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Wilson disease: Clinical manifestations, diagnosis, and natural history

Author: Michael L Schilsky, MD, FAASLD
Section Editors: Elizabeth B Rand, MD, Bruce A Runyon, MD, FAASLD, Michael J Aminoff, MD, DSc
Deputy Editor: Kristen M Robson, MD, MBA, FACG
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Oct 2021. | This topic last updated: May 21, 2021.
INTRODUCTION
Wilson disease (hepatolenticular degeneration) is a genetic disorder of copper metabolism with an autosomal recessive pattern of
inheritance due to mutations that lead to impaired function of the intracellular copper transporter ATP7B. It is found worldwide, with a
prevalence of approximately one case in 30,000 live births in most populations. Impaired biliary copper excretion leads to accumulation
of copper in several organs, most notably the liver, brain, and cornea. Over time, the liver is progressively damaged and eventually
becomes cirrhotic. The rate at which this occurs varies between patients. A small percent of patients (approximately 5 percent) develop
acute injury (without encephalopathy) that progresses to acute liver failure, most often in the setting of advanced fibrosis of the liver. In
addition, patients may develop neurologic and psychiatric complications, which can be severe.
This topic will review the clinical manifestations, diagnosis, and natural history of Wilson disease. The epidemiology, pathogenesis, and
treatment of Wilson disease, as well as a detailed discussion of the individual tests used to diagnose Wilson disease, are discussed
separately. (See "Wilson disease: Epidemiology and pathogenesis" and "Wilson disease: Diagnostic tests" and "Wilson disease: Treatment
and prognosis".)
CLINICAL MANIFESTATIONS
The clinical manifestations of Wilson disease are predominantly hepatic, neurologic, and psychiatric, with many patients having a
combination of symptoms [1]. A non-immune hemolysis is also a common finding in patients with acute liver failure due to Wilson
disease, but may occur episodically independent of liver failure.
Patients may present with a wide variety of symptoms (especially those with neurologic symptoms) [2,3]. Even within a given family,
patients often present with different symptoms [4]. There is wide variability in the reported rates of the different clinical manifestations
seen at the time of presentation [2,5-15]:
● Liver disease: 18 to 84 percent of patients

● Neurologic symptoms: 18 to 73 percent of patients
● Psychiatric symptoms: 10 to 100 percent of patients
The wide variability in the estimates may in part be attributable to lead-time bias with respect to the age at which a patient is seen, as
well as ascertainment bias based upon the clinical specialty to which the patient was referred (eg, to pediatricians where neurologic
presentations are less likely, or to neurologists who are likely to see patients with neurologic symptoms).
Regardless of whether clinical manifestations are initially present, patients often develop other clinical manifestations as the disease
progresses (eg, patients who present with liver disease may subsequently develop neurologic or psychiatric symptoms). Conversely, liver
failure may develop in those whose neurologic or psychiatric symptoms led to the diagnosis of Wilson disease.
Age at symptom onset — The mechanisms for copper excretion are not well developed in newborns and begin to function more
efficiently within the first year of life. For patients with Wilson disease, a critical ATP7B-dependent copper excretory pathway fails to
develop or is dysfunctional, and copper accumulation that begins at birth continues throughout life, gradually producing clinical disease
[16]. The majority of patients with Wilson disease are diagnosed between the ages of 5 and 35 years (mean age of 13 years) [17], though
this disorder has been diagnosed in younger patients and in patients in their eighth decade [1,13,17,18]. In a study of 143 children with
Wilson disease, 21 children (15 percent) presented with symptoms or abnormal liver function tests before the age of five years [18]. (See
"Wilson disease: Epidemiology and pathogenesis".)
Children most often initially present with liver disease at an average age of 9 to 13 years [19,20], with Wilson disease accounting for 8 to
10 percent of chronic active hepatitis in children [21]. Children diagnosed through family screening because of an affected sibling are
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often asymptomatic. In most patients, liver disease progresses silently, often until adolescence and beyond, when complications of
cirrhosis or acute liver failure may develop. In some patients, neurologic or psychiatric manifestations precede overt liver disease.
While children are more likely to present with hepatic manifestations and rarely with neurologic symptoms, adolescents and adult
patients present more often with neurologic manifestations. The mean age at presentation for patients with neurologic symptoms
ranges between 15 and 21 years [2,19,22,23].
The variability in the age of onset of Wilson disease probably reflects differences in mutations and penetrance, extragenic factors, and
environmental influences including diet [24]. (See "Wilson disease: Epidemiology and pathogenesis", section on 'Pathogenesis'.)
Hepatic disease — The liver is the initial site of copper accumulation in patients with Wilson disease, and there are several different
clinical manifestations due to hepatic copper accumulation [25,26]. Hepatic manifestations range from asymptomatic biochemical
abnormalities often with steatosis to acute hepatitis and acute liver failure (with an associated Coombs-negative hemolytic anemia),
chronic hepatitis, and cirrhosis. Regardless of presenting symptoms, some degree of liver disease, even if only histologic change, is
usually present at the time Wilson disease is diagnosed [27].
The signs, symptoms, laboratory findings, and imaging findings in patients with hepatic Wilson disease vary with the degree of liver
damage [1,2,28].
Signs and symptoms of hepatic Wilson disease may include:
● Kayser-Fleischer rings, visible in about 50 percent of patients at the time of presentation with hepatic disease (seen with all forms
of liver involvement)
● Asymptomatic (steatosis, chronic hepatitis, compensated cirrhosis)
● Abdominal pain (acute hepatitis, acute liver failure)
● Jaundice (acute hepatitis, acute liver failure with hemolytic anemia, cirrhosis)
● Hepatomegaly (acute and chronic hepatitis, acute liver failure)
● Splenomegaly (cirrhosis with portal hypertension)
● Ascites (cirrhosis with portal hypertension)
● Upper gastrointestinal bleeding (cirrhosis with varices or portal hypertensive gastropathy)
● Peripheral stigmata of chronic liver disease (cirrhosis)
● Mental status changes due to hepatic encephalopathy (acute liver failure, cirrhosis with hepatic insufficiency and portosystemic
shunting)
Laboratory test findings may include:
● Low level of serum ceruloplasmin (seen with all forms of liver involvement, though not as consistently with acute liver failure)
● Elevated aminotransferases (all forms of liver involvement)
● Thrombocytopenia (cirrhosis with splenomegaly)
● Coagulopathy (cirrhosis with hepatic insufficiency or acute liver failure)
● Coombs-negative hemolytic anemia (often seen in conjunction with acute liver failure, but can occur as episodic hemolysis without
liver failure)
Abdominal imaging may show:
● Hepatic steatosis (chronic hepatitis)

● Hepatomegaly (hepatic inflammation)
● A small, nodular liver (cirrhosis)
● Splenomegaly (cirrhosis)
The frequencies of various findings have been reported in several series [1,13,19,20,29-32]:
● Low ceruloplasmin: 95 percent with asymptomatic or chronic presentation

