Advertisement

Zinc Monotherapy Is Not as Effective as Chelating Agents in Treatment of Wilson Disease

Published:December 27, 2010DOI:https://doi.org/10.1053/j.gastro.2010.12.034

      Background & Aims

      Wilson 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.

      Methods

      Patients in tertiary care centers were retrospectively analyzed (n = 288; median follow-up time, 17.1 years) for adherence to therapy, survival, treatment failure, and adverse events from different treatment regimens (chelators, zinc, or a combination). Hepatic treatment failure was defined as an increase in activity of liver enzymes (aspartate aminotransferase, alanine aminotransferase, and γ-glutamyltransferase) >2-fold the upper limit of normal or >100% of baseline with an increase in urinary copper excretion.

      Results

      The median age at onset of Wilson disease was 17.5 years. Hepatic and neuropsychiatric symptoms occurred in 196 (68.1%) and 99 (34.4%) patients, respectively. Hepatic treatment failure occurred more often from zinc therapy (14/88 treatments) than from chelator therapy (4/313 treatments; P < .001). Actuarial survival, without transplantation, showed an advantage for chelating agents (P < .001 vs zinc). Changes in treatment resulted mostly from adverse events, but the frequency did not differ between groups. Patients who did not respond to zinc therapy showed hepatic improvement after reintroduction of a chelating agent.

      Conclusions

      Treatments with chelating agents or zinc salt are effective in most patients with Wilson disease; chelating agents are better at preventing hepatic deterioration. It is important to identify patients who do not respond to zinc therapy and have increased activities of liver enzymes, indicating that a chelating agent should be added to the therapeutic regimen.

      Keywords

      Abbreviations used in this paper:

