Liver Copper Research Articles

Complications of Liver Transplant in Adult Patients With the Hepatic Form of Wilson Disease.

Wilson disease is an autosomal, recessive, inherited disorder of copper metabolism that results in the accumulation of copper in many organs and tissues. This disease is mainly characterized by dysfunction due to copper accumulation in the liver, kidney, brain, cornea, bone, heart, and blood cells. The clinical spectrum is broad in Wilson disease. Asymptomatic Wilson disease may be present, but findings related to the involvement of an individual organ or multiple organ failure can be seen. These findings can include neurologic and neuropsychiatric complications. Our aim here was to examine the neurologic complications and our clinical experience in patients who underwent liver transplant for Wilson disease in our clinic. We retrospectively reviewed the medical records of transplant patients with Wilson disease who were seen at Baskent University Faculty of Medicine Transplantation Science between 2005 and 2017. Patient demographics, neurologic complaints, findings from neurologic examinations, and imaging findings were recorded. We also recorded the presence of the Kayser-Fleischer ring, serum ceruloplasmin, 24-hour copper urine levels, and levels of dry copper in liver in each patient. Our study included 19 patients who ranged in age range from 18 to 44 years (mean age of 26 years). Seven of 19 patients (36.8%) had neurologic symptoms, including epileptic seizures in 2 patients (10.5%), encephalopathy in 1 patient (5.2%), tremor in 3 patients (15.7%), and headache in 1 patient (5.2%). The cause of these long-term neurologic complications was the immunosuppressive drugs. Patients with epileptic seizures were provided with seizure control medication (levetiracetam). Tremor did not need treatment. In Wilson disease, neurologic complications can be severe. The most common complication seen in our patients was tremor. Early diagnosis and treatment may slow down neurologic disability.

Effects of Dietary Copper on Growth Performance, Slaughter Performance and Nutrient Content of Fecal in Growing Goslings from 28 to 70 Days of Age

ABSTRACT A dose-response experiment with four dietary copper concentrations (4.17, 8.17, 12.17 and 16.17 mg/kg) was conducted to estimate the growth performance, slaughter performance, nutrient content of fecal and liver copper concentrations of growing Goslings from 28 to 70 d of age. Two hundred healthy male Yangzhou geese with similar body weight were randomized to four groups with five replicates per treatment and ten geese per replicate. Average daily feed intake, average daily gain and feed conversion ratio of geese for each pen were measured from 28 to 70 d of age. At 70 d of age, two geese were selected randomly from each pen and slaughtered to evaluate carcass quality. Metabolism experiment was conducted with five male geese from each group (one goose per pen) which body weight was close to the mean weight of the group from 64 to 70 d of age. Significant effects of dietary copper was found on body weight, feed conversion ratio, carcass yield, fecal copper concentrations and liver copper concentrations. Body weight, feed conversion ratio and carcass yield showed significant quadratic response to increase dietary copper concentration, while fecal copper concentration and liver copper concentration showed a significant linear response. The result showed that dietary Cu addition can improve growth by increasing the use of the feeding stuff and improving carcass yield in growing Goslings. Furthermore, taking into consideration, the optimal level of Gosling dietary copper was between 8.77 and 11.6 mg/kg from 28 to 70 days of age.

Variation of Metallothionein I and II Gene Expression in the Bank Vole (Clethrionomys glareolus) Under Environmental Zinc and Cadmium Exposure

The main idea of the study was to assess how environmental metal pollution activates defence responses at transcription levels in the tissues of bank voles (Clethrionomys glareolus). For this purpose, the metallothioneine (MT) genes expression (a well known biomarker of exposure and response to various metals) was measured. The real-time PCR method was used for relative quantification of metallothionein I and metallothionein II expressions in the livers, kidneys and testes of bank voles from six populations exposed to different contaminants, mainly zinc, cadmium and iron. The assessment of Zn, Cu and Fe concentrations in the tissues allowed to study the MTs gene expression responses to these metals. ANOVA analysis showed differences between populations in terms of metal concentration in tissues, livers and kidneys. Student T test showed significant differences in metal concentration between unpolluted and polluted sites only for the liver tissue: significantly lower Zn levels and significantly higher Fe levels in the unpolluted sites. Kruskal–Wallis test performed on CT data shows differences in the gene expressions between populations for both MT genes for liver and testes. In the liver metallothionein I gene expression was upregulated in populations considered as more polluted (up to 7.5 higher expression in Miasteczko Śląskie comparing to Mikołajki). Expression of metallothionein II revealed a similar pattern. In kidneys, differences in expression of both MT genes were not that evident. In testes, MT upregulation in polluted sites was noted for metallothionein II. For metallothionein however, we found downregulation in populations from more contaminated sites. The expressions of both MTs were positively influenced by cadmium in kidney (concentration data from the previous study) and zinc and copper in liver, while cadmium had effects only on the liver MT II gene expression. Positive relationship was obtained for lead and metallothionein II expression in the liver.

