Wilson Disease

Practice Essentials

Wilson disease is a rare autosomal recessive inherited disorder of copper metabolism that is characterized by excessive deposition of copper in the liver, brain, and other tissues (see the image below). Wilson disease is often fatal if not recognized and treated when symptomatic.

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Wilson disease biopsy specimen with rhodanine stain (stain specific for copper deposition).

Signs and symptoms

Hepatic dysfunction is the presenting feature in more than half of patients. Although the condition may manifest as acute hepatitis, the three major patterns of hepatic involvement are as follows:

• Chronic active hepatitis
• Cirrhosis (the most common initial presentation)
• Fulminant hepatic failure

Signs of fulminant hepatic failure include the following:

• Ascites and prominent abdominal veins
• Spider nevi
• Palmar erythema
• Digital clubbing
• Hematemesis
• Jaundice

Neuropsychiatric features

Most patients who present with neuropsychiatric manifestations have cirrhosis. The most common presenting neurologic feature is asymmetric tremor, which is variable in character and may be predominantly resting, postural, or kinetic.

Frequent early symptoms include the following:

• Difficulty speaking
• Excessive salivation
• Ataxia
• Masklike facies
• Clumsiness with the hands
• Personality changes

Late manifestations (now rare because of earlier diagnosis and treatment) include the following:

• Dystonia
• Spasticity
• Grand mal seizures
• Rigidity
• Flexion contractures

Psychiatric features (10%-20% of patients) include the following:

• Emotional lability
• Impulsiveness
• Disinhibition
• Self-injurious behavior

Psychiatric abnormalities associated with Wilson disease has been divided into the following four basic categories:

• Behavioral
• Affective
• Schizophrenic-like
• Cognitive

Musculoskeletal manifestations

• The arthropathy of Wilson disease is a degenerative process that resembles premature osteoarthritis
• Symptomatic joint disease usually arises late in the course of the disease, frequently after age 20 years
• The arthropathy generally involves the spine and large appendicular joints (eg, knees, wrists, hips)
• Osteochondritis dissecans, chondromalacia patellae, and chondrocalcinosis have also been described

Hematologic and renal manifestations

• Coombs-negative acute intravascular hemolysis (10%-15%)
• Urolithiasis
• Hematuria

Kayser-Fleischer rings

• Formed by the deposition of copper in the Descemet membrane in the limbus of the cornea
• The color may range from greenish gold to brown
• Well-developed rings may be readily visible to the naked eye or with an ophthalmoscope set at +40
• When not visible to the unaided eye, the rings may be identified using slit-lamp examination or gonioscopy
• Observed in up to 90% of individuals with symptomatic Wilson disease and almost invariably present in those with neurologic manifestations
• No longer considered pathognomonic of Wilson disease unless accompanied by neurologic manifestations, as they may also be observed in patients with chronic cholestatic disorders

Additional manifestations

• Skeletal abnormalities (eg, osteoporosis, osteomalacia, rickets, spontaneous fractures, polyarthritis)
• Cardiac manifestations (eg, rhythm abnormalities, increased autonomic tone)
• Skin pigmentation and a bluish discoloration at the base of the fingernails (azure lunulae)

See Presentation for more detail.

Diagnosis

Considerations in the workup of Wilson disease are as follows:

• Serum ceruloplasmin levels are less than 20 mg/dL (reference range, 20-40 mg/dL) in approximately 90% of all patients with Wilson disease
• The urinary copper excretion rate is greater than 100 mcg/day (reference range, < 40 mcg/day) in most patients with symptomatic Wilson disease, but it may also be elevated in other cholestatic liver diseases
• In a patient with Kayser-Fleischer rings, a serum ceruloplasmin level < 20 mg/dL and 24-hour urine copper excretion >40 mcg/day establish the diagnosis of Wilson disease
• Hepatic copper concentration (criterion standard) on a liver biopsy specimen is >250 mcg/g of dry weight even in asymptomatic patients; a normal result (15-55 mcg/g) effectively excludes the diagnosis of untreated Wilson disease, but elevation may be found in other chronic hepatic disorders
• Radiolabeled copper testing directly assays hepatic copper metabolism
• Genetic testing is limited to screening of family members for an identified mutation detected in the index patient
• Brain imaging shows characteristic findings; MRI appears to be more sensitive than CT in detecting early lesions
• Abdominal imaging findings are neither sensitive nor specific
• Resting ECG abnormalities include left ventricular or biventricular hypertrophy, early repolarization, ST segment depression, T-wave inversion, and various arrhythmias
• Electron microscopic detection of copper-containing hepatocytic lysosomes is helpful in the diagnosis of the early stages of Wilson disease, in addition to the quantification of hepatic copper by atomic absorption spectrophotometry

See Workup for more detail.

