SOCIETY PAPER

Wilson’s Disease in Children: A Position Paper by the

Hepatology Committee of the European Society for
Paediatric Gastroenterology, Hepatology and Nutrition

Piotr Socha, Wojciech Janczyk, yAnil Dhawan, zUlrich Baumann, §Lorenzo D’Antiga,
jj
Stuart Tanner, ôRaffaele Iorio, #Pietro Vajro, Roderick Houwen, yyBjörn Fischler,
zz
Antal Dezsofi, §§Nedim Hadzic, jjjjLoreto Hierro, ôôJörg Jahnel, ##Valérie McLin,

Valerio Nobili, yyyFrancoise Smets, zzzHenkjan J. Verkade, and §§§Dominique Debray
Downloaded from https://journals.lww.com/jpgn by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3qIsdRDyoedGISXC2qct1gUfUMxpi+1sNepsErJLAfsmbQoHU4gJ/kw== on 04/12/2018

ABSTRACT

Background: Clinical presentations of Wilson’s disease (WD) in childhood

What Is Known
ranges from asymptomatic liver disease to cirrhosis or acute liver failure,
whereas neurological and psychiatric symptoms are rare. The basic diag-  Guidelines on diagnosis and treatment of Wilson’s
nostic approach includes serum ceruloplasmin and 24-hour urinary copper
disease concerning mainly adults.
excretion. Final diagnosis of WD can be established using a diagnostic
scoring system based on symptoms, biochemical tests assessing copper
metabolism, and molecular analysis of mutations in the ATP7B gene. What Is New
Pharmacological treatment is life-long and aims at removal of copper excess
by chelating agents as D-penicillamine, trientine, or inhibition of intestinal  The most updated systematic review of literature
copper absorption with zinc salts. Acute liver failure often requires liver related mainly to management of Wilson’s disease
transplantation. This publication aims to provide recommendations for in childhood.
diagnosis, treatment, and follow-up of WD in children.  Specific criteria for diagnosis of Wilson’s disease in
Methods: Questions addressing the diagnosis, treatment, and follow-up of children, including diagnosis in early childhood
WD in children were formulated by a core group of ESPGHAN members. A and screening.
systematic literature search on WD using MEDLINE, EMBASE, Cochrane  Recommendations on choice of therapy depending
Database from 1990 to 2016 was performed focusing on prospective and on age and severity of liver damage in children with
retrospective studies in children. Quality of evidence was assessed according Wilson’s disease.
to the GRADE system. Expert opinion supported recommendations where the
evidence was regarded as weak. The ESPGHAN core group and ESPGHAN
Hepatology Committee members voted on each recommendation, using the
nominal voting technique.
Key Words: children, diagnosis, hepatitis, liver, treatment, Wilson’s disease

(JPGN 2018;66: 334–344)

Received April 23, 2017; accepted August 11, 2017.

From the Department of Gastroenterology, Hepatology, Nutritional Hospitals Geneva, Geneva, Switzerland, the Hepatometabolic Unit,
Disorders and Pediatrics, The Children’s Memorial Health Institute, Bambino Gesu Children’s Hospital, Rome, Italy, the yyyUniversité Cath-
Warsaw, Poland, the yPaediatric Liver GI and Nutrition Center, King’s olique de Louvain-IREC-Cliniques Universitaires Saint-Luc-Pediatric
College Hospital, London, UK, the zDivision of Paediatric Gastroenterol- Gastroenterology and Hepatology Unit, Brussels, Belgium, the
ogy and Hepatology, Department of Paediatric Kidney, Liver and Meta- zzzDepartment of Paediatrics, University of Groningen, University Medi-
bolic Diseases, Hannover Medical School, Hannover, Germany, the cal Center Groningen, Groningen, The Netherlands, and the §§§Pediatric
§Paediatric Hepatology, Gastroenterology and Transplantation, Hospital Hepatology Unit, Centre National de Référence de la Maladie de Wilson,
Papa Giovanni XXIII, Bergamo, Italy, the jjChildren’s Hospital, Sheffield, Hôpital Necker-APHP, Paris, France.
UK, the ôDepartment of Translational Medical Science, Section of Address correspondence and reprint requests to Wojciech Janczyk, MD and
Pediatrics, University of Naples Federico II, Naples, the #Dipartimento Piotr Socha, MD, PhD, Department of Gastroenterology, Hepatology,
di Medicina e Chirurgia, University of Salerno, Fisciano SA, Italy, the Nutritional Disorders and Pediatrics, The Children’s Memorial Health
Department of Paediatrics, Wilhelmina Children’s Hospital, University Institute, Al. Dzieci Polskich 20, 04-730 Warszawa, Poland
Medical Center Utrecht, Utrecht, The Netherlands, the yyDepartment of (e-mail: [email protected], [email protected]).
Paediatrics, CLINTEC, Karolinska Institute, Karolinska University Hos- Drs Socha and Janczyk contributed equally to this article.
pital, Stockholm, Sweden, the zzFirst Department of Paediatrics, Sem- ‘‘ESPGHAN is not responsible for the practices of physicians and provides
melweis University, Budapest, Hungary, the §§Paediatric Centre for guidelines and position papers as indicators of best practice only. Diagnosis
Hepatology, Gastroenterology and Nutrition, King’s College Hospital, and treatment is at the discretion of physicians’’.
London, UK, the jjjjPaediatric Hepatology Service, Hospital Infantil Copyright # 2017 by European Society for Pediatric Gastroenterology,
Universitario ‘‘La Paz,’’ Madrid, Spain, the ôôDepartment of Paediatrics Hepatology, and Nutrition and North American Society for Pediatric
and Adolescent Medicine, Medical University of Graz, Graz, Austria, the Gastroenterology, Hepatology, and Nutrition
##Paediatric Gastroenterology Unit, Department of Pediatrics, University DOI: 10.1097/MPG.0000000000001787

334 JPGN  Volume 66, Number 2, February 2018

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JPGN  Volume 66, Number 2, February 2018 Wilson’s Disease in Children

W ilson’s disease (WD) is an autosomal recessive genetic

disorder of copper metabolism with an estimated preva-
lence of approximately 1:30,000 (1). It is caused by mutations in the
EMBASE, MEDLINE, Cochrane Database of Systematic Reviews,
and Cochrane Central Register of Controlled Clinical Trials. The
following key words, WD, symptoms, diagnosis, liver, ceruloplas-
min, copper, treatment, penicillamine, zinc, trientine, and children,
ATP7B gene encoding a copper transporting P-type ATPase
required for copper excretion into the bile (2). This defect results were used to identify relevant articles. Articles in languages other
in progressive toxic accumulation of copper in the liver that begins than English and French, animal studies, and abstracts presented
in infancy when copper-containing solids are introduced in the diet. only during conference proceedings were excluded.
With increasing copper overload over time, deposition of copper in Using the GRADE system (1 for strong recommendation; 2
other organs, such as the nervous system, corneas, kidneys, and for weak recommendation), the quality of evidence of each recom-
heart, occurs usually during the second decade or later. If WD is not mendation was graded as follows (5):
recognized and adequately treated, the progression of liver disease
to cirrhosis and liver failure can be rapid or irreversible brain 1. High (A): Further research is unlikely to change our confidence
damage can occur. Diagnosis of WD is difficult in children because in the estimate of effect.
they are often asymptomatic and conventional criteria established 2. Moderate (B): Further research is likely to have impact on our
for adults may not be appropriate (3,4). confidence in the estimate of effect and may change
The aim of this position paper was to recommend appropriate the estimate.
steps for diagnosis, treatment, and follow-up of children with WD. 3. Low (C) Any estimate of effect is very uncertain.

METHODS Consensus Meeting and Voting

A core group of ESPGHAN members (P.S., W.J., A.D.,
L.D.A., S.T., R.I., P.V., R.H.) formulated questions relevant for A first draft of the position paper was discussed with the
the diagnosis and treatment of WD in children, which were agreed ESPGHAN Hepatology Committee members. The core group and
by the ESPGHAN Hepatology Committee (B.F., A.D., N.H., L.H., Hepatology Committee members voted on each recommendation,
J.J., V.M., V.N., F.S., H.V., U.B., D.D.). To approach these ques- using the nominal voting technique. Expert opinion supported
tions, systematic reviews, prospective, and retrospective cohort or recommendations where the evidence was regarded as weak.
controlled studies from 1986 to 2016 in children <18 years and Recommendations were accepted if they received >75%
adults if evidence in children was lacking were searched in positive votes and are presented in Table 1.

