Efficacy and safety of D-penicillamine, trientine and zinc in pediatric Wilson disease patients

Efficacy and safety of D-penicillamine, trientine and zinc in pediatric Wilson disease patients | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy and safety of D-penicillamine, trientine and zinc in pediatric Wilson disease patients Eun Joo Lee, Min Hyung Woo, Jin Soo Moon, Jae Sung Ko This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3470008/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Objectives Wilson disease (WD) is a rare genetic disease affecting copper metabolism and the biliary tract’s copper excretion. Lifelong medication is necessary to prevent liver failure, neurological complications, and death. Although D-penicillamine (DPA), trientine, and zinc are used to treat Wilson disease (WD), there is limited research on the long-term outcomes of these drugs, especially in children. This study aimed to evaluate the effecacy and safety of DPA, trientine, and zinc in patients diagnosed with WD during childhood. Methods Ninety out of 92 patients were included in the analysis, excluding two patients who underwent liver transplantation without drug treatment due to an acute liver failure diagnosis. Treatment outcomes and reasons for discontinuation of therapy in 148 treatment blocks (37 DPA, 50 trientine, and 61 zinc) were analyzed using Kaplan-Meier analysis. Results The median age at diagnosis was 8.3 years. There was a statistically significant difference in drug changes due to treatment ineffectiveness among the three drugs: trientine (22/50, 44%), zinc (15/61, 25%), and DPA (2/37, 5%) (all p < 0.05). Regarding drug changes due to adverse effects, the rate was the highest for DPA, followed by zinc and trientine. There were significant differences between DPA and zinc, zinc and trientine (all p < 0.05), but no significant difference was observed between DPA and zinc (p = 0.22). Conclusions In pediatric WD, DPA, zinc, and trientine have therapeutic effects in that order. However, DPA and zinc were associated with more adverse effects than trientine. wilson disease D-penicillamine trientine zinc pediatric Figures Figure 1 Introduction Wilson disease (WD) is a genetic disease caused by mutations in ATP7B, an ATPase responsible for the excretion of copper from the liver into bile ( 1 ). Initially, copper deposition occurs in the liver; however, as the disease progresses, copper accumulates in other organs, including the brain. The clinical symptoms of WD vary depending on the affected organ, leading to variations in the age at symptom onset. Hepatic symptoms typically manifest after 2 years of age, whereas neurological and psychiatric symptoms usually arise after 10 years old ( 2 – 6 ). Recently, genetic testing has facilitated the diagnosis of WD, allowing the identification of asymptomatic individuals before 2 years of age ( 7 ). Lifelong treatment is necessary to maintain a negative copper balance; because failure to do so can result in liver failure or neurological complications leading to death ( 8 ). Treatment options consist of chelators, which enhance copper excretion in urine by eliminating copper deposits, and zinc, which inhibits copper absorption in the intestinal tract ( 9 ). An adult study demonstrated that zinc monotherapy is less effective than chelator therapy in patients with declining liver function ( 10 ); however, no relevant studies have been conducted in children. Moreover, there is currently no separate analysis of trientine in both pediatric and adult populations. Although the therapeutic and adverse effects of WD drugs may vary among toddlers, adolescents, and adults, few studies have compared these drugs, particularly in children. This study aimed to compare the therapeutic and adverse effects of D-penicillamine (DPA), trientine, and zinc in children with WD. Methods Study population We conducted a retrospective review of the charts of 92 patients diagnosed with WD at the Seoul National University Children’s Hospital from January 2005 to August 2021. The diagnosis of WD in all patients was reassessed using the Leipzig score ( 11 ). We collected data on patients’ sex, age at diagnosis, initial blood tests, and symptoms at the time of diagnosis. Throughout the study period, two pediatric hepatologists treated patients with WD. The patients were administered either a monotherapy of one of the three drugs (DPA, trientine, or zinc) or a combination therapy consisting of zinc and either of the chelators. For patients with neurologic symptoms, trientine and zinc were preferentially used as treatments, while asymptomatic patients received zinc treatment. There were no other principles guiding the treatment approach. At the time of diagnosis, we recorded data including age, sex, presence of splenomegaly, fatty liver, and liver cirrhosis based on imaging findings, as well as the presence of Kayser–Fleischer rings. The initial manifestations at the time of diagnosis were classified into three categories: hepatic, neurologic, and mixed presentation. This study was approved by the Institutional Review Board (IRB) of the Seoul National University Children’s Hospital (IRB No. 1909-111-1066), Korea. Patient monitoring and treatment Patients visited the outpatient clinic within 1 month of diagnosis, and the follow-up period was extended by 1–2 months thereafter that. The follow-up period was set at 6 months when the patient’s LFT and symptoms remained stable. In cases where stability was not achieved, monitoring was performed at intervals of 2–4 months. If there was a change in treatment during the follow-up period, the reason for the change was investigated, which included factors such as treatment adverse effects, treatment ineffectiveness, drug unavailability, and patient’s request. Treatment ineffectiveness was considered when aspartate aminotransferase and alanine aminotransferase levels were more than twice the upper limit of normal, even though the maximum drug dose was administered. The duration of each treatment block was tracked until drug discontinuation or the end of the study period. Analysis of treatment effectiveness and adverse effect Kaplan-Meier analysis was used to examine the reasons for drug changes resulting from adverse drug effects and ineffectiveness. Other factors influencing drug changes, such as patient requests or drug unavailability, were also censored. We specifically analyzed cases of monotherapy involving the three drugs, excluding those involving a combination of zinc and chelators from the analysis. The p-value was determined using the log-rank test (Mantel-Cox test). A univariate Cox regression model was used to assess the relation of sex, age at diagnosis, age at the start of treatment, and liver cirrhosis at the time of diagnosis with drug discontinuation resulting from adverse drug effects and ineffectiveness. If the p-value was found to be less than 0.2, a multivariate Cox regression model was performed using backward selection. In the analysis, statistical significance was defined as a p-value ≤ 0.05. Results Patients Ninety-two patients diagnosed with WD were included in the evaluation, of whom 46 were female (50%) (Table 1 ). The median age at diagnosis was 8.3 years (interquartile range [IQR] 1.35–2.83), and the average follow-up period was 7.9 years (IQR 2.0–14.9). Among the 86 patients (93.5%) presenting with hepatic symptoms, 64 were diagnosed incidentally through blood tests without exhibiting any symptoms related to liver disease. Two patients presented with neurological symptoms, and four patients had a mixed presentation of both liver and neurological symptoms. Table 1 Demographic data and number of patients with discontinued treatments within the study period Abbreviations: K-F, Kayser–Fleischer rings. Total patients