Management

Features of treatment of Wilson disease are as follows:

• The mainstay of therapy is lifelong use of chelating agents (eg, penicillamine, trientine)
• Symptoms, particularly neurologic ones, may worsen with initiation of chelation
• Surgical decompression or transjugular intrahepatic shunting (TIPS) is reserved for recurrent or uncontrolled variceal bleeding unresponsive to standard conservative measures
• Orthotopic liver transplantation is curative

Other treatments for Wilson disease include the following:

• Anticholinergics, baclofen, GABA antagonists, and levodopa to treat parkinsonism and dystonia
• Antiepileptics to treat seizures
• Neuroleptics to treat psychiatric symptoms
• Protein restriction, lactulose, or both to treat hepatic encephalopathy

See Treatment and Medication for more detail.

• References

Background

Wilson disease is a rare autosomal recessive inherited disorder of copper metabolism. The condition is characterized by excessive deposition of copper in the liver, brain, and other tissues. The major physiologic aberration is excessive absorption of copper from the small intestine and decreased excretion of copper by the liver. (See Etiology.) The available evidence suggests that substantial increases in copper concentrations in the central nervous system persist for a long time during chelating treatment and that local accumulation of iron in certain brain nuclei may occur during the course of the disease.^[1]

The genetic defect, localized to arm 13q, has been shown to affect the copper-transporting adenosine triphosphatase (ATPase) gene (ATP7B) in the liver.^[2] Patients with Wilson disease more often initially present with hepatic manifestations when identified in the first decade of life as compared with more neuropsychiatric illness later, and the latter most commonly occurs during the third decade. The diagnosis is established by no individual test but requires the use of some combination of serum ceruloplasmin level, urinary copper excretion, presence of Kayser-Fleischer rings, and hepatic copper content when biopsy is required. (See Etiology, Presentation, and Workup.)

Although it is extremely rare in clinical practice, Wilson disease is important because it is often fatal if not recognized and treated when symptomatic. Often, the diagnosis is not made until adulthood, despite manifestations of the disease beginning to develop in childhood. (See Differentials, Treatment, and Medication.)

Staging

The natural history of Wilson disease may be considered in four stages, as follows:

• Stage I - The initial period of accumulation of copper within hepatic binding sites
• Stage II - The acute redistribution of copper within the liver and its release into the circulation
• Stage III - The chronic accumulation of copper in the brain and other extrahepatic tissue, with progressive and eventually fatal disease
• Stage IV - Restoration of copper balance by the use of long-term chelation therapy

Patient education

For patient education information, see the Digestive Disorders Center, as well as Cirrhosis.

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Etiology

The normal estimated total body copper content is 50-100 mg, and the average daily intake 2-5 mg, depending on an individual’s intake of legumes, meats, shellfish, and chocolate. Copper is an important component of several metabolic enzymes, including lysyl oxidase, cytochrome c oxidase, superoxide dismutase, and dopamine beta-hydroxylase.

Around 50%-75% of intestinal copper is absorbed and then transported to the hepatocytes. This pathway is intact in Wilson disease. After copper reaches the hepatocyte, it is incorporated into copper-containing enzymes and copper-binding proteins (CBPs), including ceruloplasmin, a serum ferroxidase. Within the liver, the majority of in-infancy (< 6 mo) CBP granules staining positive may be normal. After six months, positive staining of CBPs for copper is almost exclusively found in association with liver diseases such as Wilson disease, chronic biliary disorders (eg, primary biliary cirrhosis, primary sclerosing cholangitis), cirrhosis/extensive fibrosis, and primary liver tumors (most often fibrolamellar hepatocellular carcinoma).

Excess copper may be rendered nontoxic by forming complexes with apo-metallothionein to produce copper-metallothionein, or it may be excreted into bile. Normal copper balance is maintained by regulation of excretion, rather than absorption, and the predominant route of copper excretion (approximately 95%) is hepatobiliary in nature.

In Wilson disease, the processes of incorporation of copper into ceruloplasmin and excretion of excess copper into bile are impaired.^[3] The transport of copper by the copper-transporting P-type ATPase is defective in Wilson disease secondary to one of several mutations in the ATP7B gene.^[4] By genetic linkage studies, Bowcock and colleagues narrowed the assignment of the Wilson disease locus to 13q14-q21.^[5]

Many of the gene defects for ATP7B are small deletions, insertions, or missense mutations. Most patients carry different mutations on each of their 2 chromosomes. More than 40 different mutations have been identified, the most common of which is a change from a histidine to a glutamine (H1069Q). Stapelbroek et al linked the H1069Q mutation to a late and neurologic presentation.^[6]

The excess copper resulting from Wilson disease promotes free radical formation that results in oxidation of lipids and proteins. Ultrastructural abnormalities in the earliest stages of hepatocellular injury, involving the endoplasmic reticulum, mitochondria, peroxisomes, and nuclei, have been identified. Initially, the excess copper accumulates in the liver, leading to damage to hepatocytes. Eventually, as liver copper levels increase, it increases in the circulation and is deposited in other organs.

