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Chen L, Fang MJ, Zhang LL, Liu YF, Han YZ, Yu XE, Xu Y. Wilson disease combined with polycystic ovary syndrome-clinical features, treatment, and outcome in Chinese patients. BMC Endocr Disord 2025; 25:78. [PMID: 40122817 PMCID: PMC11931747 DOI: 10.1186/s12902-025-01899-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 03/10/2025] [Indexed: 03/25/2025] Open
Abstract
OBJECTIVE We aimed to analyze the clinical features, treatment, and prognosis of Wilson disease (WD) combined with polycystic ovary syndrome (PCOS), and to explore the correlation between endocrine abnormalities and liver damage. PATIENTS AND METHODS The clinical data of 40 female patients of WD combined with PCOS (PCOS-WD) were retrospectively analyzed. 43 age- and BMI-matched patients of PCOS with non-WD (PCOS-NWD) were performed as the control group. The patients of PCOS-WD were assigned to adolescent group (n = 18) and reproductive age group (n = 22) according to the age onset of PCOS, and also assigned to normal testosterone group (n = 18) and elevated testosterone group (n = 22) according to the testosterone level. The clinical features, laboratory tests, imaging examinations, treatment, and outcome of all patients were analyzed, and correlation analysis was processed between gonadal hormone and liver damage parameters. RESULTS The testosterone level was significantly higher in the PCOS-NWD than in the PCOS-WD patients (Z=-2.306, P = 0.021). The clinical hyperandrogenism was significantly more prevalent in adolescent group within PCOS-WD patients (P = 0.025), while the serum alanine aminotransferase was significantly higher in reproductive age group (Z=-2.572, P = 0.010). The hepatic fibrosis index was significantly higher in elevated testosterone group than in normal testosterone group (Z = -2.190, P = 0.029), while the progesterone level was lower in elevated testosterone group (Z = 2.394, P = 0.017). The testosterone level was positively correlated with the hepatic fibrosis index (P = 0.039, R = 0.328). In followed-up observations, no significant difference was found in menstrual cycle and pregnancy outcomes between progesterone combined with copper chelation therapy and copper chelation therapy alone. CONCLUSION PCOS is an important endocrine comorbidity of female WD patients. The extent of liver damage in WD patients may be related to the hormonal imbalance of PCOS. The study recommends routine screening for PCOS in adolescent WD patients. Testosterone levels may serve as a valuable reference for informing treatment decisions. Copper chelation therapy with or without progesterone is beneficial to the recovery of patients with PCOS-WD.
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Affiliation(s)
- Lin Chen
- Institute of Neurology, Anhui University of Chinese Medicine, No. 357, Changjiang Middle Road, Hefei, 230061, China
| | - Ming-Juan Fang
- Institute of Neurology, Anhui University of Chinese Medicine, No. 357, Changjiang Middle Road, Hefei, 230061, China
| | - Liang-Liang Zhang
- Institute of Neurology, Anhui University of Chinese Medicine, No. 357, Changjiang Middle Road, Hefei, 230061, China
| | - Yong-Feng Liu
- Institute of Neurology, Anhui University of Chinese Medicine, No. 357, Changjiang Middle Road, Hefei, 230061, China
| | - Yong-Zhu Han
- Institute of Neurology, Anhui University of Chinese Medicine, No. 357, Changjiang Middle Road, Hefei, 230061, China
| | - Xu-En Yu
- Institute of Neurology, Anhui University of Chinese Medicine, No. 357, Changjiang Middle Road, Hefei, 230061, China.
| | - Yin Xu
- Institute of Neurology, Anhui University of Chinese Medicine, No. 357, Changjiang Middle Road, Hefei, 230061, China.