TABLE 1. Recommendations of the ESPGHAN Hepatology Committee

1 WD should be considered in the differential diagnosis of children older than 1 year presenting with any sign of liver disease ranging from
asymptomatically increased serum transaminases to cirrhosis with hepatosplenomegaly and ascites or ALF. Grade 1A (level of agreement: 86%)
2 WD should be ruled out in any teenager with unexplained cognitive, psychiatric, or movement disorder. Grade 1A (96%)
3 Diagnostic testing for WD in suspected patients should include liver function tests (serum transaminases, conjugated and total bilirubin; alkaline
phosphatase and prothrombin time/INR), serum ceruloplasmin, and 24-hour urinary copper. Grade 1A (96%)
4 The Ferenci scoring system should be applied to children for diagnosis of WD. Mutation analysis of the ATPB7 gene may facilitate the diagnosis.
Grade 1A (91%)
5 Copper estimation in the liver tissue could be helpful in children where the diagnosis is uncertain. Grade 1C (100%)
6 Once WD diagnosis is confirmed in the proband, WD should be sought in first degree relatives including siblings, offspring, and parents by
performing liver function tests, explorations of copper metabolism, and targeted molecular analysis. Grade 1A (100%)
7 Given its safety profile, zinc salts, preferably zinc acetate, could be used in presymptomatic children identified through family screening, or as
maintenance therapy after de-coppering with chelators as long as serum transaminase levels remain normal. Grade 2C (96%)
8 Children with signs of significant liver disease, such as cirrhosis or abnormal INR, should be preferably treated with copper chelating agents. Grade
2B (96%)
9 Dietary restriction of copper-rich foods is advised until remission of symptoms and normalization of liver enzymes in children treated with copper
chelating agents. Grade 2C (82%)
10 Children with ALF or decompensated liver cirrhosis should be transferred to and managed in pediatric liver transplantation centers. Grade 1A
(100%)
11 Children with decompensated liver cirrhosis should be treated with a chelating agent or a combination of zinc salts and a chelating agent that may
preclude the need for a liver transplantation. The King’s Wilson index should be monitored for prognostic assessment and timely decision for LT.
Grade 2B (96%)
12 Because liver transplantation corrects the enzymatic defect, chelating agents or zinc treatment is no longer required after transplantation. Grade
1A (96%)
13 All children should be closely followed-up during the first month following initiation of therapy, then every 1 to 3 months until remission, and
every 3 to 6 months thereafter. Grade 1C (100%)
14 Monitoring includes physical examination, biochemical tests (ie, blood cell count, liver function tests, urea, creatinine, proteinuria), serum copper,
and 24-hour urinary copper to assess efficacy, overdosage, or non-adherence to therapy and adverse events. Grade 1C (96%)
15 Evidence for non-adherence to zinc can be assessed by measuring serum zinc levels and/or urinary zinc/copper 24-hour excretion. Grade 2B
(91%)
16 If increased transaminases remain or relapse despite treatment, poor compliance should be suspected. Grade 2B (96%)
17 The occurrence of penicillamine-related adverse events should prompt discontinuation and switching to trientine or zinc salts according to the
severity of liver disease. Grade 2B (100%)

Voting results are indicated in brackets for each recommendation.

ALF ¼ acute liver failure; LT ¼ liver transplantation; WD ¼ Wilson’s disease.

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Socha et al JPGN  Volume 66, Number 2, February 2018

When Should Wilson’s Disease Be Suspected in Although neurological/psychiatric symptoms usually

Children? develop in the second or third decade of life, they may occasionally
be seen before 10 years of age (19–22) (Table 1) and have been
The accumulation of copper in diverse organs accounts for reported in 4% to 6% of pediatric cases with hepatic onset (9,10,15).
the wide range of clinical manifestations shown in Table 2. Most Mild cognitive impairment such as working memory and language
children present with liver disease (6) ranging from incidental difficulties, however, seems quite frequent (23). Kayser-Fleischer
finding of increased serum transaminases in otherwise asymptom- rings, caused by copper deposition on Descemet membrane, are
atic children >1 year of age (7), acute hepatitis, hepatomegaly, usually not seen on slit lamp examination in children with asymp-
hyperechogenic liver on ultrasound to acute liver failure (ALF) or tomatic or mild liver disease, but are almost always present in
cirrhosis (8–12). WD may present at any age between 3 and 74 years children with neurological involvement (11).
(average 13.2 years), but WD is rarely symptomatic before 5 years Acute hemolysis has been described as the initial presen-
of age (13,14). In a pediatric series of 100 children from tation of WD, sometimes apparently precipitated by infection or
Bangladesh, chronic liver disease (76%), most often limited to drugs, and is prominent in fulminant WD. The prevalence of
increased serum transaminases, was the most common presenting acute hemolysis was 6.9% in a recent retrospective study of 321
feature (15). The finding of another possible cause of liver dys- patients with WD with an average onset of 12.6 years (ranging
function, such as acute viral hepatitis A, nonalcoholic fatty liver from 7 to 20 years) (24). But, an earlier onset at 3 years of age
disease or nonalcoholic steatohepatitis (16), and autoimmune hep- has been reported (14). Several other extrahepatic manifestations
atitis (AIH) should not exclude WD. Low-titer autoantibodies have also been described in children, usually as case reports
(mainly antinuclear antibodies) are commonly found in patients (Table 2).
with WD (17), but cases of WD and concomitant AIH have been Recommendations of the ESPGHAN Hepatology Committee
reported (17,18). are shown in Table 1.

TABLE 2. Clinical presentations of Wilson’s disease in childhood

Clinical symptoms Age at onset of symptoms References

Hepatic >2 y (6–15,17,18)

Incidental finding of increased serum transaminases
Acute hepatitis
Hepatomegaly
Fatty liver
Acute liver failure with hemolysis
Portal hypertension: esophageal varices, splenomegaly, low platelet count
Decompensated cirrhosis with ascites
Neurological and psychiatric Usually >15 y (20–22,25–28)
Dysarthria Case reports 7–9 y
Dysphagia, excessive salivation
Mood/behavior changes including depression, irritability
Incoordination (eg, handwriting deterioration)
Declining performance at school
Resting and intention tremors
Gait disturbance, dystonia, rigidity
Mask-like face, risus sardonicus,
Stroke-like symptoms
Ophthalmic >10 y (10,28)
KF rings at slit lamp examination
Haematological > 7 years (24)
Acute/chronic hemolytic anemia
Other Case reports, age cannot be defined
Renal (29)
Renal tubular dysfunction (Fanconi syndrome, tubular acidosis, aminoaciduria)
Nephrolithiasis
Nephrocalcinosis
Cardiac (30)
Cardiomyopathy, subclinical dysfunction
Arrhythmia
Endocrine
Hypoparathyroidism (31)
Other
Pancreatitis (32)
Skin lipomas (33)
Skeletal
Rickets/osteopenia/osteoporosis (34–36)
Arthropathy

KF ¼ Kayser-Fleischer.

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JPGN  Volume 66, Number 2, February 2018 Wilson’s Disease in Children

TABLE 3. Explorations of copper metabolism

Normal values High suspicion of WD

Serum ceruloplasmin 20–40 mg/dL <10 mg/dL

24-Hour urinary copper excretion <40 mg (<0.65 mmol) >100 mg (1.6 mmol)
Liver copper content <50 mg/g dry weight >250 mg/g dry weight (>4 mmol/g dry weight)

WD ¼ Wilson’s disease.