● Kayser-Fleischer rings: 50 percent with hepatic disease; 98 percent with neurologic or psychiatric presentation
● Acute liver failure: 5 percent
● Hepatomegaly and/or splenomegaly: 15 to 49 percent
● Jaundice, anorexia, and vomiting: 14 to 44 percent
● Fatty liver: 13 percent
● Ascites and/or edema: 5 to 50 percent
● No symptoms: 5 to 23 percent
● Variceal hemorrhage: 3 to 10 percent
● Hemorrhagic diathesis: 3 to 8 percent
● Hemolysis: 1 to 20 percent
Acute hepatitis and acute liver failure — Patients with Wilson disease, most often children or young adults, may develop acute
hepatitis that is indistinguishable from acute viral hepatitis, with elevated aminotransferase levels, jaundice, and abdominal pain [1]. The
degree of aminotransferase elevation in patients with Wilson disease is usually less compared with patients with acute viral hepatitis or
ischemic hepatitis. In some patients, the symptoms will resolve spontaneously (though Wilson disease is still present and requires
treatment), whereas others may rapidly deteriorate and develop acute liver failure. Acute liver failure refers to the rapid (typically in less
than 8 to 12 weeks) development of severe acute liver injury with impaired synthetic function with coagulopathy and encephalopathy in
a person who previously had a normal liver. In Wilson disease, the development of acute liver failure differs in that it is development of
acute-on-chronic liver disease, as most patients have advanced fibrosis or cirrhosis at the time of development of acute liver failure [33].
(See "Acute liver failure in adults: Etiology, clinical manifestations, and diagnosis", section on 'Introduction'.)
Wilson disease accounts for approximately 5 percent of patients with acute liver failure who are referred for emergency transplantation.
The female to male ratio of patients with acute liver failure due to Wilson disease is 2:1 to 4:1 [1,34].
Features seen in patients with acute liver failure due to Wilson disease include:
● A Coombs-negative hemolytic anemia. This is usually present in patients with acute liver failure due to Wilson disease and results
from the effects of excess copper ions on the red blood cell membrane in the circulation due to hepatic copper release following
cellular necrosis [26,35-38]. (See "Overview of hemolytic anemias in children" and "Diagnosis of hemolytic anemia in adults".)
● Serum aminotransferases that are typically less than 2000 international unit/L. The ratio of the AST to ALT is often >2.
● The alkaline phosphatase may be normal or markedly subnormal (<40 international unit/L), and the ratio of the alkaline
phosphatase (international unit/L) to total bilirubin (mg/dL) is typically <4.
● Low uric acid levels.
● A coagulopathy that is unresponsive to vitamin K.
● Rapidly progressive renal failure.
Levels of ceruloplasmin are less reliable for diagnosing acute liver failure due to Wilson disease because ceruloplasmin is an acute phase
reactant which may elevate levels [33] or levels can be depressed due to severe hepatic synthetic dysfunction.
Chronic hepatitis and cirrhosis — Patients with chronic hepatitis due to Wilson disease are often asymptomatic from their liver
disease. Such patients are typically diagnosed through family screening, after being found to have abnormal liver tests, or after
presenting with neurologic or psychiatric manifestations of Wilson disease. In addition, Wilson disease often results in hepatic steatosis
and may be diagnosed in a patient being evaluated for nonalcoholic fatty liver disease [28].
Most of these patients have a low level of serum ceruloplasmin, but only 50 percent have Kayser-Fleischer rings. Almost all have liver
copper concentrations of >250 mcg/g dry weight liver, but some have levels as low as 75 mcg, with normal being less than 40 mcg [39].
As the disease progresses, patients develop hepatic fibrosis and may present with evidence of compensated or decompensated
cirrhosis, such as jaundice, ascites, thrombocytopenia, splenomegaly, palmar erythema, and variceal hemorrhage. In addition, patients
may come to attention when abdominal imaging obtained for other reasons reveals evidence of cirrhosis or is suggestive of portal
hypertension. (See "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Clinical manifestations'.)
Cirrhosis is present at the time of diagnosis of Wilson disease in approximately 35 to 45 percent of patients overall [39-41], including
those presenting with neuropsychiatric symptoms or who are asymptomatic [23,34,39,42]:
● In a series that included 14 patients over the age of 40 years who presented with neurologic symptoms and underwent liver biopsy,
significant fibrosis was present in 10 (71 percent; 9 with cirrhosis and 1 with advanced fibrosis) [23].
● In a series with 34 patients with neurologic Wilson disease, 14 (41 percent) were found to have cirrhosis [39].
● In a study that included 18 asymptomatic patients detected through screening because of an affected sibling, two (11 percent) had
cirrhosis at the time of diagnosis [39].
Neurologic manifestations — The reported neurologic manifestations of Wilson disease are broad and diagnosing neurologic Wilson
disease can be challenging because patients present in a myriad of ways. Nearly all (98 percent) of patients with Wilson disease with
neurologic manifestations have Kayser-Fleischer rings. Neurologic symptoms may be very subtle or may be rapidly progressive, leading
to severe disability over the course of months [1]. In patients with known cirrhosis, neurologic manifestations may be mistaken for
hepatic encephalopathy.
The majority of patients with neurologic Wilson disease fall into one of several categories: dysarthric, dystonic, tremulous,
pseudosclerotic (tremor with or without dysarthria), or parkinsonian [2]. Initially, only one symptom may be present, but as the disease
progresses, complex combinations of neurologic signs and symptoms may develop.
Some of the more common neurologic manifestations include:
● Dysarthria – 85 to 97 percent of patients with neurologic Wilson disease

