A multidisciplinary approach to the diagnosis and management of Wilson disease: Executive summary of the 2022 Practice Guidance on Wilson disease from the American Association for the Study of Liver Diseases

This is an executive summary of the extensively rewritten guidance regarding the diagnosis and management of Wilson disease (WD). The full Guidance document with comprehensive text, complete references, and supplementary materials (“A Multidisciplinary Approach to the Diagnosis and Management of Wilson Disease: 2022 Practice Guidance on Wilson Disease from the American Association for the Study of Liver Diseases”) is available on the American Association for the Study of Liver Diseases (AASLD) website (https://doi.org/10.1002/hep.32801). This executive summary provides a condensed overview, including the clinical algorithms, tables, and full complement of guidance statements.

The new guidance was developed with the support and oversight of the AASLD Practice Guidelines Committee. The AASLD Practice Guidelines Committee chose to commission a guidance rather than a guideline because of the paucity of randomized controlled trials on this topic. This document was developed by (1) formal review and analysis of the recently published international literature on WD, (2) guideline policies of the AASLD, and (3) the authors’ experience. Guidance statements are evidence‐based whenever possible. Where evidence is unavailable or inconsistent, guidance statements are based on expert consensus opinion. This Guidance is intended for use by physicians and other health professionals. As clinically appropriate, guidance statements should be tailored to the needs of individual patients.

INTRODUCTION

Copper is an essential metal required for many metalloproteins’ function. A fraction of dietary copper (average 2–5 mg/day) is absorbed by enterocytes in the duodenum and proximal small intestine to obtain the recommended intake of 0.9 mg/day. Absorbed copper transported in the portal circulation, mainly in association with albumin, is avidly removed by the liver. Hepatocytes utilize copper for metabolic needs, incorporate copper into nascent ceruloplasmin, and transport excess copper into bile. Most excess copper is excreted through this biliary pathway into feces; only a minor amount is renally excreted. Impaired biliary copper excretion leads to hepatic copper retention.

Wilson disease (WD; hepatolenticular degeneration) was first comprehensively described in 1912 by neurologist Kinnier Wilson as “progressive lenticular degeneration,” a familial, lethal neurological disease accompanied by cirrhosis. Subsequently the role of copper in its pathogenesis and the autosomal recessive pattern of inheritance were established. Following localization to chromosome 13, the gene ATP7B (adenosine triphosphatase [ATPase] copper transporting beta) associated with WD was identified as encoding a metal‐transporting P‐type ATPase, ATP7B, found mainly in hepatocytes. ATP7B facilitates intracellular transmembrane transport of copper. Absent or impaired ATP7B function decreases biliary copper excretion, resulting in toxic copper accumulation. Eventually exceeding storage capacity, hepatic copper is released into the bloodstream and deposits in other organs, notably the brain, kidneys, and cornea. Loss of functional ATP7B also diminishes hepatocellular copper incorporation into ceruloplasmin. The resulting apoceruloplasmin has a shorter circulating half‐life, causing lower steady‐state levels of circulating ceruloplasmin.

WD occurs worldwide with an estimated prevalence of approximately 30 per million population¹; however, newer data suggest higher prevalence.² Age of diagnosis ranges from infancy to late in life. WD can present clinically as liver disease, a progressive neurological disorder (hepatic dysfunction being less apparent or occasionally absent), a psychiatric illness, or as a combination of these. WD presents with isolated liver disease more often in children and younger adults. Age of presentation for symptomatic WD is both younger and older than generally appreciated: mainly 3–55 years‐old. WD is increasingly diagnosed in children who are less than 5 years‐old^3,4 and in adults in their early 70s and 80s.⁵ Symptoms at any age are frequently nonspecific. WD is diagnosed through biochemical or genetic findings in asymptomatic individuals. No genotype–phenotype correlations exist; modifying factors are not well delineated.⁶ WD was uniformly fatal before medical therapy was introduced in the early 1950s. Treatment has evolved extensively since then.

CLINICAL SPECTRUM OF DISEASE

The clinical spectrum of WD is wide‐ranging. Pediatric patients (less than 18 years‐old) often present with exclusively hepatic disease, but this varies worldwide. In contrast, adults present with hepatic disease with or without concurrent neuropsychiatric disease. The broad spectrum of liver disease that ranges from asymptomatic to cirrhosis and acute liver failure (ALF) (ES‐Table 1) necessitates heightened clinical suspicion for the diagnosis. Screening first‐degree relatives of patients with WD or others with abnormal liver tests may identify affected but “asymptomatic” individuals lacking clinical symptoms. Copper‐induced damage may already be present in the liver and other organs of asymptomatic patients. Untreated, patients who are asymptomatic with organ damage typically progress to symptomatic WD unless treated. Thus, their timely identification is critical. Some patients who are asymptomatic may recognize subtle symptoms of WD on a systems’ review.

ES‐TABLE 1 - Clinical patterns of disease in Wilson disease

Hepatic	• Asymptomatic hepatomegaly • Isolated splenomegaly • Persistently elevated serum aminotransferase activity (AST, ALT) • Fatty liver • Acute hepatitis, varying severity including acute liver injury (ALI) • Resembling autoimmune hepatitis • Cirrhosis—compensated or decompensated • Acute liver failure
Neurological	• Dysarthria • Movement disorders (tremor, involuntary movements) • Pseudobulbar palsy • Drooling, transfer dysphagia • Rigid dystonia • Dysautonomia • Seizures • Sleep disorders, insomnia
Psychiatric	• Depression • Bipolar disorder/bipolar spectrum • Neurotic behaviors • Personality changes • Psychosis
Other systems	• Eye: Kayser–Fleischer rings, sunflower cataracts • Renal abnormalities: aminoaciduria and nephrolithiasis • Skeletal abnormalities: premature osteoporosis and arthritis • Cardiomyopathy, dysrhythmias • Pancreatitis • Hypoparathyroidism • Infertility, repeated miscarriages

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Specific instances when a diagnosis of WD should be considered include patients with ALF, particularly when nonimmune hemolytic anemia is present, or with autoimmune hepatitis (AIH). Patients with ALF due to WD frequently display a characteristic constellation of findings: acute intravascular hemolysis, severe coagulopathy, relatively modest elevations from serum aminotransferases, normal or subnormal serum alkaline phosphatase, and progression to renal failure. Differentiating WD from AIH can be difficult. All pediatric patients presenting the clinical picture of AIH and adults with atypical AIH or poor response to standard corticosteroid therapy should be investigated for WD.^7,8 WD should be considered in the differential diagnosis of patients presenting with clinical or histopathologic features of NAFLD.^9,10 Notably, children may have extensive macrovesicular steatosis without prominent hepatic inflammation in either disorder. Aceruloplasminemia, multidrug resistance protein 3 (MDR3) deficiency, and certain congenital disorders of glycosylation may resemble WD. A few rare pediatric disorders mimic WD and deserve specific consideration in patients manifesting abnormalities of copper metabolism but not fitting clinical and genetic criteria for WD (ES‐Table 2).

ES‐TABLE 2 - Rare genetic diseases resembling Wilson disease

Disorder	Gene	Serum ceruloplasmin	Hepatic Cu	24‐h basal urinary Cu	Possible mechanism(s)	Typea
Aceruloplasminemia	CP	Absent	Normal; ↑Fe	Normal	No production of ceruloplasmin	Clinical
MDR3 deficiency	ABCB4	Normal		May be ↑	Copper retention due to cholestasis	Clinical
MEDNIK syndromeb	AP1S1	Very low	May be ↑	↑ (2.5 μmol /24‐h)	Protein production + metal (Cu) excretion abnormality	Mechanistic
Mn retention–1c	SLC30A10	Normal	Slightly ↑	??	Hepatic Mn excretion abnormality	Mechanistic
Mn retention–2c	SLC39A14	Not reported			Hepatic Mn uptake abnormality	Mechanistic
Nieman–Pick type Cd	NPC1, NPC2	Low or slightly low	Mildly ↑ (between 100 and 250 μg/g dry weight)	Normal	Defective interaction with ATP7B	Mechanistic
PGM1–CDG	PGM1	Low	Mildly ↑ (between 50 and 250 μg/g dry weight)	Normal	(Golgi dysfunction)	Clinical, mechanistic
CCDC115–CGDe	CCDC115	Low or very low	Slightly ↑	Normal or mildly ↑	Abnormality in protein production pathway affecting ATP7B function (Golgi dysfunction)	Clinical, mechanistic
TMEM119–CDGe	TMEM199	Low	Not reported	Normal or mildly ↑	(Golgi dysfunction)	Clinical, mechanistic

Abbreviations (except “Gene,” column 2): CDG, congenital disorder of glycosylation; Cu, copper; Fe, iron; MEDNIK, intellectual (Mental) disability, enteropathy, deafness, neuropathy, ichthyosis, keratoderma; Mn, manganese; PGM1, phosphoglucomutase 1; WD, Wilson disease.

Abbreviations for genes (column 2): ABCB4, ATP‐binding cassette subfamily B member 4; AP1B1, adaptor related protein complex 1 subunit beta 1; AP1S1, adaptor related protein complex 1 subunit sigma 1; ATP7B, ATPase copper transporting beta; CCDC115, coiled‐coil domain containing 115; CP, ceruloplasmin; NPC1, NPC intracellular cholesterol transporter 1; NPC2, NPC intracellular cholesterol transporter 2; SLC30A10, solute carrier family 30 member 10; SLC39A14, solute carrier family 39 member 14; TMEM119, transmembrane protein 119.

^aSee text for definition of type.

^bMEDNIK syndrome displays very low serum ceruloplasmin, elevated basal 24‐h urinary copper excretion, and hepatic copper retention; neurological features are atypical for WD, including severe intelectual (Mental) disability, deafness, and peripheral neuropathy. A related disorder associated with mutations in AP1B1 has low serum copper and ceruloplasmin but no evident hepatic damage.

^cBoth disorders of manganese transport can present in childhood with a parkinsonian movement disorder; the SCL30A10 disorder may also have hepatic involvement (fatty liver, cirrhosis); brain MRI findings differentiate from WD.

^dClinical findings in Niemann‐Pick type C are mainly neurological; serum ceruloplasmin may be subnormal.

^eClinical findings may include neurological disorder and dyslipidemia. In PGM1‐CDG, clinical features are distinctly unlike WD.

Neurological assessment

Neurological manifestations of WD are extremely variable, mainly reflecting damage to the central nervous system. Neurological symptoms (ES‐Table 3) including involuntary movements, tremor, dystonic smile, and dysarthria are due to extrapyramidal involvement, but pyramidal tract and cerebellar involvement also occurs.^11–14 Expert evaluation is desirable. Most patients with neurologic WD also have underlying hepatic disease, though not all have cirrhosis. Psychiatric symptoms frequently accompany neurologic WD.