Stuehler et al reported that base pair changes in the MURR1 gene were associated with an earlier presentation of Wilson disease.^[7] MURR1 had previously been established to cause canine copper toxicosis in Bedlington terriers.

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Epidemiology

In the United States, the carrier frequency is 1 per 90 individuals. The prevalence of Wilson disease is 1 per 30,000 individuals.

Worldwide, the incidence of Wilson disease is 10-30 million cases, and the heterozygote carrier rate is 1 case per 100 persons, with the genetic mutation frequency varying from 0.3%-0.7%. In Japan, the rate is 1 case per 30,000 population, compared with 1 case per 100,000 population in Australia. The increased frequency in certain countries is due to high rates of consanguinity. The fulminant presentation of Wilson disease is more common in females than in males.

Age-related presentations

A German study of patients with Wilson disease illustrated that patients presenting earlier show predominantly hepatic symptoms (15.5 [9.6] y), while those presenting later more often present with neurological symptoms (20.2 [10.8] y).^[8]

Thomas and colleagues reviewed the mutations found in the ATP7B gene, and their findings suggested a wide age span in the onset of Wilson disease, perhaps wider than previously considered typical. Mutations that completely disrupt the gene can produce liver disease in early childhood, at a time when Wilson disease may not be considered in the differential diagnosis.^[9]

In general, the upper age limit for considering Wilson Disease is 40 years and the lower age limit is 5 years, although the disorder has been detected in children younger than 3 years and in adults older than 70 years.^[10]

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Prognosis

Patients with a prognostic index (ie, score) of 7 or greater should be considered for liver transplantation (see Table 1, below). All patients in the study associated with this prognostic index who exceeded this score died within 2 months of diagnosis, irrespective of the institution of appropriate medical therapy.

Table. Prognostic Index in Fulminant Wilsonian Hepatitis

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See Table

Prognosis after liver transplantation is relatively good. In a study involving 55 patients with Wilson disease who underwent hepatic transplantation, the 1-year survival rate was 79% and the overall survival rate was 72% at 3 months to 20 years. Another study of 32 patients reported a 1-year survival of 90.6%, a 5-year survival rate of 83.7%, and a 10-year survival rate of 79.9% after living donor liver transplantation.^[11]

Important clues for the diagnosis of Wilson disease that a clinician must recognize are a younger patient with hemolytic anemia, impaired hepatic synthetic function, and normal alkaline phosphatase values.

Complications

The major complications in patients with untreated Wilson disease are those associated with acute liver failure, chronic hepatic dysfunction with either portal hypertension or hepatocellular carcinoma, and the sometimes-relentless course to cirrhosis, which is characterized by a progressive lassitude, fatigue, anorexia, jaundice, spider angiomas, splenomegaly, and ascites. Bleeding from varices, hepatic encephalopathy, hepatorenal syndrome, and coagulation abnormalities occur as liver failure ensues. Death occurs, generally at age 30 years, if emergent liver transplantation is not performed.

Unfortunately, Wilson disease has other systemic consequences of copper overload. Most patients who present with neuropsychiatric manifestations have cirrhosis. The reported percentage of patients with psychiatric symptoms as the presenting clinical feature is 10%-20%. The range of psychiatric abnormalities associated with Wilson disease extends from behavioral/mood state disturbances through movement disorders (occasionally choreoathetoid) or parkinsonian features. These features, on occasion, can be made worse with chelation therapy.

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History

Wilson disease has a range of clinical manifestations, from an asymptomatic state to fulminant hepatic failure, chronic liver disease with or without cirrhosis, neurologic, and psychiatric manifestations.^[2]

Consider hepatic Wilson disease in the differential diagnosis of any unexplained chronic liver disease, especially in individuals younger than 40 years.^[12] The condition may also manifest as acute hepatitis. Hepatic dysfunction is the presenting feature in more than half of patients. The three major patterns of hepatic involvement are as follows: (1) chronic active hepatitis, (2) cirrhosis, and (3) fulminant hepatic failure. The most common initial presentation is cirrhosis.

Neuropsychiatric symptoms

An estimated 50% of patients with Wilson disease have neurologic or psychiatric symptoms.^[13] Most patients who present with neuropsychiatric manifestations have cirrhosis. The most common presenting neurologic feature is asymmetrical tremor, occurring in approximately half of individuals with Wilson disease. The character of the tremor is variable and may be predominantly resting, postural, or kinetic. Kayser-Fleischer rings are seen in at least 98% of patients with neurological Wilson disease who have not received chelation therapy.

Frequent early symptoms include difficulty speaking, excessive salivation, ataxia, masklike facies, clumsiness with the hands, and personality changes.

