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Cognitive impairments affect millions of people worldwide with an increasing prevalence. Research on their etiology and treatment is developing, nevertheless significant gaps remain. Trientine (TETA), as a copper chelator, has been shown to have beneficial effects in different human chronic diseases such as diabetic cardiomyopathy and neuropathy. Here, we examined the impact of TETA on AlCl3-induced neurocognitive dysfunctions and molecular changes in the hippocampus of rats.Thirty-six male Wistar rats (weighing 200-250 g) were randomly divided into four groups including control, TETA (100 mg/kg/day), AlCl3 (100 mg/kg/day), and AlCl3 (100 mg/kg/day)+TETA (100 mg/kg/day), and received chemicals by gavage for 30 days. At the end of the treatment, the open field maze, elevated plus maze, novel object recognition memory test, and shuttle box test were done. Then after, brain-derived neurotrophic factor (BDNF), glycogen synthase kinase-3 β (GSK-3β), acetylcholinesterase activity, oxidative stress markers, and inflammatory mediators were measured in the hippocampus.AlCl3 increased anxiety-like behaviors and impaired recognition and short-term memory. TETA was able to improve AlCl3-induced anxiety-like behaviors and short-term memory dysfunction. In the AlCl3-treated group, there was a significant increase in GSK-3β, oxidative stress, pro-inflammatory and pro-apoptotic markers, and decreased BDNF in the hippocampus. Co-administration of TETA was able to decrease lipid peroxidation, inflammation, GSK-3β, and acetylcholinesterase activity, and increase BDNF in the hippocampus compared with AlCl3-treated rats.It can be concluded that TETA was able to improve neurobehavioral and neurocognitive functions by alleviating oxidative stress, inflammation, and pro-apoptotic pathways leading to the normalization of BDNF and GSK-3β., Competing Interests: Authors declare that there is no conflict of interest., (Thieme. All rights reserved.)

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., (© 2024. The Author(s).)

Background and Aims: Trientine (TRI) and D-penicillamine (PEN) are used to treat copper overload in Wilson disease. Their main mode of action is thought to be through the facilitation of urinary copper excretion. In a recent study, TRI was noninferior to PEN despite lower 24-hour urinary copper excretion than PEN. We tested whether TRI and/or PEN also inhibit intestinal copper absorption., Approach and Results: Sixteen healthy volunteers were examined with positron emission tomography (PET)/CT 1 and 15 hours after an oral Copper-64 ( 64 Cu) dose. They then received 7 days of either PEN or TRI (trientine tetrahydrochloride), after which the 64 Cu PET/CT scans were repeated. Venous blood samples were also collected. Pretreatment to posttreatment changes of the hepatic 64 Cu uptake reflect the effect of drugs on intestinal absorption. 64 Cu activity was normalized to dose and body weight and expressed as the mean standard uptake value. TRI (n=8) reduced hepatic 64 Cu activity 1 hour after 64 Cu dose from 6.17 (4.73) to 1.47 (2.97) standard uptake value, p <0.02, and after 15 hours from 14.24 (3.09) to 6.19 (3.43), p <0.02, indicating strong inhibition of intestinal 64 Cu absorption. PEN (n=8) slightly reduced hepatic standard uptake value at 15 hours, from 16.30 (5.63) to 12.17 (1.44), p <0.04., Conclusions: In this mechanistic study, we show that TRI inhibits intestinal copper absorption, in addition to its cupriuretic effect. In contrast, PEN has modest effects on the intestinal copper absorption. This may explain why TRI and PEN are equally effective although urinary copper excretion is lower with TRI. The study questions whether the same therapeutic targets for 24-hour urinary excretion apply to both drugs., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Neurological deterioration, soon after anti-copper treatment initiation, is problematic in the management of Wilson's disease (WD) and yet reports in the literature are limited. The aim of our study was to systematically assess the data according to early neurological deteriorations in WD, its outcome and risk factors., Methods: Using PRISMA guidelines, a systematic review of available data on early neurological deteriorations was performed by searching the PubMed database and reference lists. Random effects meta-analytic models summarized cases of neurological deterioration by disease phenotype., Results: Across the 32 included articles, 217 cases of early neurological deterioration occurred in 1512 WD patients (frequency 14.3%), most commonly in patients with neurological WD (21.8%; 167/763), rarely in hepatic disease (1.3%; 5/377), and with no cases among asymptomatic individuals. Most neurological deterioration occurred in patients treated with d-penicillamine (70.5%; 153/217), trientine (14.2%; 31/217) or zinc salts (6.9%; 15/217); the data did not allow to determine if that reflects how often treatments were chosen as first line therapy or if the risk of deterioration differed with therapy. Symptoms completely resolved in 24.2% of patients (31/128), resolved partially in 27.3% (35/128), did not improve in 39.8% (51/128), with 11 patients lost to follow-up., Conclusions: Given its occurrence in up to 21.8% of patients with neurological WD in this meta-analysis of small studies, there is a need for further investigations to distinguish the natural time course of WD from treatment-related early deterioration and to develop a standard definition for treatment-induced effects., (© 2023. The Author(s).)

