Enf Wilson

The n e w e ng l a n d j o u r na l of m e dic i n e
Review Article
Dan L. Longo, M.D., Editor
Current and Emerging Issues

in Wilson’s Disease
Eve A. Roberts, M.D., Ph.D., and Michael L. Schilsky, M.D.
T
From the Departments of Paediatrics, he history of Wilson’s disease reflects modern biomedical
Medicine, and Pharmacology and Toxi- progress. Samuel Kinnier Wilson’s 1912 description of “progressive lenticu-
cology, University of Toronto, and the
Hospital for Sick Children Research Insti- lar degeneration,” a lethal neurodegenerative disorder associated with inap-
tute — both in Toronto; and the History parent hepatic cirrhosis, was based on clinical and pathological observations. The
of Science and Technology Programme, disorder was subsequently renamed “hepatolenticular degeneration,” reflecting the
University of King’s College, Halifax, NS,
Canada (E.A.R.); and the Departments of importance of the hepatic component. At mid-century, advances in biochemistry
Medicine and Surgery, Yale University had established the etiologic role of copper and the diagnostic relevance of ceru-
School of Medicine, New Haven, CT loplasmin. Lifesaving medical treatment was introduced in the mid-1950s. Liver
(M.L.S.). Dr. Roberts can be contacted at
the Division of Gastroenterology, Hepa- transplantation became an option in the 1970s. Subsequent advances in genetics
tology, and Nutrition, Hospital for Sick led to the identification of ATP7B (ATPase copper transporting beta), the gene associ-
Children, 555 University Ave., Toronto, ated with Wilson’s disease. Recently devised scoring systems quantitatively describe
ON M5G 1X8, Canada.
the disorder, facilitate its diagnosis, or prognosticate the clinical outcome. Innova-
N Engl J Med 2023;389:922-38. tive diagnostic methods, treatments, and monitoring approaches are in development,
DOI: 10.1056/NEJMra1903585
Copyright © 2023 Massachusetts Medical Society.
serving as bellwethers for future biomedical advances. Comprehensive contempo-
rary reviews are available elsewhere.1-3
Cl inic a l Pr e sen tat ion

Wilson’s disease may present as liver disease, a neurologic disorder, a psychiatric
illness, or a combination of these disorders. Hepatic Wilson’s disease, which tends
to develop earlier than neuropsychiatric Wilson’s disease, ranges from mild liver
disease to cirrhosis; in children, fatty liver is common. Infrequently, Wilson’s dis-
ease manifests as acute liver failure. In patients with Wilson’s disease, neurologic
movement disorders involve either increased movement, with tremor or dystonia, or
decreased movement, resembling parkinsonian rigidity. Tremors, poor coordina-
tion, and loss of fine motor control may occur early. Dysarthria is often the first
prominent symptom. Drooling and difficulty swallowing indicate pseudobulbar
involvement. Sleep disorders and restless legs syndrome are increasingly recog-
nized. In general, cognitive function is intact; however, subtle deficits in executive
ability4,5 or integrative capabilities6 may occur. Clumsiness, loss of athletic skills,
or deterioration in school performance may be initial features in adolescents. Psy-
chiatric Wilson’s disease is highly variable, although depression is common. Bipo-
lar disorder may occur, and psychosis may develop.7,8 Anxiety disorders, including
phobias and compulsive behaviors, have been reported, as has aggressive or anti-
social behavior. Kayser–Fleischer rings are the main ophthalmologic sign. Other
manifestations include renal, cardiac, musculoskeletal, and endocrine conditions
(Fig. 1). Wilson’s disease can manifest at any age, although usually before the age of
50 years; older age does not rule it out.
922 n engl j med 389;10 nejm.org September 7, 2023
The New England Journal of Medicine

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Copyright © 2023 Massachusetts Medical Society. All rights reserved.
Current and Emerging Issues in Wilson’s Disease
Neurologic features:
Eyes
Dysarthria, tremor, dystonia,
Kayser–Fleischer rings, sunflower
and athetosis
cataracts
Psychiatric disorders
Pituitary gland
Panhypopituitarism
Parathyroid glands
Hypoparathyroidism
Heart Muscle
Arrhythmias, cardiomyopathy Rhabdomyolysis,
Duchenne’s muscular
dystrophy–like weakness
Liver
Steatosis, hepatitis, cirrhosis,
and ALF-WD Pancreas
Pancreatitis
Kidneys
Renal tubular dysfunction,
aminoaciduria
Reproductive system
Amenorrhea, infertility
Bones
Osteopenia, osteoporosis
Reproductive system
Deformity: osteomuscular Testicular dysfunction
condition
Erythrocytes
Hemolysis
Joints
Arthritis
Figure 1. Clinical Manifestations of Wilson’s Disease.

Wilson’s disease may have manifestations apart from typical hepatic and neuropsychiatric features. The salmon-colored boxes indicate
features that may be present initially or develop despite treatment. Acute liver failure due to Wilson’s disease is more common in wom-
en than in men (female to male ratio, 2–4:1). Sunflower cataracts are radiating, multicolored central opacities in the lens. Tremor in neu-
rologic Wilson’s disease can range from a fine tremor of the hands to tremor involving the head to the characteristic “wing beating”
tremor. ALF-WD denotes acute liver failure due to Wilson’s disease. The photograph of the Kayser–Fleischer ring on slit-lamp examina-
tion is courtesy of Jeffrey G. Odel, M.D., from the Edward S. Harkness Eye Institute, Columbia University Irving Medical Center, and the
photomicrograph of liver histologic findings showing mild steatosis in Wilson’s disease (hematoxylin and eosin staining) is courtesy of
Dhanpat Jain, M.D., from the Department of Pathology, Yale University.
n engl j med 389;10 nejm.org September 7, 2023 923

A Cu2+ Intracellular Copper Adequacy

Cu+
Holo-ceruloplasmin
Reductase CTR1 Hepatocyte
Cu+
Nucleus
Trans-Golgi
CCS network
ATOX1 Apical
COX17 membrane
SOD1
Glutathione ATP7B MRP2
Mitochondrion Metallothionein
B Cu2+Cu2+ Intracellular Copper Excess

Cu+
Holo-ceruloplasmin
Cu+
Nucleus
Trans-Golgi
CCS network
ATOX1 Apical
COX17 membrane
SOD1
Glutathione ATP7B MRP2
C Cu2+ Wilson's Disease