      γ-GT (γ-glutamyltransferase), OLT (orthotopic liver transplantation), WD (Wilson disease)
      See editorial on page 1132.
      Wilson disease (WD) is an inborn copper storage disorder leading to hepatic and neurologic symptoms caused by an impaired hepatocellular utilization and biliary excretion of copper.
      • Ala A.
      • Walker A.P.
      • Ashkan K.
      • et al.
      Wilson's disease.
      • Gitlin J.D.
      Wilson disease.
      A characteristic of WD is a remarkable heterogeneity in clinical presentation, reflected by a complex diagnostic scoring system.
      • Ferenci P.
      • Caca K.
      • Loudianos G.
      • et al.
      Diagnosis and phenotypic classification of Wilson disease.
      In terms of liver disease, the severity ranges from asymptomatic to acute liver failure, and neurologic symptoms can present independent of the liver disease.
      The overall therapeutic approach is the generation of a negative copper balance. This can be achieved either by medical therapy or liver transplantation when the time frame for a rescue with medical treatment is not wide enough.
      • Dhawan A.
      • Taylor R.M.
      • Cheeseman P.
      • et al.
      Wilson's disease in children: 37-year experience and revised King's score for liver transplantation.
      • Petrasek J.
      • Jirsa M.
      • Sperl J.
      • et al.
      Revised King's College score for liver transplantation in adult patients with Wilson's disease.
      • Nazer H.
      • Ede R.J.
      • Mowat A.P.
      • et al.
      Wilson's disease: clinical presentation and use of prognostic index.
      The treatment regimens suggested by current guidelines
      • Roberts E.A.
      • Schilsky M.L.
      Diagnosis and treatment of Wilson disease: an update.
      include copper chelators and/or zinc salts. Fundamental differences between these are the distinct mode of function of zinc via reduction of the intestinal uptake of copper
      • Brewer G.J.
      • Hill G.M.
      • Prasad A.S.
      • et al.
      Oral zinc therapy for Wilson's disease.
      • Hoogenraad T.U.
      • Koevoet R.
      • de Ruyter Korver E.G.
      Oral zinc sulphate as long-term treatment in Wilson's disease (hepatolenticular degeneration).
      and the induction of the endogenous chelator methallotheionein.
      • Hill G.M.
      • Brewer G.J.
      • Prasad A.S.
      • et al.
      Treatment of Wilson's disease with zinc. I. Oral zinc therapy regimens.
      • Cousins R.J.
      Absorption, transport, and hepatic metabolism of copper and zinc: special reference to metallothionein and ceruloplasmin.
      Independent of the chosen medical regimen, nonadherence or discontinuation of medical therapy in terms of noncompliance is associated with the risk of intractable hepatic decompensation.
      • Scheinberg I.H.
      • Jaffe M.E.
      • Sternlieb I.
      The use of trientine in preventing the effects of interrupting penicillamine therapy in Wilson's disease.
      • Walshe J.M.
      • Dixon A.K.
      Dangers of non-compliance in Wilson's disease.
      A theoretical, sequential treatment concept in WD has been suggested based on limited trials and experience. It is a concept that differentiates between initial therapy and subsequent maintenance therapy, based on the hypothesis that after a treatment phase with the more effective chelating agents, less dosage or alternative treatment with zinc in decoppered patients might be sufficient to upkeep copper homeostasis. However, only very limited data are available to decide when and under which conditions a patient can be switched to zinc maintenance therapy and vice versa. Thus, in clinical practice, chelating agents are often continued, although zinc therapy might be more appropriate. Even concerning first-line therapy, the knowledge on long-term efficacy is still limited and restricted to few and small trials and decades of clinical experience in smaller cohorts due to the rarity of the disease and the nonuniformity of clinical presentations. Here, most data exist on the chelator d-penicillamine, which was the first oral chelating agent introduced into therapy.
      • Walshe J.M.
      Wilson's disease; new oral therapy.
      d-penicillamine has been shown to be effective, especially in symptomatic patients with liver disease.
      • Walshe J.M.
      Copper chelation in patients with Wilson's disease A comparison of penicillamine and triethylene tetramine dihydrochloride.
      • Grand R.J.
      • Vawter G.F.
      Juvenile Wilson disease: histologic and functional studies during penicillamine therapy.
      • Lau J.Y.
      • Lai C.L.
      • Wu P.C.
      • et al.
      Wilson's disease: 35 years' experience.
      • Czlonkowska A.
      • Gajda J.
      • Rodo M.
      Effects of long-term treatment in Wilson's disease with D-penicillamine and zinc sulphate.
      The alternative chelator trientine has also been shown to be an effective initial therapy for patients, even for those patients with decompensated liver disease.
      • Scheinberg I.H.
      • Jaffe M.E.
      • Sternlieb I.
      The use of trientine in preventing the effects of interrupting penicillamine therapy in Wilson's disease.
      • Walshe J.M.
      Copper chelation in patients with Wilson's disease A comparison of penicillamine and triethylene tetramine dihydrochloride.
      • Dubois R.S.
      • Rodgerson D.O.
      • Hambidge K.M.
      Treatment of Wilson's disease with triethylene tetramine hydrochloride (trientine).
      • Saito H.
      • Watanabe K.
      • Sahara M.
      • et al.
      Triethylene-tetramine (trien) therapy for Wilson's disease.
      Zinc salts have already been used as the primary treatment
      • Brewer G.J.
      • Yuzbasiyan-Gurkan V.
      • Lee D.Y.
      • et al.
      Treatment of Wilson's disease with zinc. VI. Initial treatment studies.
      • Walshe J.M.
      Diagnosis and treatment of presymptomatic Wilson's disease.
      in asymptomatic or only neurologically affected patients, but even with the restriction to asymptomatic or decoppered patients with WD, the efficacy of zinc monotherapy is still under debate. Overall, various series suggest a favorable outcome,
      • Czlonkowska A.
      • Gajda J.
      • Rodo M.
      Effects of long-term treatment in Wilson's disease with D-penicillamine and zinc sulphate.
      • Linn F.H.
      • Houwen R.H.
      • van Hattum J.
      • et al.
      Long-term exclusive zinc monotherapy in symptomatic Wilson disease: experience in 17 patients.
      • Hoogenraad T.U.
      • Van Hattum J.
      • Van den Hamer C.J.
      Management of Wilson's disease with zinc sulphate Experience in a series of 27 patients.
      • Brewer G.J.
      • Dick R.D.
      • Johnson V.D.
      • et al.
      Treatment of Wilson's disease with zinc: XV long-term follow-up studies.
      but nonresponse or worsening under zinc therapy seems to occur to a certain degree
      • Walshe J.M.
      • Munro N.A.
      Zinc-induced deterioration in Wilson's disease aborted by treatment with penicillamine, dimercaprol, and a novel zero copper diet.
      • Lang C.J.
      • Rabas-Kolominsky P.
      • Engelhardt A.
      • et al.
      Fatal deterioration of Wilson's disease after institution of oral zinc therapy.
      ; thus, some investigators recommend the restriction of its use to patients who do not tolerate chelating agents well. Combination therapy using zinc in conjunction with a chelating agent (administered at widely spaced intervals during the day to avoid interference) has a theoretical basis in both blocking copper uptake and eliminating excess copper. However, rigorously designed series and safety data are not available. Reports are limited to patients who present with decompensated chronic liver disease, but they suggest a favorable outcome for combination therapy with d-penicillamine plus zinc
      • Dhawan A.
      • Taylor R.M.
      • Cheeseman P.
      • et al.
      Wilson's disease in children: 37-year experience and revised King's score for liver transplantation.
      • Santos Silva E.E.
      • Sarles J.
      • Buts J.P.
      • et al.
      Successful medical treatment of severely decompensated Wilson disease.
      or trientine plus zinc.
      • Askari F.K.
      • Greenson J.
      • Dick R.D.
      • et al.
      Treatment of Wilson's disease with zinc. XVIII. Initial treatment of the hepatic decompensation presentation with trientine and zinc.
      A clinically relevant limitation in the long-term use of every medication might be the occurrence of severe adverse events. This holds true especially for d-penicillamine; previous smaller studies reported severe adverse events such as bone marrow toxicity, elastosis cutis, nephrotoxicity, or lupus-like syndrome, leading to the discontinuation of d-penicillamine in up to 30% of patients.
      • Medici V.
      • Trevisan C.P.
      • D'Inca R.
      • et al.
      Diagnosis and management of Wilson's disease: results of a single center experience.
      • Walshe J.M.
      Wilson's disease presenting with features of hepatic dysfunction: a clinical analysis of eighty-seven patients.
      The alternative chelator trientine has been reported to have a better safety profile, although relevant adverse events like anemia have been observed. So far, few adverse events, such as gastritis or copper deficiency anemia, have been reported with zinc therapy.
      Because of limited outcome reports in small cohorts of patients and the notion that most recommended therapies are not based on controlled trails, the present study evaluated the value of zinc therapy versus chelation therapy in regard to outcome, treatment failure, and adverse events in a large patient population observed over a long period.

