Digestive and Liver Disease
Volume 39, Issue 7 , Pages 601-609, July 2007

Wilson disease—A practical approach to diagnosis, treatment and follow-up

  • V. Medici

      Affiliations

    • Department of Surgical and Gastroenterological Sciences, Gastroenterology Section, Via Giustiniani 2, University Hospital of Padova, 35128 Padova, Italy
    • Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of California Davis Medical Center, 4150 V Street, Suite 3500 PSSB, 95817 Sacramento, CA, USA
    • ,
  • L. Rossaro

      Affiliations

    • Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of California Davis Medical Center, 4150 V Street, Suite 3500 PSSB, 95817 Sacramento, CA, USA
    • ,
  • G.C. Sturniolo

      Affiliations

    • Department of Surgical and Gastroenterological Sciences, Gastroenterology Section, Via Giustiniani 2, University Hospital of Padova, 35128 Padova, Italy
    • Corresponding Author InformationCorresponding author. Tel.: +39 049 8212890; fax: +39 049 8760820.

Received 10 October 2006; accepted 23 December 2006.

Article Outline

Abstract 

Wilson disease is an inherited, autosomal recessive, copper accumulation and toxicity disorder that affects about 30 individuals per million. This rare disease is caused by mutations in the gene encoding a copper-transporting P-type ATPase, which is important for copper excretion into bile, leading to copper accumulation in the liver. Toxic copper concentrations can also be found in the brain and kidney, and clinical phenotypes include hepatic, haemolytic, neurologic and psychiatric diseases. Diagnosis is based on the combination of clinical features and findings such as increased urinary copper excretion, reduced levels of serum ceruloplasmin, high concentrations of copper in liver tissues and Kayser–Fleischer rings. Genetic studies are also becoming available for clinical use, but the utility of direct mutation analysis is limited. Wilson disease can be treated, and early diagnosis is essential: the goal of therapy is to reduce copper accumulation either by enhancing its urinary excretion or by decreasing its intestinal absorption. Medical therapies include penicillamine, trientine, zinc and tetrathiomolibdate. Liver transplantation is a relatively successful treatment option when medical therapy fails or in case of acute liver failure, even though it is also characterized by short- and long-term complications.

Keywords: Copper, Diagnosis, Liver transplantation, Wilson disease

 

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1. Introduction 

Wilson disease is an inherited, autosomal recessive, copper accumulation disorder that affects about 30 individuals per million population [1]. It is due to a dysfunction of a copper-transporting P-type ATPase that has a crucial role in copper excretion into the bile [2], [3], [4]. The gene encoding this P-type ATPase, ATP7B, is located on chromosome 13q14.3 and numerous gene mutations can impair the protein's function [5], [6], leading to copper accumulation mainly in the liver, but also in the brain, cornea and kidney.

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2. Clinical features 

Most patients present with Wilson disease between the first and the fourth decades of life [7], although age at presentation can vary from 2-years-old [8] to 70-years-old [9]. The main clinical presentations of Wilson disease include hepatic, haemolytic, neurological and psychiatric disease.

2.1. Hepatic features 

Hepatic involvement can vary from asymptomatic to hepatomegaly, fatty liver and acute hepatitis, with high serum transaminases, liver failure, jaundice and cirrhosis. Haemolysis can occur in acute liver failure and this is one of the signs most often overlooked in the diagnosis of Wilson disease. Kayser–Fleischer rings, caused by copper deposition on Descemet's membrane in the cornea, are seen in 50–60% of patients with mainly hepatic features of Wilson disease [10].

2.2. Neurological features 

Neurological disorders usually develop in the third decade of life and are the presenting symptoms of Wilson disease in 40–50% of patients [11]. Typically, these involve hypokinetic speech, tremor, dystonia, incoordination and dysphagia; the patient may appear to have Parkinson's disease because the copper typically accumulates in the basal ganglia. Kayser–Fleischer rings are observable in virtually all patients with neurological involvement [12].