ES‐TABLE 3 - Summary of neurological symptoms at presentation of Wilson disease based on four independent case series^11–14

Neurological manifestations at onset	% of patients	Treatments
Dysarthria	46–97	Speech therapy
Gait abnormality/ataxia/cerebellar	28–75	Physical therapy, assistive device
Dystonia	38–69	Trihexyphenidyl, botulinum toxin (for focal symptoms), clonazepam
Parkinsonism	12–58	Carbidopa/levodopa, dopamine agonist
Postural tremor	55	Primidone, propranolol, clonazepam
Dysphagia	50	Swallow therapy, thickeners
Chorea/athetosis	6–30	Neuroleptics, VMAT2 inhibitors
Seizures	6–28	Anticonvulsants
Rest tremor	4	Carbidopa/levodopa, dopamine agonist

Abbreviation: VMAT2, vesicular monoamine transporter‐2.

Psychiatric assessment

Psychiatric manifestations, also reflecting central nervous system involvement, include depression, bipolar disorder, and occasionally psychosis; behavioral changes and mood instability are common.^15,16 Psychiatric symptoms can occur initially or with other symptoms. Approximately two‐thirds of patients had psychiatric symptoms at the beginning of their illness, with or without hepatic or neurological findings. The average time between the onset of psychiatric symptoms and diagnosis of WD was 2.4 years.¹⁶ Many with psychiatric features of WD have extensive liver injury or cirrhosis but frequently no symptomatic liver disease. In adults, the most common conditions include mood disorders (depressive or bipolar spectrum), psychotic disorders, sleep disturbances and subtle cognitive dysfunction.

Extrahepatic involvement

Ophthalmological features include Kayser–Fleischer (KF) rings, sunflower cataracts, and corneal nerve alterations. Self‐limited hemolytic anemia may occur episodically or along with ALF. Other extrahepatic manifestations may be present at the time of diagnosis of WD. Renal abnormalities often present as Fanconi syndrome; endocrine problems include hypoparathyroidism and pancreatitis but are rare. Infertility or repeated miscarriages may occur in women of child‐bearing age not yet diagnosed as having WD. Cardiac abnormalities (cardiomyopathy and arrhythmias) and musculoskeletal problems (osteopenia/osteoporosis) may be present initially or develop later.

Guidance statements 1–5

1. WD should be considered in any individual with liver abnormalities of uncertain cause. Age alone should not be the basis for eliminating a diagnosis of WD.
2. WD must be excluded in any patient with unexplained liver disease associated with neurological or psychiatric disorder. Assessment by a neurologist specializing in movement disorders may be advantageous. Psychiatric evaluation is essential for any patient with WD presenting with psychiatric or neuropsychiatric features of WD.
3. WD should be suspected in any patient presenting with ALF with nonimmune hemolytic anemia including acute intravascular hemolysis. These patients require urgent evaluation for liver transplantation.
4. Evaluation for WD is critical in patients exhibiting recurrent self‐limited nonimmune hemolysis.
5. At clinical presentation, WD may involve organ systems besides the liver and nervous system (such as renal, musculoskeletal, cardiac, or endocrine).

DIAGNOSTIC TESTING

Since Wilson's initial description, diagnostic advances have enabled evaluation for WD and establishment of the diagnosis in individuals in whom the disorder is suspected prior to their development of neurological symptoms. These include recognition of KF rings, identification of low serum ceruloplasmin concentration in most patients, detection of liver disease by biochemical testing, imaging, and liver biopsy for histology and measurement of tissue copper concentration. The new development is genotype analysis by direct examination for disease‐specific ATP7B mutations, including by whole‐exome/genome sequencing.

The initial approach to diagnosis includes searching for a family history of WD or early death from liver disease or early onset neurological or psychiatric illness, a physical examination for signs of liver or neurological disease, and then biochemical testing for liver disease, followed by specific testing of copper metabolism. An ophthalmologic examination for KF rings should be performed by slit lamp or anterior segment optical coherence tomography, a corneal imaging method that easily distinguishes and can quantify various anterior segment abnormalities.^17,18 Laboratory testing should begin with clinical biochemical liver tests, blood counts, and coagulation parameters to assess for liver disease. Tests of copper metabolism specific for WD include serum ceruloplasmin, serum copper, basal 24‐h urinary copper excretion and liver biopsy for histology, histochemistry, and copper quantification. Genetic testing for ATP7B mutations may be used as an initial test if there is a high enough pretest probability for performing this more expensive test or if it is being used for family screening where two disease‐specific mutations, one on each allele, were identified in the proband.

Serum ceruloplasmin

The results of testing parameters of copper metabolism relevant to WD (serum ceruloplasmin, serum copper, urinary copper excretion, hepatic parenchymal copper) must be considered in context. Ceruloplasmin is synthesized in hepatocytes as a metalloprotein containing six copper atoms per molecule (holoceruloplasmin) and secreted into the circulation. Physiologically, a small proportion of the protein lacking copper (apoceruloplasmin) is also secreted, but its circulating half‐life is shorter. A serum level of ceruloplasmin <14.0 mg/dl is more specific for the diagnosis of WD than 20 mg/dl (positive predictive value [PPV] = 100% for <14, whereas PPV of 20 mg/dl = 48%) in the population studied¹⁹; however, an extremely low serum ceruloplasmin level (<5 mg/dl) is highly predictive of WD. Modestly subnormal levels of ceruloplasmin (between 14 and 20 mg/dl) suggest that further evaluation is necessary, as these values overlap with those found in simple heterozygotes. Serum ceruloplasmin within the normal range does not exclude the diagnosis of WD. Moreover, low serum ceruloplasmin occurs in other conditions (ES‐Table 4).

ES‐TABLE 4 - Other disorders associated with low serum ceruloplasmin

Nonselective renal protein loss

Protein‐losing enteropathy

Severe chronic liver disease with global hepatic synthetic deficit

Neurological disorders (cervical dystonia)

Absolute copper deficiency

Improper formulation of TPN omitting copper

After gastric or bariatric surgery

Chronic Ingestion of zinc in excess

Menkes disease

Aceruloplasminemia

MEDNIK syndrome (AP1S1 disorder)

AP1B1 disorder

Congenital glycosylation disorder

PGM1‐CDG

CCDC115‐CGD

TMEM119‐CDG

Niemann‐Pick type C

Abbreviations: AP1B1, adaptor related protein complex 1 subunit beta 1 (gene); AP1S1, adaptor related protein complex 1 subunit sigma 1 (gene); CCDC115, coiled‐coil domain containing 115; CDG, congenital disorder of glycosylation; MEDNIK, intellectual (Mental) disability, enteropathy, deafness, neuropathy, ichthyosis, keratoderma; PGM1, phosphoglucomutase 1; TMEM119, transmembrane protein 119; TPN, total parenteral nutrition.

Serum copper

Most of the copper measured as serum copper is contained within ceruloplasmin. Serum copper concentration can be informative but requires critical assessment. In copper deficiency states and typically in WD, serum copper will be low. With severe liver injury, WD may display paradoxically high serum copper due to the release of hepatocellular copper.

Non‐ceruloplasmin‐bound copper (NCC) is important in the etiopathogenesis of organ damage. The serum NCC concentration was proposed as a diagnostic test for WD but was found useful for monitoring. The estimated NCC is flawed.²⁰ It is dependent upon the adequacy of the methods available commercially for measuring serum ceruloplasmin. If the immunological measurement overestimates holoceruloplasmin (enzymatically active ceruloplasmin containing copper), the estimated NCC cannot be interpreted because it may be zero or a negative number. Alternate methods for NCC are being developed, a direct measurement²¹ and an indirect quantification of “exchangeable copper,”^22,23 but await further validation. Specialized methodology is being developed for NCC in patients on a chelator currently in development, bis‐choline tetrathiomolybdate.

Urinary copper

Basal urinary copper excretion in WD is typically >100 μg (>1.6 μmol)/24‐h in patients who are symptomatic, but a lower reference value of >40 μg/24‐h (>0.6 μmol/24‐h) may indicate WD in individuals who are asymptomatic or children with WD and therefore should prompt clinical correlation and further investigation. The d‐penicillamine challenge test has been validated only in children. It may be performed to obtain further evidence for the diagnosis of WD in symptomatic children if basal 24‐h urinary copper excretion is <100 μg/24‐h (<1.6 μmol/24‐h).²⁴ Recent reevaluation showed that the d‐penicillamine challenge test is not sufficiently sensitive in patients with asymptomatic WD.²⁵

Liver biopsy

Liver biopsy for histology, although no longer routinely required for establishing a diagnosis of WD, can aid in diagnosis of WD by identifying findings consistent with WD and permitting disease staging/grading. Histological findings in liver biopsies in WD are often nonspecific. Early changes include mild steatosis, with very small fat droplets at first, increasing to accumulation of larger fat droplets, as in NAFLD. Hepatocyte swelling with spotty hepatocyte necrosis and small collections of lymphocytes in the parenchyma is an early, nonspecific finding. The changes are often scattered throughout the lobule but may be more pronounced in the periportal areas. An AIH‐like pattern of injury may be present, with parenchymal mononuclear inflammatory infiltrate and interface hepatitis. Portal and periportal fibrosis may progress to portal–portal bridging and finally cirrhosis. The cirrhosis is typically coarsely nodular. In late stages, hepatocytes vary greatly in size and show prominent ballooning degeneration and Mallory–Denk bodies. Enlarged hepatocytes with granular eosinophilic cytoplasm due to large numbers of mitochondria (oncocytic cells) may be present.²⁶ With ALF due to WD, the liver shows multilobular confluent necrosis, almost always superimposed upon cirrhosis, that has no distinguishing features, although abundant glycogen nuclei with relatively mild steatosis may suggest WD, and numerous apoptotic hepatocytes may be seen.

Electron microscopic evaluation, mainly for detection of abnormal mitochondrial structure,^27,28 may be prospectively considered when performing liver biopsy because it aids in the diagnosis of WD, particularly if the diagnosis is unclear, most notably in pediatric patients.

Copper is heterogeneously deposited in the liver in WD, varying from lobule to lobule in early disease and from nodule to nodule in cirrhosis. This variability may lead to negative histochemical staining results for copper deposition, especially in small samples. Because histochemical stains for copper in general have poor sensitivity and a negative stain does not exclude the diagnosis of WD, quantitative copper analysis of the liver biopsy is preferred. Hepatic parenchymal copper content >250 μg/g dry weight provides critical diagnostic information²⁹ and should be obtained when the diagnosis is not straightforward and in younger patients. In untreated patients, normal hepatic copper content (<50 μg/g dry weight) almost always excludes a diagnosis of WD. Further diagnostic testing is indicated for patients with intermediate copper concentrations (70–250 μg/g dry weight), especially if there is active liver disease or other symptoms of WD.⁹ For quantitative copper determinations, adequate size of the liver biopsy sample is critically important. Biopsies for quantitative copper determination should be taken with a disposable suction or cutting needle and placed dry in a copper‐free container. To prevent autolysis, tissue should be frozen immediately or vacuum‐dried for shipment, according to the directions of the local laboratory. Paraffin embedded specimens can be analyzed for copper content but require additional laboratory processing.