      Patients and Methods

       Patients

      This retrospective cohort study included 288 patients with WD examined at the University Hospital Heidelberg (Germany) and the University Hospital Vienna (Austria) between 1954 and 2008. We reviewed the diagnoses of WD using the Leipzig score.
      • Ferenci P.
      • Caca K.
      • Loudianos G.
      • et al.
      Diagnosis and phenotypic classification of Wilson disease.
      Uncertain cases of WD were excluded from further analysis. The ATP7B mutational analysis was performed as previously described.
      • Weiss K.H.
      • Merle U.
      • Schaefer M.
      • et al.
      Copper toxicosis gene MURR1 is not changed in Wilson disease patients with normal blood ceruloplasmin levels.
      • Weiss K.H.
      • Runz H.
      • Noe B.
      • et al.
      Genetic analysis of BIRC4/XIAP as a putative modifier gene of Wilson disease.
      Data on initial presentation and on the development of clinical and laboratory parameters under therapy were recorded. We categorized patients into subgroups on the basis of symptoms present at the time of diagnosis: asymptomatic, hepatic, neurologic, or mixed presentation. The presence of Kayser–Fleischer rings or liver cirrhosis was recorded. A diagnosis of cirrhosis was based on histology or on the presence of typical findings in imaging in combination with the presence of clinical signs of portal hypertension. We used Pearson's χ2 test and Fisher exact test (for sample sizes <5) to compare the study collective between the 2 centers for the categorized parameters (Table 1). The Mann–Whitney U test was used in the comparison of median onset and diagnosis, and the Kruskal–Wallis test was used for the comparison of laboratory parameters at the time of diagnosis.
      Table 1Study Population by Center
      TotalHeidelbergViennaP value
      No. of patients28822365
      Sex (female/male)165/123132/9033/33.202
      Kayser-Fleischer rings at diagnosis (%)133/258 (52.6)102/258 (51.8)31/258 (50).445
      Hepatic presentation (%)196 (68.1)155 (69.5)41 (63.1).292
      Neurologic presentation (%)99 (34.4)74 (33.2)25 (38.5).555
      No symptoms at diagnosis (%)32 (11.1)24 (10.8)8 (12.3).824
      Liver cirrhosis at diagnosis (%)101/274 (36.9)76/274 (35.2)25/274 (38.5).765
      Diagnosis by family screening (%)50 (17.4)40 (17.9)10 (15.4).712
      Presentation as fulminant WD (%)19 (6.6)17 (7.6)2 (3.1).261
      Median age at onset (y) (n = 218)17.51 (1.36–51.11)16.34 (1.36–51.11)19.02 (5.33–49.93).066
      Median age at diagnosis (y) (n = 288)18.37 (0.74–56.96)17.64 (0.74–56.96)19.9 (1.23–55.06).027
      No. of patients younger than 18 y at time of diagnosis (%)139/288 (48.2)115/223 (51.6)24/65 (36.9).048
      Time onset to diagnosis (mo) (n = 218)12.64 (0–384.3)12.97 (0–384.3)12.18 (0–303.8).938

       Approach to Monitoring and Medical Therapy

      Patients with a stable course were seen in the tertiary centers approximately once a year. After initiation or change of medical therapy, the patients were followed up more closely (3, 6, and 12 months). In principle, all treatments were used in both centers, but zinc therapy was only used as second-line or third-line therapy in the Vienna patients. In line with current guidelines, our overall recommendation was to start symptomatic patients on chelation treatment. First-line therapy with zinc was used in patients with a neurologic or asymptomatic presentation without signs of liver dysfunction. The same criteria applied when patients were electively switched to zinc maintenance therapy.

       Analysis of Treatment Changes

      Different treatment regimens were classified in the retrospective analysis of changes in treatment: (1) chelation therapy (d-penicillamine and trientine), (2) zinc salts, and (3) a combination of a chelator and zinc.
      We analyzed patient records for adverse events and treatment efficacy. Initial and subsequent therapies as well as changes in treatment regimens were recorded in detail. We categorized the reasons for discontinuation as adverse events, pregnancy, patient demand, treatment failure, death, liver transplantation, or other. We analyzed these events of change/discontinuation of treatment using the Kaplan–Meier estimation. We calculated the duration of the therapy for each treatment block until a change of medication or until the end of the follow-up period. Treatment blocks with a follow-up of <6 months were censored (chelator, n = 32; zinc, n = 7; combination, n = 11), which excluded patients directly undergoing liver transplantation. Comparable calculations were performed for the different reasons for discontinuation. We established P values for this calculation using the pairwise log-rank test (Mantel–Cox test).

       Analysis of Nonresponse to Therapy (Hepatic Treatment Failure)

      The event of treatment failure was defined as follows. The treating physician had to have classified the treatment change in the file as a nonresponse to treatment and as being unrelated to adverse events. The corresponding treatments must have been ongoing and unchanged for more than 6 months before discontinuation. Two of the 3 liver enzymes (aspartate aminotransferase [ALT], alanine aminotransferase [ALT], or γ-glutamyltransferase [γ-GT]) had to be at least 2 times greater than the upper limit of normal or 2 times greater than the baseline level at the time of discontinuation. Furthermore, in patients receiving zinc therapy, urinary zinc levels had to be elevated by more than 35 μmol/day. Additionally, urinary copper excretion had to show an increase over time, reflecting a positive copper balance. An increase was considered significant when in 3 consecutive measurements in at least 3-month intervals the urinary copper excretion was greater than the upper limit of normal and increased continuously.
      All zinc treatments were subclassified as “nonresponse to zinc therapy” or “response to zinc therapy” according to the occurrence or nonoccurrence of the event “treatment failure”, respectively. We analyzed the course of laboratory values in these 2 groups via an independent comparison of median values at different time points by using the Mann–Whitney U test.

       Statistical Methods

      Calculations were performed using SPSS for Windows software version 15.0 (SPSS Inc, Chicago, IL). P < .05 was considered significant.

      Results

       Initial Presentation of Study Group

      A total of 288 patients (165 female) were included in the analysis. Hepatic symptoms were present in 196 patients (68.1%) and neurologic symptoms in 99 patients (34.4%). Thirty-two patients (11.1%) were diagnosed as being in an asymptomatic state. At diagnosis, 19 patients (6.6%) presented as fulminant WD with hepatic failure. Over the course of the observation period, 21 patients underwent liver transplantation due to hepatic failure. The characteristics of the patients and median ages at onset and diagnosis are shown in Table 1. Laboratory parameters at diagnosis were available for a subgroup of patients. These laboratory findings are given in Supplementary Table 1, grouped by presentation (hepatic, neurologic, mixed, and asymptomatic). The patients were primarily treated with chelation therapy (n = 244; 220 d-penicillamine, 24 trientine), zinc salts (n = 23), or a combination of a chelator and zinc (n = 11, d-penicillamine and zinc; n = 3, trientine and zinc).