Aims: Hypertrophic cardiomyopathy (HCM) is characterised by left ventricular hypertrophy (LVH), myocardial fibrosis, enhanced oxidative stress and energy depletion. Unbound/loosely bound tissue copper II ions are powerful catalysts of oxidative stress and inhibitors of antioxidants. Trientine is a highly selective copper II chelator. In preclinical and clinical studies in diabetes, trientine is associated with reduced LVH and fibrosis, and improved mitochondrial function and energy metabolism. Trientine was associated with improvements in cardiac structure and function in an open-label study in patients with HCM., Methods: The Efficacy and Mechanism of Trientine in Patients with Hypertrophic Cardiomyopathy (TEMPEST) trial is a multicentre, double-blind, parallel group, 1:1 randomised, placebo-controlled phase II trial designed to evaluate the efficacy and mechanism of action of trientine in patients with HCM. Patients with a diagnosis of HCM according to the European Society of Cardiology Guidelines and in New York Heart Association classes I-III are randomised to trientine or matching placebo for 52 weeks. Primary outcome is change in left ventricular (LV) mass indexed to body surface area, measured using cardiovascular magnetic resonance. Secondary efficacy objectives will determine whether trientine improves exercise capacity, reduces arrhythmia burden, reduces cardiomyocyte injury, improves LV and atrial function, and reduces LV outflow tract gradient. Mechanistic objectives will determine whether the effects are mediated by cellular or extracellular mass regression and improved myocardial energetics., Conclusion: TEMPEST will determine the efficacy and mechanism of action of trientine in patients with HCM., Trial Registration Numbers: NCT04706429 and ISRCTN57145331., Competing Interests: Competing interests: Relationships with industry are as follows: Univar Solutions B.V. has gifted the investigational medicinal product. Univar Solutions B.V. have had no role in trial design, the preparation or approval of this manuscript, and the decision to submit the manuscript for publication. Univar Solutions B.V. conducted a factual accuracy check of this manuscript, but any decisions to incorporate comments were made solely at the discretion of the authors. BR is advisor for Axcella Therapeutics and patent inventor of a new oxygen sensitive MRI approach USPTO, Serial No. 16/674,104, Nov 5, 2019 Serial No. GB 1818147.9, Nov 7, 2018. CAM has served as an advisor for AstraZeneca, Boehringer Ingelheim and Lilly Alliance, Novartis, PureTech Health and HAYA Therapeutics; and has received research support from Amicus Therapeutics, Guerbet Laboratories Limited and Roche., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

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.

Background: The main mechanism underlying cancer dissemination is the epithelial to mesenchymal transition (EMT). This process is orchestrated by cytokines like TGFβ, involving "non-canonical" AKT- or STAT3-driven pathways. Recently, the alteration of copper homeostasis seems involved in the onset and progression of cancer., Methods: We expose different breast cancer cell lines, including two triple negative (TNBC) ones, an HER2 enriched and one cell line representative of the Luminal A molecular subtype, to short- or long-term copper-chelation by triethylenetetramine (TRIEN). We analyse changes in the expression of EMT markers (E-cadherin, fibronectin, vimentin and αSMA), in the levels and activity of extracellular matrix components (LOXL2, fibronectin and MMP2/9) and of copper homeostasis markers by Western blot analyses, immunofluorescence, enzyme activity assays and RT-qPCR. Boyden Chamber and wound healing assays revealed the impact of copper chelation on cell migration. Additionally, we explored whether perturbation of copper homeostasis affects EMT prompted by TGFβ. Metabolomic and lipidomic analyses were applied to search the effects of copper chelation on the metabolism of breast cancer cells. Finally, bioinformatics analysis of data on breast cancer patients obtained from different databases was employed to correlate changes in kinases and copper markers with patients' survival., Results: Remarkably, only HER2 negative breast cancer cells differently responded to short- or long-term exposure to TRIEN, initially becoming more aggressive but, upon prolonged exposure, retrieving epithelial features, reducing their invasiveness. This phenomenon may be related to the different impact of the short and prolonged activation of the AKT kinase and to the repression of STAT3 signalling. Bioinformatics analyses confirmed the positive correlation of breast cancer patients' survival with AKT activation and up-regulation of CCS. Eventually, metabolomics studies demonstrate a prevalence of glycolysis over mitochondrial energetic metabolism and of lipidome changes in TNBC cells upon TRIEN treatment., Conclusions: We provide evidence of a pivotal role of copper in AKT-driven EMT activation, acting independently of HER2 in TNBC cells and via a profound change in their metabolism. Our results support the use of copper-chelators as an adjuvant therapeutic strategy for TNBC., (© 2022. The Author(s).)

A 7 yr old castrated male Cavalier King Charles spaniel presented for evaluation of liver enzyme elevations. Abdominal ultrasound revealed a small liver with mixed echogenicity, small hypoechoic nodules, and an irregular surface. Histologic examination and copper quantification of the liver obtained by laparoscopy diagnosed copper-associated hepatitis. One month later the dog developed hyperkeratosis of all four foot pads and ulcerations of feet, legs, and rectum. Punch biopsies confirmed superficial necrolytic dermatitis. After a total of 2 mo of chelation with no changes to medications, skin lesions began to improve, continuing over the following 6 wk to almost complete resolution. At this point the skin lesions returned and had minimal response to four amino acids infusions. The dog was switched from penicillamine to trientine. Zinc acetate was initiated 6 wk after the switch to trientine, and skin improvement was noted soon thereafter. At the time of death, skin lesions were improving and the dog was clinically comfortable. Copper-associated hepatitis should be considered as a possible etiology for superficial necrolytic dermatitis. Treatment of superficial necrolytic dermatitis is often unrewarding, and copper chelation, when copper-associated hepatitis has been confirmed, represents another therapeutic option., (© 2022 by American Animal Hospital Association.)