Neurological imaging

Imaging modalities such as magnetic resonance imaging (MRI) are of limited value in determining the extent of clinical neurological disease but may help initially to support a diagnosis of WD and exclude other neurological disorders. MRI findings consistent with WD include signal changes in the basal ganglia, thalami, pons, and white matter, as well as atrophy. The so‐called “face of the giant panda sign,” which consists of increased T2 signal in the midbrain, has been considered pathognomonic for WD, but several other findings are more commonly seen. In patients with WD and abnormal neurological findings, serial imaging examinations may correlate with progression or recovery.

Genetic analysis

Mutation analysis by sequencing the entire ATP7B gene is possible and should be performed on individuals in whom the diagnosis is difficult to establish by clinical and biochemical testing. ATP7B mutation analysis is efficient for testing of first‐degree family members of a proband with identified mutations. Specific testing for known mutations can be used for family screening of first‐degree relatives of patients with WD. Various resources are available for assessing pathogenicity of a specific ATP7B variant (ES‐Table 5). Discussion with a clinical geneticist, as well as correlation with clinical phenotype, may be helpful to interpret the results, especially when variants of unknown significance are identified. Formal genetic counseling may be valuable for patients and their families.

ES‐TABLE 5 - Resources available for evaluating ATP7B gene variants

	URL	Comments
Public domain databases
ClinVar	https://www.ncbi.nlm.nih.gov/clinvar/	National Center for Biotechnology Information (NCBI)
gnomAD	https://gnomad.broadinstitute.org/
VarSome	https://landing.varsome.com/varsome‐clinical
Proprietary databases
Human Gene Mutation Database	http://www.hgmd.org	University of Cardiff83
WilsonGen	https://clingen.igib.res.in/WilsonGen/	CSIR Institute of Genomics and Integrative Biology, Delhi84
University of Alberta Wilson Disease Mutation Database	(Previously) www.medgen.med.ualberta.ca/database.html	Limited or no access at the present time85

Abbreviation: ATP7B, ATPase copper transporting beta.

Guidance statements 6–11

• 6 Once WD is considered, a detailed personal and family medical history should be conducted and a physical examination focused on evidence of liver, neurological, and psychiatric disease performed. Assessment should include the following:

• liver biochemistries;
• complete blood count and international normalized ratio (INR);
• serum ceruloplasmin and, in some patients, serum copper;
• basal 24‐h urinary copper excretion;
• slit lamp or optical tomography examination for KF rings;
• neurological evaluation; and
• molecular genetic investigation of ATP7B (depending on logistics).

• 7 An extremely low serum ceruloplasmin level (<5 mg/dl) more strongly suggests a diagnosis of WD than modestly subnormal levels. Serum ceruloplasmin by itself is insufficient for making a diagnosis of WD. Serum ceruloplasmin within the normal range does not exclude the diagnosis of WD.
• 8 Basal 24‐h urinary excretion of copper in WD is typically >100 μg/24‐h (>1.6 μmol/24‐h) in symptomatic patients, but a lower reference value of >40 μg/24‐h (>0.6 μmol/24‐h) may indicate WD in individuals who are asymptomatic or children and therefore requires clinical correlation and further investigation.
• 9 Liver biopsy for histology can aid in the diagnosis of WD by identifying findings consistent with WD and permitting disease staging/grading. It may also suggest an alternative or concurrent diagnosis of liver disease. It allows quantification of liver tissue copper. Hepatic parenchymal copper content >250 μg/g dry weight occurs in most patients; a lower content still above normal occurs less frequently but should prompt other confirmatory testing. In untreated patients, normal hepatic copper content (<50 μg/g dry weight) almost always excludes a diagnosis of WD. Electron microscopic evaluation of liver tissue may aid in diagnosis of WD, notably in pediatric patients.
• 10 If neurological evaluation reveals abnormalities, radiologic imaging of the brain, preferably by MRI, should be considered to establish baseline status and exclude other potential causes.
• 11 Genetic testing for ATP7B mutations may be performed as part of a routine evaluation. It can provide diagnostic confirmation when biochemical testing is not definitive. It is efficient for screening first‐degree relatives of a proband.

DIAGNOSTIC STRATEGIES FOR SYMPTOMATIC WD

A methodical approach may facilitate diagnosis of WD. To this end, algorithms provide a structured approach to diagnosis (hepatic: ES‐Figure 1A,B; neurologic: ES‐Figure 2A,B). Algorithms can identify situations where diagnosis is complicated. In ES‐Figures 1–3, such situations are portrayed as “gray zones.” ES‐Table 6 is an annex to ES‐Figures 1–3, providing a checklist of key considerations for the approach to sorting out situations characterized as being in the “gray zone.”

ES‐FIGURE 1: Algorithmic approach to diagnosis of Wilson disease (WD) in a patient with unexplained liver disease: (A) KF rings found and (B) KF rings absent. Numbers in parentheses indicate corresponding Leipzig score, where a sum ≥4 indicates that WD is highly likely (for details, see ES‐Table 7). Minimum ULN for basal 24‐h urinary Cu is taken as 40 μg/24‐h. Genetic testing means analyzing the gene associated with WD (ATP7B) sequence to establish presence on each allele of a disease‐associated mutation. Gray zones identify situations where algorithm mandates critical review—see ES‐Table 6. ATP7B, adenosine triphosphatase copper transporting beta; CPN, ceruloplasmin; Cu, copper; KF, Kayser–Fleischer; ULN, upper limit of normal.

ES‐FIGURE 2: Algorithmic approach to diagnosis of Wilson disease (WD) in a patient with a neurological disorder: (A) KF rings found, and (B) KF rings absent. Presentation of WD as a neurological disorder without KF rings is rare but poses important challenges diagnostically. Numbers in parentheses indicate corresponding Leipzig score, where a sum ≥4 indicates that WD is highly likely (for details, see ES‐Table 7). Minimum ULN for basal 24‐h urinary Cu is taken as 40 μg/24‐h. Genetic testing means analyzing the gene associated with WD (ATP7B) to establish presence on each allele of a disease‐associated mutation. Gray zones identify situations where algorithm mandates critical review—see ES‐Table 6. ATP7B, adenosine triphosphatase copper transporting beta; CPN, ceruloplasmin; Cu, copper; KF, Kayser–Fleischer; ULN, upper limit of normal.

ES‐FIGURE 3: Screening for Wilson disease (WD) in first‐degree relatives of an individual who has a secure diagnosis of WD (proband). The first step is to identify all first‐degree relatives. If the proband's gene associated with WD (ATP7B) genotype is known, then genetic testing is the most efficient screening strategy. Otherwise, clinical testing is required. If clinical testing is inconclusive and genetic testing remains unavailable, then repeat noninvasive assessment (shown in box) should be performed at 6–12 months. Treatment trial may be considered. Genetic testing means analyzing ATP7B sequence to establish presence on each allele of a disease‐associated mutation. ATP7B, adenosine triphosphatase copper transporting beta; CPN, ceruloplasmin; Cu, copper; KF, Kayser–Fleischer; ULN, upper limit of normal.

ES‐TABLE 6 - Checklist for dealing with “gray areas” in the diagnostic algorithms provided

Type of problem	Specific issues	Action
Accuracy of laboratory data	Serum ceruloplasmin—known confounders	See ES‐
	24‐h urinary copper—incomplete collection or contamination	• Confirm technical adequacy of assay • Check creatinine level • Repeat testing
	Liver [Cu]—was specimen large enough? Stored properly?	Check report and/or discuss with pathologist.
	Competence/completeness of genetic analysis	• Review protocols • Consult clinical geneticist • Confirm trans (not cis) mutations
Adequacy of clinical assessment	Neurological assessment	• Expert review for specifying relevant findings • Brain MRI
	Kayser–Fleischer rings	Repeat exam or optical tomography to determine whether present or not.
	Psychiatric assessment (only implied in algorithms)	Expert consultation/review
Data available but not accounted for in algorithms	Liver biochemistries	• Normal LFTs would likely preclude a liver biopsy. • Abnormal LFTs support WD or some other liver disorder: biopsy may be performed.
	Liver histology	• Findings may support WD or provide basis for alternative diagnosis. • Consider examining ultrastructure (by EM) as findings may support WD, notably in children.
Emerging problems not well accounted for in algorithms	Hepatic Cu <250 μg/g dry weight but above suggested revisions of that threshold (e.g., >75 μg/g dry weight) and well above normal	• Reevaluate, with genetic analysis if not yet performed. • Treatment trial.
	Only one mutation found, but along with a VUS	• Repeat clinical/biochemical evaluation in 6–12 months or until clear diagnosis reached. • In silico assessment of VUS.
	Screening reveals affected infant/toddler who is entirely healthy	Reevaluate every 6 months: plan to start treatment at 3 years‐old unless earlier evidence of organ damage.

Abbreviations: Cu, copper; EM, electron microscopy; LFT, biochemical liver test; MRI, magnetic resonance imaging; VUS, variant of unknown significance; WD, Wilson disease.

Likewise, scoring systems have been developed to facilitate diagnosis and prognosis. Diagnostic scoring systems include the Leipzig score (ES‐Table 7) for general diagnosis,³⁰ which is validated in adult and pediatric patients, and several biochemical indices for identifying ALF due to WD.³¹ The first prognostic score, the Nazer score, has been superseded by the New Wilson Index (NWI; ES‐Table 8).³² These scores must be evaluated in clinical context. They are helpful for WD patients whose presentation is not classic. In general, all such scoring systems require regular review, revision, and revalidation.