       Reasons for Discontinuation of Treatment

      The median follow-up period was 17.1 years (range, 0.4–54.1 years). Discontinuation of treatments was analyzed using Kaplan–Meier estimation. Changes in medical treatment were common events in the study cohort, resulting in a total of 481 treatment blocks (345 chelation therapy, 95 zinc therapy, and 41 combination therapy). Of these, 431 (313 chelation therapy [243 d-penicillamine], 88 zinc therapy, and 30 combination therapy) were suitable for analysis. The resulting Kaplan–Meier curve for adherence to treatment, regardless of the reasons for discontinuing medication, is shown in Figure 1A. The numbers of discontinued treatments are given in Table 2.
      Figure thumbnail gr1
      Figure 1(A) Discontinuation of treatment due to (A) any cause, (B) adverse events, (C) treatment failure, and (D) OLT or death analyzed by the Kaplan–Meier estimation.
      Table 2Number of Discontinued Treatments With a Duration Greater Than 6 Months Within the Study Period Listed by Reason for Stopping or Change of Therapy
      Reason for discontinuationNo. of discontinued treatmentsP values (pairwise log-rank test)
      Chelator (n = 313 analyzed)Zinc (n = 88 analyzed)Combination (n = 30 analyzed)TotalChelator vs zincChelator vs combinationZinc vs combination
      OLT102113.011.679.202
      Death22.07All events censored.436
      OLT or death104115<.001.696.140
      Treatment failure414119<.001.238.065
      Adverse events99109118.318.457.454
      Pregnancy33.667.679.171
      Patient demand18321.114.075.013
      Other2171240.218<.001.035
      Total1553526216.006.001.521
      NOTE. P values for comparison between treatments were established using the Mantel–Cox test.
      Discontinuation due to adverse events (Figure 1B) was most common in patients receiving chelation therapy, with 99 (87 d-penicillamine, 12 trientine) of 313 treatments stopped for this reason, but this did not reach statistical significance. The analysis of the combined event “orthotopic liver transplantation (OLT) or death” showed less progression toward death or OLT under chelator treatment (10/313 events; 7 d-penicillamine, 3 trientine) compared with zinc therapy (4/88 events; P < .001; log-rank test; Figure 1D).
      A change in medication due to patient demand was observed in 18 chelation treatments and 3 combination treatments. In most cases, this was associated with a fear of chelator-associated adverse effects despite the lack of clinical findings or laboratory parameters demonstrating such adverse events at that time. The category “other reasons for discontinuation” included changes or discontinuation due to financial aspects, discontinuation due to the nonavailability of health care, discontinuation due to poor compliance, and discontinuation due to problems with drug intake. In this group, we also included 6 combination treatments that were stopped because the treating physician feared a pharmacologic interaction between zinc and the chelating agent. A further 7 zinc treatments that were stopped by the treating physician due to a suspected hepatic or neurologic nonresponse were classified in the category “other” because these treatments did not match the criteria of “treatment failure” as outlined in Patients and Methods.

       Discontinuation Due to Treatment Failure

      Treatment failure was most frequently observed in patients receiving zinc therapy (Figure 1C). Cases with treatment failure were analyzed in detail and are presented in Table 3. We further analyzed the occurrence of event treatment failure for other factors and found no statistically significant results for comparisons with sex (P = .507), neurologic presentation (P = .156), hepatic presentation (P = .636), asymptomatic presentation (P = .809), or the presence of liver cirrhosis at diagnosis (P = .855).
      Table 3Details of Patients Who Failed to Respond to Treatment
      Patient no.SexDiagnosis by family screeningInitial presentationKayser-Fleischer rings at diagnosisLiver cirrhosis at diagnosisEvent “treatment failure” occurredFirst-line therapyRescue therapy
      Under therapy withTime on this medication (y)Time from diagnosis to failure (y)
      7FemaleNoHepaticNoneNoneZinc9.9317.05d-penicillamineTrientine
      15MaleNoHepaticYesYesZinc1.1634.75d-penicillamineTrientine
      25FemaleNoAsymptomaticYesNoneZinc3.637.99d-penicillamineTrieninte
      31FemaleYesHepaticNot determinedNoneZinc1.0013.01d-penicillamined-penicillamine
      39FemaleYesHepaticNoneYesZinc3.113.11ZincTrientine
      69MaleNoMixedYesYesZinc1.1827.26d-penicillamined-penicillamine
      72FemaleNoNeurologicalYesNoneZinc18.3434.35d-penicillamineTrientine
      88FemaleYesAsymptomaticNoneNoneTrientine1.4514.06d-penicillamineZinc (in follow-up: zinc failure; final successful rescue treatment: d-penicillamine)
      88FemaleYesAsymptomaticNoneNoneZinc3.9418.00d-penicillamined-penicillamine
      91MaleYesHepaticNoneNoneZinc2.706.65d-penicillamined-penicillamine
      94FemaleNoHepaticNoneNoneZinc3.503.75d-penicillamineCombination
      94FemaleNoHepaticNoneNoneTrientine2.3014.90d-penicillamined-penicillamine
      104MaleYesHepaticNoneNoneZinc0.670.83Zincd-penicillamine
      127MaleNoNeurologicNoneNoneZinc1.061.96ZincCombination
      135MaleYesHepaticYesNoneZinc2.5215.33d-penicillamineTrientine
      177FemaleNoNeurologicNoneYesTrientine0.500.76Zincd-penicillamine
      184MaleNoHepaticYesYesd-penicillamine26.6826.68d-penicillamineTrientine
      205MaleNoHepaticNot determinedYesZinc8.338.50d-penicillamineOLT
      215MaleNoHepaticNoneNoneCombination2.082.08Combinationd-penicillamine

       Nonresponse to Zinc Therapy

      In patients with nonresponse to zinc therapy, an increase in liver enzyme levels was noted (Figure 2) compared with zinc responders. Most importantly, no statistically significant differences were observed concerning serum and urinary zinc levels (Figure 3).
      Figure thumbnail gr2
      Figure 2Course of AST and γ-GT levels of patients under zinc treatment, grouped by treatment response. Patients with a nonresponse to zinc treatment showed significantly higher liver enzyme levels.
      Figure thumbnail gr3
      Figure 3Course of serum and urinary zinc levels of patients under zinc treatment, grouped by treatment response. No statistically significant differences were observed, suggesting an adequate compliance in the nonresponder group.
      The comparison of the time course of other laboratory values (alkaline phosphatase, choline esterase, international normalized ratio, bilirubin, serum copper, ceruloplasmin, non–ceruloplasmin-bound copper) revealed no statistically significant differences between the responder and nonresponder groups at any time point (data not shown).