Researchers continue to explore drug targets to treat the characteristic pathologies of Alzheimer's disease (AD). Some drugs relieve the pathological processes of AD to some extent, but the failed clinical trials indicate that multifunctional agents seem more likely to achieve the therapy goals for this neurodegenerative disease. Herein, a novel compound named melatonin-trientine (TM) has been covalently synthesized with the natural antioxidant compounds melatonin and the metal ion chelator trientine. After toxicological and pharmacokinetic verification, we elucidated the effects of intraperitoneal administration of TM on AD-like pathology in 6-month-old mice that express both the β-amyloid (Aβ) precursor protein and presenilin-1 (APP/PS1). We found that TM significantly decreased Aβ deposition and neuronal degeneration in the brains of the APP/PS1 double transgenic mice. This result may be due to the upregulation of iron regulatory protein-2 (IRP2), insulin degrading enzyme (IDE), and low density lipoprotein receptor related protein 1 (LRP1), which leads to decreases in APP and Aβ levels. Additionally, TM may promote APP non-amyloidogenic processing by activating the melatonin receptor-2 (MT2)-dependent signaling pathways, but not MT1. In addition, TM plays an important role in blocking γ-secretase, tau hyperphosphorylation, neuroinflammation, oxidative stress, and metal ion dyshomeostasis. Our results suggest that TM may effectively maximize the therapeutic efficacy of targeting multiple mechanisms associated with AD pathology., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The silver anniversary of the discovery of the Wilson disease gene ATP7B was a couple of years ago, and we continue to make progress both in our understanding of copper transportation using animal models as well as earlier diagnosis by availing of genetic testing. Wilson disease is multisystemic and the hepatic manifestations are seen more frequently in childhood, whereas neurologic manifestations are more common in adults; presentation may range from subtle changes to end-stage liver disease with or without encephalopathy as well as neuropsychiatric manifestations. Treatment remains with zinc and chelating agents such as D-penicillamine and trientine but newer agents and gene therapy are in clinical trials. Liver transplantation becomes necessary when medical therapy is not enough. Molecular diagnosis and genetic counseling is important., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Wilson's disease (WD), a rare genetic disorder responsible for copper accumulation in the body, is fatal if left untreated. Although there are effective treatments, adherence to treatment tends to be low. We evaluated the medication adherence of 139 patients using the Morisky scale. Adherence was correlated with age at diagnosis and at inclusion in the study, the form of the disease, the treatment, the duration of treatment, delivery and storage problems, depression, anxiety, the level of education, and the biological data. 32.4% of the patients had low adherence; their levels of exchangeable copper were significantly higher than those of the patients with high or medium adherence (P = .049). The average age of the patients at the time of the study was significantly higher in those with high adherence than in those with medium or low adherence (P = .043). 75.9% of the patients with high adherence had a neurological form and 26.7% of the patients with low adherence were asymptomatic (P = .0090). The duration of treatment was significantly longer in the patients with high adherence than in those with medium or low adherence (P = .0192). The type of treatment (chelators or zinc) had no impact on the level of adherence. Forty-four percent of the patients experienced problems dispensing and storing medications. Despite the availability of effective treatments for this rare disease, adherence problems occur with Wilson's disease in particular in asymptomatic patients. Although different factors are involved, sustained multidisciplinary management on a case-by-case basis is necessary., (© 2021 SSIEM.)

The bis-Schiff base of N,N'-1,10-bis(naringin) triethylenetetraamine (1) was prepared, as a copper(II) ion chelator, compound 1 was used for Alzheimer's disease therapy in vitro. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay of compound 1 showed that this Schiff base could promote PC12 cells proliferation, and also, compound 1 could inhibit Cu 2+ -amyloid-β (Aβ) 1-42 mediated cytotoxicity on PC12 cells. The thioflavine T (ThT) assay showed that 1 can effectively attenuate Cu 2+ -induced Aβ 1-42 aggregation. In addition, compound 1 is determined to be potent antioxidants on the basis of in vitro antioxidant assay, it can effectively decease the level of reactive oxygen species (ROS) in Cu 2+ -Aβ 1-42 -treated PC12 cells and elevate the superoxide dismutase (SOD) activity in Cu 2+ -Aβ 1-42 -treated PC12 cells. The results show that N,N'-1,10-bis(naringin) triethylenetetraamine is a potential agent for therapy of Alzheimer's disease.

Introduction:  In this article, the prevalence of the Morbus Wilson disease in Germany is determined. This is based on nationwide data of drug prescriptions and contractional data of outpatient offices. The prevalence is set in ratio to the found prevalence of prescriptions in Germany., Method:  The descriptive evaluation is based on the database of the Central Research Institute of Ambulatory Health Care (Zi) in Germany. Additionally, data of the Federal Office of Statistics regarding inpatient treatment are available., Results:  It can be seen that there is a notable difference between the prevalence of patients undergoing therapy and the patients with verified diagnoses. In total, prevalence is increasing. The incidence on hand and the given dynamic of the patient population could indicate that, possibly, there is an increased rate of misdiagnosis in the first year of diagnosis. According to data, the hepatic form is the more often diagnosed form. The human genetic diagnostic increases, on average, are most distinct., Attributes:  Wilson Disease, Prevalence, Incidence, Trientine, Trientintetrahydrochlorid, D-Penicillamin, Zinc acetat, Zinc., Competing Interests: KHW ist in beratender oder sprechender Tätigkeit für Alexion, Univar BV, GMP-orphan, Vivet therapeutics, Ultragenyx, Eisai, Chiesi, Novartis, Bayer tätig., (Thieme. All rights reserved.)

Idiopathic copper toxicosis (ICT) is characterized by marked copper deposition, Mallory-Denk body (MDB) formation and severe hepatic injury. Although the characteristics are apparently different from Wilson disease, large amounts of copper accumulate in the liver of the patients. We extensively treated a patient with ICT to reduce the body copper, however, the patient needed liver transplantation. Previous liver biopsy revealed high copper content. But extirpated liver contained an extremely small amount of copper, although MDBs and severe inflammation remained. These phenomena suggest abnormal copper metabolism is not the principle cause of ICT but some other abnormality must exist.

