Background
Wilson disease (WD) [
1] is a disorder of copper metabolism mediated by autosomal recessive inherited mutations of the
ATP7B gene on chromosome 13q. More than 700 different mutations in this gene causing WD have been described [
2]. Mutations lead to copper transporter dysfunction with subsequent copper deposition in the liver and other organs. The most frequent manifestations encompass copper deposition in the cornea (Kayser–Fleischer rings) [
3‐
5], hepatic abnormalities including acute liver failure and liver cirrhosis [
6‐
8], and impairment of the central nervous system with neurologic manifestations including tremor and ataxia [
9] as well as psychiatric symptoms. Less common features, such as (cardio-)myopathy [
10,
11], renal abnormalities [
12‐
14], hemolytic anemia [
13,
15‐
17] and pancreatitis [
18], have also been described. The disease can manifest at any age, with a majority of patients being diagnosed between 5 and 35 years of age (mean: 13 years of age) [
19‐
21]. The estimated prevalence of WD is approximately 1:30,000 [
22,
23], occurring in approximately three thousand patients in Germany (estimated population in Germany on 31 Dec 2021: 83.2 million; data source: The Federal Statistical Office of Germany,
http://www.destatis.de/; accessed on 01 Aug 2022).
Lifetime therapy and regular monitoring are necessary to avoid the otherwise progressive copper overload and subsequent fatal outcome of this disease [
20]. Copper removal as well as prevention of reaccumulation are achieved by copper chelators, e.g., D-penicillamine (DPA) as a first-line drug or trientine. Zinc salts, which interfere with intestinal copper absorption, are also applied in patients [
20,
21]. Further strategies include dietary recommendations to avoid copper-rich dietary components [
21]. Liver transplantation (LT) is performed in cases of acute liver failure (ALF) or decompensated liver cirrhosis [
20,
21].
Several guidelines for WD management have been issued, e.g., by the American Association for the Study of Liver Diseases (AASLD) in 2003, 2008 [
24] and 2022 [
21], by the European Association for the Study of the Liver (EASL) in 2012 [
20] and by the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) in 2018 [
25]. German guidelines were published by the German Society for Neurology in 2012 [
26].
Whereas the medical care of highly prevalent liver diseases such as nonalcoholic fatty liver disease (NAFLD) has been described in Germany [
27], data on the medical care of patients with orphan liver diseases are scarce. Therefore, in this study, we analyzed the medical care of WD patients in Germany.
Discussion
In this study, we evaluated the medical care of WD patients at German university hospitals. We sent a questionnaire to 108 departments in 36 German university centers and received the questionnaire back from 58% of the departments. The three disciplines of pediatrics, neurology and gastroenterology were distributed equally among the participating departments. The departments indicated that a total of approximately 950 patients are treated in their outpatient clinics annually, presumably covering approximately one-third of the expected WD patients in Germany.
WD mainly presents with a hepatologic or neurologic phenotype, but its symptoms can vary widely. Information about the prevalence of clinical manifestations varies heavily in the literature, e.g., regarding hepatic symptoms between 15 [
31] and 84% [
32]. In our survey, most centers reported a high prevalence of hepatic and/or neurologic symptoms in their patients at the time of diagnosis. Other manifestations at the time of diagnosis did not occur to any noteworthy extent. A limiting factor was the circumstance that the proportions of symptoms in the centers might be unbalanced due to varying numbers of patients in the institutions. Nevertheless, our results are in line with the literature.
Due to its manifold symptoms, its variable clinical course, and complex biochemical tests that are sometimes difficult to interpret, the establishment of a diagnosis of WD can be challenging. The use of gene panels in groups with certain phenotypes could provide a quicker diagnostic approach but is often not applied in the first place, and inconclusive and often complex biochemical test results can delay diagnosis. In particular, patients with neurologic manifestations experience longer time periods between the onset of symptoms and diagnosis, with a delay of up to several years [
33]. Guidelines recommend the use of algorithms for diagnosis, e.g., based on the Leipzig score by Ferenci et al. [
20,
21,
25,
26,
28]. In contrast, the proportion of departments using the Leipzig score was markedly low; only 51% of all responding departments indicated its use in their clinical routine. Nevertheless, the most relevant parameters of the Leipzig score were used for diagnostics by most departments on a regular basis. Serum ceruloplasmin, serum copper and copper excretion in 24-h urine were used by almost all departments to establish the diagnosis of WD. The determination of unbound copper, referred to as “free copper” or nonceruloplasmin-bound copper concentration (NCC) [
34], was less common. Usually, NCC is not measured directly but is calculated from total serum copper and ceruloplasmin [
35]. A rather new method of copper evaluation is the direct determination of exchangeable copper (CuEXC) [
36], which has been proposed to have a very high sensitivity and specificity for WD [
37]. CuEXC has not yet been implemented in the European guidelines, but is mentioned, e.g., in the American AASLD and pediatric ESPGHAN guidelines, as a promising and valuable monitoring parameter [
21,
25]. In our survey, most departments stated that CuEXC was not determined. CuEXC determination may become more relevant after implementation in recent guidelines. It must be taken into account, however, that the difference between CuEXC (measured free copper) and NCC as calculated free copper might not be obvious in all laboratories or understood by all survey participants. Additionally, the actual number of laboratories determining CuEXC might diverge.