Number of patients 92 Sex Male (%) 46 (50.0) Female (%) 46 (50.0) Age at diagnosis (y), median (IQR) 8.34 (5.8–13.2) Clinical manifestation Hepatic (%) 86 (93.5) Neurologic (%) 2 (2.2) Mixed (%) 4 (4.3) K-F ring at diagnosis (%) 15 (16.3) Liver cirrhosis at diagnosis (%) 15 (16.3) Fatty liver at diagnosis (%) 20 (28.1) Splenomegaly at diagnosis (%) 15 (16.3) Abnormal brain MRI finding at diagnosis (%) 7 (7.6) Acute liver failure at diagnosis (%) 7 (7.6) Liver transplantation (%) 4 (4.3) Death 0 Patients with Medication Changes Number of patients 90 No (%) 37 (41.1) 1 time (%) 14 (15.6) 2 times (%) 16 (17.8) 3 times (%) 13 (14.4) 4 times (%) 6 (6.7) 5 times (%) 4 (4.5) Abbreviations: K-F, Kayser–Fleischer rings. Of the patients with hepatic presentation, seven were diagnosed with acute liver failure, and four of them received liver transplantation during their initial admission. As two of these patients underwent immediate liver transplantation without medication treatment, they were subsequently excluded from further analysis, including Kaplan-Meier analysis. Among the 90 patients who received medication, 37 remained on the same medication without any changes. Fourteen patients changed their medication once, while 16, 13, 6, and four patients switched their medication two, three, four, and five times, respectively (Fig. 1 A).. Of the 225 treatment blocks, 23 cases involving combination therapy and 54 cases in which changes were not attributed to ineffectiveness or adverse effects were excluded. Therefore, a total of 148 treatment blocks (37 DPA, 50 trientine, 61 zinc) were included in the analysis. Discontinuation of treatment due to treatment effectiveness When treatment changes were made due to inadequate drug efficacy, trientine was the most frequently chosen option in 22 of 50 cases (44%), followed by DPA in two of 37 cases (5%), and zinc in 15 of 61 cases (25%). Statistical significance was observed when comparing trientine with both DPA and zinc (P < 0.5). Similarly, a significant difference observed between DPA and zinc (Fig. 1 A). Discontinuation of treatment due to drug adverse effect Out the of 37 patients in the DPA group, 16 (45%) changed their medications owing to drug adverse effects. In the trientine group, 2 of the 50 patients (4%) experienced medication changes due to adverse effects. In the zinc group, 14 out of 61 patients (23%) switched medications due to adverse drug effects. DPA exhibited a significantly higher incidence of adverse effects than trientine (P = 0.001). However, no statistically significant difference was observed between DPA and zinc (P = 0.220). The proportion of cases in which zinc medication changes were prompted by adverse effects was significantly higher than that of trientine (P = 0.024) (Fig. 1 B). The types of adverse effects associated with the three drugs and the time of onset after treatment initiation were categorized into three periods: within 4 weeks, within 1 year, and after 1 year. The details are presented in Table 2 . Of the 16 patients who experienced adverse reactions to DPA, six switched their medication within 4 weeks, and six did so within 1 year of starting treatment. Hair loss was reported in two patients after 15 and 8 years of DPA use. One patient developed idiopathic thrombocytopenic purpura after eight years of use. Another patient experienced vasculitis after approximately five years of treatment, which resulted in a permanent condition requiring ongoing treatment. There were two cases of discontinuation of the drug due to adverse effects of trientine: double vision after taking trientine for 6 months and twisting movements of the arm after taking it for 2 years. Fourteen patients experienced adverse effects of zinc, and all had gastrointestinal symptoms such as abdominal pain, nausea, and heartburn. In one patient with DPA-induced vasculitis, ongoing treatment was required as a permanent condition, and in all other patients, symptom related adverse effects improved after discontinuation of the drug. Table 2 Details of side effects and number of patients according to the duration of drug administration Onset of side effects after treatment initiation DPA (n = 16) Trientine (n = 2) Zinc (n = 14) < 4wks Rash, 3 Pancytopenia, 2 Fever, 1 Abdominal pain, 2 Nausea, 3 1year Hair loss, 2 Vasculitis, 1 Idiopathic thrombolytic purpura, 1 Twisting movements of the arm, 1 Heartburn, 1 Discontinuation of treatment due to any cause Overall discontinuation of therapy, regardless of the reasons, there was no significant difference among the three drugs (all P > 0.05). Determinant of drug survival due to any cause Cox regression analysis was used to examine the association between sex, age at diagnosis, age at the start of drug treatment, liver cirrhosis at diagnosis, and drug discontinuation. However, the analysis revealed that none of these four factors showed a significant relationship with drug discontinuation. Discussion WD is a genetic disease that ca be treated. The early initiation of medication is crucial to prevent complications arising from the accumulation of copper in the liver and other organs. In the past, the prevalence of WD was estimated to be approximately 30 per 1 million people ( 12 ); however, with the rise in genetic testing for diagnosis, there has been an increase in the rate of early detection. Recent reports from Hong Kong indicate an annual incidence rate of 1.4 per 1 million people ( 13 ), while in Thailand, the annual incidence was reported to be 2.7 ( 14 ). A recent study conducted in Korea utilized the National Health Insurance Service (NHIS) database from 2010 to 2016. The findings revealed an annual incidence rate of 3.8 for WD, with 43.1% of patients diagnosed before the age of 20 years ( 15 ). Consequently, there is a pressing need for active research focused on the diagnosis and treatment of WD in children across Asia. However, to date, there is a scarcity of comparative studies examining the efficacy and potential adverse effects of WD treatment, particularly in the pediatric population. Guidelines for the management of WD in adults advocate the use of chelators as the first-line treatment ( 9 ). For pediatric patients, European guidelines recommend using DPA and trientine as the initial treatment for children with significant liver disease, such as cirrhosis or abnormal INR, whereas zinc therapy is recommended for presymptomatic patients or as maintenance therapy after decoppering with chelators ( 16 ). DPA has been ued as a treatment for WD since the 1950s ( 17 ). However, it is associated with known adverse effects; that occur in approximately 30% of patients ( 18 – 20 ). Notably, owing to the potential for significant neurological deterioration as a serious adverse effect, DPA is not recommended as a treatment option for patients presenting with neurological symptoms ( 21 – 23 ). In this study, the incidence of adverse effects was relatively high (approximately 45%) among the patients treated with DPA. However, among the 16 patients who experienced adverse effects, only one case of irreversible complications was reported. The patient was diagnosed with WD at 5 years of age and switched to DPA at 8 years of age. Despite previous treatment with trientine and a combination of trientine and zinc, no improvement in liver function was observed. After taking DPA for 5 years, the patient developed symptoms such as pulmonary hemorrhage, microscopic hematuria, and proteinuria at approximately 13 years of age. Subsequent kidney biopsy confirmed pauci-immune crescentic glomerulonephritis, leading to diagnosis of D-penicillamine-induced ANCA-associated vasculitis ( 24 ). In this study, only two patients had neurological symptoms as the initial symptom of the disease, and DPA was not used as the first treatment