In 2005, a score was developed to describe the neurological signs and symptoms commonly found in Wilson disease patients [13]. The most representative and easiest to apply for the purpose of a retrospective neurological assessment were: six signs (rigidity, bradykinesia, ataxia, tremors, dyskinesia, dystonia) and four functions (eating, walking, talking, self care and dressing). Each item scores a maximum of 3, higher scores coinciding with milder symptoms or less-impaired functions. The maximum score is 30. The score is mainly of descriptive value and particularly useful for retrospective analysis; it can be used not only by neurologists, but also by gastroenterologists or hepatologists.

2.3. Psychiatric features 

Psychiatric symptoms can occur before (most likely 2 or 3 years before) hepatic and neurological symptoms become manifest. Patients may develop psychiatric and behavioural abnormalities, e.g. depression (sometimes leading to attempted suicide), paranoia, hallucinations and delusions, irritability, loss of sexual inhibitions or declining performance at school or at work [14]. Behavioural and cognitive symptoms can be reversed by 1–2 years of continuous treatment [15].

2.4. Other features 

Endocrine, renal, cardiac and skeletal presentations of Wilson disease occur in fewer than 10% of patients. Endocrine features of Wilson disease include hypoparathyroidism [16], menstrual irregularities and infertility [17]. Renal features include nephrolithiasis and aminoaciduria [18]. Cardiac features include cardiomyopathy and rhythm disorders [19]. Skeletal features include arthritis and premature osteoporosis [20]. Up to 25% of patients may present with more than one organ or system involved.

2.5. Phenotypic classification 

The first phenotypic classification of Wilson disease is attributable to Uzman et al. [21], while a new classification was developed in 2001 [22]. The latter distinguishes the disease's presentation as hepatic or neurological. The disease is classified as hepatic after ruling out any neurological symptoms. A classification of H1 is attributed to acute hepatic Wilson disease presenting as jaundice in previously healthy subjects; H2 describes chronic hepatic Wilson disease presenting as or evolves into end-stage liver disease. The disorder is classified as neurological if neuropsychiatric symptoms are apparent at diagnosis: N1 is used for neuropsychiatric disease associated with symptomatic liver disease (i.e. patients with cirrhosis at diagnosis) and N2 to classify neuropsychiatric disease with no associated symptomatic liver disease (the apparent absence of liver disease needs to be confirmed by liver biopsy). NX is used when the patient has not been investigated for any presence of liver disease.

Box 1. Practical guidelines on when to suspect Wilson disease


•Unexplained liver disease: increased AST or ALT levels, hepato- and splenomegaly, steatosis or features of chronic liver disease, at any age of onset, especially under the age of 40.

•Unexplained neurological disease, behavioural and/or psychiatric problems, with or without any associated liver disease, at any age of onset.

•Family history: first-degree relatives of any patient diagnosed as having Wilson disease. Always bear in mind that all newborn babies physiologically have ceruloplasmin levels that are 50% of the normal adult values, making diagnosis uncertain in the first 2–3 months of life. As the effects of the disease do not become apparent until about 3 years of age, diagnostic testing is not done in infancy.

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3. Diagnosis 

The diagnosis of Wilson disease is based on a very broad combination of laboratory tests and clinical features. The diagnosis is straightforward in most cases, as properly investigated patients usually reveal some of the classical clinical and biochemical features. The most useful laboratory tests for diagnostic purposes are those measuring 24-h urinary copper excretion, hepatic copper concentration, serum free copper concentration and ceruloplasmin concentration. Screening individuals for mutations responsible for the disease may also aid diagnosis and detecting Kayser–Fleischer rings can be useful.

3.1. 24-h urinary copper excretion 

A urinary copper concentration greater than 100μg/24h (>1.6μmol/24h) is considered diagnostic for Wilson disease. This level is reached in most symptomatic patients, but a level of 40–100μg does not enable Wilson disease to be ruled out in asymptomatic patients, so they require further testing [23]. In individuals who are heterozygous for Wilson disease, moreover, urinary copper excretion is rarely above 70μg/24h. The utility of this measurement is further limited by the fact that high urinary copper levels can be found in other chronic liver diseases too (e.g. primary biliary cirrhosis, primary sclerosing cholangitis, Alegille syndrome and autoimmune hepatitis) [24]. Estimating urinary copper excretion may also be misleading due to improper of the 24-h urine collection or to copper contamination. Preservatives used for routine analysis may contain mercuric oxide (i.e. Stabilur), which interferes with all metal testing. If both urinalysis and metal testing are ordered, a separate urine specimen (containing no additive) has to be used for the metal testing.