Late manifestations (now rare because of earlier diagnosis and treatment) include dystonia, spasticity, grand mal seizures, rigidity, and flexion contractures.

One study described four distinct diagnostic categories based on patients' major neurologic findings, as follows^[14] :

• Patients in the parkinsonian group (45%) - Distinguished by paucity of expression and movement
• Patients in the pseudosclerotic group (24%) - Had tremor resembling multiple sclerosis
• Patients in the dystonic group (15%) - Characterized by hypertonicity associated with abnormal limb movements.
• Patients in the choreic group (11%) - Predominantly characterized by choreoathetoid abnormal movements associated with dystonia

Psychiatric features include emotional lability, impulsiveness, disinhibition, and self-injurious behavior. The reported percentage of patients with psychiatric symptoms as the presenting clinical feature is 10%-20%. The range of psychiatric abnormalities associated with Wilson disease has been divided into four basic categories, as follows:

• Behavioral
• Affective
• Schizophrenic-like
• Cognitive

Musculoskeletal symptoms

Skeletal involvement is a common feature of Wilson disease, with more than half of patients exhibiting osteopenia on conventional radiologic examination.

The arthropathy of Wilson disease is a degenerative process that resembles premature osteoarthritis. Symptomatic joint disease, which occurs in 20%-50% of patients, usually arises late in the course of the disease, frequently after age 20 years. The arthropathy generally involves the spine and large appendicular joints, such as knees, wrists, and hips. Osteochondritis dissecans, chondromalacia patellae, and chondrocalcinosis have also been described.

Hematologic symptoms

Hemolytic anemia is a recognized, but rare (10%-15%), complication of the disease. Coombs-negative acute intravascular hemolysis most often occurs as a consequence of oxidative damage to the erythrocytes by the higher copper concentration. Any patient in whom acute hepatic failure occurs with a Coombs-negative intravascular hemolysis, modest elevations in serum aminotransferases, and a low serum alkaline phosphatase or ratio of alkaline phosphatase to bilirubin of less than 2 must be considered for a diagnosis of Wilson disease.

Renal symptoms

The Wilson disease gene is expressed in kidney tissue; therefore, any renal manifestations may be primary or secondary to release of copper from the liver.

Clinically, patients may resemble those with Fanconi syndrome, demonstrating defective renal acidification and excess renal losses of amino acids, glucose, fructose, galactose, pentose, uric acid, phosphate, and calcium. The frequency of renal manifestations is variable.

Urolithiasis, found in up to 16% of patients with Wilson disease, may be the result of hypercalciuria or poor acidification.

Hematuria and nephrocalcinosis are reported, and proteinuria and peptiduria can occur before treatment as part of the disease process and after therapy as adverse effects of D-penicillamine.^[15]

Fulminant Wilson disease

Although no individual clinical or laboratory finding is definitively diagnostic for fulminant Wilson disease, the combination of low serum transaminases, low serum alkaline phosphatase, hemolysis, and evidence of renal Fanconi syndrome is characteristics of a fulminant presentation of Wilson disease. Critically important is early recognition.

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Physical Examination

Hepatic symptoms

Hepatic insufficiency and cirrhosis may slowly develop and can result in signs of fulminant hepatic failure, including the following:

• Ascites and prominent abdominal veins
• Spider nevi
• Palmar erythema
• Digital clubbing
• Hematemesis
• Jaundice

Neurologic symptoms

Central nervous system (CNS) pathology in patients with Wilson disease results from copper deposition in the basal ganglia. The resulting signs include the following:

• Drooling
• Dysphagia
• Dystonia
• Incoordination
• Difficulty with fine motor tasks
• Masklike facies
• Gait disturbance

Ophthalmologic symptoms

Kayser-Fleischer rings are formed by the deposition of copper in the Descemet membrane in the limbus of the cornea. The color may range from greenish gold to brown; when well developed, rings may be readily visible to the naked eye or with an ophthalmoscope set at +40. When not visible to the unaided eye, the rings may be identified using slit-lamp examination or gonioscopy.

Kayser-Fleischer rings are observed in up to 90% of individuals with symptomatic Wilson disease and are almost invariably present in those with neurologic manifestations.

Although Kayser-Fleischer rings are a useful diagnostic sign, they are no longer considered pathognomonic of Wilson disease unless accompanied by neurologic manifestations. They may also be observed in patients with chronic cholestatic disorders, such as partial biliary atresia, primary biliary cirrhosis, primary sclerosing cholangitis, and cryptogenic cirrhosis.

Kayser-Fleischer rings consist of electron-dense granules rich in copper and sulfur. The rings form bilaterally, initially appearing at the superior pole of the cornea, then the inferior pole, and, ultimately, circumferentially.

Sunflower cataract appears to be a rare and reversible ophthalmologic finding in Wilson disease.^[16] This finding may occur only at the time of diagnosis of Wilson disease and is thus not a pathognomonic sign.

