I

i REVIEWS

Wilson’s Disease: Current Status JOSEPHC. YARZE,M.D., PAUL MARTIN, M.D., SANTIAGOJ. MuAoz, M.D., LAWRENCES. FRIEDMAN,M.D., Philadelphia, Pennsylvania

OBJECTIVE: To review current concepts about the pathogenesis, clinical manifestations, and treatment of Wilson’s disease, with an emphasis on recent developments. DATA IDENTIFICATION: Published information was identified using MEDLINE and through extensive manual searching of bibliographies in identified sources. RESULTS: The basic biochemical alteration responsible for deranged hepatobiliary copper homeostasis in Wilson’s disease has yet to be identified. The gene for Wilson’s disease has been mapped to chromosome 13, but the function of its gene product has not yet been determined. The clinical manifestations of Wilson’s disease are varied and often nonspecific and include a range of hepatic, neurologic, and psychiatric findings. Penicillamine remains the drug of choice for the treatment of Wilson’s disease, but recent experience suggests that trientine and zinc may be safe, effective alternatives. All three drugs are probably safe for use in pregnant patients with Wilson’s disease. Liver transplantation is the only effective treatment for Wilsonian fuhninant hepatic failure and corrects the underlying metabolic defect. CONCLUSIONS: Wilson’s disease is a disorder of hepatobiliary copper excretion manifested predominantly by hepatic and neurologic copper toxicosis and inherited in an autosomal recessive pattern. Although the specific underlying biochemical defect remains to be defined, specific therapy is available and usually successful. Maintaining a high index of suspicion is critical in diagnosing this readily treatable inherited disease.

From the Division of Gastroenterology and Hepatology, Department of Medicine, Jefferson Medical College. Philadelphia, Pennsylvania. Requests for reprints should be addressed to Lawrence S. Friedman, M.D., Jefferson Medical College, 465 Main Building, 132 South 10th Street, Philadelphia, Pennsylvania 19107. Manuscript submitted February 4.1991, and accepted in revised form September 21, 1991.

P

rogressive hepatolenticular degeneration was described by S.A. Kinnier Wilson [l] in 1912. Wilson noted this to be a familial syndrome characterized by cirrhosis and progressive degeneration of the lens of the eye. Since Wilson’s original description, much has been learned regarding the genetic basis, pathogenesis, natural history, histologic features, and treatment of Wilson’s disease (WD). However, the underlying biochemical defect responsible for the deranged copper homeostasis of WD remains to be elucidated.

GENETICS In 1921, Hall [2] reported the hereditary nature of WD, and the autosomal recessive mode of inheritance was later confirmed by Bearn [3]. The prevalence of WD has been estimated to be approximately 30 per million and the frequency of heterozygous carriers one per 90 persons [4], although lower prevalence rates have been suggested [5]. Heterozygous carriers neither develop the disease nor require specific treatment; however, they may exhibit mild abnormalities of copper (Cu) metabolism, which can result in diagnostic confusion. The gene responsible for WD has recently been mapped to chromosome 13 [6]; cloning of the gene and characterization of its product are eagerly awaited.

PATHOGENESIS The clinical sequelae of WD result from excessive deposition of Cu in various body tissues. Although much attention has focused on low serum ceruloplasmin levels as a pathogenic factor in WD, recent studies suggest that low ceruloplasmin levels result from reduced transcription of the ceruloplasmin gene or reduced translation of ceruloplasmin mRNA secondary to the as yet undefined underlying metabolic defect [7,8]. Additional evidence refuting a primary role for hypoceruloplasminemia in the pathogenesis of WD includes: (1) the finding of normal ceruloplasmin levels in up to 15% of patients with WD [9]; (2) the occurrence of hypoceruloplasminemia in about 10% to 20% of heterozygous carriers, who do not develop symptomatic tissue Cu toxicosis [lo]; (3) a lack of correlation between the clinical severity of WD and serum ceruloplasmin levels; (4) the failure of the administration of ceruloplasmin to correct abnormal Cu homeostasis in June

