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.

Research advances in the pathogenesis, phenotype-genotype relationship, and pharmacotherapy of hepatolenticular degeneration / 临床肝胆病杂志

In hepatolenticular degeneration, also known as Wilson's disease (WD), the binding of copper to ceruloplasmin is impaired, resulting in the deposition of free copper mainly in the liver, brain, and other organs. The prevalence rate of WD was 1/30 000. In clinical practice, most WD patients are young adults and are characterized by extrapyramidal symptoms, liver cirrhosis, Kayser-Fleischer ring of the cornea, low serum ceruloplasmin level ( 100 mg/L). At present, pharmacotherapy is the main treatment method for WD, and in some cases of end-stage liver disease or acute liver failure, liver transplantation is an option to improve survival rate. This article reviews the research advances in the pathogenesis of hepatolenticular degeneration, phenotype-genotype relationship, and pharmacotherapy in China and globally.

Application of a low copper diet guidance based on food exchange portions in children with hepatolenticular degeneration / 中国当代儿科杂志

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.

Clinical features of Wilson's disease: An analysis of 83 cases / 临床肝胆病杂志

Objective To summarize the clinical features of patients with Wilson's disease (WD). Methods A retrospective analysis was performed for the clinical data of 83 patients with WD who were admitted to The Third Hospital of Hebei Medical University from April 2013 to August 2021, including clinical manifestations, Imaging examinations, laboratory examinations, liver histopathological examinations, and ATP7B gene testing results. The patients were divided into groups based on different clinical types. A one-way analysis of variance was used for comparison between groups. Results The youngest age was 3 years for the 83 patients with WD, among whom 39 (46.99%) had an age of ≤18 years, with a mean age of 21.16±14.87 years for all 83 patients. Of all patients, 63.86% had liver-type WD, 31 patients (37.35%) had developed liver cirrhosis at the time of consultation, and 5 patients (6.2%) attended the hospital due to acute or acute-on-chronic liver failure. Of all patients, 62(74.69%) were positive for corneal K-F ring, and the positive rate of K-F ring was 66.04% in the patients with liver-type WD. Among the 83 patients, 79(95.18%) had a reduction in blood ceruloplasmin, and 73(87.95%) had an increase in 24-hour urine copper. The liver histopathological results of 25 patients showed varying degrees of inflammation, fibrosis, steatosis, and copper particle deposition in liver tissue. The ATP7B gene testing results of 25 patients showed that c.2333G > T/p.R778L of exon 8 was the most common mutation site. Conclusion Most patients with WD have the manifestation of liver diseases, and the examinations of corneal K-F ring, serum ceruloplasmin, and 24-h urine copper have their own limitations. Liver pathology and ATP7B gene testing can be performed when it is unable to make a confirmed diagnosis.

Research advances in animal models of Wilson's disease / 临床肝胆病杂志

Wilson's disease (WD) is a rare autosomal recessive disorder with a complex pathogenesis involving multiple systems, multiple visceral organs, and the complex copper homeostasis regulation system within the body. The liver is the most common organ for copper deposition, and liver injury is the earliest and most common manifestation of WD; therefore, it is important to find an ideal animal model for WD research. By summarizing the animal models of WD commonly used in the world, this article systematically summarizes the background, liver and nervous manifestations, and application of different models and compares the characteristics of different animal models, so as to provide a reference for the application of various animal models of WD.

Diagnosis and treatment of acute liver failure in children with Wilson's disease / 临床肝胆病杂志

Acute liver failure (ALF) is a rare and extremely severe clinical form of Wilson's disease (WD), characterized by progressive aggravation of jaundice and significant coagulation disorder with acute intravascular hemolysis. There is a high risk of severe complications such as hepatic encephalopathy and acute renal failure, and the disease progresses rapidly after onset and has a high mortality rate. At present, it is difficult to diagnose WD presenting as ALF in the early stage due to a lack of unified indicators for rapid diagnosis. Liver transplantation was considered the only effective treatment method for this disease in the past; however, recent studies have shown that medical treatment without liver transplantation can achieve autologous liver relief and recovery in some patients with WD-ALF.

