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• W2000597587 abstract "See “Zinc monotherapy is not as effective as chelating agents in treatment of Wilson disease” by Weiss KH, Gotthardt DN, Klemm D, et al, on page 1189. See “Zinc monotherapy is not as effective as chelating agents in treatment of Wilson disease” by Weiss KH, Gotthardt DN, Klemm D, et al, on page 1189. Wilson disease is an excellent example of contemporary translational medical science. First described in 1912, early clinical observations remain informative. In the mid-20th century the relevance of copper and ceruloplasmin was clear; genetic studies indicated an autosomal recessive pattern of inheritance. Oral chelators provided effective treatment. In 1993, the gene whose mutations result in Wilson disease was identified: ATP7B, encoding a metal-transporting P-type ATPase (the Wilson ATPase), mainly expressed in the liver where it participates in both production of holoceruloplasmin and excretion of copper into bile.1Bull P.C. Thomas G.R. Rommens J.M. et al.The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene.Nat Genet. 1993; 5: 327-337Google Scholar, 2Tanzi R.E. Petrukhin K. Chernov I. et al.The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene.Nat Genet. 1993; 5: 344-350Google Scholar Subsequent research in cellular and molecular biology has addressed many of the conundrums of Wilson disease.3La Fontaine S. Mercer J.F. Trafficking of the copper-ATPases, ATP7A and ATP7B: role in copper homeostasis.Arch Biochem Biophys. 2007; 463: 149-167Google Scholar There is renewed interest in research relating to the physiology of all metals. Metals play an important role in human physiology and in organisms throughout the phyla. Each metal has a functional optimum, and too little or too much of that metal leads to dysfunction. This is reminiscent of Aristotle's concept of virtue: it is located on a continuum between 2 extremes, vices of insufficiency and surfeit, respectively. For example, the virtue of courage was contrasted with the vices of cowardice (insufficiency) and rash risk-taking (excess). We might, therefore, envision a virtue theory of metals. With copper, severe deficiency owing to a genetic defect in copper uptake causes Menkes disease, a multisystemic but mainly severe neurologic disease, and copper overload is found in Wilson disease. Similarly with iron, there are diseases of excess (hereditary hemochromatosis) and deficiency. These 2 metals are redox active: they can shuttle between 2 valence states, a feature that accounts for their metabolic versatility, but explains also how they can generate oxidative stress through the Fenton reaction. Copper and iron are metabolically interrelated. Ceruloplasmin is a ferroxidase, which requires incorporation of copper to be active. In aceruloplasminemia, iron accumulates in the liver. However, hepatic iron accumulation is prominent in the Wilsonian LEC rat. Zinc is essential for the function of numerous enzymes and transcription factors and for neurotransmission. When it is severely deficient, acrodermatitis enterohepatica develops. Zinc interacts with copper in enzymes such as superoxide dismutase 1, and it can affect, or even regulate, copper uptake. It is not redox active and does not generate activated oxygen species in experimental models where copper does.4Seth R. Yang S. Choi S. et al.In vitro assessment of copper-induced toxicity in the human hepatoma line, Hep G2.Toxicol In Vitro. 2004; 18: 501-509Google Scholar We do not know much about the perils of zinc overload: most reports describe the effects of copper insufficiency consequent to zinc excess. With certain metals, such as calcium, effects of surfeit or insufficiency are not necessarily related simply to genetic makeup. Metals interact in physiologic systems and influence each other's action and toxicity. They may share uptake and excretion pathways. In some cases, 1 metal can borrow another's pathway: for example, pathways for copper, including the uptake transporter CTR1 and the Cu-transporting P-type ATPases, participate in the intracellular disposition of cisplatin.5Safaei R. Howell S.B. Copper transporters regulate the cellular pharmacology and sensitivity to Pt drugs.Crit Rev Oncol Hematol. 