Background & Aims: Wilson disease (WD) is a rare disorder of copper metabolism. The objective of this systematic review was to determine the comparative effectiveness and safety of common treatments of WD., Methods: We included WD patients of any age or stage and the study drugs D-penicillamine, zinc salts, trientine and tetrathiomolybdate. The control could be placebo, no treatment or any other treatment. We included prospective, retrospective, randomized and non-randomized studies. We searched Medline and Embase via Ovid, the Cochrane Central Register of Controlled Trials, and screened reference lists of included articles. Where possible, we applied random-effects meta-analyses., Results: The 23 included studies reported on 2055 patients and mostly compared D-penicillamine to no treatment, zinc, trientine or succimer. One study compared tetrathiomolybdate and trientine. Post-decoppering maintenance therapy was addressed in one study only. Eleven of 23 studies were of low quality. When compared to no treatment, D-penicillamine was associated with a lower mortality (odds ratio 0.013; 95% CI 0.0010 to 0.17). When compared to zinc, there was no association with mortality (odds ratio 0.73; 95% CI 0.16 to 3.40) and prevention or amelioration of clinical symptoms (odds ratio 0.84; 95% CI 0.48 to 1.48). Conversely, D-penicillamine may have a greater impact on side effects and treatment discontinuations than zinc., Conclusions: There are some indications that zinc is safer than D-penicillamine therapy while being similarly effective in preventing or reducing hepatic or neurological WD symptoms. Study quality was low warranting cautious interpretation of our findings., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Urinary copper excretion rates and non-caeruloplasmin associated copper concentrations are increased in patients with Wilson disease. However, there is little literature describing the monitoring of these parameters over the long term., Methods: This is a monocentric retrospective study including data collected between 2003 and 2015 from 321 patients with Wilson disease by chart review. The patients were under therapy with D-penicillamine, trientine, or zinc. 24-h urinary copper excretion rates, non-caeruloplasmin associated copper, and total serum copper concentrations were determined at the start of therapy, as well as 6, 12, 18, 24, 36, and ≥ 60 months after the start of therapy. For patients taking chelating agents, all parameters were measured while under continued therapy, as well as after a 48-h dose interruption. A mathematical formula to predict 24-h urinary copper excretion rates under different therapies was established., Results: In all treatment groups, urinary copper excretion rates decreased over time, but the inter-individual variation of the results was high. Non-caeruloplasmin associated copper concentrations tended to decline over time, but with a higher variation of results than that observed for urinary copper excretion rates., Conclusion: Due to their variability, urinary copper excretion rates and serum copper concentrations are less than ideal parameters by which to monitor the benefit of a copper-reducing therapy. Urinary copper excretion rates seem to be more suitable than non-caeruloplasmin associated copper concentrations for this purpose., (© 2018 SSIEM.)

Immunoglobulin A nephropathy is the most common primary glomerulonephritis worldwide, and it can be associated with liver disease. However, cases of Immunoglobulin A nephropathy secondary to Wilson's disease are very rare. A 20-year-old Japanese man presented with microscopic hematuria, proteinuria, and renal dysfunction. A renal biopsy showed mesangial cell proliferation, immunoglobulin A deposition, and electron-dense deposit in the mesangial areas, all of which are consistent with Immunoglobulin A nephropathy. Computed tomography of the abdomen showed liver atrophy and splenomegaly, and the diagnosis of Wilson's disease was confirmed with decreased serum ceruloplasmin levels, increased urinary copper excretion, Kayser-Fleischer rings and copper deposition in the liver biopsy. The patient was treated successfully with trientine hydrochloride and zinc acetate and showed improvement in renal manifestations. Wilson's disease is a rare cause of secondary Immunoglobulin A nephropathy. We recommend that Wilson's disease should be considered the cause of secondary Immunoglobulin A nephropathy in juvenile patients with hematuria, proteinuria, and splenomegaly and suggest measuring the serum ceruloplasmin concentrations, urinary copper excretion, and evaluating Kayser-Fleischer rings in these patients.

Background/purpose: This study aimed to investigate the epidemiology, the preference of medication, and the potential outcome of Wilson disease in Taiwan. We aimed to provide better therapeutic options for patients with Wilson disease based on the data generated from this study., Methods: We utilized the National Health Insurance Research Database (NHIRD), which stores clinical records of nearly 99% of Taiwan's residents. The database used is a random sample of two-million out of 23-million beneficiaries in Taiwan's NHIRD in 2005. The integrated medical records of these two-million cases were collected from 2000 to 2011. Subjects of Wilson disease were identified as those with International Classification of Diseases, Ninth Revision (ICD-9) code 275.1 and the specific prescription drugs (including d-penicillamine, zinc, and trientine) in either outpatient clinic or inpatient records., Results: During the study period, 66 cases of Wilson disease were identified. The male to female ratio was 1.75. The average prevalence rate was 1.81 per 100,000 and the average annual diagnosis rate was 0.22 per 100,000. The diagnosis was mostly established at 20-24 and 10-14 years of age, followed by 25-29 years. Fifty four of all subjects (81.8%) started the treatment with d-penicillamine, compared with zinc (12.1%) and trientine (6.1%). Among these 66 cases, 27 (40.9%) had liver cirrhosis and three (4.5%) underwent liver transplantation due to liver failure., Conclusion: d-penicillamine is still the most popular prescription of Wilson disease, followed by zinc monotherapy. Although chronic liver injury cannot be avoided, a favorable potential outcome is well demonstrated in this population-based study., (Copyright © 2017. Published by Elsevier B.V.)

Wilson's disease (WD) is a rare inherited disorder of copper metabolism causing toxic hepatic and neural copper accumulation. Clinical symptoms vary widely, from asymptomatic disease to acute liver failure or chronic liver disease with or without neuropsychiatric symptoms. Continuation of specific medical treatment for WD is recommended during pregnancy, but reports of pregnancy outcomes in WD patients are sparse. In a retrospective, multicenter study, 282 pregnancies in 136 WD patients were reviewed. Age at disease onset, age at conception, and WD-specific treatments were recorded. Maternal complications during pregnancy, rate of spontaneous abortions, and birth defects were analyzed with respect to medical treatment during pregnancy. Worsening of liver function tests was evident during 16 of 282 (6%) pregnancies and occurred in undiagnosed patients as well as in those under medical treatment. Liver test abnormalities resolved in all cases after delivery. Aggravation of neurological symptoms during pregnancy was rare (1%), but tended to persist after delivery. The overall spontaneous abortion rate in the study cohort was 73 of 282 (26%). Patients with an established diagnosis of WD receiving medical treatment experienced significantly fewer spontaneous abortions than patients with undiagnosed WD (odds ratio, 2.853 [95% confidence interval, 1.634-4.982]). Birth defects occurred in 7 of 209 (3%) live births., Conclusion: Pregnancy in WD patients on anticopper therapy is safe. The spontaneous abortion rate in treated patients was lower than that in therapy-naïve patients. Although the teratogenic potential of copper chelators is a concern, the rate of birth defects in our cohort was low. Treatment for WD should be maintained during pregnancy, and patients should be monitored closely for hepatic and neurological symptoms. (Hepatology 2018;67:1261-1269)., (© 2017 by the American Association for the Study of Liver Diseases.)

