REVIEW

Wilson Disease: Clinical Presentation, Treatment, and Survival Wolfgang Stremmel, MD; Karl-Wilhelm Meyerrose, MD; Claus Niederau, MD; Harald Hefter, MD, PhD; Georg Kreuzpaintner, MD; and Georg Strohmeyer, MD

• Objective: To evaluate the diagnostic features, clinical course, and overall long-term survival of patients with Wilson disease. • Design: Retrospective cohort study with a mean follow-up period of 14.2 years. • Setting: A university medical center and a community hospital. • Patients: Fifty-one consecutive patients with Wilson disease were evaluated between 1957 and 1989. • Interventions: Patients were treated with D-penicillamine (600 to 1800 mg/d). Two patients with end-stage liver disease had liver transplantation. • Main Results: Initial symptoms occurred at a mean age of 15.5 years. At diagnosis, the most common neurologic signs were dysarthria, tremor, writing difficulties, and ataxia followed by hypersalivation and headache. Somatic symptoms included abdominal pain, hepatomegaly, splenomegaly, cirrhosis of the liver, and thrombocytopenia. The mean serum concentrations of ceruloplasmin and copper were 44 mg/L and 4.7 jjimol/L, respectively. The mean basal urinary copper excretion was 5.5 jimol/d, and the mean hepatic copper concentration was 19.6 |xmol/g dry weight. Free serum copper concentration (mean, 2.7 jjimol/L) was a reliable indicator of disease and was useful in assessing the effectiveness of therapy (values < 1.6 |mmol/L). Treatment with D-penicillamine improved most of the hematologic and neurologic abnormalities but had little effect on hepatomegaly and splenomegaly and did not reverse cirrhosis. Two patients died of fulminant hepatic failure during the observation period, whereas two others with end-stage liver disease had successful liver transplantation and remain asymptomatic. Longterm survival of patients with Wilson disease was similar to that of age- and sex-matched controls. • Conclusion: Our results suggest that long-term treatment of patients with Wilson disease with D-penicillamine can relieve symptoms and improve prognosis.

W i l s o n disease, a copper-overload disease, is inherited as an autosomal recessive trait. The genetic frequency has been estimated at 1 in 200 and the prevalence of the disease, as high as 1 in 30 000 (1). Gene linkage analysis has localized the genetic defect on chromosome 13 near the esterase D locus (2). The resulting, as yet undefined, molecular defect impairs excretion of copper by the liver, causing large amounts of this essential heavy metal to accumulate in the liver, brain, and other organs (3). A decrease in levels of serum ceruloplasmin, the main copper-transporting protein in blood, is a characteristic feature of Wilson disease. This reduction is caused, at least in part, by a decrease in the transcription (possibly translational or post-translational) of the ceruloplasmin gene located on chromosome 3 (4). Wilson disease that is untreated causes progressive damage of liver and brain. Until the late 1940s patients usually died before reaching 30 years of age. The prognosis improved substantially after the introduction of the copper-chelating agent D-penicillamine in the 1950s by Walshe (5). Since that time, D-penicillamine has been the treatment of choice for Wilson disease. The association of toxic side effects with D-penicillamine stimulated the search for alternative therapies. Trientine, another copper-chelating agent without reported side effects, is currently available (6, 7). Administration of metal antagonists that inhibit intestinal copper absorption has also produced successful results (8). The antagonist used most often is zinc in the form of zinc sulfate or acetate (9, 10). More recently, tetrathiomolybdate has also been reported to be effective (11). To prevent serious complications, Wilson disease should be treated as early as possible using any of these regimens. Initial symptoms of Wilson disease are frequently nonspecific, and delays between the time of symptom onset, diagnosis, and institution of therapy are common. Our study evaluated the clinical courses of 51 patients with Wilson disease who were treated using D-penicillamine and other regimens. Patients were evaluated by initial clinical presentation; effect of D-penicillamine on clinical signs and symptoms; side effects of D-penicillamine treatment; outcome of liver transplantation in patients with end-stage liver disease; and overall longterm survival.

Annals of Internal Medicine. 1991;115:720-726.

Methods

From Heinrich-Heine University Hospital, Diisseldorf, Federal Republic of Germany. For current author addresses, see end of text.