Cu+
Apo-ceruloplasmin
Cu+ Nucleus
Trans-Golgi Fat droplets

CCS ↓LXR–RXR network
ATOX1 Apical
COX17 membrane
SOD1
MRP2
Glutathione
Patho gene sis a nd Gene t ic s disease.9,10 The gene product ATP7B is a multi-
functional, intracellular P1-type ATPase, found
ATP7B, on chromosome 13q14, is the only gene mainly in the liver. In hepatocytes, ATP7B expe-
with mutations that are associated with Wilson’s dites biliary copper excretion when intracellular

Figure 2 (facing page). Hepatocellular Disposition of copper levels are elevated (Fig. 2). In addition,
Copper in Healthy Persons and in Those with Wilson’s ATP7B transports copper into the Golgi appara-
Disease. tus for incorporation into apo-ceruloplasmin,
As shown in Panel A, under conditions of intracellular producing the ferroxidase holo-ceruloplasmin, a
copper adequacy, copper is taken up from the portal metalloprotein containing most of the copper in
circulation, where it is loosely attached to albumin and
the circulation under physiologic conditions. In
other molecules, by interacting with one or more re-
ductases and CTR1 (copper transporter 1) on the hepa- Wilson’s disease, functional ATP7B is decreased
tocellular membrane. CTR2 (copper transporter 2), not or absent, and excessive copper accumulates in
shown, is also involved in copper disposition, but its hepatocytes. Serum copper levels are low because
actions are not fully understood. Copper is not “free” of decreased holo-ceruloplasmin levels. As copper-
within the hepatocyte: metallochaperones direct it to
induced liver injury progresses, extrahepatic sites
targets (CCS [copper chaperone for superoxide dis-
mutase] to SOD1 [superoxide dismutase type 1], COX17 — notably, the central nervous system — are
(cytochrome c oxidase copper chaperone) to mitochon- affected. Animal models of Wilson’s disease in-
dria, and ATOX1 [antioxidant 1 copper chaperone] to clude the toxic milk mouse, the Atp7b−/− mouse,
ATP7B [ATPase copper transporting beta] in the trans- and the Long–Evans Cinnamon rat and its related
Golgi network), or it may interact with glutathione,
LPP rat.
which is abundant in the cytoplasm. Other mecha-
nisms besides COX17 appear to contribute to mito- Numerous ATP7B variants have been identified,
chondrial uptake of copper. The disposition of copper including approximately 600 pathogenic vari-
within mitochondria is complicated, governed by variants.11 The most common gene alterations are
ous transporters, metallochaperones, and accessory missense mutations, deletions, and insertions,
proteins. Some copper is sequestered in metallothio-
occurring in nearly all 21 exons of ATP7B. Most
nein. ATP7B mainly expedites the transfer of copper in
nascent holo-ceruloplasmin, which is secreted into the persons with Wilson’s disease are compound
plasma compartment but also contributes to biliary ex- heterozygotes. Determining the pathogenicity of
cretion of copper. As shown in Panel B, under condi- any given gene alteration or, with compound
tions of intracellular copper excess, CTR1 function is heterozygosity, the functional effect of paired
reversibly decreased, and ATP7B migrates from the
different mutations, is difficult. Pathogenic mu-
trans-Golgi network in vesicles of the endosomal–
lysosomal compartment and directly promotes biliary tations typically cause nonproduction of ATP7B,
excretion of copper, which may also be excreted as cop- misfolded ATP7B that is subject to degradation,
per–glutathione through MRP2 (multidrug resistance– or messenger RNA dysfunction, but some muta-
associated protein 2, also called cMOAT [canalicular tions result in structurally normal yet nonfunc-
multispecific organic anion transporter 1]). ATP7B thus
tional ATP7B.11 No convincing genotype–pheno-
appears to have a sensing capability for intracellular
copper levels. As shown in Panel C, in Wilson’s dis- type correlation has been found. Variants that
ease, functional ATP7B is absent. Copper is taken up do not produce any ATP7B or that produce non-
from the portal circulation. A condition of extreme in- functional ATP7B may cause earlier, more severe
tracellular copper excess develops, shown here at an liver disease.12,13 The role of epigenetic factors is
early-to-intermediate stage of development. CTR1 func-
being investigated.14
tion is substantially reduced, in part reflecting de-
creased CTR1 expression. Metallothionein is induced Wilson’s disease occurs worldwide, with an
and binds copper, until saturated, in the cytoplasm. estimated prevalence of approximately 30 cases
Copper is transiently taken up into the nucleus, leading per 1 million population.15,16 Some data suggest
to its enlargement and altered gene expression. Lipid a higher allelic prevalence,17-19 raising the possi-
metabolism is disturbed, giving rise to fat droplets.
bility of variable penetrance. The predominant
Decreased expression or action of the liver X receptor–
retinoid X receptor (LXR–RXR) complex may contribute pathogenic variant in northern European popu-
to abnormal lipid metabolism and the cellular inflam- lations is p.H1069Q.20 Some geographically iso-
matory response. Mitochondria become overloaded lated populations have limited sets of ATP7B mu-
with copper and structurally damaged; COX17 is not tations.16 Molecular genetic evaluation can be an
down-regulated. ATP7B-mediated biliary excretion of
efficient strategy for diagnosing Wilson’s disease
copper is absent. The MRP2 pathway only partially
compensates. Copper is not incorporated into nascent in such populations or in pedigrees for which the
ceruloplasmin; thus, apo-ceruloplasmin is secreted into proband’s genotype is known. ATP7B analysis
the circulation, where it has a shorter half-life than holo- helps in distinguishing Wilson’s disease from
ceruloplasmin. Over time, some copper–metallothio- other genetic and metabolic disorders. In general,
nein aggregates are taken up by lysosomes, in which
analysis of the entire gene and its promoter re-
copper is detectable histochemically.
gion is preferred, with attention to intron–exon