Diagnostic Tests for Wilson’s Disease in Children Total Serum Copper

The diagnosis of WD is usually straightforward in children Total serum copper (which includes non–ceruloplasmin-
with advanced liver disease, as the classical biochemical features of bound copper or ‘‘free copper’’ and copper incorporated in
disturbed copper metabolism (Table 3) are usually present. ceruloplasmin) is usually decreased in proportion to the decreased
Establishing a diagnosis of WD in young asymptomatic children serum ceruloplasmin. However, in patients with WD with severe
with mild liver disease is, however, often challenging given that liver injury, serum copper may be within the normal range or
ceruloplasmin levels and urinary copper excretion may be normal, markedly elevated in the setting of ALF due to the release of
and Kayser-Fleischer rings absent. copper from liver tissue stores and the increase in free copper in the
blood. The serum non–ceruloplasmin-bound copper concentration
Liver Function Tests can be estimated from the serum copper and serum ceruloplasmin
levels, but is dependent on the adequacy of the methods for
In acute presentation of WD with liver failure, typical measuring both serum copper and ceruloplasmin (3,4). Total serum
findings are total high bilirubin levels (>300 mmol/L, >17.5 copper has a poor diagnostic value but could be more valuable for
mg/dL) combined with relatively low serum transaminases levels monitoring of pharmacotherapy. Very low values may signal
(100–500 IU/L), low serum alkaline phosphatase level thought to systemic copper depletion that can occur in some patients with
result from zinc deficiency, and a low alkaline phosphatase (IU/ prolonged treatment.
L)—to—total bilirubin (mg/dL) ratio <1 (37,38). These findings
are, however, not pathognomonic of WD.
Urinary Copper Excretion
Ceruloplasmin In asymptomatic children or children with mild liver disease,
urinary copper values are often normal. The reported optimal basal
Ceruloplasmin is a copper-carrying protein that is bound to urinary copper diagnostic cut-off value is 40 mg /24 hours (0.65
90% of the circulating copper in normal individuals. Serum cerulo- mmol)/24 hours) with a sensitivity of 78.9% and a specificity of
plasmin concentration is low in neonates, then gradually rises with 87.9% (44). The penicillamine challenge test (ie. 0.5 g D-penicil-
age and peaks in mid childhood before declining slightly during lamine given at the beginning of the 24-hour urine collection and 12
puberty (39). The youngest age suitable for testing serum ceruloplas- hours later) is unreliable to rule out the diagnosis in asymptomatic
min for the diagnosis of WD is 1 year. The concentration of children with a sensitivity of 12% and 46% at the established cut-off
ceruloplasmin is reduced <20 mg/dL in most patients with WD diagnostic value of 1575 mg/24 hours (25 mmol/24 hours) (44,47).
because of its impaired biosynthesis and the short half-life of the Lowering the cut-off to 5 times the upper normal limit of basal-
copper-free molecule apoceruloplasmin. Decreased levels of serum urinary copper excretion (200 mg/24 hours; 3.2 mmol/24 hours)
ceruloplasmin are, however, also found in approximately 20% of increased the sensitivity to 88% respectively at the cost of consid-
heterozygous carriers, patients with liver failure, malabsorption, erable loss in specificity (24.1%) (44). Importantly, plastic or acid-
glycosylation disorders, Menkes disease, protein caloric malnutri- washed glass containers should be used for urine collection to avoid
tion, nephrotic syndrome, protein-losing enteropathy, acquired cop- contamination with copper.
per deficiency, and hereditary aceruloplasminemia (40–44). Two
main studies aimed at evaluating the diagnostic accuracy of serum
ceruloplasmin for the diagnosis of WD (40,44). The best WD Mutation Analysis
diagnostic threshold of serum ceruloplasmin was <14 mg/dL (sen-
sitivity 93% and specificity 100%) in a series of 57 WD adults and More than 500 mutations within the ATP7B gene (locus
children with liver dysfunction and/or neurological deficits (40), and 13q14.3.) have been identified and most affected individuals are
<20 mg/dL (sensitivity 95% and specificity 84.5%) in a series of compound heterozygotes (48). Predominant mutations have been
40 clinically asymptomatic children with elevated serum transami- reported in specific populations, such as in Eastern Europe
nases (44). (H1069Q), Spain (Met645Arg), Sardinia (c-441 427del15),
On the other hand, up to 20% of children and adults with WD Japan (229insC, Arg778Leu), Costa Rica (Asp1279Ser), and
may have normal serum ceruloplasmin levels, as reported in China, Korea, and Taiwan (Arg778Leu) facilitating molecular
patients carrying bi-allelic missenses mutations of the ATPB7 gene diagnosis (49–53). Next-generation sequencing can identify
(45,46). Ceruloplasmin levels may increase in patients with WD both mutant alleles in 95% of affected subjects, but several
with histologically active chronic hepatitis, in pregnant women, or limitations should be considered (54). First, molecular defects
women on estrogens. In addition, misleadingly elevated serum outside the coding regions and in adjacent intron/exon junctions
levels may be seen when using the immunological-nephelometric of the gene and deletions can still be missed using these
assay which measures both ceruloplasmin and the biologically techniques. Second, their high-yield comes with the risk of
inactive apoform (45,46), the reason why the enzymatic assay identifying variants of unknown significance which pose diag-
measuring oxidase activity should be the preferred method (46). nostic difficulties.

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Socha et al JPGN  Volume 66, Number 2, February 2018

Liver Biopsy and Liver Copper Content hyaline glycogen–containing vacuoles in the nuclei, portal fibrosis,
and inflammation resembling AIH with interportal fibrous bridging
In equivocal cases, measurement of liver copper content is or cirrhosis (62). Copper deposition may be demonstrable by
recommended as the next step for diagnosis of WD. A copper rhodanine, orcein, or rubeanic acid staining but has limited diag-
content <250 mg/g dry weight (normal <50 mg/g dry weight) in nostic value: negative staining does not exclude increased liver
non-cholestatic patients is considered diagnostic for WD in adult copper content (62), whereas positive staining is seen in many liver
series. Lower concentrations are reported in up to 20% of patients diseases associated with impaired bile secretion (63).
with WD possibly related to sampling error because the distribution
of copper in the liver is not homogeneous (3,4,11,55–58). The Scoring System
accuracy of liver copper measurement is improved with an
adequately sized specimen (preferably >1 cm long, min. 0.5 cm) In 2001, an international consensus of experts proposed a
that should be placed on a small piece of paper for drying, and in a scoring system to facilitate the diagnosis of WD (referred to as the
dry plastic copper-free container for atomic absorption analysis on Ferenci score), using the previously discussed biochemical param-
fresh tissue. It has also been proposed that 2 liver biopsy passes be eters and molecular diagnostics. It was subsequently adopted for the
performed and that an entire core of the sample be used for copper Eurowilson database (Table 4) (64). The identification of only 1
determination (57,58). The most comprehensive study analyzed disease-causing mutation appears adequate to confirm the diagnosis
liver samples from 691 patients with various liver diseases, includ- of WD only in the presence of definite clinical symptoms and
ing 178 with WD (58). Mean liver copper content was significantly biochemical signs of impaired copper metabolism. Otherwise in
higher in patients with WD with liver dysfunction than in asymp- asymptomatic children, identification of 2 disease-causing muta-
tomatic patients or patients with neurological dysfunction without tions becomes necessary to confirm the diagnosis of WD with
signs of liver disease (P ¼ 0.001). All patients with WD with liver certainty (64,65). In children the Ferenci score provided a relatively
dysfunction had liver copper levels more than 250 mg/g dry weight, good combination of sensitivity and specificity for the diagnosis of
but a high proportion (47.8%) of patients with primary biliary WD in children—98.14% and 96.59%, respectively in 1 study (66),
cirrhosis or primary sclerosing cholangitis also had liver copper and 90% and 91.6%, respectively in the other (44). In this latest
values 250 mg/g dry weight. study, considering 40 mg/24 hours instead of 100 mg/24 hours as the
There have been only a few studies evaluating the diagnostic urinary copper excretion cut-off increased the sensitivity of the
accuracy of liver copper content in children with WD (44). Liver scoring system to 93% with no change in the specificity (44).
copper content is increased physiologically in early infancy up to
14 months of age (59), in healthy heterozygotes and in cases of Other Tests
chronic cholestastic diseases such as biliary atresia (60,61). Nicas-
tro et al (44) reported an increase in liver copper >250 mg/g dry Other tests are being used in some centers to improve diag-
weight in 28 of 30 WD children with mild liver disease (mean 813 nosis. These include the measurement of the incorporation of
mg/g dry weight). Among patients with WD, 2 children (7%) had radiolabeled copper into ceruloplasmin which is impaired in WD
liver copper level <75 mg/g dry weight, whereas 4 (6%) of 24 (67), and the measurement of serum exchangeable copper (68,69).
controls had liver copper levels >50 mg/g dry weight. Liver copper Exchangeable copper corresponds to the labile fraction of copper in
exceeded 250 mg/g of dry weight in 2 children with congenital the serum complexed to albumin and other peptides. Recently,
disorders of glycosylation mimicking WD. relative exchangeable copper (namely exchangeable copper-to-total
Liver histology alone cannot be used to establish the diag- copper ratio) has been reported to provide 100% sensitivity and 100%
nosis of WD. The main features are nonspecific and include specificity for the diagnosis of WD in adults with a cut off value of
microvesicular and macrovesicular fatty deposition, Mallory 15% and also showed promising results for family screening of