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patients with WD [ll]; and, most convincingly, (5) the localization of the gene for ceruloplasmin to chromosome 3 [12], in contrast to the gene for WD, which is on chromosome 13 [6]. In normal persons, approximately half of dietary Cu is absorbed from the gastrointestinal tract, and only a negligible amount (less than 70 pg/d) is excreted in the urine; an amount similar to that absorbed is excreted in the bile [13]. Intestinal Cu absorption and reabsorption of Cu excreted via the biliary tract is similar in patients with WD, heterozygotes, and normal control subjects [14,15]. Thus, Cu overload in WD is not due either to increased intestinal reabsorption of Cu excreted via the biliary tract or to decreased urinary Cu excretion. The aforementioned observations suggest that the defect in Cu homeostasis in WD is localized to the liver or biliary tract [13,16,17]. Several hypotheses have been advanced to explain this defect in the biliary excretion of Cu: (1) hepatic synthesis of a high-affinity Cu-binding protein [18]; (2) deficiency of biliary Cu-binding proteins [15,19,20]; (3) persistence into adulthood of the fetal mode of Cu metabolism as a result of a mutation in a controller gene [21]; or (4) a lysosomal defect in hepatocytes [22]. Although support for a decrease in biliary Cu excretion as a result of a lysosomal defect is based on the study of only one patient [22], this remains the most plausible hypothesis. Either enhanced retention of Cu by a lysosomal protein or impaired transport of Cu across lysosomal or canalicular membranes is possible.

CLINICAL MANIFESTATIONS The clinical manifestations of WD relate to the gradual, progressive poisoning of tissues with excess free Cu. A conceptual scheme to account for the variability of the clinical course considers four stages of disease [23,24]. Initially (stage l), the patient is asymptomatic as Cu accumulates in the hepatocytic cytosol. As the hepatocytic cytosol becomes saturated with Cu, some Cu redistributes into hepatocytic lysosomes [25], while some Cu is released into the circulation (stage 2). If this redistribution occurs gradually (as in the majority of patients), the disease may remain clinically silent through stage 2. Conversely, if the shift in Cu is rapid, the patient may present with fulminant hepatic failure (FHF) or acute intravascular hemolysis [26]. Subsequently, Cu accumulation within hepatocyte lysosomes and continued extrahepatic redistribution result in cirrhosis and neurologic, ophthalmologic, and renal dysfunction (stage 3). If WD is diagnosed at this stage and irreversible organ damage has not yet supervened, institution of therapy may result in normalization of the Cu balance (stage 4), followed by resolution of symptoms. 644

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WD is predominantly a disease of children, adolescents, and young adults. In children, hepatic manifestations predominate, whereas in adolescents and adults, neuropsychiatric manifestations are more frequent. Symptoms rarely occur before age 6, and half of the patients are symptomatic by age 15. Onset after age 40 is rare, but patients presenting in the fifth and sixth decades have been described [27]. Overall, the initial clinical manifestations are hepatic in 42%, neurologic in 34%, psychiatric in lo%, and hematologic, endocrinologic, or renal in less than 10% of cases. Approximately 25% of patients have evidence of involvement of more than one organ system at presentation [28]. Hepatobiliary Hepatic manifestations of WD encompass a broad spectrum of acute and chronic liver diseases. Most commonly, the course is chronic and characterized by features of postnecrotic cirrhosis [29]. Progressive hepatic insufficiency with portal hypertension and splenomegaly, gastroesophageal varices, ascites [29], and spontaneous bacterial peritonitis may ensue [30]. In some cases, cirrhosis remains well compensated, and the results of standard liver biochemical tests may be normal. Because the manifestations of Wilsonian cirrhosis are nonspecific, a young patient may be incorrectly diagnosed as having cryptogenic or alcoholic cirrhosis or even idiopathic thrombocytopenic purpura [4]. WD accounts for less than 5% of cases of chronic active hepatitis (CAH), but CAH occurs in about 10% to 30% of patients with WD [31,32]. As for cirrhosis, there are no distinguishing characteristics of CAH due to WD, and an incorrect diagnosis of either viral or drug-induced chronic hepatitis may be made. In CAH due to WD, the serum ceruloplasmin level may be elevated into the normal range because ceruloplasmin is an acute-phase reactant. WD can present as an episode of acute hepatitis, which usually subsides spontaneously and may be attributed mistakenly to a viral infection [4]. Associated hemolytic anemia should raise the possibility of WD. In a minority of patients, WD presents as FHF with rapidly progressive jaundice, coagulopathy, and encephalopathy [26,33]. Supportive medical therapy is generally unsuccessful in these cases, and death often supervenes unless liver transplantation is performed (see below). FHF may also occur if chelation therapy is inadvertently discontinued in a previously treated patient with WD. In these persons, the prognosis is extremely poor, with a mortality rate of about 75% within 2.5 years [34]. Certain features may suggest the possibility of Wilsonian as opposed to viral FHF: (1) associated intravascular, Coombs’-negative hemolytic anemia, probably due