Guidelines for the diagnosis and treatment of hepatolenticular degeneration (2022 edition) / 中华肝脏病杂志

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.

Pregnancy management of hepatolenticular degeneration in pregnancy / 中国综合临床

Hepatolenticular degeneration (HLD) is Wilson's disease, which is an autosomal recessive inherited disease caused by gene abnormality and copper transport disorder in liver cells. The pregnancy of HLD patients is safe. During pregnancy, the treatment of eliminating copper should be continued, the dosage of drugs should be reduced according to the condition, and regular monitoring should be done. HLD patients with satisfactory copper control had better pregnancy outcomes than untreated HLD patients. The treatment during pregnancy should be individualized, and perinatal care should be coordinated by obstetrics, hepatology, liver transplantation, genetic counseling, pharmacy, anesthesiology, pediatrics and other disciplines.

Characteristics of attentional bias in Wilson disease patients with different levels of state-trait anxiety / 中华行为医学与脑科学杂志

Objective:To investigate the characteristics of attention bias in Wilson disease(WD) patients with different levels of state-trait anxiety.Methods:The emotional Stroop paradigm and the state-trait anxiety inventory(STAI) were used to evaluate the anxiety level and the characteristics of attention bias in 49 inpatients with WD.SPSS 25.0 software was used for statistical analysis.Independent sample t-test was used for comparison between the two groups.Multiple linear regression analysis was used to evaluated the influencing factors of attentional bias response time. Results:(1) In WD patients, the response times measured under the positive, negative and neutral words in the high trait anxiety group((867.0±172.1)ms, (877.0±167.7)ms, (898.4±169.8)ms, respectively) were significantly higher than the low trait anxiety group((771.9±128.9)ms, (770.9±110.4)ms, (778.4±120.1)ms, respectively) and the differences were statistically significant( t=-2.183, -2.605, -2.847, all P<0.05). The response times under the positive, negative and neutral word measured in the high state anxiety group((866.9±171.9)ms, (867.8±173.8)ms, (889.8±173.5)ms, respectively) were higher than those of the low state anxiety group((771.9±129.2)ms, (780.4±109.3)ms, (787.3±123.0)ms, respectively) and the differences were statistically significant( t=-2.177, -2.116, -2.378, all P<0.05). (2) Multiple linear regression analysis showed that the total score of trait anxiety ( B=4.584, 4.671, 5.376, P=0.020, 0.015, 0.008) and age ( B=9.314, 7.864, 7.505, P=0.002, 0.008, 0.014) were the influencing factors of response times measured under the positive, negative and neutral emotion words. Conclusion:Anxiety will lead patients with WD to show more negative attention bias, and trait anxiety can significantly predict the characteristics of attention bias.

Etiology and Pathogenesis of Hepatolenticular Degeneration Caused by Latent Toxin Blocking Collaterals / 中国实验方剂学杂志

Hepatolenticular degeneration（HLD），also known as Wilson disease （WD）， is a genetic disorder characterized by copper metabolism disorder caused by ATP7B gene mutation. Specifically， due to the ceruloplasmin synthesis disorder induced by gene mutation，copper cannot be excreted through bile，which results in pathological deposition of copper in various organs and damage to organs such as the brain and the liver. The incidence of WD in Chinese is significantly higher than that in the world. Copper chelating agents， such as D-penicillamine and dimercaptosuccinic acid， are used as the main therapeutic agents in western medicine. However， many clinical adverse events limit the application of these drugs. Traditional Chinese medicine （TCM） has its characteristics in the treatment of WD. As confirmed by long-term research on TCM clinical diagnosis and treatment，MD has become TCM dominant disease. In spite of many views about the etiology and pathogenesis of WD，a consensus has not been reached so far. Based on the theory of latent pathogen in TCM and the pathological mechanism of excessive deposition of copper ions in the body，this study proposed that latent toxin is the key etiology of WD，and further elaborated that the latent toxin of WD was inherited from parents and occurred in children and adolescents，which was hidden in the liver and the kidney and damaged the brain. The latent toxin， Yang in nature and dispersing in property， is prone to transform into dampness-heat to block Qi movement and produce phlegm leading to stasis. Furthermore， this study determined latent toxin blocking collaterals as the basic pathogenesis of WD and revealed the complex clinical manifestations of latent toxin blocking collaterals such as liver collaterals，brain collaterals，kidney collaterals，spleen collaterals，stomach collaterals，lung collaterals，heart collaterals， and uterus collaterals. Treatment should follow the basic therapeutic principles of resolving pathogens，removing toxins， and dredging collaterals. This study is expected to provide a theoretical basis for syndrome differentiation and treatment of WD in TCM.