Fifty-one patients with clinical, biochemical, and histologic evidence of Wilson disease were identified between 1957 and 1989 in the departments of medicine at the university hospital in Diisseldorf and at the community hospital in Gummersbach.

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Patients were initially referred to the hospital by general practitioners for evaluation of unknown hepatic or neurologic disease or for verification of a suspected diagnosis of Wilson disease. Although there was no prospective protocol for diagnosis and treatment, the following applies to all study patients: A diagnosis of Wilson disease was suggested by the patient's clinical features and by results from biochemical tests, including measurements of liver function, transaminases, and enzymes, which indicated cholestatic liver disease. To exclude other liver diseases, determinations of serum iron and ferritin concentrations, hepatitis B serologic testing, and assessment of antimitochondrial antibodies and antibodies related to autoimmune hepatitis were done. To evaluate copper metabolism, we obtained serum concentrations of ceruloplasmin (normal range, 200 to 400 mg/L) and copper (normal range, 15.7 to 23.6 jLimol/L) as well as determinations of urinary copper excretion (baseline, < 0.6 //xnol/d; after stimulation with D-penicillamine, 1.6 to 9.4 /xmol/d). Ceruloplasmin values of less than 200 mg/L, serum copper values of less than 12.6 /xmol/L, and urinary copper levels greater than 1.6 /i,mol/d (after penicillamine stimulation, > 16 /rniol/d) were suggestive of Wilson disease. To calculate the "free" (nonceruloplasmin) serum copper concentration, the amount of copper associated with ceruloplasmin (0.047 /xmol/mg) was subtracted from the total amount of serum copper. The presence of Kayser-Fleischer rings combined with abnormal results of copper metabolism tests were considered pathognomonic for Wilson disease. The diagnosis was confirmed by results of liver biopsy with quantitative determination of liver copper content (normal range, 0.2 to 0.9 jiimol/g dry weight; Wilson disease, > 3.9 /xmol/g dry weight). Rhodamine staining to detect intracellular copper deposition and histologic evaluation of biopsy specimens were also done. The presence of cirrhosis was established by the evidence of diffuse fibrosis and nodule formation as described elsewhere (12). All patients were treated with D-penicillamine in daily doses of 600 to 1800 mg which were adjusted individually. In two patients with severe side effects caused by D-penicillamine, trientine was used as an alternative copper-chelating agent (7). Reduction of dietary copper intake was confined to avoidance of food rich in copper (13). Liver transplantation was done in two patients with end-stage liver disease. After transplantation, the patients were followed closely to assess clinical improvement, liver copper content, and laboratory measurements of copper metabolism. Radiocopper tests were done as previously described (14, 15). None of the 51 patients was lost to follow-up. Follow-up data were obtained by sending a questionnaire to the patient and to his or her physician. Two patients died during the study period from fulminant hepatic failure at a time when liver transplantation was not available. Survival was calculated using the product-limit estimator method, as described by Kaplan and Meier (16). The expected survival curve was calculated using a computer program that applied the age- and sex-specific death rates for the inhabitants of West Germany to each patient according to the period during which he or she was observed during the study (12). The total observed and expected survival curves were not formally statistically compared, but the 95% confidence intervals for patient survival were calculated for comparison with survival of the normal population. Because a symmetric confidence interval (CI) is not appropriate to survival values above 0.9, the variance was calculated from the log of the survival function. An interval of 2 SD for the survival rate of the patients was considered to be the 95% CI. Curves for expected survival that were beyond the limit of the confidence interval were considered to differ significantly from curves for observed survival. Curves lying within these limits were not considered to differ significantly from curves for observed survival.

Results Fifty-one patients (21 men and 30 women) were diagnosed with Wilson disease from 1957 to 1989 in the departments of medicine of the university hospital in

Table 1. Clinical Characteristics at Diagnosis in 51 Patients with Wilson Disease Characteristics

Number of Patients

Neurologic manifestations Dysarthria Tremor Writing difficulties Ataxic gait Asthenia Hypersalivation Psychiatric symptoms Nervousness Headache Hypomimia Dizziness Convulsions Abdominal manifestations Hepatomegaly Splenomegaly Abdominal pain Jaundice Ascites Gynecomastia Esophageal varices Diarrhea Vomiting Hematologic abnormalities Thrombocytopenia Hemolysis Anemia Leukopenia Other symptoms and signs Kayser-Fleischer rings Arthralgia Gigantism Bone deformities Keratitis

26 24 18 16 16 6 6 5 4 4 2 1 25 25 21 7 7 6 5 4 2 11 5 4 4 34 5 5 2 2

Diisseldorf and the community hospital in Gummersbach. These two centers serve a population of about 1.5 million people. This figure suggests a disease prevalence of 1 in 30 000, which is identical to that observed in eastern Germany (1). Patients were followed for a mean of 14.2 years with a range of 1 to 32 years. Mean ages at the appearance of first symptoms and at the time of diagnosis were 15.5 years and 17.2 years, respectively. Thus, the mean time lag between the onset of initial symptoms and a definitive diagnosis was 1.7 years. The delay from symptom onset to time of diagnosis was 18 years for one patient. Clinical Presentation Clinical features at the time of diagnosis are summarized in Table 1. Of the 51 study patients, 31 had neurologic manifestations of Wilson disease. The predominant symptoms were dysarthria, tremor, writing difficulties, ataxic gait, and asthenia. Rare neurologic symptoms included hypersalivation, psychiatric symptoms, nervousness, headache, dysphagia, hypomimia, dizziness, and convulsions. Hematologic abnormalities were seen in 16 of 51 patients. Twenty-two percent of patients had thrombocytopenia. Other abnormalities included hemolytic anemia and leukopenia. Abdominal symptoms and findings were present in 34 of the 51 patients. Splenomegaly, hepatomegaly, and

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Figure 1. Characteristic histologic features of liver specimen biopsies from 51 patients with Wilson disease at diagnosis. The percentage of patients with the feature is shown. abdominal pain were the predominant features; jaundice was seen in 7 patients. Complications of cirrhosis including ascites, gynecomastia, and esophageal varices were seen in 10% to 14% of patients. Sixty-seven percent of patients showed a Kayser-Fleischer ring, which indicated a diagnosis of Wilson disease in all cases. Rare clinical features included gigantism, arthalgia, deformity of bones, and keratitis. Diagnosis Diagnosis of Wilson disease was based on the detection of Kayser-Fleischer rings and the following laboratory findings: low serum concentrations of ceruloplasmin and copper, elevated free serum copper concentration and elevated urinary copper excretion, and liver copper content greater than 3.9 /tmol/g dry weight. Evaluation of these findings in all 51 patients showed an elevated liver copper content with a mean value of 19.6 /xmol/g dry weight (range, 5.5 to 32.4 /tmol/g) and an increased free serum copper concentration with a mean value of 2.7 /tmol/L (range, 0.6 to 13.2 jumol/L). Serum ceruloplasmin levels were decreased in 93% of patients (mean value at diagnosis, 44 ± 31 mg/L; range, 0 to 206

mg/L), and urinary copper excretion was elevated in 90% of patients (mean value at diagnosis without penicillamine, 5.5 ± 2.9 /xmol/d; range, 0.5 to 19.7 jmiol/d). Total serum copper levels were decreased in 87% of patients (mean value at diagnosis, 4.7 ± 3 . 4 /x,mol/L; range, 1.1 to 23.0 ^cmol/L), whereas Kayser-Fleischer rings were only detectable in 67% of patients. Histologic findings in liver specimens included: increased range of nuclear size, lipofuscin deposition, vacuolated nuclei, and ballooning of hepatocytes (Figure 1). Increased hemosiderin deposition was a frequent, but unexplained, finding in these patients. Fortyone percent of patients had cirrhosis, and 35% had fibrosis of the liver. Evaluation of patients by clinical course showed that 9 patients were asymptomatic (most were diagnosed by family screening), 23 patients had hepatocerebral manifestations of disease, 8 had predominantly cerebral symptoms, and 11 had predominantly hepatic symptoms. The various clinical courses of Wilson disease were compared with regard to diagnostic features, including laboratory parameters of copper metabolism and presence of Kaiser-Fleischer ring (Table 2). The wide range of interindividual variation in copper metabolism is particularly remarkable. Mean values of all determinations, however, were characteristic of Wilson disease, but they did not differ significantly (P > 0.05) among the various subgroups. Expected decreases in liver copper content in patients with cerebral symptoms or with severe liver disease (and, therefore, lower copper storing capacity) could not be confirmed by our data. Three asymptomatic patients had a liver copper content greater than 33 ^mol/g dry weight, which was higher than that in symptomatic patients and may be explained by the natural course of copper accumulation in Wilson disease (8). The Kayser-Fleischer ring was present in all patients with cerebral symptoms but was absent in asymptomatic patients and in some patients with a predominantly hepatic course. Effect of Treatment on Clinical Features and Survival All patients were treated with D-penicillamine at doses of 600 to 1800 mg/d as maintenance therapy and were placed on a copper-reduced diet. The effectiveness

Table 2. Diagnostic Variables in Patients with Wilson Disease by Course Variable

Ceruloplasmin, mg/L mean range Serum copper, funol/L mean range Free serum copper, yjnollL mean range Hepatic copper, ixmollg dry wt mean range Kayser-Fleischer ring, n

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All Patients (n = 51)

Asymptomatic (n = 9)

Hepatic Course (n= 11)

Cerebral Course (« = 8)

Hepatocerebral Manifestations (n = 23)

38 11 to 136

48 0 to 206

38 0 to 148

49 0 to 177

3.7 1.1 to 14.4

5.2 1.2 to 23.0

4.6 1.1 to 7.8

5.0 1.3 to 13.0

4.7

1.9 0.6 to 5.6

2.9 0.8 to 13.2

3.2 0.8 to 4.6

2.7 0.8 to 6.5

2.7

15.9 5.5 to 38.6 0

22.7 12.3 to 29.1 3

14.6 10.3 to 23.8 8

21.4 14.9 to 32.4 23

19.6

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34

Figure 2. Comparison of clinical signs and symptoms before and after long-term treatment with D-penicillamine. The percentage of patients with the clinical manifestation is shown. A: neurological symptoms; B: clinical symptoms; C: hematological symptoms.

of this therapy was monitored using the calculated free serum copper concentration, which was less than 1.6 /xmol/L in all cases. To evaluate clinical improvement after long-term treatment with D-penicillamine, we compared the frequency of symptoms at diagnosis with that after therapy (Figure 2). Improvement was seen in most neurologic symptoms, including dysarthria, tremor, ataxic gait, difficulties in writing, and hypersalivation (Figure 2a). Abdominal pain disappeared almost completely in the majority of patients, whereas hepatomegaly and splenomegaly were reversible in only a few patients, as were cirrhosis and portal hypertension (Figure 2b). Most of the hematologic abnormalities also improved (Figure 2c). Although Kayser-Fleischer rings faded in almost all patients, they remained detectable in 25% of cases (Figure 2b). Side effects associated with D-penicillamine therapy that occurred early in the treatment courses of 13 of our 51 patients included skin rash (4 patients), gastrointestinal discomfort (4 patients), hair loss (3 patients), leukopenia (3 patients), stomatitis (2 patients), furunculosis (1 patient), and thrombocytopenia (1 patient). Later complications of treatment included nephropathy (three patients), polyneuropathy (two patients), and skin disorders including pemphigus and elastosis (two patients). In most of these cases, dose reduction or short-term interruption of D-penicillamine treatment and reapplication at slowly increasing doses succeeded in overcoming these side effects. Replacement of D-penicillamine with trientine was necessary in two patients who suffered from nephrosis and from pemphigus of the oral

mucosa and elastosis of the skin, respectively. Treatment with this alternative copper-chelating agent was effective in achieving clinical improvement and stabilization of low body copper content. No side effects have been observed in association with trientine. Two patients died during the observation period due to acute fulminant hepatitis and hepatic failure at a time when liver transplantation was not available. Liver transplantation was done, however, in two other patients with end-stage liver disease. An 18-year-old woman had a fulminant course of Wilson disease resulting in hepatic failure, and a 21-year-old woman had severe portal hypertension and frequent massive bleedings from esophageal varices. Liver transplantation was successful in both patients. During respective postoperative observation periods of 3 and 4 years, the clinical symptoms of Wilson disease, including Kayser-Fleischer rings, resolved in these two patients. After transplantation, the copper content of the transplanted liver and the results of radiocopper tests remained normal. Laboratory measures of serum copper metabolism became normal immediately after transplantation. Ceruloplasmin levels and serum copper concentration increased, whereas urinary copper excretion decreased to normal levels. These features have remained normal without additional copper-reducing therapy, which suggests that the metabolic defect in Wilson disease is resolved by liver transplantation. Treatment regimens using copper-chelating agents and liver transplantation have substantially improved the prognosis of patients with Wilson disease during the