The European EASL guidelines as well as the American AASLD guidelines recommend regular routine monitoring, at least biannually [
20,
21]. The pediatric ESPGHAN guidelines state that children should be monitored every 3–6 months after the initial therapy and remission phase [
25]. Longer intervals between monitoring visits are proposed by the neurologic German guidelines, which state that routine monitoring should be carried out every one to two years [
26]. On average, 84% of the participating departments indicated utilizing a monitoring interval of 6 months or less. We therefore conclude that monitoring is performed in adequate intervals, as recommended by international guidelines. The following investigations are recommended for routine monitoring [
21,
25,
26]: physical and neurologic examination, serum copper and ceruloplasmin, liver enzymes and INR, complete blood count and urine analysis. In addition to rarely performing neurologic examinations during routine monitoring, most departments performed these monitoring components frequently. Only the neurologic German guidelines recommend performing a cMRI every 4–6 years to detect latent changes [
26], whereas the American guidelines state that repeated cMRI is not useful in general [
21]. All departments stated that they performed cMRI less than once a year (n = 44/52) or never (n = 8/52) in routine monitoring.
In addition to an early diagnosis, effective medical therapy is another key factor affecting the prognosis of WD patients. Treatment takes place in two phases: after the initial phase of removing and detoxifying accumulated tissue copper, the goal of lifelong medical therapy is to prevent copper reaccumulation and disease progression. If treatment is initiated early and adherence is high, the prognosis for WD patients is good, and life expectancy is normal [
29]. The only reason to terminate pharmaceutical therapy in WD is a history of LT. Medical therapy encompasses copper chelators, such as DPA and trientine. The European and German guidelines recommend the monitoring of chelator treatment adequacy for both DPA and trientine by measuring the 24-h urinary copper excretion, while on treatment, two days after chelator cessation [
20,
26]. Cessation of chelator therapy was reported by 48% of all departments. In line with heterogeneous guideline statements, the proportion of departments interrupting chelator therapy was low in departments of pediatrics (15%) and high in departments of neurology/gastroenterology (70%). In addition to chelator therapy, treatment with zinc salts (e.g., sulfate, acetate, gluconate) to block enteral copper absorption has been established since the early 1960s [
20,
21,
38,
39]. Zinc therapy may be less effective than chelator therapy [
40] but may be used for maintenance therapy as well as for asymptomatic or presymptomatic patients, especially in pediatric patients [
20,
41]. Zinc can be used as monotherapy or combined with chelators [
20,
21,
26]. Zinc monotherapy can be effective and safe in WD patients with neurologic manifestations, but should be used cautiously in cases of hepatic manifestation because of potential hepatic deterioration [
20,
21]. Due to having a better tolerance profile with fewer side effects, zinc salt therapy has become more popular, especially in departments of pediatrics [
20,
21,
25,
41]. In our survey, 43% of the departments stated that zinc salts are used for WD monotherapy. Fifty-eight percent of the departments of pediatrics reported the use of zinc salt monotherapy. It is likely that the need to treat patients with better tolerated medication is higher in the pediatric setting. Zinc salts in combination with chelators are used by a minority of departments (28%). On average, departments used the first-line drug DPA in 72% and the second-line drug trientine in 19% of their patients.
In this context, the AASLD guidelines suggest lower chelator dosages or a shift to zinc monotherapy for stable patients, indicating that these patients have usually already been treated for 1–5 years [
21]. The liver function of WD patients usually normalizes after 1–2 years of treatment [
20]. The improvement of symptoms in neurologic WD patients might be slower and still noticeable after 3 years of DPA treatment [
42]. Most departments (81%) reevaluate the initial treatment of WD patients to check if a reduction of medication is possible, usually after two years (49%) or between two and five years (26%) after starting therapy.