Clinical Efficacy of Gandou Fumu Granules on Wilson Disease with Liver-kidney Deficiency and Phlegm-blood Stasis / 中国实验方剂学杂志

ObjectiveTo observe the clinical efficacy of Gandou Fumu granules （GDFM） in the treatment of Wilson disease （WD） with liver-kidney deficiency and phlegm-blood stasis. MethodNinety WD patients in The First Affiliated Hospital of Anhui University of Chinese Medicine were randomly divided into a control group （45 cases） and a treatment group （45 cases）. All patients were treated with sodium 2，3-dimercaptopropane-1-sulfonate （DMPS）， while those in the treatment group received additional GDFM. All patients were treated for four courses （32 days）. The traditional Chinese medicine （TCM） syndrome scores，clinical effective rate，24 h urinary copper，ceruloplasmin （CER），tumor necrosis factor-α（TNF-α），interleukin-1β（IL-1β），interleukin-6 （IL-6），superoxide dismutase （SOD），glutathione peroxidase （GSH-Px） and malondialdehyde （MDA） levels of the two groups before and after treatment were observed. ResultAfter treatment， the TCM syndrome scores of the two groups decreased （P<0.01），and the score of TCM syndrome in the treatment group was lower than that of the control group （P<0.01）. The total effective rate of the treatment group was 82.22% （37/45）， higher than 57.78% （26/45） of the control group （χ2=6.402，P<0.05）. There was no significant difference in CER before and after treatment in both groups. The post-treatment 24 hour urinary copper increased （P<0.01）， which was higher in the treatment group than that in the control group （P<0.05）. The TNF-α，IL-1β， and IL-6 levels were significantly reduced in both groups after treatment（P<0.01），and the above indicators in the treatment group were significantly lower than those in the control group （P<0.01）. After treatment，the SOD level increased and the MDA level decreased in the control group （P<0.01）， while no significant difference in GSH-Px level was observed. The SOD and GSH-Px levels increased and the MDA level decreased in the treatment group （P<0.01）. After treatment， SOD and GSH-Px levels of the treatment group were higher than those in the control group， while the MDA level was lower than that in the control group（P<0.05，P<0.01）. ConclusionGDFM can improve the TCM syndrome score and clinical efficacy，enhance the copper removing effect，and inhibit the inflammatory response and antioxidative stress in the treatment of WD with liver and kidney deficiency and phlegm-blood stasis.

Clinical Efficacy of Gandouling Combined with Short-term Decoppering on Hepatic Fibrosis of Wilson's Disease Based on Transient Elastography / 中国实验方剂学杂志