boundaries and the possibility, although rare, of out other diagnoses. The Unified Wilson’s Dis-
large deletions. ease Rating Scale (UWDRS)25 and the Global As-
Given the evidence of possible variable pene- sessment Scale for Wilson’s Disease26 (both de-
trance in Wilson’s disease,16,20 differentiating scribed in the Supplementary Appendix, available
genetic Wilson’s disease — the isolated finding with the full text of this article at NEJM.org) are
of a genotype that is consistent with the disease descriptive neurologic scoring systems for stan-
— from asymptomatic Wilson’s disease associ- dardizing neurologic findings in patients with
ated with organ damage is particularly impor- Wilson’s disease. Identifying and characterizing
tant because this distinction influences treat- ATP7B mutations may aid in the diagnosis. A geno-
ment. This issue poses challenges for managing type with two ATP7B pathogenic variants (in trans)
cases of Wilson’s disease that are identified by is compelling evidence of Wilson’s disease.
means of general population screening or newborn
screening. Emerging Di agnos t ic
A pproache s
Cl inic a l Di agnosis
New diagnostic strategies are in development. One
The clinical diagnosis of Wilson’s disease involves candidate approach involves determining the rela-
a detailed medical history taking and physical tive exchangeable copper (REC). The REC is the
examination focused on liver, neurologic, and ratio of circulating exchangeable copper (CuEXC),
psychiatric disease. Laboratory assessment in- representing bioavailable copper not bound with-
cludes liver biochemical and serum ceruloplasmin in ceruloplasmin, to total serum copper. In pa-
levels and basal 24-hour urinary copper excretion. tients with Wilson’s disease, the REC exceeds
The serum ceruloplasmin level alone is not ad- 18.5%.27,28 More extensive validation of the REC
equate for diagnosis, although a very low level as a diagnostic tool is needed, including critical
(<5 mg per deciliter) strongly suggests Wilson’s assessment of CuEXC measurement.
disease. Ceruloplasmin levels of less than 14 mg A novel approach to diagnosis involves pro-
per deciliter in one study (from Hong Kong)21 teomics-based methods developed initially for
and less than 11.5 mg per deciliter in another newborn screening. Selected ATP7B peptides
study (from Spain)22 were identified as diagnostic were quantified in proteolyzed dried blood spots
cutoff points. The ceruloplasmin level can be by combining immunocapture involving mono-
normal in Wilson’s disease, although a normal clonal antibodies to ATP7B with targeted mass
value is uncommon. Basal 24-hour urinary copper spectroscopy involving multiple reaction moni-
excretion is typically more than 40 μg, with higher toring. Levels of recovered ATP7B peptide were
values in symptomatic patients. lower in patients with Wilson’s disease than in
Kayser–Fleischer rings, due to corneal copper controls.11,29 Further validation of initial diagnos-
deposition in Descemet’s membrane, are visual- tic cutoff points was largely successful in distin-
ized by means of slit-lamp examination or opti- guishing patients from carriers and unaffected
cal tomography. The rings are often absent in controls. This technology may be useful for inter-
younger patients and are also absent in 50% of preting the functional effect of ATP7B variants of
patients with hepatic Wilson’s disease. Liver biopsy unknown significance.
for histologic examination and copper quantifica- Another diagnostic approach uses positron
tion establishes the degree of liver damage and emission tomography (PET) to quantify copper
rules out competing diagnoses. Metallothionein incorporation into ceruloplasmin, which was
immunohistochemical staining may be informa- previously evaluated with plasma ratios.30 Recent
tive.23 The hepatic parenchymal copper level is studies in humans with the use of 64Cu PET ex-
classically more than 250 μg per gram of dry amined differences between oral and intravenous
weight, but values exceeding 70 μg per gram war- administration of radiocopper, especially with re-
rant further investigation. spect to the effect on copper distribution in or-
In many patients with Wilson’s disease and gans.31,32 In addition to distinguishing among
neurologic findings, brain magnetic resonance patients with Wilson’s disease, simple heterozy-
imaging (MRI) identifies structural abnormali- gotes, and unaffected persons, this technology
ties in the basal ganglia and elsewhere,24 ruling could be used to evaluate the efficacy of cell trans-

plantation or gene therapy for the treatment of nosis. These disorders include autoimmune hep-
Wilson’s disease.33 atitis and metabolic dysfunction–associated
steatotic liver disease, both of which are prob-
lematic, especially in children. Genetic disorders
Di agnos t ic Sc or ing S ys tems
with a clinical presentation that can resemble
Leipzig Score hepatic Wilson’s disease include MDR3 deficiency
The Leipzig score, devised in 2001, is based on and various congenital disorders of glycosylation.
clinical and laboratory findings, including the Since the Leipzig score may not distinguish MDR3
ATP7B genotype.34 It was validated in adults and deficiency from Wilson’s disease,42,43 genetic test-
children35,36 and critiqued, leading to a minor ing is required. Aceruloplasminemia may re-
modification.37 A more extensive modification semble neurologic Wilson’s disease clinically but
has been developed specifically for children,38 is characterized by a normal level of copper in the
with the exclusion of some components, includ- liver; genetic testing is definitive.
ing ATP7B analysis, which may be unavailable, de- Recently, disorders that mimic Wilson’s disease
laying the diagnosis. A novel measure — a triad of mechanistically have been identified (Table 1).
a low-for-age serum alkaline phosphatase level, a These very rare disorders, which share pathogenic
serum zinc level of less than 11 μmol per liter, and cellular mechanisms with Wilson’s disease, occur
a ratio of aspartate aminotransferase to alanine primarily in children. They somewhat resemble
aminotransferase of 2 or higher — was substi- Wilson’s disease and warrant diagnostic consid-
tuted. Initial validation looked promising. False eration in the right clinical setting.44-47 However,
positive Leipzig scores have been encountered one of these disorders, the Huppke–Brendel syn-
with some disorders that mimic Wilson’s disease. drome, was misdiagnosed as Wilson’s disease in
an adult.48
Diagnosis of Acute Liver Failure
Due to Wilson’s Disease
Scr eening of Fir s t-Degr ee
Acute liver failure due to Wilson’s disease is typi- R el at i v e s
cally characterized by distinctive clinical findings:
severe coagulopathy and hepatic encephalopathy, Accurate and timely diagnosis of Wilson’s dis-
acute intravascular hemolysis, moderate elevations ease is important for the first-degree relatives of
of serum aminotransferase levels, normal or sub- an affected person. Screening of all first-degree
normal serum alkaline phosphatase levels, and relatives, not just siblings, is mandatory. Identi-
progression to renal failure. Acute liver failure fying other persons with Wilson’s disease in the
may be the first manifestation of Wilson disease, pedigree positions them for the most favorable
despite established underlying chronic liver dam- treatment outcomes.49-51 The assessment may be
age. Analysis of data from the multicenter Acute based on the ATP7B genotype analysis, a com-
Liver Failure Study Group showed that a combi- prehensive clinical and biochemical evaluation,
nation of two ratios (a ratio of alkaline phospha- or both.3
tase to total bilirubin of <4 and a ratio of aspartate
aminotransferase to alanine aminotransferase of Pro gnosis
>2.2) was 100% sensitive and specific for diag-
nosing Wilson’s disease in the study cohort.39 Clinically evident Wilson’s disease is relentlessly
Further validation of these ratios is in progress. progressive and ultimately fatal, if untreated. With
Two studies indicate that the combined ratios consistent, effective medical treatment, however,
may not work well for diagnosing acute liver the longevity of patients with Wilson’s disease is
failure due to Wilson’s disease in children and close to that of the general population.51-53 This
adolescents.40,41 “treated natural history” is very favorable but is
dependent on treatment adherence and numerous
social factors, including political and socioeco-
Disor der s Th at Mimic
W il son’s Dise a se nomic stability and medication that is available
and affordable. Both hepatocellular carcinoma
Several disorders resemble Wilson’s disease close- and cholangiocarcinoma can develop, but the risk
ly enough to be included in the differential diag- is lower among patients with Wilson’s disease

