Wilson's disease: clinical management and therapy

Abstract

Wilson's disease is a rare autosomal recessive genetic disease resulting from copper toxicity, primarily in brain and liver [1Brewer G.J. Wilson's disease: a clinician's guide to recognition. Kluwer Academic, Boston2001Google Scholar, 2Scheinberg I.H. Sternlieb I. Smith Jr, L.H. Wilson's disease. Major problems in internal medicine. vol. 23. WB Saunders, Philadelphia1984Google Scholar, 3Schilsky M.L. Wilson disease: genetic basis of copper toxicity and natural history.Semin Liver Dis. 1996; 16: 83-95Crossref PubMed Scopus (130) Google Scholar]. The disease is caused by mutations in the ATP7B gene, which functions in a biliary copper excretory pathway [4Bull P.C. Thomas G.R. Rommens J.M. Forbes J.R. Cox D.W. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene.Nat Genet. 1993; 5: 327-337Crossref PubMed Scopus (1695) Google Scholar, 5Tanzi R.E. Petrukhin K. Chernov I. Pellequer J.L. Wasco W. Ross B. et al.The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene.Nat Genet. 1993; 5: 344-350Crossref PubMed Scopus (1177) Google Scholar, 6Yamaguchi Y. Heiny M.E. Gitlin J.D. Isolation and characterization of a human liver cDNA as a candidate gene for Wilson disease.Biochem Biophys Res Commun. 1993; 197: 271-277Crossref PubMed Scopus (473) Google Scholar]. Failure of biliary excretion of excess copper leads to a slow accumulation of copper to the point of toxicity. In Western countries patients typically present with liver or neurologic disease in the second and third decades of life, although overall age of presentation can be quite broad (age 5–60 years). Patients presenting with liver disease may present with a hepatitis or recurrent hepatitis picture, cirrhosis, or liver failure [1Brewer G.J. Wilson's disease: a clinician's guide to recognition. Kluwer Academic, Boston2001Google Scholar, 7Brewer G.J. Fink J.K. Hedera P. Diagnosis and treatment of Wilson's disease.Semin Neurol. 1999; 19: 261-270Crossref PubMed Scopus (49) Google Scholar]. Patients presenting neurologically have symptoms of a movement disorder, often with dysarthria, dysphagia, incoordination, tremor, and dystonia occurring in any combination [1Brewer G.J. Wilson's disease: a clinician's guide to recognition. Kluwer Academic, Boston2001Google Scholar, 7Brewer G.J. Fink J.K. Hedera P. Diagnosis and treatment of Wilson's disease.Semin Neurol. 1999; 19: 261-270Crossref PubMed Scopus (49) Google Scholar]. Often patients present with behavioral abnormalities before developing neurologic symptoms [1Brewer G.J. Wilson's disease: a clinician's guide to recognition. Kluwer Academic, Boston2001Google Scholar, 7Brewer G.J. Fink J.K. Hedera P. Diagnosis and treatment of Wilson's disease.Semin Neurol. 1999; 19: 261-270Crossref PubMed Scopus (49) Google Scholar]. These include depression, loss of emotional control, inability to focus on tasks, loss of inhibitions, and occasionally, bizarre behavior. Screening tests include 24 h urine copper, Kayser-Fleischer ring examination by slit lamp, and serum copper and ceruloplasmin assays. The definitive diagnostic test is percutaneous liver biopsy with quantitative assay of copper. Mutation analysis is generally not useful because of the large number of causative mutations. Once a patient is diagnosed, full siblings can be genotyped by comparing their haplotypes to that of the patient. Penicillamine has been available longer than the other anticopper drugs [[8]Walshe J.M. Penicillamine, a new oral therapy for Wilson's disease.Am J Med. 1956; 21: 487-495Abstract Full Text PDF PubMed Scopus (524) Google Scholar], and is therefore best known to physicians. However, it has serious short-comings of toxicity and neurologic worsening [[9]Brewer G.J. Terry C.A. Aisen A.M. Hill G.M. Worsening of neurologic syndrome in patients with Wilson's disease with initial penicillamine therapy.Arch Neurol. 