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Gupta A, Sen Sarma M, Kumar A, Meena K, Baishya B, Mathias A, Mishra AK, Rao NK, Singh N, Singh P. Probing and gauging of D-Penicillamine xenobiotics in hepatic Wilson disease patients. Biophys Chem 2024; 313:107306. [PMID: 39121649 DOI: 10.1016/j.bpc.2024.107306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 07/15/2024] [Accepted: 08/02/2024] [Indexed: 08/12/2024]
Abstract
D-penicillamine (PA) is the primary chelator of choice to treat Wilson disease (WD). There are limitations in obtaining comprehensive data on PA metabolites in biological specimens by conventional approaches. Hence, the aim of the present was to identify the major hepatic PA metabolites and draw clear conclusions of the drug's xenobiotic in WD. Urine samples were collected from children with hepatic WD (n = 63, aged 14.8 ± 4 years) 5 h after PA administration (16.3 ± 3.8 mg/kg/day) and age-matched healthy volunteers comprised as controls (n = 30). High-resolution 800 MHz nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry was applied to reveal unambiguous appraisals of different excretory by-products of PA metabolism. Four new products comprising penicillamine disulphide (PD), penicillamine cysteine disulphide (PCD), S-methyl penicillamine (SMP), and N-acetyl penicillamine (NAP) of PA xenobiotic metabolites were identified using high-resolution NMR spectroscopy. Quantitative levels of PCD and SMP were approximately three-fold higher than those of PD and NAP, respectively. High-resolution NMR identifies the major PA metabolites with certainty. Reduction, sulfation, and methylation are the predominant pathways of PA metabolism. There is a potential application for assessing therapeutic monitoring of chelation in hepatic WD.
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Affiliation(s)
- Ashish Gupta
- Centre of Biomedical Research, SGPGIMS Campus, Lucknow, Uttar Pradesh, India.
| | - Moinak Sen Sarma
- Department of Pediatric Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Science, Lucknow, Uttar Pradesh, India.
| | - Anuj Kumar
- Centre of Biomedical Research, SGPGIMS Campus, Lucknow, Uttar Pradesh, India
| | - Khushbhu Meena
- Centre of Biomedical Research, SGPGIMS Campus, Lucknow, Uttar Pradesh, India
| | - Bikash Baishya
- Centre of Biomedical Research, SGPGIMS Campus, Lucknow, Uttar Pradesh, India
| | - Amrita Mathias
- Department of Pediatric Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Science, Lucknow, Uttar Pradesh, India
| | - Amresh Kumar Mishra
- Department of Pediatric Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Science, Lucknow, Uttar Pradesh, India
| | - Neeraj Kumar Rao
- Department of Pediatric Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Science, Lucknow, Uttar Pradesh, India
| | - Nitu Singh
- Department of Pediatric Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Science, Lucknow, Uttar Pradesh, India
| | - Parul Singh
- Department of Pediatric Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Science, Lucknow, Uttar Pradesh, India
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Srinivasan R, Dominic S, George A. Clinical and laboratory profile and outcome in children with Wilson disease: an observational study in South India. Paediatr Int Child Health 2024; 44:131-140. [PMID: 39245999 DOI: 10.1080/20469047.2024.2396716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 08/21/2024] [Indexed: 09/10/2024]
Abstract
BACKGROUND Wilson disease is an autosomal recessive disorder owing to defective copper metabolism which causes abnormal accumulation of copper and damage to the liver, brain, kidneys and other organs. AIM To describe the clinical features, laboratory investigations and outcome of Wilson disease in children. METHODS A retrospective observational study was conducted in the paediatric department of a tertiary- care hospital in South India by reviewing medical records between January 2018 and March 2023. The diagnosis of Wilson disease was confirmed by the presence of low serum ceruloplasmin and/or high urine copper excretion in combination with clinical and ophthalmological features. RESULTS A total of 32 cases were analysed. The mean (SD) age at presentation was 110 (36) months with a M:F ratio of 1.6:1. Isolated hepatic involvement was seen in 19 (60%) patients while 13 (40%) patients had a neurological presentation, either as an isolated entity or in combination with hepatic manifestations. Low serum ceruloplasmin levels were detected in 31 (96%) patients. Urine copper levels were elevated in all patients. Twenty-one patients were commenced on D penicillamine while 11 patients were treated with a combination chelation therapy with zinc. Eighteen patients (56%) were on regular follow-up. CONCLUSION The clinical presentation of Wilson disease in children is diverse, varying from the more common hepatic or neurological manifestations to the less common atypical forms of the disease. Diagnosis is based on clinical and ophthalmological features in combination with biochemical abnormalities in the form of low ceruloplasmin and high urinary copper. The majority of patients can be medically managed with chelation therapy.