ES‐TABLE 7 - Leipzig score for diagnosis of Wilson disease (with commentary)

Parameters	Points
Specific clinical features
Kayser–Fleischer rings (by slit‐lamp examination)
Present	2
Absent	0
Neuropsychiatric symptoms suggestive of WD (or typical features on brain MRIa)
Present	2
Absent	0
Coombs‐negative (nonimmune) hemolytic anemia (plus high serum copper)
Present	1
Absent	0
Laboratory tests
24‐h urinary copper excretion (in the absence of acute hepatitis)—ULN modifiedb
Normal	0
1–2× ULN	1
>2× ULN	2
Normal but >500 μg/day 1 day after challenge with 2× 500 mg d‐penicillamine (see notec)	2
Liver copper quantitatived
Normal (ULN = 50 μg/g dry weight)	−1
Up to 5× ULN	1
>5× ULN	2
Rhodanine‐positive hepatocytes (only if quantitative copper measurement not available)
Absent	0
Present	1
Serum ceruloplasmin (nephelometric assay, LLN = 20 mg/dle)
Normal	0
10–20	1
<10	2
Mutation analysis (ATP7B)
Disease‐causing mutations on both chromosomes	4
Disease‐causing mutation on one chromosome	1
No disease‐causing mutation detected	0
Total score (not available: scores 0)
Assessment of the WD‐diagnosis score f
4 or more: Diagnosis of Wilson disease highly likely
2–3: Diagnosis of Wilson disease probable, do more investigations
0–1: Diagnosis of Wilson disease unlikely

Abbreviations: ATP7B, ATPase copper transporting beta (gene associated with WD); EEG, electroencephalogram; LLN, lower limit of normal; MRI, magnetic resonance imaging; ULN, upper limit of normal; WD, Wilson disease.

^aDetailed MRI or EEG studies are only needed if neurological symptoms cannot be excluded with certainty by clinical neurological examination.

^bULN for children was subsequently modified to 40 μg/d; accruing experience indicates that this ULN is appropriate for adults.

^cThis criterion is likely not stringent enough; diagnostic threshold in original publication was >1600 μg/24‐h.

^dLiver biopsy is not mandatory for diagnosis and evaluation of patients with exclusively neurological findings. Histopathological assessment of liver was considered to be important for research protocols.

^eOther values may apply when ceruloplasmin is measured by oxidase assay (generally not available in routine clinical laboratories).

^fCertain disorders can reach “diagnostic” score values; see section on clinical mimics and ES‐Table 2.

TABLE 8 - New Wilson Index (NWI) prognostic scoring system for WD in conventional units

Points assigned	0	1	2	3	4
Bilirubin, mg/dl (μmol/L)	0–5.8 (0‐100)	5.9–8.7 (101‐150)	8.8–11.7 (151‐200)	11.8–17.5 (201‐300)	>17.5 (>300)
INR	0–1.29	1.3–1.6	1.7–1.9	2.0–2.4	≥2.5
AST, IU/L	0–100	101–150	151–200	201–300	>300
WBC (×106/ml)	0–6.7	6.8–8.3	8.4–10.3	10.4–15.3	≥15.4
Albumin, mg/dl	>4.5	3.4–4.4	2.5–3.3	2.1–2.4	≤2.0

Note: Like the Nazer index, the NWI³² assigns points to serum [total] bilirubin, AST, and coagulation capacity (here, INR; previously in Nazer score: prothrombin time). In contrast, the NWI also assigns points also to WBC and serum albumin. Values here have been converted from Systeme Internationale (SI) to conventional units (bilirubin in SI units provided in parentheses). The points assigned for each of the five parameters are summed to generate the score. A score of ≥11 is a strong predictor of mortality without liver transplantation. On receiver‐operator curve analysis in adults,⁸⁷ the NWI performed better than the Nazer score and MELD.

Abbreviations: AST, aspartate aminotransferase; INR, international normalized ratio; MELD, Model of End‐Stage Liver Disease; NWI, New Wilson Index; SI, Système Internationale; WBC, white blood cell count; WD, Wilson disease.

Guidance statements 12 and 13

• 12 Diagnostic scoring systems may aid clinicians in establishing or refuting a diagnosis of WD in patients not meeting classic descriptions of the disease and are also useful for purposes of research studies on WD.
• 13 Prognostic scoring systems may help in determining the potential for successful medical therapy for WD. Applying such a score serially over time may be critical to improve accuracy.

SCREENING FOR WD

Family screening

First‐degree relatives of patients newly diagnosed with WD must be screened for WD. If available, and if disease‐specific mutations are identified in the proband, genetic testing for ATP7B mutations should be obtained and may be used as primary screening. Alternatively, clinical and biochemical assessment should include the following: brief history relating to jaundice, liver disease, and features of neurological or psychiatric involvement; physical examination; serum copper, ceruloplasmin, liver function tests including aminotransferases, albumin, and both conjugated and unconjugated bilirubin; slit lamp examination for KF rings; basal 24‐h urinary copper excretion (screening algorithm: ES‐Figure 3). Individuals identified as having an ATP7B genotype consistent with WD require clinical evaluation of extent of organ damage and clinical features.

Newborn and prenatal screening

Certain features render WD suitable for population screening of infants: it is prevalent enough, effective treatment exists and mitigates the severity of clinical disease, and its genetic basis is known; however, no inexpensive and reliable testing strategy has yet been established. A proteomic approach to identifying abnormal ATP7B protein in dried blood spots is in development.³³ Prenatal testing based on genotypic analysis can be performed; diagnosis in the neonatal period also permits timely treatment.³⁴

Guidance statement 14

• 14 First‐degree relatives of patients newly diagnosed with WD must be screened for WD. Within a pedigree where there is one or more individuals with WD, any person with signs or symptoms consistent with WD, irrespective of closeness of relationship, should be evaluated for WD. Available strategies are genotype assessment of ATP7B and comprehensive clinical evaluation (summarized in ES‐Figure 3).

TREATMENT–GENERAL PRINCIPLES

The mainstay of treatment for WD remains lifelong oral pharmacotherapy (ES‐Table 9) and dietary copper restriction. Liver transplantation, which corrects the underlying hepatic defect in WD, is reserved for severe cases and those resistant to pharmacotherapy. The goals of WD treatment depend upon the phase of disease (ES‐Figure 4) and must consider both drug safety and efficacy in the individual patient. The approach to treatment initiation depends on whether the patient is symptomatic or not and whether organ damage is present. Patients who are symptomatic have clinically evident disease that is usually hepatic or neuropsychiatric but may involve other organ systems. Individuals with asymptomatic WD have no clinical symptoms at all. Some have no evidence of organ damage. Others who are asymptomatic have biochemical, histological, or imaging evidence of organ damage. Asymptomatic WD is often identified simply on the basis of family screening, sometimes by genotype alone. Distinguishing symptomatic and asymptomatic individuals with evidence of organ damage (asymptomatic active disease) from those asymptomatic individuals who have no organ damage helps in determining the choice and dosage of medications for primary treatment of WD, although studies systematically exploring this approach are lacking. Treatment with chelating agents is recommended as initial treatment for patients who are symptomatic or asymptomatic with WD with active disease, though some reports suggest that treatment with zinc may be adequate for selected patients. Although these considerations also apply broadly to children less than 3 years‐old, determining exactly when to start treatment and what treatment to choose involves factors such as growth and development; moreover, treatment should be individualized to the extent of WD‐related organ damage.

ES‐TABLE 9 - Currently available oral treatments for Wilson disease

Drug	Mode of action	Neurological worsening	Side effects	Comments
d‐Penicillamine	General chelator induces renal excretion of copper	10%–20% during initial phase of treatment	• Fever, rash, proteinuria, lupus‐like reaction • Aplastic anemia • Leukopenia • Thrombocytopenia • Nephrotic syndrome • Degenerative changes in skin • Elastosis perforans serpiginosa • Serous retinitis • Hepatotoxicity • Colitis	Reduce dose for surgery to promote wound‐healing and during pregnancy
Trientine	General chelator induces renal excretion of copper	10%–15% during initial phase of treatment	• Gastritis • Aplastic anemia rare • Sideroblastic anemia • Colitis	Reduce dose for surgery to promote wound‐healing and during pregnancy
Zinc	Metallothionein inducer, blocks intestinal copper absorption	Can occur during initial phase of treatment	• Gastritis • Biochemical pancreatitis • Zinc accumulation • Possible changes in immune function	No dosage reduction for surgery or pregnancy

ES‐FIGURE 4: Customizing WD treatment to the character of clinical disease: treatment goals with respect to the liver are dependent on phase of disease. With effective treatment started early and taken consistently, WD survival approximates to the normal survival of the population. “Rescue” options directed at WD include an intensive medical treatment protocol with temporally dispersed combination of oral chelator and zinc, and liver transplantation. WD, Wilson disease.

Along with primary treatment of WD, patients with advanced liver disease must be treated for any complications of portal hypertension. Elastography may be informative in hepatic WD,³⁵ but its role is evolving. Patients with WD who manifest neurological or psychiatric symptoms may benefit from treatments directed at those symptoms along with WD therapy. As with all patients with chronic liver disease, patients with WD require immunization against hepatitis A and B, unless already immune to these viruses. They should have immunizations directed against potentially life‐threatening intercurrent infections (such as influenza, varicella, COVID‐19, pneumococcal). They should maintain general good health, including normal body weight and cardiovascular fitness.

Disease symptoms and biochemical abnormalities stabilize in most patients within 6–18 months after initiation of consistent therapy. An oral chelator at a reduced dose or zinc can then be used for maintenance therapy. Transitioning to maintenance therapy entails clinical and biochemical monitoring in the first 2–6 months (as opposed to standard 6‐month intervals) to ensure effective therapy. Patients who are asymptomatic without evidence of organ damage may be treated initially either with the lower maintenance dose of a chelating agent or with zinc. Monitoring of therapy includes clinical examination and biochemical testing to demonstrate clinical improvement or stability, depending on whether the patient was symptomatic or not at the start of treatment. Checking adherence and treatment‐induced adverse effects regularly is important to achieve best outcomes. Failure to comply with lifelong therapy has led to recurrent or new symptoms and liver failure, the latter requiring liver transplantation for survival.