       Neurologic Deterioration Under Therapy

      Neurologic worsening was observed within each treatment regimen, with 31 patients affected with chelator therapy (d-penicillamine, 22/243 [9.1%]; trientine, 9/102 [8.8%]), 9 patients with zinc therapy (9/95 [9.5%]), and 3 patients with combination therapy (3/41 [7.3%]); P values were not significant. A subgroup analysis that only included patients with a neurologic presentation at onset did not reveal significant differences between the treatment groups (P values not significant, data not shown). Eight of 9 patients with neurologic worsening with zinc therapy were switched to zinc maintenance therapy after a previous treatment with a chelating agent (5 d-penicillamine, 3 trientine). In all cases, their neurologic course of symptoms was at least considered stable at the beginning of zinc treatment. At the time of neurologic worsening, these patients had been receiving zinc therapy for a mean of 38.4 months (range, 12–109 months), suggesting that neurologic worsening was unrelated to the previous chelation therapy.

      Discussion

      Untreated WD is a fatal disorder and requires lifelong medical therapy to maintain copper homeostasis. However, the choice of which medical therapy remains an individual decision, because only very few prospective data are available.
      This study represents one of the largest series of patients with WD; 288 patients were observed with a median follow up of 17.1 years at 2 European WD centers. The age at onset and the diagnostic delay between onset and diagnosis were comparable to that of former studies.
      • Medici V.
      • Trevisan C.P.
      • D'Inca R.
      • et al.
      Diagnosis and management of Wilson's disease: results of a single center experience.
      • Pellecchia M.T.
      • Criscuolo C.
      • Longo K.
      • et al.
      Clinical presentation and treatment of Wilson's disease: a single-centre experience.
      • Taly A.B.
      • Meenakshi-Sundaram S.
      • Sinha S.
      • et al.
      Wilson disease: description of 282 patients evaluated over 3 decades.
      In our cohort, the majority of patients (68.1%) presented with liver disease.
      The major aim of this study was an assessment of long-term treatment outcome and reasons for discontinuation of medical therapy. Both are closely related because any switch of a medication points to an unsatisfactory efficacy of the treatment regimen, regardless of the reason for discontinuation.
      Surprisingly, the overall discontinuation of therapy in our study cohort was significantly more frequent in patients receiving zinc monotherapy or combination therapy than chelation therapy. This was unexpected because a known limitation of d-penicillamine therapy is the occurrence of adverse events, leading to the discontinuation of such therapy in up to 30% of patients.
      • Medici V.
      • Trevisan C.P.
      • D'Inca R.
      • et al.
      Diagnosis and management of Wilson's disease: results of a single center experience.
      • Walshe J.M.
      Wilson's disease presenting with features of hepatic dysfunction: a clinical analysis of eighty-seven patients.
      In line with these reports, our long-term data indicated clinically relevant adverse events with chelation therapy throughout the whole observation period. However, we also observed an unexpectedly high rate of discontinued zinc treatments due to adverse events (10/88 treatments; see Table 2). As a result, the Kaplan–Meier estimate comparing the occurrence of adverse events under zinc versus chelation therapy (Figure 1B) did not reach statistical significance. All of the adverse events reported with zinc monotherapy were related to gastrointestinal symptoms, in particular gastritis and nausea, and thus its spectra were in line with previous data.
      • Brewer G.J.
      • Hill G.M.
      • Prasad A.S.
      • et al.
      Oral zinc therapy for Wilson's disease.
      • Czlonkowska A.
      • Gajda J.
      • Rodo M.
      Effects of long-term treatment in Wilson's disease with D-penicillamine and zinc sulphate.
      • Brewer G.J.
      • Dick R.D.
      • Johnson V.D.
      • et al.
      Treatment of Wilson's disease with zinc: XV long-term follow-up studies.
      • Medici V.
      • Trevisan C.P.
      • D'Inca R.
      • et al.
      Diagnosis and management of Wilson's disease: results of a single center experience.
      However, reasons other than adverse events have to be responsible for the high rate of discontinued zinc treatments. The important end point of the combined event “liver transplantation or death” was more frequently observed with zinc monotherapy (Figure 1D), but this small number cannot account for the overall finding. However, this result does hint to a partially unsatisfactory response of zinc monotherapy and as a consequence is an underlying explanation for the high number of discontinued zinc treatments. Under continuous treatment, an elevation of liver enzyme levels (AST, ALT, γ-GT) and an increase in copper excretion are worrying events and possibly indicate a failure of treatment. The reasons for treatment failure in general can be incorrect diagnosis, poor compliance, incorrect dosage, or just the wrong medication in terms of a lack of efficacy. In this well-defined WD cohort, a hepatic treatment failure was significantly observed more frequently with zinc monotherapy than the other treatment regimens, including a chelator (Figure 1C). As a clinical consequence of this, a new concept of nonresponse with zinc therapy has to be proposed. For nearly all treatments in which an insufficient hepatic response (failure) was noted, a change in medical treatment regimen led to hepatic improvement. As a rescue therapy, patients treated with zinc were again put on a chelator, excluding one patient who underwent OLT. Patients with an unsatisfactory response to d-penicillamine were switched to trientine or vice versa. Here, an important observation was the normalization of elevated liver enzyme levels in zinc nonresponders after the reintroduction of a chelating agent. In principle, these findings are consistent with previous case reports that reported both a hepatic worsening with zinc therapy as well as its reversal after the reintroduction of a chelator.
      • Lang C.J.
      • Rabas-Kolominsky P.
      • Engelhardt A.
      • et al.
      Fatal deterioration of Wilson's disease after institution of oral zinc therapy.
      • Shimon I.
      • Moses B.
      • Sela B.A.
      • et al.
      Hemolytic episode in a patient with Wilson's disease treated with zinc.
      The reasons for this unexpected and disappointing outcome of zinc therapy are not clear. On one hand, its lower decoppering potential might account for a reaccumulation of copper over time.
      • Hill G.M.
      • Brewer G.J.
      • Prasad A.S.
      • et al.
      Treatment of Wilson's disease with zinc. I. Oral zinc therapy regimens.
      • Brewer G.J.
      • Hill G.M.
      • Dick R.D.
      • et al.
      Treatment of Wilson's disease with zinc: III Prevention of reaccumulation of hepatic copper.
      Zinc has to be taken separately from meals at least twice daily to be effective.
      • Brewer G.J.