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Affiliation(s)
- Ranjini Srinivasan
- Department of Pediatrics, St John's Medical College Hospital, Bengaluru, India
| | - Shilpa Dominic
- Department of Pediatrics, St John's Medical College Hospital, Bengaluru, India
| | - Antony George
- Department of Pediatrics, St John's Medical College Hospital, Bengaluru, India
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Panda K, Lal BB, Sood V, Khanna R, Alam S. Relapse following withdrawal of D-penicillamine from combination (D-penicillamine + zinc) therapy in hepatic Wilson disease. J Pediatr Gastroenterol Nutr 2024; 78:1017-1026. [PMID: 38695602 DOI: 10.1002/jpn3.12128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 12/11/2023] [Accepted: 12/24/2023] [Indexed: 06/16/2024]
Abstract
OBJECTIVES Long-term D-penicillamine (D-pen) therapy in Wilson disease (WD) has numerous adverse effects which advocates its withdrawal, but with an inherent risk of relapse. This prospective observational study was conducted with the objective of evaluating incidence of relapse following withdrawal of D-pen from combination (D-pen + zinc) therapy in maintenance phase of previously symptomatic hepatic WD. METHODS Hepatic WD patients <18 years of age and on combination therapy for >2 years with 6 months of biochemical remission were included. Biochemical remission was defined as achievement of (i) aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤1.5 times upper limit of normal (ULN), (ii) serum albumin >3.5 g/dL, international normalized ratio (INR) <1.5 and (iii) 24-h urinary copper excretion (UCE) <500 mcg/day, nonceruloplasmin-bound-copper (NCC) <15 mcg/dL. After D-pen withdrawal, monthly liver function test (LFT) and INR and 3 monthly UCE and NCC were done till 1 year or relapse (elevation of AST/ALT/both >2 times ULN or total bilirubin >2 mg/dL), whichever occurred earlier. RESULTS Forty-five patients enrolled with median combination therapy duration of 36 months. Sixty percent of them had their index presentation as decompensated cirrhosis. Fourteen patients (31.8%) relapsed (cumulative incidence: 4 at 3 months, 11 at 6 months, and 14 at 12 months after D-pen discontinuation). All relapsers had index presentation as decompensated cirrhosis. On Cox-regression, ALT at D-pen withdrawal was an independent predictor of relapse (hazard ratio [HR]: 1.077, 95% confidence interval [CI]: 1.014-1.145, p = 0.017) with area under the receiver operating characteristic (AUROC) of 0.860. ALT ≥40 U/L predicted risk of relapse with 85.7% sensitivity, 70.9% specificity. CONCLUSION Incidence of relapse after withdrawal of D-pen from combination therapy is 31.8% in hepatic WD. ALT ≥40 U/L, at the time of D-pen stoppage, predicts future relapse.
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Affiliation(s)
- Kalpana Panda
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Bikrant B Lal
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Vikrant Sood
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Rajeev Khanna
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Seema Alam
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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Sarma MS, Ravindranath A. Pediatric acute viral hepatitis with atypical variants: Clinical dilemmas and natural history. World J Hepatol 2022; 14:944-955. [PMID: 35721282 PMCID: PMC9157701 DOI: 10.4254/wjh.v14.i5.944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 02/20/2022] [Accepted: 05/07/2022] [Indexed: 02/06/2023] Open
Abstract
Classical acute viral hepatitis (AVH) has an uncomplicated outcome. Acute liver failure has a grave prognosis. Atypical manifestations of AVH are a group of disorders that causes significant morbidity and dilemmas in children. These include prolonged cholestasis, relapsing hepatitis, ascitic form of AVH, late-onset hepatic failure (LOHF), intravascular hemolysis, and provoking an autoimmune trigger leading to autoimmune hepatitis. These entities cause significant liver dysfunction or worsening and are often difficult to differentiate from chronic liver disease (CLD). Ascitic form of AVH, LOHF, decompensated CLD and acute-on-chronic liver failure have significant overlapping features that need to be carefully dissected out. In many cases, only on long-term follow-up, these clinical entities can be separately identified. Intravascular hemolysis is usually caused by associated glucose-6-phosphate dehydrogenase deficiency. Rarely CLD such as Wilson disease and autoimmune hepatitis can also present with hemolysis in the initial presentation, which can mimic AVH with hemolysis. Identifying deviations from typical manifestations aid in avoiding unnecessary investigations, allowing focused therapy and alleviating anxiety.