TABLE 4. Diagnostic score in Wilson’s disease, agreed at a consensus meeting (64)

Score 1 0 1 2 4

Kayser-Fleischer rings Absent Present

Neuropsychiatric symptoms suggestive of WD (or typical Absent Present
brain MRI)
Coombs negative hemolytic anemia þ high serum copper Absent Present
Urinary copper (in the absence of acute hepatitis) Normal 1–2  ULN >2  ULN, or normal but
>5  ULN 1 day after
challenge with 2  0.5 g
D-penicillamine
Liver copper quantitative Normal <5  ULN (<250 mg/g) >5  ULN (>250 mg/g)
Rhodanine positive hepatocytes (only if quantitative Cu Absent Present
measurement is not available)
Serum ceruloplasmin (nephelometric assay) >0.2 g/L 0.1–0.2 g/L <0.1 g/L
Disease-causing mutations detected None 1 2

Assessment of the Wilson’s disease diagnostic score

0–1: Unlikely 2–3:Probable 4 or more: highly likely

MRI ¼ magnetic resonance imaging; ULN ¼ upper limit of normal; WD ¼ Wilson’s disease.

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JPGN  Volume 66, Number 2, February 2018 Wilson’s Disease in Children

• Clinical evaluaon for hepato-splenomegaly, ascites, K-F ring

• Liver tests: ALT/AST, bilirubin total/direct, INR, AP
I step • Biochemical tests of copper metabolism: serum ceruloplasmin, 24h urinary copper excreon

• Molecular tesng (common mutaons, whole gene sequencing)

II step

• Liver copper (if molecular tesng inclonclusive or not available)

III step
Ferenci score calculated at each step; 4 points or more confirm diagnosis- once diagnosis is confirmed
further tesng is not required to start therapy

FIGURE 1. Diagnostic approach to Wilson’s disease. ALT ¼ alanine aminotransferase; AP ¼ alkaline phosphatase; AST ¼ aspartate aminotransferase.

asymptomatic patients (68,70). Further studies are needed to evaluate and the monitoring of compliance and early detection of
its diagnostic accuracy in children with liver disease. complications. Prognosis is excellent provided compliance to ther-
Recommendations of the ESPGHAN Hepatology Committee apy is adequate.
are shown in Table 1.
The diagnostic approach is illustrated in Figure 1. Treatment Options
D-penicillamine was introduced in 1956, and remains the
standard treatment for WD. It chelates copper and favors its urinary
The Importance of Family Screening for Wilson’s excretion. Experimentally, D-penicillamine also has a copper
Disease ‘‘detoxifying’’ effect by inducing the endogenous hepatic metal-
lothionein, a cytosolic metal-binding protein, which sequesters
Genetic counseling is essential for families of patients with copper and thereby limiting damage to the liver.
WD, and screening first-degree relatives is recommended by both D-penicillamine has been shown to efficiently prevent the
European and American guidelines (3,4). progression of disease in asymptomatic children. This drug
It is essential to screen siblings of any patient newly diag- improved liver symptoms in more than 80% of symptomatic
nosed with WD because the chance of being a homozygote and children within a mean time of 16 months (28), including those
developing clinical disease is 25%. Assessment should include presenting with liver failure but no hepatic encephalopathy (76).
physical examination, serum ceruloplasmin, liver function tests, Worsening of neurologic symptoms has, however, been reported
and molecular testing for ATP7B mutations or haplotype studies if (77,78).
not available. Newborn screening is not warranted and screening Significant adverse effects are reported with the use of
may be delayed until 1 to 2 years of age. D-penicillamine resulting in drug withdrawal in up to 30% of cases
The occurrence of WD in 2 consecutive generations has been in children or adults (3,12,28,79,80). Early adverse effects include
reported in apparently nonconsanguineous families suggesting a sensitivity reactions characterized by fever and cutaneous erup-
benefit for screening WD in offspring of an affected parent (71–74). tions, neutropenia or thrombocytopenia, lymphadenopathy, and
Moreover, the risk of occurrence of WD in offspring is increased in proteinuria. Other adverse effects that may occur at any time in
consanguineous families and in specific populations with a high the medium- and long-term include a lupus-like syndrome charac-
carrier frequency. terized by hematuria, proteinuria, arthralgia, bone marrow toxicity
Finally, considering the possibility of late onset of WD, with severe thrombocytopenia or aplasia, and skin changes related
parents of a child newly diagnosed with WD should also be to D-penicillamine’s anticollagen effects such as elastosis perfor-
screened by performing liver tests, explorations of copper metabo- ans serpiginosa, cutis laxa, pemphigus, lichen planus, and aphthous
lism, and suitable genetic testing, as illustrated in a recently stomatitis (81). Elevations in serum antinuclear antibodies are
reported family (75). frequent, but there is no clear correlation with the development
of immune-mediated diseases (82).
Treatment of Children With Wilson’s Disease In children, the dose of D-penicillamine is usually increased
progressively to 20 mg/kg/day given in 2 or 3 doses, with close
Treatment is based on the removal of copper excess by follow-up for the occurrence of adverse events such as hypersensi-
chelating agents such as D-penicillamine, trientine, or by blocking tivity and proteinuria, hematologic toxicity warranting immediate
the intestinal copper absorption with zinc salts. Dietary copper discontinuation and switching to trientine or zinc salts (83)
restriction does not prevent accumulation in WD, and there is a lack (Table 5). As food inhibits the absorption of D-penicillamine, this
of evidence that it improves the outcome once chelators are drug should be administered 1 hour before or 2 hours after meals.
initiated. However, avoiding copper-rich food (shellfish, nuts, There is lack of recent evidence as to pyridoxine deficiency in
chocolate, mushrooms, and organ meats) is advised until remission patients receiving penicillamine; hence, there has been variable
of symptoms and biochemical abnormalities (3). Treatment should personal practice in its supplementation. Moreover, pyridoxine
be initiated upon diagnosis in presymptomatic children identified intake is relatively high as many food products are supplemented
by family screening as soon as 2 to 3 years of age, promptly in with water-soluble vitamins.
symptomatic children to prevent progression of liver and/or neuro- Trientine, triethylene tetramine hydrochloride, was initially
logical disease. High-quality evidence is lacking to estimate the introduced in 1969 as a second-line chelating agent in patients with
optimal first-line treatment choice in WD. Treatment is life-long WD who developed adverse events related to D-penicillamine (84).

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Socha et al JPGN  Volume 66, Number 2, February 2018

TABLE 5. Dosage and treatment monitoring

Zinc salts D-penicillamine Trientine

Dosage in children Zinc acetate, zinc sulphate Starting dose: 150–300 mg/day, Starting dose: 20 mg/kg/day or
Age >16 years and body weight >50 kg: 150 gradually increasing once a week 1000 mg (max 1500 mg) in

mg day in 3 divided doses. up to 20 mg/kg/day given in 2 or young adults given in 2 or 3
Age 6–16 years and body weight <50 kg: 75 3 divided doses or 1000 mg (max divided doses.

mg day in 3 divided doses 1500 mg) in young adults given Maintenance dose: 900–1500 mg/

younger than 6 years of age: 50 mg day in 2 in 2 or 4 divided doses. day in 2 or 3 divided doses.
divided doses Maintenance dose: 10–20 mg/kg/
day up to 750 mg–1000 mg/day
in 2 divided doses
Administration 1 hour before meal or 2 hours after meal 1 hour before meal or 2 hours after 1 hour before meal or 3 hours after
meal meal
Adequacy of treatment Urinary copper excretion: 30–75 mg (0.5– Urinary copper excretion: 200–500 Urinary copper excretion: 200–500
parameters 1.2 mmol/L) /24 hours on maintenance mg (3–8 mmol/L)/24 hours on mg (3–8 mmol/L)/24 hours on
treatment maintenance treatment maintenance treatment
Serum zinc level >125 mg/dL
Urinary zinc >2 mg/24 h on maintenance
treatment
Liver function Usually 2–6 months, ALT normalization Usually 2–6 months Usually 2–6 months
improvement within 1 year
Indication for a drug Persistent ALT >3 upper limit of normal Poor tolerance or side effects, for Poor tolerance or side effects, for
change and/or INR >1.5 example, hypersensitivity example, allergic reactions,
Poor tolerance, for example, nausea, reactions, fever, neutropenia, arthralgia, sideroblastic anemia
abdominal pain, gastric ulcerations thrombocytopenia,
lymphadenopathy or proteinuria

ALT ¼ alanine aminotransferase.