1987; 44: 490-493Crossref PubMed Scopus (308) Google Scholar], and is being replaced by other equally effective, and less toxic, drugs. Penicillamine is a reductive chelator, and acts to mobilize copper from hepatic and other stores, and cause its excretion in the urine. The usual dose is 1.0 g/day, given as 500 mg twice daily or 250 mg four times daily. Each dose should be given at least half an hour before meals or at least 2 h after meals. It is not uncommon in a newly treated patient to see urinary excretion of 5–10 mg of copper/day (normal is 20–50 μg/day, in untreated Wilson's it typically ranges from 100 to 1000 μg/day). As treatment proceeds the freely available copper pool is lessened, and the urine copper decreases, often to 750–2000 μg/day. Pyridoxine in a dose of 25 mg/day must be taken by patients on penicillamine therapy to avoid pyridoxine deficiency. Penicillamine is fully effective in Wilson's disease as long as the patient complies adequately. Compliance and the copper status of the patient may be monitored by 24 h urine copper, but this is often difficult to interpret since urine copper with penicillamine treatment is a result of both the therapeutic effect of the drug and the body loading of copper. A better monitoring tool is non-ceruloplasmin plasma copper. To determine this value, a plasma (or serum) copper is determined at the same time as a plasma ceruloplasmin (Cp) is assayed. Each mg/dl of Cp contains 3 μg/dl of copper. This is simply subtracted from the plasma copper expressed in μg/dl. For example, if plasma copper is 40 μg/dl, and Cp is 10 mg/dl, 10×3=30, subtracted from 40=10. The normal value is 10–15, and in untreated Wilson's disease it is often 30–50. Maintaining this value below 25 is indicative of adequate control. Monitoring frequencies for efficacy are suggested in Table 1A.Table 1Suggested monitoring for efficacy and toxicityDrugFor efficacyFor toxicityA. Penicillamine or Trientine24 h urine copper and non-ceruloplasmin plasma copper at 1, 3, 6, 12, 18 and 24 months, then annuallyBlood counts, liver function tests, creatinine and urinalysis weekly for 1 month, then biweekly for 2 months, then monthly for 3 months, then every 6 months for 2 years, then annuallyPatients to report any adverse reaction at onceB. Zinc24 h urine copper and zinc every 3 months for 6 months, then every 6 months for 2 years, then annuallyNo laboratory studies necessaryIt is good practice to monitor blood counts, liver function test, creatinine, and urinalysis annuallyPatients to report any adverse reaction at onceC. Tetrathiomolybdate (assuming an8–16 weeks course of initial therapy)Weekly neurologic examination or telephone interview, about neurologic statusBlood counts and liver function tests every 2 weeks Open table in a new tab The side effects of penicillamine are numerous and often serious [1Brewer G.J. Wilson's disease: a clinician's guide to recognition. Kluwer Academic, Boston2001Google Scholar, 7Brewer G.J. Fink J.K. Hedera P. Diagnosis and treatment of Wilson's disease.Semin Neurol. 1999; 19: 261-270Crossref PubMed Scopus (49) Google Scholar, 10Brewer G.J. Yuzbasiyan-Gurkan V. Wilson disease.Medicine. 1992; 71: 139-164Crossref PubMed Scopus (358) Google Scholar]. There is an initial hypersensitivity involving 20–25% of patients. Other acute and subacute side effects include bone marrow suppression and proteinuria. Longer term side effects include autoimmune diseases such as systemic lupus erythematosus and Goodpasture's syndrome, effects on immune suppression leading to risk of infection, effects on skin such as wrinkling, and deleterious effects on vascular collagen. Monitoring frequencies for toxicity are suggested in Table 1A. When used as initial therapy for neurologic patients, there is a high risk of neurologic worsening, currently estimated at 50% [[9]Brewer G.J. Terry C.A. Aisen A.M. Hill G.M. Worsening of neurologic syndrome in patients with Wilson's disease with initial penicillamine therapy.Arch Neurol. 1987; 44: 490-493Crossref PubMed Scopus (308) Google Scholar]. Half of the patients who worsen never recover to their pre-penicillamine baseline. The mechanism is believed to be due to mobilization of hepatic copper with a resulting increase in brain copper levels. Thus, penicillamine should never be given as initial treatment to patients with neurologic symptoms, since safer treatment alternatives are available. Trientine was introduced in 1982 [[11]Walshe J.M. Treatment of Wilson's disease with trientine (triethylene tetramine) dihydrochloride.Lancet. 