WILSON’S

to erythrocyte destruction by the sudden release of Cu from necrotic hepatocytes into the circulation [35,36]; (2) relatively low serum aminotransferase levels [26,33,36]; (3) low or even undetectable serum alkaline phosphatase levels (and a correspondingly low ratio of alkaline phosphatase to total serum bilirubin) [37]; and (4) a disproportionately low serum alanine aminotransferase level compared with the serum aspartate aminotransferase level, as in alcohol-induced liver injury with pyridoxine deficiency [38]. Given the substantial longevity of many patients with WD, it is somewhat surprising that hepatocellular carcinoma (HCC) is uncommon in Wilsonian cirrhosis [39]. Studies in animal models of hepatic carcinogenesis suggest that Cu overload may protect against the development of HCC [40]. In support of this hypothesis, HCC is also relatively uncommon in primary biliary cirrhosis and sclerosing cholangitis, which are also characterized in part by hepatic Cu overload. Patients with WD are predisposed to small, faceted, calcified (pigment) gallstones, because of intermittent hemolysis [41]. Neurologic Neurologic manifestations of WD commonly appear in adolescence or early adulthood and are usually chronic but occasionally acute in presentation. Invariably Kayser-Fleischer cornea1 rings are present (see below). Cirrhosis may be subclinical. Early neurologic findings may include a tremor (resting, intention, or postural), dysarthria, sialorrhea, incoordination (especially of fine movements), and ataxia. An adolescent may present with a deteriorating performance in school and athletics because of handwriting difficulties and a loss of dexterity. Later, oropharyngeal dysphagia, grimacing, and “wing-beating” of the extremities may be seen. Late findings, now rare due to earlier diagnosis and treatment, include dystonia, spasticity, rigidity, and seizures (grand ma1 or partial complex). Cognitive and sensory function is typically preserved. The neurologic manifestations of WD appear to result from anatomic disruption of the basal ganglia, deep cerebral cortical layers, cerebellum, and, less commonly, brainstem. The putamen is generally most severely involved, with diffuse, symmetric softening, atrophy, and cavitation. Although the anatomic changes of the central nervous system (CNS) are localized, excess Cu is distributed throughout the brain [42]. Despite the frequent demonstration of anatomic changes in the CNS by computed tomography and magnetic resonance imaging, the observed abnormalities do not correlate reliably with clinical findings and are not helpful prognostically [43,44].