- elemental zinc.

There have been only rare reports of allergic reactions, arthralgias, also induces hepatocyte metallothionein, and as D-penicillamine
muscle cramps, and sideroblastic anemia induced by trientine (85– may have copper detoxifying effect. Most studies evaluating the
87). Given its safety profile it is being increasingly used as first-line clinical efficacy of zinc when applied as first-line monotherapy in
chelation therapy, although there is a lack of robust clinical studies the various clinical presentations of WD showed that zinc had a
evaluating the efficiency of trientine in treating WD compared to D- better tolerance profile than penicillamine and could be safely used
penicillamine. Similar efficacy of trientine compared to D-penicil- for treatment of presymptomatic children (90,92–94). Treatment
lamine was shown in 1 large study in WD adults with liver failure was however reported in symptomatic children presenting
symptoms (88). First-line treatment with trientine was, however, with liver disease (79,91,95,96) and patients who relapsed on zinc
associated with a higher risk of neurologic worsening of symptom- improved after reintroduction of a chelating agent (91). Initiation of
atic neurologic patients compared to D-penicillamine. The only therapy with zinc salts presents also risk of neurological deteriora-
available pediatric study analyzed the efficacy of trientine as tion as is observed with other treatment modalities (91,98).
second-line therapy in 16 children with D-penicillamine intolerance Different formulations of zinc salts are available: zinc sul-
or adverse events. Liver function normalized in the majority of fate, zinc acetate, and zinc gluconate. Gastrointestinal problems,
children, but trientine did not improve accompanying neurological such as nausea, vomiting, epigastric pain, gastric/duodenal mucosal
or psychiatric symptoms (86). ulceration, or erosion have been reported mainly with zinc sulfate,
The recommended dose of trientine in children is 20 mg/kg/ and may particularly alter the child’s quality of life and lead to poor
day in 2 to 3 divided doses. Recently, a small prospective pilot study adherence (95,99). Gastrointestinal symptoms may resolve when
in adults with WD has suggested that a once daily trientine regimen switching formulation from zinc sulfate to zinc acetate. Anemia
at a dose of 15 mg/kg provided good efficacy and safety but it related to iron deficiency, isolated increase of serum amylase, and
should be further evaluated as maintenance therapy to improve lipase levels (zinc containing enzymes) without clinical and radio-
compliance (89). Trientine also chelates iron, and therefore if iron logical features of pancreatitis may also be observed.
supplementation is necessary, it should be administered at a differ- The recommended dosage is 25 mg twice daily of elemental
ent time of the day. The drug is best given 1 hour before or 2 to 3 zinc in children younger than 5 years of age, 75 mg/day (if body
hours after food for optimal absorption (Table 5). Trientine tablets weight <50 kg) or 150 mg/day (if body weight >50 kg) in 3 divided
must be kept refrigerated, which could be a problem for patients doses in children older than 5 years of age (3,92,94). Zinc should not
residing in or travelling to hot countries. be taken with food because it interferes with its absorption, and
Zinc salts are being increasingly used as first-line therapy for dietary copper restriction is not recommended because zinc blocks
the treatment of presymptomatic patients and for maintenance copper absorption from the intestinal track (Table 5).
therapy after initial decoppering with a chelator, but the efficacy
of zinc monotherapy in symptomatic patients with liver disease is
still under debate (90–96). The postulated mode of action of zinc is Treatment Strategy
the induction of metallothionein in enterocytes (97). Copper Treatment should be individually tailored to the clinical
absorbed in the small intestine is thereby sequestered in enterocytes condition of the child defined by the type and severity of organ
which at the end of their life cycle carry copper into the lumen. Zinc involvement. A clinically relevant limitation in the long-term use of

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JPGN  Volume 66, Number 2, February 2018 Wilson’s Disease in Children

D-penicillamine is the occurrence of severe adverse events. Lack of TABLE 6. Wilson’s disease scoring system to predict the outcome of
adherence and underdosage are the main risk factors for an unfa- children with hepatic decompensation (King’s Wilson index) by Dha-
vorable clinical course. To improve adherence to the life-long wan et al (8)
therapy, the treatment scheme should be as simple as possible.
Pediatric hepatologists vary in the approaches they use in the Bilirubin, Leukocytes, Albumin,
care for children with WD (100). In asymptomatic children or Score mmol/L INR AST 109/L g/L
children with only mild liver symptoms, all available treatments
have proven effective (28,86,90,92–94). In symptomatic patients 0 0–100 0–1.29 0–100 0–6.7 >45
with WD, current guidelines favor the use of chelating agents (D- 1 101–150 1.3–1.6 101–150 6.8–8.3 34–44
penicillamine, trientine) as first-line therapy (3,4). 2 151–200 1.7–1.9 151–200 8.4–10.3 25–33
A sequential treatment in WD could be proposed based on 3 201–300 2.0–2.4 201–300 10.4–15.3 21–24
the hypothesis that after a treatment phase with the more effective 4 >300 >2.5 >300 >15.3 0–20
chelating agents, smaller dosage or alternative treatment with zinc
in de-coppered patients may be sufficient to upkeep copper homeo- AST ¼ aspartate aminotransferase.
11 points and above - urgent listing for liver transplantation.
stasis. However, only limited data are available to decide when and
under which conditions a patient can be switched to zinc mainte-
nance therapy and vice versa. WI is reported to be 93% sensitive, 98% specific, with a positive
Combination therapy using zinc in conjunction with a predictive value of 93% (8). Although useful, the WI may, however,
chelating agent (administered at widely spaced intervals during not be entirely accurate and continued investigation of predictors of
the day to avoid interference and given 1 hour before or 2 hours after outcome in WD is necessary.
meals) has a theoretical basis in both blocking copper uptake and Recommendations of the ESPGHAN Hepatology Committee
eliminating excess copper, and thus may be synergistic effect. are shown in Table 1.
Reports have been limited to patients who present with decom-
pensated chronic liver disease, and suggest a favorable outcome for
combination therapy with D-penicillamine and zinc (8,76) or with Monitoring Efficacy, Safety, and Compliance to
trientine and zinc (79,101). Recommendations of the ESPGHAN Treatment
Hepatology Committee are shown in Table 1.
Treatment of WD should aim at normal physical examination
and normal liver function tests. Patients must avoid alcohol con-
Indications for Liver Transplantation in Children sumption and potential hepatotoxic drug therapy.
With Wilson’s Disease Monitoring should be performed once a week at initiation of
therapy, especially while increasing penicillamine dosages, every 1
Indications for liver transplantation (LT) are rare (<1%), to 3 months until remission and every 3 to 6 months afterwards.
including patients with ALF or those with progression of liver Nonadherence to therapy can lead to life-threatening deterioration
dysfunction to liver failure despite drug therapy (102). Excellent and monitoring intervals should be shorter, especially in adoles-
post-LT outcomes are reported (103,104). Actual patient survival cents, in whom compliance is uncertain.
rates were 87% at 5, 10, and 15 years in a French series of 75 adults Monitoring includes physical examination (search for new
and 46 children (median age: 14 years, range 7–17 years) trans- WD symptoms or related to therapeutic adverse events of therapy)
planted between 1985 and 2009 for ALF (53%), decompensated and liver function tests, which should normalize progressively
cirrhosis (41%), or severe neurological disease (6%) (103). In within 3 to 12 months. Twenty-four–hour urinary copper excretion
another study analyzing the United Network for Organ Sharing should increase after initiation of therapy with D-penicillamine or
database including 170 children with WD who underwent LT trientine, followed by a decrease once liver function tests return to
between 1987 and 2008, 1- and 5-year survival were 90.1% and normal indicating a reduction in the body load of copper. In general
89%, respectively (104). In both studies, patients transplanted for presymptomatic children excrete less copper than those with symp-
end-stage chronic liver disease had better long-term survival than tomatic disease. Urinary copper excretion should lie between 200
patients transplanted for ALF. Extracorporeal liver support systems and 500 mg/24 hours during maintenance therapy with D-penicil-
as a bridge to LT may improve the outcome (105,106). Neurological lamine or trientine. Monitoring of patients on zinc therapy must
and especially psychiatric involvement may show little improve- ensure a reduction in urinary copper excretion (initially <100 mg/24
ment with transplantation but LT cannot be considered as a therapy h, and between 30 and 75 mg/24 h on maintenance therapy); low
for patients with severe neuropsychiatric involvement (107,108). levels below 30 mg/24 h suggest zinc overdosage. In addition, serum
Children presenting with decompensated liver cirrhosis with zinc levels and urinary zinc excretion should be maintained above
liver failure but no hepatic encephalopathy can be often rescued 125 mg/dL and 1.5 to 2 g/day, respectively; lower levels generally
with chelation treatment. Response to medical treatment may take indicate poor compliance to therapy (110).
time with improvement of prothrombin time after a minimum of It is important to also monitor blood cell counts, and screen
1 month and normalization within 3 months to 1 year or more (76). any therapeutic-related adverse events (such as proteinuria). Neu-
Close follow-up and monitoring of clinical status for hepatic tropenia and anemia may be due to failed iron mobilization, with
encephalopathy, ascites, sepsis, and liver function tests is required transaminase elevation due to increased hepatic iron accompanied
in specialized LT units to timely listing the child on the transplant by increased ferritin indicating over treatment. Temporary discon-
list, a decision that is extremely challenging. In 1986, Nazer et al tinuation of therapy, with close observation, is warranted followed
(109) devised a scoring system to predict the outcome of patients by reintroduction of therapy at a reduced dose (Table 5).
including adults and children with hepatic decompensation in the Yearly slit-lamp examination should document fading or
setting of WD. In 2005, the score was re-examined in the pediatric disappearance in patients with Kayser-Fleischer (KF) rings if they
population by Dhawan et al (8) who proposed a new scoring system are being adequately ‘‘decoppered.’’ Appearance of KF rings in
(King’s Wilson index [WI]) that had a better positive predictive patients with persisting abnormalities of liver function tests
value for mortality without transplantation (Table 6) (8,102). The on maintenance therapy indicates noncompliance. Search for