TREATMENT—AVAILABLE MEDICATIONS

Currently available oral treatments for WD (ES‐Table 9) were developed to treat patients who are symptomatic, but their role has evolved to include patients who are asymptomatic and long‐term maintenance therapy. The bis‐choline salt of tetrathiomolybdate, a potent oral chelator, is not yet available; its phase III clinical trial has completed enrollment. Local variations in drug availability and cost may influence choice of treatment.

d‐Penicillamine

Pharmacology

Penicillamine was the first oral treatment for WD; the preferred drug is the d‐penicillamine isomer. It promotes urinary copper excretion. After starting on d‐penicillamine, 24‐h urinary copper excretion often is >1000 μg/day. It may also induce metallothionein. d‐Penicillamine may bind metals other than copper and can be used as treatment to remove other metals, such as mercury or lead.

d‐Penicillamine is rapidly absorbed from the gastrointestinal tract. If taken with a meal, its absorption is decreased overall by approximately 50%. Total bioavailability is estimated at 40%–70%. Once absorbed, most d‐penicillamine circulates bound to plasma proteins. d‐Penicillamine excretion is mainly renal. The excretion half‐life of d‐penicillamine ranges from approximately 1.7 to 7 h.^36–38

Initially d‐penicillamine in WD was used for treatment of patients who were symptomatic, and numerous studies demonstrated effectiveness.³⁹ A severe or “paradoxical” worsening of neurological symptoms was initially attributed uniquely to d‐penicillamine; however, subsequent series showed that neurological worsening also occurred with trientine and zinc, although most frequently with d‐penicillamine. In one series, neurological worsening most often occurred in patients with neurologic WD.¹³

d‐Penicillamine use is associated with numerous adverse effects. Severe adverse effects requiring the drug discontinuation occur in approximately 30%.^40,41 Early sensitivity reactions marked by fever and cutaneous eruptions, lymphadenopathy, neutropenia or thrombocytopenia, and proteinuria may occur during the first 1–3 weeks. d‐Penicillamine should be discontinued immediately if early sensitivity occurs; alternate treatment for WD should be substituted. Later reactions are diverse. Nephrotoxicity, indicated by proteinuria or appearance of cellular elements in the urine, requires immediate discontinuation of d‐penicillamine. Bone marrow toxicity includes severe thrombocytopenia or total aplasia that may be irreversible despite discontinuation of therapy.

Other adverse effects similarly require discontinuation of d‐penicillamine and institution of alternate WD treatment. Dermatological toxicities include progeric changes in the skin, elastosis perforans serpiginosa, pemphigus or pemphigoid lesions, lichen planus, and aphthous stomatitis. Other late reactions include a lupus‐like syndrome marked by hematuria, proteinuria, and positive antinuclear antibody and, with higher dosages of d‐penicillamine no longer typically used for treating WD, Goodpasture syndrome. Very late adverse effects include nephrotoxicity, severe allergic response upon restarting the drug after prior discontinuation, myasthenia gravis, polymyositis, loss of taste, immunoglobulin A depression, and serous retinitis. Hepatotoxicity has been reported, as has colitis.

Therapeutics

Incremental dosing may enhance tolerability of d‐penicillamine: starting with 250–500 mg/day, then increasing by 250‐mg increments every 4–7 days to approximately 1000–1500 mg/day (15–20 mg/kg/day to a maximum of 2000 mg/day) in 2–4 divided doses. This “start low and go slow” approach is strongly recommended to avoid neurological worsening, but no controlled studies are available. Maintenance dose in adults is 10–15 mg/kg/day (approximately 750–1000 mg per day) administered in two divided doses. Dosing in children is 20 mg/kg/day rounded off to the nearest 250 mg and given in two or three divided doses; the dose may be reduced to 10–15 mg/kg for maintenance. d‐Penicillamine should be administered 1 h prior to or 2 h after meals, as food inhibits its absorption. Closer proximity to meals may be acceptable if it ensures adherence; however, effectiveness of treatment then needs to be closely monitored. Dose should be temporarily reduced in order to promote good wound‐healing after surgery. Pyridoxine (25–50 mg by mouth daily) is routinely administered to patients on d‐penicillamine, although interference with pyridoxine action is rarely encountered because the racemic mixture of d,l‐penicillamine is no longer in use.

Treatment targets—d‐penicillamine

Patients with asymptomatic WD should remain asymptomatic on treatment. For patients with symptomatic liver disease, improvement in synthetic function and clinical signs such as jaundice and ascites begins during the first 2–6 months of treatment, with further recovery possible over time. Failure to adhere to therapy has led to progression of liver disease and liver failure in 1–12 months following treatment discontinuation, resulting in death or liver transplantation. Nonadherence has also led to the development of new neurological or psychiatric symptoms.

Adequacy of treatment is monitored in terms of maintaining clinical and biochemical stability and by measuring 24‐h urinary copper excretion on treatment. This is highest immediately after starting treatment when it may exceed 1000–2000 μg/24‐h. With chronic (maintenance) treatment, urinary copper excretion should be approximately 200–500 μg/24‐h (3–8 μmol/24‐h). Serum NCC shows normalization with effective treatment. Values of 24‐h urinary copper excretion >500 μg/24‐h in treated patients previously excreting 200–500 μg/24‐h suggest insufficient drug action (nonadherence to medication, poor drug absorption, inadvertently low dosing), acute liver injury (ALI), or excessive liberalization of dietary copper. Urinary copper excretion <100 μg/24‐h may signal overtreatment following excessive copper removal or, occasionally, nonadherence. With overtreatment, serum copper and exchangeable copper are very low, as is the NCC (typically <5 μg/dl), although the estimated NCC may not accurately reflect this. With nonadherence to therapy, serum copper and exchangeable copper increase, and NCC may be elevated (>25 μg/dl).

With d‐penicillamine treatment, serum ceruloplasmin may initially decrease and remain low. With hepatic recovery on chronic treatment, it may increase. By contrast, a decrease in serum ceruloplasmin in chronically treated patients may indicate overtreatment and often is associated with neutropenia, sideroblastic anemia, and hemosiderosis.

Trientine

Pharmacology

Trientine (triethylenetetramine dihydrochloride; 2,2,2‐tetramine or “trien”; also available as triethylenetetramine tetrahydrochloride) has a polyamine‐like structure chemically distinct from penicillamine. Like d‐penicillamine, its primary action is promotion of renal copper excretion. Urinary copper excretion typically is >1000 μg copper per day with treatment initiation and decreases over time. Additionally, administered with food in healthy subjects, trientine blocks dietary copper absorption.⁴² Whether trientine is a weaker chelator of copper than d‐penicillamine is controversial; however, adjustments of trientine dose can compensate for possible differences.

Data on trientine pharmacokinetics are limited. Trientine is poorly absorbed from the gastrointestinal tract: much of what is absorbed is metabolized and inactivated. The median t½ for absorption is approximately 1.5 h in patients with WD.⁴³ Biotransformation of trientine is probably through phase II conjugation pathways for polyamines, which trientine resembles structurally.⁴² These acetylation pathways are separate from N‐acetyltransferase 1 (NAT1) and N‐acetyltransferase 2 (NAT2). The excretion t½ is approximately 3 h. Only approximately 1% of the administered trientine and approximately 8% of the biotransformed trientine metabolite, acetyltrien, ultimately appear in urine. Recent studies suggest that the pharmacokinetics for trientine dihydrochloride is similar in normal controls and in patients with WD, notably both adult and pediatric patients.⁴³

Bioequivalence between trientine dihydrochloride and trientine tetrahydrochloride has not yet been established because of differences in pharmacokinetics and bioavailability. Switching between these formulations may require assessment for individual dose adjustments.

Trientine has few side effects. No hypersensitivity reactions have been reported, although a fixed drug reaction was observed in one patient. Pancytopenia is rare. Colitis can develop in rare patients on trientine, as with d‐penicillamine.⁴⁴ Esophageal irritation can occur; therefore, trientine should be taken with ample fluid. Coadministration of trientine and iron should be avoided because the trientine‐iron complex is toxic. Lupus‐like reactions were reported in some patients with WD treated with trientine; however, these patients were almost all treated previously with d‐penicillamine. The true frequency of lupus‐like reactions with trientine as initial treatment is unknown. Accumulated clinical experience suggests that adverse effects due to d‐penicillamine resolve when trientine is substituted for d‐penicillamine and do not recur.

Therapeutics

Trientine is effective treatment for WD, indicated especially in patients who are intolerant of d‐penicillamine. It may be preferable initial treatment in patients with WD and severe thrombocytopenia or neutropenia due to congestive splenomegaly. Paradoxical neurological worsening after beginning treatment with trientine appears less common than with d‐penicillamine, although a head‐to‐head comparison of initial treatment has never been made. Trientine was effective initial therapy for patients, even with decompensated liver disease at the outset. Available data suggest that trientine is safe and effective in pediatric patients with WD.^45,46 The tetrahydrochloride form of trientine was approved in 2022 by the Food and Drug Administration (FDA) for previously treated, d‐penicillamine‐tolerant patients with WD.

Typical adult dosage for initial treatment is approximately 15‐20 mg/kg/day (to 2000 mg daily maximum) in 2–3 divided doses. As with d‐penicillamine, the dose for initial therapy with trientine should be ramped up slowly over several (2–4) weeks to enhance tolerability. Dosage for maintenance therapy is typically 10–15 mg/kg/day. In children, the initial dose generally used is 20 mg/kg/day rounded off to the nearest 250 mg, given in two or three divided doses, started incrementally. Exceeding 20 mg/kg/day may be associated with increased adverse effects.⁴⁶ Maintenance treatment can be 10–15 mg/kg/day, but normal growth often compensates for actual dose modification. Trientine should be administered 1 h before or 2 h after meals. Once‐daily dosing of trientine in patients who are clinically stable may be safe and enhance adherence, but it requires confirmatory studies.⁴⁷ The dose should be temporarily reduced to promote good wound‐healing after surgery. The dihydrochloride formulation of trientine should be stored refrigerated. Newer packaging can improve ambient temperature stability for trientine dihydrochloride. The tetrahydrochloride form of trientine is stable at ambient temperature.

Treatment targets—trientine

On trientine, patients patients with asymptomatic WD should remain asymptomatic. For patients with symptomatic liver disease, improvement in synthetic function and clinical signs such as jaundice and ascites occur during the first 2–6 months of treatment with further recovery possible over time. Failure to adhere to therapy has led to progression of liver disease and liver failure, or development of new neurological or psychiatric symptoms.

Adequacy of treatment is monitored in terms of maintaining clinical and biochemical stability and by measuring 24‐h urinary copper excretion on treatment. Urinary copper excretion upon initiation of treatment is often >1000 μg/24‐h but decreases over time on treatment to approximately 3–10 times the upper limit of normal (typically approximately 150–500 μg/24‐h).⁴⁸ Generally, with nonadherence to therapy, urinary copper rises. On chronic dosing, urinary copper excretion higher than treatment goal may reflect nonadherence, but it can also be because of poor drug absorption, unintentionally low dosing, or intercurrent ALI. Values of urinary copper excretion <100 μg/24‐h may indicate some degree of copper deficiency because of overtreatment. In such a situation, serum copper is expected to be lower than pretreatment values. Reversible sideroblastic anemia and neutropenia may be present. Overtreatment can result in hepatic iron overload in patients with WD, similar to that observed for d‐penicillamine. In contrast, when low urinary copper excretion accompanies nonadherence, serum copper increases toward or exceeding pretreatment values.