2005; 53: 13-23Google Scholar At one time, Wilson disease was among the few causes of cirrhosis for which effective medical treatment was available. d-Penicillamine, still the standard treatment for Wilson disease, has formidable toxicities in many patients.6Walshe J.M. Wilson's disease presenting with features of hepatic dysfunction: a clinical analysis of eighty-seven patients.Q J Med. 1989; 70: 253-263Google Scholar Trientine, which differs from d-penicillamine structurally, is an effective chelator, with fewer adverse effects.7Scheinberg I.H. Jaffe M.E. Sternlieb I. The use of trientine in preventing the effects of interrupting penicillamine therapy in Wilson's disease.N Engl J Med. 1987; 317: 209-213Google Scholar It is accepted an as excellent alternative to d-penicillamine, but remains in therapeutic limbo as an orphan drug. In the 1970s, Hoogenraad et al8Hoogenraad T.U. Koevoet R. de Ruyter Korver E.G. Oral zinc sulphate as long-term treatment in Wilson's disease (hepatolenticular degeneration).Eur Neurol. 1979; 18: 205-211Google Scholar showed that zinc was an effective treatment for Wilson disease. Extensive clinical investigations by Brewer et al9Brewer G.J. Dick R.D. Johnson V.D. et al.Treatment of Wilson's disease with zinc XVI: treatment during the pediatric years.J Lab Clin Med. 2001; 137: 191-198Google Scholar have established its efficacy in numerous important clinical scenarios relating to Wilson disease. Given in large doses, zinc interferes with the absorption of copper by a distinctive mechanism of action. Although it competes with copper for uptake into enterocytes, its main effect is induction of metallothionein in enterocytes. This metallothionein has a greater affinity for copper than for zinc and preferentially binds copper from the intestinal contents. Copper thus bound to metallothionein is not absorbed but excreted in the feces with normal enterocyte turnover.10Yuzbasiyan-Gurkan V. Grider A. Nostrant T. et al.Treatment of Wilson's disease with zinc: X Intestinal metallothionein induction.J Lab Clin Med. 1992; 120: 380-386Google Scholar Zinc may also induce hepatocellular metallothionein and thus stabilize hepatocellular copper11Lee D.Y. Brewer G.J. Wang Y.X. Treatment of Wilson's disease with zinc VII. Protection of the liver from copper toxicity by zinc-induced metallothionein in a rat model.J Lab Clin Med. 1989; 114: 639-645Google Scholar; hepatic parenchymal copper concentration does not necessarily decrease during treatment with zinc.12Brewer G.J. Hill G.M. Dick R.D. et al.Treatment of Wilson's disease with zinc: III Prevention of reaccumulation of hepatic copper.J Lab Clin Med. 1987; 109: 526-531Google Scholar Zinc is recognized as maintenance treatment for Wilson disease. The typical daily dose of zinc for treating Wilson disease is an order of magnitude greater than the maximum recommended daily dietary intake. The actual zinc salt used therapeutically does not affect efficacy but may determine tolerability. A logistical problem is that zinc requires 3 times a day dosing, preferably well away from meals. Proper adherence to this medical regimen can be difficult for anyone with erratic daily schedules and meal times. Modifying the dosage to the easier twice daily regimen may result in inadequate treatment. The reported clinical experience with zinc therapy in Wilson disease is mostly small cases series describing relatively short treatment durations. A recent systematic review of treatment for Wilson disease found only a handful of analyzable studies and only 1 randomized, controlled trial: it concluded that zinc was overall as effective as d-penicillamine and much better tolerated, although perhaps less favorable for liver disease.13Wiggelinkhuizen M. Tilanus M.E. Bollen C.W. et al.Systematic review: clinical efficacy of chelator agents and zinc in the initial treatment of Wilson disease.Aliment Pharmacol Ther. 2009; 29: 947-958Google Scholar The large, retrospective study reported in this issue of Gastroenterology14Weiss K.H. Gotthardt D.N. Klemm D. et al.Zinc monotherapy is not as effective as chelating agents in treatment of Wilson disease.Gastroenterology. 