● Gait abnormalities/ataxia – 30 to 75 percent
● Dystonia – 11 to 69 percent
● Tremor – 22 to 55 percent
● Parkinsonism – 19 to 62 percent
● Drooling – 48 to 86 percent
Other neurologic manifestations include:
● Risus sardonicus (sardonic expression produced by dystonic spasm of the facial muscles)
● Chorea
● Athetosis
● Cognitive impairment/dementia
● Seizures
● Hyperreflexia
● Myoclonia
● Urinary incontinence
● Autonomic dysfunction
Magnetic resonance imaging (MRI) or computed tomographic (CT) scanning of the brain may reveal structural abnormalities in the basal
ganglia in patients with neurologic Wilson disease [43]. Common findings in the regions of the basal ganglia include increased density
on CT scan and hyperintensity on T2-weighted MRI images. Other findings include hyperintensities in the tectal-plate and central pons.
Simultaneous involvement of the basal ganglia, thalamus, and brainstem is highly suggestive of Wilson disease [44].
Cerebrospinal fluid (CSF) copper concentrations in patients with neurologic Wilson disease are elevated three to fourfold relative to
those in patients without Wilson disease or with Wilson disease without neurologic signs [45]. These values fall with treatment [46] but
are not typically followed for clinical purposes as the gradual disappearance of Kayser-Fleischer rings indicates dissipation of copper in
the central nervous system.
Dysarthria — Among patients with neurologic Wilson disease, dysarthria is the most common neurologic symptom. The type of
dysarthria may vary: patients may have ataxic dysarthria (irregular word spacing and volume), or the speech may be athetoid,
hypophonic, or spastic [2].
Dystonia — Dystonia associated with Wilson disease may range in severity from mild to debilitating and often worsens with disease
progression [2]. It may be focal, segmental, multifocal, or generalized. While it can occur unilaterally, it may eventually become bilateral
or generalized. In some patients with severe dystonia, contractures may develop and may only be corrected surgically by tendon
lengthening. (See "Etiology, clinical features, and diagnostic evaluation of dystonia".)
Focal manifestations of dystonia include blepharospasm, cervical dystonia (torticollis), writer's cramp, and a dystonic facial expression in
which the patient appears to have an exaggerated smile (risus sardonicus). With focal dystonia of the vocal cords, muscles of
articulation, or swallowing muscles, patients may develop dysphonia, dysarthria, or dysphagia, respectively.
Tremor — Tremors in Wilson disease may occur at rest or with action and may have multiple position and task-dependent
characteristics [2]. Some of the tremors seen include:
● A tremor that resembles essential tremor (variable amplitude and frequency, with arm and sometimes head and leg involvement).
Unlike essential tremor, the tremor in patients with Wilson disease often persists in its asymmetry and may not involve the voice.
(See "Overview of tremor", section on 'Essential tremor'.)
● An intention (kinetic) tremor (low amplitude, medium-to-high frequency), seen most often in a distal upper extremity. Intention
tremors typically increase in severity as the patient's hand moves closer to its target. (See "Overview of tremor", section on
'Cerebellar tremor'.)
● A postural tremor that occurs when the patient assumes a particular position. The classic tremor associated with Wilson disease is
a wing-beating tremor, though it is not the most common type of tremor [2]. The tremor is a low-frequency, high-amplitude tremor
that is most prominent when the patient's arms are held outstretched laterally or with the arms extended in front of the patient
with the palms facing downward and the elbows flexed. The tremor increases in amplitude with increased duration of posture
holding. The name comes from the fact that the movement of the patient's arms may be reminiscent of a bird's flapping wings.
● A unilateral rest tremor may be present, but is rarely seen in isolation. When present, it is typically accompanied by postural and
intention tremors that often dominate the clinical picture [7].
Parkinsonism — Parkinsonian features that may be seen in Wilson disease include bradykinesia, cogwheel rigidity, and postural
instability. Parkinsonism is rarely an isolated clinical feature in patients with Wilson disease and is typically accompanied by other
neurologic deficits. [2].
Choreoathetosis — Chorea is characterized by rapid and unpredictable contractions affecting mostly distal limbs, but it can also affect
the face and trunk. The movements are involuntary and non-patterned with variable speed, timing, and direction, flowing from one body
part to another. In less severe cases, this can result in an appearance of fidgetiness. The unpredictable nature of chorea is a feature that
distinguishes it from tremor and dystonia [47]. When severe and with proximal muscle involvement, choreic movements may result in
violent, uncontrolled flailing movements of the extremities (ballism). Athetosis refers to slower writhing movements with a sinuous
quality. The term choreoathetosis is used when typical choreic movements coexist with athetosis. (See "Overview of chorea".)
Chorea as an initial clinical feature is more often seen in younger patients (≤16 years). It has been reported in 20 percent of patients with
a young age of symptom onset, compared with 3 percent of patients with an older age of onset [9]. It typically is not present in isolation
[2].
Cerebellar ataxia — Cerebellar ataxia is generally not seen as the sole neurologic manifestation of Wilson disease [2]. The ataxia is
typically not clinically relevant, and frank limb ataxia is uncommon.
Patients with cerebellar ataxia have difficulty changing voluntary force levels abruptly, with impaired acceleration and braking [48]. This
leads to [49]:
● Overshoot in point-to-point movements (dysmetria)