      • Yuzbasiyan-Gurkan V.
      • Johnson V.
      • et al.
      Treatment of Wilson's disease with zinc XII: dose regimen requirements.
      Because compliance was not assessed in this study, inadequate intake of the zinc medication cannot be ruled out as a cofactor, but we observed no difference in serum and urinary zinc levels between zinc responders and nonresponders and found an elevation of these parameters in both groups. This is of relevance, because serum and urinary zinc levels with zinc therapy should be above the upper normal limit; otherwise, this might indirectly indicate poor compliance.
      • Roberts E.A.
      • Schilsky M.L.
      Diagnosis and treatment of Wilson disease: an update.
      Thus, the finding of comparable serum and urinary zinc levels in the zinc responder and zinc nonresponder groups strengthens the argument that hepatic worsening with zinc therapy is not associated with poor compliance. In this context, the current data emphasize the fact that elevated serum or urinary zinc levels alone do not reflect a proper response to zinc treatment. In fact, elevated serum or urinary zinc levels do not even indicate that patients are adherent long-term but only before the period of testing.
      This raises the question as to whether there are predictive factors identifying the subgroup of patients with an insufficient response to zinc therapy. Constitutional risk factors for the failure of zinc therapy were not evident in our cohort, because this event was not associated with sex, genotype, presentation, degree of liver dysfunction, or age. Here, other factors such as nutrition or compliance might play a role, but these factors could not be analyzed in detail. An analysis of the course of laboratory findings in zinc nonresponders showed an early elevation of γ-GT levels (P = .036 after 6 months). The aminotransferase (AST/ALT) levels increased over time as well. Likewise, changes were noted for non–ceruloplasmin-bound copper; however, these findings did not reach statistical significance, probably due to the limited number of available parameters. Concerning the elevation of ALT and γ-GT levels, these findings are in line with a recently published series of 17 patients that showed a similar, but not statistically significant, trend with zinc monotherapy.
      • Linn F.H.
      • Houwen R.H.
      • van Hattum J.
      • et al.
      Long-term exclusive zinc monotherapy in symptomatic Wilson disease: experience in 17 patients.
      Overall, an implication of these findings might be the recommendation to follow liver function tests (namely AST, ALT, and γ-GT) and urinary copper excretion under zinc therapy closely. An increase in these parameters or the development of new symptoms should prompt the reintroduction of chelating agents to prevent hepatic deterioration. Similarly, normal liver enzyme levels might be considered as a precondition before a chelator-based therapy is electively switched to zinc maintenance therapy.
      On the other hand, arguments for the use of zinc include reports of a satisfactory response
      • Czlonkowska A.
      • Gajda J.
      • Rodo M.
      Effects of long-term treatment in Wilson's disease with D-penicillamine and zinc sulphate.
      • Linn F.H.
      • Houwen R.H.
      • van Hattum J.
      • et al.
      Long-term exclusive zinc monotherapy in symptomatic Wilson disease: experience in 17 patients.
      • Hoogenraad T.U.
      • Van Hattum J.
      • Van den Hamer C.J.
      Management of Wilson's disease with zinc sulphate Experience in a series of 27 patients.
      • Brewer G.J.
      • Dick R.D.
      • Johnson V.D.
      • et al.
      Treatment of Wilson's disease with zinc: XV long-term follow-up studies.
      in patients with neurologic WD when neurologic deterioration after the initiation of therapy is a concern, especially with d-penicillamine treatment.
      • Walshe J.M.
      • Yealland M.
      Chelation treatment of neurological Wilson's disease.
      • Brewer G.J.
      • Terry C.A.
      • Aisen A.M.
      • et al.
      Worsening of neurologic syndrome in patients with Wilson's disease with initial penicillamine therapy.
      However, neurologic worsening occurred with all treatment regimens to a comparable amount in our cohort, weakening the argument for the preferential use of zinc in these patients. However, to finally elucidate this question, prospective trials using standardized neurologic rating scales would be desirable.
      Another important aspect is the relevance of combined therapy using chelators and zinc. The rationale for such a combination is to enhance therapeutic efficacy by using 2 drugs that have different mechanisms of action and thus might be synergistic. This combination seems to be the primary treatment option for patients with decompensated hepatic WD in an intensive care setting, as previously suggested by the results of a small prospective trial (n = 9) using the combination of trientine and zinc.
      • Askari F.K.
      • Greenson J.
      • Dick R.D.
      • et al.
      Treatment of Wilson's disease with zinc. XVIII. Initial treatment of the hepatic decompensation presentation with trientine and zinc.
      Consistently, in our cohort, deterioration in terms of treatment failure, death, or OLT was extremely rare with combination therapy. However, in clinical practice, this regimen is hard to maintain for a lifetime because the possibility of one drug compromising the efficacy of the other requires strict and complex medication time schedules in relation to meals, with sufficient time lags between intakes of the different medications. In contrast to recent reports,
      • Pellecchia M.T.
      • Criscuolo C.
      • Longo K.
      • et al.
      Clinical presentation and treatment of Wilson's disease: a single-centre experience.
      in our study, combination therapy was also associated with a high rate of adverse events. This might represent the summation of the different spectra of adverse events observed under the chelators and zinc, but this remains speculative because the overall number of combination treatments analyzed in this study was limited.
      In conclusion, the primary role of zinc monotherapy may remain as a medical treatment alternative for asymptomatic or neurologically affected patients. In some cases, however, its use might be associated with a risk of hepatic deterioration, independent of the initial presentation of the patient. Therefore, monitoring for the development of new neurologic or hepatic symptoms in these patients, as well as the assessment of liver function tests and urinary copper excretion, is necessary to detect signs of inadequate response to treatment, even after years of unchanged therapy. Despite neurologic normalization, the development or maintenance of normal liver function tests, namely AST, ALT, and γ-GT, should be considered a primary treatment target. In our analysis, we primarily compared zinc salts with chelating therapy, regardless of whether d-penicillamine or trientine was used. Addressing the differences between chelating therapies, the drugs used, and the dosages was beyond the scope of this study and should be dealt with in further multicenter studies.

