ; blood ; Male ; Middle Aged ; Minimally Invasive Surgical Procedures ; methods ; Orosomucoid ; metabolism ; Perioperative Period ; Serum Albumin ; metabolism ; Serum Albumin, Human ; Transferrin ; metabolism ; Tumor Necrosis Factor-alpha ; blood ; beta 2-Microglobulin ; blood

Animals ; Antimicrobial Cationic Peptides ; physiology ; Carrier Proteins ; physiology ; Cation Transport Proteins ; physiology ; Ceruloplasmin ; physiology ; Female ; Ferritins ; physiology ; Hemochromatosis Protein ; Hepcidins ; Histocompatibility Antigens Class I ; physiology ; Humans ; Iron ; metabolism ; Iron-Regulatory Proteins ; physiology ; Membrane Proteins ; physiology ; Placenta ; metabolism ; Pregnancy ; Transferrin ; physiology

OBJECTIVETo provide right time points in selection of right aged animals and the normal physiological data of TX mice.

METHODS7-12 months old TX and DL mice were studied, each group contained 3 female and 3 male mice of TX or DL mice. The concentration of copper in the serum, dry tissues (liver, brain and kidney), together with copper biochemistry indexes were measured. The liver histopathology was observed under light microscopy and electron microscope.

RESULTSTransaminase increased significantly only in 10 and 11-month- old (AST(TX10) = 218.3 U/L, AST(TX11) = 197.5 U/L, AST(DL10) = 171.5 U/L, AST(DL11) = 165.0 U/L, P(10) less than 0.001, P(11) = 0.022), but the copper concentration of liver, brain and kidney was significantly increased during 7-12 month old (the average concentration of copper, Liver(TX) = (750.0 +/- 85.5) mg/kg, Brain(TX) = (39.7 +/- 2.2)mg/kg, Kidney(TX) = (29.8 +/- 5.0) mg/kg, Liver(DL) = (11.6 +/- 1.5) mg/kg, Brain(DL) = (16.8 +/- 0.9) mg/kg, Kidney(DL) = (14.2 +/- 1.0) mg/kg, t = 21.16, 23.60, 7.47, for all these organs P less than 0.05).

CONCLUSIONTX mice is a suitable model of liver disease with natural recovery, so selecting animal model of suitable time point is very important.

Animals ; Aspartate Aminotransferases ; blood ; Brain ; metabolism ; Ceruloplasmin ; metabolism ; Copper ; metabolism ; Disease Models, Animal ; Female ; Kidney ; metabolism ; Liver ; metabolism ; pathology ; Liver Diseases ; blood ; metabolism ; pathology ; Male ; Mice ; Mice, Inbred Strains ; Time Factors