Additional symptoms

Skeletal abnormalities in patients with Wilson disease widely vary and include osteoporosis, osteomalacia, rickets, spontaneous fractures, and polyarthritis.

Cardiac manifestations, such as rhythm abnormalities and increased autonomic tone, have been described in patients with Wilson disease. Autopsy findings have included hypertrophy, small vessel disease, and focal inflammation.^[17]

Patients with Wilson disease exhibit signs of anemia, presumably due to oxidative injury of the cell membrane caused by excess copper. Skin pigmentation and a bluish discoloration at the base of the fingernails (azure lunulae) have been described in patients with Wilson disease.

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Approach Considerations

The presence of Kayser-Fleischer rings and ceruloplasmin levels of less than 20 mg/dL in a patient with neurologic signs or symptoms suggest a diagnosis of Wilson disease. If a patient is asymptomatic, exhibits isolated liver disease, and lacks corneal rings, the coexistence of a hepatic copper concentration of more than 250 mg/g of dry weight and a low serum ceruloplasmin level is sufficient to establish a diagnosis. Therefore, in the absence of Kayser-Fleischer rings or neurologic abnormalities, a liver biopsy for quantitative copper determination is essential to establish the diagnosis of Wilson disease.

Genetic diagnosis

First- and second-degree relatives of patients with confirmed Wilson disease must be screened for this condition.^[2]

Linkage analysis has been used in family studies for presymptomatic testing; however, the multiplicity of mutations (>200 mutations of ATP7B have been identified) that require screening in individuals without affected family members is large, making such analysis impractical. Therefore, the use of molecular testing is currently limited to screening of family members for an identified mutation detected in the index patient.

Abdominal imaging

Computed tomography (CT) scanning, magnetic resonance imaging (MRI), ultrasonography, and nuclear medicine studies of the liver have been uninformative, with findings neither specific nor sensitive for Wilson disease.

Electrocardiography

Resting electrocardiographic abnormalities include left ventricular or biventricular hypertrophy, early repolarization, ST segment depression, T-wave inversion, and various arrhythmias.

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Serum Ceruloplasmin

Serum ceruloplasmin levels are low in newborns and gradually rise within the first 2 years of life. Approximately 90% of all patients with Wilson disease have ceruloplasmin levels of less than 20 mg/dL (reference range, 20-40 mg/dL). (Ceruloplasmin is an acute phase reactant and may be increased in response to hepatic inflammation, pregnancy, estrogen use, or infection.)

Falsely low ceruloplasmin levels may be observed in any protein deficiency state, including nephrotic syndrome, malabsorption, protein-losing enteropathy, and malnutrition. Ceruloplasmin levels may also be decreased in 10%-20% of Wilson Disease gene heterozygotes, who do not develop Wilson disease and do not require treatment.

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Urinary Copper Excretion and Hepatic Copper Concentration

Urinary copper excretion

The urinary copper excretion rate is greater than 100 mcg/d (reference range, < 40 mcg/d) in most patients with symptomatic Wilson disease. The rate may also be elevated in other cholestatic liver diseases.

The sensitivity and the specificity of this test are suboptimal for use as a screening test; however, it may be useful to confirm the diagnosis and to evaluate the response to chelation therapy.

In an institutional study of 32 patients treated with d-penicillamine (DPA) with routine follow-up studies, 24-hour urinary copper excretion analysis 48 hours after interruption of chelating therapy was a reliable method to confirm patient compliance.^[18] The investigators noted that normalization of copper excretion was observed in 91% of reportedly compliant patients, with an 87% specificity and 77% sensitivity.

Hepatic copper concentration

This test is regarded as the criterion standard for diagnosis of Wilson disease. A liver biopsy with sufficient tissue reveals levels of more than 250 mcg/g of dry weight even in asymptomatic patients. Special collection vials are available to help avoid contamination.

A normal hepatic copper concentration (reference range, 15-55 mcg/g) effectively excludes the diagnosis of untreated Wilson disease. An elevated hepatic copper concentration may be found in other chronic hepatic (mostly cholestatic) disorders.

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Genetic Testing

Mutation analysis is an especially valuable diagnostic strategy for certain well-defined populations exhibiting a limited spectrum of ATP7B mutations. Pedigree analysis using haplotypes based on polymorphisms surrounding the the ATP7B gene are also commercially available from specific clinical laboratories.^[10]

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Radiolabeled Copper

Radiolabeled copper testing directly assays hepatic copper metabolism. Blood is collected at 1, 2, 4, 24, and 48 hours after oral ingestion of radiolabeled copper (⁶⁴ Cu or⁶⁷ Cu) for radioactivity in serum. In all individuals, radioactivity promptly appears after absorption, followed by hepatic clearance. In healthy people, reappearance of the radioactivity in serum occurs as the labeled copper is incorporated into newly synthesized ceruloplasmin and released into the circulation.