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Socha et al JPGN  Volume 66, Number 2, February 2018

appearance of changes at magnetic resonance imaging of the brain 23. Favre E, Lion-Francois L, Canton M, et al. Cognitive abilities of
may be useful in patients noncompliant to therapy (111). children with neurological and liver forms of Wilson’s disease.
J Pediatr Gastroenterol Nutr 2017;64:436–9.
24. Walshe JM. The acute haemolytic syndrome in Wilson’s disease—a
Key Recommendations review of 22 patients. QJM 2013;106:1003–8.
25. Pendlebury ST, Rothwell PM, Dalton A, et al. Strokelike presentation
Appropriate steps for diagnosis, treatment and follow-up of of Wilson disease with homozygosity for a novel T766R mutation.
children with WD were discussed collectively between the core Neurology 2004;63:1982–3.
group and ESPGHAN hepatology members. An agreement was 26. Leinweber B, Moller JC, Scherag A, et al. Evaluation of the Unified
obtained on the recommendations shown in Table 1. Wilson’s Disease Rating Scale (UWDRS) in German patients with
treated Wilson’s disease. Mov Disord 2008;23:54–62.
27. Ben-Pazi H, Jaworowski S, Shalev RS. Cognitive and psychiatric
REFERENCES phenotypes of movement disorders in children: a systematic review.
1. Reilly M, Daly L, Hutchinson M. An epidemiological study of Dev Med Child Neurol 2011;53:1077–84.
Wilson’s disease in the Republic of Ireland. J Neurol Neurosurg 28. Manolaki N, Nikolopoulou G, Daikos GL, et al. Wilson disease in
Psychiatry 1993;56:298–300. children: analysis of 57 cases. J Pediatr Gastroenterol Nutr 2009;
2. Bandmann O, Weiss KH, Kaler SG. Wilson’s disease and other 48:72–7.
neurological copper disorders. Lancet Neurol 2015;14:103–13. 29. Di Stefano V, Lionetti E, Rotolo N, et al. Hypercalciuria and ne-
3. Roberts EA, Schilsky ML. Diagnosis and treatment of Wilson disease: phrocalcinosis as early feature of Wilson disease onset: description of a
an update. Hepatology 2008;47:2089–111. pediatric case and literature review. Hepat Mon 2012;12:e6233.
4. European Association for Study of Liver. Clinical practice guidelines: 30. Elkiran O, Karakurt C, Selimoglu A, et al. Subclinical diastolic
Wilson’s disease. J Hepatol 2012;56:671–85. dysfunction in children with Wilson’s disease assessed by tissue
5. Guyatt GH, Oxman AD, Schunemann HJ, et al. GRADE guidelines: a Doppler echocardiography: a possible early predictor of cardiac in-
new series of articles in the Journal of Clinical Epidemiology. J Clin volvement. Acta Cardiol 2013;68:181–7.
Epidemiol 2011;64:380–2. 31. Fatima J, Karoli R, Jain V. Hypoparathyroidism in a case of Wilson’s
6. Iorio R, D’Ambrosi M, Mazzarella G, et al. Early occurrence of disease: rare association of a rare disorder. Indian J Endocrinol Metab
hypertransaminasemia in a 13-month-old child with Wilson disease. 2013;17:361–2.
J Pediatr Gastroenterol Nutr 2003;36:637–8. 32. Weizman Z, Picard E, Barki Y, et al. Wilson’s disease associated with
7. Iorio R, Sepe A, Giannattasio A, et al. Hypertransaminasemia in pancreatitis. J Pediatr Gastroenterol Nutr 1988;7:931–3.
childhood as a marker of genetic liver disorders. J Gastroenterol 33. Schaefer M, Gotthardt DN, Didion C, et al. Increased prevalence of
2005;40:820–6. subcutaneous lipomas in patients with Wilson disease. J Clin Gastro-
8. Dhawan A, Taylor RM, Cheeseman P, et al. Wilson’s disease in enterol 2015;49:e61–3.
children: 37-year experience and revised King’s score for liver trans- 34. Quemeneur AS, Trocello JM, Ea HK, et al. Miscellaneous non-
plantation. Liver Transpl 2005;11:441–8. inflammatory musculoskeletal conditions. Musculoskeletal conditions
9. Iorio R, D’Ambrosi M, Marcellini M, et al. Serum transaminases in associated with Wilson’s disease. Best Pract Res Clin Rheumatol
children with Wilson’s disease. J Pediatr Gastroenterol Nutr 2011;25:627–36.
2004;39:331–6. 35. Weiss KH, Van de Moortele M, Gotthardt DN, et al. Bone deminer-
10. Sanchez-Albisua I, Garde T, Hierro L, et al. A high index of suspicion: alisation in a large cohort of Wilson disease patients. J Inherit Metab
the key to an early diagnosis of Wilson’s disease in childhood. Dis 2015;38:949–56.
J Pediatr Gastroenterol Nutr 1999;28:186–90. 36. Selimoglu MA, Ertekin V, Doneray H, et al. Bone mineral density of
11. Merle U, Schaefer M, Ferenci P, et al. Clinical presentation, diagnosis children with Wilson disease: efficacy of penicillamine and zinc
and long-term outcome of Wilson’s disease: a cohort study. Gut therapy. J Clin Gastroenterol 2008;42:194–8.
2007;56:115–20. 37. Tissieres P, Chevret L, Debray D, et al. Fulminant Wilson’s disease in
12. Giacchino R, Marazzi MG, Barabino A, et al. Syndromic variability of children: appraisal of a critical diagnosis. Pediatr Crit Care Med
Wilson’s disease in children. Clinical study of 44 cases. Ital J 2003;4:338–43.
Gastroenterol Hepatol 1997;29:155–61. 38. Sallie R, Katsiyiannakis L, Baldwin D, et al. Failure of simple
13. Lin LJ, Wang DX, Ding NN, et al. Comprehensive analysis on clinical biochemical indexes to reliably differentiate fulminant Wilson’s dis-
features of Wilson’s disease: an experience over 28 years with 133 ease from other causes of fulminant liver failure. Hepatology 1992;
cases. Neurol Res 2014;36:157–63. 16:1206–11.
14. Wilson DC, Phillips MJ, Cox DW, et al. Severe hepatic Wilson’s 39. Kelly J, Raizman JE, Bevilacqua V, et al. Complex reference value
disease in preschool-aged children. J Pediatr 2000;137:719–22. distributions and partitioned reference intervals across the pediatric
15. Rukunuzzaman M. Wilson’s disease in Bangladeshi children: analysis age range for 14 specialized biochemical markers in the CALIPER
of 100 cases. Pediatr Gastroenterol Hepatol Nutr 2015;18:121–7. cohort of healthy community children and adolescents. Clin Chim Acta
16. Roberts EA, Yap J. Nonalcoholic fatty liver disease (NAFLD): ap- 2015;450:196–202.
proach in the adolescent patient. Curr Treat Options Gastroenterol 40. Mak CM, Lam CW, Tam S. Diagnostic accuracy of serum cerulo-
2006;9:423–31. plasmin in Wilson disease: determination of sensitivity and specificity
17. Yener S, Akarsu M, Karacanci C, et al. Wilson’s disease with by ROC curve analysis among ATP7B-genotyped subjects. Clin Chem
coexisting autoimmune hepatitis. J Gastroenterol Hepatol 2004; 2008;54:1356–62.
19:114–6. 41. Gitlin JD. Aceruloplasminemia. Pediatr Res 1998;44:271–6.
18. Milkiewicz P, Saksena S, Hubscher SG, et al. Wilson’s disease with 42. Mandato C, Brive L, Miura Y, et al. Cryptogenic liver disease in four
superimposed autoimmune features: report of two cases and review. children: a novel congenital disorder of glycosylation. Pediatr Res
J Gastroenterol Hepatol 2000;15:570–4. 2006;59:293–8.
19. Machado A, Chien HF, Deguti MM, et al. Neurological manifestations 43. Costa LS, Pegler SP, Lellis RF, et al. Menkes disease: importance of
in Wilson’s disease: report of 119 cases. Mov Disord 2006;21:2192–6. diagnosis with molecular analysis in the neonatal period. Rev Assoc
20. Abdel Ghaffar TY, Elsayed SM, Elnaghy S, et al. Phenotypic and Med Bras (1992) 2015;61:407–10.
genetic characterization of a cohort of pediatric Wilson disease 44. Nicastro E, Ranucci G, Vajro P, et al. Re-evaluation of the diagnostic
patients. BMC Pediatr 2011;11:56. criteria for Wilson disease in children with mild liver disease. Hepa-
21. Kalra V, Khurana D, Mittal R. Wilson’s disease—early onset and tology 2010;52:1948–56.
lessons from a pediatric cohort in India. Indian Pediatr 2000;37: 45. Gromadzka G, Schmidt HH, Genschel J, et al. Frameshift and non-
595–601. sense mutations in the gene for ATPase7B are associated with severe
22. Dening TR, Berrios GE. Wilson’s disease: a longitudinal study of impairment of copper metabolism and with an early clinical manifes-
psychiatric symptoms. Biol Psychiatry 1990;28:255–65. tation of Wilson’s disease. Clin Genet 2005;68:524–32.