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Psychiatric Although an uncommon cause of psychiatric illness, WD should be considered in any young patient with the new onset of a psychiatric illness, especially when associated with neurologic abnormalities. Behavioral, affective, psychotic, and neurotic disorders may be seen. Psychiatric disturbances may play a critical role in the deterioration of an individual’s performance at work or school. Psychiatric manifestations are thought to arise from a combination of cerebral Cu toxicosis and the patient’s desperate reaction to an apparently progressive, mysterious neurologic disease [4]. Ophthalmologic Kayser-Fleischer rings are invariable in patients with neurologic manifestations of WD. The rings are typically 1 to 3 mm in diameter, green, yellow, or brown, and located at the periphery of the cornea (Figure 1). They begin as crescents in the superior quadrant and subsequently extend to the inferior, lateral, and medial regions, respectively, until they become circumferential and broader, and spread centrally from the limbus. With therapy, the rings fade in the reverse order in which they formed [45]. The rings consist of electron-dense granules containing both Cu and sulfur. Although the excess Cu is distributed uniformly throughout the cornea, sulfur-Cu complexes (possibly a Cu-metallothionein complex) are found only in Descemet’s membrane [46]. Kayser-Fleischer rings may be seen with the unaided eye, but a slit-lamp examination is often necessary for their detection. Kayser-Fleisher rings are not pathognomonic for WD and may be seen in a variety of other hepatobiliary diseases [47] or as a result of topical ocular application of Cu-containing solutions and ocular chalcosis (a Cu-containing foreign body). Sunflower cataracts consist of green, goldenbrown, or grey granular Cu deposits in the lens of the eye and appear as discoid opacities in the anterior lens capsule, with petal-like fronds that radiate toward the lens periphery like a sunflower [48]. Sunflower cataracts are less frequent than, but usually associated with, Kayser-Fleisher rings. They may also occur in ocular chalcosis. Sunflower cataracts tend to fade and disappear more rapidly than Kayser-Fleisher rings in response to therapy. Neither Kayser-Fleisher rings nor sunflower cataracts affect vision significantly. Hematologic The possibility of WD should be considered in any young patient with nonspherocytic, Coombs’negative intravascular hemolysis of unclear etiology, which may be the initial manifestation in 10% to 15% of cases [36,49]. Severe hemolysis frequently June

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manifestations immobility.

that

result

in contractures

and

Dermatologic Hyperpigmentation of the skin (localized or diffuse) is a rare presenting manifestation [62]. Bluish lunulae of the fingernails [63] and acanthosis nigricans [64] have been reported.

Figure 1. Kayser-Fleischer Philadelphia, PA).

ring

(courtesy

of J. Bilyk,

Cardiac Congestive heart failure and cardiac arrhythmias have been reported in patients with WD. Interstitial fibrosis, small-vessel sclerosis, and focal perivascular myocarditis have been observed in association with cardiac hypertrophy, but Cu excess has not been found consistently in cardiac tissue [65]. Recently, autonomic dysfunction, characterized by orthostatic hypotension and an abnormal response to the Valsalva maneuver, has been reported in patients with WD [66].

M.D.,

Endocrine The most frequent endocrinologic disturbances in patients with WD are gynecomastia and delayed puberty due to hepatic dysfunction [28]. Primary or secondary amenorrhea due to liver disease is a common presentation in symptomatic females [67,68]. There is some evidence that menstrual abnormalities may also be caused by primary ovarian disturbances [69]. Glucose intolerance [70] and parathyroid insufficiency have been reported [71].

occurs in the setting of Wilsonian fulminant hepatitis, probably due to rapid release of Cu from necrotic hepatocytes [26,49], with resulting free Cu oxidative injury to erythrocyte membrane phospholipids, hemoglobin, and other erythrocytic enzymes [50,51]. Renal The most clinically significant renal disorders that may occur in WD are proximal or distal renal tubular acidosis (RTA) [52-541, which are believed to result from the effects of Cu toxicity on the renal tubules [4]. Occasionally, WD may be associated with reductions in both renal plasma flow and glomerular filtration rate.