Heterozygotes exhibit a slow, lower-level reappearance of radioactivity rather than the continued fall in radioactivity seen in persons with Wilson disease, but there may be considerable overlap between the two types of patients. Patients with Wilson disease, even those with normal ceruloplasmin levels, do not exhibit the secondary rise in radioactivity.

An algorithm for the diagnosis of Wilson disease adapted from the American Association for the Study of Liver Diseases (AASLD) Practice Guidelines is outlined below.

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Approach to the diagnosis of Wilson disease (WD) in a patient with unexplained liver disease. KF = Kayser-Fleischer ring; CPN = ceruloplasmin. From th....

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Cranial CT Scanning

The cranial lesions observed on CT scans are typically bilateral and are classified into two general categories: (1) well-defined, slitlike, low-attenuation foci involving the basal ganglia, particularly the putamen, and (2) larger regions of low attenuation in the basal ganglia, thalamus, or dentate nucleus.

Widening of the frontal horns of the lateral ventricles and diffuse cerebral and cerebellar atrophy, which correlate histologically with widespread neuronal loss, have also been described. (See the image below.)

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Computed tomography (CT) scan in a 15-year-old boy who presented with central nervous system findings consistent with Wilson disease. The CT scan reve....

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Brain MRI

MRI of the brain appears to be more sensitive than CT scanning in detecting early lesions of Wilson disease. MRI studies have identified focal abnormalities in the white matter, pons, and deep cerebellar nuclei. These lesions, measuring 3-15 mm in diameter, are typically bilateral, appearing with low signal intensity on T1-weighted images and with high signal intensity on T2-weighted images, representing cell loss and gliosis. Other studies describe decreased signal intensity in the putamen and other parts of the basal ganglia, which may represent either copper or iron ferritin deposition.

A characteristic "face of the giant panda" sign has been described, formed by high signal intensity in the tegmentum (except for the red nucleus), preserved signal intensity of the lateral portion of the pars reticulata of the substantia nigra, and hypointensity of the superior colliculus.

Results from a study by Tarnacka et al indicated that relative to the thalamus, the basal ganglia are more sensitive to ongoing degenerative changes and portal-systemic encephalopathy in Wilson disease. The authors used proton magnetic resonance spectroscopy (MRS) in 37 patients with newly diagnosed Wilson disease to identify the pathomechanism of the disease's cerebral pathology, specifically looking at the globus pallidus and thalamus to assess cerebral metabolic changes in myoinositol, choline, creatine, N-acetyl-aspartate, lipid, glutamine, and glutamate levels and ratios.^[19]

The investigators speculated that N-acetyl-aspartate/creatine ratio reductions seen in hepatically and neurologically impaired patients in the study may have indicated an association between neurodegeneration and all presentations of Wilson disease. In addition, they suggested that observed decreases in myoinositol and choline and an increase in neurologic glutamate may have been due to portosystemic shunting.^[19]

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PET Scanning

Positron emission tomography (PET) scanning reveals a significantly reduced regional cerebral metabolic rate of glucose consumption in the cerebellum, striatum, and, to a lesser extent, in the cortex and thalamus.

PET scan analyses of patients with Wilson disease have also demonstrated a marked reduction in the activity of dopa-decarboxylase, indicative of impaired function of the nigrostriatal dopaminergic pathway.

These abnormalities improve with chelation therapy, indicating a reversible component of striatal neuron injury.

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Electron Microscopy

Electron microscopic studies on ultrathin sections reveal numerous electron-dense lysosomes and residual bodies. The elemental analysis in transmission electron microscopy with electron energy loss spectroscopy, and in scanning electron microscopy with energy dispersive x-ray analysis, shows copper-specific signals of electron-dense accumulations inside these dark lysosomes and residual bodies.

The electron microscopic detection of copper-containing hepatocytic lysosomes is helpful in the diagnosis of the early stages of Wilson disease, in addition to the quantification of hepatic copper by atomic absorption spectrophotometry.

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Histologic Findings

Hepatic

The earliest changes detectable with light microscopy include glycogen deposition in the nuclei of periportal hepatocytes and moderate fatty infiltration. The lipid droplets, which are composed of triglycerides, progressively increase in number and size, sometimes resembling the steatosis induced by ethanol. Hepatocyte mitochondria typically exhibit heterogeneity in size and shape, with increased matrix density, separation of the normally apposed inner and outer mitochondrial membranes, widened intercristal spaces, and an array of vacuolated and crystalline inclusions within the matrix. With progression of disease, copper protein is sequestered in lysosomes and is visible as electron-dense pericanalicular granules.

