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The Veterinary Clinics of North... May 2017Copper-associated hepatitis is recognized with increasing frequency in dogs. The disease is characterized by centrolobular hepatic copper accumulation, leading to... (Review)
Review
Copper-associated hepatitis is recognized with increasing frequency in dogs. The disease is characterized by centrolobular hepatic copper accumulation, leading to hepatitis and eventually cirrhosis. The only way to establish the diagnosis is by histologic assessment of copper distribution and copper quantification in a liver biopsy. Treatment with the copper chelator d-penicillamine is the most commonly used treatment. In addition, a low-copper/high-zinc diet can help prevent accumulation or reaccumulation of hepatic copper. Mutations in the copper metabolism genes COMMD1 or ATP7A and ATP7B have been associated with hepatic copper concentrations in Bedlington terriers and Labrador retrievers respectively. In the Labrador retriever, dietary copper intake contributes strongly to the disease phenotype.
Topics: Animals; Biomarkers; Chelating Agents; Copper; Dog Diseases; Dogs; Hepatitis, Animal; Humans; Penicillamine
PubMed: 28063745
DOI: 10.1016/j.cvsm.2016.11.011 -
Annals of Translational Medicine Apr 2019The availability of effective therapies distinguishes Wilson disease (WD) from other inherited neurometabolic diseases. The cause of hepatic, neurologic or psychiatric... (Review)
Review
The availability of effective therapies distinguishes Wilson disease (WD) from other inherited neurometabolic diseases. The cause of hepatic, neurologic or psychiatric symptoms is copper overload and subsequent copper toxicity. Diagnosed WD patients require life-long pharmacologic therapy that is focused on reversal of copper overload with maintenance of a long-term negative copper balance. This is associated with the rapid control of free or non-ceruloplasmin bound copper that is mostly responsible for acute cytotoxic effects. Currently available therapies can be divided into chelators and zinc salts. They have different mechanisms of action and the onset of efficacy that influences their selection in acute and chronic stages of therapy. We review the use of D-penicillamine and trientine for chelation therapies, including the required monitoring of therapy for its efficacy and possible overtreatment with iatrogenic copper deficiency. Additionally, the use of zinc salts is also discussed, including a possibility of its use for the initial therapy in an acute stage of the disease. Supportive and symptomatic therapies for liver failure and neuropsychiatric symptoms are also reviewed.
PubMed: 31179303
DOI: 10.21037/atm.2019.03.18 -
Tremor and Other Hyperkinetic Movements... 2018Wilson disease (WD) is an inherited neurometabolic disorder that results in excessive copper deposition in the liver and the brain, affecting children and young adults.... (Review)
Review
BACKGROUND
Wilson disease (WD) is an inherited neurometabolic disorder that results in excessive copper deposition in the liver and the brain, affecting children and young adults. Without treatment the disease is invariably fatal. Though treatments for WD have been available since the 1950s, the disease continues to be associated with considerable morbidity and mortality because of missed diagnosis, and delayed or inadequate treatment. In this paper we survey WD-related literature in order to review recent advances in WD treatment.
METHODS
We performed a literature search using the PubMed database for articles relating to WD and its medical treatment. We reviewed the articles, and cross-references of relevant articles, to summarize the current practices for treatment of WD.
RESULTS
The survey shows that if WD is properly treated, in most patients the liver can be stabilized, even severe neurological disability reversed, and patients can resume normal lives.
DISCUSSION
Medical treatment for WD includes use of copper chelators (penicillamine, trientine, dimercaprol, dimercaptopropane sulfonate, and ammonium tetrathiomolybdate) and drugs that decrease gastrointestinal copper absorption. Our knowledge of the treatment approaches has benefited from the large systematic clinical studies that have been conducted over the last decade. For each drug used to treat WD, we surveyed its development, indication for use, dosing, efficacy, and adverse effects.
Topics: Hepatolenticular Degeneration; Humans
PubMed: 29520330
DOI: 10.7916/D841881D -
Current Opinion in Urology Sep 2018The incidence of pediatric nephrolithiasis is on the rise, with a significant related morbidity and a concomitant relevant increase in healthcare costs. The purpose of... (Review)
Review
PURPOSE OF REVIEW
The incidence of pediatric nephrolithiasis is on the rise, with a significant related morbidity and a concomitant relevant increase in healthcare costs. The purpose of this review is to portray the current epidemiology and cause of renal stones in children, to provide a framework for appropriate clinical evaluation on an individual basis, and a guidance regarding treatment and prevention for the significant risk of lifelong recurrence and deriving complications.
RECENT FINDINGS
The early identification of modifiable risk factors and other abnormalities is essential, to prevent related morbidity, the onset of chronic kidney disease, and the associated increased risk of developing other diseases. The implementation of risk reduction strategies, including dietary modifications and targeted pharmacological therapies, will significantly influence stone recurrences and preserve renal function.
SUMMARY
Future research is desirable, with the aim to strengthen personalized conservative management of pediatric nephrolithiasis as first-line treatment.