Consideration of a diagnosis of Wilson disease is still the critical factor in testing for and establishing disease diagnosis. In association with other clinical and biochemical tests, liver biopsy results and molecular genetic testing can also be used to generate a score for diagnosing Wilson disease. Medical therapy is effective for most patients; liver transplant can rescue those with acute liver failure or those with advanced liver disease who fail to respond to or discontinue medical therapy. Treatment monitoring must be done at regular intervals and includes clinical evaluation, liver tests and blood counts, and copper metabolic parameters., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Wilson disease (WD) is a genetic disorder of copper metabolism that can be treated successfully with pharmacologic treatment. Two groups of drugs are currently used: chelators (e.g., d-penicillamine and trientine), which increase urinary copper excretion, and zinc salts, which inhibit copper absorption in the digestive tract. The mechanisms of action lead to a negative copper balance, stopping pathologic accumulation of copper in the tissues and clearing affected organs of copper overload. Due to a lack of prospective clinical trials, the use of drugs depends mainly on center experience and the accessibility in different countries or regions. This chapter presents the different reports and recommendations regarding WD treatment. In addition to the different expert opinions on pharmacologic agents, there are a few axioms regarding WD treatment: treatment should start immediately after diagnosis, even in clinically presymptomatic cases; the patient should be treated for life, making compliance a key factor in treatment success; and the treatment should be monitored regularly via liver and hematologic tests, neurologic examination, and copper metabolism, modifying the treatment accordingly. Other drugs proposed for WD treatment (e.g., tetrathiomolybdate) are in clinical trials and lack current recommendations. Thus, only the currently available options for WD pharmacologic treatment are discussed., (© 2017 Elsevier B.V. All rights reserved.)

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.

Continuation of treatment is recommended for pregnant women with Wilson disease. Therapy options include the copper chelating agents d-penicillamine and trientine. However, there are still uncertainties concerning a possible teratogenic risk. In this case series, we report on the outcome of 20 pregnancies with maternal chelator exposure at least during the first trimester. Of these 20 pregnancies documented by the German Embryotox Project, 14 were prospectively ascertained and 6 were retrospective. No major birth defects were observed. Three of the 14 prospective cases resulted in a spontaneous abortion, and one pregnancy was electively terminated. Our results do not support the hypothesis of teratogenicity based on earlier case reports of congenital anomalies. Therefore our study may contribute to reassure women needing chelation therapy during pregnancy. However, it must be taken into account that the sample size of this case series is too limited to make final conclusions on teratogenic effects., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Extrapyramidal signs are neurological dysfunction commonly associated with Wilson's disease (WD). In addition, cognitive dysfunction has been reported in the early stages of WD. In this report, we describe a 49-year-old woman presenting with memory impairments and without Parkinsonian or extrapyramidal signs. She was diagnosed with WD based on the presence of Kayser-Fleischer rings around the irises of her eyes and two ATP7B gene mutations, R778L at exon 8 and A874V at exdyon 11. Serial magnetic resonance imaging analysis and neuropsychological tests showed improvements following treatment with trientine.

Background and Aims: Current guidelines favor the use of chelating agents (d-penicillamine, trientine) in first line therapy of symptomatic Wilson disease patients. Development of chelator induced immunological adverse events are a concern especially under d-penicillamine therapy. This study assessed the prevalence of co-existing or therapy-related immune-mediated diseases in Wilson disease patients, and evaluated the role of antinuclear antibodies in therapy monitoring., Methods: We retrospectively analyzed 235 Wilson disease patients. Medical regimens were classified and analyzed in relation to adverse events and antinuclear antibody courses., Results: Coexisting immune-mediated diseases were evident in 19/235 (8.1%) patients, of which 13/235 (5.5%) had pre-existing autoimmune diseases. Six patients (2.6%) developed an autoimmune disease under therapy, all of them under long-term d-penicillamine treatment. Data relating to antinuclear antibody courses during treatment and adverse events were available for patients treated with d-penicillamine (n = 91), trientine (n = 58), and zinc salts (n = 58). No significant increase in antinuclear antibody titers in patients treated with d-penicillamine (16/91; 17.6%), trientine (12/58; 20.7%), and zinc (7/58; 12.1%) were found., Conclusion: Under long-term d-penicillamine therapy a minority of patients developed immune-mediated disease. Elevations in antinuclear antibodies were found frequently, but no correlations were evident between increases in antinuclear antibodies and the development of immune-mediated diseases or medical regimes. Thus, the value of antinuclear antibodies for monitoring adverse events under chelator therapy seems to be limited.

Wilson's disease (WD), also called hepatolenticular degeneration, is an autosomal recessive inheritance disorder of copper metabolism characterized by the multiple mutations in the ATP-ase 7B gene of chromosome 13q. About half of the WD patients have neurological or psychiatric symptoms. As WD is a kind of medicable or nearly curable neurodegenerative disease in the field of medicine, early consideration/examination and without delay/ life-long treatment usually lead to better prognoses. The drugs, also named as anticopper agents, are commonly used in clinics including D-penicillamine, trientine, sodium dimercaptosuccinate, dimercaptosuccinic acid, zinc and tetrathiomolybdate. This provides detailed reviews about these medicines.