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Figure 3. Cumulative survival in 51 patients with Wilson disease compared with that of an age- and sexmatched control population. A 95% CI was calculated as described in the Methods. Survival time was slightly reduced in the patients during the early period of follow up; that is, the actual survival rates were slightly below the lower limit of the confidence interval calculated for expected survival in the patients. After 15 years of observation, the expected survival rates were inside the confidence interval and thus did not differ from the observed survival. Later in the study period, statistical uncertainty exists in predicting patient survival because of the small number of subjects observed.

last decades. Figure 3 shows overall survival of our 51 patients with Wilson disease compared with age- and sex-matched controls. The deaths of two patients who had acute hepatic failure at the beginning of the study, resulted in an apparent reduction in survival detectable in only the early years of the observation period. After long-term follow up, however, survival in our patients was found to be similar to that seen in the disease-free population. Discussion Our retrospective study of 51 patients with Wilson disease shows that this rare inborn metabolic disorder results in hepatic, neurologic, and hematologic abnormalities with a broad spectrum of clinical features. Many of the initial clinical symptoms are nonspecific and may be misleading in establishing a definitive diagnosis. These include abdominal pain, headache, adynamia, and nervousness. The most common clinical signs and symptoms were dysarthria, tremor, writing difficulties, ataxic gait, hepatomegaly and splenomegaly, and thrombocytopenia. We conclude, therefore, that in young patients with unclear neurologic disorders, liver disease, or hematologic abnormalities such as thrombocytopenia, hemolysis, anemia, or leukopenia, a diagnosis of Wilson disease must be excluded. Kayser-Fleischer rings are considered almost pathognomonic for Wilson disease. They are only present, however, in about 70% of patients and may be absent in early stages of copper accumulation. A low serum ceruloplasmin concentration was found in 93% of our patients. Only in the rare setting of Wilson disease with acute or fulminant liver involvement, may ceruloplasmin levels be normal (probably because ceruloplasmin is an acute phase-reactant). Hypoceruloplasminemia may arise, however, as a result of the nephrotic syndrome, protein-losing enteropathy, or malabsorption, all of which can be easily distinguished from Wilson disease. Rare inherited ceruloplasmin deficiency is not related to Wilson disease and is not necessarily associated with clinical symptoms (17). Because ceruloplasmin is the main copper-transporting protein in blood, total se724

rum copper levels are often decreased (87% of our patients), whereas the level of free, nonceruloplasminbound copper is elevated and is therefore responsible for excess copper deposition in various tissues. Determination of the serum free-copper concentration represents the most reliable finding for the initial diagnosis of Wilson disease. This value is calculated from the difference between total serum copper concentration and the amount of copper bound to ceruloplasmin (0.047 fjumol copper per mg of ceruloplasmin). The mean free serum copper concentration in our patients was elevated to 2.7 jLtmol/L at the time of diagnosis and decreased in all patients during treatment to levels below 1.6 /i,mol/L, indicating the effectiveness of the copper-reducing therapy. Moreover, this nonceruloplasmin copper is readily filtered by the kidneys and accounts for the increased urinary copper excretion seen in Wilson disease. Accordingly, almost all symptomatic patients have a urinary copper excretion greater than 1.6 /xmol/d. Urinary copper levels are often also elevated, however, in patients with cirrhosis, chronic active hepatitis, or cholestasis. This measurement, therefore, does not distinguish these entities from Wilson disease, despite administration of D-penicillamine, an agent that further increases urinary copper excretion. To confirm the suspected diagnosis of Wilson disease, hepatic copper concentration should be determined. In all patients with untreated Wilson disease the hepatic copper content is elevated to levels greater than 3.9 /rniol/g dry weight. An elevated hepatic copper level itself does not, however, establish the diagnosis, because this finding may also be present in cholestatic syndromes (for example, primary biliary cirrhosis) and in patients with Indian childhood cirrhosis (8, 18). These patients are readily distinguished from those with Wilson disease by their clinical features, serologic test results, hepatic histologic results, and ceruloplasmin concentrations. In some centers, incorporation of ^radiocopper into ceruloplasmin is used to detect abnormal copper metabolism in patients with suspected Wilson disease (19). These patients incorporate significantly less ^radiocopper into newly synthesized ceruloplasmin