1982; 1: 643-647Abstract PubMed Scopus (308) Google Scholar] as an alternative treatment for Wilson's disease patients intolerant of penicillamine and has been approved by the US FDA for that purpose. Trientine is also a chelator and acts similarly to penicillamine, although in a somewhat gentler manner. The dose and precautions about food intake are identical to penicillamine. However, the amount of urine copper is much less, perhaps in the 1.0–3.0 mg/day range for newly treated patients, rapidly tailing off to 1.0 mg/day or less. Trientine is also fully effective in Wilson's disease as long as the patient complies with therapy. Compliance and the copper status of the patient are monitored identically to penicillamine, with non-ceruloplasmin plasma copper being a better monitoring tool than 24 h urine copper. (Please see the preceding section on penicillamine to find out how to calculate and interpret non-ceruloplasmin plasma copper.) Suggested monitoring for efficacy of trientine is shown in Table 1A. Trientine shares some of the same side effects as penicillamine but at a much lower frequency [1Brewer G.J. Wilson's disease: a clinician's guide to recognition. Kluwer Academic, Boston2001Google Scholar, 7Brewer G.J. Fink J.K. Hedera P. Diagnosis and treatment of Wilson's disease.Semin Neurol. 1999; 19: 261-270Crossref PubMed Scopus (49) Google Scholar]. The most common perhaps, is proteinuria, occurring in 2–5% of patients. Suggested monitoring for trientine toxicity is shown in Table 1A. The risk of neurologic worsening in neurologically presenting patients, when trientine is used as initial therapy, is less than with penicillamine, a little lower than 20% [[12]Brewer G.J. Schilsky M. Hedera P. Carlson M.D. Fink J.K. Askari F.K. et al.Double blind study of initial therapy of neurological Wilson's disease (abstract).J Invest Med. 2003; : 51Google Scholar]. Zinc was approved in 1997 by the US FDA for the maintenance therapy of Wilson's disease [[13]Brewer G.J. Dick R.D. Johnson V.D. Brunberg J.A. Kluin K.J. Fink J.K. Treatment of Wilson's disease with zinc: XV long-term follow-up studies.J Lab Clin Med. 1998; 132: 264-278Abstract Full Text PDF PubMed Scopus (220) Google Scholar]. Zinc acts by a novel mechanism. It induces intestinal cell metallothionein and inhibits the absorption of copper [14Hall A.C. Young B.W. Bremner I. Intestinal metallothionein and the mutual antagonism between copper and zinc in the rat.J Inorg Biochem. 1979; 11: 57-66Crossref PubMed Scopus (147) Google Scholar, 15Menard M.P. McCormick C.C. Cousins R.J. Regulation of intestinal metallothionein biosynthesis in rats by dietary zinc.J Nutr. 1981; 111: 1353-1361Crossref PubMed Scopus (79) Google Scholar, 16Oestreicher P. Cousins R.J. Copper and zinc absorption in the rat: mechanism of mutual antagonism.J Nutr. 1985; 115: 159-166PubMed Google Scholar, 17Lee 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: 639-645PubMed Google Scholar, 18Yuzbasiyan-Gurkan V. Grider A. Nostrant T. Cousins R.J. Brewer G.J. Treatment of Wilson's disease with zinc: X. Intestinal metallothionein induction.J Lab Clin Med. 1992; 120: 380-386PubMed Google Scholar]. The dose is 150 mg/day, in three divided doses, each dose separated from food and beverages other than water by at least 1 h. Zinc is fully effective in Wilson's disease as long as the patient complies with therapy. The monitoring system for compliance and copper status with zinc therapy is superior to those with penicillamine and trientine therapy. That is because the urinary excretion of copper with zinc therapy is solely related to the body loading of ‘freely available’ copper, and has nothing to do with the direct therapeutic action of the drug. Thus, during maintenance therapy, a target of 50–125 μg/day urine copper should be sought, and any progressive elevations above that level a cause for concern that the zinc is not being taken as prescribed. This situation does not call for a change in medication, but does call for a discussion with the patient on compliance. As a bonus, the 24 h urine zinc can be measured on the same sample, and used to determine compliance. Urine zinc should