for these patients. DPA administration was started at 150–300 mg/day, and the dose was gradually increased to 20 mg/kg while monitoring the effects and side effects. None of the patients taking DPA developed new neurological symptoms while taking the drug. Although DPA had a relatively high incidence of adverse effects, it was more effective than other drugs. Among the patients treated with DPA, only two of 37 (5%) showed no improvement and required a change in medication. Initially, DPA was the first-line treatment for both patients, but it was subsequently switched to trientine. However, even with trientine, there was no improvement in drug efficacy, necessitating a change in treatment to a combination therapy involving zinc. Weiss et al. compared chelator and zinc monotherapy in the study involving 288 adults with WD. The treatment effect of chelator was significantly greater than that of zinc, but there was no significant difference in adverse effects sufficient to change the treatment. ( 10 ) A recent systematic review examining the treatment of WD in both pediatric and adult patients reported similar treatment effects between DPA and zinc but with a higher occurrence of adverse effects associated with DPA ( 25 ). Patients treated with DPA showed a significantly higher frequency of neurological deterioration than those treated with zinc. (RR: 1.96, 95% CI: 1.31–2.93%, p = 0.001). It is important to exercise caution when interpreting the therapeutic effect of the drug, as the studies included in the systematic review employed varying doses of DPA and zinc. Trientine was introduced as a second-line treatment for adverse effects of DPA in 1969 ( 26 , 27 ). Currently, it is used as first-line treatment along with DPA for symptomatic patients with WD, with trientine being the preferred option in the presence of neurological symptoms ( 8 ). In this study, only two patients experienced reversible adverse effects. Among the 50 patients who received trientine, 22 switched to another medication because of its low therapeutic efficacy. However, during the follow-up period, six of the 22 patients were re-treated with trientine. Of these, three patients demonstrated a positive therapeutic response to trientine and continued with trientine monotherapy. Considering potential changes in copper absorption, metabolism, and pharmacokinetics with age among pediatric patients, further studies on sequential therapy in WD will be necessary. Zinc is recommended as a maintenance treatment for symptomatic patients with WD and as a first-line treatment for asymptomatic patients ( 9 ). In this study, all of the adverse effects associated with zinc were gastrointestinal symptoms. Previous studies have reported additional adverse effects of zinc, including copper deficiency-related anaemia, neutropenia, sensorimotor neuropathy, myelopathy, and worsening of neurological symptoms ( 28 – 30 ), but in this study, there were no adverse effects other than gastrointestinal symptoms. Zinc treatment is generally considered relatively tolerable in children ( 31 – 33 ). Importantly, this study found that zinc was significantly more effective than trientine, a chelator, in treating WD. Therefore, zinc therapy can be effectively utilized in the early diagnosis and treatment of pediatric WD. This study is limited by its retrospective nature and being conducted at a single centre. However, it is the first study to compare the treatment effectiveness and adverse effects of DPA, trientine, and zinc in the real-world practice of pediatric patients with WD. In conclusion, DPA, zinc, and trientine have therapeutic effects in that order, but DPA and zinc each have more adverse effects than trientine in pediatric WD. Abbreviations D-penicillamine (DPA), Wilson disease (WD) Declarations Ethics approval and consent to participate This study was approved by the Institutional Review Board (IRB) of the Seoul National University Children’s Hospital (IRB No. 1909-111-1066), Korea Consent for publication Not applicable Availability of data and materials The datasets of the study are not publicly available due to patient privacy and confidentiality. Anonymized data can be made available from the corresponding author upon reasonable request. Competing interests The authors declare that they have no competing interests Funding Grant No 0420193020 from Seoul National University Hospital Research Fund. Authors' contributions JSK designed the study, and critically reviewed the manuscript. JSM conceptualized and designed the original study. MHW collected, analyzed and interpreted the data. EJL analyzed, interpreted the data and wrote the draft of the manuscript. All authors have reviewed the final manuscript and approved its submission Acknowledgement This study is supported by grant No 0420193020 from Seoul National University Hospital Research Fund. References Ala A, Walker AP, Ashkan, et al. Wilson's disease. Lancet. 2007;369(9559):397-408. Dening TR, Berrios GE. Wilson's disease: a longitudinal study of psychiatric symptoms. Biol Psychiatry. 1990;28(3):255-65. Rukunuzzaman M. Wilson's Disease in Bangladeshi Children: Analysis of 100 Cases. Pediatr Gastroenterol Hepatol Nutr. 2015;18(2):121-7. Dhawan A, Taylor RM, Cheeseman P, et al. Wilson's disease in children: 37-year experience and revised King's score for liver transplantation. Liver Transpl. 2005;11(4):441-8. Iorio R, D'Ambrosi M, Marcellini M, et al. Serum transaminases in children with Wilson's disease. J Pediatr Gastroenterol Nutr. 2004;39(4):331-6. Abdel Ghaffar TY, Elsayed SM, Elnaghy S, et al. Phenotypic and genetic characterization of a cohort of pediatric Wilson disease patients. BMC Pediatr. 2011;11:56. Hahn SH. Population screening for Wilson's disease. Ann N Y Acad Sci. 2014;1315:64-9. Aggarwal A, Bhatt M. Update on Wilson disease. Int Rev Neurobiol. 2013;110:313-48. European Association for Study of L. EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol. 2012;56(3):671-85. Weiss KH, Gotthardt DN, Klemm D, et al. Zinc monotherapy is not as effective as chelating agents in treatment of Wilson disease. Gastroenterology. 2011;140(4):1189-98 e1. Ferenci P, Caca K, Loudianos G, et al. Diagnosis and phenotypic classification of Wilson disease. Liver Int. 2003;23(3):139-42. Frydman M. Genetic aspects of Wilson's disease. J Gastroenterol Hepatol. 1990;5(4):483-90. Cheung KS, Seto WK, Fung J, et al. Epidemiology and natural history of Wilson's disease in the Chinese: A territory-based study in Hong Kong between 2000 and 2016. World J Gastroenterol. 2017;23(43):7716-26. Lai CH, Tseng HF. Population-based epidemiologic study of Wilson's disease in Taiwan. Eur J Neurol. 2010;17(6):830-3. Choe EJ, Choi JW, Kang M , et al. A population-based epidemiology of Wilson's disease in South Korea between 2010 and 2016. Sci Rep. 2020;10(1):14041. Socha P, Janczyk W, Dhawan A, et al. Wilson's Disease in Children: A Position Paper by the Hepatology Committee of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2018;66(2):334-44. Walshe JM. Wilson's disease; new oral therapy. Lancet. 1956;270(6906):25-6. Medici V, Trevisan CP, D'Inca R, et al. Diagnosis and management of Wilson's disease: results of a single center experience. J Clin Gastroenterol. 2006;40(10):936-41. Weiss KH, Thurik F, Gotthardt DN, et al. Efficacy and safety of oral chelators in treatment of patients with Wilson disease. Clin Gastroenterol Hepatol. 2013;11(8):1028-35 e1-2. Walshe JM. Wilson's disease presenting with features of hepatic dysfunction: a clinical analysis of eighty-seven patients. Q J Med. 1989;70(263):253-63. Litwin T, Dziezyc K, Karlinski M, et al. Early neurological worsening in patients with Wilson's disease. J Neurol Sci. 2015;355(1-2):162-7. Brewer GJ, Terry CA, Aisen AM, et al. Worsening of neurologic syndrome in patients with Wilson's disease with initial penicillamine therapy. Arch Neurol. 