Early Onset of Wilson Disease: Diagnostic Challenges.

The aim of the study was to analyze the clinical presentations, diagnosis, and treatment of patients ages ≤5 years with early onset Wilson disease (WD). Data from 143 pediatric patients with WD treated at our center between January 1996 and November 2015 were retrospectively analyzed. A review of the 143 pediatric patients with WD identified 21 (10 girls, 11 boys) with first symptoms or abnormal liver function test results at age ≤5 years. The diagnosis of WD was confirmed in 8 patients younger than 5 years. At baseline the mean serum alanine aminotransferase level was 222 U/L and the mean serum aspartate aminotransferase level was 130 U/L. The mean serum ceruloplasmin concentration in 16 tested patients was <20 mg/dL. Of the 15 patients who underwent urinary copper excretion testing, 8 had levels between 40 and 100 μg/day, with only 4 having levels >100 μg/day. Liver copper quantification was >250 μg/g dry weight in 16 patients. The most common mutation was p.H1069Q, with compound heterozygosity in 5 patients and homozygosity in 9. Sixteen patients were treated with zinc salts and 5 with D-penicillamine. Both treatments were effective, with no serious side effects observed after 3 to 24 months. WD can present as early as 2 years of age. Because biochemical tests may be less sensitive in very young children, diagnoses may require a combination of tests. If molecular tests are inconclusive, liver copper content should be measured.

A Discussion on the Management of Wilson Disease

Prof Peter Ferenci opened the meeting by providing a background to Wilson disease (WD), an enigmatic condition where no two cases are the same. He explored the aetiology, peak age of presentation, and long-term outlook. Dr Gideon Hirschfield considered the wide variation in WD symptom presentation, the lack of a diagnostic gold standard, and the difficulties around choosing WD endpoints for clinical trials. He went on to consider how study endpoints have evolved over time, and how, in real-life clinical practice, therapies need to be tolerable for patients with negative copper balances. Prof Anil Dhawan focussed on diagnostic challenges in paediatric WD, reviewing the size of liver biopsies needed for measurement of liver copper dry weight, the penicillamine challenge test, and Leipzig scores. Regarding treatment, he stressed that improvements in liver scores take time on chelation therapy, making it important not to rush patients to transplant. Prof Dhawan explored the development of disease severity scores for transplantation, including the revised cut-off points for the Nazer score. He provided reassuring data around the success of living related liver transplantation from parents heterozygous for WD and raised the possibility of auxiliary liver transplants. Prof Karl Heinz Weiss considered three WD cases reflecting different aspects of the condition. The neurological case showed deterioration of neurological symptoms after starting D-penicillamine. This, Prof Weiss speculated, may relate to treatment causing shifts in the copper pool from bound copper to unbound copper. The second case involved a young woman with WD who was planning a pregnancy; Prof Weiss showed the importance of patients remaining with therapies they are used to. Finally, he considered a patient with decompensated cirrhosis referred for liver transplantation but for whom, when reassessed with the modified Nazer score, the level did not indicate the need for transplantation. The patient showed side effects with one treatment but subsequently did well on a second treatment and was delisted for transplant.

Spatial investigation of the elemental distribution in Wilson’s disease liver after d-penicillamine treatment by LA-ICP-MS

At present, the copper chelator d-penicillamine (DPA) is the first-line therapy of Wilson’s disease (WD), which is characterized by an excessive copper overload. Lifelong DPA treatments aim to reduce the amount of detrimental excess copper retention in the liver and other organs. Although DPA shows beneficial effect in many patients, it may cause severe adverse effects. Despite several years of copper chelation therapy, discontinuation of DPA therapy can be linked to a rapidly progressing liver failure, indicating a high residual liver copper load. In order to investigate the spatial distribution of remaining copper and additional elements, such as zinc and iron, in rat and human liver samples after DPA treatment, a high resolution (spotsize of 10μm) laser ablation-inductively coupled plasma-mass spectrometry (LA‐ICP‐MS) imaging method was applied. Untreated LPP‐/− rats, an established animal model for WD, appeared with a high overall copper concentration and a copper distribution of hotspots distributed over the liver tissue. In contrast, a low (>2-fold decreased) overall copper concentration was detected in liver of DPA treated animals. Importantly, however, copper distribution was highly inhomogeneous with lowest concentrations in direct proximity to blood vessels, as observed using novel zonal analysis. A human liver needle biopsy of a DPA treated WD patient substantiated the finding of an inhomogeneous copper deposition upon chelation therapy. In contrast, comparatively homogenous distributions of zinc and iron were observed. Our study indicates that a high resolution LA‐ICP‐MS analysis of liver samples is excellently suited to follow efficacy of chelator therapy in WD patients.