be over 2.0 mg/day in well complying patients. Monitoring recommendations for efficacy of zinc are given in Table 1B. Zinc has an excellent safety profile. The only toxicity is gastric irritation in 5–10% of patients [[13]Brewer G.J. Dick R.D. Johnson V.D. Brunberg J.A. Kluin K.J. Fink J.K. Treatment of Wilson's disease with zinc: XV long-term follow-up studies.J Lab Clin Med. 1998; 132: 264-278Abstract Full Text PDF PubMed Scopus (220) Google Scholar]. Often the offending dose is the first one in the morning, and the simple maneuver of taking the first dose of the day mid-morning, rather than before breakfast, is effective in preventing irritation. In stubborn cases, the dose can be taken with a little protein (a piece of meat, or some jello), because protein interferes the least with zinc action. The preparation of zinc approved by the FDA was zinc acetate, trade name Galzin® (Gate Pharmaceuticals, North Wales, PA). Zinc as zinc sulfate, zinc gluconate, or other salts, can often be obtained in health food stores or at a pharmacy. The advantage of Galzin® is that it is a pharmaceutical product, and thus has been rigorously tested as to dose accuracy and lack of contaminants, which is generally not true for health food supplements. TM is not yet commercially available, but is expected to be soon. TM acts by yet another novel mechanism. It forms a tripartite complex with protein, copper, and itself [19Mills C.F. El-Gallad T.T. Bremner I. Effects of molybdate, sulfide, and tetrathiomolybdate on copper metabolism in rats.J Inorg Biochem. 1981; 14: 189-207Crossref PubMed Scopus (66) Google Scholar, 20Bremner I. Mills C.F. Young B.W. Copper metabolism in rats given di- or trithiomolybdates.J Inorg Biochem. 1982; 16: 109-119Crossref PubMed Scopus (66) Google Scholar, 21Mills C.F. El-Gallad T.T. Bremner I. Weham G. Copper and molybdenum absorption by rats given ammonium tetrathiomolybdate.J Inorg Biochem. 1981; 14: 163-175Crossref PubMed Scopus (71) Google Scholar, 22Gooneratne S.R. Howell J.M. Gawthorne J.M. An investigation of the effects of intravenous administration of thiomolybdate on copper metabolism in chronic Cu-poisoned sheep.Br J Nutr. 1981; 46: 469-480Crossref PubMed Scopus (70) Google Scholar, 23Mason J. The biochemical pathogenesis of molybdenum-induced copper deficiency syndromes in ruminants: towards the final chapter.Ir Vet J. 1990; 43: 18-21Google Scholar]. If given with meals, TM complexes food and endogenously secreted copper with available protein and renders that complex unabsorbable. Thus, TM puts the patient into an immediate negative copper balance. If given away from food, TM is absorbed into the blood stream and forms the three way complex with freely available copper and albumin. This copper is no longer available for cellular uptake, and in this manner the toxic copper in Wilson's disease is rapidly titrated. TM has been used in Wilson's disease for the initial treatment of the neurologically presenting patient [24Brewer G.J. Dick R.D. Yuzbasiyan-Gurkan V. Tankanow R. Young A.B. Kluin K.J. Initial therapy of patients with Wilson's disease with tetrathiomolybdate.Arch Neurol. 1991; 48: 42-47Crossref PubMed Scopus (182) Google Scholar, 25Brewer G.J. Dick R.D. Johnson V. Wang Y. Yuzbasiyan-Gurkan V. Kluin K. et al.Treatment of Wilson's disease with ammonium tetrathiomolybdate. I. Initial therapy in 17 neurologically affected patients.Arch Neurol. 1994; 51: 545-554Crossref PubMed Scopus (147) Google Scholar, 26Brewer G.J. Johnson V. Dick R.D. Kluin K.J. Fink J.K. Brunberg J.A. Treatment of Wilson disease with ammonium tetrathiomolybdate. II. Initial therapy in 33 neurologically affected patients and follow-up with zinc therapy.Arch Neurol. 1996; 53: 1017-1025Crossref PubMed Scopus (157) Google Scholar, 27Brewer G.J. Hedera P. Kluin K.J. Carlson M. Askari F. Dick R.B. et al.Treatment of Wilson disease with ammonium tetrathiomolybdate. III. Initial therapy in a total of 55 neurologically affected patients and follow-up with zinc therapy.Arch Neurol. 