Background & Aims: Wilson disease (WD) is an autosomal recessive disorder of copper metabolism. Alterations of copper metabolism have been associated with changes in coagulation factors. The aim of the present study was the analysis of coagulation factors in WD patients., Methods: 100 patients attending a tertiary WD outpatient clinic were analyzed in a prospective cross sectional cohort study. Out of peripheral venous blood samples coagulation factors were assessed including: full blood count, INR, partial thromboplastin time (PTT), clotting factors II, V, VII, VIII, IX, X, XI, XII, XIII, von Willebrand factor/-antigen, fibrinogen, antithrombin III, protein S, protein C, activated protein C (APC) resistance. Subgroup analyses of the blood tests were performed for sex, initial clinical presentation, WD treatment and liver function., Results: Subgroup analysis by liver function showed decreased levels of factors II, V, VII and X. Subgroup analysis by gender or clinical course of the disease did not reveal significant coagulation changes. In patients treated with trientine significantly decreased levels of factors II, VII and antithrombin III and increased von Willebrand factor/-antigen levels were detected. Factor VIII levels were significantly reduced in patients receiving zinc., Conclusion: Although significant differences of some coagulation parameters in subgroup analysis were found, no clinically relevant alterations of the coagulation system in WD patients could be detected.

A 37-year-old male patient presented with psychiatric symptoms, dysarthria, limb dystonia, increased tendon reflexes, and a Kayser-Fleischer ring in his late teens. Laboratory examinations showed decreased concentrations of serum copper and ceruloplasmin, and increased urinary copper levels. Magnetic resonance imaging (MRI) showed high-signal-intensity lesions in the bilateral putamen, globus pallidus, thalamus, and brainstem on T2-weighted images (T2WI). Based on the MRI results and laboratory data, we diagnosed this patient with Wilson's disease (WD). He was treated with trientine hydrochloride and zinc acetate. Four months after the initiation of treatment, the patient'symptoms began to improve. On a follow-up MRI that was obtained 6 years after treatment, the high-signal-intensity lesions on the T2WI had disappeared completely. However, the low-signal-intensity lesions in the basal ganglia had spread to the caudate nuclei. Here, we discuss the characteristics of the MRI changes in WD following treatment. The Pathological basis for the low-signal-intensity lesions on T2WI in WD remains unclear. Our results suggest that this lesion may reflect the accumulation of materials other than copper.

The present review provides an update of the general principles for the investigation and use of chelating agents in the treatment of intoxications by metals. The clinical use of the old chelators EDTA (ethylenediamine tetraacetate) and BAL (2,3-dimercaptopropanol) is now limited due to the inconvenience of parenteral administration, their own toxicity and tendency to increase the neurotoxicity of several metals. The hydrophilic dithiol chelators DMSA (meso-2,3-dimercaptosuccinic acid) and DMPS (2,3-dimercapto-propanesulphonate) are less toxic and more efficient than BAL in the clinical treatment of heavy metal poisoning, and available as capsules for oral use. In copper overload, DMSA appears to be a potent antidote, although d-penicillamine is still widely used. In the chelation of iron, the thiols are inefficient, since iron has higher affinity for ligands with nitrogen and oxygen, but the new oral iron antidotes deferiprone and desferasirox have entered into the clinical arena. Comparisons of these agents and deferoxamine infusions are in progress. General principles for research and development of new chelators are briefly outlined in this review., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

In the present review we provide an update of the appropriate use of chelating agents in the treatment of intoxications with compounds of mercury, lead and copper. The relatively new chelators meso-2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercapto-propanesulphonate (DMPS) can effectively mobilize deposits of mercury as well as of lead into the urine. These drugs can be administered orally and have relatively low toxicity compared to the classical antidote dimercaptopropanol (BAL). d-Penicillamine has been widely used in copper overload, although 2,3-dimercaptosuccinic acid or tetrathiomolybdate may be more suitable alternatives today. In copper-toxicity, a free radical scavenger might be recommended as adjuvant to the chelator therapy., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Wilson's disease is a genetic disorder caused by a malfunction of ATPase 7B that leads to high accumulation of copper in the organism and consequent toxic effects. We propose a gentle therapy to eliminate the excessive copper content with oral administration of insoluble non-resorbable polymer sorbents containing selective chelating groups for copper(II). Polymeric beads with the chelating agents triethylenetetramine, N,N-di(2-pyridylmethyl)amine, and 8-hydroxyquinoline (8HQB) were investigated. In a preliminary copper uptake experiment, we found that 8HQB significantly reduced copper uptake (using copper-64 as a radiotracer) after oral administration in Wistar rats. Furthermore, we measured organ radioactivity in rats to demonstrate that 8HQB radiolabelled with iodine-125 is not absorbed from the gastrointestinal tract after oral administration. Non-resorbability and the blockade of copper uptake were also confirmed with small animal imaging (PET/CT) in mice. In a long-term experiment with Wistar rats fed a diet containing the polymers, we have found that there were no signs of polymer toxicity and the addition of polymers to the diet led to a significant reduction in the copper contents in the kidneys, brains, and livers of the rats. We have shown that polymers containing specific ligands could potentially be novel therapeutics for Wilson's disease., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Wilson's disease is an autosomal recessively inherited copper overload disorder that leads to hepatic and/or neurologic symptoms. More than a century after the first description of Wilson's disease, the available medical treatment options have not been standardized. The efficacy of the commonly used drugs is satisfactory for hepatic disease, but disappointing in the neurologic patients, including the risk of neurologic deterioration after the initiation of chelation therapy. An approach to overcome this problem is the careful and systematic assessment of biochemical response patterns and the quantitative monitoring of symptoms using validated rating scales. Standardized dosage strategies that address changes in copper pools might improve adherence and reduce side effects. Such an approach may reduce long-term morbidity. In this paper, we discuss considerations for an effective medical treatment and requirements for future studies in Wilson's disease., (© 2014 New York Academy of Sciences.)