1987;44(5):490-3. Kalita J, Kumar V, Chandra S, et al. Worsening of Wilson disease following penicillamine therapy. Eur Neurol. 2014;71(3-4):126-31. Kang S, Cho MH, Hyun H, et al. A Pediatric Case of a D-Penicillamine Induced ANCA-associated Vasculitis Manifesting a Pulmonary-Renal Syndrome. J Korean Med Sci. 2019;34(24):e173. Tang S, Bai L, Hou W, et al. Comparison of the Effectiveness and Safety of d-Penicillamine and Zinc Salt Treatment for Symptomatic Wilson Disease: A Systematic Review and Meta-Analysis. Front Pharmacol. 2022;13:847436. Walshe JM. Copper chelation in patients with Wilson's disease. A comparison of penicillamine and triethylene tetramine dihydrochloride. Q J Med. 1973;42(167):441-52. Dixon HB, Gibbs K, Walshe JM. Preparation of triethylenetetramine dihydrochloride for the treatment of Wilson's disease. Lancet. 1972;1(7755):853. Hoogenraad TU, Dekker AW, van den Hamer CJ. Copper responsive anemia, induced by oral zinc therapy in a patient with acrodermatitis enteropathica. Sci Total Environ. 1985;42(1-2):37-43. Foubert-Samier A, Kazadi A, Rouanet M, et al. Axonal sensory motor neuropathy in copper-deficient Wilson's disease. Muscle Nerve. 2009;40(2):294-6. Dziezyc K, Litwin T, Sobanska A, et al. Symptomatic copper deficiency in three Wilson's disease patients treated with zinc sulphate. Neurol Neurochir Pol. 2014;48(3):214-8. Castilla-Higuero L, Romero-Gomez M, Suarez E, Castro M. Acute hepatitis after starting zinc therapy in a patient with presymptomatic Wilson's disease. Hepatology. 2000;32(4 Pt 1):877. Marcellini M, Di Ciommo V, Callea F, et al. Treatment of Wilson's disease with zinc from the time of diagnosis in pediatric patients: a single-hospital, 10-year follow-up study. J Lab Clin Med. 2005;145(3):139-43. Eda K, Mizuochi T, Iwama I, et al. Zinc monotherapy for young children with presymptomatic Wilson disease: A multicenter study in Japan. J Gastroenterol Hepatol. 2018;33(1):264-9. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3470008","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":273125428,"identity":"e64fc3b8-460a-4aba-953e-6b97a21059fa","order_by":0,"name":"Eun Joo Lee","email":"","orcid":"","institution":"Yonsei University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Eun","middleName":"Joo","lastName":"Lee","suffix":""},{"id":273125429,"identity":"97a20fb2-6f70-4626-abde-4ed3635f4be5","order_by":1,"name":"Min Hyung Woo","email":"","orcid":"","institution":"Seoul National University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Min","middleName":"Hyung","lastName":"Woo","suffix":""},{"id":273125430,"identity":"585275b8-3a73-438b-8436-5cdfb6282ccd","order_by":2,"name":"Jin Soo Moon","email":"","orcid":"","institution":"Seoul National University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jin","middleName":"Soo","lastName":"Moon","suffix":""},{"id":273125431,"identity":"da3aa706-c662-43ea-95b3-b4464542aa6b","order_by":3,"name":"Jae Sung Ko","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAtklEQVRIiWNgGAWjYBACCQaGBIYPUA5jA7FaGGeQqoWBmYckLZLtDY8/2/y5k9jAfvgB48w9RGiR5jmQJp3b9iyxgSfNgHHDMyK0yEkkpDHnNhxObGDIYWB8cIA4LcmfLf4AtfC/IVKLtERCgjQDG1CLBNCWDcRokew5kCbZ23bYuE3imcHBGcRokTjek/zhx5/Dsv38yQ8f9hCjhYGBJwFMsQExcRoYGNiJVTgKRsEoGAUjFgAAGNI4aNRtu4UAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-3064-2974","institution":"Seoul National University College of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Jae","middleName":"Sung","lastName":"Ko","suffix":""}],"badges":[],"createdAt":"2023-10-20 13:41:46","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3470008/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3470008/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":51331472,"identity":"7f0f64fd-233b-477b-8b8a-4d69d2eed679","added_by":"auto","created_at":"2024-02-19 17:53:35","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":87148,"visible":true,"origin":"","legend":"\u003cp\u003eA. Discontinuation of treatment due to treatment ineffectiveness\u003c/p\u003e\n\u003cp\u003eB. Discontinuation of treatment due to adverse effects\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3470008/v1/7754a6edd7e6a341a67f0044.png"},{"id":51332852,"identity":"0add9208-7da7-4f4d-ab88-fd35a6dc5112","added_by":"auto","created_at":"2024-02-19 18:01:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":484411,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3470008/v1/bebb1efd-2074-4df5-a987-29d7de4a048a.pdf"}],"financialInterests":"","formattedTitle":"Efficacy and safety of D-penicillamine, trientine and zinc in pediatric Wilson disease patients","fulltext":[{"header":"Introduction","content":"\u003cp\u003eWilson disease (WD) is a genetic disease caused by mutations in ATP7B, an ATPase responsible for the excretion of copper from the liver into bile (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Initially, copper deposition occurs in the liver; however, as the disease progresses, copper accumulates in other organs, including the brain. The clinical symptoms of WD vary depending on the affected organ, leading to variations in the age at symptom onset. Hepatic symptoms typically manifest after 2 years of age, whereas neurological and psychiatric symptoms usually arise after 10 years old (\u003cspan additionalcitationids=\"CR3 CR4 CR5\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Recently, genetic testing has facilitated the diagnosis of WD, allowing the identification of asymptomatic individuals before 2 years of age (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Lifelong treatment is necessary to maintain a negative copper balance; because failure to do so can result in liver failure or neurological complications leading to death (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Treatment options consist of chelators, which enhance copper excretion in urine by eliminating copper deposits, and zinc, which inhibits copper absorption in the intestinal tract (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). An adult study demonstrated that zinc monotherapy is less effective than chelator therapy in patients with declining liver function (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e); however, no relevant studies have been conducted in children. Moreover, there is currently no separate analysis of trientine in both pediatric and adult populations.\u003c/p\u003e \u003cp\u003eAlthough the therapeutic and adverse effects of WD drugs may vary among toddlers, adolescents, and adults, few studies have compared these drugs, particularly in children.\u003c/p\u003e \u003cp\u003eThis study aimed to compare the therapeutic and adverse effects of D-penicillamine (DPA), trientine, and zinc in children with WD.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eWe conducted a retrospective review of the charts of 92 patients diagnosed with WD at the Seoul National University Children\u0026rsquo;s Hospital from January 2005 to August 2021. The diagnosis of WD in all patients was reassessed using the Leipzig score (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). We collected data on patients\u0026rsquo; sex, age at diagnosis, initial blood tests, and symptoms at the time of diagnosis. Throughout the study period, two pediatric hepatologists treated patients with WD. The patients were administered either a monotherapy of one of the three drugs (DPA, trientine, or zinc) or a combination therapy consisting of zinc and either of the chelators. For patients with neurologic symptoms, trientine and zinc were preferentially used as treatments, while asymptomatic patients received zinc treatment. There were no other principles guiding the treatment approach.