      Acknowledgments

      P.F. and W.S. contributed equally to this work.
      The authors thank the patients for their help and willingness to participate in this study and Mr Hinz for validating the statistical design and analysis.

      Supplementary material

      Supplementary Table 1Laboratory Parameters of 129 Patients at Diagnosis, Grouped by Presentation
      ParameterLimits of normalData available (no. of patients)Median (range)PresentationP value
      HepaticMixedNeurologicAsymptomatic
      ALT<35 U/L11167.92 (10–3743)99.06 (16–3743)28.21 (17–272)20 (10–140)20.38 (10–168).000
      AST<35 U/L10748 (6–2106)71.58 (19–2106)32 (19–108)20 (6–58)32.69 (16–102).000
      γ-GT<40 U/L10664 (12–1530)108 (18–1530)67.5 (31–406)30 (14–87)32 (12–72).000
      Alkaline phosphatase40–130 U/L96108.89 (14–946)114 (14–946)107.07 (40–171)85 (52–190)192.96 (96–310).021
      Bilirubin<1.0 mg/dL950.9 (0.1–23)1.1 (0.2–23)0.54 (0.2–1.4)0.83 (0.1–3.8)0.49 (0.2–0.9).011
      Choline esterase4.26–11.25 kU/L825.32 (1–15.4)4.72 (1–12.47)4.78 (2.61–6.26)7.42 (2.23–12.48)8.52 (2.67–15.4).051
      Lipase<51 U/L4826 (6–222)29 (6–222)23 (8–39)23.72 (13–29)13.78 (14–14).113
      Total protein in serum60–80 g/L8670.85 (6–94)70 (6–94)69.1 (64–77)74.8 (66–82)72.7 (68–77).056
      Quick value70%–125%8272 (17–137)65 (17–110)76 (41–106)82 (23–104)93 (61–137).037
      Creatinine0.1–1.3 mg/dL950.8 (0.38–11.14)0.79 (0.38–1.7)0.98 (0.44–11.14)0.98 (0.53–1.8)0.72 (0.65–1.43).057
      Urea<45 mg/dL7521 (5–101)20.5 (5–101)25 (10–52)24 (11–45)21 (9–29).353
      Copper in urine0.94 μmol/day683.24 (0.11–104)2.9 (0.18–104)5 (0.11–37.9)1.89 (0.18–18.89)4.53 (1.9–13.78).285
      Copper in serum12–14 μmol/L999 (1–29)10 (1–29)7.9 (1–27)8.65 (1–19)10.45 (6–24).496
      Ceruloplasmin0.2–0.6 g/L1150.104 (0.01–0.94)0.11 (0.02–0.27)0.085 (0.01–0.18)0.09 (0.01–0.39)0.14 (0.05–0.94).093
      Non–ceruloplasmin-bound copper<10 μg/dL853.67 (0.42–26.2)3.63 (0.42–26.2)3.92 (0.59–18.2)3.73 (0.55–11.73)3.89 (1.59–7.1).982
      NOTE. P values were established using the Kruskal–Wallis test.