HEPATICPATHOLOGY

Rheumatologic Osteomalacia, rickets, osteoporosis, osteoarthritis, polyarthritis, localized bone demineralization, spontaneous fractures, fragmentation of marginal bone (near joints), osteochondritis, peri- and intraarticular calcifications, joint hypermobility, and chondromalacia patellae may occur in patients with WD [55-571. Although the radiologic findings tend to be more dramatic than the clinical symptoms, musculoskeletal symptoms may occasionally be presenting complaints. Some of the pathologic changes may be due to Cu deposition in cartilage and synovium [58,59]. It has been hypothesized that Cu may cause collagen and proteoglycan degradation and that consequent tissue damage may be mediated by oxygen-derived free radicals [59-611. Other pathogenic factors include systemic acidosis with hypercalciuria and hyperphosphaturia due to RTA, chronic liver disease, and severe neurologic 646

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The earliest histopathologic changes in the liver on light microscopy in asymptomatic patients with WD are macrovesicular fat deposition in hepatocytes, glycogen degeneration of hepatocyte nuclei, and Kupffer cell hypertrophy [72-741. Hepatic steatosis may relate to ultrastructural abnormalities of mitochondria and perixosomes that may lead to diminished lipid oxidation and accumulation of triglycerides in hepatocytes [75,76]. Over time, hepatocellular necrosis and stromal collapse are seen, and ultimately fibrosis and macronodular, postneerotic cirrhosis ensue, presumably due to the steatosis, excess Cu, or both. As this metamorphosis occurs, hepatic steatosis and the ultrastructural mitochondrial alterations regress [75]. Progression to cirrhosis occurs at a variable rate, depending in part on the degree of hepatocellular inflammation and necrosis. Histochemical staining for excess Cu is unreliable. Cu may be detected in histologic sections of the liver with rubeanic acid, rhodanine, and Timm’s silver sulfide staining. The rhodanine stain is the most reproducible and provides a satisfactory screening method for identifying excess tissue Cu.

WILSON’S

Timm’s silver sulfide staining is the most sensitive but least reproducible technique and also stains iron and zinc. Orcein, which stains for a previously ill-defined intracellular Cu-binding protein now believed to be lysosomal metallothionein, may also be used [77,78]. Early in WD, Cu is distributed diffusely within the hepatocyte cytosol and detectable histochemically only by the most sensitive staining techniques because the concentration of Cu at any given site is low [25,‘79]. Orcein staining is characteristically negative in early WD, because of the relatively small amount of lysosomal Cu. As WD evolves, Cu localizes to both the hepatocyte cytoplasm and lysosomes, and histochemical staining is more reliable. With advanced disease, hepatic Cu content decreases, as Cu is distributed to other body tissues, but Cu in the liver is localized to lysosomes and can be detected with relatively insensitive stains due to high focal concentrations of the metal. Unfortunately, late in WD, Cu is generally distributed heterogeneously in the liver, present diffusely throughout certain nodules but undetectable in others, and sampling errors are possible, in contrast to other cholestatic disorders that are characterized by more uniform hepatic Cu distribution [79,80]. Thus, for a variety of reasons-insensitivity of staining techniques, redistribution of Cu within hepatocytes over the course of WD, and the heterogeneity of Cu deposition within the liver-hepatic histochemical staining for Cu cannot be relied on to diagnose WD.

DIAGNOSIS (1) Kayser-Fleischer rings (see above): These rings, detectable reliably by slit-lamp examination, are not specific for WD. Although Kayser-Fleischer rings are invariably seen in patients with neurologic manifestations of WD, they may be absent in patients with hepatic WD. Therefore, in a patient with liver disease, the absence of these rings does not exclude WD. (2) Serum ceruloplasmin: Ceruloplasmin is a blue az-glycoprotein with a molecular weight of approximately 132,000 d. The gene for ceruloplasmin has been mapped to chromosome 3 [12]. Each ceruloplasmin molecule contains six prosthetic Cu atoms, and more than 90% of the Cu circulating in serum is bound to ceruloplasmin. The normal serum concentration of ceruloplasmin is 20 to 40 mg/dL and is determined by either an immunocytochemical or enzymatic technique. Although the vast majority of patients with WD have low ceruloplasmin levels (less than 20 mg/dL) , some patients have levels in the low-normal range (20 to 30 mg/dL), due to hepatic inflammation or a neoplasm, pregnancy, or use of estrogen [9,81,82].