Zinc (zinc salts)

Pharmacology

Zinc was first used to treat WD by Schouwink in the Netherlands in the early 1960s. Unlike d‐penicillamine and trientine, zinc inhibits the intestinal absorption of copper by inducing enterocyte metallothionein, an endogenous chelator with a greater affinity for copper than for zinc. Ingested copper taken up into the enterocytes binds to cytoplasmic metallothionein more avidly than zinc. The copper‐metallothionein is excreted in the feces as enterocytes are shed in normal turnover. Because copper also enters the gastrointestinal tract from saliva and gastric secretions, zinc treatment generates a negative balance for copper and removes tissue copper, albeit relatively slowly. Zinc may also induce hepatocellular metallothionein, thus potentially enhancing hepatoprotection.

A proportion of ingested zinc is absorbed, raising serum zinc levels and resulting in increased renal zinc excretion. Some foods interfere with enterocyte zinc absorption. In particular, phytates from grains bind zinc but not protein, so the latter may be used at times as a buffer to increase gastric tolerability.

Zinc has very few side effects. Gastric irritation is the most common adverse effect occurring in 30%–40% of patients. It may be dependent on the type of zinc salt. In one survey, approximately 38% of patients changed the zinc salt used to treat their WD because of gastrointestinal symptoms.⁴⁹ Gastric irritation can be severe. In one pediatric case, zinc sulfate was associated with gastric perforation.⁵⁰ Early neurological worsening is uncommon with zinc but may occur.⁵¹ Elevation in serum lipase or amylase may occur without clinical or radiologic evidence of pancreatitis. Zinc may be utilized in patients with WD and impaired renal function when chelation therapy requiring urinary copper excretion might be ineffective.

Therapeutics

Although zinc is currently reserved for maintenance treatment of WD, it is also used as first‐line therapy, most commonly but not exclusively for patients who are asymptomatic. It appears to be equally as effective as d‐penicillamine but much better tolerated.⁵² Reports in adults indicate good efficacy,^51,53 which is possibly better in those with neurologic WD. In children with mild or asymptomatic WD, zinc treatment as primary therapy appears effective,⁵⁴ although some express caution.⁵⁰ Some individuals with severe disease were reported as doing well on zinc monotherapy. “Combination” treatment with chelator plus zinc has been advocated as treatment for severe disease: each is given at widely spaced intervals during the day, never simultaneously.

Zinc treatment is ineffective in some patients with WD. In initial studies, some patients failed to achieve adequate blockage of dietary copper absorption. Hepatic deterioration was occasionally reported on zinc monotherapy, fatal in one case^51,53; however, it is unknown whether these patients were properly adherent to their therapy.

Dosing is in milligrams of elemental zinc. Zinc must be taken at least twice daily to be effective, though thrice daily is recommended to ensure efficacy. For larger children and adults, 150 mg/day is administered in three divided doses. For children <50 kg in body weight, the dose is 75 mg/day in three divided doses.⁵⁵ The dose is not well defined for children who are less than 5‐years‐old; however, 50 mg/day in two divided doses was recommended, similar to a weight‐based dose. The actual salt used does not appear to change efficacy as measured by the percent reaching goals for urinary copper excretion and normalization of serum alanine aminotransferase (ALT)⁴⁹ but may affect tolerability.

Treatment targets—zinc

Adequacy of zinc treatment is judged by maintaining clinical and biochemical stability, or by improvement on therapy, and by measuring 24‐h urinary copper excretion, which should be <100 μg (<1.6 μmol)/24‐h on stable treatment. ALT normalization may be a good marker of effective treatment as well, and it positively correlates with the maintenance of 24‐h urinary copper excretion <100 μg/24‐h.^49,51 Additionally, elevated NCC normalizes with effective treatment; the estimated NCC may indicate this normalization.

Zinc lacks efficacy in a small subset of patients with WD, but it is impossible to prospectively identify patients who will not respond to treatment. Failure of zinc therapy in those in whom it was initially effective is most often associated with nonadherence (missing doses or poor absorption due to taking it with food). Rarely, it may be because of underdosing if the childhood dose is not adjusted upward as children grow. Overtreatment with zinc is suspected when urinary copper excretion is very low, associated with lower serum copper and lower ceruloplasmin concentrations. It necessitates a reduction of the zinc dosage or a brief interruption of therapy, especially if hematologic or neurological adverse effects are present. These include development of a sideroblastic anemia with leukopenia or neutropenia or neurological deficits such as ataxia or peripheral neuropathy. Neurological changes from zinc therapy for WD are uncommon but develop when copper depletion is severe and prolonged, usually after 5–15 years or more of treatment.⁵⁶

Long‐term adherence to treatment is an important issue with zinc treatment for WD. The three‐times‐daily dosage regimen stipulated to be strictly away from meals can prove problematic for some patients, particularly for adolescents and young adults. Zinc appeared more efficacious in neurologic WD than in hepatic WD, where more treatment failures occurred.⁵¹ Clinical monitoring needs to be stringent. Rise in serum aminotransferases may be an early sign of poor adherence or treatment failure. Finding 24‐h urinary copper excretion higher than target (≥100 μg/24‐h) suggests poor adherence or increased dietary copper intake. Urinary excretion of zinc, with target values of >1–2 mg/24‐h, may be measured to check adherence. Urinary zinc content correlates positively with the patient's total daily dosage of zinc.⁴⁹ Serum zinc levels may be informative and should be >125 mg/dl.

Guidance statements 15–18

• 15 All patients with a newly‐established diagnosis of WD should be initiated on lifelong medical therapy for WD. Timing of treatment in children who are less than 3 years‐old should be individualized to the degree of organ damage.
• 16 Initial treatment for symptomatic patients with WD should include a chelating agent (d‐penicillamine or trientine). Trientine may be better tolerated.
• 17 Treatment of asymptomatic patients with WD can be a chelating agent (d‐penicillamine or trientine at a lower dose than for initial therapy) or zinc.
• 18 The suitability for transition to maintenance therapy for WD includes time on therapy (generally more than 1 year) and favorable clinical and biochemical response to therapy. Maintenance therapy may be a lower dose of chelating agent (d‐penicillamine or trientine) or full‐dose zinc.

Nutrition

Limiting dietary copper intake is another aspect of WD treatment. The average diet is replete with copper and replenishes normal losses of this trace element. The median copper intake from foods in the United States is 1–1.6 mg/day.⁵⁷ Although there is no firm consensus on how strictly dietary copper should be limited in WD,^58,59 WD cannot be treated exclusively by dietary measures. A few foods with very high concentrations of copper (nuts, chocolate, most shellfish, soy‐based products, mushrooms, organ meats) should be avoided, at least in the first year of treatment. Infants and toddlers require individualized dietary adjustments, as do vegans/vegetarians. Patients with WD with impaired swallowing or undernutrition because of advanced neurological or hepatic disease require specialized nutritional supplementation. In some situations, such as with well water, drinking water may need to be tested for copper content.

Guidance statements 19 and 20

• 19 Patients with WD should avoid intake of foods and water containing high concentrations of copper, especially during the first year of treatment. Supervision by a registered dietitian (RD) may help to avoid overly restrictive meal patterns or undue anxiety about diet.
• 20 Patients with WD unable to maintain adequate nutritional intake require dietary management that includes supplements formulated to meet dietary needs while avoiding excess copper intake. Arranging for participation by a knowledgeable RD may be helpful.

MONITORING OF TREATMENT

The goal of treatment monitoring is to confirm treatment efficacy by demonstrating clinical and biochemical improvement or stability, ensure adherence to medication and diet, and identify adverse side effects in a timely fashion. The minimum recommended frequency of monitoring is twice annually. More frequent monitoring is required during treatment initiation, for those experiencing worsening of symptoms or medication side effects, and in individuals suspected of noncompliance with therapy. A careful history should include questions about psychiatric symptoms, especially depression. Physical examination should seek evidence of liver disease and neurological abnormalities and, for patients on d‐penicillamine, cutaneous changes. Repeat examination for KF rings should be performed if there is a question of the patient's adherence. Biochemical parameters (ES‐Table 10) are helpful.

ES‐TABLE 10 - General laboratory parameter targets for Wilson disease treatment modalities, including findings with excessive or inadequate treatment

	Treatment initiationa	Maintenance treatment				Overtreatment			Treatment failure on chronic therapy (nonadherence, drug failure)
	Urinary copper	24‐h urinary Cu excretion, μg/24‐h	NCC, μg/dl	AST, ALT	TBili, INR	24‐h urinary Cu excretion, μg/24‐h	NCC, μg/dl	Other	24‐h urinary Cu excretion, μg/24‐h	NCC, μg/dl	AST, ALT
d‐Penicillamine	Increases	~200–500 (≈3–8 μmol/24‐h)	5–15	Trend to normalb	↓	<100	<5	↓↓CPN, ↓↓Cu;	>500 (previously in range)c	>25	↑
								sideroblastic anemia; ↓WBC;
								↑Fe indices
Trientine	Increases	~150–500 (≈2.4–8 μmol/24‐h)	5–15	Trend to normalb	↓	<100	<5	↓↓CPN, ↓↓Cu;	>500 (previously in range)c	>25	↑
								sideroblastic anemia; ↓WBC;
								↑Fe indices;
Zinc	No change, then ↓	<100 (<1.6 μmol/24‐h)	5–15	Trend to normalb	↓	<20	<5	↓↓CPN, ↓↓Cu;	>100 (previously normal/near‐normal)	>25	↑
								sideroblastic anemia; ↓WBC;
								↑Fe indices;

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPN, ceruloplasmin; Cu, copper; Fe, iron; INR, international normalized ratio; NCC, non‐ceruloplasmin‐bound copper; TBili, total bilirubin; WBC, white blood cell count; WD, Wilson disease.

^aFailure to achieve these patterns on initiation of treatment constitutes one kind of treatment failure. Subsequent failure to achieve profiles described under “Maintenance treatment” suggests treatment failure.

^bRecurrent elevation of serum aminotransferases after a period of normalization suggests loss of drug efficacy or intercurrent hepatic injury, not necessarily nonadherence.

^cInitially 24‐h urinary copper excretion may drop below the achieved target range because of drug failure or nonadherence and then increase gradually over time with continued ineffective treatment. Reinstitution of oral chelator will yield a sizeable increase in urinary copper excretion whereas starting zinc will lead to decreased urinary excretion of copper.

Treatment failure

Treatment failure may occur with any WD medication early during treatment initiation or later while on maintenance therapy. Treatment failure should prompt a thorough evaluation for concurrent disease and nonadherence. If these are excluded, pharmacological therapy should be reevaluated and likely altered. For patients with advanced liver disease or who progress to liver failure, evaluation for liver transplantation should be considered. Currently, no surrogate markers are established for evaluating treatment failure.

