WILSON DISEASE

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CHAPTER 108 WILSON DISEASE

Wilson Disease is an autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene. The gene product, a P-type adenosine triphosphatase (ATPase), is necessary for both the incorporation of copper into ceruloplasmin and its excretion into bile. The disease is associated with increased hepatic copper storage which leads to a clinically heterogeneous illness marked by cirrhosis of the liver and degenerative changes in the basal ganglia.

During the second half of the 19th century, a condition termed pseudosclerosis was distinguished from multiple sclerosis by the lack of ocular signs. In 1902, Kayser observed green corneal pigmentation in one such patient.¹ Fleischer, who had also noted the green pigmentation of the cornea in 1903, commented on the association of the corneal rings with pseudosclerosis.² In 1912, Wilson provided the classic description of the disease and its pathological anatomy but failed to mention the abnormal corneal pigmentation.³

EPIDEMIOLOGY

The worldwide prevalence of Wilson disease is 1 per 30,000, with a carrier frequency of 1 per 90. In the United States, the frequency is about 1 per 55,000. The condition occurs in all races and ethnic groups, with a particularly high incidence in Eastern European Jews, in Italians from southern Italy and Sicily, and in people from some of the smaller islands of Japan—groups with high rates of inbreeding.

CLINICAL FEATURES

Wilson disease is a progressive condition with a tendency toward temporary clinical improvement and arrest of symptoms.⁴ The presenting symptoms can be neurological, hepatic, psychiatric, or, less frequently, hematological. Symptoms at onset are listed in Table 108-1.

TABLE 108-1 Clinical Manifestations at Onset of Wilson’s Disease

Symptoms	Percentage^*
Hepatic or Hematologic Abnormalities	35
Behavioral Abnormalities	25
Neurological Abnormalities	40
“Pseudosclerotic” form: one or more of the following:	40
Resting or intentional tremor
Dysarthria or scanning speech
Diminished dexterity or mild clumsiness
Unsteady gait
Tremor alone	33
Dysarthria alone	5
“Dystonic” form: One or more of the following:	60
Hypophonic speech or mutism
Drooling
Rigid mouth, arms, or legs
Seizures	1
Chorea or small-amplitude twitches	<1

Table prepared with the assistance of Drs. I. H. Scheinberg and I. Sternlieb, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York.

* Percentages are approximate.

In the experience of Gow and colleagues,⁵ of symptomatic patients aged 7 to 58 years, 22% presented with fulminant hepatic failure, 54% presented with liver abnormalities, 10% with neurological features, and 4% with hemolysis. In 10% of patients, hepatic and neurological symptoms were concurrent.

In a fair number of cases, primarily in young children, initial symptoms are hepatic, such as jaundice or portal hypertension, and the disease can assume a rapidly fatal course without any detectable neurological abnormalities.^6,⁷ In many of these patients, an attack of what appears to be acute viral hepatitis heralds the onset of Wilson disease.⁸ The manifestation with hepatic symptoms is common among affected children in the United States. In the series of Werlin and associates,⁹ who surveyed patients in the Boston area, the primary mode of manifestation was hepatic in 61% of patients younger than 21 years. In about 10% of affected children in the United States, Wilson disease manifests as an acute or intermittent, Coombs’ test–negative, nonspherocytic anemia that is accompanied by leukopenia and thrombocytopenia.⁹

When neurological symptoms predominate, the manifestations are so varied that it is impossible to describe a characteristic clinical picture. As a rule, the appearance of neurological symptoms is delayed until 10 to 20 years of age, and the disease progresses at a slower rate than in the hepatic form. Symptoms of basal ganglia damage usually predominate, but cerebellar symptoms are occasionally in the foreground. Tremors and rigidity are the most common early signs. The tremor may be of the intention type, or it may be the alternating resting tremor of parkinsonism. More commonly, especially when the disease is in its more advanced stages, the tremor is localized to the arms and is best described by the term wing beating. The tremor is often absent when the arms are at rest; it develops after a short latent period when the arms are extended. The beating movements may be confined to the muscles of the wrist, but it is more common for the arm to be thrown up and down in a wide arc. The movements increase in severity; at times, they reach a point at which the patient is thrown off balance. The tremor may affect both arms but is usually more severe in one.

Rigidity and spasms of the muscles are often present. In some instances, typical parkinsonian rigidity involves all muscles. Torticollis, tortipelvis, and other dystonic postures are not uncommon. Many patients have a fixed open-mouth smile with drooping of the lower jaw and excess salivation. Spasticity of the laryngeal and pharyngeal muscles can lead to dysarthria and dysphagia. A nearly pure Parkinson-like syndrome with progressive choreoathetosis or hemiplegia has also been described.¹⁰

Tendon reflexes are increased, but extensor plantar responses are exceptional. In essence, Wilson disease is a disorder of motor function; despite often widespread cerebral atrophy, there are no sensory symptoms or reflex alterations.

When Wilson disease manifests during childhood, the first signs are usually bulbar; these can include indistinct speech and difficulty in swallowing. A rapidly progressive dystonic syndrome is not unusual. Such patients can present with acute dystonia, rigidity, and fever, with an occasional elevation of serum creatine phosphokinase level.¹¹

Behavioral and personality disorders were noted in Wilson’s original description of the disease.³ These are almost invariable and predominate in about one third of patients.^12,¹³ They include impaired school or work performance, depression, mood swings, and frank psychosis. Of patients who show primarily neurological symptoms, about two thirds have had psychiatric problems before the diagnosis of Wilson disease is made. Minor intellectual impairment can also be observed, but seizures and mental deterioration are not prominent features of the disease.

The intracorneal ring-shaped pigmentation, first noted by Kayser and Fleischer,^1,² might be evident to the naked eye or might appear only on slit-lamp examination. The color of the Kayser-Fleischer ring varies from yellow to green to brown. It is the consequence of copper deposition close to the endothelial surface of Descemet’s membrane. The ring can be complete or incomplete. It occurs in 79% of patients who present with hepatic symptoms and in all patients who present with cerebral or a combination of cerebral and hepatic symptoms.^5,⁷ “Sunflower” cataracts are less commonly encountered, as are azure lunulae of the fingernails.¹⁴ Hypercalciuria and nephrocalcinosis are not uncommon and can be presenting signs of Wilson disease.¹⁵

Without treatment, death ensues within 1 to 3 years after the onset of neurological symptoms and is usually a result of hepatic insufficiency.

NEUROIMAGING

Computed tomographic scans usually reveal ventricular dilatation and diffuse atrophy of the cortex, cerebellum, and brainstem. About half the patients have symmetrical hypointensities in the head of the caudate, pallidum, substantia nigra, and red nuclei. The histopathology of Wilson disease suggests that these hypointensities are secondary to the presence of protein-bound copper in the thalamus and basal ganglia. Cortical atrophy and focal lesions in cortical white matter are also noted. Increased CT density resulting from copper deposition is not observed.

T2-weighted magnetic resonance imaging demonstrates symmetrical areas of increased signal intensity in the putamen, particularly in its outer rim; in the thalami; in the head of the caudate nucleus; and in the globus pallidus (Fig. 108-1). In the series of King and coworkers, the midbrain was abnormal in 77% of patients with Wilson disease.¹⁶ Involvement included primarily the tegmentum but also included the substantia nigra and the mesencephalic tectum. Abnormalities are also seen in the pons and the cerebellum. These areas are hypointense on T1-weighted images.¹⁷ Correlation with the clinical picture is not good in that magnetic resonance imaging can produce normal findings in patients with neurological symptoms and abnormal findings in patients with no neurological symptoms.^16,¹⁸

Figure 108-1 Wilson disease. Coronal T2-weighted magnetic resonance images of a 22-year-old man with Wilson disease who presented with tremor and Kayser-Fleischer rings. There are bilateral hyperintense thalamic lesions. Spin-echo sequences with Siemens MAGNETOM Sonata at 1.5 tesla were used.

(Courtesy of Dr. Franklin Moser, Division of Neuroradiology, Cedars Sinai Medical Center, Los Angeles.)

Positron emission tomography demonstrates a widespread depression of glucose metabolism; the greatest focal hypometabolism is observed in the lenticular nucleus. This abnormality precedes any alteration visible on computed tomography ¹⁹ and improves with chelation therapy.²⁰ In addition, a reduction in dopamine D2 receptor binding and loss of striatal dopamine transporters have been documented.^21,²²

DIAGNOSIS

When Wilson disease manifests with neurological manifestations, the diagnostic features include progressive extrapyramidal symptoms, which commence after the first decade of life; abnormal liver function; aminoaciduria; cupriuria; and absence or decreased serum levels of ceruloplasmin. In the experience of Gow and colleagues ⁵ and of Steindl and coworkers,²³ the diagnosis is more difficult to establish in patients who present with hepatic symptoms, particularly those who present in fulminant hepatic failure.

The presence of a Kayser-Fleischer ring is the single most important diagnostic feature; its absence in a patient with neurological symptoms virtually rules out the diagnosis of Wilson disease. The ring is not seen in the majority of presymptomatic patients, nor is it seen in 33% of patients who present with hepatic symptoms.⁵

Absence or low serum level of ceruloplasmin is of lesser diagnostic importance; approximately 5% to 20% of patients with Wilson disease have normal levels of the copper protein. Ceruloplasmin levels are abnormally low in about 10% of persons heterozygous for the Wilson disease gene. Because gene carriers constitute about 1% of the population, there are 40 times more gene carriers with low ceruloplasmin values than patients with Wilson disease and low ceruloplasmin values. In affected families, the differential diagnosis between heterozygous and presymptomatic homozygous patients is of utmost importance, inasmuch as it is generally accepted that presymptomatic homozygous patients should be treated preventively.²⁴

Several workers have stressed the diagnostic value of measuring 24-hour urine copper concentrations.²⁵ In the experience of Gow and colleagues,⁵ however, 41% of patients who had a nonfulminant manifestation of Wilson disease, including all those with a neurological manifestation, had normal urinary copper excretion (<100 μg/24 hours).

The “gold standard” study for the diagnosis of Wilson disease is liver biopsy.²⁵ When this procedure is undertaken, it is advisable to perform histological studies with stains for copper and copper-associated proteins and chemical quantitation for copper. In all confirmed cases of Wilson disease, hepatic copper levels are greater than 3.9 μmol/g dry weight (237.6 μg/g), in comparison with a normal range of 0.2 to 0.6 μmol/g (20 to 50 μg/g dry tissue).

Therefore, when low ceruloplasmin levels are found on routine screening and are unaccompanied by any abnormality of hepatic function or copper excretion, the patient is much more likely to be heterozygous for the Wilson disease gene than is a presymptomatic patient with Wilson disease.⁴ However, this supposition should be confirmed by liver biopsy.

ETIOLOGY AND PATHOPHYSIOLOGY

Pathological Anatomy

The abnormalities in copper metabolism result in a deposition of the metal in several tissues. Anatomically, the liver exhibits focal necrosis that leads to a coarsely nodular, postnecrotic cirrhosis. The nodules vary in size and are separated by bands of fibrous tissues of different widths. Some hepatic cells are enlarged and contain fat droplets, intranuclear glycogen, and clumped pigment granules; other cells are necrotic, with regenerative changes in the surrounding parenchyma.²⁶

Electron microscopic studies indicate that copper is initially spread diffusely within the cytoplasm, probably as the monomeric metallothioneine complex. Later in the course of the disease, the metal is sequestered within lysosomes, which become increasingly sensitive to rupture.⁴ Copper probably initiates and catalyzes oxidation of the lysosomal membrane lipids, which results in lipofuscin accumulation. Within the kidneys, the tubular epithelial cells can degenerate, and their cytoplasm can contain copper deposits.

In the brain, particularly in patients whose symptoms commenced before the onset of puberty, the basal ganglia have a brick-red pigmentation; spongy degeneration of the putamen frequently leads to the formation of small cavities.³ Lesser degenerative changes are seen in the brainstem, the dentate nucleus, the substantia nigra, and the convolutional white matter.

Microscopic studies reveal loss of neurons, axonal degeneration, and large numbers of protoplasmic astrocytes, including giant forms termed Alzheimer cells. These cells are not specific for Wilson disease; they can also be seen in the brains of patients dying in hepatic coma or as a result of argininosuccinic aciduria or other disorders of the urea cycle. Opalski cells, also seen in Wilson disease, are generally found in gray matter. They are large cells with a rounded contour and finely granular cytoplasm. They probably represent degenerating astrocytes.

Molecular Genetics and Biochemical Pathology

Cellular copper transport consists of three processes: copper uptake, intracellular distribution and use, and copper excretion.²⁷

The site of copper absorption is probably in the proximal portion of the gastrointestinal tract. The metallothioneins, a family of low-molecular-weight metal-binding proteins containing large amounts of reduced cysteine, are involved in regulating copper absorption at high copper intakes. In addition to playing a role in the intestinal transport of copper, metallothioneins are probably also involved in the initial hepatic uptake of copper.

After its intestinal uptake, copper enters the plasma, where it is bound to albumin in the form of cupric ion. Within 2 hours, the absorbed copper is incorporated into a liver protein. Cellular copper uptake is facilitated by Ctr1, a membrane protein that transports the metal in a high-affinity, metal-specific manner. The concentration of copper in normal liver ranges from 20 to 50 μg/g dry weight. Once within the hepatocyte, copper is bound to metallochaperones, a family of proteins that deliver it to various specific sites. The chaperone Atox1, through direct interaction with the P-type ATPase (ATP7B) of Wilson disease, delivers copper to the hepatic secretory pathway for excretion into bile. Within the hepatocyte cytoplasm, copper is complexed to what is probably a polymeric form of metallothionein. Last, copper can combine with apoceruloplasmin to form ceruloplasmin, which then reenters the circulation.²⁸ More than 95% of serum copper is in this form.²⁷

The gene for Wilson disease has been mapped to chromosome 13q14.3-q21.1. It has been cloned and encodes a copper-transporting P-type ATPase that is expressed in many tissues, including the brain.²⁹ The ATPase is present in two forms: one form is probably localized to the late endosomes, in which it is involved in the delivery of copper to apoceruloplasmin.³⁰ The other form, believed to represent a cleavage product, is found in mitochondria.^31,³² More than 300 gene mutations have been described. Some mutations are population-specific; others are common in many nationalities. The majority are missense mutations, small insertions, or deletions.³³ Most patients with Wilson disease have compound heterozygosity.³⁴ A complete list of mutations is maintained at http://www.medicalgenetics.med.ualberta.ca/wilson/index.php. Although several workers have attempted to correlate genotype and phenotype, the same mutation can present vastly different clinical pictures.³⁵

The genetic mutation induces extensive changes in copper homeostasis. Normally, the amount of copper in the body is kept constant through excretion from the liver into the bile. The two fundamental defects in Wilson disease are (1) reduced biliary transport and excretion of copper and (2) impaired formation of plasma ceruloplasmin.²⁷ Biliary excretion of copper is between 20% and 40% of normal, and fecal output of copper is also reduced.³⁶ Apoceruloplasmin is present in the livers of patients with Wilson disease, but because of a lack of copper available for incorporation, apoceruloplasmin is rapidly degraded.

Of most importance, copper accumulates within liver. At first, it is firmly bound to copper proteins, such as ceruloplasmin and superoxide dismutase, or is complexed with metallothionein in the cupric form. When the copper load overwhelms the binding capacity of metallothionein, cytotoxic cupric copper is released, which causes damage to hepatocyte mitochondria and peroxisomes.^37,³⁸ Ultimately, copper leaks from the liver into blood, where it is taken up by other tissues, including the brain, which in turn are damaged by copper.

More than 95% of serum copper is in the form of ceruloplasmin. Ceruloplasmin is a ferroxidase with multiple functions. It is involved principally in peroxidation of ferrous to ferric transferrin. In addition, it is believed to control the release of iron into plasma from cells in which the metal is stored in the form of ferritin. Although it is not involved in copper transport from the intestine, it is considered to be the major vehicle for the transport of copper from the liver and to function as a copper donor in the formation of a variety of copper-containing enzymes. The concentration of ceruloplasmin in plasma is normally between 20 and 40 mg/dL.

Two other biochemical abnormalities are consistently found in patients with Wilson disease:

1. Low to low-normal plasma levels of iron-binding globulin can be demonstrated in the asymptomatic carrier and suggests that Wilson disease may also encompass a disorder of iron metabolism. This may result from the deficiency of hephaestin, a ceruloplasmin homolog that has been implicated in intestinal iron transport and may be involved in the transfer of iron from tissue cells to plasma transferrin.³⁹ Iron deposition in the liver is increased,⁴⁰ and an increase in cerebral iron uptake can be demonstrated by positron emission tomography.⁴¹

2. Persistent aminoaciduria is most marked during the later stages but may be noted in some asymptomatic patients. The presence of other tubular defects (e.g., impaired phosphate resorption in patients without aminoaciduria) suggests that a toxic action of the metal on renal tubules causes the aminoaciduria.

TREATMENT

Even though it is clear that all patients with Wilson disease, whether symptomatic or asymptomatic, require treatment, there is no current consensus as to the optimal means of treating Wilson disease. The aims of treatment are initially to remove the toxic amounts of copper and secondarily to prevent tissue reaccumulation of the metal.^25,⁴²

Treatment can be divided into two phases: the initial phase, when toxic copper levels are brought under control, and maintenance therapy. There is no currently agreed-upon regimen for treatment of the new patient with neurological or psychiatric symptoms. In the past, most centers recommended starting patients on D-penicillamine (600 to 3000 mg/day). Although this drug is effective in promoting urinary excretion of copper, adverse reactions during the initial and maintenance phases of treatment are seen in approximately 25% of patients. These include worsening of neurological symptoms during the initial phases of treatment, which frequently are irreversible. Skin rashes, gastrointestinal discomfort, and hair loss are also encountered. During maintenance therapy, polyneuropathy, polymyositis, and nephropathy may occur. Some of these adverse effects can be prevented with pyridoxine (25 mg/day).

Because of these side effects, many institutions now advocate initial therapy with ammonium tetrathiomolybdate (60 to 300 mg/day, administered in six divided doses, three with meals and three between meals). Tetrathiomolybdate forms a complex with protein and copper and, when given with food, blocks the absorption of copper. The major drawback to using this drug is that it still has not been approved for general use in the United States.

Triethylene tetramine dihydrochloride (trientine) (500 mg twice a day, given at least 1 hour before or 2 hours after meals) is another chelator that increases urinary excretion of copper. It is less effective than penicillamine or ammonium tetrathiomolybdate, but the incidence of toxicity and hypersensitivity reactions is lower than in the former.^42a

Zinc acetate (50 mg of elemental zinc acetate three times a day) acts by inducing intestinal metallothionein, which has a high affinity for copper and prevents its entrance into blood. Zinc is far less toxic than penicillamine but is much slower acting. Diet does not play an important role in the management of Wilson disease, although Brewer recommended restriction of liver and shellfish during the first year of treatment.⁴²

Zinc is the optimal drug for maintenance therapy and for the treatment of the presymptomatic patient. Trientine in combination with zinc acetate has been suggested for patients who present in hepatic failure.

Liver transplantation can be helpful in the patient who presents in end-stage liver disease. The procedure appears to correct the metabolic defect and can reverse neurological symptoms.⁴³ Schumacher and colleagues⁴⁴ also recommended its use for patients with normal liver function but whose neurological symptoms have not responded to the various chelating agents.

With these regimens, gradual improvement in neurological symptoms occurs. As a rule, brainstem auditory evoked potentials improve within 1 month of the onset of therapy; the somatosensory evoked responses return to normal somewhat more slowly.⁴⁵ The Kayser-Fleischer ring begins to fade within 6 to 10 weeks after the onset of therapy and disappears completely in a couple of years.⁴⁶ Neurological symptoms start improving 5 to 6 months after therapy begins and are generally gone in 24 months. As shown by serial neuroimaging studies, a significant regression of lesions occurs within thalamus and basal ganglia (Fig. 108-2A and B).¹⁸ Successive biopsies reveal a reduction in the amount of hepatic copper. Total serum copper and ceruloplasmin levels decrease, and the aminoaciduria and phosphaturia diminish.

Figure 108-2 Wilson disease. A, Coronal T2-weighted magnetic resonance images in a 22-year-old woman with Wilson disease, 3 months after the disease had been diagnosed and at the start of penicillamine therapy. There are bilateral hyperintense thalamic lesions that are hypointense on T1-weighted images. B, Images in the same patient after 13 months of penicillamine therapy. There has been a significant regression of the thalamic lesions. Spin-echo sequences (recovery time, 2.5 milliseconds; echo time, 90 milliseconds) with Siemens MAGNETOM 6.3, operating at 1.5 tesla, were used.

(Courtesy of Dr. I. Prayer, Zentral Institut für Radiodiagnose und Ludwig Boltzmann Institut, University of Vienna, Austria.)

As a rule, patients who begin therapy before the evolution of symptoms remain healthy. Patients who have had exclusively hepatic disease do well, and in 80%, hepatic functions return to normal. Approximately 40% of children who present with neurological symptoms become completely asymptomatic and remain so for 10 or more years. Patients with the mixed hepatocerebral picture do poorly. Fewer than 25% recover completely, and approximately 25% continue to deteriorate, often with the appearance of seizures. In all forms of the disease, the earlier therapy begins, the better the outlook is.⁷

When symptom-free patients with Wilson disease discontinue chelation therapy, their hepatic function deteriorates in 9 months to 3 years, a rate that is far more rapid than deterioration after birth.⁴⁷

There is accumulating evidence that oxidative damage caused by free radical formation can play a significant role in producing cell damage in Wilson disease. Gu and coworkers ³⁷ have noted severe mitochondrial dysfunction in the livers of patients with Wilson disease, with significant reduction in the activities of all enzyme complexes involved in oxidative phosphorylation. Other findings pointing to oxidative stress are the reduction in the plasma levels of various antioxidants, such as ascorbate and urate, and the increase of allantoin, a possible marker of free radical generation.⁴⁸ These findings provide experimental support for the addition of antioxidants such as ascorbate or vitamin E to the therapeutic regimen of all patients with Wilson disease.

KEY POINTS

• Wilson disease is a progressive condition with a tendency toward temporary clinical improvement and arrest of symptoms.

• The gene for Wilson disease has been mapped to chromosome 13q14.3-q21.1. It encodes a copper-transporting P-type ATPase that is expressed in many tissues, including the brain.

• The two fundamental defects in Wilson disease are (1) reduced biliary transport and excretion of copper and (2) impaired formation of plasma ceruloplasmin.

• Presenting symptoms can be neurological, hepatic, psychiatric, or, less frequently, hematological.

• Behavioral or personality disorders are almost invariable and predominate in about one third of patients.

• The Kayser-Fleischer ring is present in all patients who present with cerebral or a combination of cerebral and hepatic symptoms. Its presence is the most important diagnostic feature.

• Aims of treatment are initially to remove the toxic amounts of copper and secondarily to prevent tissue reaccumulation of the metal.