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The serum ceruloplasmin level may decrease into the abnormal range with treatment of Wilsonian hepatitis. A low serum ceruloplasmin level is not diagnostic of WD. Low serum ceruloplasmin levels may be found in about 10% to 20% of heterozygotes for WD [lo], patients with FHF of any etiology [26], about 25% of children with CAH [83], normal neonates, [84], and patients with intestinal malabsorption, nephrosis, or malnutrition [85]. Hypoceruloplasminemia may also be seen in hereditary hypoceruloplasminemia, which is unassociated with Cu retention and toxicosis [86]. Despite these limitations, determination of the serum ceruloplasmin concentration is the best screening test for WD. Certainly, a serum ceruloplasmin level over 30 mg/dL virtually excludes WD. However, hypoceruloplasminemia alone is insufficient for a diagnosis of WD. (3) Nonceruloplasmin serum Cu: Nonceruloplasmin or free serum Cu accounts for only about 10% of the total serum Cu pool and is loosely complexed to albumin and amino acids. In normal adults, the serum concentration of free Cu varies from 5 to 12 pg/dL. In untreated WD, the serum concentration of free Cu is consistently elevated [87], as it often is in other cholestatic liver diseases [88]. The value of free serum Cu measurements in the diagnosis of WD recently has been emphasized [87]. (4) Total serum Cu: Total serum Cu represents the Cu contained in ceruloplasmin and the nonceruloplasmin (free) fraction. The normal range is 70 to 150 pg/dL. In most patients with WD, the total serum Cu level, reflecting the ceruloplasmin fraction, is decreased (usually less than 80 pg/dL), and offers no advantage over the serum ceruloplasmin level as a screening tool. (5) Urinary Cu excretion: In normal individuals, less than 70 pg/d of Cu is excreted in the urine, and this is derived predominantly from the free (nonceruloplasmin) fraction, which is readily filterable by the glomerulus. Patients with WD and saturated hepatic Cu stores generally excrete greater than 100 kg/d of Cu in the urine 1891. The most dramatically elevated values are seen in patients with massive hepatocellular necrosis, in whom the large hepatic Cu stores have been released into the circulation. Hypercupriuria is nonspecific and may be seen in a variety of other hepatobiliary diseases, including primary biliary cirrhosis and CAH [83,90]. This nonspecificity cannot be overcome by utilizing penicillamine to facilitate increased urinary Cu excretion [90,91], although the value of this test has been recently reported in children with WD in the absence of FHF [92]. Monitoring urinary Cu excretion is, however, useful in assessing the response to chelation therapy. Cu-free containers must be used for June

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a

a

"0

10

20

30

40

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HOURS Figure ingestion cellaneous (Modified

2.

Serum 6%~ concentrations of a 2-mg dose of radiocopper. liver diseases. B. Patients with permission from [102].)

(mean

f

SE) after the with misWilson’s disease.

A. Patients with

collections. Early in treatment, Cu excretion rises dramatically and may reach levels of 1,000 to 2,000 fig/d. As decoppering ensues, the urinary Cu excretion drops to less than 100 pg/d, at which point the dose of the chelating agent may be decreased. A subsequent rise in Cu excretion during treatment may reflect intermittent noncompliance with therapy. (6) Hepatic Cu concentration: In the normal adult, the Cu concentration varies from 15 to 55 Kg/g dry weight of liver and can be measured by spectrophotometric methods, atomic absorption, or neutron activation analysis. To ensure an accurate determination, the biopsy apparatus and containers must be free of Cu contamination. Either a disposable steel needle or a reusable needle washed in 0.1 M EDTA and rinsed with demineralized water must be used for liver biopsy. The plastic syringe used for biopsy should contain 5% dextrose in water, not saline, which may dissolve sufficient Cu from a brass hub to affect the results [4]. A tissue 648