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Affiliation(s)
- Moinak Sen Sarma
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Aathira Ravindranath
- Division of Pediatric Gastroenterology, Apollo BGS Hospitals, Mysuru 570023, Karnataka, India
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Zhou J, Zhang Q, Zhao Y, Chen M, Zhou S, Cheng Y. Early Diagnosis of Wilson’s Disease in Children in Southern China by Using Common Parameters. Front Genet 2022; 13:788658. [PMID: 35222532 PMCID: PMC8867696 DOI: 10.3389/fgene.2022.788658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Accepted: 01/14/2022] [Indexed: 11/13/2022] Open
Abstract
Objective: The aim of the study was to develop the early diagnostic criteria for Wilson’s disease (WD) in young children in southern China by using alanine aminotransferase (ALT) elevation as the first manifestation.Methods: A cross-sectional retrospective analysis of the clinical data and genetic test results of children with WD in southern China in the past 4 years and the follow-up of their short-term prognosis were performed in this study.Results: A total of 30 children (5.08 ± 2.06 years old) with elevated ALT as the first manifestation of WD in southern China were enrolled in this study, including 14 females and 16 males. Specifically, in all of the 30 cases (100%), the serum ceruloplasmin (CP) level was decreased, whereas the 24-h urinary copper level was increased. The genetic mutation test of the ATP7B gene was used to confirm the diagnosis. In particular, the two mutation sites, including p.R778L and p.I1148T, had the highest mutation frequencies, approximately 23.0 and 10.7%, respectively. Through follow-up, most of the children had good recovery.Conclusion: Early diagnosis and treatment of WD would substantially increase the survival rate and have a better prognosis. In addition, in 5-year-old children from southern China, early diagnosis could be performed quickly by referring to the following three parameters: elevated ALT, decreased ceruloplasmin level, and increased 24-h urinary copper level. It lays a foundation for further studies with a larger sample size.
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Affiliation(s)
- Jianli Zhou
- Department of Gastroenterology, Shenzhen Children’s Hospital, Shenzhen, China
| | - Qiao Zhang
- Department of Gastroenterology, Shenzhen Children’s Hospital, Shenzhen, China
| | - Yuzhen Zhao
- Department of Gastroenterology, Shenzhen Children’s Hospital, Shenzhen, China
| | - Moxian Chen
- Co-Innovation Center for Sustainable Forestry in Southern China, Key Laboratory of National Forestry and Grassland Administration on Subtropical Forest Biodiversity Conservation, College of Biology and the Environment, Nanjing Forestry University, Nanjing, China
| | - Shaoming Zhou
- Department of Gastroenterology, Shenzhen Children’s Hospital, Shenzhen, China
- *Correspondence: Shaoming Zhou, ; Yongwei Cheng,
| | - Yongwei Cheng
- Department of Gastroenterology, Shenzhen Children’s Hospital, Shenzhen, China
- *Correspondence: Shaoming Zhou, ; Yongwei Cheng,
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Seetharaman J, Sarma MS. Chelation therapy in liver diseases of childhood: Current status and response. World J Hepatol 2021; 13:1552-1567. [PMID: 34904029 PMCID: PMC8637676 DOI: 10.4254/wjh.v13.i11.1552] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 05/07/2021] [Accepted: 08/20/2021] [Indexed: 02/06/2023] Open
Abstract
Chelation is the mainstay of therapy in certain pediatric liver diseases. Copper and iron related disorders require chelation. Wilson’s disease (WD), one of the common causes of cirrhosis in children is treated primarily with copper chelating agents like D-penicillamine and trientine. D-Penicillamine though widely used due its high efficacy in hepatic WD is fraught with frequent adverse effects resulting discontinuation. Trientine, an alternative drug has comparable efficacy in hepatic WD but has lower frequency of adverse effects. The role of ammonium tetra-thiomolybdate is presently experimental in hepatic WD. Indian childhood cirrhosis is related to excessive copper ingestion, rarely seen in present era. D-Penicillamine is effective in the early part of this disease with reversal of clinical status. Iron chelators are commonly used in secondary hemochromatosis of liver in hemolytic anemias. There are strict chelation protocols during bone marrow transplant. The role of iron chelation in neonatal hemochromatosis is presently not in vogue due to its poor efficacy and availability of other modalities of therapy. Hereditary hemochromatosis is rare in children and the use of iron chelators in this condition is limited.