2011; 140: 1189-1198Abstract Full Text Full Text PDF Scopus (135) Google Scholar addresses important issues in the therapy of Wilson disease. Patient cohorts from 2 large European centers were combined to examine long-term treatment outcomes, and the study is composed of 288 adult patients (165 women) with a median follow-up of 17 years (range, 0.4–54). Approximately two thirds of these patients had hepatic symptoms; only a very small proportion (6.6%) presented with fulminant Wilsonian liver failure. Most patients were treated with a chelator, usually d-penicillamine, as initial treatment, and just 23 patients received zinc monotherapy as primary treatment. The authors formulated specific definitions of treatment failure (based on a specified rise in serum aminotransferases or basal urinary copper excretion). Zinc proved to be less safe and efficacious than generally thought. Treatment failure occurred in patients switched from d-penicillamine to zinc, on average 15 years after diagnosis and in some cases much later. A few patients failed to respond favorably to zinc as primary treatment, although their serum and urinary zinc levels were similar to those found in responders. Temporally dispersed combination therapy of a chelator and zinc was discontinued in 6 patients because the physician suspected that the chelator and zinc were interacting. Although these results are rather surprising, they are similar to the experience (median follow-up, 14 years; range, 2–30) reported by Linn et al15Linn F.H. Houwen R.H. van Hattum J. et al.Long-term exclusive zinc monotherapy in symptomatic Wilson disease: experience in 17 patients.Hepatology. 2009; 50: 1442-1452Google Scholar regarding 17 Wilson disease patients treated exclusively with zinc. They found that zinc monotherapy was more effective for neurologic than for hepatic Wilson disease. Hepatic disease progressed significantly in some patients. Both groups report a role for chelation therapy to improve hepatic status in these patients with unfavorable response to zinc. Although retrospective reviews are routinely regarded with skepticism, these data deserve our attention. Poor adherence to the zinc regimen, as well as a relatively lower dose of zinc for hepatic as opposed to neuropsychiatric Wilson disease patients, was a favored explanation for the findings from the Utrecht group. It is a recognized weakness of the paper from Weiss et al14Weiss K.H. Gotthardt D.N. Klemm D. et al.Zinc monotherapy is not as effective as chelating agents in treatment of Wilson disease.Gastroenterology. 2011; 140: 1189-1198Abstract Full Text Full Text PDF Scopus (135) Google Scholar that compliance was not documented clinically in the cohort; however, laboratory data relating to zinc levels and urinary excretion were at least consistent with adequate compliance. Regarding early treatment failures, they speculate that some individuals may be “zinc nonresponders.” There are other candidate explanations for late treatment failures: inadequate decoppering and actual zinc toxicity. Reported data are conflicting as to whether hepatic copper is decreased with chronic zinc treatment for Wilson disease. There have been hints that zinc is toxic in some Wilson disease patients.16Lang C.J. Rabas-Kolominsky P. Engelhardt A. et al.Fatal deterioration of Wilson's disease after institution of oral zinc therapy.Arch Neurol. 1993; 50: 1007-1008Google Scholar, 17Castilla-Higuero L. Romero-Gomez M. et al.Acute hepatitis after starting zinc therapy in a patient with presymptomatic Wilson's disease.Hepatology. 2000; 32: 877Google Scholar Our knowledge of zinc disposition in cells has advanced greatly over the past 10 years.18Colvin R.A. Holmes W.R. Fontaine C.P. et al.Cytosolic zinc buffering and muffling: their role in intracellular zinc homeostasis.Metallomics. 2010; 2: 306-317Google Scholar It has become evident that zinc can be toxic when it accumulates in cells beyond what is needed for normal cellular function. In the early 1990s, when zinc was being developed as a treatment for Wilson disease, the consensus was that zinc was essentially nontoxic.19Vallee B.L. Falchuk K.H. The biochemical basis of zinc physiology.Physiol Rev. 1993; 73: 79-118Google Scholar Recently, zinc cytotoxicity has been extensively investigated in neuronal systems.20Sensi S.L. Paoletti P. Bush A. et al.Zinc in the physiology and pathology of the CNS.Nat Neurosci Rev. 2009; 10: 780-791Google Scholar At optimal concentrations, zinc is not a pro-oxidant and it activates certain antioxidant defense mechanisms; nevertheless, oxidative stress seems to play an important role in zinc cytotoxicity. The mechanism is indirect. Metallothionein not only modulates the action of zinc intracellularly but can potentiate zinc mobilization in a redox-active fashion.21Krezel A. Hao Q. Maret W. The zinc/thiolate redox biochemistry of metallothionein and the control of zinc ion fluctuations in cell signaling.Arch Biochem Biophys. 