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sample of 10 mg, or most of a 2-cm biopsy core, is needed for quantitative Cu analysis. In untreated WD, the hepatic Cu concentration is typically elevated to 250 to 3,000 pg/g dry weight [93]; rarely, values less than 250 pg/g dry weight may be found because of a sampling error. Heterozygotes generally have mildly elevated hepatic Cu concentrations ranging from 55 to 250 pg/g dry weight [93]. Elevated hepatic Cu content is not specific for WD and may also be seen in a variety of cholestatic disorders, including extrahepatic biliary obstruction, biliary atresia, primary sclerosing cholangitis, primary biliary cirrhosis [94,95], intrahepatic cholestasis of childhood [96], Indian childhood cirrhosis [97,98], and CAH [99]. These diseases can usually be differentiated from WD on clinical, biochemical, and histologic grounds. (7) Radiocopper incorporation into ceruloplasmin: Demonstration of decreased incorporation of orally administered radiolabeled Cu into newly synthesized ceruloplasmin may occasionally be useful in confirming a diagnosis of WD. Soon after oral ingestion of radiocopper (2 mg of cupric acetate, which contains 0.4 mCi of 64Cu, in 100 to 150 mL of fruit juice or ginger ale), labeled Cu appears in the serum and is complexed to albumin and amino acids. The serum radiocopper concentration reaches its maximum within 1 or 2 hours, then rapidly declines, corresponding to prompt clearance of Cu by the liver. In normal persons, a secondary rise in serum radiocopper concentration follows and continues gradually over the ensuing 48 hours, as radiocopper is incorporated into newly synthesized ceruloplasmin. This gradual secondary rise in the serum radiocopper concentration also occurs in persons with liver diseases other than WD, but is absent in patients with WD (Figure 2) [loo-1021. The curve for heterozygous carriers falls intermediate between those for normal and homozygous individuals. It is not surprising that persons with WD and hypoceruloplasminemia lack a secondary rise in the serum radiocopper curve, but there is also a lack of radiocopper incorporation into ceruloplasmin in the occasional patient with WD and a normal serum ceruloplasmin level. The clinical importance of this test, therefore, rests in its ability to identify patients suspected of having WD despite a normal serum ceruloplasmin level. (8) Diagnostic approach: In the vast majority of patients with WD, the presence of both KayserFleischer rings and hypoceruloplasminemia confirms the diagnosis. When these rings are absent, hypoceruloplasminemia in conjunction with a hepatic Cu concentration greater than 250 rg/g dry weight is sufficient for diagnosis. If hypoceruloplasminemia is absent, the presence of KayserFleischer rings in conjunction with a hepatic Cu

WILSON’S

concentration greater than 250 pglg dry weight is generally confirmatory. If there is still doubt about the diagnosis of WD, a radiocopper incorporation study can be done. A radiocopper incorporation study may also be useful when the serum ceruloplasmin concentration is normal and a liver biopsy is contraindicated or yields a borderline Cu concentration.