2003; 60: 379-385Crossref PubMed Scopus (187) Google Scholar] and is currently being investigated for the initial treatment of the hepatic presentation as well. The dose is 120 mg/day, 20 mg three times/day with meals, and 60 mg at bedtime away from food, given for eight weeks, concomitant with zinc therapy. The measure of efficacy has been the rate of neurological deterioration, which has been less than 5% with TM [[27]Brewer G.J. Hedera P. Kluin K.J. Carlson M. Askari F. Dick R.B. et al.Treatment of Wilson disease with ammonium tetrathiomolybdate. III. Initial therapy in a total of 55 neurologically affected patients and follow-up with zinc therapy.Arch Neurol. 2003; 60: 379-385Crossref PubMed Scopus (187) Google Scholar] (compared to 50% for penicillamine and a little less than 20% for trientine [[12]Brewer G.J. Schilsky M. Hedera P. Carlson M.D. Fink J.K. Askari F.K. et al.Double blind study of initial therapy of neurological Wilson's disease (abstract).J Invest Med. 2003; : 51Google Scholar]). Suggested monitoring for TM efficacy is given in Table 1C. TM has a good safely profile [12Brewer G.J. Schilsky M. Hedera P. Carlson M.D. Fink J.K. Askari F.K. et al.Double blind study of initial therapy of neurological Wilson's disease (abstract).J Invest Med. 2003; : 51Google Scholar, 27Brewer G.J. Hedera P. Kluin K.J. Carlson M. Askari F. Dick R.B. et al.Treatment of Wilson disease with ammonium tetrathiomolybdate. III. Initial therapy in a total of 55 neurologically affected patients and follow-up with zinc therapy.Arch Neurol. 2003; 60: 379-385Crossref PubMed Scopus (187) Google Scholar]. There is a 10–15% incidence of overtreatment anemia/leukopenia, responsive to lowering the dose. There is also a 10–15% incidence of a mild further increase in transaminase enzymes, probably due to TM's ability to shift copper out of hepatic metallothionein pools. This, too, is quickly responsive to lowering the dose. Currently a study is underway to see if a lower dose given longer will preserve efficacy and reduce side effects. Suggested monitoring for TM toxicity is given in Table 1C. Fig. 1 presents an overview of anticopper drug recommendations for initial therapy of various types of newly diagnosed patients. This figure can be used as a guide for initial therapy as we proceed through a discussion of specific patient types. Recommended drug choices for various types of liver disease presentations are given in Table 2. If the patient simply has transaminase elevations, or cirrhosis and transaminase elevations, but no evidence of hepatic decompensation in terms of low albumin, elevated bilirubin, and prolonged prothrombin time, the patient may be treated as a maintenance phase patient with zinc or trientine.Table 2Anticopper drug choices for initial therapy of hepatic patientsPatient typeDrug choiceExperimental1st2ndTransaminase elevations, no hepatic failureZincTrientineCirrhosis present, no hepatic failureZincTrientineHepatic failureaSee Table 3 for classification of hepatic failure. Mild or moderateTrientine plus zincPenicillamine plus zincTM plus zinc SevereHepatic transplantTrientine plus zinca See Table 3 for classification of hepatic failure. Open table in a new tab If the patient does have evidence of hepatic decompensation, triage must be carried out to see if the patient is likely to survive with medical anticopper therapy, or if it is likely transplantation will need to be carried out for survival. It must be emphasized that the Child-Turcotte-Pugh scores, and other scores worked out for patients with liver failure from causes other than Wilson's disease, are not appropriate for classification of Wilson's disease patients for transplantation. For example, the nine patients with liver failure presented in Ref. [[28]Askari F.K. Greenson J. Dick R.D. Johnson V.D. Brewer G.J. Treatment of Wilson's disease with zinc. XVIII. Initial treatment of the hepatic decompensation presentation with trientine and zinc.J Lab Clin Med. 2003; 142: 385-390Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar] all had Child-Turcotte-Pugh scores calling for transplantation, yet all were treated successfully with medical therapy. Table 3A provides guidance based upon our personal experience in Wilson's disease, in that the mild to moderate group are likely to survive with medical therapy, while the severe group should usually be transplanted. The