342 www.jpgn.org

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

JPGN  Volume 66, Number 2, February 2018 Wilson’s Disease in Children

46. Merle U, Eisenbach C, Weiss KH, et al. Serum ceruloplasmin oxidase 71. Firneisz G, Szonyi L, Ferenci P, et al. The other mutation is found:
activity is a sensitive and highly specific diagnostic marker for follow-up of an exceptional family with Wilson disease. Am J Gastro-
Wilson’s disease. J Hepatol 2009;51:925–30. enterol 2004;99:2504–5.
47. Muller T, Koppikar S, Taylor RM, et al. Re-evaluation of the peni- 72. Maier-Dobersberger T, Mannhalter C, Rack S, et al. Diagnosis of
cillamine challenge test in the diagnosis of Wilson’s disease in Wilson’s disease in an asymptomatic sibling by DNA linkage analysis.
children. J Hepatol 2007;47:270–6. Gastroenterology 1995;109:2015–8.
48. Kenney SM, Cox DW. Sequence variation database for the Wilson 73. Dufernez F, Lachaux A, Chappuis P, et al. Wilson disease in offspring
disease copper transporter, ATP7B. Hum Mutat 2007;28:1171–7. of affected patients: report of four French families. Clin Res Hepatol
49. Caca K, Ferenci P, Kuhn HJ, et al. High prevalence of the H1069Q Gastroenterol 2013;37:240–5.
mutation in East German patients with Wilson disease: rapid detection 74. Dziezyc K, Gromadzka G, Czlonkowska A. Wilson’s disease in
of mutations by limited sequencing and phenotype-genotype analysis. consecutive generations of one family. Parkinsonism Relat Disord
J Hepatol 2001;35:575–81. 2011;17:577–8.
50. Margarit E, Bach V, Gomez D, et al. Mutation analysis of Wilson 75. Brunet AS, Marotte S, Guillaud O, et al. Familial screening in Wilson’s
disease in the Spanish population—identification of a prevalent sub- disease: think at the previous generation! J Hepatol 2012;57:1394–5.
stitution and eight novel mutations in the ATP7B gene. Clin Genet 76. Santos Silva EE, Sarles J, Buts JP, et al. Successful medical treatment
2005;68:61–8. of severely decompensated Wilson disease. J Pediatr 1996;128:285–7.
51. Loudianos G, Dessi V, Lovicu M, et al. Molecular characterization of 77. Medici V, Trevisan CP, D’Inca R, et al. Diagnosis and management of
Wilson disease in the Sardinian population—evidence of a founder Wilson’s disease: results of a single center experience. J Clin Gastro-
effect. Hum Mutat 1999;14:294–303. enterol 2006;40:936–41.
52. Nanji MS, Nguyen VT, Kawasoe JH, et al. Haplotype and mutation 78. Kalita J, Kumar V, Chandra S, et al. Worsening of Wilson disease
analysis in Japanese patients with Wilson disease. Am J Hum Genet following penicillamine therapy. Eur Neurol 2014;71:126–31.
1997;60:1423–9. 79. Wiggelinkhuizen M, Tilanus ME, Bollen CW, et al. Systematic review:
53. Wu Z, Wang N, Murong S, et al. Identification and analysis of clinical efficacy of chelator agents and zinc in the initial treatment of
mutations of the Wilson disease gene in Chinese population. Chin Wilson disease. Aliment Pharmacol Ther 2009;29:947–58.
Med J (Engl) 2000;113:40–3. 80. Czlonkowska A, Litwin T, Karlinski M, et al. D-penicillamine versus
54. Glenn TC. Field guide to next-generation DNA sequencers. Mol Ecol zinc sulfate as first-line therapy for Wilson’s disease. Eur J Neurol
Resour 2011;11:759–69. 2014;21:599–606.
55. Ferenci P, Steindl-Munda P, Vogel W, et al. Diagnostic value of 81. Ranucci G, Di Dato F, Leone F, et al. Penicillamine-induced elastosis
quantitative hepatic copper determination in patients with Wilson’s perforans serpiginosa in Wilson’s disease: is useful switching to zinc?
disease. Clin Gastroenterol Hepatol 2005;3:811–8. J Pediatr Gastroenterol Nutr 2017;64:e72–3.
56. Gow PJ, Smallwood RA, Angus PW, et al. Diagnosis of Wilson’s 82. Seessle J, Gotthardt DN, Schafer M, et al. Concomitant immune-
disease: an experience over three decades. Gut 2000;46:415–9. related events in Wilson disease: implications for monitoring chelator
57. Liggi M, Mais C, Demurtas M, et al. Uneven distribution of hepatic therapy. J Inherit Metab Dis 2016;39:125–30.
copper concentration and diagnostic value of double-sample biopsy in 83. Brewer GJ, Yuzbasiyan-Gurkan V, Young AB. Treatment of Wilson’s
Wilson’s disease. Scand J Gastroenterol 2013;48:1452–8. disease. Semin Neurol 1987;7:209–20.
58. Yang X, Tang XP, Zhang YH, et al. Prospective evaluation of the 84. Walshe JM. Treatment of Wilson’s disease with trientine (triethylene
diagnostic accuracy of hepatic copper content, as determined using tetramine) dihydrochloride. Lancet 1982;1:643–7.
the entire core of a liver biopsy sample. Hepatology 2015;62: 85. Perry AR, Pagliuca A, Fitzsimons EJ, et al. Acquired sideroblastic
1731–41. anaemia induced by a copper-chelating agent. Int J Hematol
59. Araya M, Koletzko B, Uauy R. Copper deficiency and excess in 1996;64:69–72.
infancy: developing a research agenda. J Pediatr Gastroenterol Nutr 86. Taylor RM, Chen Y, Dhawan A. Triethylene tetramine dihydrochloride
2003;37:422–9. (trientine) in children with Wilson disease: experience at King’s
60. Sato C, Koyama H, Satoh H, et al. Concentrations of copper and zinc in College Hospital and review of the literature. Eur J Pediatr
liver and serum samples in biliary atresia patients at different stages of 2009;168:1061–8.
traditional surgeries. Tohoku J Exp Med 2005;207:271–7. 87. Condamine L, Hermine O, Alvin P, et al. Acquired sideroblastic
61. Bayliss EA, Hambidge KM, Sokol RJ, et al. Hepatic concentrations of anaemia during treatment of Wilson’s disease with triethylene tetra-
zinc, copper and manganese in infants with extrahepatic biliary atresia. mine dihydrochloride. Br J Haematol 1993;83:166–8.
J Trace Elem Med Biol 1995;9:40–3. 88. Weiss KH, Thurik F, Gotthardt DN, et al. Efficacy and safety of oral
