Prevalence, Incidence, and Treatment Pattern of Wilson's Disease Using National Health Insurance Data From 2010-2020, Korea.

BACKGROUND: Wilson's disease (WD) is an autosomal recessive disorder in which copper (Cu) accumulates in organs, particularly in the liver and central nervous system. This study aimed to investigate the prevalence, incidence, and treatment patterns of WD patients in Korea. METHODS: National Health Insurance System (NHIS) claims data from 2010 to 2020 were analyzed. patients with WD as a primary or additional diagnosis at least once were identified using the International Classification of Diseases (ICD)-10 disease code E83.0 and a record for a registration program for rare intractable diseases in Korea. RESULTS: The average age- and sex-adjusted prevalence and incidence of WD between 2010 and 2020 were 3.06/100,000 and 0.11/100,000, respectively. The mean age of the patients with newly diagnosed WD was 21.0 ± 15.9 years. Among the 622 WD incident cases during the study period, 19.3% of the patients had liver cirrhosis and 9.2% had received liver transplantation. Psychological and neurological diseases were present in 40.7% and 48.1% of the patients, respectively. Regarding the diagnosis of WD, liver biopsy was performed in only 51.6% of new cases. D-penicillamine, trientine, or zinc were prescribed in 81.5% of the incident cases, and the treatment uptake rates decreased with increasing age. CONCLUSION: The prevalence of WD in Korea is 3.06/100,000 and approximately 1,800 patients use medical services annually. A significant proportion of patients are diagnosed at the cirrhotic stage and not treated with Cu-chelating therapeutics, suggesting the need for early diagnosis and adequate treatment to improve prognosis.

Neurological worsening in Wilson disease - clinical classification and outcome.

BACKGROUND & AIMS: Prevention of neurological worsening (NW) under therapy is an unmet need in the management of Wilson disease (WD). In this study, we aimed to characterize the occurrence, associated outcomes and potential reversibility of NW in WD. METHODS: From a total cohort of 457 patients with WD, 128 patients with WD and neurological features at any time point (all Caucasian, 63 females, median age at diagnosis 22 years) were identified by chart review at University Hospital Heidelberg and grouped according to initial presentation. The timing and occurrence of NW was assessed following a structured clinical examination during clinical visits. RESULTS: Early NW (within the first 3 months of therapy) was observed in 30 out of 115 (26.1%) patients with neurological or mixed presentation and never in patients with a purely hepatic or asymptomatic presentation (0%). Late NW (after >12 months) was seen in a further 23 (20%) with neurological or mixed presentation and in 13 out of 294 (4.4%) patients with a hepatic or asymptomatic presentation. The median time from start of treatment to late NW was 20 months. Only three patients experienced NW between 3 and 12 months. NW was observed with D-penicillamine, trientine and zinc therapy and was reversible in 15/30 (50%) with early NW and in 29/36 (81%) with late NW. CONCLUSIONS: In this study, we identified two peaks in NW: an early (≤3 months) treatment-associated peak and a late (>12 months of treatment) adherence-associated peak. Early paradoxical NW was attributed to treatment initiation and pre-existing neurological damage, and was not observed in those with a hepatic or asymptomatic presentation. Late NW is likely to be associated with non-adherence. IMPACT AND IMPLICATIONS: In patients with Wilson disease, defined as an excess accumulation of copper which can damage the liver, brain and other vital organs, neurological worsening can occur despite chelation therapy. The study identifies different patterns of 'early' (<3 months) vs. 'late' (>12 months) neurological worsening in relation to initiation of chelation therapy and establishes possible causes and the potential for reversibility. These data should be useful for counseling patients and for guiding the optimal management of chelation therapy.

Experience on switching trientine formulations in Wilson disease: Efficacy and safety after initiation of TETA 4HCl as substitute for TETA 2HCl.