ObjectiveTo explore the accuracy of clinical common serum fibrosis indexes hyaluronic acid （HA）， type Ⅳ collagen （CⅣ）， laminin （LN）， and type Ⅲ procollagen peptide （PⅢNP）， in combination with liver stiffness measurement （LSM， measured by transient elastography） and non-invasive markers of fibrosis aspartate aminotransferase to platelet ratio index （APRI） and fibrosis-4 （FIB-4） in the prediction of the hepatic fibrosis of Wilson's disease （WD） and to observe the clinical effect of Gandouling （GDL）. MethodThe data of 76 WD patients were collected and the LSM， serum fibrosis indexes （HA， PⅢNP， CⅣ， LN）， APRI， and FIB-4 before treatment were recorded. The correlation of LSM with serum fibrosis indexes， APRI， and FIB-4 was discussed via Pearson′s correlation analysis. According to the therapeutic schemes， patients were classified into the control group （36 cases） and treatment group （40 cases）. Patients in control group were treated with sodium dimercaptopropylsulfonate （DMPS）， while those in the treatment group received GDL in addition to the western medicine therapy. The treatment lasted 6 courses （8 days/course） and the influence of GDL on the indictors was evaluated. ResultHA， CⅣ， LN， PⅢNP， APRI， and FIB-4 were in positive correlation with LSM （r=0.517， 0.438， 0.281， 0.457， 0.778， 0.847， P<0.01）. HA， CⅣ， LN， and PⅢNP in the treatment group were lower after treatment than before treatment （P<0.05， P<0.01）. HA， CⅣ， and LN in the control group were lower after treatment than before treatment （P<0.05， P<0.01）， and PⅢNP showed no significant difference. LSM， FIB-4， and APRI in both groups decreased after treatment （P<0.05）. After treatment， LSM， FIB-4， APRI， HA， and PⅢNP in the treatment group were lower than those in the control group （P<0.05， P<0.01）， but CⅣ and LN demonstrated no significant difference from the control group. ConclusionLSM in combination with serum fibrosis indexes （HA， PⅢNP， CⅣ， LN）， FIB-4， and APRI can help accurately identify the level of the hepatic fibrosis in WD. Moreover， on the basis of decoppering by western medicine， GDL can significantly improve the liver function and hepatic fibrosis of WD patients.

A case of leukoencephalopathy with vanishing white matter confirmed by gene report reinterpretation / 中华神经科杂志

Leukoencephalopathy with vanishing white matter (VWM) is one of the most prevalent inherited childhood white-matter disorders, and the pathogenic gene has been confirmed as EIF2B gene. VWM is characterized by chronic progressive neurological deterioration with cerebellar ataxia, usually less prominent spasticity and relatively mild mental decline. There are episodes of rapid and major neurological deterioration provoked by stresses, such as fever, minor physical trauma and acute fright, which is a characteristic clinical feature of VWM. Brain magnetic resonance imaging findings are diagnostic in almost all patients,and the disappearance of the cerebral white matter occurs in a diffuse "melting away" pattern. The onset of VWM can be at any age from fetal stage to adult stage, and the clinical phenotypes vary immensely. Gene diagnosis is the golden standard for VWM. This article reported a patient with a course of 17 years, who was misdiagnosed as Wilson′s disease because of low serum ceruloplasmin, and was finally diagnosed as VWM by reinterpretation of whole exome sequencing, which is worthy of clinicians′ vigilance and consideration.

Adult cerebral hepatolenticular degeneration: report of one case with literature review / 中华全科医师杂志

A 26-year-old male presented with tremor of bilateral shoulders and hands as the major symptom and also had cognitive and emotional abnormalities for more than 1 year, who was diagnosed as cerebral hepatolenticular degeneration (HLD) in Tongji Hospital of Huazhong University of Science and Technology in October 2021. The serum ceruloplasmin and urine copper levels of the patient were 0.023 g/L and 3760.00 μg/24 h, respectively, and the Kayser-Fleischer (K-F) ring was seen in the cornea. Genetic testing revealed a homozygous mutation of ATP7B gene c.2975C>T (p.Pro992Leu), while transcranial sonography (TCS) showed lenticular nucleus hyper-echogenicity. The literature was searched using hepatolenticular degeneration and transcranial sonography as key words; and 9 articles involving 150 HLD cases were obtained. The lenticular nucleus hyper-echogenicity was presented in 76.9% HLD patients (150/195), while only in 12.7% healthy subjects (17/134) ( P<0.001), suggesting that advanced transcranial sonography can detect the metal deposition and may be used for diagnosis of cerebral HLD.