\u003c/p\u003e \u003cp\u003eAt the time of diagnosis, we recorded data including age, sex, presence of splenomegaly, fatty liver, and liver cirrhosis based on imaging findings, as well as the presence of Kayser\u0026ndash;Fleischer rings. The initial manifestations at the time of diagnosis were classified into three categories: hepatic, neurologic, and mixed presentation.\u003c/p\u003e \u003cp\u003e This study was approved by the Institutional Review Board (IRB) of the Seoul National University Children\u0026rsquo;s Hospital (IRB No. 1909-111-1066), Korea.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003ePatient monitoring and treatment\u003c/h2\u003e \u003cp\u003ePatients visited the outpatient clinic within 1 month of diagnosis, and the follow-up period was extended by 1\u0026ndash;2 months thereafter that. The follow-up period was set at 6 months when the patient\u0026rsquo;s LFT and symptoms remained stable. In cases where stability was not achieved, monitoring was performed at intervals of 2\u0026ndash;4 months. If there was a change in treatment during the follow-up period, the reason for the change was investigated, which included factors such as treatment adverse effects, treatment ineffectiveness, drug unavailability, and patient\u0026rsquo;s request. Treatment ineffectiveness was considered when aspartate aminotransferase and alanine aminotransferase levels were more than twice the upper limit of normal, even though the maximum drug dose was administered.\u003c/p\u003e \u003cp\u003eThe duration of each treatment block was tracked until drug discontinuation or the end of the study period.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eAnalysis of treatment effectiveness and adverse effect\u003c/h2\u003e \u003cp\u003eKaplan-Meier analysis was used to examine the reasons for drug changes resulting from adverse drug effects and ineffectiveness. Other factors influencing drug changes, such as patient requests or drug unavailability, were also censored. We specifically analyzed cases of monotherapy involving the three drugs, excluding those involving a combination of zinc and chelators from the analysis. The p-value was determined using the log-rank test (Mantel-Cox test).\u003c/p\u003e \u003cp\u003eA univariate Cox regression model was used to assess the relation of sex, age at diagnosis, age at the start of treatment, and liver cirrhosis at the time of diagnosis with drug discontinuation resulting from adverse drug effects and ineffectiveness. If the p-value was found to be less than 0.2, a multivariate Cox regression model was performed using backward selection. In the analysis, statistical significance was defined as a p-value\u0026thinsp;\u0026le;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003ePatients\u003c/h2\u003e\n \u003cp\u003eNinety-two patients diagnosed with WD were included in the evaluation, of whom 46 were female (50%) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). The median age at diagnosis was 8.3 years (interquartile range [IQR] 1.35\u0026ndash;2.83), and the average follow-up period was 7.9 years (IQR 2.0\u0026ndash;14.9). Among the 86 patients (93.5%) presenting with hepatic symptoms, 64 were diagnosed incidentally through blood tests without exhibiting any symptoms related to liver disease. Two patients presented with neurological symptoms, and four patients had a mixed presentation of both liver and neurological symptoms.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eDemographic data and number of patients with discontinued treatments within the study period Abbreviations: K-F, Kayser\u0026ndash;Fleischer rings.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"3\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal patients\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNumber of patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e92\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e46 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e46 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge at diagnosis (y), median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e8.34 (5.8\u0026ndash;13.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eClinical manifestation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHepatic (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e86 (93.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNeurologic (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e2 (2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMixed (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e4 (4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eK-F ring at diagnosis (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e15 (16.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLiver cirrhosis at diagnosis (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e15 (16.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFatty liver at diagnosis (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e20 (28.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSplenomegaly at diagnosis (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e15 (16.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAbnormal brain MRI finding at diagnosis (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e7 (7.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAcute liver failure at diagnosis (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e7 (7.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLiver transplantation (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e4 (4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDeath\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePatients with Medication Changes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNumber of patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e90\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e37 (41.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 time (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e14 (15.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 times (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e16 (17.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 times (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e13 (14.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 times (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e6 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 times (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e4 (4.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eAbbreviations: K-F, Kayser\u0026ndash;Fleischer rings.\u003c/p\u003e\n \u003cp\u003eOf the patients with hepatic presentation, seven were diagnosed with acute liver failure, and four of them received liver transplantation during their initial admission. As two of these patients underwent immediate liver transplantation without medication treatment, they were subsequently excluded from further analysis, including Kaplan-Meier analysis.\u003c/p\u003e\n \u003cp\u003eAmong the 90 patients who received medication, 37 remained on the same medication without any changes. Fourteen patients changed their medication once, while 16, 13, 6, and four patients switched their medication two, three, four, and five times, respectively (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eA)..\u003c/p\u003e\n \u003cp\u003eOf the 225 treatment blocks, 23 cases involving combination therapy and 54 cases in which changes were not attributed to ineffectiveness or adverse effects were excluded. Therefore, a total of 148 treatment blocks (37 DPA, 50 trientine, 61 zinc) were included in the analysis.