928
Table 1. Rare Genetic Diseases Mimicking Wilson’s Disease.*
Basal 24-hr Hepatic Hepatic

Serum Urinary Parenchymal Histologic
Disorder Gene Clinical Features Onset Ceruloplasmin Copper Copper Assessment
Clinical mimics
The
Aceruloplasminemia CP Neurologic disorder, iron accu- Adulthood Absent Normal Normal Iron overload
mulation in liver
MDR3 deficiency (progressive ABCB4 Cholestatic liver disease, normal Childhood; less Normal Increased May be in- Cholestasis
familial intrahepatic biliary system, possible jaun- often, adult- creased
cholestasis type 3) dice and gallstones, cholesta- hood
sis of pregnancy
n engl j med 389;10

Mechanistic mimics
MEDNIK syndrome AP1S1 Neurologic disorder with intellec- Childhood Very low Increased Increased Chronic injury, cir-
tual disability, deafness, pe- rhosis
ripheral neuropathy; hepatic
nejm.org
copper retention
n e w e ng l a n d j o u r na l
MEDNIK-like syndrome AP1B1 Similar to MEDNIK but with no Childhood Low NA Normal NA

of
apparent hepatic damage

Hypermanganesemia with
dystonia
September 7, 2023
Type 1 SLC30A10 Parkinsonian movement dis- Childhood; less Normal Normal Normal or Cirrhosis, fatty liver,
order; fatty liver, cirrhosis; often, adult- mildly in- some stainable

m e dic i n e
polycythemia; severe hyper- hood creased copper

manganesemia
Type 2 SLC39A14 Developmental delay; progres- Infancy, toddler- Normal NA Normal No hepatic involve-
sive dystonia and bulbar hood, or child- ment
dysfunction; parkinsonian hood
features
Niemann–Pick type C NPC1, Neurologic disorder: dysarthria, Childhood or Low or slightly Normal or possi- May be mod- Possible fatty liver
NPC2 ataxia; oculomotor abnor- young adult- low bly increased erately
malities hood increased
Basal 24-hr Hepatic Hepatic
Serum Urinary Parenchymal Histologic
Disorder Gene Clinical Features Onset Ceruloplasmin Copper Copper Assessment
Both clinical and mechanistic
mimics
PGM1-CDG PGM1 Systemic form: hepatopathy, Childhood or Low Normal NA Steatosis, cholesta-
bifid uvula (with or without adulthood sis; possible
cleft palate and with or with- slight fibrosis
out Pierre Robin sequence),
growth retardation, rhab-
domyolysis, hypoglycemia,
dilated cardiomyopathy
CCDC115-CDG CCDC115 Hepatosplenomegaly; psycho- Childhood or Low or very low Normal or mildly May be mildly Steatosis, fibrosis,
motor disability, hypotonia, adulthood increased increased necrosis; pro-
or both; dysmorphism; hy- gressive choles-
percholesterolemia; possible tatic liver disease
liver failure
TMEM119-CDG TMEM119 Mild hepatopathy, hypercholes- Childhood or Low Normal Normal or Steatosis, mild fi-
terolemia adulthood mildly in- brosis; abnormal
creased mitochondria
(fragmented cris-
n engl j med 389;10

tae) possible
COG2-CDG COG2 Mild hepatopathy; developmental Infancy Low NA NA NA
delay, microcephaly, spastic
quadriplegia
nejm.org
Unclassified mimic
Huppke–Brendel syndrome SLC33A1 Congenital cataracts, hearing Childhood; adult- Low or very low Increased† Normal† Normal
loss, developmental delay, hood (rare)
cerebellar hypoplasia

* Data are from Schilsky et al.3 CDG denotes congenital disorder of glycosylation; MEDNIK intellectual (mental) disability, enteropathy, deafness, neuropathy, ichthyosis, and keratoder-
September 7, 2023
ma; NA not available; and PGM1 phosphoglucomutase 1.
† This information is based on one case in an adult. Data are not available for these values in children.

929
than among those with other chronic liver dis- hydrochloride) remain the principal treatments
eases.54,55 (Tables 2 and 3). The recently approved tetrahy-
Prognostic scoring systems attempt to identify drochloride version of trientine, which was shown
patients who are seriously ill with hepatic Wilson’s to be noninferior to penicillamine,59 is stable at
disease and are not likely to have an adequate ambient temperatures. Zinc salts are effective as
response to medical treatment. The New Wilson maintenance therapy. Extensive European expe-
Index (NWI), which includes measures of hepatic rience indicates that zinc can serve as primary
damage and inflammatory response, replaced the therapy; however, it may not always be effective
Nazer score. The NWI, validated in adults and for hepatic Wilson’s disease in the long term.60
children, has some unreliability at the break- Neurologic worsening may occur when any of
point (i.e., scores near or straddling the dividing these drugs (most notably, penicillamine) is start-
line between favorable and unfavorable outcomes ed. Thus, the starting dose of oral chelators is
[survival vs. liver transplantation or death]). It low and gradually increased.
may be most informative when applied serially. Once the diagnosis of Wilson’s disease is es-
Similar scores that have been developed more tablished, lifelong medical therapy should begin,
recently40,56 require broader validation. Currently, preferably with a chelator in symptomatic patients.
none of the prognostic scoring systems are vali- Asymptomatic patients with evidence of organ
dated for neurologic or psychiatric Wilson’s damage on imaging studies, histologic assess-
disease. Standard MRI cannot be used to predict ment, or biochemical tests should also be treated
the outcomes with treatment, although larger with chelation. Those without evidence of organ
destructive brain lesions typically carry a worse damage can be treated with lower-dose chelation
prognosis. Preliminary data suggest that quanti- therapy or zinc. When to initiate treatment in
tative analytic techniques may reveal prognostic children younger than 3 years of age (and what
information in patients with neurologic Wilson’s treatment to choose) remains unclear.61 Treat-
disease.24 Scoring systems such as the UWDRS ment should be individualized according to the
can help document clinically detectable neuro- degree of organ damage, but the need for adequate
logic deficits. Serial application of these scoring copper availability in early development must be
systems may define the disease trajectory. considered. Wilson’s disease cannot be treated suc-
Functional MRI (fMRI), which measures cessfully by dietary modification alone. Copper-
changes in connectivity within the brain, has rich foods should be avoided. Supervision by a
prognostic potential for patients with neurologic registered dietitian is valuable for patients with
Wilson’s disease. A pilot study comparing 30 pa- Wilson’s disease who are on restricted diets, such
tients who had neurologic Wilson’s disease with as vegetarians.
appropriate controls showed structural and func-
tional changes on MRI and fMRI, irrespective of Orthotopic Liver Transplantation
the clinical neurologic manifestations of the dis- Most patients with Wilson’s disease can be treat-
ease.57 The findings were diverse and included ed medically; however, liver transplantation can be
thinning in the bilateral prefrontal cortex. Struc- lifesaving. It should be reserved for patients with
tural changes, including altered functional con- acute liver failure or decompensated chronic liver
nectivity, were more extensive and numerous in disease who do not have a response to medical
patients with neurologic Wilson’s disease (as de- treatment. Neurologic Wilson’s disease as the
fined by an abnormal UWDRS score) than in primary indication for transplantation remains
those with isolated hepatic disease. Longitudinal controversial. Unaffected (simple) heterozygotes
fMRI data may reveal more about the prognosis may serve as living donors for segmental liver
and response to treatment. transplantation. Outcomes with respect to patient
and graft survival are excellent.3
Cur r en t T r e atmen t
T r e atmen t Moni t or ing
Medical Therapy
The advent of oral chelators revolutionized treat- Establishing clear treatment targets, along with
ment for Wilson’s disease: both penicillamine criteria for insufficient treatment and overtreat-
(provided as D-penicillamine) and trientine (di- ment, is critical. Treatment monitoring is based

on clinical evaluation, along with liver biochem- represent improvements in existing pharmaco-
ical testing and measurement of 24-hour urinary therapies. Treating concurrent hepatic disorders
copper excretion (Table 2). New elevations in also improves clinical outcomes.
serum aminotransferase levels are often the ear-
liest signal of treatment failure. When treatment New Chelators
is initiated or modified or when symptoms are Tetrathiomolybdate (TTM) is a well-known cop-
highly variable, monitoring is performed more per-specific chelator with very high affinity for
frequently and is individualized on the basis of binding copper (approximately 10−19 kD). The
symptom severity or disease complications. Sub- bis-choline salt, which is more stable than am-
sequently, during maintenance therapy, clinical monium-TTM, appeared to be effective in mobi-
examination and biochemical monitoring are used lizing tissue copper in Wilson’s disease,65 but its
to verify ongoing clinical stability and detect any further development was recently discontinued.
treatment failure, including that from nonadher- Methanobactin, a peptide produced by the
ence or concurrent disease. bacterium Methylosinus trichosporium OB3b, binds
New monitoring methods focus on accurate copper with very high affinity (10−19-21 kD).66 Ad-
assessment of a patient’s copper status during ministration of methanobactin to LPP rats during
treatment. Non–ceruloplasmin-bound copper, the the phase of acute liver injury decreased hepatic
bioavailable fraction of circulating copper loose- copper and increased biliary excretion of copper,
ly associated with albumin, histidine, and vari- thus halting the process and lessening hepatic
ous proteins, is used for cellular uptake and for mitochondrial injury.67 Another study in LPP rats
renal excretion. Bioavailable copper plays an im- showed that methanobactin attenuated the cumu-
portant role in the pathogenesis of extrahepatic lative oxidative injury from diet-induced hepatic
Wilson’s disease. However, measuring it is diffi- steatosis, added to copper-induced injury.68 These
cult. The calculated estimate, although previously findings underscore the importance of hepatic
promoted for monitoring, is notoriously unreli- mitochondria in Wilson’s disease and show the
able and has never been validated as a diagnostic convergence of copper-induced mitochondrial oxi-
test.30,62 With inadequate or failed treatment of dative injury with other cytotoxic processes.
Wilson’s disease, non–ceruloplasmin-bound cop-
per is increased. Monitoring of non–ceruloplas- Restoration of ATP7B Function
min-bound copper and urinary copper excretion Restoring or improving ATP7B transport func-
in patients receiving chelation or zinc therapy tion is a goal for both repurposed older therapeu-
should reflect the adequacy of treatment and even tics and new therapeutics that have been tested
predict overtreatment. Recent studies have focusedonly in vitro. Curcumin was used in vitro to res-
on accurate measurement of non–ceruloplasmin- cue the subcellular localization of the misfolded
bound copper with the use of chromatographic gene products such as p.R778L and several other
protein speciation and inductively coupled plas- ATP7B mutants.69,70 Some molecules — namely,
ma–mass spectrometry.63,64 Such an assay for inhibitors of stress kinases p38 and JNK, which
non–ceruloplasmin-bound copper was used as a are currently in development — restore the intra-
primary end point in a recent clinical trial,59 but
cellular trafficking of mutated ATP7B. In these
it requires validation for broader use in guiding cell models, the mutated ATP7B protein is con-
therapy. fined to the endoplasmic reticulum; the pharma-
cologic effect involves inhibiting some degrada-
tion pathways of the endoplasmic reticulum.71
Emerging T r e atmen t s
Only specific mutations would be susceptible to
Emerging treatments include new chelators and such rehabilitation; eligible mutations include
novel interventions aimed at curing Wilson’s dis- p.H1069Q and p.R778L.
ease by rehabilitating the abnormal ATP7B or
correcting the genetic abnormality (Table 3). The Amelioration of Copper-Induced Hepatic
objective of curative therapy is to make pharma- Injury
cotherapy and dietary restriction unnecessary. Reducing copper-induced cellular injury is an-
Some emerging treatments may serve as adjunc- other option for augmenting treatment in patients
tive therapy to existing treatments, and others with Wilson’s disease. In Atp7b−/− mice, activa-

932
Table 2. Current Drug Therapy for Wilson’s Disease.*
Metallothionein Inducer to Inhibit Intestinal

Absorption and Promote Fecal Excretion of
Variable General Chelators to Increase Renal Excretion of Copper Copper
Penicillamine Trientine (Dihydrochloride) Elemental Zinc

Dosage† Initial dose: 15–20 mg/kg/day (maximum, Initial dose: 15–20 mg/kg/day (maximum, Initial dose: 50 mg thrice daily; maintenance
2000 mg/day) in 2–4 divided doses; 2000 mg/day) in 2–3 divided doses; dose: 50 mg thrice daily
maintenance dose: 10–15 mg/kg/day maintenance dose: 10–15 mg/kg/day in
The
in 2 divided doses (total dose, approxi- 2 divided doses

mately 750–1000 mg/day)
Consequences of initiation of treatment Urinary copper increases; paradoxical neuro- Urinary copper increases; paradoxical neuro- Urinary copper stays the same, then de-
logic worsening in 10–20% of patients logic worsening in 10–20% of patients creases; paradoxical neurologic worsen-
ing uncommon
Adverse effects Early: fever, rash, proteinuria, lupus-like Gastritis, aplastic anemia (rare), sideroblas- Gastritis, biochemical pancreatitis, zinc
reaction; over time: aplastic anemia, leu- tic anemia, colitis, hepatotoxicity (rare) accumulation, possible changes in im-
n engl j med 389;10

kopenia, thrombocytopenia, nephrotic mune function
syndrome, degenerative changes in skin,
elastosis perforans serpiginosa, serous
retinitis, colitis, hepatotoxicity
nejm.org
Target for monitoring during treatment: Approximately 200–500 μg/24 hr (3–8 Approximately 150–500 μg/24 hr (2.4–8.0 <100 μg/24 hr (<1.6 μmol/24 hr)
n e w e ng l a n d j o u r na l
urinary copper excretion μmol/24 hr) μmol/24 hr)

of
General considerations Should be taken apart from food intake; Dose is for the conventional dihydrochloride Specific salt does not affect efficacy but may
start at 5–10 mg/kg/day and increase formulation (tetrahydrochloride formu- affect tolerability; should not be taken
gradually over 2–4 wk to full initial dose; lation pending); should be taken apart with food; thrice-daily dosing preferred;
routinely given with oral pyridoxine (25– from food intake; start at 5–10 mg/kg/ twice-daily dosing is minimal effective
September 7, 2023
50 mg/day); temporarily decrease dose day and increase gradually over 2–4 wk dose; once-daily dosing is ineffective; no

by 25–50% for pregnancy or surgery to to full initial dose; temporarily decrease dose reduction for pregnancy or surgery;
m e dic i n e
avoid interference with wound healing dose by 25–50% for pregnancy or sur- indicators of adherence: urinary zinc
gery to avoid interference with wound excretion >2 mg/24 hr with typical adult
healing; may also inhibit intestinal ab- dosage; serum zinc level >125 μg/dl
sorption of copper
Signs of treatment failure with long-term
therapy‡
Urinary copper excretion >500 μg/24 hr (previously within target >500 μg/24 hr (previously within target >100 μg/24 hr (previously within or close to
range)§ range)§ target range)
AST and ALT Elevated (previously improved or failing to Elevated (previously improved or failing to Elevated (previously improved or failing to
improve from start of treatment) improve from start of treatment) improve from start of treatment)
tion of the liver X receptor–retinoid X receptor
per kilogram per day in 2 to 4 divided doses; trientine — start at 5 to 10 mg per kilogram per day, gradually increasing over 2 to 4 weeks to 20 mg per kilogram per day in 2 to 4 divided dos-
ineffective treatment, 24-hour urinary copper excretion increases gradually over time and exceeds the target range. Reinstitution of an oral chelator will yield a sizable increase in urinary
es (>20 mg/kg/day associated with adverse effects); zinc — 25 mg thrice daily, except that in small children, the dose is 25 mg twice daily (dose for infants not determined). Teenagers
§ The 24-hour urinary copper excretion may initially drop below the achieved target range because of loss of cupriuresis, reflecting drug failure or nonadherence. With the continuation of
Metallothionein Inducer to Inhibit Intestinal
Absorption and Promote Fecal Excretion of
Sideroblastic anemia; leukopenia; iron accu-
† Doses shown are for adults. Dosing in children is as follows: penicillamine — start at 5 to 10 mg per kilogram of body weight per day, gradually increasing over 2 to 4 weeks to 20 mg
complex by the liver X receptor agonist T0901317
mulation; in rare cases, new neurologic

decreased markers of liver fibrosis and inflam-
matory cytokines, improving liver function, lipid
profiles, and liver histologic features.72 It may be
features of copper deficiency

Elemental Zinc
<20 μg/24 hr
possible to reduce inflammation and injury by

Copper
Very low
targeting other cellular pathways involved in the

injury response to copper. Copper-induced down-
regulation of nuclear receptor farnesoid X recep-
tor and retinoid X receptor function was reversed
by zinc treatment in Atp7b−/− mice.73
Gene Therapy and Gene Repair

Advances in molecular genetics and gene therapy
Sideroblastic anemia, leukopenia, iron accu-
give hope that a cure for Wilson’s disease is pos-

sible. Liver transplantation provided the proof of

Trientine (Dihydrochloride)
principle that targeting the liver alone will re-

store normal copper balance. Preclinical studies

<100 μg/24 hr
using viral vectors with modified ATP7B constructs

General Chelators to Increase Renal Excretion of Copper
Very low
in rodent models of Wilson’s disease showed

restoration of copper balance and prevention of
copper-induced hepatic injury. Naturally hepato-
* Data are from Schilsky et al.3 ALT denotes alanine aminotransferase, and AST aspartate aminotransferase.
tropic viral vectors, such as lentivirus, allow direct

targeting of liver cells and provide the opportu-
copper excretion, whereas initiation of zinc therapy will lead to decreased urinary excretion of copper.
nity for a one-time treatment. However, current

experience with lentiviral gene delivery is limit-
ed. Concerns persist about the potential for off-
Sideroblastic anemia, leukopenia, iron accu-
target DNA integration of introduced DNA. Use

‡ Treatment failure may be due to nonadherence, drug failure, or intercurrent liver injury.
of adeno-associated virus for extrachromosomal

delivery of DNA was initially limited by the size
of the DNA that could be packaged. However,

Penicillamine
<100 μg/24 hr
smaller yet functional ATP7B constructs74 have

Very low
been created and can now be used for Wilson’s

disease. Successful hepatocyte transfection and
correction of the metabolic defect in rodent mod-
els, as defined by prolonged survival, improved
histologic features, and decreased hepatic cop-
per levels, was shown independently by various
groups.74-76
Unresolved questions for the use of this
Serum ceruloplasmin level as compared
therapy in humans are dosing, which is depen-

Signs of overtreatment with long-term
dent on vector packaging and transfection effi-

ciency, and the duration of transgene expression.
can take the adult dose for zinc.
It is not yet known whether barriers to use in

Urinary copper excretion
patients with prior exposure to specific serotypes

with baseline level
— notably, patients with neutralizing antibodies

that can block uptake — can be overcome so that
Other features
the therapy could be administered repeatedly.

therapy
Phase 1 and 2 studies using adeno-associated

virus vectors for Wilson’s disease are ongoing
Variable
(ClinicalTrials.gov numbers, NCT04884815 and

NCT04537377).

Table 3. Status of Current and Future Therapies for Wilson’s Disease.*
Therapy Status Comments

Medical therapy
Chelators: penicillamine, trientine, zinc (acetate, gluco- Available Lifelong administration required; reversal of
nate, sulfate, or another salt); temperature-stable liver damage can occur over time
trientine
New chelators
Bis-choline TTM Development discontinued Lifelong administration required
Methanobactin In development May be suitable for intermittent therapy; ca-
pable of decreasing hepatic parenchymal
copper through biliary excretion
Pharmacologic rehabilitation of mutated ATP7B In development
Augmentation of cell-protective responses In development
Liver transplantation
Deceased donor; living donor (segmental transplanta- Available Copper metabolism restored to normal; re-
tion) quires lifelong immunosuppression with
its potential complications; donor may be
simple heterozygote (one ATP7B muta-
tion)
Auxiliary transplantation Available Developed for patients with acute liver failure;
limited immunosuppression may be pos-
sible
Transplantation of hepatocytes from unaffected person In development Requires lifelong immunosuppression; may
require cells from more than one donor;
may need to be repeated if cell survival not
adequate or if cell population does not ex-
pand; safe techniques for selective expan-
sion of the population of donor cells must
be developed
Hepatocyte transplantation plus gene repair (through
CRISPR technology) or gene replacement
Patient’s induced pluripotent stem cells treated to re- In development Lifelong immunosuppression probably not
pair ATP7B mutation or replace with wild-type needed; safe techniques for selective ex-
ATP7B, then transformed into hepatocytes and pansion of the population of repaired cells
reintroduced must be developed
Patient’s hepatocytes reprogrammed into liver progeni- In development Lifelong immunosuppression probably not
tor cells, treated to repair ATP7B mutation or needed; safe techniques for selective ex-
replace with wild-type ATP7B, then transformed pansion of the population of repaired cells
into hepatocytes and reintroduced must be developed
Gene replacement: wild-type ATP7B expressed in patient’s In development Transfection of all hepatocytes probably not
hepatocytes after being introduced in vivo necessary, but high transfection rate desir-
able; safety of integrating delivery virus
into recipient’s genome not clear; potential
for development of antibodies to viral or
transfected proteins in recipient; unknown
whether multiple transfections will be
required
* Data are from Schilsky.58 CRISPR denotes clustered regularly interspaced short palindromic repeats, and TTM tetrathiomolybdate.
Gene repair is another attractive future appli- correction of suitable ATP7B mutations and there-
cation for Wilson’s disease.77 Somatic gene modi- by restoring functional copper transport in hepa-
fication can be achieved with the use of such tocytes. The goal is to achieve copper transport
methods as CRISPR-Cas (clustered regularly inter- equivalent to that in an unaffected simple hetero-
spaced short palindromic repeats associated with zygote without altering the germline cells. The
a Cas endonuclease) genome editing, allowing large number of pathogenic ATP7B variants makes

it potentially costly to establish the technique for meet special needs at school and in the work-
patients who have uncommon mutations. Newer place. Patients with Wilson’s disease and cirrho-
technology may permit repair by substitution of sis should undergo screening for hepatic neopla-
larger segments that encompass regions with sia, and treatment for portal hypertension and
multiple mutations, potentially reducing the cost its complications may be warranted.
of development and expanding the number of pa- The importance of a multidisciplinary team is
tients who would be candidates for this treatment. especially evident with respect to pregnancy. Fer-
Since certain types of mutations are not suitable tility appears to be normal and pregnancy out-
for gene repair, this therapeutic approach would comes are typically favorable in treated patients
be limited to a subgroup of patients with Wilson’s with Wilson’s disease that is clinically stable.82-84
disease. Treatment must be continued throughout preg-
nancy. The teratogenic risk of available medica-
Innovative Strategies for Liver-Cell tions is poorly established, except for penicilla-
Transplantation mine. The doses of both penicillamine and
Hepatocyte transplantation has been tested in trientine should be reduced by 25 to 50% during
rodent models of Wilson disease.78,79 At present, pregnancy. Associated liver disease may require
human hepatocyte transplantation requires im- management by a specialist. Wilson’s disease can
munosuppression to prevent rejection of the manifest initially during pregnancy and must be
transplanted cells. Unlike liver transplantation, distinguished from the HELLP (hemolysis, elevat-
hepatocyte transplantation may not correct com- ed liver-enzyme levels, and a low platelet count)
plications of portal hypertension. Innovative cell syndrome, thrombotic thrombocytopenia purpura,
transplantation strategies to avoid the need for and similar rare disorders.
immunosuppression are being developed. The suit-
ability of autologous liver progenitor cells (gener- A dher ence a s a n Emerging Issue
ated from hepatocytes) or nonhepatic stem cells,
either of which can be transformed into hepato- The importance of adherence to treatment for
cytes, is being investigated. Ex vivo gene therapy Wilson’s disease is increasingly recognized. Ad-
to express wild-type ATP7B or repair existing herence is a major challenge for patients, who
ATP7B mutations is performed before cells are must take, at a minimum, twice-daily medication
reintroduced into the patient. The results of proof- for the rest of their lives or risk severe clinical
of-principle studies in animal models for each deterioration.85 Although patients who receive an
strategy were recently reported.80,81 early diagnosis by means of molecular genetic
testing have the best outcome with well-tolerated,
effective treatment, such patients are also likely
M a nagemen t of W il son’s Dise a se
to become nonadherent, since they may not rec-
In general, the diagnosis and treatment of Wil- ognize the risks associated with untreated Wil-
son’s disease benefit from a team approach. The son’s disease. Innovative methods for supporting
team typically is customized according to the pa- adherence are being developed for other chronic
tient’s needs. It may include specialists in hepatol- diseases and warrant testing for Wilson’s disease.
ogy, neurology, psychiatry, and clinical genetics; Factors in achieving good adherence include
an internist, general pediatrician, or family physi- regular clinical assessments and a broadly sup-
cian; and ancillary specialists such as a registered portive approach that is team-based, if possible.
dietitian, physiotherapist or occupational therapist, Improved methods for monitoring treatment,
speech therapist, and genetic counselor. Adjunc- along with clear benchmarks for treatment ade-
tive medical therapies for neurologic symptoms quacy, facilitate general management. Monitoring
of Wilson’s disease, such as parkinsonism, dys- should be closer in patients for whom nonadher-
tonia, and chorea, may be warranted. Some pa- ence is suspected. Concurrent disease, increased
tients may benefit from psychotropic medication dietary copper, taking medication too close to
or counseling. A dietitian can streamline meal meals, or societal barriers to obtaining medica-
patterns and help prevent undue anxiety about tion (supply shortages and cost) may account for
excess dietary copper intake. Physical and occu- treatment failure that is otherwise attributed to
pational therapists can assist with strategies to nonadherence. Strong family and social supports

are essential, with clear communication to all disease, apart from liver transplantation. Fine-
health care providers and the patient. tuned monitoring will establish the effectiveness
and durability of these therapies. Continued efforts
to describe the complicated pathobiology of Wil-
C onclusions
son’s disease entail expanding the focus on gene
Current advances in the diagnosis, treatment, and expression and mutated gene-product dysfunc-
multidisciplinary management of Wilson’s disease tion to include an assessment of how different
are important. Future population screening is tissues respond to intracellular alterations caused
likely to identify patients earlier in the course of by defective ATP7B. This approach enlarges the
the disease. Novel treatments will address un- scope from genomic to postgenomic issues and
met needs and furnish new options for individu- will further enhance our understanding of Wil-
alizing treatment. Gene therapy or gene repair has son’s disease.
the potential to provide the first cures for Wilson’s Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
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Hum Gene Ther Clin Dev 2019;30:29-39. induced pluripotent stem cell-derived he- Copyright © 2023 Massachusetts Medical Society.
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The n e w e ng l a n d j o u r na l of m e dic i n e

Dan L. Longo, M.D., Editor

Current and Emerging Issues

Cl inic a l Pr e sen tat ion

922 n engl j med 389;10 nejm.org September 7, 2023

The New England Journal of Medicine

Figure 1. Clinical Manifestations of Wilson’s Disease.

n engl j med 389;10 nejm.org September 7, 2023 923

A Cu2+ Intracellular Copper Adequacy

B Cu2+Cu2+ Intracellular Copper Excess

C Cu2+ Wilson's Disease

Trans-Golgi Fat droplets

924 n engl j med 389;10 nejm.org September 7, 2023

The New England Journal of Medicine

n engl j med 389;10 nejm.org September 7, 2023 925

926 n engl j med 389;10 nejm.org September 7, 2023

The New England Journal of Medicine

n engl j med 389;10 nejm.org September 7, 2023 927

Basal 24-hr Hepatic Hepatic

n engl j med 389;10

The New England Journal of Medicine

apparent hepatic damage

Copyright © 2023 Massachusetts Medical Society. All rights reserved.

polycythemia; severe hyper- hood creased copper

n engl j med 389;10

The New England Journal of Medicine

Copyright © 2023 Massachusetts Medical Society. All rights reserved.

930 n engl j med 389;10 nejm.org September 7, 2023

The New England Journal of Medicine

n engl j med 389;10 nejm.org September 7, 2023 931

Metallothionein Inducer to Inhibit Intestinal

Penicillamine Trientine (Dihydrochloride) Elemental Zinc

in 2 divided doses (total dose, approxi- 2 divided doses

n engl j med 389;10

urinary copper excretion μmol/24 hr) μmol/24 hr)

The New England Journal of Medicine

Copyright © 2023 Massachusetts Medical Society. All rights reserved.

tion of the liver X receptor–retinoid X receptor

Sideroblastic anemia; leukopenia; iron accu-

mulation; in rare cases, new neurologic

features of copper deficiency

possible to reduce inflammation and injury by

targeting other cellular pathways involved in the

Gene Therapy and Gene Repair

give hope that a cure for Wilson’s disease is pos-

sible. Liver transplantation provided the proof of

principle that targeting the liver alone will re-

store normal copper balance. Preclinical studies

using viral vectors with modified ATP7B constructs

in rodent models of Wilson’s disease showed

tropic viral vectors, such as lentivirus, allow direct

nity for a one-time treatment. However, current

target DNA integration of introduced DNA. Use

of adeno-associated virus for extrachromosomal

of the DNA that could be packaged. However,

smaller yet functional ATP7B constructs74 have

been created and can now be used for Wilson’s

therapy in humans are dosing, which is depen-

dent on vector packaging and transfection effi-