guidance in Table 3A can be supplemented with that in Table 3B, which is a recapitulation of the Nazer et al. [[29]Nazer H. Ede R. Mowat A.R.W. Wilson's disease: clinical presentation and use of prognostic index.Gut. 1986; 27: 1377-1381Crossref PubMed Scopus (207) Google Scholar] scoring system. The Nazer score can be calculated using the bilirubin, AST, and prolongation of the prothrombin time. The original data of Nazer et al. [[29]Nazer H. Ede R. Mowat A.R.W. Wilson's disease: clinical presentation and use of prognostic index.Gut. 1986; 27: 1377-1381Crossref PubMed Scopus (207) Google Scholar] indicates that patients with scores of 6 or below were likely to survive on penicillamine therapy, while those with scores of 7 or above were not. However, with a combination of trientine and zinc, we have successfully treated patients with Nazer scores as high as 9 [[28]Askari F.K. Greenson J. Dick R.D. Johnson V.D. Brewer G.J. Treatment of Wilson's disease with zinc. XVIII. Initial treatment of the hepatic decompensation presentation with trientine and zinc.J Lab Clin Med. 2003; 142: 385-390Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar].Table 3A. Classification of hepatic failure, based on our experience with Wilson's diseaseNormal valueMildModerateSevereLaboratory test Serum total bilirubin0.2–1.2 mg/dl<88–15>15 Serum AST10–35 IU/L<150150–250>250 Serum ALT10–35 IU/L<150150–250>250 Serum albumin3.5–4.5 g/dl>2.5<2.5<2.5 Prolongation of prothrombin time0 s<88–15>15Clinical findings Fluid accumulationNoneOften small amountModerate amountLarge amount Bleeding due to low coagulation factorsNoneUsually notBleeding may be presentBleeding often present Hepatic encephalopathyNoneNoneNoneMay be presentB. Classification of hepatic failure based upon the prognostic index of Nazer et al. (modified with permission)Laboratory measurementNormal valueScore (in points)01234Serum bilirubin0.2–1.2 mg/dl<5.85.8–8.88.8–11.711.7–17.5>17.5Serum aspartate transferase (AST)10–35 IU/L<100100–150151–200201–300>300Prolongation of prothrombin time (seconds)–<44–89–1213–20>20Reprinted from: Kluwer Academic Publishers, Boston, Wilson's Disease: A Clinician's Guide to Recognition, Diagnosis, and Management. 2001, George J Brewer, pages 80 and 81, Chapter 6. Initial treatment of patients who present with liver disease, Tables 6.1 and 6.2, with kind permission of Springer Science and Business Media. Open table in a new tab Reprinted from: Kluwer Academic Publishers, Boston, Wilson's Disease: A Clinician's Guide to Recognition, Diagnosis, and Management. 2001, George J Brewer, pages 80 and 81, Chapter 6. Initial treatment of patients who present with liver disease, Tables 6.1 and 6.2, with kind permission of Springer Science and Business Media. Currently the recommended initial therapy for patients in hepatic failure to be treated medically is a combination of trientine and zinc (Fig. 1 and Table 2). The drugs must be separated from each other, as well as from food, by at least an hour. Trientine is chosen over penicillamine because of its lower toxicity. Zinc is added because it is an inducer of hepatic metallothionein, which will help bind potentially toxic copper in the liver. Using this combination we have successfully treated patients with Nazer scores as high as 9, without any treatment failures [[29]Nazer H. Ede R. Mowat A.R.W. Wilson's disease: clinical presentation and use of prognostic index.Gut. 1986; 27: 1377-1381Crossref PubMed Scopus (207) Google Scholar]. The combination should be continued until liver function tests are well on their way to improvement (usually 4–6 months) and then maintenance therapy should begin with just one of the drugs. We prefer zinc for maintenance therapy. It has been shown that during maintenance therapy there is no advantage of giving two anticopper drugs, and there are some disadvantages including difficulty with compliance, drug toxicity and increased potential for developing copper deficiency [[30]Brewer G.J. Yuzbasiyan-Gurkan V. Johson V. Dick R.D. Wang Y. Treatment of Wilson's disease with zinc. XI. Interaction with other anticopper agents.J Am Coll Nutr. 1993; 12: 26-30PubMed Google Scholar]. Liver function should