Testing urinary copper excretion after penicillamine challenge can be useful, though this test has only been standardized in a pediatric population [25], and it has never been validated in heterozygous carriers of Wilson disease. This test involves administering 500mg of penicillamine at the baseline and then again 12h after starting the 24h urine collection. If the final urinary copper concentration is greater than 1600μg/24h, then a diagnosis of Wilson disease is more likely than other liver diseases (e.g. autoimmune chronic active hepatitis, primary sclerosing cholangitis or acute liver failure) [25].

3.2. Hepatic copper concentration 

In almost all patients, the liver's copper content is more than 250μg/g dry weight (normal <50μg/g dry weight) and may even be as high as 3000μg/g dry weight [26]. Patients with severe cirrhosis occasionally have a liver copper content below 250μg/g dry weight because of an uneven distribution of copper in the liver parenchyma. The hepatic copper concentration is reportedly lower than 250μg/g dry weight in up to 20% of Wilson patients, especially among those with mainly neuropsychiatric involvement [27], [28]. These results derive from our limited experience on 35 patients [28] and from Ferenci's study on 114 patients [27], whose hepatic copper was measured at different centers and in different conditions.In addition, the variability of hepatic copper may also be due to sampling error or the poor reliability of a single copper determination. Measuring hepatic copper nonetheless remains the best diagnostic test. Histochemical methods for detecting excess copper in the liver are unreliable [29].

3.3. Serum copper concentration 

The plasma free copper concentration (i.e. copper not bound to ceruloplasmin) is considered useful for the diagnosis of Wilson disease, but it can only be calculated after measuring the total concentration of copper and ceruloplasmin in plasma. Since the amount of copper bound to ceruloplasmin is about 3.15μg/mg of ceruloplasmin, the serum free copper concentration is calculated as the difference between the serum copper concentration (μg/dL) and three times the ceruloplasmin concentration (mg/dL) [30]. The serum free copper concentration is more than 25μg/dL in most untreated patients (normal value <15μg/dL), but it may also be higher than normal in patients with acute liver failure or chronic cholestasis [31] and its validity as a test depends on how well ceruloplasmin was measured (the enzymatic method appears to be advisable, though not universally accepted) [32]. This test is probably more useful during the follow-up, to assess response to treatment, than as a single diagnostic tool.

3.4. Ceruloplasmin concentration 

Ceruloplasmin is a copper-carrying protein that is bound to 90% of the circulating copper in normal individuals. The normal concentration of ceruloplasmin is 200–400mg/L, and a serum ceruloplasmin level below 200mg/L (20mg/dL) is suggestive of Wilson disease. The clinical utility of this measurement is limited, however, by the fact that ceruloplasmin concentrations under 200mg/L can be found in 1% of controls, in 10% of heterozygous Wilson disease carriers and in patients with copper deficiency [33], Menkes disease, hereditary hypoceruloplasminemia [34], malabsorption, nephrotic syndrome and chronic liver failure. What's more, normal ceruloplasmin concentrations are recorded in about 20% of Wilson disease patients. There is still some debate as to whether the immunological-nephelometric method is comparable with enzymatic assay (oxidase activity) for determining ceruloplasmin serum concentration, especially in patients with liver disease. Enzymatic activity is the biologically relevant parameter, whereas the immunonephelometric method measures both ceruloplasmin and the biologically inactive apo-form. The enzymatic method should consequently be preferred for the diagnosis of Wilson disease [35], though a weak correlation was found between ceruloplasmin protein concentration and oxidase activity in patients with different degrees of hepatic involvement [32]. A more recent study on 33 Wilson patients demonstrated a good correlation between the two tests [36].