Clinically, treatment failure includes progressive hepatic, neurological, or psychiatric disease. Failure of therapy at treatment initiation represents failure to stabilize disease either clinically or biochemically (or both) and, unique to the liver, progression of hepatic fibrosis. With hepatic disease, failure includes onset of decompensation (new onset of ascites, encephalopathy, or variceal bleeding) or inability to stabilize a patient with decompensated cirrhosis (refractory ascites, severe encephalopathy, or worsening jaundice and coagulopathy). For neurological disease, treatment failure involves symptom progression despite therapy, in particular the paradoxical acceleration of neurological disease or development of new symptoms. There may be worsening psychiatric disease, including onset of psychosis, worsening depression, or mania.

Biochemically, treatment failure during treatment initiation involves the inability to prevent worsening or exacerbation of liver injury. Inability to reduce serum aminotransferases to less than twice (i.e., <2 times) upper limit of normal over time indicates probable treatment failure; however, the time interval for achieving improvement may depend on the magnitude of the initial elevation. Synthetic function of the liver may take longer to respond to therapy than aminotransferases, which is typically 3–18 months. INR is a good measure of synthetic function, as is albumin, apart from its confounders such as nutrition and acute‐phase variability. Serum bilirubin, though potentially confounded by hemolysis or concurrent Gilbert syndrome, should decrease approximately as fast as synthetic function improves. For patients with cirrhosis, the Model of End‐Stage Liver Disease (MELD) score may be calculated and followed, with the expectation that it will decrease as synthetic function and bilirubin improve. Patients with a MELD score >15 who are failing to improve after 3 months should be considered for evaluation for liver transplantation.

The 24‐h urinary copper excretion on treatment should be measured at least annually but should be repeated sooner (typically in 3–6 months) after changes in dosing or medication. Over time, with continued adequate treatment, it decreases from initial high values to lower amounts.^48,60 For patients on oral chelators, measurement after a temporary (48‐h) washout period off drug⁴⁸ may be informative for assessing adequacy of treatment.

Progression of hepatic fibrosis despite therapy also constitutes treatment failure because of failure of pharmacotherapy or from liver injury from an unrelated process. Monitoring with elastography or by serum‐based assays such as Fibrosis‐4 (Fib‐4) Index or aspartate aminotransferase/platelet ratio may be helpful; however, liver biopsy remains the gold standard. The biopsy can be valuable for grading and staging injury and diagnosing concurrent disease.

For patients on maintenance therapy who, by definition, had achieved clinical stability, worsening disease or onset of new symptoms (e.g., neurological symptoms in someone with only hepatic disease) or progressive hepatic fibrosis constitutes treatment failure. It is important to exclude concurrent disease and to distinguish treatment failure from undertreatment (inadequate dosage of therapy) or ineffective pharmacotherapy. Undertreatment may arise from nonadherence to treatment or diet, and dose alteration or stricter supervision and close monitoring may be sufficient to restore stability. For those with pharmacological failure, a change in treatment is appropriate and can be immediately accomplished without any weaning strategy. It is uncertain whether addition of a second therapy to an ongoing treatment is better than just changing treatment or a dose adjustment alone: this needs to be individualized, as there are insufficient data for guidance.

Guidance statements 21–24

• 21 For regular monitoring, liver biochemistries and INR, complete blood count and routine urinalysis (especially for those on chelation therapy with d‐penicillamine or trientine), and physical examination should be performed regularly, at least twice per year. Patients receiving chelation therapy require a complete blood count and urinalysis regularly, no matter how long they have been on treatment.
• 22 The 24‐h urinary copper excretion while on medication, or in patients on d‐penicillamine or trientine after a temporary period (48 h) off drug, should be measured yearly, and more frequently if there are questions regarding adherence or if the medication dosage is adjusted. Serum copper and ceruloplasmin may be followed for trends: very high or very low serum copper or serum copper disproportionately high for simultaneous serum ceruloplasmin. These may disclose exogenous copper intake (higher copper) or total‐body depletion (lower copper and ceruloplasmin).
• 23 Overtreatment of WD by pharmacological therapy directed at removing or detoxifying copper may be indicated by development of cytopenias or retention of tissue iron associated with raised serum ferritin. It is confirmed by a low serum copper and a very low 24‐h urinary copper output. For oral chelators, 24‐h urinary copper excretion disproportionately low for the dose of chelator being administered (below therapeutic target, specifically <100 μg/24‐h or<1.6 μmol/24‐h) suggests overtreatment. For zinc therapy, 24‐h urinary copper <20 μg/24‐h (<0.3 μmol/24‐h) suggests overtreatment. Once overtreatment is confirmed, dose reduction or brief interruption of medical therapy should be instituted, with close follow‐up for reassessment.
• 24 Treatment failure may occur during treatment initiation or while on chronic treatment. It can complicate any WD medication. Concurrent diseases and nonadherence must be excluded. Pharmacological therapy should be revised in patients with treatment failure; however, with more advanced liver disease or liver failure, liver transplantation may be required.

ADHERENCE

Once WD is conclusively diagnosed and treatment has been initiated, pharmacological treatment is lifelong. The survival of WD patients who receive effective pharmacological treatment approaches the normal longevity of their country.⁶¹ With hepatic WD, effective treatment instituted early makes it unlikely that neurological abnormalities will develop.⁶² Effective treatment is efficacious, well tolerated, and actually taken consistently by the patient. Some degree of nonadherence to lifelong pharmacological therapy for WD occurs in at least 50% of patients throughout their lives. A well‐defined treatment plan, with regular clinical and biochemical assessments, and a broadly supportive approach, team‐based if possible, with inclusion of family and support individuals, contribute to achieving good adherence. Patients failing to achieve treatment targets should be carefully evaluated and followed more frequently. For those on chelation or zinc therapy, an increase in urinary copper excretion along with worsening liver tests might indicate nonadherence, though other considerations must include problems with medication absorption or inactive medication. Dietary nonadherence to a low copper diet may also contribute to poor outcomes in some patients.

Guidance statement 25

• 25 Ensuring adherence to a well‐defined treatment plan for WD is critically important for patients to achieve good outcomes with therapy. Regular clinical assessments and a broadly supportive approach, team‐based if possible, are elements of achieving good adherence. Monitoring frequency should be increased in patients where nonadherence is suspected.

TREATMENT IN SPECIFIC CLINICAL SITUATIONS

Decompensated cirrhosis

Patients with WD presenting initially with chronic liver disease and decompensated cirrhosis, typically with hypoalbuminemia, coagulopathy, jaundice, and ascites, but variable encephalopathy, were traditionally treated with chelation therapy. Recently, “combination” therapy, with either d‐penicillamine or trientine plus zinc, has been utilized as an intensive regimen for severe disease. The two medications must be temporally dispersed throughout the day in at least four doses, with usually 4–5 h between administration of either drug to avoid having chelator bind the zinc and compromise efficacy. For example, elemental zinc (50 mg in adults, 25 mg in children) is taken as the first and third doses, and trientine (approximately 10 mg/kg) as the second and fourth doses. Any patient starting this regimen should also be simultaneously evaluated for liver transplantation. Patients slow to respond or failing this regimen should be promptly considered for liver transplant. Prognostic scoring systems such as the NWI, especially when applied serially, may help identify patients who will respond or fail treatment. Those who respond may be transitioned to full‐dose zinc or full‐dose trientine (or d‐penicillamine) as monotherapy after approximately 3–6 months when disease stabilization should be evident. This treatment strategy remains investigational despite some supportive data.

Guidance statements 26–27

• 26 Patients with WD and severe hepatic disease (irrespective of severity of their neurological disease) may respond to an intensive medical regimen. They require liver transplantation evaluation as back‐up. Longitudinal assessment with a prognostic scoring system may help identify those where medical therapy is likely to succeed.
• 27 Patients with WD and advanced chronic liver disease who fail to respond to or tolerate medical therapy should be considered promptly for liver transplantation.

Treatment of acute liver injury

ALI discussed here describes severe acute liver injury due to WD with coagulopathy unresponsive to vitamin K administration but without associated hepatic encephalopathy. Although these patients may fulfill the traditional liver transplantation criteria, they may respond to an intensive medical regimen as for decompensated cirrhosis (chelation combined with zinc). Use of oral chelation therapy has led to survival and improvement of liver function in select patients, especially (but not only) if their NWI score is <11.^32,63 However, liver transplantation should be considered in those presenting with ALI, especially if the NWI score is >10 and fails to decrease over time. Some patients presenting with ALI progress to ALF, and these patients require liver transplantation.

Treatment of ALF due to WD

Patients with ALF due to WD require liver transplantation, which is lifesaving because recovery with medical therapy alone is rare. Optimal medical management typically requires that liver transplantation be available to the center where the patient is treated. Treatment with oral chelators may contribute to stabilization so long as renal function is intact or renal support is being provided; however, acute hypersensitivity reactions and marrow suppression are a concern for their use if transplant is imminent. Where chelation cannot be used, zinc may be administered, despite its slow onset of action.

Aggressive medical management according to established protocols for ALF (including treatment of hyperammonemia and detection and management of cerebral edema), with early consideration of apheresis or renal replacement therapy to rapidly remove circulating copper, may stabilize the patient with WD awaiting transplantation. Plasmapheresis, plasma exchange, albumin dialysis, exchange transfusion, renal replacement therapy, molecular absorbance recirculating system (MARS), or combinations of these treatments can reduce hemolysis and help prevent renal tubular injury from copper and copper complexes until liver transplantation is possible.^64,65 In rare cases (<10% overall), the patient may respond well enough that liver transplantation is not required.^66,67 This very low rate of survival without liver transplantation highlights the importance of an expedited transplant evaluation.

Patients with ALF due to WD are appropriately afforded the highest category of priority for liver transplantation by the United Network for Organ Sharing, status 1A, and by Eurotransplant despite the recognition of the underlying chronic liver injury with advanced fibrosis in these patients.

Liver transplantation for WD

Indications

Liver transplantation is indicated for patients with WD with decompensated liver disease unresponsive to medical therapy, or ALI progressing to ALF, or ALF with the classic presentation (intravascular hemolysis, relatively low serum aminotransferases, very low serum alkaline phosphatase, progressive hepatic encephalopathy). Certain other types of patients with WD may require liver transplantation.

Patients with WD and progressive chronic liver failure must also be considered for liver transplantation. They are often older by 10–20 years than those with ALF due to WD⁶⁸ and are frequently identified with more advanced liver disease, increasing their probability of treatment failure. Others include patients in whom therapy has become ineffective, usually because of nonadherence but rarely because of intrinsic failure of drug action. These patients often present with jaundice, ascites, hepatic encephalopathy, varices, and other complications of portal hypertension. Unresectable hepatocellular carcinoma (HCC) is also an indication for liver transplant if the tumor is confined to the liver without vascular invasion according to Milan criteria and thus meets suitable criteria for transplantation.