Concentration of Zinc, Copper, Iron, Calcium, and Magnesium in the Serum, Tissues, and Urine of Streptozotocin-Induced Mild Diabetic Rat Model.

The present study aimed to investigate, in the streptozotocin-induced mild diabetic rat model, the zinc (Zn), copper (Cu), iron (Fe), calcium (Ca), and magnesium (Mg) concentration in serum, liver, and kidney tissues, and urine samples from adult Wistar rats treated neonatally with streptozotocin (STZ). Diabetes was induced by subcutaneous administration of streptozotocin (100mg/Kg) in female Wistar rats of 2days old (STZ, n=10). Control group (CG, n=10) received only sodium-citrate buffer. The mineral concentrations were measured by atomic absorption spectrophotometry. The validity and accuracy were checked by conventional methods. STZ neonatal injection successfully leaded to mild diabetes in the adult rats. Serum concentrations of Zn, Cu, Fe, Ca, and Mg showed no changes (p>0.05) due to diabetes. The Zn, Fe, Ca, and Mg concentrations in liver and kidney tissues were not different (p>0.05) between STZ and CG. The mean values of Cu were higher (p<0.05) in liver and kidney samples from STZ as compared to CG. Urine minerals concentrations (Zn, Cu, Fe and Ca) in STZ-rats group were lower (p<0.05) than CG. However, the content of all evaluated minerals in the excreted urine were higher (p<0.01) in STZ-rats during a 24h collection period. Urinary excretion of Zn, Cu, Fe, Ca, and Mg was strongly correlated with urinary volume during the 24h period (r>0.7; p<0.001). Observed changes in mineral metabolism of STZ-induced mild diabetes model could be due to the endocrine imbalance associated with the diabetic condition.

Lead from spent ammunition: a source of exposure and poisoning in bald eagles

Ongoing occurrence of elevated levels of lead in bald eagles (Haliaeetus leucocephalus) following the ban on lead shot for waterfowl hunting led us to hypothesize that spent lead from ammunition, which is present in fi eld residues of white-tailed deer (Odocoileus virginianus), represented a source of lead exposure in eagles. We conducted a case-control study using data from 1,277 bald eagles admitted for rehabilitation from January 1996 through December 2009. A multivariate logistic regression model was used to predict the odds of elevated lead levels using admission date in relation to deer hunting season, recovery location in relation to deer hunting zones, and age as predictors. We also assessed mean liver copper concentrations from eagles with elevated lead levels and from eagles with background lead levels, because most high velocity rifl e bullets that are used for deer hunting are jacketed in copper. We found 334 bald eagles with elevated lead levels out of 1,277 bald eagles we examined. We detected signifi cantly increased odds for elevated lead levels based on season (late fall and early winter), deer hunting rifl e zone, and age (adult birds). The mean liver copper concentration was higher (P = 0.02) in eagles with elevated lead levels. These combined results supported our hypothesis that eagles are acquiring lead from hunter-shot deer. Further research is needed to determine whether this exposure to lead is having a population-level impact.

Chapter 5 - Pathogenesis of Wilson disease

Wilson disease is an autosomal-recessive disorder originating from a genetic defect in the copper-transporting ATPase ATP7B that is required for biliary copper secretion and loading of ceruloplasmin with copper. Impaired ATP7B function in Wilson disease results in excessive accumulation of copper in liver, brain, and other tissues. Toxic copper deposits may induce oxidative stress, modify expression of genes, directly inhibit proteins, and impair mitochondrial function, leading to hepatic, neuropsychiatric, renal, musculoskeletal, and other symptoms. Hepatocyte dysfunction initially manifests as steatosis and later may progress to other hepatic phenotypes such as acute liver failure, hepatitis, and fibrosis. In the brain, copper accumulates in astrocytes, leading to impairment of the blood-brain barrier and consequent damage to neurons and oligodendrocytes. Basal ganglia and brainstem are the brain regions with highest susceptibility to copper toxicity and their lesions lead to various combinations of movement and psychiatric disorders. This chapter will give an overview of the essential requirement of copper for biologic processes and the molecular mechanisms employed by cells to maintain their copper levels in a proper range. We will specify the physiologic functions of ATP7B and the consequences of its dysfunction and summarize the current knowledge on the pathogenesis of liver and neuropsychiatric disease. Finally, we will describe the consequences of copper overload in Wilson disease in other tissues.