● In multijoint movements, breakdown of normal coordination of joint rotations, with trajectory abnormalities (dyssynergia)
● Breakdown in the rhythm of repetitive, alternating single movements, such as finger tapping (dysrhythmia)
Dysfunction in the vermis or paleocerebellum results in truncal and gait ataxia. (See "Causes and evaluation of neurologic gait disorders
in older adults", section on 'Cerebellar ataxia'.)
Cognitive impairment — Two main categories of cognitive impairment in Wilson disease have been described, a frontal syndrome and
subcortical dementia, with some patients having features of both [2]. In patients with cognitive impairment, the findings can be subtle
and may only be recognized retrospectively. In addition, some have suggested that the apparent cognitive impairment may be primarily
the result of psychiatric and motor manifestations of Wilson disease [14,50]. In those with new changes in cognition, it is important to
exclude hepatic encephalopathy that may be reversible.
Patients with a frontal syndrome may demonstrate impulsivity, promiscuity, impaired judgement, apathy, executive dysfunction (poor
planning and decision making), decreased attention, and emotional lability. When severe, patients may have pseudobulbar features
(sudden outbursts of inappropriate laughter or tearfulness). (See "Frontotemporal dementia: Clinical features and diagnosis", section on
'Behavioral variant FTD'.)
Findings in subcortical dementia include slowed thinking, memory loss, and executive dysfunction. It lacks cortical signs such as aphasia,
apraxia, or agnosia.
Other neurologic features — Seizures, while rarely the presenting feature, are seen in approximately 6 percent of patients with Wilson
disease and have been associated with the initiation of chelation therapy but may occur later on [51]. Other neurologic manifestations
include hyperreflexia, tics, and unusual stereotyped movements [2]. Dysautonomia, such as abnormal cardiac responses to the Valsalva
maneuver, may occur in patients with Wilson disease, but when present is usually found in those with other neurologic signs and
symptoms due to Wilson disease [52]. It is thought to be due to central nervous system involvement.
Behavioral and psychiatric symptoms — Behavioral and psychiatric symptoms are more common in patients with neurologic
involvement than in patients with hepatic involvement [50,53]. However, psychiatric symptoms may precede the recognition of hepatic
or neurologic Wilson disease by a significant period of time. The most common behavioral and psychiatric symptoms include depression
(reported in 20 to 30 percent of patients with Wilson disease), personality change, incongruous behavior, and irritability [2,50]. However,
behavioral and psychiatric symptoms due to Wilson disease are often misdiagnosed (eg, they may be attributed to puberty). As a result,
it is uncommon for patients to be diagnosed with Wilson disease when the only manifestations are behavioral or psychiatric, and
diagnosis may be delayed significantly in these individuals.
Behavioral and psychiatric manifestations of Wilson disease include [1,2,25,50,54-56]:
● Depression
● Declining school performance
● Personality changes (which may be subtle)
● Irritability
● Impulsiveness
● Labile mood
● Sexual exhibitionism
● Inappropriate behavior
● Dysthymia
● Bipolar affective disorder
● Psychosis
Hemolysis — Infrequently, Coombs-negative hemolytic anemia may be the initial symptom of Wilson disease and is not uniformly
associated with acute liver failure [19,57]. In a series of 283 patients, hemolytic anemia was the sole presenting feature in only three
patients (1 percent), but it was present in a 19 of 77 patients (28 percent) who had jaundice at presentation [19]. The hemolytic anemia
may occur as a single acute episode, or it may be low-grade, episodic, or chronic.
Patients reporting a history of jaundice prior to the diagnosis of Wilson disease may have had previously unrecognized hemolysis [58]. If
acute hepatitis and hemolysis due to Wilson disease develop during pregnancy, it may be mistaken for HELLP syndrome. In those with
acute liver failure due to Wilson disease, a hemoglobin <10 g/dL is associated with a 94 percent sensitivity but only 76 percent specificity
for this diagnosis [33]. (See "Overview of hemolytic anemias in children" and "Diagnosis of hemolytic anemia in adults" and "HELLP
syndrome (hemolysis, elevated liver enzymes, and low platelets)".)
Ocular manifestations — Kayser-Fleischer rings are brownish rings that are due to fine, pigmented, granular deposits of copper in
Descemet's membrane in the cornea ( picture 1). Kayser-Fleisher rings are thought to reflect copper within the central nervous
system, and they dissipate over time with treatment directed towards the removal of copper. Kayser-Fleischer rings are a characteristic
feature of Wilson disease and are seen in approximately 98 percent of patients with neurologic manifestations, but only 50 percent of
patients with hepatic manifestations. While often only detected by slit-lamp examination (typically done in a patient already suspected of
having Wilson disease), Kayser-Fleischer rings are sometimes visible without a slit-lamp examination when they are sizable, especially in
those with lighter colored irises where the contrast between the background color makes it more obvious. Optical tomography has been
applied to visualize Kayser-Fleischer rings and has the advantage of providing an objective observation that also permits quantitation of
the ring size [59]. However, Kayser-Fleisher rings are rarely the first finding in a patient with Wilson disease. (See "Wilson disease:
Diagnostic tests" and "Slit lamp examination".)
Sunflower cataracts are another ocular manifestation of Wilson disease and occur when copper deposits accumulate in the lens. These,
too, are generally seen with a slit-lamp examination.
Other manifestations — Wilson disease can cause abnormalities related to copper deposition in other organs. Other manifestations of
Wilson disease that are less common include [1,60-62]:
● Fanconi syndrome, in which proximal tubular dysfunction leads to glucosuria, aminoaciduria, hypouricemia, and proximal renal
tubular acidosis. (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis", section on 'Proximal
(type 2) RTA'.)
● Nephrolithiasis secondary to distal renal tubular acidosis. (See "Nephrolithiasis in renal tubular acidosis".)
● Arthropathy with features of premature arthritis and occasionally chondrocalcinosis, most commonly in the knee.
● Gigantism.
● Cardiomyopathy.
● Myopathy.
● Hypoparathyroidism.
● Pancreatitis.
● Impotence.
● Infertility or repeated spontaneous abortions.
● A variety of dermatologic disorders. These include blue lunulae (lunulae ceruleae), acanthosis nigricans, and pretibial
hyperpigmentation. Dermatologic manifestations may also occur from treatment with penicillamine, including progeric change to
the skin (commonly seen around the neck), bullous pemphigoid, elastosis perforans serpiginosa, and pseudoxanthoma elasticum
[63-65].
DIFFERENTIAL DIAGNOSIS
Abnormal liver tests or cirrhosis — Abnormal aminotransferases may be seen in many liver disorders, including viral hepatitis, alcohol
use disorder, autoimmune hepatitis, hepatotoxicity due to drugs or supplements, hereditary hemochromatosis, and alpha-1 antitrypsin
deficiency. In patients with Wilson disease, the serum aminotransferases are usually mildly to moderately elevated, and the aspartate
aminotransferase (AST) concentration is usually higher than the alanine aminotransferase (ALT) concentration. (See "Approach to the
patient with abnormal liver biochemical and function tests".)
Similarly, in patients presenting with cirrhosis, other causes of chronic liver disease, such as viral hepatitis, need to be considered. (See
"Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis".)
Acute liver failure — Acute liver failure has many causes, including toxin ingestion, viral hepatitis, ischemia, inherited metabolic
diseases, and autoimmune hepatitis. Among patients with acute liver failure due to Wilson disease, the serum aminotransferases are
typically less than 2000 units/L with an AST/ALT ratio of >2 [33,34]. In addition, the alkaline phosphatase level is typically normal or
subnormal, with an alkaline phosphatase (international unit/L) to total bilirubin (mg/dL) ratio of <4. Finally, patients with acute liver
failure due to Wilson disease typically develop a Coombs-negative hemolytic anemia and may have a low uric acid level. (See "Acute liver
failure in adults: Etiology, clinical manifestations, and diagnosis" and "Acute liver failure in children: Etiology and evaluation".)
Neurologic manifestations — The neurologic manifestations of Wilson disease are numerous and can mimic other neurologic
disorders, especially any type of movement disorder. Disorders that should be considered include essential tremor, young-onset
Parkinson disease, and generalized dystonia. Disorders that may rarely mimic Wilson disease include Huntington disease, pantothenate
kinase-associated neurodegeneration (Hallervorden-Spatz disease), idiopathic torsion dystonia, chorea-acanthocytosis, and benign
familial chorea. The presence of Kayser-Fleischer rings, seen in approximately 98 percent of patients with neurologic Wilson disease, can
help differentiate Wilson disease from other disorders. In addition, patterns of injury on magnetic resonance imaging (MRI) or computed
tomography (CT) of the brain may suggest the diagnosis of Wilson disease [66]. (See "Overview of tremor" and "Etiology, clinical
features, and diagnostic evaluation of dystonia" and "Bradykinetic movement disorders in children" and "Neuroacanthocytosis", section
on 'Chorea-acanthocytosis' and "Neuroacanthocytosis", section on 'Mcleod syndrome' and "Neuroacanthocytosis", section on
'Huntington disease-like 2'.)
Psychiatric manifestations — The differential diagnosis for the psychiatric manifestations of Wilson disease includes disorders such as
depression, bipolar disorder, schizophrenia, dementia, and drug abuse. As with the neurologic manifestations, the presence of Kayser-
Fleischer rings can often help differentiate patients with Wilson disease from these other disorders. (See "Unipolar depression in adults:
Assessment and diagnosis" and "Bipolar disorder in adults: Epidemiology and pathogenesis" and "Schizophrenia in adults: Clinical
manifestations, course, assessment, and diagnosis".)
DIAGNOSIS
The diagnosis of Wilson disease starts with recognition of the clinical features suggestive of the disease or identification of family
members who require screening. Testing begins with serologic testing (liver biochemical tests, a complete blood count, and serum
ceruloplasmin level), an ocular slit-lamp examination (or optical tomography), and 24-hour urinary copper excretion ( algorithm 1).
Only approximately one-half of patients ultimately diagnosed with Wilson disease present with the classic clinical picture of a patient
between the ages of 5 and 35 years with a decreased serum ceruloplasmin and detectable Kayser-Fleischer rings [26]. Family screening
of siblings should now begin with mutation analysis for ATP7B mutations if the identified patient (proband) has been tested and both
mutations are identified. (See 'Clinical manifestations' above.)
When to consider Wilson disease — Wilson disease should be considered in any patient with unexplained liver, neurologic, or
psychiatric abnormalities or in a first-degree relative of a patient with Wilson disease. A scoring system for helping to determine the
need to continue with diagnostic testing for Wilson disease and determine the certainty of diagnosis was developed at an international
meeting in Leipzig [31]. This scoring system included clinical and laboratory testing, and results yielded three categories of patients:
those in whom other diagnoses should be considered, those in whom further diagnostic testing is needed, and those in whom there is
certainty as to diagnosis.
Patients are allotted points if any of the following are present (if information is missing for a given item, the patient is assigned 0 points
for that item):
● Kayser-Fleischer rings (2 points)
● Neuropsychiatric symptoms suggestive of Wilson disease (2 points)
● Coombs-negative hemolytic anemia with high serum copper (1 point)
● Urinary copper in the absence of acute hepatitis
• One to two times the upper limit of normal (1 point)