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eDiscontinuation of treatment due to treatment effectiveness\u003c/h2\u003e\n \u003cp\u003eWhen treatment changes were made due to inadequate drug efficacy, trientine was the most frequently chosen option in 22 of 50 cases (44%), followed by DPA in two of 37 cases (5%), and zinc in 15 of 61 cases (25%). Statistical significance was observed when comparing trientine with both DPA and zinc (P\u0026thinsp;\u0026lt;\u0026thinsp;0.5). Similarly, a significant difference observed between DPA and zinc (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eA).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003eDiscontinuation of treatment due to drug adverse effect\u003c/h2\u003e\n \u003cp\u003eOut the of 37 patients in the DPA group, 16 (45%) changed their medications owing to drug adverse effects. In the trientine group, 2 of the 50 patients (4%) experienced medication changes due to adverse effects. In the zinc group, 14 out of 61 patients (23%) switched medications due to adverse drug effects.\u003c/p\u003e\n \u003cp\u003eDPA exhibited a significantly higher incidence of adverse effects than trientine (P\u0026thinsp;=\u0026thinsp;0.001). However, no statistically significant difference was observed between DPA and zinc (P\u0026thinsp;=\u0026thinsp;0.220). The proportion of cases in which zinc medication changes were prompted by adverse effects was significantly higher than that of trientine (P\u0026thinsp;=\u0026thinsp;0.024) (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eB).\u003c/p\u003e\n \u003cp\u003eThe types of adverse effects associated with the three drugs and the time of onset after treatment initiation were categorized into three periods: within 4 weeks, within 1 year, and after 1 year. The details are presented in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. Of the 16 patients who experienced adverse reactions to DPA, six switched their medication within 4 weeks, and six did so within 1 year of starting treatment. Hair loss was reported in two patients after 15 and 8 years of DPA use. One patient developed idiopathic thrombocytopenic purpura after eight years of use. Another patient experienced vasculitis after approximately five years of treatment, which resulted in a permanent condition requiring ongoing treatment. There were two cases of discontinuation of the drug due to adverse effects of trientine: double vision after taking trientine for 6 months and twisting movements of the arm after taking it for 2 years. Fourteen patients experienced adverse effects of zinc, and all had gastrointestinal symptoms such as abdominal pain, nausea, and heartburn. In one patient with DPA-induced vasculitis, ongoing treatment was required as a permanent condition, and in all other patients, symptom related adverse effects improved after discontinuation of the drug.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eDetails of side effects and number of patients according to the duration of drug administration\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"6\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOnset of side effects\u003c/p\u003e\n \u003cp\u003eafter treatment initiation\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDPA (n\u0026thinsp;=\u0026thinsp;16)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTrientine (n\u0026thinsp;=\u0026thinsp;2)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eZinc (n\u0026thinsp;=\u0026thinsp;14)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;4wks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRash, 3\u003c/p\u003e\n \u003cp\u003ePancytopenia, 2\u003c/p\u003e\n \u003cp\u003eFever, 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAbdominal pain, 2\u003c/p\u003e\n \u003cp\u003eNausea, 3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;1year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRash, 2\u003c/p\u003e\n \u003cp\u003eNausea, 1\u003c/p\u003e\n \u003cp\u003eProteinuria, 2\u003c/p\u003e\n \u003cp\u003eBreast enlargement, 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDouble vision, 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAbdominal pain, 4\u003c/p\u003e\n \u003cp\u003eNausea, 2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;1year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHair loss, 2\u003c/p\u003e\n \u003cp\u003eVasculitis, 1\u003c/p\u003e\n \u003cp\u003eIdiopathic thrombolytic purpura, 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTwisting movements\u003c/p\u003e\n \u003cp\u003eof the arm, 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHeartburn, 1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003eDiscontinuation of treatment due to any cause\u003c/h2\u003e\n \u003cp\u003eOverall discontinuation of therapy, regardless of the reasons, there was no significant difference among the three drugs (all P\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eDeterminant of drug survival due to any cause\u003c/h2\u003e\n \u003cp\u003eCox regression analysis was used to examine the association between sex, age at diagnosis, age at the start of drug treatment, liver cirrhosis at diagnosis, and drug discontinuation. However, the analysis revealed that none of these four factors showed a significant relationship with drug discontinuation.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eWD is a genetic disease that ca be treated. The early initiation of medication is crucial to prevent complications arising from the accumulation of copper in the liver and other organs. In the past, the prevalence of WD was estimated to be approximately 30 per 1\u0026nbsp;million people (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e); however, with the rise in genetic testing for diagnosis, there has been an increase in the rate of early detection. Recent reports from Hong Kong indicate an annual incidence rate of 1.4 per 1\u0026nbsp;million people (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), while in Thailand, the annual incidence was reported to be 2.7 (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). A recent study conducted in Korea utilized the National Health Insurance Service (NHIS) database from 2010 to 2016. The findings revealed an annual incidence rate of 3.8 for WD, with 43.1% of patients diagnosed before the age of 20 years (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Consequently, there is a pressing need for active research focused on the diagnosis and treatment of WD in children across Asia. However, to date, there is a scarcity of comparative studies examining the efficacy and potential adverse effects of WD treatment, particularly in the pediatric population.\u003c/p\u003e \u003cp\u003eGuidelines for the management of WD in adults advocate the use of chelators as the first-line treatment (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). For pediatric patients, European guidelines recommend using DPA and trientine as the initial treatment for children with significant liver disease, such as cirrhosis or abnormal INR, whereas zinc therapy is recommended for presymptomatic patients or as maintenance therapy after decoppering with chelators (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDPA has been ued as a treatment for WD since the 1950s (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). However, it is associated with known adverse effects; that occur in approximately 30% of patients (\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Notably, owing to the potential for significant neurological deterioration as a serious adverse effect, DPA is not recommended as a treatment option for patients presenting with neurological symptoms (\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn this study, the incidence of adverse effects was relatively high (approximately 45%) among the patients treated with DPA. However, among the 16 patients who experienced adverse effects, only one case of irreversible complications was reported. The patient was