Taurine Normalizes the Levels of Se, Cu, Fe in Mouse Liver and Kidney Exposed to Arsenic Subchronically.

To evaluate the benefits of taurine on the homeostasis of trace elements induced by toxic metals, we investigated the concentration of Selenium (Se), Copper (Cu), Iron (Fe) and Manganese (Mn) in mouse liver and kidney after arsenic exposure for 2 months. The experimental animals were divided into control group, arsenic exposure group (1, 2, 4 ppm) and taurine protective group randomly. Concentrations of serum, liver and kidney trace elements such as Se, Cu, Fe, Mn were measured by Inductively Coupled Plasma-Mass Spectrometry. Our results showed that the concentration of Cu was higher, however, the concentration of Se and Fe was lower in mice liver and kidney exposed to arsenic. The levels of Se, Cu, Fe were alleviated by co-administered with taurine. Furthermore, there was no difference in the concentration of Mn between the three groups. Our finding suggests that taurine may relieve the disturbed levels of Se, Cu and Fe in liver and kidney induced by arsenic.

Hepatic concentrations of copper and other metals in dogs with and without chronic hepatitis.

Defects in copper metabolism have been described in several dog breeds, and recently, it has been suggested that changes in other essential trace elements could be involved in the pathogenesis of hepatic disease. This study measured hepatic copper accumulation and its interactions with other essential trace and toxic metals in dogs diagnosed with chronic hepatitis. Liver samples of 20 chronic hepatitis and 20 healthy dogs were collected. Samples were acid digested, and essential metals (cobalt, copper, iron, manganese, molibdenum, selenium and zinc) and toxic metals (arsenic, cadmium, mercury and lead) were analysed by inductively-coupled plasma mass spectrometry. Copper concentrations were significantly higher in dogs affected by hepatic disease than in controls. Dogs having chronic hepatitis with liver copper concentration greater than 100 mg/kg wet weight showed statistically higher cobalt, manganese and zinc concentrations than dogs having chronic hepatitis with liver copper concentrations less than 100 mg/kg wet weight and controls. Toxic metal concentrations were low - in all cases below the threshold associated with toxicity in dogs. Dogs with chronic hepatitis not only have increased concentrations of copper in the liver but also increased concentrations of cobalt, manganese and zinc; measurement of these elements may perhaps aid in diagnosis of liver disease in dogs.

Rat liver mitochondrial dysfunction by addition of copper(II) or iron(III) ions

Increased copper (Cu) and iron (Fe) levels in liver and brain are associated to oxidative stress and damage with increased phospholipid oxidation process. The aim of this work was to assess the toxic effects of Cu2+ and Fe3+ addition to rat liver mitochondria by determining mitochondrial respiration in states 3 (active respiration) and 4 (resting respiration), and phospholipid peroxidation. Both, Cu2+ and Fe3+ produced decreases in O2 consumption in a concentration-dependent manner in active state 3: both ions by 42% with malate-glutamate as complex I substrate (concentration for half maximal response (C50) 60μM Cu2+ and 1.25mM Fe3+), and with succinate as complex II substrate: 64–69% with C50 of 50μM Cu2+ and with C50 of 1.25mM of Fe3+. Respiratory control decreased with Cu2+ (C50 50μM) and Fe3+ (C50 1.25-1-75mM) with both substrates. Cu2+ produced a 2-fold increase and Fe3+ a 5-fold increase of thiobarbituric acid-reactive substances (TBARS) content from 25μM Cu2+ (C50 40μM) and from 100μM Fe3+ (C50 1.75mM). Supplementations with Cu2+ and Fe3+ ions induce mitochondrial dysfunction with phospholipid peroxidation in rat liver mitochondria. Although is proved that a Fenton/Haber Weiss mechanism of oxidative damage occurs in metal-ion induced mitochondrial toxicity, slightly different responses to the metal ions suggest some differences in the mechanism of intracellular toxicity. The decreased rates of mitochondrial respiration and the alteration of mitochondrial function by phospholipid and protein oxidations lead to mitochondrial dysfunction, cellular dyshomeostasis and cell death.