3.5. Kayser–Fleischer rings 

The presence of Kayser–Fleischer rings indicates that free copper has been released into the circulation. Other ophthalmological findings include sunflower cataracts, which are the sign of copper deposition in the lens. Kayser–Fleischer rings are seen in 50–60% of patients with mainly hepatic disease, whereas almost all patients with mainly neuropsychiatric symptoms are positive for ophthalmological signs [37]. Kayser–Fleischer rings are not found in all Wilson disease patients, however, and they are not completely specific for the disorder—they can occur in patients with chronic cholestatic diseases and in neonatal cholestasis [38]. The rings may disappear after long-term therapy, though their presence does not correlate with disease severity [39].

3.6. Genetic testing 

Given the variability of the biochemical and clinical features of Wilson disease, mutation analysis is becoming more and more essential to confirm a suspicion of the disorder. Nearly 300 ATP7B mutations have been identified to date. When mutations responsible for Wilson disease are detected, the condition can be confirmed, but a negative result cannot exclude a diagnosis of Wilson disease. Some populations had proved to have a limited number of predominant mutations, such as in Eastern Europe (H1069Q) [40], Sardinia (c-441_427del15) [41], Korea (Arg778Leu) [42], Iceland (2007del7) [43], Japan (229insC, Arg778Leu) [44], Spain (Met645Arg) [45] and China (Arg778Leu) [46]. In these geographical areas, utilization of mutation analysis may be a useful diagnostic method. For the time being, genetic testing is mainly limited to the screening of first-degree relatives of Wilson disease patients, since haplotype analysis is excellent for genotyping the full siblings of an index case [47]. While it is true that a negative result cannot rule out a diagnosis of Wilson disease, many laboratories now sequence the complete gene as well as the promoter. The availability of this technique is limited, and standardization is not well-established.

3.7. Diagnostic index 

A diagnostic score was proposed in 2001 [22], based on the following parameters: 24-h urinary copper, hepatic copper concentration, ceruloplasmin, presence of ATP7B gene mutations, presence of Kayser–Fleischer rings, neuropsychiatric symptoms or brain MRI findings compatible with copper deposition, and haemolytic anaemia. After assigning a score from 0 to 2 to each parameter, the final score would indicate the likelihood of the diagnosis (≥4 certain; 2–3 likely; 0–1 unlikely).

In the case of fulminant Wilson disease, the diagnosis may be more difficult because many of the copper metabolism parameters described – including serum and urinary copper, and serum ceruloplasmin levels – may not be specific or diagnostic. In 1991, Berman described the ALP/Bb<2 and AST/ALT>4 ratios as being highly specific for fulminant Wilson disease [48], but these correlations were not confirmed by subsequent validation studies [49], [50], [13].

Box 2. Practical clinical tips to consider in the work-up for Wilson disease


•Always keep a high index of suspicion.

•Wilson disease can be diagnosed in all age groups.

•There is no gold standard for diagnosis, which relies on a combination of clinical and laboratory findings.

•The key clinical findings are liver disease (from mild to severe) and neuropsychiatric disease (in combination or alone).

•The key findings are urinary copper levels >100μg/24h, hepatic copper levels >250μg/g d.w., ceruloplasmin levels <200mg/L and Kayser–Fleischer rings.

•Mutation analysis may provide a definitive diagnosis, but some variants may not be responsible for the disease.

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4. Therapy 

The goal of therapy is to reduce copper accumulation, either by enhancing its urinary excretion or by reducing its intestinal absorption. The options available for the treatment of Wilson disease are all the more effective the sooner they are initiated.

4.1. d-Penicillamine 

d-Penicillamine (d-PCA) mobilizes copper and forms copper–penicillamine complexes that are excreted in the urine. Most patients with a mainly hepatic Wilson disease phenotype experience a clinical improvement after 6–8 weeks of treatment, but it may take 6–12 months for the change to be noticeable [51]. It is best to start patients on lower doses, gradually increasing it up to the therapeutic range in order to improve its tolerability [26]. For instance, d-PCA treatment is started at 125mg/day for the first week, then the dose is raised by 125mg every week up to a dose of 1.0–1.5g/day. d-PCA can induce vitamin B6 deficiency so a daily dose of 25mg of pyridoxine (vitamin B6) is usually added to the treatment regimen.