• >2 times the upper limit of normal (2 points)
• Normal, but >5 times the upper limit of normal after challenge with two doses of 0.5 g D-penicillamine (2 points)
● Liver copper quantitative measurement
• Normal (-1 point)

• Up to five times the upper limit of normal (1 point)
• >5 times the upper limit of normal (2 points)
● Rhodanine positive hepatocytes (if unable to obtain quantitative copper measurement) (1 point)
● Serum ceruloplasmin (based on using a nephelometric assay with a normal value >20 mg/dL)
• Normal (0 points)
• 10 to 20 mg/dL (1 point)
• <10 mg/dL (2 points)
● Mutation analysis
• Disease causing mutations on both chromosomes (4 points)

• Disease causing mutations on one chromosome (1 point)
• No disease causing mutation (0 points)
If the score is ≥4, Wilson disease is highly likely; if it is 3, the diagnosis is probable, but more investigation is warranted (eg, obtaining a
liver biopsy if not already done); if it is ≤2, Wilson disease is unlikely.
Serum aminotransferases are usually mildly to moderately elevated in patients with Wilson disease diagnosed in a presymptomatic
stage. The degree of elevation correlates poorly with the extent of histologic injury [30,67]. The aspartate aminotransferase (AST)
concentration is usually higher than the alanine aminotransferase concentration (ALT). (See 'Hepatic disease' above.)
Neurologic disorders in patients with Wilson disease include a parkinsonian-like rest tremor, rigidity, clumsiness of gait, slurring of
speech, facial grimacing (risus sardonicus), and drooling. Patients may also present with psychiatric problems, ranging from subtle
personality changes and deteriorating performance at school, to overt depression or psychosis. (See 'Neurologic manifestations' above
and 'Behavioral and psychiatric symptoms' above.)
While the majority of patients diagnosed with Wilson disease are between the ages of 5 and 35 years, Wilson disease has been
diagnosed in patients as young as 18 months of age and in patients who are in their 70s. (See 'Age at symptom onset' above.)
In particular, Wilson disease should be considered in ( table 1) [34,68]:
● Patients with liver abnormalities of uncertain etiology, especially in those with liver disease accompanied by neurologic or
psychiatric symptoms or with a family history of Wilson disease.
● Pediatric patients, and less commonly adults, with clinical features suggestive of autoimmune hepatitis, especially if there is no
response or inadequate response to standard treatments for autoimmune hepatitis with glucocorticoids, as there have been rare
instances of concurrent disease. (See "Overview of autoimmune hepatitis".)
● Patients with nonalcoholic fatty liver disease or nonalcoholic steatohepatitis (steatosis is a common finding in Wilson disease) with
atypical features for nonalcoholic fatty liver disease (such as absence of obesity) or who are under the age of 35 years. (See
"Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults".)
● Patients with acute liver failure with features suggestive of Wilson disease. (See 'Acute hepatitis and acute liver failure' above.)
● First-degree relatives of a patient diagnosed with Wilson disease.
Initial evaluation — The initial evaluation of a patient suspected of having Wilson disease starts with noninvasive testing (serologic
tests, ocular examination, and determination of urinary copper excretion) ( algorithm 1). Additional testing, such as a liver biopsy, may
be required if the initial testing is inconclusive.
We start the evaluation with:
● Determination of liver biochemical tests to look for evidence of active inflammation and to assess the AST to ALT ratio (often >2 in
patients with Wilson disease).
● A complete blood count to look for anemia (followed by testing for Coombs-negative hemolytic anemia if indicated) (see "Diagnosis
of hemolytic anemia in adults") and to look for the presence of thrombocytopenia, which might indicate hypersplenism due to
portal hypertension.
● Measurement of the serum ceruloplasmin concentration. (See "Wilson disease: Diagnostic tests", section on 'Serum ceruloplasmin
concentration'.)
● Measurement of the serum copper concentration. (See "Wilson disease: Diagnostic tests", section on 'Serum copper
concentration'.)
● An ocular slit-lamp examination. (See "Wilson disease: Diagnostic tests", section on 'Ocular slit-lamp examination'.)
● Determination of 24-hour urinary copper excretion. (See "Wilson disease: Diagnostic tests", section on 'Urinary copper excretion'.)
● Tests to rule out other causes of hepatic, neurologic, or psychiatric symptoms that could mimic Wilson disease. (See 'Differential
diagnosis' above.)
● Molecular testing for ATP7B mutations in siblings of affected patients (if such testing is available for the proband).
Interpretation of test results — Our interpretation of the initial laboratory test results and our approach to additional testing is as
follows. This approach is similar to that outlined in a consensus guideline from the American Association for the Study of Liver Diseases (
table 1 and algorithm 2 and algorithm 1) [34,68] and a guideline from the European Association for the Study of the Liver [1].
Low ceruloplasmin (<20 mg/dL or 200 mg/L), low serum copper concentration
● Kayser-Fleischer rings present:
• A diagnosis of Wilson disease is established if the 24-hour urinary copper excretion is >40 mcg (0.64 micromol).
• If urinary copper excretion is ≤40 mcg (0.64 micromol), a liver biopsy should be obtained to stain for copper and to determine
the hepatic copper concentration, or molecular genetic testing for ATP7B mutations may be performed. (See "Wilson disease:
Diagnostic tests", section on 'Liver biopsy'.)
● Kayser-Fleischer rings absent:
• A diagnosis of Wilson disease is established if the 24-hour urinary copper excretion is >100 mcg (1.6 micromol). However, in the
setting of acute liver injury, urinary copper may be elevated to this level, and further testing such as liver biopsy or molecular
testing is suggested.
• If the urinary copper excretion is ≤100 mcg (1.6 micromol), a liver biopsy should be obtained to determine the hepatic copper
concentration, or molecular genetic testing for ATP7B mutations may be performed.
Normal or elevated ceruloplasmin (≥20 mg/dL or 200 mg/L), normal serum copper concentration
● Kayser-Fleischer rings present:
• A liver biopsy should be obtained to stain for copper and to determine the hepatic copper concentration, regardless of urinary
copper excretion, or molecular genetic testing for ATP7B mutations may be performed. (See "Wilson disease: Diagnostic tests",
section on 'Liver biopsy'.)
● Kayser-Fleischer rings absent:
• A diagnosis of Wilson disease is excluded if the urinary copper excretion is ≤40 mcg (0.64 micromol).
• If the urinary copper excretion is >40 mcg (0.64 micromol), a liver biopsy should be obtained to stain for copper and to
determine the hepatic copper concentration, or molecular genetic testing for ATP7B mutations may be performed.
Hepatic copper concentration — Patients who undergo a liver biopsy should have their hepatic copper concentration determined (see
"Wilson disease: Diagnostic tests", section on 'Hepatic copper concentration'):
● A diagnosis of Wilson disease is established if the hepatic copper concentration is ≥250 mcg/g dry weight (4 micromol/g dry
weight).
● A diagnosis of Wilson disease is excluded if the hepatic copper concentration is <50 mcg/g dry weight (0.8 micromol/g dry weight).
Rarely, sampling variation (eg, sampling only scar tissue in a patient with cirrhosis) may lead to a falsely normal hepatic copper
concentration in a patient with Wilson disease [26,39,69,70]. If the urinary copper excretion is >100 mcg (1.6 micromol), the patient
most likely has Wilson disease.
If the hepatic copper concentration is between 50 and 250 mcg/g dry weight, especially if histology reveals evidence of active liver
disease, molecular genetic testing for ATP7B mutations is indicated to establish the diagnosis. Molecular genetic testing is also indicated
if there is suspicion of sampling variation leading to a falsely normal hepatic copper concentration. (See "Wilson disease: Diagnostic
tests", section on 'Genetic testing'.)
Scoring system for establishing a diagnosis of Wilson disease — Criteria were developed at a consensus meeting held at an
international meeting on Wilson and Menkes disease in Leipzig, Germany [31]. This scoring system was the first to give weighted
numeric values for the testing described above. These include specific biochemical testing (including ceruloplasmin, urine copper, and
hepatic copper), clinical manifestations of Wilson disease (presence of Kayser-Fleischer rings and neurologic manifestations), and
molecular testing for ATP7B mutations. A score of only 1 or 2 after all the testing is done excludes Wilson disease, while a score of 3
suggests further evaluation is needed and a score of 4 or more is diagnostic for Wilson disease. This scoring system has been validated
in adults and children and also has been incorporated into European Association for the Study of the Liver guidelines for the diagnosis
and treatment of Wilson disease ( table 2) [1].