In WD, most asymptomatic patients are detected by family screening [
20]. Since genetic testing has become more available and affordable, guidelines suggest genetic screening for members of a WD patient´s family [
20,
21,
26]. Family screening was recommended by most departments (84%) in our survey. We emphasize the need to perform family screening to identify asymptomatic patients.
A structured transitional program from pediatrics to adult medicine was available in a fourth of departments (27%). Regarding the necessity of lifelong therapy, the need for good monitoring and the risk of noncompliance [
43], transition programs can be helpful.
Guidelines provide recommendations regarding pregnancy and breastfeeding. As there is an increased risk of developing WD among the children of WD patients, genetic counseling and haplotype analysis of patients´ partners is recommended [
20]. Despite reports of teratogenic effects, guidelines declare that treatment should be continued throughout pregnancy [
20,
21,
26]. Cessation of therapy can lead to clinical deterioration, including ALF and spontaneous abortion [
21,
44,
45]. Due to possible teratogenicity, chelator reduction is recommended at the beginning of pregnancy as early as possible [
20,
21]. A reduced chelator dose is also recommended for the last trimester to prevent copper deficiency in the unborn child as well as to improve wound healing in the mother in case of cesarean section [
21,
26]. To our surprise, the recommended dose reduction was carried out in only 46% of all departments. Twenty-five percent of all departments stated that they do not make therapy adjustments during pregnancy. Breastfeeding is not recommended during chelator therapy because of drug excretion into breast milk, although reports suggest that there is no harm for children of breastfeeding mothers under chelator therapy [
20,
26,
46]. The American guidelines propose that the pros and cons of breastfeeding should be discussed with patients individually [
21]. In our study, only 14% of all departments stated that women were advised to avoid breastfeeding. Although the number of departments answering our questionnaire about procedures for women with WD was low and the power of statements might be limited, we assume, due to the inconsistency of answers, that more studies should be conducted for WD in pregnant or breastfeeding women.
Some foods contain high levels of copper, such as shellfish, chocolate/cocoa and mushrooms [
21,
26]. Guidelines recommend the avoidance of these dietary components, at least in the first year of treatment [
20,
21,
26]. In this context, professional nutrition counseling is offered in 63% of the departments of our survey.
In cases of ALF or progressive, decompensating liver cirrhosis, LT may be the only therapeutic option. WD is the primary indication for 1% of all LTs in Europe. WD is the underlying disease in up to 12% of all ALF patients who are listed for emergency LT [
20,
21,
47]. In 2021, 834 LTs were performed in Germany. Five patients (0.6%) had WD (data source: Eurotransplant,
https://www.eurotransplant.org; data provided on 18 Aug 2022 upon request req235.2022). Although LT is a rare event for WD patients, 72% of the departments of gastroenterology reported at least one patient at their site who has undergone LT within the last decade.
Taken together, the medical care of WD patients in Germany follows recommendations by international guidelines. Nevertheless, there are only a few institutions which utilize a multidisciplinary approach. Many departments have only a few patients with WD. Certain recommendations are applied inconsistently, such as the cessation of chelator therapy before determination of 24-h urinary copper excretion. We therefore propose the establishment of larger, multidisciplinary centers to improve the medical care of WD patients.
The present study had some limitations. We analyzed the medical care of patients with WD using a retrospective approach. We received data from 63 departments (return rate: 58%). It is unclear whether other departments did not participate due to a lack of patients, interest, time or other reasons. Therefore, we must accept the risk of potential bias in our survey. We sent the questionnaire to the departments (head of department or person with managerial responsibility), but due to data protection issues, the questionnaires were completed anonymously. We do not know who filled out the survey. Nevertheless, we expect that the head of department filled out the questionnaire or that a delegated expert assistant answered the questions. The data we received might, at least in part, rely on rough estimates. Patients could be seen by different specialties simultaneously, but due to data privacy and logistical reasons, the listing of patients by name to detect the number of patients who simultaneously attend different departments would not have been feasible. A relevant number of departments returned the survey but did not answer all questions, especially if the number of patients was low. Nevertheless, we are convinced that our study adequately enables the analysis of the medical situation for patients with WD at German university centers.