begin improving 3 or 4 months after therapy is initiated and will continue to improve, and in most patients become normal, by 12 months [[28]Askari F.K. Greenson J. Dick R.D. Johnson V.D. Brewer G.J. Treatment of Wilson's disease with zinc. XVIII. Initial treatment of the hepatic decompensation presentation with trientine and zinc.J Lab Clin Med. 2003; 142: 385-390Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar]. Some liver damage, and in many cases frank cirrhosis, will remain in most patients. The patient may have lifelong cirrhosis, portal hypertension, hypersplenism, and esophageal and/or gastric varices. Except for the varices, these abnormalities generally do not present any medical problems assuming normal liver function tests. Variceal bleeding seems to be at its highest risk in the first 2–3 years of therapy, and then the risk decreases. The risk of liver cancer is low compared to other causes of cirrhosis, probably less than 1 in 400 lifelong. Recommended drug choices for patient presenting with the neurologic or psychiatric form of the disease are given in Fig. 1 and Table 4A. A major problem exists with the initial therapy of neurologic patients in that all of the drugs currently available commercially have defects in treating these patients. Penicillamine has a high rate (estimated at about 50%) of causing neurologic worsening [[9]Brewer G.J. Terry C.A. Aisen A.M. Hill G.M. Worsening of neurologic syndrome in patients with Wilson's disease with initial penicillamine therapy.Arch Neurol. 1987; 44: 490-493Crossref PubMed Scopus (308) Google Scholar], probably by mobilizing hepatic copper and temporarily further elevating brain copper. About half of the patients who worsen never recover to their prepenicillamine baseline. Trientine, which is a chelator like penicillamine, appears to have about a 20% risk of causing neurologic worsening in these patients [[12]Brewer G.J. Schilsky M. Hedera P. Carlson M.D. Fink J.K. Askari F.K. et al.Double blind study of initial therapy of neurological Wilson's disease (abstract).J Invest Med. 2003; : 51Google Scholar]. We believe zinc is too slow acting to be optimal for these patients, and the disease may progress during the 4–6 months zinc requires to gain control of neurologic copper toxicity. Indeed, one of three patients we treated with zinc alone had serious progression of tremor. The Hoogenraad group in the Netherlands use zinc alone, but have never reported any details on whether there has been progression in some of their patients [[31]Hoogenraad T.U. Van Hattum J. Van den Hamer C.J.A. Management of Wilson's disease with zinc sulfate. Experience in a series of 27 patients.J Neurol Sci. 1987; 77: 137-146Abstract Full Text PDF PubMed Scopus (154) Google Scholar].Table 4A. Anticopper drug choices initial therapy of neurologic/psychiatric patients1st Choice2nd Choice3rd ChoiceTetrathiomolybdate and ZincZinc aloneTrientine and ZincB. Anticopper drug choices for maintenance therapy and therapy of the presymptomatic, and pregnant patient1st Choice2nd ChoiceZincTrientineC. Anticopper drug choices for the pediatric patient.Type of patientRecommendationInitial hepaticAs in Table 2, with appropriate dose adjustmentInitial neurologicAs above, with appropriate dose adjustmentMaintenance or presymptomaticAs above, with appropriate dose adjustment Open table in a new tab Because of the lack of a good drug for this type of patient we have developed tetrathiomolybdate (TM) for treating patients presenting with neurologic disease. In an open label study, only 2 of 55 patients reached quantitative neurologic function scoring criteria for neurologic worsening during initial treatment [[27]Brewer G.J. Hedera P. Kluin K.J. Carlson M. Askari F. Dick R.B. et al.Treatment of Wilson disease with ammonium tetrathiomolybdate. III. Initial therapy in a total of 55 neurologically affected patients and follow-up with zinc therapy.Arch Neurol. 2003; 60: 379-385Crossref PubMed Scopus (187) Google Scholar]. These deteriorations maybe the result of the natural history of the disease, whereas penicillamine and trientine deteriorations may be primarily drug catalyzed effects. This low rate of deterioration with TM was co