diagnosed with WD at 5 years of age and switched to DPA at 8 years of age. Despite previous treatment with trientine and a combination of trientine and zinc, no improvement in liver function was observed. After taking DPA for 5 years, the patient developed symptoms such as pulmonary hemorrhage, microscopic hematuria, and proteinuria at approximately 13 years of age. Subsequent kidney biopsy confirmed pauci-immune crescentic glomerulonephritis, leading to diagnosis of D-penicillamine-induced ANCA-associated vasculitis (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn this study, only two patients had neurological symptoms as the initial symptom of the disease, and DPA was not used as the first treatment for these patients. DPA administration was started at 150\u0026ndash;300 mg/day, and the dose was gradually increased to 20 mg/kg while monitoring the effects and side effects. None of the patients taking DPA developed new neurological symptoms while taking the drug. Although DPA had a relatively high incidence of adverse effects, it was more effective than other drugs. Among the patients treated with DPA, only two of 37 (5%) showed no improvement and required a change in medication. Initially, DPA was the first-line treatment for both patients, but it was subsequently switched to trientine. However, even with trientine, there was no improvement in drug efficacy, necessitating a change in treatment to a combination therapy involving zinc. Weiss et al. compared chelator and zinc monotherapy in the study involving 288 adults with WD. The treatment effect of chelator was significantly greater than that of zinc, but there was no significant difference in adverse effects sufficient to change the treatment. (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) A recent systematic review examining the treatment of WD in both pediatric and adult patients reported similar treatment effects between DPA and zinc but with a higher occurrence of adverse effects associated with DPA (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Patients treated with DPA showed a significantly higher frequency of neurological deterioration than those treated with zinc. (RR: 1.96, 95% CI: 1.31\u0026ndash;2.93%, p\u0026thinsp;=\u0026thinsp;0.001). It is important to exercise caution when interpreting the therapeutic effect of the drug, as the studies included in the systematic review employed varying doses of DPA and zinc.\u003c/p\u003e \u003cp\u003eTrientine was introduced as a second-line treatment for adverse effects of DPA in 1969 (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Currently, it is used as first-line treatment along with DPA for symptomatic patients with WD, with trientine being the preferred option in the presence of neurological symptoms (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). In this study, only two patients experienced reversible adverse effects. Among the 50 patients who received trientine, 22 switched to another medication because of its low therapeutic efficacy. However, during the follow-up period, six of the 22 patients were re-treated with trientine. Of these, three patients demonstrated a positive therapeutic response to trientine and continued with trientine monotherapy. Considering potential changes in copper absorption, metabolism, and pharmacokinetics with age among pediatric patients, further studies on sequential therapy in WD will be necessary.\u003c/p\u003e \u003cp\u003eZinc is recommended as a maintenance treatment for symptomatic patients with WD and as a first-line treatment for asymptomatic patients (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). In this study, all of the adverse effects associated with zinc were gastrointestinal symptoms. Previous studies have reported additional adverse effects of zinc, including copper deficiency-related anaemia, neutropenia, sensorimotor neuropathy, myelopathy, and worsening of neurological symptoms (\u003cspan additionalcitationids=\"CR29\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e), but in this study, there were no adverse effects other than gastrointestinal symptoms. Zinc treatment is generally considered relatively tolerable in children (\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). Importantly, this study found that zinc was significantly more effective than trientine, a chelator, in treating WD. Therefore, zinc therapy can be effectively utilized in the early diagnosis and treatment of pediatric WD.\u003c/p\u003e \u003cp\u003eThis study is limited by its retrospective nature and being conducted at a single centre. However, it is the first study to compare the treatment effectiveness and adverse effects of DPA, trientine, and zinc in the real-world practice of pediatric patients with WD.\u003c/p\u003e \u003cp\u003eIn conclusion, DPA, zinc, and trientine have therapeutic effects in that order, but DPA and zinc each have more adverse effects than trientine in pediatric WD.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eD-penicillamine (DPA), Wilson disease (WD)\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Institutional Review Board (IRB) of the Seoul National University Children’s Hospital (IRB No. 1909-111-1066), Korea\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets of the study are not publicly available due to patient privacy and confidentiality. Anonymized data can be made available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGrant No 0420193020 from Seoul National University Hospital Research Fund.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJSK designed the study, and critically reviewed the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eJSM conceptualized and designed the original study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMHW collected, analyzed and interpreted the data.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEJL analyzed, interpreted the data and wrote the draft of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll authors have reviewed the final manuscript and approved its submission\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is supported by grant No 0420193020 from Seoul National University Hospital Research Fund.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eAla A, Walker AP, Ashkan, et al. Wilson\u0026apos;s disease. Lancet. 2007;369(9559):397-408.\u003c/li\u003e\n \u003cli\u003eDening TR, Berrios GE. Wilson\u0026apos;s disease: a longitudinal study of psychiatric symptoms. Biol Psychiatry. 1990;28(3):255-65.\u003c/li\u003e\n \u003cli\u003eRukunuzzaman M. Wilson\u0026apos;s Disease in Bangladeshi Children: Analysis of 100 Cases. Pediatr Gastroenterol Hepatol Nutr. 2015;18(2):121-7.\u003c/li\u003e\n \u003cli\u003eDhawan A, Taylor RM, Cheeseman P, et al. Wilson\u0026apos;s disease in children: 37-year experience and revised King\u0026apos;s score for liver transplantation. Liver Transpl. 2005;11(4):441-8.\u003c/li\u003e\n \u003cli\u003eIorio R, D\u0026apos;Ambrosi M, Marcellini M, et al. Serum transaminases in children with Wilson\u0026apos;s disease. J Pediatr Gastroenterol Nutr. 2004;39(4):331-6.\u003c/li\u003e\n \u003cli\u003eAbdel Ghaffar TY, Elsayed SM, Elnaghy S, et al. Phenotypic and genetic characterization of a cohort of pediatric Wilson disease patients. BMC Pediatr. 2011;11:56.\u003c/li\u003e\n \u003cli\u003eHahn SH. Population screening for Wilson\u0026apos;s disease. Ann N Y Acad Sci. 2014;1315:64-9.\u003c/li\u003e\n \u003cli\u003eAggarwal A, Bhatt M. Update on Wilson disease. Int Rev Neurobiol. 2013;110:313-48.\u003c/li\u003e\n \u003cli\u003eEuropean Association for Study of L. EASL Clinical Practice Guidelines: Wilson\u0026apos;s disease. J Hepatol. 2012;56(3):671-85.\u003c/li\u003e\n \u003cli\u003eWeiss KH, Gotthardt DN, Klemm D, et al. Zinc monotherapy is not as effective as chelating agents in treatment of Wilson disease. Gastroenterology. 