Detección del polimorfismo p.K952L en pacientes cubanos con la enfermedad de Wilson

RESUMEN Fundamento La enfermedad de Wilson es una entidad rara con patrón de herencia autosómico recesivo, a causa de las mutaciones en el gen ATP7B, lo cual provoca la acumulación de cobre en tejidos y órganos. En la literatura se informan más de 800 polimorfismos. Objetivo identificar el polimorfismo p.K952L en los pacientes cubanos con diagnóstico clínico presuntivo de enfermedad de Wilson. Métodos se realizó un estudio descriptivo, en el Centro Nacional de Genética Médica y el Instituto Nacional de Gastroenterología, que incluyó 35 pacientes con diagnóstico clínico de la enfermedad de Wilson. La extracción del ADN fue por la técnica de precipitación salina; y la amplificación del fragmento de interés, mediante la técnica de Reacción en Cadena de la Polimerasa. Además, se empleó la técnica de Polimorfismo Conformacional de Simple Cadena para la determinación de los cambios conformacionales y la presencia del polimorfismo p.K952L. Resultados en el exón 12 se identificaron los cambios conformacionales denominados b y c, que correspondieron al polimorfismo p.K952L en estado heterocigótico y homocigótico, respectivamente. La frecuencia alélica del polimorfismo p.K952L fue de 38,6 %. Las manifestaciones más frecuentes en los pacientes que presentaron este polimorfismo fueron las hepáticas. Conclusión Se identificó el polimorfismo p.K952L en 21 pacientes cubanos con diagnóstico clínico de enfermedad de Wilson, lo cual posibilita ampliar los estudios moleculares por métodos indirectos.

ABSTRACT Background Wilson's disease is a rare entity with an autosomal recessive inheritance pattern, due to mutations in the ATP7B gene, which causes the accumulation of copper in tissues and organs. More than 800 polymorphisms are reported in the literature. Objective to identify the p.K952L polymorphism in Cuban patients with a presumptive clinical diagnosis of Wilson's disease. Methods a descriptive study was carried out at the Medical Genetics National Center and the Gastroenterology National Institute, which included 35 patients with a Wilson's disease clinical diagnosis. DNA extraction was by saline precipitation technique; and the amplification of the fragment of interest, by means of the Polymerase Chain Reaction technique. In addition, the Simple Chain Conformational Polymorphism technique was used to determine the conformational changes and the presence of the p.K952L polymorphism. Results in exon 12 the conformational changes called b and c were identified, which corresponded to the polymorphism p.K952L in the heterozygous and homozygous state, respectively. The allelic frequency of the p.K952L polymorphism was 38.6%. The most frequent manifestations in patients with this polymorphism were liver. Conclusion The p.K952L polymorphism was identified in 21 Cuban patients with a clinical diagnosis of Wilson's disease, which makes it possible to extend molecular studies by indirect methods.

Enfermedad de Wilson: experiencia de un centro de referencia en Colombia / Wilson's disease: Experience of a reference center in Colombia

Resumen Introducción: la enfermedad de Wilson es una enfermedad heterogénea causada por mutaciones en el gen ATP7B. La presentación clínica es variable, en fenotipos hepáticos y neuropsiquiátricos. El objetivo de este estudio es describir una cohorte retrospectiva de pacientes. Materiales y métodos: estudio retrospectivo descriptivo de pacientes atendidos en el Hospital Pablo Tobón Uribe desde enero de 2004 a septiembre de 2017. Resultados: se reportaron 27 pacientes, 17 hombres y 10 mujeres. El tiempo de seguimiento medio fue de 2,18 años, el 40% presentó síntomas neurológicos; el 29%, psiquiátricos; y el 85%, alteración hepática. En el laboratorio, el 85% presentó ceruloplasmina baja; 55%, cobre urinario alto; en casos con biopsia hepática, 7 tenían depósito de cobre en coloraciones especiales. En neuroimágenes, el 84% presentó hallazgos sugestivos de enfermedad de Wilson y en 3 casos se documentó una mutación genética patogénica. Durante el seguimiento, el 51% mejoró clínica o bioquímicamente, el 11% se mantuvo estable y el 18% se deterioró. El 88% de los casos sobrevivió al final del seguimiento. Conclusiones: este estudio es la cohorte retrospectiva más grande de Colombia. Los resultados son base para nuevos estudios poblacionales buscando de manera activa la enfermedad para documentarla en su fase preclínica y, de este modo, impactar en el pronóstico.