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than do normal subjects. This examination is less conclusive in patients with normal ceruloplasmin concentrations, patients with increased hepatic copper concentrations due to other forms of liver disease, heterozygous carriers of the Wilson disease gene, or patients who cannot have a liver biopsy because of contraindications. Wilson disease has recently been diagnosed using closely linked DNA markers (20). It remains to be established whether this diagnostic procedure will prove to be more sensitive and specific than other tests for the detection of homozygous and heterozygous patients with Wilson disease. D-Penicillamine effectively reduces excess copper stores and thus improves clinical symptoms in most patients with Wilson disease. The greatest improvements were observed in regard to nonspecific complaints, abdominal pain, and hematologic alterations. Signs and symptoms caused by irreversible organ damage, such as cirrhosis of the liver, and some neurologic disorders, such as dysarthria, often cannot be improved substantially. Side effects of D-penicillamine were observed in 13 of our 51 patients. Some of these toxic effects may be caused by hypersensitivity, by the fact that D-penicillamine is an antimetabolite of pyridoxine, or by the drug's direct action on collagen (10, 21). It is also conceivable that this chelator leads to deficiencies in essential trace metals, especially zinc. Our experience suggests that these adverse reactions are, however, less severe than those seen in patients who receive D-penicillamine for the treatment of rheumatoid arthritis, systemic sclerosis, or primary biliary cirrhosis. In the latter diseases D-penicillamine treatment resulted in severe complications, such as nephrotic and aplastic syndromes or systemic lupus erythematosus, in as many as 30% of patients (10). Whether the less severe side effects observed in patients with Wilson disease are caused by its chelation with free copper remains to be established. Treatment with D-penicillamine is generally considered to be safe and does not appear to pose a substantial risk to the fetuses of pregnant patients with Wilson disease (22, 23). In cases of adverse reactions to D-penicillamine treatment, however, alternative copper-depleting procedures must be used. Trientine, zinc, and (more recently) tetrathiomolybdate have shown similar success rates in the treatment of large numbers of patients with Wilson disease (7, 9, 10, 11, 24). Our experience indicated that trientine was effective, and the drug was not associated with any side effects. A daily dose of 1 g of trientine induces cupriuresis similar to that induced by 1 g of penicillamine (7). Some patients, however, may require as much as a twofold increase in the oral dose of trientine compared with that of D-penicillamine, indicating that trientine must be tritrated according to the clinical effect in the individual patient. The efficacy of copper-reducing therapy is monitored by improvement of clinical symptoms, a return to normal of liver function test results, and disappearance of Kayser-Fleischer rings. The calculated serum free-copper concentration is the best biochemical indicator of the effectiveness of copper-reducing therapy (25, 26). Longterm treatment with any of the copper-depleting agents

occasionally results in a mild sideroblastic anemia and leukopenia caused by copper deficiency (7, 25). These side effects may be treated conservatively in a specialized center using low-dose copper infusion (7, 25). The prognosis of end-stage liver disease is poor in patients with Wilson disease. Fulminant hepatic failure or complications of cirrhosis with portal hypertension and recurrent massive bleedings from esophageal varices contribute to poor outcomes in these patients. In these situations liver transplantation is the only therapy that proved to be successful. In our two patients who had liver transplantation, copper metabolism normalized immediately after transplantation and remains normal, indicating that the metabolic defect may be confined to the liver and may be resolved by implantation of a healthy liver. It is unknown, however, whether copper may reaccumulate in the future. Our study and previous observations have shown that an effective copper-reducing therapy exists, as does emergency treatment for patients with Wilson disease. Although these treatment regimens were shown to be effective in improving the patient's symptoms and test results, the effect of therapy on prognosis remains unknown. We therefore compared the overall survival rate of our 51 patients with that of a normal age- and sexmatched sample. Only two patients died during the observation period of hepatic failure at a time when liver transplantation was not available. All other patients were alive at the end of the study period, and long-term survival was not significantly affected (see Figure 3). The major problem in patients with Wilson disease is one of disabling complications due to irreversible organ and cell damage at the time of copper accumulation in the organism. In particular, neurologic disorders resulting in motor and speech abnormalities may not be reversed by copper-reducing therapy. Future clinical research in this field, therefore, needs to emphasize the early detection of this metabolic disorder (27). Screening procedures that use DNA probes may provide a useful tool to detect homozygous patients in infancy. Advances in molecular biologic techniques to define the genetic defect are therefore eagerly expected in the near future. It should be emphasized that in any undefined neurologic disorder, liver disease, or hematologic abnormality affecting infants or young adults, a diagnosis of Wilson disease must be excluded. The most reliable diagnostic test of copper metabolism is the determination of the free serum copper concentration, which is also important in the monitoring of therapeutic effectiveness. When a diagnosis of Wilson disease is established in a patient's family, screening, in particular of the siblings, must be done to detect asymptomatic carriers of the disease. Acknowledgments: The authors thank Professor Lange for providing patient records; Professors Wesch and Feist for doing radiocopper tests; Burke West, MD, for discussions; and Mrs. Marlies Hilbert for preparation of the manuscript. Grant Support: By grant STR 92/4-1 from the Deutsche Forschungsgemeinschaft, Bonn, Federal Republic of Germany. Requests for Reprints: Wolfgang Stremmel, MD, Department of Medicine, University of Diisseldorf, Moorenstrasse 5, 4000 Dusseldorf, Federal Republic of Germany.