Approximately 30% of patients have hypersensitive reactions in the first month of treatment (fever, rash, lymphadenopathy) [52]. These early side effects are usually transient, but temporary drug withdrawal and corticosteroids may be required. Late drug reactions can be seen even after years of uneventful treatment. The most common of these late side effects involve the skin (degenerative changes, elastosis perforans serpiginosa) [53] and joints (arthropathy), or may be mediated by immunological effects (lupus-like reactions, nephrotic syndrome, myasthenia gravis, Goodpasture syndrome) [52]. Bone marrow depression, which can present as aplastic anaemia, neutropenia and thrombocytopenia, may develop as an early or late side effect, so a full blood count is needed before the treatment is started. Neurological symptoms reportedly become more severe in about 50% of patients taking d-PCA [54].

4.2. Trientine 

Trientine is a copper chelator, taking effect primarily by enhancing urinary copper excretion. It is used as an alternative to d-PCA, both in the event of tolerance and as front-line treatment because it has fewer side effects. It is thought to act by mobilizing tissue copper, albeit to a lesser degree than d-PCA (hence the more limited side effects) [55]. The usual starting dose of trientine is 750–1500mg, divided between 2–3 doses a day, with 750–1000mg as a maintenance dose. It should be taken before meals or 2h afterwards. Trientine is probably less toxic than d-PCA. No early hypersensitivity reactions have been reported; late adverse reactions include lupus-like syndrome with proteinuria and moderate sideroblastic anaemia [56]. The risk of neurological symptoms becoming worse when trientine is used as first-line therapy is reportedly 26% [57].

4.3. Zinc 

Zinc increases the levels of intestinal cell metallothionein [58], [59], a protein with a strong affinity for copper. The tight link formed between copper and metallothionein inhibits further copper absorption and promotes its loss in the faeces as enterocytes are shed due to normal cell turnover. Zinc may also increase metallothionein levels in hepatocytes, i.e. the copper binding to metallothionein forms non-toxic complexes in the liver, resulting in little or no change in the total hepatic copper concentration [60]. Zinc is used mainly as a front-line therapy in patients who have not (or not yet) developed symptoms [61], for maintenance therapy and for patients with a mainly neuropsychiatric involvement, because a worsening of the neurological picture is very uncommon in such cases (10% in our experience) [28]. Zinc sulfate should be administered at a dose of 220mg/day three times daily (corresponding to 150mg of elemental zinc a day), at least 1h before meals [62].

Zinc is generally well tolerated. Gastric irritation is the most frequent problem (10–15%) [62], but this can be overcome by replacing zinc sulfate with zinc acetate, or by taking the first daily dose mid-morning rather than before breakfast. A mild, harmless increase in serum amylase and lipase concentrations [63] (that is not due to pancreatitis), a 20% reduction of high-density lipoprotein cholesterol in male patients [64] (compensated by a reduction in total cholesterol) have been described.

4.4. Combination therapies 

The combined use of d-PCA and zinc is not recommended, as it does not make sense to administer a metal with a chelating agent capable of neutralizing its effect. A previous study [65] failed to demonstrate any advantage of such a combined treatment.

A highly experimental approach involves using trientine combined with zinc for 6–8 weeks, then switching to zinc maintenance therapy. This strategy was used to treat nine patients presenting with hepatic decompensation [66], whose liver function improved, with a normalization of their Child–Turcotte–Pugh score, and even a markedly reduced liver fibrosis.

If doses of chelators and zinc are to be administered in combination, the interval between them must be as wide as possible; this means taking medication numerous times during the day and this is very likely to have a negative effect on compliance.