Screening family members — First-degree relatives of patients diagnosed with Wilson disease should be screened for the disease (
algorithm 2). Among siblings, molecular genetic testing based upon the proband should be performed if possible. Genotyping for
polymorphisms around the Wilson disease gene may also be performed; however, direct mutation analysis has become more available,
and targeted testing of siblings makes this very specific and more economical. (See "Wilson disease: Diagnostic tests", section on
'Genetic testing'.)
For the child of a patient with Wilson disease and in those individuals where molecular genetic testing is not possible, the evaluation
with clinical and biochemical testing is the same as that for a patient with clinical features suggestive of Wilson disease. (See 'Initial
evaluation' above.)
NATURAL HISTORY
Progression of disease — Untreated, Wilson disease is universally fatal [1]. Copper accumulation in the liver eventually leads to the
development of cirrhosis, and among patients with neurologic Wilson disease, the neurologic disease may progress until the patient
becomes severely dystonic, akinetic, and mute. Progression is usually gradual, but sudden deterioration may also occur. The majority of
patients will die from liver disease (cirrhosis or acute liver failure), while the remainder die due to complications that arise due to
progressive neurologic disease.
Survival — Data are lacking regarding life expectancy among untreated patients with Wilson disease. One study found that the median
survival following the development of neurologic symptoms was approximately five years [51]. Patients who develop acute liver failure
due to Wilson disease have an acute mortality rate of at least 95 percent in the absence of a liver transplantation, with death occurring in
days to weeks [1,5].
The prognosis for patients who receive and are adherent to treatment for Wilson disease is excellent, even in some who already have
advanced liver disease. In patients without advanced liver disease, life expectancy is normal, though treatment may lead to worsening of
neurologic symptoms in a fraction of patients, most often during the initiation of therapy [13,42].
Among patients requiring liver transplantation, most commonly for acute liver failure or advanced liver disease unresponsive to therapy,
one-year survival following transplantation had been reported to be 79 to 90 percent [34,71]. Results from the United Network for Organ
Sharing's Scientific Registry for Transplant in the United States found survival rates at one and five years for adults transplanted between
1987 and 2008 (n = 400) were 88 and 86 percent, respectively. For children transplanted between 2002 and 2008 (n = 170), the one- and
five-year survival rates were 90 and 89 percent, respectively [71]. Survival was higher in adults and children undergoing transplantation
for chronic liver disease compared with those undergoing transplantation for acute liver failure. (See "Wilson disease: Treatment and
prognosis".)
Cancer risk — Patients with Wilson disease, especially those with cirrhosis, are probably at increased risk for hepatocellular carcinoma
(HCC). Whether they are at higher risk for other malignancies is unclear. Occasional reports have described HCC and cholangiocarcinoma
occurring in the setting of Wilson disease, and screening for HCC is recommended for patients with cirrhosis due to Wilson disease [72-
74]. (See "Surveillance for hepatocellular carcinoma in adults", section on 'Patients with cirrhosis'.)
One of the largest series to address the association of Wilson disease with cancer included a total of 363 patients seen at three centers
in England since 1955, eleven of whom had been diagnosed with cancer [74]. The cancers included cholangiocarcinoma (three patients),
poorly differentiated adenocarcinoma of undetermined primary site (five patients) and HCC (three patients). The incidence of cancer
appeared to be related to the duration of disease. No cancers were seen in patients followed for less than 10 years, compared with an
incidence of 4.2 percent in those followed for 10 to 19 years, 5.3 percent for those followed for 20 to 29 years, and 15 percent for those
followed for 30 to 39 years.
Whether the risk of cancer was increased compared with the general population is difficult to determine from this report since it did not
include a control group. The higher incidence of cancer in those followed for longer may have been at least in part related to their older
age and longer duration of follow-up. On the other hand, the types of cancer seen (occurring in organs affected by copper deposition)
support a possible association with Wilson disease.
The risk for developing HCC in patients with Wilson disease was also examined in two studies from Europe. In the first study, the
prevalence of hepatobiliary malignancies in 1186 patients with Wilson disease was 1.2 percent, and the incidence was 0.28 per 1000
person-years [75]. In the second study, 130 patients were followed for a mean of 15 years, and two patients with HCC were found: one at
time of diagnosis and the other after 50 years of treatment [76]. The estimated annual HCC risk was 0.09 percent for patients overall and
was 0.14 percent for patients with cirrhosis. In both of these studies, the annual incidence of HCC did not reach thresholds for which
screening and surveillance for HCC are recommended (cost-effectiveness models suggest that in patients with cirrhosis, surveillance
becomes cost-effective once the annual incidence of HCC exceeds 1.5 to 2 percent). However, given the ability to change survival with
detection of early lesions, it may still be useful to do screening and surveillance by ultrasound, but the cost-effectiveness is not certain.
(See "Surveillance for hepatocellular carcinoma in adults".)
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately.
(See "Society guideline links: Inherited liver disease".)
SUMMARY AND RECOMMENDATIONS
● The clinical manifestations of Wilson disease are predominantly hepatic, neurologic, and psychiatric, with many patients having a
combination of symptoms. (See 'Clinical manifestations' above.)
● The majority of patients with Wilson disease are diagnosed between the ages of 5 and 35, though it has been diagnosed in
younger patients and in patients in their eighth decade of life. (See 'Age at symptom onset' above.)
● Hepatic manifestations include acute liver failure with a Coombs-negative hemolytic anemia, acute hepatitis, chronic hepatitis,
cirrhosis, steatosis, and asymptomatic liver biochemical abnormalities. Regardless of presenting symptoms, some degree of liver
disease is usually present at the time of diagnosis of Wilson disease. (See 'Hepatic disease' above.)
● The reported neurologic manifestations of Wilson disease are broad, and diagnosing neurologic Wilson disease can be challenging
because patients present in many different ways. The majority of patients with neurologic Wilson disease have dysarthria and/or
movement disorders. Initially, it is common for one symptom to be present (often unilaterally), but as the disease progresses,
complex combinations of neurologic signs and symptoms may develop. (See 'Neurologic manifestations' above.)
● Behavioral and psychiatric symptoms are more common in patients with neurologic involvement than in patients with hepatic
involvement. The most common behavioral and psychiatric symptoms include depression (reported in 20 to 30 percent of patients
with Wilson disease), personality change, incongruous behavior, and irritability.
● Other clinical manifestations of Wilson disease include Coombs-negative hemolytic anemia and Kayser-Fleischer rings. (See
'Hemolysis' above and 'Ocular manifestations' above and 'Other manifestations' above.)
● In patients with clinical features suggestive of Wilson disease, we start by obtaining liver biochemical tests, a complete blood count,
serum ceruloplasmin and copper levels, an ocular slit-lamp examination, and a 24-hour urinary copper excretion ( algorithm 1).
The results of these tests determine the need for additional testing. (See 'Diagnosis' above.)
● Untreated, Wilson disease is universally fatal. Copper accumulation in the liver eventually leads to the development of cirrhosis,
and among patients with neurologic Wilson disease, the neurologic disease may progress until the patient becomes severely
dystonic, akinetic, and mute. The majority of patients will die from liver disease (cirrhosis or acute liver failure), while the remainder
die due to complications of progressive neurologic disease. (See 'Natural history' above.)
● The prognosis for patients who receive and are adherent to treatment for Wilson disease is excellent, even in some who already
have advanced liver disease. In patients without advanced liver disease, life expectancy is normal, though treatment may lead to
worsening of neurologic symptoms in a fraction of patients. Among patients requiring liver transplantation, survival following
transplantation is excellent. (See "Wilson disease: Treatment and prognosis".)
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Topic 83837 Version 29.0
GRAPHICS
Kayser-Fleischer ring
Kayser-Fleischer ring (arrow) in a patient with advanced