62. Johncilla M, Mitchell KA. Pathology of the liver in copper overload. chelators in treatment of patients with Wilson disease. Clin Gastro-
Semin Liver Dis 2011;31:239–44. enterol Hepatol 2013;11:1028–35.
63. Miyamura H, Nakanuma Y, Kono N. Survey of copper granules in 89. Ala A, Aliu E, Schilsky ML. Prospective pilot study of a single daily
liver biopsy specimens from various liver abnormalities other than dosage of trientine for the treatment of Wilson disease. Dig Dis Sci
Wilson’s disease and biliary diseases. Gastroenterol Jpn 1988;23: 2015;60:1433–9.
633–8. 90. Mizuochi T, Kimura A, Shimizu N, et al. Zinc monotherapy from time
64. Ferenci P, Caca K, Loudianos G, et al. Diagnosis and phenotypic of diagnosis for young pediatric patients with presymptomatic Wilson
classification of Wilson disease. Liver Int 2003;23:139–42. disease. J Pediatr Gastroenterol Nutr 2011;53:365–7.
65. Caprai S, Loudianos G, Massei F, et al. Direct diagnosis of Wilson 91. Weiss KH, Gotthardt DN, Klemm D, et al. Zinc monotherapy is not as
disease by molecular genetics. J Pediatr 2006;148:138–40. effective as chelating agents in treatment of Wilson disease. Gastro-
66. Koppikar S, Dhawan A. Evaluation of the scoring system for the enterology 2011;140:1189.e1–98.e1.
diagnosis of Wilson’s disease in children. Liver Int 2005;25:680–1. 92. Ranucci G, Di Dato F, Spagnuolo MI, et al. Zinc monotherapy is
67. Lyon TD, Fell GS, Gaffney D, et al. Use of a stable copper isotope effective in Wilson’s disease patients with mild liver disease diagnosed
(65Cu) in the differential diagnosis of Wilson’s disease. Clin Sci in childhood: a retrospective study. Orphanet J Rare Dis 2014;9:41.
(Lond) 1995;88:727–32. 93. Abuduxikuer K, Wang JS. Zinc mono-therapy in pre-symptomatic
68. El Balkhi S, Trocello JM, Poupon J, et al. Relative exchangeable Chinese children with Wilson disease: a single center, retrospective
copper: a new highly sensitive and highly specific biomarker for study. PLoS One 2014;9:e86168.
Wilson’s disease diagnosis. Clin Chim Acta 2011;412:2254–60. 94. Marcellini M, Di Ciommo V, Callea F, et al. Treatment of Wilson’s
69. El Balkhi S, Poupon J, Trocello JM, et al. Determination of ultra- disease with zinc from the time of diagnosis in pediatric patients: a
filtrable and exchangeable copper in plasma: stability and reference single-hospital, 10-year follow-up study. J Lab Clin Med 2005;
values in healthy subjects. Anal Bioanal Chem 2009;394:1477–84. 145:139–43.
70. Trocello JM, El Balkhi S, Woimant F, et al. Relative exchangeable 95. Santiago R, Gottrand F, Debray D, et al. Zinc therapy for Wilson
copper: a promising tool for family screening in Wilson disease. Mov disease in children in French pediatric centers. J Pediatr Gastroenterol
Disord 2014;29:558–62. Nutr 2015;61:613–8.

www.jpgn.org 343

Copyright © ESPGHAN and NASPGHAN. All rights reserved.

Socha et al JPGN  Volume 66, Number 2, February 2018

96. Linn FH, Houwen RH, Van Hattum J, et al. Long-term exclusive zinc 104. Arnon R, Annunziato R, Schilsky M, et al. Liver transplantation for
monotherapy in symptomatic Wilson disease: experience in 17 pa- children with Wilson disease: comparison of outcomes between
tients. Hepatology 2009;50:1442–52. children and adults. Clin Transplant 2011;25:E52–60.
97. Brewer GJ. Zinc therapy induction of intestinal metallothionein in 105. Nagata Y, Uto H, Hasuike S, et al. Bridging use of plasma exchange
Wilson’s disease. Am J Gastroenterol 1999;94:301–2. and continuous hemodiafiltration before living donor liver transplanta-
98. Litwin T, Dziezyc K, Karlinski M, et al. Early neurological worsening tion in fulminant Wilson’s disease. Intern Med 2003;42:967–70.
in patients with Wilson’s disease. J Neurol Sci 2015;355:162–7. 106. Rustom N, Bost M, Cour-Andlauer F, et al. Effect of molecular
99. Wiernicka A, Janczyk W, Dadalski M, et al. Gastrointestinal side adsorbents recirculating system treatment in children with acute liver
effects in children with Wilson’s disease treated with zinc sulphate. failure caused by Wilson disease. J Pediatr Gastroenterol Nutr
World J Gastroenterol 2013;19:4356–62. 2014;58:160–4.
100. Sturm E, Piersma FE, Tanner MS, et al. Controversies and variation in 107. Medici V, Mirante VG, Fassati LR, et al. Liver transplantation for
diagnosing and treating children with Wilson disease: results of an Wilson’s disease: the burden of neurological and psychiatric disorders.
international survey. J Pediatr Gastroenterol Nutr 2016;63:82–7. Liver Transpl 2005;11:1056–63.
101. Askari FK, Greenson J, Dick RD, et al. Treatment of Wilson’s disease 108. Yagci MA, Tardu A, Karagul S, et al. Influence of liver transplantation
with zinc. XVIII. Initial treatment of the hepatic decompensation on neuropsychiatric manifestations of Wilson disease. Transplant Proc
presentation with trientine and zinc. J Lab Clin Med 2003;142: 2015;47:1469–73.
385–90. 109. Nazer H, Ede RJ, Mowat AP, et al. Wilson’s disease: clinical pre-
102. Fischer RT, Soltys KA, Squires RH Jr et al. Prognostic scoring indices sentation and use of prognostic index. Gut 1986;27:1377–81.
in Wilson disease: a case series and cautionary tale. J Pediatr Gastro- 110. Brewer GJ, Yuzbasiyan-Gurkan V, Lee DY, et al. Treatment of
enterol Nutr 2011;52:466–9. Wilson’s disease with zinc. VI. Initial treatment studies. J Lab Clin
103. Guillaud O, Dumortier J, Sobesky R, et al. Long term results of liver Med 1989;114:633–8.
transplantation for Wilson’s disease: experience in France. J Hepatol 111. Hermann W. Morphological and functional imaging in neurological and
2014;60:579–89. non-neurological Wilson’s patients. Ann N Y Acad Sci 2014;1315:24–9.

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