Abstract Introduction: Wilson's disease is a heterogeneous disorder caused by mutations in the ATP7B gene. Its clinical presentation is variable in hepatic and neuropsychiatric phenotypes. The aim of this study is to describe a retrospective cohort of patients. Materials and methods: A descriptive retrospective study was carried out in patients treated at the Hospital Pablo Tobón Uribe from January 2004 to September 2017. Results: 27 patients were reported, 17 men and 10 women. The mean follow-up time was 2.18 years. 40% of the patients had neurological symptoms, 29% psychiatric symptoms, and 85% hepatic impairment. Lab tests showed that 85% had low ceruloplasmin and 55% had increased urinary copper. In cases that underwent liver biopsy, 7 had special copper colorations. Neuroimaging revealed that 84% had findings suggestive of Wilson's disease and a pathogenic genetic mutation was documented in 3 cases. During follow-up, 51% improved clinically or biochemically, 11% remained stable, and 18% deteriorated. 88% of cases survived at the end of follow-up. Conclusions: This study is the largest retrospective cohort carried out in Colombia. The results are the basis for new population-based studies actively seeking this disease to describe its preclinical development and thus impact prognosis.

The utility of quantitative susceptibility mapping in the diagnosis of Wilson′s disease / 中华神经科杂志

Early diagnosis and treatment is the key to improve the prognosis and reduce the disability of Wilson′s disease. Conventional magnetic resonance imaging sequences are difficult to detect early brain lesions in Wilson′s disease, especially in preclinical patients. Quantitative susceptibility mapping (QSM) is a recently developed magnetic resonance post-processing technique, which is very sensitive to magnetic metal deposition in the brain. QSM can be used for quantitative analysis of metal deposition in the basal ganglia of Wilson′s disease and is expected to be an imaging technique for early diagnosis and condition assessment of Wilson′s disease.

Value of common clinical indices and noninvasive liver fibrosis scores in the diagnosis of advanced liver fibrosis in hepatic-type Wilson’s disease in China / 临床肝胆病杂志

ObjectiveTo investigate the association of common clinical indices and noninvasive liver fibrosis scores with hepatic-type Wilson’s disease (WD) in Chinese patients and their ability to identify advanced liver fibrosis. MethodsA retrospective analysis was performed for the clinical data of 236 Chinese patients with WD who were diagnosed and treated in Beijing YouAn Hospital and China-Japan Friendship Hospital from May 1996 to April 2020. A total of 26 patients with hepatic-type WD who underwent liver pathological examination and had complete clinical data were enrolled; the METAVIR score was used to determine liver fibrosis stage, and the patients were divided into advanced liver fibrosis (F3 and F4 stages) group and non-advanced liver fibrosis (F0, F1, and F2 stages) groups. Three noninvasive liver fibrosis scores ［Sheth index, aspartate aminotransferase-to-platelet ratio index (APRI), and fibrosis-4 (FIB-4) index］ were calculated for both groups, and the above indices and related clinical indices were compared between the two groups. The independent samples t-test or the Mann-Whitney U test was used for comparison of continuous data between two groups, and the Fisher’s exact test was used for comparison of categorical data between two groups. The Spearman rank correlation test was used for further analysis of indices with statistical significance, and the clinical indices and scoring criteria correlated with liver fibrosis degree were screened out; the receiver operating characteristic (ROC) curve was plotted, and the area under the ROC curve (AUC) was calculated. ResultsMost of the patients in this study developed the disease in childhood and adolescence, and among these patients, 10 (38.5%) had positive K-F ring and 17 (65%) were in the stage of advanced liver fibrosis. There were significant differences between the advanced liver fibrosis group and the non-advanced liver fibrosis group in white blood cell count (WBC) (Z=-2.102, P=0.036), hemoglobin (Hb) (t=-2.860, P=0009), platelet count (PLT) (t=-4.053, P＜0.001), direct bilirubin (DBil) (Z=-2.130, P=0.033), albumin (Alb) (t=-2.875, P=0.008), and Sheth index (Z=-3.369, P=0.001). WBC, Hb, PLT, and Alb were negatively correlated with liver fibrosis degree in WD patients (r=-0.587, -0.610, -0.656, and -0.411, all P＜0.05), and DBil and Sheth index were positively correlated with liver fibrosis degree (r=0.486 and 0.711, both P＜0.05). The ROC curve analysis showed that WBC, DBil, Sheth index, Hb, PLT, and Alb had an AUC of ＞0.7, among which Sheth index had the largest AUC of 0.908, with a sensitivity of 70.6%, a specificity of 100.0%, a positive predictive value of 100.0%, and a negative predictive value of 64.3%. ConclusionSheth index has a better diagnostic efficiency than the other clinical indices alone and can well identify advanced liver fibrosis in Chinese patients with hepatic-type WD.