      References

        • Ala A.
        • Walker A.P.
        • Ashkan K.
        • et al.
        Wilson's disease.
        Lancet. 2007; 369: 397-408
        • Gitlin J.D.
        Wilson disease.
        Gastroenterology. 2003; 125: 1868-1877
        • Ferenci P.
        • Caca K.
        • Loudianos G.
        • et al.
        Diagnosis and phenotypic classification of Wilson disease.
        Liver Int. 2003; 23: 139-142
        • Dhawan A.
        • Taylor R.M.
        • Cheeseman P.
        • et al.
        Wilson's disease in children: 37-year experience and revised King's score for liver transplantation.
        Liver Transpl. 2005; 11: 441-448
        • Petrasek J.
        • Jirsa M.
        • Sperl J.
        • et al.
        Revised King's College score for liver transplantation in adult patients with Wilson's disease.
        Liver Transpl. 2007; 13: 55-61
        • Nazer H.
        • Ede R.J.
        • Mowat A.P.
        • et al.
        Wilson's disease: clinical presentation and use of prognostic index.
        Gut. 1986; 27: 1377-1381
        • Roberts E.A.
        • Schilsky M.L.
        Diagnosis and treatment of Wilson disease: an update.
        Hepatology. 2008; 47: 2089-2111
        • Brewer G.J.
        • Hill G.M.
        • Prasad A.S.
        • et al.
        Oral zinc therapy for Wilson's disease.
        Ann Intern Med. 1983; 99: 314-319
        • Hoogenraad 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: 205-211
        • Hill G.M.
        • Brewer G.J.
        • Prasad A.S.
        • et al.
        Treatment of Wilson's disease with zinc. I. Oral zinc therapy regimens.
        Hepatology. 1987; 7: 522-528
        • Cousins R.J.
        Absorption, transport, and hepatic metabolism of copper and zinc: special reference to metallothionein and ceruloplasmin.
        Physiol Rev. 1985; 65: 238-309
        • Scheinberg 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: 209-213
        • Walshe J.M.
        • Dixon A.K.
        Dangers of non-compliance in Wilson's disease.
        Lancet. 1986; 1: 845-847
        • Walshe J.M.
        Wilson's disease; new oral therapy.
        Lancet. 1956; 270: 25-26
        • Walshe J.M.
        Copper chelation in patients with Wilson's disease.
        Q J Med. 1973; 42: 441-452
        • Grand R.J.
        • Vawter G.F.
        Juvenile Wilson disease: histologic and functional studies during penicillamine therapy.
        J Pediatr. 1975; 87: 1161-1170
        • Lau J.Y.
        • Lai C.L.
        • Wu P.C.
        • et al.
        Wilson's disease: 35 years' experience.
        Q J Med. 1990; 75: 597-605
        • Czlonkowska A.
        • Gajda J.
        • Rodo M.
        Effects of long-term treatment in Wilson's disease with D-penicillamine and zinc sulphate.
        J Neurol. 1996; 243: 269-273
        • Dubois R.S.
        • Rodgerson D.O.
        • Hambidge K.M.
        Treatment of Wilson's disease with triethylene tetramine hydrochloride (trientine).
        J Pediatr Gastroenterol Nutr. 1990; 10: 77-81
        • Saito H.
        • Watanabe K.
        • Sahara M.
        • et al.
        Triethylene-tetramine (trien) therapy for Wilson's disease.
        Tohoku J Exp Med. 1991; 164: 29-35
        • Brewer G.J.
        • Yuzbasiyan-Gurkan V.
        • Lee D.Y.
        • et al.
        Treatment of Wilson's disease with zinc. VI. Initial treatment studies.
        J Lab Clin Med. 1989; 114: 633-638
        • Walshe J.M.
        Diagnosis and treatment of presymptomatic Wilson's disease.
        Lancet. 1988; 2: 435-437
        • Linn 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: 1442-1452
        • Hoogenraad T.U.
        • Van Hattum J.
        • Van den Hamer C.J.
        Management of Wilson's disease with zinc sulphate.
        J Neurol Sci. 1987; 77: 137-146
        • Brewer G.J.
        • Dick R.D.
        • Johnson V.D.
        • et al.
        Treatment of Wilson's disease with zinc: XV long-term follow-up studies.
        J Lab Clin Med. 1998; 132: 264-278
        • Walshe J.M.
        • Munro N.A.
        Zinc-induced deterioration in Wilson's disease aborted by treatment with penicillamine, dimercaprol, and a novel zero copper diet.
        Arch Neurol. 1995; 52: 10-11
        • Lang 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: 1007-1008
        • Santos Silva E.E.
        • Sarles J.
        • Buts J.P.
        • et al.
        Successful medical treatment of severely decompensated Wilson disease.
        J Pediatr. 1996; 128: 285-287
        • Askari F.K.
        • Greenson J.
        • Dick R.D.
        • et al.
        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: 385-390
        • Medici V.
        • Trevisan C.P.
        • D'Inca R.
        • et al.
        Diagnosis and management of Wilson's disease: results of a single center experience.
        J Clin Gastroenterol. 2006; 40: 936-941
        • Walshe J.M.
        Wilson's disease presenting with features of hepatic dysfunction: a clinical analysis of eighty-seven patients.
        Q J Med. 1989; 70: 253-263
        • Weiss K.H.
        • Merle U.
        • Schaefer M.
        • et al.
        Copper toxicosis gene MURR1 is not changed in Wilson disease patients with normal blood ceruloplasmin levels.
        World J Gastroenterol. 2006; 12: 2239-2242
        • Weiss K.H.
        • Runz H.
        • Noe B.
        • et al.
        Genetic analysis of BIRC4/XIAP as a putative modifier gene of Wilson disease.
        J Inherit Metab Dis. 2010 Jun 2; ([Epub ahead of print])
        • Pellecchia M.T.
        • Criscuolo C.
        • Longo K.
        • et al.
        Clinical presentation and treatment of Wilson's disease: a single-centre experience.
        Eur Neurol. 2003; 50: 48-52
        • Taly A.B.
        • Meenakshi-Sundaram S.
        • Sinha S.
        • et al.
        Wilson disease: description of 282 patients evaluated over 3 decades.
        Medicine (Baltimore). 2007; 86: 112-121
        • Shimon I.
        • Moses B.
        • Sela B.A.
        • et al.
        Hemolytic episode in a patient with Wilson's disease treated with zinc.
        Isr J Med Sci. 1993; 29: 646-647
        • Brewer G.J.
        • Hill G.M.
        • Dick R.D.
        • et al.
        Treatment of Wilson's disease with zinc: III.
        J Lab Clin Med. 1987; 109: 526-531
        • Brewer G.J.
        • Yuzbasiyan-Gurkan V.
        • Johnson V.
        • et al.
        Treatment of Wilson's disease with zinc XII: dose regimen requirements.
        Am J Med Sci. 1993; 305: 199-202
        • Walshe J.M.
        • Yealland M.
        Chelation treatment of neurological Wilson's disease.
        Q J Med. 1993; 86: 197-204
        • Brewer G.J.
        • Terry C.A.
        • Aisen A.M.
        • et al.
        Worsening of neurologic syndrome in patients with Wilson's disease with initial penicillamine therapy.
        Arch Neurol. 1987; 44: 490-493