4.5. Tetrathiomolybdate 

Tetrathiomolybdate has two mechanisms of action [67]. First, it complexes copper in the intestinal lumen, preventing its absorption. Second, once it has been absorbed, it complexes copper with albumin in the blood and makes the copper unavailable for cellular uptake. Tetrathiomolybdate has been proposed as initial treatment for patients with neurological signs and symptoms [68], but its use is restricted by the limited clinical experience with the drug and it is not commercially available in the USA or the European Union. Neurological Wilson disease patients have been treated with doses of tetrathiomolybdate varying from 120 to 410mg/day for 8 weeks [68]. A randomized, double-blind, controlled, two-arm study on 48 Wilson disease patients with a neurological presentation was recently performed: patients were treated with trientine (500mg twice a day) or tetrathiomolybdate (20mg three times a day with meals and 20mg three times a day between meals) for 8 weeks [57]. Fewer patients on tetrathiomolybdate experienced a neurological deterioration than those on trientine, and about 15% of patients on tetrathiomolybdate experienced only mild side effects, which included bone marrow toxicity (anaemia, thrombocytopenia and neutropenia) and rising aminotransferase levels, but both effects were reportedly transient and responded to suspension of the drug. We reported on a case of acute hepatitis with high transaminases, signs of cholestasis and a marked increase in cholesterol and triglycerides [69] after tetrathiomolybdate treatment in a neurological Wilson patient, whose neurological functions remained stable throughout the course of therapy.

4.6. Diet 

Foods rich in copper (e.g. liver, chocolate, nuts, mushrooms and shellfish) should be avoided, at least in the early years after diagnosis. More stringent dietary measures are unpleasant, impractical and probably fail to postpone the progression of disease [70]. Drinking water usually contains less than 0.2mg copper per liter but up to 10% of domestic drinking water has copper levels that may be too high for Wilson patients, so it should be tested.

4.7. Liver transplantation 

Liver transplantation is the ultimate treatment for patients with Wilson disease. Survival rates reportedly range from 100% at 33 months [71] to 62% at 1 year [72]. We have reported overall patient survival rates at 6 and 12 months and 5 and 10 years after transplantation of 89.1, 89.1, 75.6, 58.8%, respectively [13].

Wilson disease patients should be considered for liver transplantation when suitable medical therapy has failed or in the case of acute liver failure, when there is no time for other therapies to take effect. Patients with a combination of hepatic and neuropsychiatric conditions warrant careful neurological assessment, but liver transplantation is contraindicated only in cases of severe neurological impairment. Neuropsychiatric symptoms are always a contraindication for liver transplantation [73], [74], [75].

A prognostic scoring system for Wilson disease was recently developed [76], after the revision of a previous scoring system proposed in 1986 [77]. The new scoring system was developed for pediatric patients and is based on bilirubin, AST and albumin levels, white cell count and INR. A score of 11 or above suggests that patients are at high risk of mortality unless liver transplantation is performed. This score revealed a sensitivity of 93% and a specificity of 97%, with a positive predictive value of 92%.

Box 3. Practical guidelines for the treatment of Wilson disease


•Start therapy as soon as possible: Wilson disease can be treated.

•Initial treatment of symptomatic patients with hepatic involvement should only include a chelating agent (d-PCA or trientine).

•Treatment of symptom-free patients or those on maintenance therapy with a mainly hepatic involvement, can safely be based on zinc salts.

•Patients with a mainly neuropsychiatric involvement should be treated from the start with zinc, while d-PCA may make their neurological function deteriorate—though this issue is still very controversial.

•Liver transplantation is a relatively successful treatment for Wilson disease – where all medical therapies have failed or in the event of acute liver failure – but it carries several short- and long-term complications. Liver transplantation is not indicated where a neuropsychiatric condition is the main clinical phenotype of Wilson disease.

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5. Wilson disease in pregnancy 

Pregnancy is not contraindicated for patients with well-managed Wilson disease and compensated liver disease, but treatment must be continued throughout pregnancy and breast feeding because its interruption could lead to acute liver failure. The safest drugs for pregnant Wilson disease patients are zinc and trientine [78]. A report from Brewer et al. [79] described 26 pregnancies in 19 women on zinc therapy throughout their pregnancy, showing that zinc protected the health of the mother and foetus during the pregnancy, with a 7.7% rate of congenital defects (one baby was born with a heart defect, another had microcephaly and died an hour after birth), as opposed to the 4% rate of major and minor congenital defects in the general population, but studies on larger groups would be needed to ascertain whether the rate of defects in zinc-treated pregnancies is actually higher than in the general population. It has also been demonstrated that zinc does not reach significantly high concentrations in breast milk [80]. The teratogenicity of d-PCA is still debated: while some authors believe there is no reason for concern regarding the use of d-PCA in pregnancy [81], cutis laxa syndrome has been reported in about 5% of babies born from mothers treated with d-PCA during pregnancy [82], as well as other severe embryopathies (micrognathia, contractures of all limbs, central nervous system abnormalities) [83].