Trastornos de la coagulación en pacientes cubanos con diagnóstico clínico de Enfermedad de Wilson / Coagulation disorders in Cuban patients with a clinical diagnosis of Wilson's disease

RESUMEN Fundamento: La enfermedad de Wilson constituye un problema de salud mundial. Las manifestaciones clínicas son muy variables, lo cual contribuye a las dificultades en el diagnóstico. La presencia de trastornos de los factores de la coagulación, asociados a ella, no es común, pero se han informado casos en la literatura. Objetivo: identificar trastornos de la coagulación y su causa molecular en pacientes cubanos con diagnóstico clínico de enfermedad de Wilson. Métodos: estudio descriptivo de 50 pacientes cubanos con diagnóstico clínico de enfermedad de Wilson, realizado en el Centro Nacional de Genética Médica, La Habana. Se extrajo el ADN de la sangre de los pacientes por precipitación salina. Se realizó la búsqueda de mutaciones en los exones: 2, 3, 6, 8, 10 y 14 del gen atp7b mediante las técnicas SSCP, digestión enzimática y secuenciación. Resultados: solo en un paciente fue identificado el trastorno de coagulación (mutación p.L708P), lo que representó el 2 % del total. El análisis de dicha mutación mostró una puntuación de 0,74, lo que significó que puede provocar daño a la proteína ATP7B. Conclusión: La frecuencia de aparición de trastornos de los factores de la coagulación en pacientes cubanos con diagnóstico clínico de enfermedad de Wilson resultó baja respecto a la informada por otros estudios. Sin embargo, hay que considerarla como una probabilidad real, y realizar las pruebas necesarias para su confirmación.

Foundation: Wilson's disease is a global health problem. Clinical manifestations are quite variable, which makes the diagnosis difficult. The presence of factor coagulation disorders associated with it is not common, but cases have been reported in literature. Objective: to identify coagulation disorders and their molecular cause in Cuban patients with a clinical diagnosis of Wilson's disease. Methods: descriptive study of 50 Cuban patients with clinical diagnosis of Wilson's disease, conducted at the National Center for Medical Genetics, Havana. DNA was extracted from patients' blood by saline precipitation. Exon mutations: 2, 3, 6, 8, 10 and 14 of the atp7b gene were searched using SSCP techniques, enzymatic digestion and sequencing. Results: only one patient was identified with coagulation disorder (mutation p.L708P), which represented 2% of the total. The analysis of this mutation showed a score of 0.74, which meant that it could cause damage to the ATP7B protein. Conclusion: The frequency of occurrence of factor coagulation disorders in Cuban patients with a clinical diagnosis of Wilson's disease was low compared to that reported by other studies. However, it must be considered as a real probability, and perform the necessary tests for confirmation.