Topics: Allopurinol; Chelating Agents; Child; Conservative Treatment; Diet; Diet Therapy; Diuretics; Diuretics, Potassium Sparing; Environment; Enzyme Inhibitors; Humans; Nephrolithiasis; Penicillamine; Potassium Citrate; Risk Factors; Sodium Chloride Symporter Inhibitors; Tiopronin
PubMed: 29901459
DOI: 10.1097/MOU.0000000000000520 -
Handbook of Clinical Neurology 2017Wilson disease (WD) is a genetic disorder of copper metabolism that can be treated successfully with pharmacologic treatment. Two groups of drugs are currently used:... (Review)
Review
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.
Topics: Chelating Agents; Copper; Enzyme Inhibitors; Hepatolenticular Degeneration; Humans; Molybdenum; Penicillamine; Prospective Studies; Trientine
PubMed: 28433101
DOI: 10.1016/B978-0-444-63625-6.00015-X -
Digestive and Liver Disease : Official... Dec 2019
Topics: Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoimmune Diseases; Autoimmunity; Chelating Agents; Clinical Deterioration; Fatal Outcome; Female; Hepatolenticular Degeneration; Humans; Immunologic Tests; Patient Care Management; Penicillamine; Renal Insufficiency
PubMed: 31669076
DOI: 10.1016/j.dld.2019.08.025 -
Journal of Trace Elements in Medicine... 2015The 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... (Review)
Review
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.
Topics: Administration, Oral; Antidotes; Benzoates; Chelating Agents; Deferasirox; Deferiprone; Deferoxamine; Heavy Metal Poisoning; Humans; Penicillamine; Poisoning; Pyridones; Succimer; Triazoles; Trientine; Unithiol
PubMed: 25457281
DOI: 10.1016/j.jtemb.2014.10.001 -
Medicine Feb 2023Hepatolenticular degeneration, also known as Wilson disease (WD), is an autosomal recessive inherited disease characterized by copper metabolism, which has complex...
RATIONALE
Hepatolenticular degeneration, also known as Wilson disease (WD), is an autosomal recessive inherited disease characterized by copper metabolism, which has complex clinical manifestations, and mainly including liver and nervous system lesions. Pregnancy combined with WD is extremely harmful to mothers and children, with high miscarriage rates, and premature birth rates and perinatal mortality.
PATIENT CONCERNS
Here we introduced the basic information of 4 pregnant women with WD. The first pregnant woman had a 16-year history of WD, stopped taking penicillamine 1 year before pregnancy. The second woman had a 3-year history of WD and was taking penicillamine regularly, unintended pregnancy occurred 1 month after stopping the drug. The third woman had a history of WD for 5 years with penicillamine treatment. The 4th woman was found to have WD due to repeated missed miscarriage with abnormal liver function, after which penicillamine was regularly taken. Fortunately, she was pregnant again a year later.
DIAGNOSES
The pregnant women in case 1 and case 2 were diagnosed with decompensated cirrhosis with coagulation dysfunction during pregnancy. The pregnant woman in case 3 was found to have liver cirrhosis by ultrasound, and the pregnant woman in case 4 did not have liver abnormalities during pregnancy.
INTERVENTIONS
The pregnant woman in case 1 began to take copper-removing drugs and take a low-copper diet after finding the aggravation of the disease in the early stage of pregnancy, and had good compliance during pregnancy. The pregnant woman in case 2 had poor compliance during pregnancy and did not receive any treatment. The pregnant woman in case 3 refused to use copper elimination drugs during pregnancy, but took a low copper diet. The pregnant woman in case 4 had good compliance during pregnancy, and she was treated with drugs and low copper diet during the whole pregnancy.
OUTCOMES
Three of the four pregnant women got a healthy baby but premature, and only the pregnant woman in case 2 had spontaneous abortion at 25 weeks.
LESSONS
After comprehensive monitoring and multidisciplinary management of professional medical staff before and after pregnancy, WD pregnant women still have the opportunity to obtain a better pregnancy outcome and improve quality of life.
Topics: Child; Pregnancy; Female; Humans; Hepatolenticular Degeneration; Copper; Abortion, Spontaneous; Quality of Life; Penicillamine
PubMed: 36800617
DOI: 10.1097/MD.0000000000032968 -
Journal of Hepatology Aug 2023Prevention 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...
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.
Topics: Female; Humans; Hepatolenticular Degeneration; Penicillamine; Trientine; Zinc; Copper
PubMed: 37116715
DOI: 10.1016/j.jhep.2023.04.007 -
Neurological Sciences : Official... Oct 2023Neurological deterioration, soon after anti-copper treatment initiation, is problematic in the management of Wilson's disease (WD) and yet reports in the literature are... (Meta-Analysis)
Meta-Analysis Review
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.
Topics: Humans; Hepatolenticular Degeneration; Penicillamine; Trientine; Copper; Nervous System Diseases
PubMed: 37311952
DOI: 10.1007/s10072-023-06895-6