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6. Management during follow-up 

The outcome of therapy has to be monitored by regular physical and neurological assessments. Corneal slit lamp evaluation to assess any improvement of the Kayser–Fleischer rings may also be helpful in the long-term follow-up. Liver function tests should be performed and laboratory data collected (e.g. blood counts, serum biochemical liver function tests, copper metabolism indices, urinalysis, 24-h urinary copper and zinc excretion) at intervals varying from 1 to 8 months, depending on the patient's clinical condition. Patients should be followed up at least twice a year, in most cases, to monitor clinical improvements, side effects of therapy and compliance, which has to be checked periodically to prevent a rapid worsening of symptoms deriving from poor compliance with the prescribed medication [84].

Compliance can be monitored by measuring 24-h urinary copper excretion, which should rise up to 200–500μg on treatment with chelating agents (i.e. d-PCA, trientine). While on zinc therapy, 24-h urinary copper excretion should be between 50 and 125μg, and zinc excretion should be at least 2mg. Compliance can also be monitored by measuring the serum free copper, which should fall with therapy, to around 10ug/dl (1.5umol/l) in most patients, where it should then remain. If it rises, the patient is not fully compliant or, in the case of children, the patient may have grown and require a larger dose.

We take liver biopsies and assay liver copper content at diagnosis, before changing the anti-copper therapy and at various intervals during follow-up. The results of a total of 66 biopsies showed no differences in hepatic copper content between follow-up biopsies from patients on either treatment – d-PCA or zinc – which lead us to conclude that liver biopsy is only indicated during follow-up [28] to explain any unexpected deterioration.

About 20% of patients have persistently high transaminase levels [85]: in such cases, it is most important to carefully assess the patient's compliance with treatment by measuring 24h urinary copper excretion. Once compliance has been demonstrated, the higher transaminases can be considered harmless in the majority of cases and are not associated with any disease progression.

Box 4. Practical guidelines for the follow-up of Wilson disease patients

A combination of gastroenterological, neurological and ophthalmological evaluations is needed. Always check compliance, since any failure to comply with the treatment is life-threatening.

•Compliance can be checked by measuring 24-hour urinary copper excretion.

•In the event of non-compliance, recommend more frequent follow-up visits and more regular laboratory tests.

•Persistently high transaminase levels are seen in 20% of patients, without any evidence of disease progression.

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7. Conclusions 

Wilson disease is a rare inherited metabolic disease leading to copper accumulation, mainly in the liver and brain. Although this accumulation of copper begins at birth, symptoms of the disorder usually appear later in life, between the ages of 3 and 40. The primary consequence for approximately 40% of Wilson patients is liver disease. In other patients, the first symptoms are neurological or psychiatric, or both. Without proper treatment, Wilson disease is generally fatal, usually by the age of 30. If treatment is begun early enough, symptomatic recovery is usually complete, and a normal length and quality of life can be expected. Even decompensated liver disease usually improves with adequate therapy. In most cases, a well-timed treatment can overcome both the hepatic and the neurological signs.

The main goal of research should consequently be early diagnosis for both hepatic and neurological Wilson disease, as well as new accurate methods for ensuring compliance with the treatment.

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Practice points 


•Suspect Wilson disease at any age of onset, but particularly under the age of 40.

•There is no gold standard for diagnosis, which is based on a combination of clinical and laboratory findings.

•Early recognition and early treatment are mandatory: Wilson disease is a treatable disorder.

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Research agenda 


•Identify new tests for early diagnosis.

•Characterize phenotype-genotype correlations.

•Consensus on diagnostic methods, treatment and follow-up.

•Establish new tests for assessing compliance.

•Discover new therapies, especially for neurological and psychiatric patients.


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Conflict of interest statement 

None declared.

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PII: S1590-8658(07)00003-5

doi:10.1016/j.dld.2006.12.095

Digestive and Liver Disease
Volume 39, Issue 7 , Pages 601-609, July 2007

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