Liver transplantation has not been recommended as primary treatment for neurologic WD because the liver disease is stabilized by medical therapy in most patients and outcomes with liver transplantation are not always beneficial. Patients with neurological or psychiatric disease due to WD had poorer outcomes and difficulties with adherence to medical regimens after liver transplantation. However, some who underwent transplantation for decompensated cirrhosis had psychiatric or neurological symptoms that improved following liver transplantation.⁶⁹ Some individuals transplanted for neurologic WD improved after liver transplantation, but detailed data on the neurological evaluations of these patients are not available. In a study with extensive characterization of severe neurological disorder in WD, mainly incapacitating dystonia or parkinsonism, liver transplantation improved neurological status in selected patients and achieved good survival; however, this was a comparatively small, uncontrolled study⁷⁰ that was insufficient to sway current recommendations. Future controlled studies are needed.

Organ donor

Most patients with WD undergoing liver transplantation in North America and Europe have received deceased donor organs; however, successful living‐donor liver transplantation is possible. Acceptable donors include nonaffected individuals or heterozygote carriers for WD.⁷¹

Outcome

Liver transplantation corrects the hepatic metabolic defects of WD and permits normalization of extrahepatic copper disposition without WD treatment. Long‐term patient and graft survivals for both adults and children continue to be excellent (ES‐Table 11).

ES‐TABLE 11 - Outcomes of liver transplantation for WD

First author, year of publication	Place	Time period	n	Population		Indication			Follow‐up, yrs	Patient survival, %			Graft survival, %
				adult	child	CLD	ALF	Neuro		1‐yr	5‐yr	10‐yr	1‐yr	5‐yr	10‐yr
Schilsky, 1994 88	USA	–	55 (62 LT)	–	–	33	21	1	2.5	79	–	–	–
Eghtesad, 199989	USA	1971–1993	45 (56 LT)	26	16	15	30	0	5	–	73	69	–	58	54
Emre, 200190	USA	1988–2000	17 (21 LT)	14	3	6	11	0	5.3	88	–	–	62	–	–
Sutcliffe, 200391	UK	1988–2000	24 (25 LT)	–	–	–			8	–	87	–	–	87	–
Wang, 200592		2001–2003	22	3	19	20	2	9	1.5	95	–	–	95	–	–
Medici, 200593	Italy	1985–2000	37 (41 LT)	–	–	8	29	0	–	–	75	60	–	70	47
Sevmis, 200894		2001–2007	24 (24 LT)	–	–	16	18	0	1.8	–	79	–	–	76	–
Cheng, 200995	China	2001–2007	36 (36 LRLT)	–	–	32	2	2	3.7	–	75	–	–	75	–
Yoshitoshi, 200996	Japan	1992–2006	32 (32 LRLT)	8	24	11	21	0	6.7	–	84	80	–	88a	83a
Arnon‐(UNOS), 201168	USA	1987–2008	570 (n/a)	400	170	–			–	–	89, ch	–	–
											86, ad
Arnon‐(UNOS), 201168	USA	2002–2008	170 (n/a)	119	51	67	103	0	–	–	100/88b, ch		–	100/82b, ch
											90/90b, ad			86/86b, ad
Guillaud, 201471	France	1985–2009	121 (140 LT)	75	46	55	59	7	6	–	87	87	–	80	79
Ferrarese, 202097	Italy	2006–2016	27 (27 LT)	27	0	24	1	2	–	–	88	83	–	88	82

Abbreviations: ad, adults; ALF, acute liver failure; ch, children; CLD, chronic liver disease; LT, liver transplant (deceased donor); LRLT, living‐related liver transplant; n/a, type not reported; neuro, neurologic WD; UK, United Kingdom; UNOS, United Network for Organ Sharing; USA, United States of America.

^aData are for ABO (blood type) compatible grafts; graft survival was 67% at 5 years and 67% at 10 years for ABO incompatible grafts.

^bResults are provided as CLD/ALF regarding indication.

Guidance statements 28–31

• 28 Patients with ALF due to WD should be referred for a liver transplant evaluation and potential liver transplantation immediately.
• 29 Patients with ALI due to WD may respond to medical therapy or may progress to ALF. They require early transplant referral and evaluation.
• 30 After liver transplantation, medical treatment specific for WD is unnecessary.
• 31 Liver failure and HCC are well‐accepted indications for liver transplantation in WD; however, neurologic WD remains a controversial indication.

Liver cancer in WD

Hepatocellular carcinoma (HCC) has been regarded as a rare complication of WD. Annual risk of HCC in patients with WD and cirrhosis was estimated as 0.14%,⁷² but HCC occurred in 7% of patients with WD in another cohort. HCC in WD may therefore be more frequent than formerly appreciated but still less frequent than in other chronic liver diseases. There is a substantial rate of intrahepatic cholangiocarcinoma (CCA) complicating WD.⁷³ Therefore, in WD, unless an apparent liver tumor meets strict radiologic criteria for HCC and cirrhosis is present, the tumor should be evaluated by biopsy. Hepatic cancer complicating WD may occur in the pediatric age‐bracket.⁷⁴

Screening and surveillance for HCC is recommended for patients with WD and cirrhosis or regressed cirrhosis and not for patients with noncirrhotic WD. Treatment of liver cancer in WD should follow standard guidelines for treatment of HCC and CCA.

Guidance statement 32

• 32 Patients with WD with cirrhosis or regressed cirrhosis should undergo screening and surveillance for HCC according to the recommended guidelines. Screening and surveillance for CCA is not indicated in WD; however, CCA should be considered in the differential diagnosis of liver tumors not meeting strict radiologic criteria for HCC.

PREGNANCY

Whenever possible, advance planning is beneficial. A multidisciplinary approach to pregnancy in WD has merit, and facilitation of communication between obstetrician and other health providers is helpful. Ideally, the patient is in good general health with clinically stable WD on therapy prior to conception. Treatment must be continued during pregnancy. Zinc is a safe option. Although d‐penicillamine (FDA category D) and trientine (FDA category C) have known teratogenic effects, limited data show safe use during pregnancy, with recommended dose reduction of approximately 50% to start during the first trimester and continued through the pregnancy to reduce possible adverse effects on the fetus and to promote postpartum wound‐healing in the mother. Monitoring of liver status by biochemical testing is recommended each trimester to assure the dose reduction for chelation has not adversely affected liver function. Switching WD treatment from an oral chelator to zinc ahead of pregnancy is an option; however, any such change must be shown to maintain the patient's good clinical condition prior to the pregnancy.

Much remains to be determined about potential abnormalities in lactation in WD. Concentrations of breast milk copper may be inadequate for the newborn's metabolic and developmental needs. Data are inconclusive as to excretion of oral chelators into breast milk. d‐Penicillamine is excreted into breast milk and has potential to harm the infant. Bioavailability of zinc in breast milk is ordinarily quite high,⁷⁵ and little is known about the effect of pharmacological doses of zinc on breast milk concentrations.^76–78

Women with WD may have increased difficulty conceiving, although stability on treatment appears to mitigate this problem.⁷⁹ Although uncommon, untreated WD is a recognized cause of recurrent spontaneous abortion. Women with liver disease presenting with repeated spontaneous abortions should be evaluated for WD. Patients with WD and decompensated cirrhosis should be counseled to avoid pregnancy because of risks to both mother and fetus. Although not mandatory, determining the partner's ATP7B genotype may identify an unsuspected heterozygote, putting the infant at risk of inheriting WD.

Guidance statements 33–35

• 33 Preconception counseling should include genetic counseling and discussion of medication safety in pregnancy and should consider the prospective mother's health.
• 34 Treatment for WD should be continued during pregnancy. d‐Penicillamine has known teratogenic potential; data for trientine are sparse. Clinical experience suggests that chelation therapy at a reduced dosage with monitoring of liver function each trimester is another option. Zinc is safe; however, if a prospective mother is switched to zinc prior to pregnancy, clinical stability on zinc should be established before the pregnancy occurs.
• 35 Breastfeeding, despite its recognized benefits, entails potential harms to the infant while a lactating mother is on treatment for WD. The pros and cons should be weighed in each case.

SYMPTOMATIC TREATMENT (NONHEPATIC)

Effective management of neurological and psychiatric manifestations of WD requires restoration of normal copper balance through medical treatment. Paradoxical neurological worsening may occur, especially if chelation is started too aggressively: it is usually transient, reflecting fluctuations in central nervous system copper, but it may be progressive. Approximately one‐third of patients with psychiatric symptoms will improve with decoppering treatment alone.⁸⁰

Treatment of neurological symptoms

Many neurological symptoms are at least partially responsive to adjunctive medical management (see ES‐Table 3). Medications to treat parkinsonism, such as carbidopa/levodopa, can be tried, but their effectiveness is variable. Treatments for dystonia can be extremely helpful but may be limited by adverse effects (trihexyphenidyl: anticholinergic effects; clonazepam: sedation; baclofen: abnormal liver tests). Focal dystonia can often be effectively treated with botulinum toxin injection that can be repeated over time. Deep brain stimulation targeting the ventral intermediate nucleus of the thalamus for tremor and the globus pallidus interna for dystonia was tried but with only variable success in a limited number of patients.⁸¹ Chorea may respond to vesicular monoamine transporter‐2 inhibitors, such as tetrabenazine, or dopamine receptor antagonists, although patients with WD may develop adverse effects from neuroleptics.⁸² A multidisciplinary approach involving speech therapy for dysarthria and dysphagia, as well as physical therapy and occupational therapy, is often helpful. Swallowing studies may identify those with dysphagia and risk of aspiration risk requiring intervention.

Treatment of psychiatric symptoms in WD

If psychiatric symptoms do not resolve with primary treatment of WD or if they are severe, psychotropic medication or psychotherapy can be utilized adjunctively. In these individuals, it is important that patients are properly evaluated by a psychiatrist and that appropriate measures for monitoring and caring for the patients' mental health are put in place. This may involve management of medical therapies or patient counseling and includes assessing the impact on families and caregivers.

Reported trials of treatments include use of psychotropic medications, such as lithium, haloperidol, tricyclic antidepressants, benzodiazepines, quetiapine, risperidone, and clozapine, as well as use of electroconvulsive therapy (ECT).¹⁶ ECT for control of acute psychosis of WD was reported for patients with extrapyramidal symptoms and psychosis. ECT may be considered for patients with WD whose symptoms are refractory to medical treatment.

Guidance statements 36–38

• 36 Effective treatment restoring normal copper balance may lead to improved neurological and psychiatric features of WD.
• 37 Adjunctive medical treatment may alleviate symptoms of neurologic WD, including parkinsonism, dystonia, and chorea.
• 38 Patients with WD with persisting or severe psychiatric features, despite adequate WD treatment, may benefit from psychotropic medications or counseling.