BACKGROUND AND AIM: This retrospective, multicenter study aims to assess the efficacy and safety in Wilson disease (WD) patients treated with trientine tetrahydrochloride (TETA 4HCl) after switch from trientine dihydrochloride (TETA 2HCl). METHODS: In total, 68 WD patients with stable copper metabolism were identified to receive TETA 4HCl (Cuprior™) after previous treatment with TETA 2HCl. We analyzed biochemical markers such as urinary copper, serum copper, non-coeruloplasmin bound copper (NCC), and transaminases as well as clinical scores (APRI; FIB-4 score) at baseline with a follow-up (FU) of 12 months. Safety of TETA 4HCl treatment was based on reported adverse events (AEs). RESULTS: The study cohort reflects a common WD cohort with a mean age of 20.3 years at diagnosis and 38.3 years at baseline. There are no significant differences concerning serum copper, NCC, transaminases, APRI, and FIB-4 score in the 3-month FU. Six-month FU revealed a decreased AST (P = 0.008), APRI (P = 0.042), and FIB-4 score (P = 0.039). GGT varied only borderline significantly in the 3-month, but not in the 6-month FU. Comparison of urinary copper within the subsets did not reveal a difference to baseline in all FUs, suggesting stable control of copper metabolism. Few AEs during TETA 4HCl treatment were reported, most commonly gastrointestinal discomfort. Only three treatments with TETA 4HCl were discontinued. CONCLUSION: Copper parameters and liver function were stable after treatment switch to TETA 4HCl. Treatment with TETA 4HCl was generally well tolerated. This study indicates that the switch from TETA 2HCl to TETA 4HCl is safe and viable.

Triethylenetetramine (TETA).

The WEEL for triethylenetetramine (TETA; CAS No. 112-24-3) was originally established in 1991 and updated in 1998 and 2009. Recent literature searches to identify new toxicity information were performed in 2016 and January 2021. No new studies or data relevant to the WEEL were identified. TETA is used in manufacturing; the hydrochloride salt of TETA is used as a copper-chelating drug in the treatment of Wilson's disease. TETA is severely irritating to the skin and eyes and produces skin sensitization; however, it is of low to moderate acute toxicity via the oral and dermal routes of exposure. In subchronic studies, signs of toxicity included multi-organ effects (lung, liver, and spleen) in mice, but not rats. TETA was genotoxic/mutagenic in short-term in vitro assays but not in in vivo assays. No data on reproductive toxicity were available. Embryo/fetal toxicity occurred at maternally toxic doses and was associated with copper deficiency. In humans, the use of TETA·2HCl for treatment of Wilson's disease during pregnancy resulted in no miscarriages or fetal abnormalities. No evidence of carcinogenicity was noted in a lifetime dermal study in mice. Based on a subchronic drinking water study in mice, 600 ppm (95 mg/kg-day) was determined to be the no-observed-adverse-effect level (NOAEL) and the point of departure (POD). This NOAEL was converted to an equivalent inhalation concentration by adjusting for respiratory rate, interindividual variability, and uncertainty. The resulting 8-h time-weighted average WEEL value of 1 ppm is expected to provide a significant margin of safety against any potential adverse health effects in workers exposed to airborne TETA.

Significant heterogeneity in the diagnosis and long-term management of Wilson disease: Results from a large multicenter Spanish study.

There is uncertainty regarding Wilson's disease (WD) management. OBJECTIVES: To assess, in a multicenter Spanish retrospective cohort study, whether the approach to WD is homogeneous among centers. METHODS: Data on WD patients followed at 32 Spanish hospitals were collected. RESULTS: 153 cases, 58% men, 20.6 years at diagnosis, 69.1% hepatic presentation, were followed for 15.5 years. Discordant results in non-invasive laboratory parameters were present in 39.8%. Intrahepatic copper concentration was pathologic in 82.4%. Genetic testing was only done in 56.6% with positive results in 83.9%. A definite WD diagnosis (Leipzig score ≥4) was retrospectively confirmed in 92.5% of cases. Chelating agents were standard initial therapy (75.2%) with frequent modifications (57%), particularly to maintenance zinc. Enzyme normalization was not achieved by one third, most commonly in the setting of poor compliance, lack of genetic mutations and/or presence of cardiometabolic risk factors. Although not statistically significant, there were trends for sex differences in number of diagnosed cases, age at diagnosis and biochemical response. CONCLUSIONS: Significant heterogeneity in diagnosis and management of WD patients emerges from this multicenter study that includes both small and large reference centers. The incorporation of genetic testing will likely improve diagnosis. Sex differences need to be further explored.

Trientine-induced Rhabdomyolysis in an Adolescent with Wilson's Disease.

BACKGROUND: Drugs are very important in the etiology of nontraumatic rhabdomyolysis. CASE DESCRIPTIONS: A 16-year-old male patient with Wilson's disease was admitted for myoclonic contractions. Oral trientine was started for neurological problems and tremor on the hands due to D-penicillamine 1 month ago. Patient was oligoanuric, and his creatine kinase level was 15197 U/L. Rhabdomyolysis was associated with trientine, and trientine treatment was stopped. Hemodiafiltration was performed. The patient began to urinate on the 24th day. CONCLUSION: This is the first pediatric patient with rhabdomyolysis induced by trientine. Drugs used should be questioned carefully in patients with rhabdomyolysis. HOW TO CITE THIS ARTICLE: Aslan N, Yavuz S, Yildizdas D, Horoz OO, Coban Y, Tumgor G, et al. Trientine-induced Rhabdomyolysis in an Adolescent with Wilson's Disease. Indian J Crit Care Med 2019;23(10):489-490.

Update on the Diagnosis and Management of Wilson Disease.

PURPOSE OF REVIEW: Exciting developments relating to Wilson disease (WD) have taken place with respect to both basic biological and clinical research. This review critically examines some of these findings and considers their implications for current thinking about WD. It is not a comprehensive review of WD as a clinical disorder. RECENT FINDINGS: The structure of the gene product of ATP7B, abnormal in WD, is being worked out in detail, along with a broader description of how the protein ATP7B (Wilson ATPase) functions in cells including enterocytes, not only in relation to copper disposition but also to lipid synthesis. Recent population studies raise the possibility that WD displays incomplete penetrance. Innovative screening techniques may increase ascertainment. New strategies for diagnosing and treating WD are being developed. Several disorders have been identified which might qualify as WD-mimics. WD can be difficult to diagnose and treat. Insights from its pathobiology are providing new options for managing WD.

The steady state pharmacokinetics of trientine in Wilson disease patients.

PURPOSE: To determine the steady state pharmacokinetics of trientine in children (≥ 12 years of age) and adult patients who had been receiving trientine dihydrochloride therapy prior to the study. METHODS: Twenty patients were exposed to trientine (trientine dihydrochloride capsules supplied by Univar) after standard oral dosing as part of ongoing therapy. Plasma trientine concentration was determined pre-dose and at 30 min, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 h post-dose. Concentrations of trientine in plasma were determined by LC-MS/MS using a validated bioanalytical method with stable labelled trientine as the internal standard. RESULTS: Trientine was generally absorbed fairly rapidly with a median Tmax of 1.49 h (range, 0.48-4.08 h). There was some variability in exposure, with a 10-fold range in Cmax, and a 13.8-fold range in AUC0-t. This variability was slightly lower when PK parameters were dose-normalised (6.7-fold range in Cmax/D and an 11.6-fold range in AUC0-t/D). The terminal half-life, which could be defined in 14 of the 20 patients, was broadly consistent between patients (range of 2.33 to 6.99 h). There was no marked difference in pharmacokinetics between adult patients (n = 16) and children (n = 4). The Cmax range was 506 to 3100 ng/mL in adults and 309 to 1940 ng/mL in children-the equivalent ranges for AUC0-t were 1240 to 17,100 ng/mL h and 1500 to 8060 ng/mL h. When PK parameters were normalised for administered dose, the Cmax/D and AUC0-t/D for children were contained within the ranges for the adult patients. CONCLUSIONS: The steady state pharmacokinetics of trientine in Wilson disease patients were broadly similar to that reported in healthy subjects.

Copper chelation by trientine dihydrochloride inhibits liver RFA-induced inflammatory responses in vivo.

OBJECTIVE: Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related death worldwide. Radiofrequency ablation (RFA) is currently performed widely for managing HCC. RFA treatment causes damage around the ablation. Trientine dihydrochloride has been used to reduce the copper in liver. METHODS: The rats were treated with trientine dihydrochloride for 5 days before liver RFA. Liver function, copper concentration, inflammation biomarkers and MDA, SOD were analyzed after RFA treatment for 2 h, 2 and 5 days. RESULTS: The results indicated that trientine dihydrochloride reduced the copper in plasma and liver tissue significantly. And trientine dihydrochloride significantly inhibited RFA-induced inflammatory gene expression in liver. Similar inhibitory effects of trientine dihydrochloride were observed on ROS-induced malondialdehyde production in liver tissues. CONCLUSION: These results suggest that pre-treatment with the selective copper chelator trientine dihydrochloride can inhibit inflammatory response effectively during and after liver RFA in vivo. Chelation of copper to a lower level before liver RFA may be a novel strategy to prevent or ameliorate inflammatory responses in liver induced by RFA and to protect the parenchyma tissues in liver during and after RFA in HCC patients.

A case of Trientine Overdose.

Wilson disease is a rare genetic hepatic and neurological disorder of copper accumulation. Trientine is usually used as a second line in the management of patients with this condition. We present a case of a large overdose of Trientine (60 g) resulting in self-limiting dizziness and vomiting with no further clinical sequelae or significant biochemical abnormalities. This case shows that Trientine has a good safety profile and hence could be used as a first line treatment in patients with Wilson's disease who suffer from psychiatric complications and who might be at risk of self-harm.

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

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 WD, there is limited research on the long-term outcomes of these drugs, especially in children. This study aimed to evaluate the efficacy 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 are associated with more adverse effects compared to trientine.

Atypical Presentation of Wilson Disease: Unravelling a Clinical and Radiological Complexity in a Rare Case.

Wilson disease (WD) is an autosomal recessive disorder marked by aberrations in copper metabolism, leading to its accumulation in vital organs such as the liver, brain, cornea, kidneys, and heart. While WD typically presents with hepatic symptoms in early childhood, neuropsychiatric manifestations are more prevalent during adolescence. This case report highlights an extraordinary instance of WD in an eight-year-old girl, characterized by intricate clinical and radiological features. The patient exhibited atypical symptoms, emphasizing the importance of recognizing diverse presentations of WD. Delayed diagnosis and treatment initiation can prove fatal in WD cases, underscoring the significance of awareness regarding these unusual clinical and radiological features to facilitate prompt intervention and prevent adverse outcomes.

Developing an analytical method for quantification of trientine based on modified silver nanoparticles.

Trientine or (N,N´-bis(2-aminoethyl)-1,2-ethanediamine (TETA) is a copper chelator and used in Wilson's disease, is aliphatic amine that does not have UV absorbing groups. In this study, the modified silver nanoparticles (AgNPs) by sodium lauryl sulfate have been used to develop an analytical method for quantification of TETA. Different concentrations of TETA were added into a particular concentration of AgNPs and absorbance of each sample was measured at 397 nm under the optimal conditions which include pH, time, salt and AgNPs volume. It was optimized by a design of experiments using response surface methodology. Then, the calibration curve was obtained based on the concentrations of TETA solution versus decrease in the absorbance of AgNPs. Selectivity of the developed method was performed in plasma and presence of common cations i.e. copper, zinc and ferrous. Under optimum conditions, linear range of this method was between 10 and 40 ng.mL- 1 with correlation coefficient (R2) of 0.996 with limit of detection and quantification of 3 ng.mL- 1 and 10 ng.mL- 1, respectively. Selectivity of established method in presence of cations eliminated by diluting because of high sensitivity of the established analytical techniques based on AgNPs. This method is suitable and low costing for quantification of TETA and does not require high equipment.

Challenges and dilemmas in pediatric hepatic Wilson's disease.

Wilson disease is an autosomal recessive disorder affecting the ATP7B gene located on chromosome 13q. This leads to copper deposition in various organs, most importantly in the liver and brain. The genetic mutations are vast, well reported in the West but poorly documented in developing countries. Hence the diagnosis is made with a constellation of clinico-laboratory parameters which have significant overlap with other liver diseases and often pose a significant dilemma for clinicians. Diagnostic scoring systems are not fool-proof. The availability and affordability of chelators in developing countries impact the drug compliance of patients. While D-penicillamine is a potent drug, its side effects lead to drug discontinuation. Trientine is cost-prohibitive in developing countries. There is no single test to assess the adequacy of chelation. Exchangeable urinary copper is an essential upcoming diagnostic and prognostic tool. In the presence of cirrhosis, hypersplenism clouds the assessment of myelosuppression of drugs. Similarly, it may be difficult to distinguish disease tubulopathy from drug-induced glomerulonephritis. Neurological worsening due to chelators may appear similar to disease progression. Presentation as fulminant hepatic failure requires rapid workup. There is a limited window of opportunity to salvage these patients with the help of plasmapheresis and other liver-assisted devices. This review addresses the challenges and clinical dilemmas faced at beside in developing countries.

Management of Children and Adolescents with Wilson Disease and Neurological Worsening Following D-Penicillamine Therapy: A Single Centre Experience.

Background: Most centers in developing countries prefer chelation therapy with D-penicillamine for the management of Wilson's disease (WD) because of its easy availability and affordability. Neurological worsening following treatment with D-penicillamine is not uncommon. However, there is a paucity of Indian data on the incidence of neurological worsening in children and adolescents with WD following chelation therapy. Our study objectives were to identify the prevalence of neurological worsening in children and adolescents with WD following chelation with D-penicillamine therapy and to describe the management options and outcomes in these patients. Materials and Methods: In this retrospective chart review, children and adolescents with an established diagnosis of WD from 2010 to 2020 were identified from the hospital electronic database. Among these patients, data of children and adolescents with neurological worsening following D-penicillamine therapy were extracted and analyzed. Results: Neurological worsening was observed in 27/122 (22.1%) children and adolescents with WD on chelation therapy with D-penicillamine. Fifteen patients with neurological worsening following D-penicillamine therapy were managed with zinc monotherapy. Four patients were managed with a combination therapy of zinc and trientine. Five patients were treated with trientine monotherapy. Re-challenging with D-penicillamine at a lower dose followed by a slow dose escalation was attempted in three patients. Gradual clinical and functional status improvement was observed in 24 cases while one patient succumbed to pneumonia. Conclusion: Children and adolescents with WD who had neurological worsening on D-penicillamine therapy may be managed with trientine. Zinc monotherapy with copper restricted diet was also found to be effective in non-affordable patients.

Hemorrhagic colitis induced by trientine in a 51-year-old patient with Wilson's disease waiting for liver transplantation: A case report.

BACKGROUND: Wilson's disease (WD) is a rare inherited disorder of copper metabolism. Treatment consists of chelating agents, but side effects are common. We describe a patient who developed colitis during trientine treatment leading to decompensation of liver cirrhosis. CASE SUMMARY: A healthy 51-year-old woman was diagnosed with liver cirrhosis due to decompensation with ascites. Etiologic evaluation raised suspicion of hereditary hemochromatosis because of compound heterozygosity HFE p.C282Y/p.H63D, and phlebotomy was started. Re-evaluation showed low ceruloplasmin, increased urinary copper excretion and the presence of Kayser-Fleischer rings. WD was confirmed by genetic analysis. Because of decompensated cirrhosis, she was referred for liver transplant evaluation. Simultaneously, treatment with trientine was initiated. Liver function initially stabilized, and the patient was not accepted for a liver transplant. Shortly after this, she developed severe hemorrhagic colitis, most probably a side effect of trientine. During that episode, she decompensated with hepatic encephalopathy. Because of a second decompensating event, she was accepted for liver transplantation, and an uneventful transplantation was carried out after clinical improvement of colitis. CONCLUSION: Despite WD being a rare disorder, it is important to consider because it can present with a plethora of symptoms from childhood to an elderly age. Colitis should be recognized as a serious adverse drug reaction to trientine treatment that can result in decompensated liver disease.

Practical insights into chronic management of hepatic Wilson's disease.

Wilson's disease (WD) is a rare inherited disorder of human copper metabolism, with an estimated prevalence of 1:30000-1:50000 and a broad spectrum of hepatic and neuropsychiatric manifestations. In healthy individuals, the bile is the main route of elimination of copper. In WD patients, copper accumulates in the liver, it is released into the bloodstream, and is excreted in urine. Copper can also be accumulated in the brain, kidneys, heart, and osseous matter and causes damage due to direct toxicity or oxidative stress. Hepatic WD is commonly but not exclusively diagnosed in childhood or young adulthood. Adherent, non-cirrhotic WD patients seem to have a normal life expectancy. Nevertheless, chronic management of patients with Wilson's disease is challenging, as available biochemical tests have many limitations and do not allow a clear identification of non-compliance, overtreatment, or treatment goals. To provide optimal care, clinicians should have a complete understanding of these limitations and counterbalance them with a thorough clinical assessment. The aim of this review is to provide clinicians with practical tools and suggestions which may answer doubts that can arise during chronic management of patients with hepatic WD. In particular, it summarises current knowledge on Wilson's disease clinical and biochemical monitoring and treatment. It also analyses available evidence on pregnancy and the role of low-copper diet in WD. Future research should focus on trying to provide new copper metabolism tests which could help to guide treatment adjustments.

Efficacy and Safety of Two Salts of Trientine in the Treatment of Wilson's Disease.

BACKGROUND: Wilson's disease (WD) is one of the few genetic disorders that can be successfully treated with pharmacological agents. Copper-chelating agents (D-penicillamine and Trientine salts) and zinc salts have been demonstrated to be effective. There are two salts of trientine. Trientine dihydrochloride salt (TETA 2HCL) is unstable at room temperature and requires storage at 2-8 °C. Trientine tetrahydrochloride (TETA 4HCL) is a more stable salt of trientine that can be stored at room temperature. No comparative study between both of the salts of trientine has been performed to date. As the two chemical forms were available in France between 1970 and 2009, we conducted a study to evaluate their efficacy and safety profiles. METHODS: This retrospective cohort study was conducted by reviewing data from the national WD registry in France. Forty-three WD patients who received TETA 2HCL or TETA 4HCL monotherapy for at least one year until 2010 were included. The primary endpoints were hepatic and neurological outcomes. Secondary endpoints were the events leading to a discontinuation of medication. RESULTS: Changes in medication were common, leading to the analysis of 57 treatment sequences of TETA 4HCL or TETA 2HCL. The mean duration of treatment sequence was significantly longer in the TETA 4 HCL group (12.6 years) than in the TETA 2HCL group (7.6 years) (p = 0.011). Ten patients experienced both trientine salts: eight stopped TETA 4 HCL (six had a hepatologic phenotype and two had a neurological phenotype) because this treatment was not available anymore (mean duration 7.4 years). Three of these patients already experienced TETA 2 HCL before the sequence. Two patients with a hepatologic phenotype (one had a previous sequence of TETA 4 HCL before) stopped TETA 2 HCL because of cold storage issues (mean duration 42.8 years). The total number of sequences was 57. All of the patients were clinically stable. No difference in efficacy was detected. Both treatments were well tolerated, except for a case of recurrence of lupus erythematosus-like syndrome in the TETA 2HCL group. The major reason for interruption of TETA 4HCL was due to a discontinuation in production of this salt. The reasons for stopping TETA 2HCL were mainly due to adherence issues largely attributed to the cold storage requirement. CONCLUSIONS: The two salts of trientine were effective in treating patients with WD. However, interruption of TETA 2HCL was frequent, linked to the cold storage requirement. As adherence to treatment is a key factor in the successful management of WD, physicians need to be even more vigilant in detecting adherence difficulties in patients receiving treatment with TETA 2HCL.

Epidemiology, treatment and burden of Wilson disease in France: A 10-year analysis of the national health insurance database.

BACKGROUND & AIMS: Wilson disease (WD) is a rare hereditary, debilitating disease that is fatal if untreated. Given its low prevalence, collecting longitudinal information on large cohorts of patients is challenging. Analysis of health insurance databases offers an approach to meet this challenge. The aim of this study was to evaluate longitudinal trends in the presentation and management of patients with WD identified in the French national health insurance database (SNDS). METHODS: This retrospective, longitudinal, observational study identified people with WD in the SNDS database through hospitalisation diagnosis codes and long-term illness status between 2009 and 2019 inclusive. For each patient, data were extracted on hospitalisations, liver transplantation, mortality, WD-specific treatments (d-penicillamine, trientine and zinc), disability status and sick leave. RESULTS: 1,928 patients with WD were identified, of whom 1,520 (78.8%) were analysed. Prevalence of WD in 2019 was estimated as 2.2 cases per 100,000. Of the 670 patients first documented between 2010 and 2019, 76.1% were hospitalised at least once for a mean duration of 4.63±10.6 days. 152 patients (10.0%) underwent liver transplantation and 205 died (13.5%). The mean age at death was 57.9 ± 23.1 years. 665 patients (43.8%) received a WD-specific treatment at least once. 167 patients (17.1%) received a government disability pension and 624 (41.1%) benefited from long-term illness status due to WD. CONCLUSIONS: Unexpectedly, less than half of patients with WD received treatment recommended in practice guidelines, which may contribute to a high disease burden in terms of hospitalisations, disability and reduced life expectancy. Improving treatment rates, building patient awareness of long-term disease impact or developing a new paradigm of treatment could make a significant contribution to reducing the disease burden.

Chelation therapy in liver diseases of childhood: Current status and response.

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.