Hereditary hemochromatosis and Wilson disease are autosomal recessive storage disorders of iron and copper overload, respectively. These metals are involved in multiple redox reactions, and their abnormal accumulation can cause significant injury in the liver and other organs. Over the last few decades clinicians have developed a much better understanding of these metals and their mechanism of action. Moreover, sophisticated molecular genetic testing techniques that make diagnostic testing less invasive are now available. This article updates and discusses the pathogenesis, diagnosis, and management of these metal storage disorders., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aims: There is mounting evidence that the transition metal copper may play an important role in the pathophysiology of Alzheimer's disease (AD). Triethylene tetramine dihydrochloride (trientine), a CuII-selective chelator, is a commonly used treatment for Wilson's disease to decrease accumulated copper, and thereby decreases oxidative stress. In the present study, we evaluated the effects of a 3-month treatment course of trientine (Trien) on amyloidosis in 7-month-old β-amyloid (Aβ) precursor protein and presenilin-1 (APP/PS1) double transgenic (Tg) AD model mice., Results: We observed that Trien reduced the level of advanced glycation end products (AGEs), and decreased Aβ deposition and synapse loss in brain of APP/PS1 mice. Importantly, we found that Trien blocked the receptor for AGEs (RAGE), downregulated β-site APP cleaving enzyme 1 (BACE1), inhibited amyloidogenic APP cleavage, and subsequently reduced Aβ levels. In vitro, in SH-SY5Y cells overexpressing Swedish mutant APP, Trien-mediated downregulation of BACE1 occurred via inhibition of the NF-κB signaling pathway., Innovation: In this study, we demonstrated for the first time that Trien inhibited amyloidogenic pathway including targeting the downregulation of RAGE and NF-κB., Conclusion: Trien might mitigate amyloidosis in AD by inhibiting the RAGE/NF-κB/BACE1 pathway. Our study demonstrates that Trien may be a viable therapeutic strategy for the intervention and treatment of AD and other AD-like pathologies.

Wilsons disease is an autosomal recessive genetic disorder in which copper accumulates in tissues, especially in the liver and the brain. The genetic defect affects the P type ATPase gene (ATP7B). More than 500 mutations causing Wilsons disease have been described. The most common mutation in Central Europe concerns H1069Q. The symptoms of Wilsons disease include hepatic or neurological conditions. The hepatic condition is manifested as steatosis, acute or chronic hepatitis or cirrhosis. The neurological conditions are most often manifested after the age of 20 as motor disorders (tremor, speech and writing disorders), which may result in severe extrapyramidal syndrome with rigidity, dysarthria and muscle contractions. The dia-gnosis is based on clinical and laboratory assessments (neurological signs, liver lesions, low ceruloplasmin, increased free serum copper, high Cu volumes in urine, KayserFleischer ring). The dia-gnosis is confirmed by a high Cu level in liver tissue or genetic proof. Untreated Wilsons disease causes death of the patient. If treated properly the survival rate approximates to the survival rate of the common population. The treatment concerns either removal of copper from the body using chelating agents excreted into the urine (Penicillamine, Trientine) or limitation of copper absorption from the intestine and reducing the toxicity of copper (zinc, ammonium tetrathiomolybdate). In the Czech Republic, Penicillamine or zinc is used. A liver transplant is indicated in patients with fulminant hepatic failure or decompensated liver cirrhosis. In the family all siblings of the affected individual need to be screened in order to treat any asymptomatic subjects.

Trientine (triethylenetetramine dihydrochloride) is a copper-chelating agent used to treat patients with Wilson's disease (WD). It has been considered safe, rarely causing neurological deterioration during initial treatment. We describe a patient diagnosed with WD who became neurologically disabled after treatment with trientine. On a fluid attenuated inversion recovery sequence, brain MRI showed increased areas of high signal intensity compared with initial brain MRI. The patient's neurological signs partially resolved after cessation of trientine treatment. Our findings suggest that treatment with trientine is associated with a risk of neurological deterioration in patients with WD., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Defective copper regulation is implicated as a causative mechanism of organ damage in diabetes. Treatment with trientine, a divalent-copper-selective chelator, improves arterial and renal structure/function in diabetes, wherein it also ameliorates left-ventricular (LV) hypertrophy. However, direct in vivo evidence that trientine can improve cardiac function in heart failure has hitherto been lacking., Methods: To determine whether trientine treatment could improve in vivo outcome, we measured cardiac function in groups of trientine-treated diabetic (TETA-DIA), non-drug-treated diabetic (DIA) and sham-treated control (SHAM) rats, by using in vivo high-field cardiac magnetic-resonance imaging (cMRI) and an ex vivo isolated-perfused working heart method. Forty age-matched animals underwent a cMRI scan after which 12 were randomized to the SHAM group and 28 underwent streptozotocin-injection; of these, 25 developed stable diabetes, and 12 were then randomized to receive no treatment for 16 weeks (DIA) and the other 13 to undergo 8-weeks' untreated diabetes followed by 8-weeks' drug treatment (TETA-DIA). Animals were studied again by cMRI at 8 and 16 weeks following disease induction, and finally by measurement of ex vivo cardiac function., Results: After eight weeks diabetes, rats (DIA/TETA-DIA) had developed significant impairment of LV function, as judged by impairment of ejection fraction (LVEF), cardiac output (CO), and LV mass (LVM)/body-mass (all P < 0.001), as well as other functional indexes. LVEF, CO (both P < 0.001) and the other indexes deteriorated further at 16 weeks in DIA, whereas trientine (TETA-DIA) improved cardiac function by elevating LVEF and CO (both P < 0.001), and also partially reversed the increase in LVM/body-mass (P < 0.05). In ex vivo hearts from DIA, the CO response to increasing preload pressure was deficient compared with SHAM (P < 0.001) whereas the preload-CO relationship was significantly improved in TETA-DIA animals (P < 0.001)., Conclusions: Trientine treatment significantly improved cardiac function in diabetic rats with substantive LV impairment. These results implicate impaired copper regulation in the pathogenesis of impaired cardiac function caused by diabetic cardiomyopathy, and support ongoing studies of trientine treatment in patients with heart failure.