neuropsychiatric Wilson disease. The dense brown copper deposits
encircle the iris. It is rare to see Kayser-Fleischer rings without the
aid of a slit lamp examination because Wilson disease is usually
recognized at an earlier stage when the rings are not as prominent.
Courtesy of Marshall M Kaplan, MD.
Graphic 65925 Version 2.0
Approach to the diagnosis of Wilson disease
* The serum copper concentration should also be determined. It is decreased in proportion to the reduction in serum
ceruloplasmin and can be used to monitor therapy.
¶ If the serum ceruloplasmin is ≥20 mg/dL (200 mg/L) and Kayser-Fleischer rings are present, a liver biopsy or
molecular genetic testing is required regardless of the 24-hour urine copper.
Δ Ensure adequate urine collection.
◊ For patients with neurologic disease but no evidence of liver disease, molecular genetic testing should be done first;
for patients with liver disease, either molecular genetic testing or liver biopsy may be done first. If molecular genetic
testing is positive, the diagnosis is confirmed. If negative, liver biopsy should be performed. On liver biopsy, a diagnosis
of Wilson disease is established if the hepatic copper concentration is ≥250 mcg/g dry weight; a diagnosis is excluded if
the hepatic copper concentration is <50 mcg/g dry weight; if the hepatic copper concentration is ≥50 and <250 mcg/g
dry weight, molecular genetic testing for mutations in ATP7B should be performed (if not already done) to establish or
exclude the diagnosis.
§ Most patients with Wilson disease are compound heterozygotes. The identification of one mutation supports the
diagnosis, and the identification of two mutations confirms the diagnosis. Refer to UpToDate topics on the diagnosis of
Wilson disease for additional discussion of genetic testing.
AASLD recommendations for diagnosis and screening for Wilson disease (WD)
Clinical features:
WD should be considered in any individual between the ages of 3 and 55* years with liver abnormalities of uncertain cause. Age alone should not be the
basis for eliminating a diagnosis of WD.
WD must be excluded in any patient with unexplained liver disease along with neurological or neuropsychiatric disorder.
In a patient in whom WD is suspected, Kayser-Fleischer rings should be sought by slit-lamp examination by a skilled examiner. The absence of Kayser-
Fleischer rings does not exclude the diagnosis of WD, even in patients with predominantly neurological disease.
Diagnostic testing:
An extremely low serum ceruloplasmin level (<50 mg/L or <5 mg/dL) should be taken as strong evidence for the diagnosis of WD. Modestly subnormal
levels suggest further evaluation is necessary. Serum ceruloplasmin within the normal range does not exclude the diagnosis.
Basal 24-hour urinary excretion of copper should be obtained in all patients in whom the diagnosis of WD is being considered. The amount of copper
excreted in the 24-hour period is typically >100 mcg (1.6 micromol) in symptomatic patients, but finding >40 mcg (>0.6 micromol or >600 nmol) may
indicate WD and requires further investigation.
Penicillamine challenge studies may be performed for the purpose of obtaining further evidence for the diagnosis of WD in symptomatic children if basal
urinary copper excretion is <100 mcg/24 hours (1.6 micromol/24 hours). Values for the penicillamine challenge test of >1600 mcg copper/24 hours (>25
micromol/24 hours) following the administration of 500 mg of D-penicillamine at the beginning and again 12 hours later during the 24-hour urine
collection are found in patients with Wilson disease. The predictive value of this test in adults is unknown.
Hepatic parenchymal copper content >250 mcg/g dry weight provides critical diagnostic information and should be obtained in cases where the
diagnosis is not straightforward and in younger patients. In untreated patients, normal hepatic copper content (<40-50 mcg/g dry weight) almost always
excludes a diagnosis of WD. Further diagnostic testing is indicated for patients with intermediate copper concentrations (70-250 mcg/g dry weight)
especially if there is active liver disease or other symptoms of WD.
Neurologic evaluation and radiologic imaging of the brain, preferably by MR imaging, should be considered prior to treatment in all patients with
neurologic WD and should be part of the evaluation of any patient presenting with neurological symptoms consistent with WD.
Mutation analysis by whole-gene sequencing is possible and should be performed on individuals in whom the diagnosis is difficult to establish by clinical
and biochemical testing. Haplotype analysis or specific testing for known mutations can be used for family screening of first-degree relatives of patients
with WD. A clinical geneticist may be required to interpret the results.
Diagnostic considerations in specific target populations:

Patients in the pediatric age bracket who present a clinical picture of autoimmune hepatitis should be investigated for WD.
Adult patients with atypical autoimmune hepatitis or who respond poorly to standard corticosteroid therapy should also be investigated for WD.
WD should be considered in the differential diagnosis of patients presenting with nonalcoholic fatty liver disease or have pathologic findings of
nonalcoholic steatohepatitis.
WD should be suspected in any patient presenting with acute hepatic failure with Coombs-negative intravascular hemolysis, modest elevations in serum
aminotransferases, or low serum alkaline phosphatase and ratio of alkaline phosphatase to bilirubin of <2.
First-degree relatives of any patient newly diagnosed with WD must be screened for WD.
*Wilson disease has been diagnosed in patients in their seventies.
Data from: Roberts EA, Schilsky ML. Diagnosis and treatment of Wilson disease: an update. Hepatology 2008; 47:2089.
Screening for Wilson disease (WD) in sibling or child of a

patient with secure diagnosis of WD
If molecular testing is available in the index patient, then this is the most
efficient screening strategy. If initial screening by blood and urine testing is
normal, then consider repeat screening in 2 to 5 years.
Conversion to SI units: CPN <20 mg/dL or 0.2 g/L; 24-hour urinary Cu >40
micrograms/day or 0.6 micromol/day.
Baseline testing = complete blood count including platelet count (CBC), liver
biochemistries, international normalized ratio (INR), serum ceruloplasmin, 24-
hour urine copper excretion; liver biopsy when appropriate.
KF: Kayser-Fleischer.
Roberts EA, Schilsky ML. Diagnosis and treatment of Wilson disease: an update. Hepatology
2008; 47:2089.
Leipzig scoring system for Wilson disease
Typical clinical symptoms and signs Other tests
KF rings Liver copper (in the absence of cholestasis)
Present 2 >5x ULN (>4 micromol/g) 2
Absent 0 0.8-4 micromol/g 1
Neurologic symptoms* Normal (<0.8 micromol/g) –1
Severe 2 Rhodanine-positive granules¶ 1
Mild 1 Urinary copper (in the absence of acute hepatitis)
Absent 0 Normal 0
Serum ceruloplasmin 1-2x ULN 1
Normal (>0.2 g/L) 0 >2x ULN 2
0.1-0.2 g/L 1 Normal, but >5x ULN after D- 2

penicillamine
<0.1 g/L 2 Mutation analysis
Coombs-negative hemolytic anemia On both chromosomes detected 4
Present 1 On one chromosome detected 1
Absent 0 No mutations detected 0
TOTAL SCORE Evaluation:
4 or more Diagnosis established
3 Diagnosis possible, more tests needed
2 or less Diagnosis very unlikely
KF: Kayser-Fleischer; ULN: upper limit of normal.
* Or typical abnormalities at brain magnetic resonance imaging.
¶ If no quantitative liver copper available.
Reproduced from: European Association for Study of Liver. EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol 2012; 56:671. Table used with the permission of Elsevier Inc. All
rights reserved.
Contributor Disclosures
Michael L Schilsky, MD, FAASLD Grant/Research/Clinical Trial Support: Alexion [Wilson disease]; GMPO [Wilson disease]; Vivet [Wilson disease]; Wilson
Disease Association [Wilson disease]. All of the relevant financial relationships listed have been mitigated. Elizabeth B Rand, MD No relevant financial
relationship(s) with ineligible companies to disclose. Bruce A Runyon, MD, FAASLD Consultant/Advisory Boards: Mallinckrodt. All of the relevant
financial relationships listed have been mitigated. Michael J Aminoff, MD, DSc Consultant/Advisory Boards: Brain Neurotherapy Bio [Parkinson
disease]. All of the relevant financial relationships listed have been mitigated. Kristen M Robson, MD, MBA, FACG No relevant financial relationship(s)
with ineligible companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level
review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

Wilson Disease - Clinical Manifestations, Diagnosis, and Natural History - UpToDate

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11/24/21, 3:57 PM Wilson disease: Clinical manifestations, diagnosis, and natural history - UpToDate

Official reprint from UpToDate®

Wilson disease: Clinical manifestations, diagnosis, and natural history

● Liver disease: 18 to 84 percent of patients

Signs and symptoms of hepatic Wilson disease may include:

Laboratory test findings may include:

Abdominal imaging may show:

● Hepatic steatosis (chronic hepatitis)

● Low ceruloplasmin: 95 percent with asymptomatic or chronic presentation

● Low uric acid levels.

● A coagulopathy that is unresponsive to vitamin K.

● Rapidly progressive renal failure.

Some of the more common neurologic manifestations include:

● Dysarthria – 85 to 97 percent of patients with neurologic Wilson disease

Other neurologic manifestations include:

● Overshoot in point-to-point movements (dysmetria)

Behavioral and psychiatric manifestations of Wilson disease include [1,2,25,50,54-56]:

● Infertility or repeated spontaneous abortions.

● Kayser-Fleischer rings (2 points)

● Neuropsychiatric symptoms suggestive of Wilson disease (2 points)

● Coombs-negative hemolytic anemia with high serum copper (1 point)

● Urinary copper in the absence of acute hepatitis

• One to two times the upper limit of normal (1 point)

● Liver copper quantitative measurement

• Normal (-1 point)

• Disease causing mutations on both chromosomes (4 points)

In particular, Wilson disease should be considered in ( table 1) [34,68]:

● First-degree relatives of a patient diagnosed with Wilson disease.

We start the evaluation with:

● Kayser-Fleischer rings present:

● Kayser-Fleischer rings absent:

● Kayser-Fleischer rings present:

● Kayser-Fleischer rings absent:

SOCIETY GUIDELINE LINKS

SUMMARY AND RECOMMENDATIONS

Use of UpToDate is subject to the Subscription and License Agreement.

Kayser-Fleischer ring (arrow) in a patient with advanced

Courtesy of Marshall M Kaplan, MD.

Graphic 65925 Version 2.0

Approach to the diagnosis of Wilson disease

Δ Ensure adequate urine collection.

Graphic 104976 Version 2.0

Diagnostic considerations in specific target populations:

*Wilson disease has been diagnosed in patients in their seventies.

Graphic 79927 Version 2.0

Screening for Wilson disease (WD) in sibling or child of a

Graphic 69940 Version 3.0

Leipzig scoring system for Wilson disease

Typical clinical symptoms and signs Other tests

KF rings Liver copper (in the absence of cholestasis)

Present 2 >5x ULN (>4 micromol/g) 2

Absent 0 0.8-4 micromol/g 1

Neurologic symptoms* Normal (<0.8 micromol/g) –1

Severe 2 Rhodanine-positive granules¶ 1

Mild 1 Urinary copper (in the absence of acute hepatitis)

Serum ceruloplasmin 1-2x ULN 1

Normal (>0.2 g/L) 0 >2x ULN 2

0.1-0.2 g/L 1 Normal, but >5x ULN after D- 2

<0.1 g/L 2 Mutation analysis

Coombs-negative hemolytic anemia On both chromosomes detected 4

Present 1 On one chromosome detected 1

Absent 0 No mutations detected 0

TOTAL SCORE Evaluation: