52.1 Clinical Features
and Laboratory Investigations So-called hepatolenticular degeneration was first described by the English neurologist S.A.K. Wilson in 1912 and has been named after him. Wilson disease (WD) is a genetically determined, autosomal reces- sive disease with a prevalence of 20 to 30 per million.
The clinical picture is extremely variable, depending among other things on the age at presentation. Pa- tients present with hepatic, neurological, or psychi- atric symptomatology in roughly equal proportions, with some overlap. In children, hepatic manifesta- tions predominate, whereas in adolescents and adults neuropsychiatric manifestations are more frequent.
Symptoms rarely occur before the age of 6, and half of the patients are symptomatic by the age of 15. Onset after the age of 40 is rare, but patients presenting in the fifth and sixth decades of life have been described.
Hepatic manifestations in WD encompass a spec- trum of acute and chronic liver diseases. Some pa- tients, usually younger ones, present with fulminant hepatic failure, leading to jaundice, hypoalbumine- mia, ascites, coagulation defects, hyperammonemia, and hepatic encephalopathy. Massive liver failure in WD is often accompanied by hemolytic anemia. How- ever, if the liver failure is less massive, only some of the features of this syndrome may be present. In old- er patients liver failure tends to be chronic and is as- sociated with portal hypertension, leading to gastric or esophageal varices and/or hypersplenism with thrombopenia or leukopenia. In addition, these patients often have hypoalbuminemia, edema, and ascites. Some patients present with a picture of acute hepatitis, which subsides spontaneously, and may be attributed mistakenly to a viral infection. In some patients cirrhosis is well compensated and the results of standard liver biochemical tests are normal. Most patients with WD, whatever their clinical presentation or presymptomatic status, have some degree of liver disease.
Patient with WD who present with neurological disease are typically in their late teens or twenties.
The signs and symptoms are usually chronic, but occasionally acute in presentation. Frequent early symptoms include tremor, speech problems, clumsi- ness, dystonia, and personality changes. The tremor may be unilateral or asymmetrical. Kayser–Fleischer rings are almost invariably present in patients with
neurological manifestations of WD. The rings are typically 1–3 mm in diameter, green, yellow, or brown, and located at the periphery of the cornea. They begin as crescents in the superior quadrant and subsequently extend to the inferior, lateral, and medi- al regions until they become circumferential and broader, spreading centrally from the limbus. Kayser–
Fleischer rings may sometimes be seen with the unaided eye, but a slit-lamp examination often is nec- essary to detect them. Adolescents may present with a deterioration of performance at school and in athlet- ics, difficulties with handwriting, and loss of dexteri- ty. Without treatment, neurological deterioration continues. The full-blown neurological picture of WD encompasses a variable combination of the following signs: dysarthria, drooling, dysphagia, grimacing, ab- normal eye movements, dystonia, rigidity, bradykine- sia, athetosis, wing beating, spasticity with increased tendon reflexes and Babinski signs, cerebellar ataxia, and tremor (resting, intention, or postural), but cog- nitive and sensory functions are typically preserved.
Seizures may occur. Because of increasing difficulty in controlling movement, the patients become unable to feed themselves, and become bedridden. Flexion contractures develop. Ultimately, the patients become helpless, are usually alert, but unable to talk.
Psychiatric and behavioral symptoms are variable and include reduced performance at school or at work, inability to cope, depression, labile moods ranging from mania to depression, sexual exhibition- ism, and psychosis. Personality changes, particularly irritability, emotionality, and increased anger are the most commonly noted problems.
Ophthalmological abnormalities include, first and foremost, the Kayser–Fleischer rings, and, less fre- quently, sunflower cataracts consisting of green, gold- en-brown, or gray granular deposits in the lens of the eye, appearing as discoid opacities in the anterior lens capsule with petal-like fronds that radiate toward the lens periphery like a sunflower. Neither Kayser–
Fleischer rings nor sunflower cataracts affect vision significantly. Kayser–Fleischer rings are found in al- most all patients with a neurological presentation and in about 30% of the patients with a hepatic presenta- tion.
Hematological presentation is rare, but WD should be considered in young patients with nonspherocyt- ic, Coombs-negative intravascular hemolysis of un- clear etiology. Severe hemolysis frequently occurs in
Wilson Disease
Chapter 52
the setting of fulminant hepatic failure and suggests a diagnosis of WD.
Patients may have abnormalities of renal tubular function with amino aciduria, proteinuria, urico- suria, hypercalciuria, hyperphosphaturia, or defective urine acidification. Occasionally, full-blown Fanconi syndrome is present. Renal stones are not uncom- mon.
Osteomalacia, rickets, osteoporosis, osteoarthritis, polyarthritis, localized bone demineralization, spon- taneous fractures, peri- and intra-articular calcifica- tions, and joint hypermobility may occur in WD.
However, musculoskeletal symptoms are rarely the presenting complaints.
Hyperpigmentation of the skin may occur. Con- gestive heart failure and cardiac dysrhythmias have been reported. The most frequent endocrinological disturbances are gynecomastia and delayed puberty due to hepatic dysfunction. Primary or secondary oli- go- or amenorrhea is common. Successful pregnancy is exceptional in untreated female WD patients, and spontaneous abortions occur frequently.
There is often an unacceptable delay in establish- ing a diagnosis of WD.Whenever the diagnosis is sus- pected, Kayser–Fleischer rings should be sought by an experienced ophthalmologist using a slit-lamp.
Kayser–Fleischer rings are almost always present in WD patients with neurological problems, but their absence does not mean the diagnosis is wrong.
Kayser–Fleischer rings are also not pathognomonic for WD, but may be seen in some other hepatobiliary diseases or as a result of topical ocular application of copper-containing solutions. In most patients sus- pected of WD, the diagnosis is confirmed by the pres- ence of both Kayser–Fleischer rings and at least one, if not all three, of the biochemical markers: low serum level of ceruloplasmin, elevated free (nonceruloplas- min) serum copper concentration, and increased uri- nary copper excretion (24-h urine copper). However, the limited value of these tests should be recognized.
Ceruloplasmin is low in about 80–90% of WD pa- tients, but some WD patients have levels in the low-to- normal range due to hepatic inflammation, hepatic neoplasm, pregnancy, or use of estrogen. A low serum ceruloplasmin level is found in up to 20% of the het- erozygotes for WD, even though they will never devel- op symptoms of WD. Low serum ceruloplasmin can also be found in other hepatic disorders, normal neonates and young infants, patients with malabsorp- tion, malnutrition, or nephrosis, and in patients with hereditary hypoceruloplasminemia. Free serum cop- per and urinary copper concentrations can be elevat- ed in other hepatobiliary diseases. In case of doubt, in particular if the ceruloplasmin level is normal and/or Kayser–Fleischer rings are absent, conditions most often seen in patients with hepatic presentation, liver biopsy for quantitative copper analysis, and micro-
scopic examination have a high diagnostic value. He- patic copper concentrations are always elevated in untreated WD patients and also higher in patients than in heterozygotes. Histological abnormalities in WD range from steatosis to cirrhosis. Liver histology is normal in heterozygotes. However, in patients with chronic cholestatic liver disease, elevations of liver copper concentrations may be similar to those in WD patients, and incidental WD cases with normal cop- per levels in single biopsies have been reported, re- lated to uneven copper distribution in the liver. In selected patients a test of incorporation of a copper isotope into serum ceruloplasmin is informative. Be- cause the biochemical copper profile of a normal neonate mimics that seen in WD and clinical manifes- tations of WD are rarely seen before the age of 6 years, conventional screening of potentially affected chil- dren should not be performed before the age of 2–3 years. DNA techniques are available for definite diag- nosis in patients suspected of WD and for distinction between presymptomatic patients and heterozygotes in families with WD and known mutations. Prenatal diagnosis is possible using DNA techniques.
52.2 Pathology
External examination of the brain usually reveals no abnormalities except for some shrinkage of the insu- lar cortex.
Within the brain parenchyma of patients with manifestations of CNS disease, lesions are invariably present in the corpus striatum, which appears shrunken. Cavitation is often present in the putamen, sometimes also in the caudate nucleus, rarely in the globus pallidus, thalamus, and red nucleus. On micro- scopic examination, neuronal loss is found in the putamen and caudate nucleus. Astrocytic prolifera- tion is present. Some astrocytes have the appearance of Alzheimer type II cells; few resemble Alzheimer type I cells. When cavities are present, variable num- bers of lipophages and siderophages are seen in rela- tion to the cavities; old and recent hemorrhages can be found. Depositions of copper have been described by some, in particular in the putamen. Less constant- ly and less severely involved nuclei are the globus pal- lidus, the subthalamic nucleus, the thalamus, dentate nucleus, substantia nigra, and other brain stem nu- clei. Opalski cells are typically present in the thala- mus, globus pallidus, and zona reticularis of the sub- stantia nigra, less often in the caudate nucleus and putamen. Opalski cells are large cells with volumi- nous cytoplasm and small nuclei. Like Alzheimer type I and type II cells, they are of astroglial origin.
Alzheimer type I cells and Opalski cells are character-
istic of WD.
In some patients destructive lesions are present in the cerebral cortex and white matter. The distribution of the cortical involvement corresponds with that of the white matter involvement. These lesions may be very impressive and exceed the lesions in the basal nuclei. The lesions are typically located in the superi- or and middle frontal gyri; widespread involvement posterior to the frontal lobes is uncommon. The changes are usually symmetrical, but may be asym- metrical. Cavitation of the white matter lesions may occur. The outer layers of the cortex always retain suf- ficient structural integrity to form a continuous shell.
In microscopic examination of the affected cortex, the deep cortical layers appear to be affected predomi- nantly, whereas the more superficial cortical layers are relatively intact. The cortical abnormalities may have a spongiform appearance.Alzheimer types I and II cells and Opalski cells may be seen in the cerebral cortex. The white matter abnormalities vary from myelin paucity and spongy white matter degenera- tion to outright necrosis with presence of sudano- philic breakdown products. There may be prolifera- tion of Alzheimer type I and type II astrocytes and Opalski cells.
The cerebellum is relatively spared. Some loss of cortical neurons may be seen. The dentate nucleus is more frequently involved. Cerebellar white matter pallor, gliosis, and degeneration have been described.
Brain stem nuclei may be involved.
In patients with fulminant liver failure, the cirrho- sis is predominantly micronodular, whereas in pa- tients with longstanding liver disease large areas of macronodular cirrhosis are found. In the periphery of the nodules, copper pigments may be demonstrated histochemically. Electron microscopy demonstrates that hepatocytes contain giant mitochondria with paracrystalline inclusions. Multivesicular rounded granules in hepatocytes are thought to be character- istic of WD.
52.3 Pathogenetic Considerations
The gene responsible for WD is ATP7B, located on chromosome 13q14.3. The gene product is a cation transporting P-type ATPase protein, called ATP7B or Wilson disease protein (WNDP). Many different mutations have been identified in WD patients. It is reasonable to assume that the type of mutation might account, at least in part, for the clinical variability observed in WD patients. However, most patients are compound heterozygotes, which hampers the study of genotype–phenotype correlations. Considerable clinical variation is seen among patients within the same family, suggesting influence of other genetic and environmental factors.
Copper is an essential trace element, being an inte- gral component of many important enzymes involved in cellular processes such as oxidative metabolism, free radical detoxification, neurotransmitter biosyn- thesis, and iron homeostasis. In excess, copper is also a very toxic ion, because it can oxidize proteins and lipids in membranes, bind to proteins and nucleic acids, and enhance the generation of free radicals.
Dietary intake of copper generally far exceeds the trace amounts required. Consequently, efficient and appropriate mechanisms must exist to ensure copper homeostasis and to transport copper to the sites where it is required without allowing toxic accumula- tion of free ions. Clearance of excess copper is achieved via the hepatobiliary route.Various proteins have been recognized to be involved in copper home- ostasis and transport: albumin for copper transport in the blood, ceruloplasmin as a copper donor to tis- sues and enzymes, and metallothionein for intracel- lular copper storage. The human copper chaperone Atox1 is a small cytosolic protein that plays a key role in the distribution of copper to the secretory pathway of the cell.Atox1 facilitates copper delivery to the pro- tein ATP7B. ATP7B translocates copper in an ATP-de- pendent manner into the lumen of the trans-Golgi network for incorporation into copper-dependent enzymes, or exports excess copper out of the cell into the bile. Under steady state conditions ATP7B is local- ized primarily in the trans-Golgi network, where it pumps copper from the cytoplasm into the trans-Gol- gi network lumen. Under elevated copper concentra- tions ATP7B undergoes a reversible, copper-mediated translocation from the Golgi to the apical canalicular membrane, where it pumps copper into the bile. Defi- ciency of ATP7B leads to failure to excrete copper from the liver into bile and to incorporate copper in- to ceruloplasmin during ceruloplasmin biosynthesis in the liver. This results in toxic accumulation of cop- per in the liver, with subsequent overflow to the kid- ney, brain, and cornea. WNDP is present in hepato- cytes, kidney, placenta, brain, heart, lung, muscle, and pancreas, but reversal of dysfunction of other organs after liver transplantation indicates that the primary genetic defect leading to copper accumulation resides in the liver.
Accumulation of copper leads to liver cirrhosis, progressive neurological damage and renal problems.
Very high free serum copper levels, in particular caused by sudden massive release of copper from the liver, may result in hemolytic crises. The cause of pathology in WD is copper toxicity. Organs affected by the disease contain elevated copper levels, and low- ering of copper leads to cessation of progression, some repair, and clinical improvement. Excess copper causes cell injury, inflammation, and cell death. Cop- per has damaging effects on mitochondria and per-
Chapter 52 Wilson Disease 394
oxisomes. Effects on microtubules, on cross-linking of DNA, and on plasma membranes, as well as inhibi- tion of a large number of enzymes, have also been shown. The state of copper is important. Copper bound to ceruloplasmin, metallothionein, or albumin is nontoxic. It is ionic copper or copper, which is easi- ly dissociable, that is toxic. Copper toxicity probably occurs because of the generation of oxidant radicals.
In this respect it is important to note that the pattern of preferential involvement of gray matter structures in WD shows some striking similarities to the pat- terns observed in respiratory chain defects and in hy- poxia. Caudate nucleus and putamen are preferential- ly affected. Other frequently involved gray matter structures are thalamus, globus pallidus, subthalamic nucleus, and periaqueductal gray matter.
52.4 Therapy
Therapeutic strategies in WD can focus on inhibition of the intestinal uptake of copper, induction of metal- lothionein to detoxify copper, and chelation. When a diagnosis of WD is made, siblings of the affected pa- tient should be screened. On average 25% of the sib- lings will be affected but still at the “presymptomatic”
phase clinically, although they always have subclinical liver disease. WD is an almost completely penetrant disease, and individuals having two mutations in the WD disease gene have an almost 100% chance of ac- quiring neurological, psychiatric, or hepatic disease or a combination of these. It is therefore important to treat these presymptomatic patients prophylactically with anti-copper medication. Patients begin to have hepatic damage from about the age of 3 or 4 years.
Patients should be treated as soon as a diagnosis has been made, but probably not during the first 1 or 2 years of their life. Treatment should be continued for life in WD patients, whether asymptomatic or symp- tomatic.
Nowadays, zinc is usually preferred as the first- choice drug in the treatment of WD patients, because it is almost completely nontoxic. Oral zinc in the form of zinc acetate or zinc sulfate inhibits intestinal cop- per absorption and promotes fecal copper excretion.
There is also evidence that zinc may induce the syn- thesis of metallothionein in enterocytes and possibly hepatocytes. Although zinc appears to be a more potent stimulus to metallothionein synthesis than copper, copper is more avid in binding to metallo- thionein. Complexed copper may then either be transferred into the portal circulation or remain com- plexed within the cytosolic fraction of the enterocyte and be excreted in the feces with sloughed cells. Zinc therapy acts slowly, producing a modestly negative copper balance. Zinc therapy is usually well tolerated, gastric irritation being the most frequent side effect.
A few highly exceptional patients have been reported who show deterioration after the institution of oral zinc therapy.
Penicillamine has been considered the drug of first choice in WD for many years. It acts by reductive chelation, reducing the copper bound to protein, thereby decreasing the affinity of the protein for cop- per and allowing the penicillamine to bind copper.
Reductive chelation is much more effective than chelators with a high affinity for copper, such as EDTA. The copper mobilized by penicillamine is ex- creted in urine. Penicillamine probably also induces hepatic metallothionein, thereby holding potentially toxic copper in a nontoxic form. Some patients im- prove clinically soon after therapy begins, whereas some may require several months of therapy before improvement occurs. In about 10–20% of WD pa- tients with neurological complaints, temporary exac- erbation of symptoms is seen with the institution of therapy. Unfortunately, some patients never recover to their pretreatment baseline. Inadvertent discontin- uation of penicillamine therapy may lead to cata- strophic clinical deterioration and death. Adverse effects of penicillamine are, unfortunately, common.
A considerable number of the patients develop an early hypersensitivity reaction to penicillamine man- dating its discontinuation. Treatment is restarted in conjunction with corticosteroids until tolerance de- velops. Long-term use of penicillamine can result in serious side effects forcing discontinuation of its use.
These side effects include induction of a variety of autoimmune-like disorders and induction of skin problems due to alterations of dermal collagen and elastin.
Triethylene tetramine dihydrochloride (trientine or trien) is both a chelator, acting primarily by en- hancing urinary excretion of copper, and an inhibitor of copper absorption in the intestine. Far less clinical experience has been gained with this drug than with penicillamine, but it can be used in WD patients who do not tolerate penicillamine. Tolerance of triethylene tetramine dihydrochloride is generally excellent. Tox- icity during the first weeks of treatment may consist of bone marrow suppression or proteinuria. Later a variety of autoimmune disorders may occur.
Ammonium tetrathiomolybdate forms a tripartite complex with copper and protein that is very stable.
Given with food, ammonium tetrathiomolybdate
complexes food copper with food protein, rendering
food copper, along with copper in saliva, gastric juice,
and intestinal secretions, unabsorbable. This puts the
patient in an immediate negative copper balance. In
addition, tetrathiomolybdate is absorbed into the
blood and complexes free copper with blood albu-
min. This complexed copper cannot be taken up by
cells and is nontoxic. This drug has a faster effect than
zinc and avoids the deteriorations that may be seen
with penicillamine.As such the drug is ideal for initial treatment. Possible side effects are related to copper deficiency and include mild bone marrow suppres- sion. In addition, mild elevations of aminotransferas- es may be seen.
Because of the ubiquity of copper in our diet, a negative copper balance cannot be achieved by di- etary modification alone. It seems prudent, however, to recommend that WD patients avoid food with a high copper content.
Despite the effectiveness of medication in most WD patients, occasional patients require liver trans- plantation because of hepatic failure. This procedure corrects the metabolic defect localized in the liver, and transplanted patients no longer need specific medication for WD.
The prognosis for WD patients has generally im- proved greatly with the advent of treatment. In partic- ular, when treatment is started in a presymptomatic stage, patients never become symptomatic. Also, the vast majority of symptomatic patients improve con- siderably or recover completely. The patients with hepatic presentation have the least optimistic prog- nosis. Assuming they survive the initial episode, the greatest risks are bleeding from esophageal varices and hepatic insufficiency. The patients with neuro- logical or psychiatric presentation have a better prog- nosis, although their quality of life can be problemat- ic if the residual deficit is considerable. It is therefore important to start treatment as early as possible, before irreparable damage has occurred. Under ade- quate treatment, successful pregnancy is possible.
Anti-copper therapy should be continued during pregnancy. Zinc is safest as both penicillamine and triethylene tetramine dihydrochloride are potentially teratogenic.
52.5 Magnetic Resonance Imaging
CT scan of the brain in WD may reveal a number of different abnormalities including mild ventricular dilatation, cortical atrophy, brain stem atrophy, hypo- dense areas in the region of the putamen, globus pal- lidus, and dentate nucleus, and white matter hypo- densities, in particular in the frontal subcortical area.
MRI most often shows lesions in the thalamus, putamen, and caudate nucleus (Figs. 52.1–52.3).
Within the putamen, the lateral rim is often most prominently affected (Fig. 52.1). Other gray matter structures which are also regularly affected are the globus pallidus, claustrum, and subthalamic nucleus.
The lesions are usually bilateral and symmetrical;
asymmetry is rare. The lesions most often have a high signal intensity on T
2-weighted images and a low sig- nal intensity on T
1-weighted images (Figs. 52.1–52.3).
These changes in signal intensity are thought to re-
flect edema, necrosis, and gliosis. In some patients, ar- eas of low signal intensity are seen in the putamen, head of the caudate nucleus, globus pallidus, and thal- amus on T
2-weighted images (Figs. 52.1 and 52.2).
The nuclei either have a generalized low signal inten- sity or have small areas of low signal intensity within the bigger high signal intensity lesion. Some assume that the low signal intensity on T
2-weighted images is related to iron deposition, as phagocytes containing iron pigment after small hemorrhages are seen in histological specimens. Others assume that the low signal intensity is related to the paramagnetic effect of copper. It is well established that copper ions in vit- ro have a pronounced effect on both T
1and T
2. An increased concentration of copper ions causes a decrease in T
1and T
2. High signal intensity on T
1- weighted images has been found in the globus pal- lidus (Fig. 52.1) and, more rarely, in the putamen, cau- date nucleus, and around the aqueduct. This may be explained by a paramagnetic effect of copper, but may also be related to hepatic dysfunction. Sometimes multiple small cavities are seen within the basal nu- clei with a signal intensity similar to that of CSF on all sequences. No contrast enhancement is seen.
Atrophy is a frequent finding. It may be focal, most frequently involving the caudate nuclei and brain stem. The atrophy may also be generalized involving the cerebral hemispheres and the cerebellum, with enlargement of subarachnoid spaces and ventricular system.
Subcortical white matter lesions are not rare in WD, in contrast to what was formerly thought. The white matter lesions are most often found in the frontal lobes, sometimes with extensions into the parietal area (Fig. 52.3). White matter lesions in other areas are rare. Their location is largely subcortical and they may not reach the ventricular wall. The over- lying cortex may also be involved (Fig. 52.3). The white matter lesions are usually large and confluent, but multiple, small, isolated lesions can also be found.
In exceptional cases the white matter lesions are cys- tic. The white matter changes are often asymmetrical (Fig. 52.3), which contrasts with the symmetry of the gray matter lesions. The posterior limb of the internal capsule and the external capsule may be affected.
Rare localizations are the splenium of the corpus callosum and the white matter of the parietal, tempo- ral, and occipital lobes. No contrast enhancement is present.
Cerebellar lesions are less frequent. Bilateral le- sions in the dentate nuclei are most often seen. The cerebellar white matter may be abnormal, especially in the area around the dentate nucleus (Fig. 52.1).
Brain stem lesions are frequent. The areas most frequently involved are the midbrain tectum and tegmentum, the red nucleus, substantia nigra, cen- tral part of the base of the pons, and pontine tegmen-
Chapter 52 Wilson Disease 396
Fig. 52.1. A 37-year-old female with WD. Note the prominent abnormalities in the basal ganglia (first row). The caudate nu- cleus is markedly atrophic. The caudate nucleus, the peripher- al rim of the putamen, and the claustrum have a high signal on proton density and T2-weighted images, whereas the central part of the putamen has a low signal. The globus pallidus has a high signal on T1-weighted images. The ventrolateral thala- mus also contains signal abnormalities, the outer rim of the
thalamus standing out separately. Additionally, the T2-weight- ed images (second and third row) show areas of high signal in the brain stem and cerebellar white matter, whereas the den- tate nucleus has a low signal. The typical “panda face” is seen on the right in the second row. Courtesy of Dr. E. Gut, Depart- ment of Neuroradiology, Kliniken Schmieder, Allensbach, Ger- many
Chapter 52 Wilson Disease 398
Fig. 52.3. A 13-year-old boy with WD.Note the involvement of the putamen and thalamus, the lateral rim of the thalamus standing out separately. Additionally, there are large focal
white matter lesions with an asymmetrical distribution. The overlying cortex is affected as well. From Hedera et al. (2002), with permission
Fig. 52.2. A 31-year-old female with WD. The T2-weighted im- ages show high signal intensity in the ventrolateral thalamus, its outer rim standing out separately. The putamen has an ab- normally low signal with some tiny high-signal-intensity areas.
The tectum and tegmentum of midbrain and pons have a high
signal. Within the midbrain, the typical panda face configura- tion is seen (second row, left). Courtesy of Dr.T. Naidich, Depart- ment of Radiology, The Mount Sinai School of Medicine, New York