The effects of zinc hydroxychloride and basic copper chloride on growth performance, carcass characteristics, and liver zinc and copper status at slaughter in yearling feedlot steers

ABSTRACT Several trace mineral sources are available for use in feedlot diets. This study was conducted to provide nutritionists with information supporting the formulation of more cost effective trace mineral supplementation programs. Crossbred yearling steers (n = 288, initial BW = 319 ± 10.2 kg), housed in 32 pens (8 pens per treatment), were used in a randomized complete block design experiment to compare the effects of Zn hydroxychloride and basic Cu chloride, fed at 2 concentrations, to Zn and Cu sulfate or Zn and Cu sulfate plus Zn and Cu amino acid complexes on feedlot performance, carcass merit, and liver mineral status at slaughter. Treatments (100% DM basis) included 90 mg/kg of Zn from Zn sulfate and 15 mg/kg of Cu from Cu sulfate; 67.5 mg/kg of Zn from Zn sulfate plus 22.5 mg/kg of Zn from Zn amino acid complex (Availa Zn; Zinpro Corporation, Eden Prairie, MN) and 11.25 mg/kg of Cu from Cu sulfate plus 3.75 mg/kg of Cu from Cu amino acid complex (Availa Cu; Zinpro Corporation); 90 mg/kg of Zn from Zn hydroxychloride (IntelliBond Z; Micronutrients, Indianapolis, IN) and 15 mg/kg of Cu from basic Cu chloride (IntelliBond C; Micronutrients); and 54 mg/kg of Zn from Zn hydroxychloride and 9 mg/kg of Cu from basic Cu chloride. No significant (P > 0.10) treatment differences were found for initial, d-28, or final BW. Average daily gain, DMI, G:F, NE recovery, carcass characteristics, and liver Cu and Zn concentrations at the time of slaughter did not differ (P > 0.10) among treatments. These results indicate that Zn hydroxychloride and basic Cu chloride were effectively absorbed and used by yearling steers and can be fed at a reduced rate compared with current industry feeding practices without negative effects on feedlot performance, carcass merit, and liver Zn and Cu status.

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

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. The rats were treated with trientine dihydrochloride for 5days before liver RFA. Liver function, copper concentration, inflammation biomarkers and MDA, SOD were analyzed after RFA treatment for 2h, 2 and 5days. 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. 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.

Accumulation of Copper in Gill, Liver, Spleen, Kidney and Muscle Tissues of Clarias gariepinus Exposed to the Metal Singly and in Mixture with Chitosan.

Accumulation of copper (Cu), applied singly and in mixture with chitosan (CT), in gill, liver, spleen, kidney and muscle tissues of Clarias gariepinus was studied after exposing the fish to no Cu (control), 5ppm Cu, 5ppm Cu+75ppm CT mixture over 1, 7 and 15days. Metal levels in tissues were determined using an ICP-AES spectrophotometer. No mortality was observed during the experiments. Highest accumulation of Cu was observed in liver while lowest accumulation was observed in muscle tissue. Exposure to Cu-CT mixture decreased Cu accumulation in liver at all exposure periods and in kidney on the 15th day compared to Cu alone. Exposure to Cu alone and Cu-CT mixture had no effect on Cu accumulation in spleen or muscle tissue. Copper accumulation increased in gill tissue compared to control when exposed to Cu alone at all exposure periods, and exposure to the Cu-CT mixture significantly increased Cu accumulation in this tissue at all exposure periods compared to Cu alone.

Wilson disease in a Bangladeshi child: A case report

Wilson disease, also known as hepatolenticular degeneration results from improper metabolism of copper due to deficiency or low level of caeruloplasmin which causes excessive accumulation of copper in liver, brain, eyes and different organs. This is not a curable disease. The patient needs a lifelong treatment but early diagnosis can prevent significant damage to the critical organs. This article presents a case study on Wilson disease and the role of radiology in helping to diagnose the disease and monitor patients with this condition.Bangladesh Med J. 2016 Jan; 45 (1): 54-56

Effect of molybdenum induced hypocuprosis on copper and molybdenum levels of plasma, hair and liver in buffalo calves