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Current Author Addresses: Drs. Stremmel, Meyerrose, Niederau, Kreuzpaintner, and Strohmeyer: Department of Medicine, University Hospital, Heinrich-Heine University, Moorenstrasse 5, 4000 Dusseldorf, Federal Republic of Germany. Dr. Hefter: Department of Neurology, University Hospital, HeinrichHeine University, Moorenstrasse 5, 4000 Dusseldorf, Federal Republic of Germany.

13.

14. References 1. Bachmann H, Lossner J, Gruss B, Ruchholtz U. Die Epidemiologic der Wilsonschen Erkrankung in der DDR und die derzeitige Problematik einer populationsgenetischen Bearbeitung. Psychiatr Neurol Med Psychol (Leipzig). 1979;31:393-400. 2. Frydman M, Bonne-Tamir B, Farrer LA, Conneally PM, Magazanik A, Ashbel S, et al. Assignment of the gene for Wilson disease to chromosome 13: linkage to the esterase D locus. Proc Natl Acad Sci USA. 1985;82:1819-21. 3. Gibbs K, Walshe JM. Biliary excretion of copper in Wilson's disease [Letter]. Lancet. 1980;2:538-9. 4. Czaja MJ, Weiner FR, Schwarzenberg SJ, Sternlieb I, Scheinberg IH, Van Thiel DH, et al. Molecular studies of ceruloplasmin deficiency in Wilson's disease. J Clin Invest. 1987;80:1200-4. 5. Walshe JM. Penicillamine, a new oral therapy for Wilson's disease. Am J Med. 1956;21:487-95. 6. Walshe JM. Treatment of Wilson's disease with trientine (triethylene tetramine) dihydrochloride. Lancet. 1982;1:643-7. 7. Scheinberg IH, Jaffe ME, Sternlieb I. The use of trientine in preventing the effects of interrupting penicillamine therapy in Wilson's disease. N Engl J Med. 1987;317:209-13. 8. Walshe JM. Copper: its role in the pathogenesis of liver disease. Semin Liver Dis. 1984;4:252-63. 9. Hoogenraad TU, Van Hattum J, Van den Hamer CJ. Management of Wilson's disease with zinc sulphate. Experience in a series of 27 patients. J Neurol Sci. 1987;77:137-46. 10. Brewer GJ, Hill GM, Prasad AS, Cossack ZT, Rabbani P. Oral zinc therapy for Wilson's disease. Am Intern Med. 1983;99:314-9. 11. Walshe JM. Tetrathiomolybdate (MoS 4 ) as an anti-copper agent in man. In: Scheinberg IH, Walshe JM; eds. Orphan Diseases and Orphan Drugs. Manchester, England: Manchester University Press; 1986:76-85. 12. Niederau C, Fischer R, Sonnenberg A, Stremmel W, Trampisch HJ,

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15.

16. 17. 18.

19. 20.

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22. 23. 24.

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1 November 1991 • Annals of Internal Medicine • Volume 115 • Number 9

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Wilson disease: clinical presentation, treatment, and survival.

To evaluate the diagnostic features, clinical course, and overall long-term survival of patients with Wilson disease...
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