2007; 463: 188-200Google Scholar Detailed studies in cell culture models indicate that exogenous zinc damages mitochondria.22Cheng W.Y. Tong H. Miller E.W. et al.An integrated imaging approach to the study of oxidative stress generation by mitochondrial dysfunction in living cells.Environ Health Perspect. 2010; 118: 902-908Google Scholar Some human population studies indicate that long-term, excessive intake of zinc can produce toxic effects.23Plum L.M. Rink L. Haase H. The essential toxin: impact of zinc on human health.Int J Environ Res Public Health. 2010; 7: 1342-1365Google Scholar A possible explanation for the relatively infrequent hepatotoxicity among Wilson disease patients treated with zinc monotherapy takes its cue from the pharmacogenetic mechanism of rare hepatotoxicities of anti-epileptic drugs. In such cases, a genetic defect in hepatic drug detoxification is undetectable unless the patient is challenged with the relevant drug. We could imagine that some patients with Wilson disease have a genetic defect in handling zinc, or coping with oxidative stress, or a mitochondrial defect predisposing to apoptosis—entirely inapparent until challenged by chronically elevated hepatocellular concentrations of zinc. Excess hepatocellular copper might enhance the defect. One way to identify weak links in the hepatocellular handling of zinc is through defining the hepatocellular Zn-metalloproteome, the set of proteins interacting with zinc in hepatocytes. An initial assessment in HepG2 cells was performed by using a zinc-charged immobilized metal affinity chromatography column as a first step for protein capture before gel electrophoresis and mass spectrometric separation.24She Y.M. Narindrasorasak S. Yang S. et al.Identification of metal-binding proteins in human hepatoma lines by immobilized metal affinity chromatography and mass spectrometry.Mol Cell Proteomics. 2003; 2: 1306-1318Google Scholar Importantly, this procedure finds functional binding sites: although widely accepted, its specificity and sensitivity are suboptimal, and identified proteins need further characterization. Recent bioinformatics studies have detailed the Zn-metalloproteome, a significant proportion of proteins in eukaryotes, in a broad spectrum of organisms.25Bertini I. Decaria L. Rosato A. The annotation of full zinc proteomes.J Biol Inorg Chem. 2010; 15: 1071-1078Google Scholar Abnormalities in the intricate hepatocellular pathways for zinc disposition might contribute to zinc “nonresponse” or cytotoxicity. Investigations comparing Cu- and Zn-metalloproteomes in hepatocytes subjected to Cu, Zn, or combined Zn-plus-Cu loading might elucidate the clinical findings. Likewise, using transcriptomics to examine how zinc excess affects hepatocellular gene expression might be highly informative (Figure 1). In conclusion, zinc is often a beneficial treatment modality in Wilson disease, but using zinc to treat Wilson disease is more complicated than it may have seemed initially. Although adherence is an important issue, other problems may sometimes arise. Some patients simply may not respond to zinc. Diminished efficacy or perhaps outright hepatotoxicity may be found in later stages of long-term treatment with zinc. These developments are usually signaled by rising serum aminotransferases and/or increased basal urinary excretion of copper. Chelation therapy is then required. Mechanistic studies are needed to understand these phenomena. Long-term zinc treatment may also have untoward effects outside of the liver by altering blood lipid profiles or diminishing immune function. Therefore, Wilson disease patients who enjoy generally good health on zinc treatment require unremitting vigilance as to their hepatic and extrahepatic clinical status. Zinc Monotherapy Is Not as Effective as Chelating Agents in Treatment of Wilson DiseaseGastroenterologyVol. 140Issue 4PreviewWilson disease is a genetic disorder that affects copper storage, leading to liver failure and neurologic deterioration. Patients are treated with copper chelators and zinc salts, but it is not clear what approach is optimal because there have been few studies of large cohorts. We assessed long-term outcomes of different treatments. Full-Text PDF" @default.
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• W2000597587 title "Zinc Toxicity: From “No, Never” to “Hardly Ever”" @default.
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