Children with both headache and hypertension present a relatively rare condition with a broad range of differential diagnoses in pediatric emergency medicine. Some possible diagnoses are potentially life-threatening conditions and merit aggressive evaluation management. We report a case of a 14-year-old girl who presented with headache and hypertension. She responded poorly to medical treatment and subsequently developed anxiety and difficulties with concentration. Three months later, she visited our ophthalmology department because of blurred vision. Ophthalmic evaluation revealed bilateral Kayser-Fleischer rings. Finally, she was diagnosed with Wilson disease. This case emphasizes that children with headache and hypertension merit aggressive evaluation and management.

Wilson's disease is a rare autosomal recessive disease characterised by the deposition of copper in the brain, liver; cornea, and other organs. The overload of copper inevitably leads to progressive liver and neurological dysfunction. Copper overload in patients with Wilson's disease is caused by impairment to the biliary route for excretion of dietary copper A combination of neurological, psychiatric and hepatic symptoms can make the diagnosis of Wilson's disease challenging. Most symptoms appear in the second and third decades of life. The disease affects between one in 30,000 and one in 100,000 individuals, and is fatal if left untreated. Five drugs are currently available to treat Wilson's disease: British Anti-Lewisite; D-penicillamine; trientine; zinc sulfate or acetate; and ammonium tetrathiomolybdate. Each drug can reduce copper levels and/or transform copper into a metabolically inert and unavailable form in the patient. The discovery and introduction of these five drugs owes more to the inspiration of a few dedicated physicians and agricultural scientists than to the resources of the pharmaceutical industry.

Background/aims: Wilson's disease (WD) is a rare inborn disease related to copper storage, leading to liver cirrhosis and neuropsychological deterioration. The aim of this study was to determine the clinical presentation and long-term outcome, and to examine the progression of hepatic histopathology in serial liver biopsies from WD patients., Materials and Methods: We carried out a retrospective analysis of 60 patients with WD treated with zinc and/or penicillamine. Demographic, clinical, and laboratory data were gathered and 40 patients underwent an initial biopsy and at least one repeat biopsy. Patients were divided into two groups: progressors (patients who presented worsening of at least one unit of fibrosis) and nonprogressors (patients who presented stable or improved fibrosis scores)., Results: A total of 33/40 (83%) patients (nonprogressors) showed stable hepatic histology or improvement. Seven of 40 (17%) patients (progressors) showed worsening of fibrosis. There was no significant correlation between the histological findings and clinical parameters or initial presentation., Conclusion: In our study cohort, liver disease was stable or improving in most of the patients, and development of progressive hepatic symptoms while under treatment was a rare event. The development of new symptoms while under treatment or progression of pre-existing symptoms was more often recorded for neurological than for hepatic symptoms.

As Wilson's disease is both preventable and treatable, the diagnosis must not be missed. Despite this, it is usually misdiagnosed. Misdiagnosis and delay in treatment are clinically relevant because if left untreated, Wilson's disease progresses to hepatic failure or severe neurologic disability, and death. Those adequately treated have a normal life span. Wilson's disease is an autosomal recessive disease caused by mutations in the ATP7B gene. Mutations in ATP7B result in abnormal copper metabolism and subsequent toxic accumulation of copper. The clinical manifestations of neurologic Wilson's disease include variable combinations of dysarthria, dystonia, tremor, parkinsonism, ataxia, and choreoathetosis. Once the possibility of Wilson's disease is considered, diagnosis is straight forward. Currently available treatments, including zinc acetate and trientine, are generally well tolerated and effective., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

This is the first report describing the liver structures of a Japanese patient with idiopathic copper toxicosis, which should be differentiated from hepatolenticular degeneration of Wilson disease. An 11-year-old Japanese boy presented with ascites associated with biochemical liver damage. Involvement of hepatitis virus was ruled out by laboratory tests. Because urinary copper excretion was increased, Wilson disease was highly suspected, but the serum level of ceruloplasmin was normal, and Kayser-Fleischer rings were not detected by slit lamp examination. Brain images were within normal limits. ATP7B analysis was negative for mutations. Liver specimen showed cirrhosis associated with chronic active hepatitis. Almost all hepatocytes were positive for orcein-stained granules. Mallory bodies were found in some hepatocytes. Fatty change was minimal, and there were no glycogenated nuclei in the parenchyma. Combined regimens of trientine and zinc for 6 months improved the decompensated state of liver function. After 2.5 years of treatment, a second liver biopsy was performed. The post-treatment liver showed complete disappearance of portal inflammation and remarkable decrease in cuprothionein granules. Mallory bodies disappeared from the parenchyma. An abundance of hepatocellular Mallory bodies and heavy copper loading limited to the liver may be specific to idiopathic copper toxicosis.

Low levels of human copper transporter 1 (hCtr1) mRNA are associated with a shorter progression-free survival after platinum-based therapy. Pretreatment with a copper-lowering agent such as trientine enhanced hCtr1-mediated platinum uptake. Therefore, we conducted a pilot study (NCT01178112) of carboplatin and trientine with the goal of resensitizing patients with advanced cancer to platinum chemotherapy. This case report reviews the outcomes of 5 patients with platinum-resistant high-grade epithelial ovarian cancer enrolled on the study to date. Overall, they tolerated treatment well. Severe adverse events that occurred in 2 patients were myelosuppression, notably anemia requiring transfusion. Dose-limiting toxicity was not observed within the first 28 days (cycle 1). After 2 cycles of therapy, partial remission was achieved in 1 patient (10+ months), stable disease in 3 patients (2, 3.5+, and 5 months, respectively), and 1 patient had progressive disease. These cases provide preliminary clinical evidence that the role of decreasing copper levels in reversing platinum resistance merits additional clinical investigation. Evaluation of this novel strategy is warranted in larger studies to assess the efficacy of this approach for treating platinum-resistant advanced epithelial ovarian cancer in patients with high copper levels., (©2012 AACR)