2011;140(4):1189-98 e1.\u003c/li\u003e\n \u003cli\u003eFerenci P, Caca K, Loudianos G, et al. Diagnosis and phenotypic classification of Wilson disease. Liver Int. 2003;23(3):139-42.\u003c/li\u003e\n \u003cli\u003eFrydman M. Genetic aspects of Wilson\u0026apos;s disease. J Gastroenterol Hepatol. 1990;5(4):483-90.\u003c/li\u003e\n \u003cli\u003eCheung KS, Seto WK, Fung J, et al. Epidemiology and natural history of Wilson\u0026apos;s disease in the Chinese: A territory-based study in Hong Kong between 2000 and 2016. World J Gastroenterol. 2017;23(43):7716-26.\u003c/li\u003e\n \u003cli\u003eLai CH, Tseng HF. Population-based epidemiologic study of Wilson\u0026apos;s disease in Taiwan. Eur J Neurol. 2010;17(6):830-3.\u003c/li\u003e\n \u003cli\u003eChoe EJ, Choi JW, Kang M , et al. A population-based epidemiology of Wilson\u0026apos;s disease in South Korea between 2010 and 2016. Sci Rep. 2020;10(1):14041.\u003c/li\u003e\n \u003cli\u003eSocha P, Janczyk W, Dhawan A, et al. Wilson\u0026apos;s Disease in Children: A Position Paper by the Hepatology Committee of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2018;66(2):334-44.\u003c/li\u003e\n \u003cli\u003eWalshe JM. Wilson\u0026apos;s disease; new oral therapy. Lancet. 1956;270(6906):25-6.\u003c/li\u003e\n \u003cli\u003eMedici V, Trevisan CP, D\u0026apos;Inca R, et al. Diagnosis and management of Wilson\u0026apos;s disease: results of a single center experience. J Clin Gastroenterol. 2006;40(10):936-41.\u003c/li\u003e\n \u003cli\u003eWeiss KH, Thurik F, Gotthardt DN, et al. Efficacy and safety of oral chelators in treatment of patients with Wilson disease. Clin Gastroenterol Hepatol. 2013;11(8):1028-35 e1-2.\u003c/li\u003e\n \u003cli\u003eWalshe JM. Wilson\u0026apos;s disease presenting with features of hepatic dysfunction: a clinical analysis of eighty-seven patients. Q J Med. 1989;70(263):253-63.\u003c/li\u003e\n \u003cli\u003eLitwin T, Dziezyc K, Karlinski M, et al. Early neurological worsening in patients with Wilson\u0026apos;s disease. J Neurol Sci. 2015;355(1-2):162-7.\u003c/li\u003e\n \u003cli\u003eBrewer GJ, Terry CA, Aisen AM, et al. Worsening of neurologic syndrome in patients with Wilson\u0026apos;s disease with initial penicillamine therapy. Arch Neurol. 1987;44(5):490-3.\u003c/li\u003e\n \u003cli\u003eKalita J, Kumar V, Chandra S, et al. Worsening of Wilson disease following penicillamine therapy. Eur Neurol. 2014;71(3-4):126-31.\u003c/li\u003e\n \u003cli\u003eKang S, Cho MH, Hyun H, et al. A Pediatric Case of a D-Penicillamine Induced ANCA-associated Vasculitis Manifesting a Pulmonary-Renal Syndrome. J Korean Med Sci. 2019;34(24):e173.\u003c/li\u003e\n \u003cli\u003eTang S, Bai L, Hou W, et al. Comparison of the Effectiveness and Safety of d-Penicillamine and Zinc Salt Treatment for Symptomatic Wilson Disease: A Systematic Review and Meta-Analysis. Front Pharmacol. 2022;13:847436.\u003c/li\u003e\n \u003cli\u003eWalshe JM. Copper chelation in patients with Wilson\u0026apos;s disease. A comparison of penicillamine and triethylene tetramine dihydrochloride. Q J Med. 1973;42(167):441-52.\u003c/li\u003e\n \u003cli\u003eDixon HB, Gibbs K, Walshe JM. Preparation of triethylenetetramine dihydrochloride for the treatment of Wilson\u0026apos;s disease. Lancet. 1972;1(7755):853.\u003c/li\u003e\n \u003cli\u003eHoogenraad TU, Dekker AW, van den Hamer CJ. Copper responsive anemia, induced by oral zinc therapy in a patient with acrodermatitis enteropathica. Sci Total Environ. 1985;42(1-2):37-43.\u003c/li\u003e\n \u003cli\u003eFoubert-Samier A, Kazadi A, Rouanet M, et al. Axonal sensory motor neuropathy in copper-deficient Wilson\u0026apos;s disease. Muscle Nerve. 2009;40(2):294-6.\u003c/li\u003e\n \u003cli\u003eDziezyc K, Litwin T, Sobanska A, et al. Symptomatic copper deficiency in three Wilson\u0026apos;s disease patients treated with zinc sulphate. Neurol Neurochir Pol. 2014;48(3):214-8.\u003c/li\u003e\n \u003cli\u003eCastilla-Higuero L, Romero-Gomez M, Suarez E, Castro M. Acute hepatitis after starting zinc therapy in a patient with presymptomatic Wilson\u0026apos;s disease. Hepatology. 2000;32(4 Pt 1):877.\u003c/li\u003e\n \u003cli\u003eMarcellini M, Di Ciommo V, Callea F, et al. Treatment of Wilson\u0026apos;s disease with zinc from the time of diagnosis in pediatric patients: a single-hospital, 10-year follow-up study. J Lab Clin Med. 2005;145(3):139-43.\u003c/li\u003e\n \u003cli\u003eEda K, Mizuochi T, Iwama I, et al. Zinc monotherapy for young children with presymptomatic Wilson disease: A multicenter study in Japan. J Gastroenterol Hepatol. 2018;33(1):264-9.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"wilson disease, D-penicillamine, trientine, zinc, pediatric ","lastPublishedDoi":"10.21203/rs.3.rs-3470008/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3470008/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjectives\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWilson disease (WD) is a rare genetic disease affecting copper metabolism and the biliary tract’s copper excretion. Lifelong medication is necessary to prevent liver failure, neurological complications, and death. Although D-penicillamine (DPA), trientine, and zinc are used to treat Wilson disease (WD), there is limited research on the long-term outcomes of these drugs, especially in children. This study aimed to evaluate the effecacy and safety of DPA, trientine, and zinc in patients diagnosed with WD during childhood.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNinety out of 92 patients were included in the analysis, excluding two patients who underwent liver transplantation without drug treatment due to an acute liver failure diagnosis. Treatment outcomes and reasons for discontinuation of therapy in 148 treatment blocks (37 DPA, 50 trientine, and 61 zinc) were analyzed using Kaplan-Meier analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe median age at diagnosis was 8.3 years. There was a statistically significant difference in drug changes due to treatment ineffectiveness among the three drugs: trientine (22/50, 44%), zinc (15/61, 25%), and DPA (2/37, 5%) (all p \u0026lt; 0.05). Regarding drug changes due to adverse effects, the rate was the highest for DPA, followed by zinc and trientine. There were significant differences between DPA and zinc, zinc and trientine (all p \u0026lt; 0.05), but no significant difference was observed between DPA and zinc (p = 0.22).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn pediatric WD, DPA, zinc, and trientine have therapeutic effects in that order. However, DPA and zinc were associated with more adverse effects than trientine.\u003c/p\u003e","manuscriptTitle":"Efficacy and safety of D-penicillamine, trientine and zinc in pediatric Wilson disease patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-19 17:53:30","doi":"10.21203/rs.3.rs-3470008/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2024-04-29T12:27:55+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-02-15T07:33:43+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-02-15T01:35:04+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-11-01T06:24:23+00:00","index":"","fulltext":""},{"type":"submitted","content":"Orphanet Journal of Rare Diseases","date":"2023-10-29T09:13:34+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"dcc84352-a50d-4145-af18-4c80d014dce0","owner":[],"postedDate":"February 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-07-01T22:06:18+00:00","versionOfRecord":[],"versionCreatedAt":"2024-02-19 17:53:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3470008","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3470008","identity":"rs-3470008","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}