The objective of this study was to determine the clinical effects, changes in concentrations of Cu and Mo in plasma, hair, liver and red cell parameters of buffalo calves fed on high Mo diet. Male buffalo calves (12), 1–1.5 year-old were assigned to either control (4) or deficient group (8) on the basis of their body weight. Control group was regularly supplemented with 30 mg of elemental copper and calves of deficient group were fed fresh green fodder sprayed with 0.04% sodium molybdate solution to provide 30 ppm of molybdenum for 180 days. Samples of blood, hair, and liver tissue were collected at regular intervals. Hemoglobin and PCV were determined in whole blood. Concentrations of copper and molybdenum were measured in plasma, hair and liver tissue. Fodder samples were analysed for proximate principles, cell wall constituents, Ca, P, Mg, Cu, Mo and Zn. Salient clinical signs were intermittent diarrhea, varying degree of skin and hair depigmentation. Bilateral swelling of hock joints and transitory lameness occured in one calf each. Daily weight gain was lower in molybdenum fed calves as compared to control however, the weight loss occurred only during 45–135 days. Plasma copper was unaffected. Copper concentration of hair and liver declined in 180 days. There was no change in plasma molybdenum concentration. Hair molybdenum content increased after 180 days of molybdenum feeding. Liver molybdenum concentration was significantly high throughout the experiment as compared to control group. Haemoglobin and PCV were not affected by excess molybdenum feeding. Hair copper concentration of 6 ppm or below may be taken as indicator of molybdenum induced copper deficiency in buffaloes.

The effect of silver on zinc and copper in rat liver and metallothionein in a time-course study

The effect of silver on zinc and copper in rat liver and metallothionein in a time-course study

Controversies and Variation in Diagnosing and Treating Children With Wilson Disease: Results of an International Survey.

Variation in care is more common in settings in which evidence-based approaches are limited. The aims of the present study were to describe consensus and variability in approaches taken by pediatric hepatologists in the management of Wilson disease (WD) in children. International case-centered, Internet-based survey of pediatric hepatologists. Survey cases were developed by consensus of the authors and were intended to identify variation in the care of children with WD. One hundred eleven of 253 clinicians responded (44%). Of these, 84% of North American and 41% of European participants used guidelines published in their respective region. Although consensus existed on the first-line diagnostic tools (serum ceruloplasmin and baseline 24-hour urinary copper excretion), survey participants did not agree on how much liver copper content was required for diagnosis: 57% considered >250 μg/g dry weight to be consistent with WD, whereas 25% considered >50 μg/g to be diagnostic. Overall, 50% of practitioners perform genetic testing in all suspected cases, and 81% perform genetic testing once they know the genotype of an index patient. For initial treatment of fulminant WD, 51% of participants chose chelation and 15% chose immediate transplantation; 47% chose listing for transplantation followed by monitoring using a disease-severity score, and then carrying out transplantation only when the score reached a critical cut-off. To treat mildly affected siblings of index patients, 43% of practitioners chose zinc. Most reported that they use chelation to treat patients with hepatic dysfunction; however, 29% of North American participants chose not to use D-penicillamine as primary therapy. From an international perspective, pediatric hepatologists vary in the approaches they use in the care for children with WD. Regional preferences and accessibility to treatments may generate variation. Unwarranted variation, however, may also contribute to differences in outcome and should be targeted to improve quality of care.

Methanobactin reverses acute liver failure in a rat model of Wilson disease.

In Wilson disease (WD), functional loss of ATPase copper-transporting β (ATP7B) impairs biliary copper excretion, leading to excessive copper accumulation in the liver and fulminant hepatitis. Current US Food and Drug Administration- and European Medicines Agency-approved pharmacological treatments usually fail to restore copper homeostasis in patients with WD who have progressed to acute liver failure, leaving liver transplantation as the only viable treatment option. Here, we investigated the therapeutic utility of methanobactin (MB), a peptide produced by Methylosinus trichosporium OB3b, which has an exceptionally high affinity for copper. We demonstrated that ATP7B-deficient rats recapitulate WD-associated phenotypes, including hepatic copper accumulation, liver damage, and mitochondrial impairment. Short-term treatment of these rats with MB efficiently reversed mitochondrial impairment and liver damage in the acute stages of liver copper accumulation compared with that seen in untreated ATP7B-deficient rats. This beneficial effect was associated with depletion of copper from hepatocyte mitochondria. Moreover, MB treatment prevented hepatocyte death, subsequent liver failure, and death in the rodent model. These results suggest that MB has potential as a therapeutic agent for the treatment of acute WD.