Despite consistently elevated hepatic copper levels in patients with Wilson disease, histochemical staining of liver biopsy specimens for copper is of little diagnostic value. Early in the disease, copper distribution is primarily cytoplasmic and is not readily apparent with rhodamine or rubeanic acid staining.

The rate of progression of the liver histology from fatty infiltration to cirrhosis is variable, although it tends to occur by 1 of 2 general processes, either with or without hepatic inflammation. The histologic picture may be histologically indistinguishable from that of chronic active hepatitis. Pathologic features include mononuclear cell infiltrates, which consist mainly of lymphocytes and plasma cells; piecemeal necrosis extending beyond the limiting plate; parenchymal collapse; bridging hepatic necrosis; and fibrosis.

The histologic pattern is one of a macronodular or mixed micro-macronodular cirrhosis, with fibrous septa (containing predominantly types I and III collagen), bile ductule proliferation, and variable septal round cell infiltration. Hepatocytes at the periphery of the nodules frequently contain Mallory hyalin. One proposed mechanism implicates copper as the inducer of fibrogenesis.

Interestingly, hepatocellular carcinoma is exceedingly rare in patients with Wilson disease compared with patients with hemochromatosis. This may be attributable to the significantly shortened life expectancy in untreated patients with Wilson disease, which does not allow time for carcinoma to develop. An increasing number of case reports suggest that the incidence will likely increase with improved survival. It has been proposed that the diminished cancer risk is due to the relatively low inflammatory component in the pathogenesis of Wilson disease.

Neurologic

Observed gross anatomical changes include degeneration and cavitation, primarily involving the putamen, globus pallidus, caudate nucleus, and thalamus. Little correlation has been observed between the degree of neurologic impairment and the neuropathologic findings. The affected areas of the brain do not possess higher copper concentrations than the unaffected portions.

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Approach Considerations

The mainstay of therapy for Wilson disease is pharmacologic treatment with chelating agents such as D-penicillamine and trientine.^[2] Other agents include sodium dimercaptosuccinate, dimercaptosuccinic acid, zinc, and tetrathiomolybdate.^[13] Zinc salts act as inductors of methallothioneins, which favor a negative copper balance and a reduction of free plasmatic copper.^[2]

The use of surgical decompression or transjugular intrahepatic shunting (TIPS) in the treatment of portal hypertension is reserved for individuals with recurrent or uncontrolled variceal bleeding that is unresponsive to standard conservative measures.

After the initiation of therapy with a chelating agent, the patient needs to be aware of potential adverse effects of the agents with which he or she is being treated. For instance, some of the concerning adverse effects are those commonly associated with penicillamine use. In addition, a patient must also be aware of the potential to develop worsening of some symptoms when chelation is started; in particular, patients with neurologic signs and symptoms can see worsening of these with chelation, and, in some instances, therapy needs to be reduced or stopped. Laboratory tests in patients started on penicillamine should include hematology and biochemical monitoring, as well as urinalysis.

With clinical progression, acute liver failure, or worsening hepatic function, the patient must be evaluated at a center with expertise in Wilson disease and the capability to perform liver transplantation.

Orthotopic liver transplantation is curative treatment for Wilson disease. Also see Liver Transplantation.

Diet

Patients should generally avoid eating foods with a high copper content, such as liver, chocolate, nuts, mushrooms, legumes, and shellfish (especially lobster). Drinking water from atypical sources (eg, well water) should be analyzed for copper content and replaced with purified water if the copper content is greater than 0.2 parts per million.

Pregnancy

Excessive intrauterine copper concentrations may be responsible for the high rate of spontaneous abortions in patients with Wilson disease. D-penicillamine (0.75-1.5 g/day) appears to pose no major risk to the fetus and should be continued throughout the pregnancy.

While pregnancy per se does not appear to have a deleterious effect on the course of treated patients, the risk of ascites or bleeding from gastroesophageal varices in pregnancy is increased for any individual with cirrhosis, regardless of the underlying etiology.

Pediatric

Pediatricians should consider Wilson disease in any child with hepatic abnormalities. The initial tests should be performed, and further workup by a pediatric gastroenterologist may be necessary if suspicion remains high.

Geriatric

Almost all patients have significant hepatic and neuropsychiatric symptoms before reaching the geriatric age group. Patients with Wilson disease who are untreated will most likely present with fulminant hepatic failure or with signs and symptoms of cirrhosis in the geriatric population. Consideration for liver transplantation is less likely with advancing age.

Neurologic deterioration with treatment

It is very important to recognize that some patients may develop worsening neurologic symptoms when therapy is initiated. In some of these instances, the chelating agent needs to be stopped and the patient should be run on zinc acetate alone. In patients on long-term treatment who show signs of progressive neurologic symptoms on chelating agents, medication compliance and dietary compliance require review, along with an assessment of the efficacy of laboratory testing.

Medicolegal concerns

Medicolegal issues may arise if the diagnosis is not considered in the face of appropirate clues.

Also critical is to provide the patient with information and to screen siblings of the index case for the possibility of Wilson disease, because the estimated frequency is 1 in 4 in situations in which the siblings have the same parents.

Consultations

Consider consultation with gastroenterologists with specialty training in hepatology for any patient with Wilson disease, especially when evidence of hepatic insufficiency is present. Consultation with surgeons may be sought for liver transplantation when deemed necessary.

• References

Long-Term Monitoring

Perform a physical examination, 24-hour urinary copper excretion assay, complete blood count (CBC), urinalysis, serum free copper measurement, and renal and liver function tests on a weekly basis for the first 4-6 weeks following initiation of chelation therapy.

The best way to monitor efficacy is to measure serum nonceruloplasmin-bound copper. This is measured by the following formula: Total serum copper (mcg/dL) - 3[ceruloplasmin (mg/dL)]. The reference range is less than 15 mcg/dL.

An adjunctive way to monitor efficacy is to measure urinary copper excretion. Urinary chelator levels usually measure 200-500 mcg/day. Urinary zinc levels usually measure less than 75 mcg/day.

Bimonthly evaluations are recommended through the first year, followed by yearly examinations thereafter. In patients with Kayser-Fleischer rings, a yearly slit-lamp examination should document fading or disappearance if patients are being adequately "decoppered."

Lifelong, uninterrupted chelation therapy is necessary in all patients with Wilson disease. Frequent follow-up with patients is necessary, secondary to patient decompensation due to noncompliance. This is one of the major causes of fulminant liver failure. Patients must avoid most alcohol consumption and potential hepatotoxic drug therapy.

• References

Molecular Adsorbents Recirculating System (MARS)

MARS is an extracorporeal liver support system using a hollow-fiber dialysis module in which the patient’s blood is dialyzed across an albumin-impregnated membrane while maintaining a constant flow of albumin-rich (20%) dialysate in the extracapillary compartment. Case reports and very small series have presented a role for this as a bridge to liver transplantation.^[20]

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Medication Summary

The mainstay of therapy for Wilson disease is the use of chelating agents and medications that block copper absorption from the gastrointestinal (GI) tract.

Zinc and penicillamine are lifelong medications for patients with Wilson disease. Dosages vary with the severity of the disorder. Another chelating agent is trientine, which may be more easily tolerated than penicillamine.^[21] Patients who do not respond to zinc therapy and who have increased activities of liver enzymes should be identified so that chelating agents may be added to the therapeutic regimen.^{[22, 23]}

Other medications used to treat Wilson disease include anticholinergics, baclofen, gamma-aminobutyric acid (GABA) antagonists, and levodopa, to treat parkinsonism and dystonia symptoms; antiepileptics to treat seizures; and neuroleptics to treat psychiatric symptoms. In addition, protein restriction, lactulose, or both are used to treat hepatic encephalopathy.

• References

Penicillamine (Cuprimine, Depen)

• Dosing, Interactions, etc.

Clinical Context:  Penicillamine forms soluble complexes with metals excreted in urine. It was the drug of choice before newer regimens were available. Because of extensive toxicities, alternative agents are used. It must be administered with pyridoxine 25 mg by mouth daily.

• References

Trientine (Syprine)

• Dosing, Interactions, etc.

Clinical Context:  Trientine is an effective oral chelator used to induce cupruresis. It is useful for patients who cannot tolerate penicillamine. It is indicated in Wilson disease if the initial presentation is hepatic. It should be administered with zinc.

• References

Dimercaprol (BAL in Oil)

• Dosing, Interactions, etc.

Clinical Context:  Dimercaprol is for refractory cases of Wilson disease that are not responding to first- or second-line chelation treatment.

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Class Summary

Chelating agents bind excess copper. Ammonium tetrathiomolybdate is an investigational chelating drug used at the University of Michigan as an initial treatment for patients who present with neurologic or psychiatric manifestations. This drug works as a chelating agent and as an inhibitor of copper absorption from the GI tract.^[24]

• References

Zinc (Galzin)

• Dosing, Interactions, etc.

Clinical Context:  Zinc is a cofactor for more than 70 types of enzymes. It is approved for patients initially treated with a chelating agent. It should be used for maintenance after initial chelation therapy. Zinc acetate is the drug of choice in presymptomatic, pregnant, pediatric populations, and in some instance for maintenance in compliant patients who have undergone copper chelation therapy. It is a second-line therapy in patients with neurologic manifestations who do not tolerate chelation as a consequence of deterioration on this therapy.

• References

Pyridoxine (Aminoxin, Pyri-500)

• Dosing, Interactions, etc.

Clinical Context:  Pyridoxine is involved in synthesis of GABA within the CNS.

• References

Class Summary

Nutrients are essential to normal growth and development, and they play a role in many metabolic processes.

• References