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Affiliation(s)
- Jayendra Seetharaman
- Department of Pediatric Gastroenterology, Sanjay Gandhi Post-graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Moinak Sen Sarma
- Department of Pediatric Gastroenterology, Sanjay Gandhi Post-graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
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Aaraj S, Khan SA, Ali N, Iqbal Malik MI, Dar FS. Wilson Disease in Children; Chelation Therapy or Liver Transplantation? A 10-Year Experience from Pakistan. Ann Transplant 2021; 26:e932606. [PMID: 34608110 PMCID: PMC8501894 DOI: 10.12659/aot.932606] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background Wilson disease (WD) is a rare genetic disorder with vast clinical presentations and a higher incidence in areas where consanguinity is common. Most patients can be treated with oral chelation, but some require advanced surgical intervention, like liver transplantation (LT). This study aims to review outcomes of WD patients presenting to a tertiary care center over a period of 10 years. Material/Methods This retrospective analysis was conducted at Shifa International Hospital, Islamabad, Pakistan. Patients <18 years who were diagnosed with WD per ESPAGHAN guidelines from 2010 to 2020 were included. Presentation, diagnosis, treatment, and LT and its complications were recorded. Follow-ups were recorded, and patients were contacted by phone in cases of interrupted follow-up. Frequencies and percentages of variables were calculated. Results A total of 48 patients with WD were identified. Symptomatic disease was seen in 45 patients, with 3 diagnosed on screening. The hepatic form was common (62.2%). Mean age at diagnosis was 9.74 (range 5–17) years, 28 (58.3%) were male, while 17 (35.4%) were female. Urinary copper was increased in all patients (645.82±528.40). Oral treatment with penicillamine was given to 34 (75.5%) patients; 4 (8.9%) died while on oral treatment. Living donor LT was performed in 11 (22.9%) patients, who had a mean King’s Wilson index of 11 (range, 6–14). Currently, all LT patients are alive, with maximum graft survival of 7 years. Conclusions LT offers a promising treatment with good outcomes in pediatric WD. However, timely diagnosis and management with oral chelation therapy can prolong survival without LT.
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Affiliation(s)
- Sahira Aaraj
- Department of Pediatrics, Shifa Tameer-e-Millat University, Shifa College of Medicine, Islamabad, Pakistan
| | - Sabeen Abid Khan
- Department of Pediatrics, Shifa Tameer-e-Millat University, Shifa College of Medicine, Islamabad, Pakistan
| | - Naurin Ali
- Department of Pediatrics, Shifa Tameer-e-Millat University, Shifa College of Medicine, Islamabad, Pakistan
| | - Munir I Iqbal Malik
- Department of Pediatrics, Shifa Tameer-e-Millat University, Shifa College of Medicine, Shifa International Hospital, Islamabad, Pakistan
| | - Faisal Saud Dar
- Department of Gastroenterology and Liver Transplant, Shifa Tameer-e-Millat University, Shifa College of Medicine, Shifa International Hospital, Islamabad, Pakistan
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