TREATMENT In the late 194Os, it was noted that a patient with WD had excessive urinary Cu excretion [103], and it was postulated that the disease might be treated by utilizing the chelating agent dimercaprol (BAL) to enhance cupriuresis and thereby deplete excessive body Cu stores. In 1951, two groups confirmed the therapeutic efficacy of BAL in the treatment of WD [104,105]. Unfortunately, BAL was impractical as long-term therapy due to the need for frequent, painful intramuscular injections and the occurrence of adverse effects. In 1955, Walshe [106] hypothesized that penicillamine, an amino acid derivative (dimethylcysteine) from the urine of patients taking penicillin, could be utilized as an alternative oral cupriuretic agent. He postulated that the sulfhydryl moiety of penicillamine might bind excess Cu and cause cupriuresis. Thus, penicillamine became the first convenient and effective treatment for this heretofore invariably progressive and fatal disease [106]. All patients with WD (homozygotes), whether asymptomatic or symptomatic, require treatment for life. With appropriate treatment, asymptomatic patients remain asymptomatic [67,107-1121, and the vast majority of symptomatic patients have improvement or resolution of their symptoms [23,67,106,113,114]. Inadvertent discontinuation of chelation therapy may result in catastrophic hepatic decompensation and death [34]. (1) Penicillamine (dimethylcysteine): Penicillamine remains the drug of first choice for the treatment of WD. Penicillamine probably produces its major effect by “decoppering” the body tissues as a result of dramatic cupriuresis [115]. As therapy is instituted, the 24-hour urinary Cu excretion usually rises to 2 to 5 mg [4]. After many months or years of therapy, the urinary Cu excretion gradually falls to less than 500 pg/d. Failure of the urinary Cu excretion to decline over time or an abrupt rise in urinary Cu excretion after an initial fall should raise the suspicion of poor compliance. It has been suggested that penicillamine may also “detoxify” Cu [116,117], either by the formation of nontoxic penicillamine-Cu complexes [118] or by penicillamineinduced synthesis of metallothionein [119], which could bind Cu in a nontoxic form. The detoxification hypothesis is consistent with rapid clinical de-

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compensation following abrupt cessation of chelation therapy [34]. The standard initial dose of penicillamine is 1 to 2 g daily in four divided doses by mouth 1/2hour before or 2 hours after eating. Critically ill patients may initially be given up to 3 to 4 g/d, for brief periods [120,121]. The dose of penicillamine may eventually be decreased to a maintenance level of 0.5 to 1 g/d, as the patient’s clinical condition improves and urinary Cu excretion diminishes. Patients should also receive oral pyridoxine 25 mg daily because of the antipyridoxine effect of penicillamine [122]. Some patients improve clinically soon after therapy begins, whereas some may require several months of therapy before substantial benefit occurs [121,122]. A recent review has emphasized that, whereas hematologic and neurologic manifestations improve with treatment in most patients, hepatomegaly and splenomegaly may not reverse with treatment [87]. In about 10% to 20% of individuals presenting with neurologic manifestations of WD, an exacerbation of symptoms is seen with the institution of therapy [120,121]. The patient and his or her family should be cautioned about the possibility of a temporary exacerbation, because discontinuation of therapy will lead to further deterioration, whereas continued therapy will ultimately be rewarding in most cases. Patients receiving penicillamine should be monitored by interval histories and physical examinations, 24-hour urinary Cu determinations, free serum Cu concentrations, complete blood and platelet counts, and urinalyses before therapy is started, weekly during the initial month of treatment, monthly during the initial year of treatment, and yearly thereafter [4,122]. A slit-lamp examination may be performed yearly to follow semiquantitatively the status of the Kayser-Fleischer rings. Fading or disappearance of these rings is a valuable objective sign of decoppering, whereas intensification or reappearance of the rings is a cause for concern and suggests either noncompliance or an inadequate dose of penicillamine [122,123]. The free serum Cu level also can be expected to return to normal with successful treatment [87]. Adverse effects of penicillamine are common. Between the first and third weeks of therapy, approximately 20% of patients develop an early hypersensitivity reaction to penicillamine, characterized by fever, a generalized pruritic maculopapular rash, lymphadenopathy usually affecting the cervical nodes and, less commonly, granulocytopenia or thrombocytopenia, or both [23,113]. At the first sign of a hypersensitivity reaction, penicillamine should be withheld until the reaction subsides. Subsequently, penicillamine can be reintroduced at a June

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reduced dosage of 0.25 g daily; corticosteroids, typically prednisone 20 to 30 mg by mouth daily, may be added to suppress recurrent hypersensitivity. The dose of penicillamine can then be increased gradually until full dosage is achieved in approximately 2 weeks, after which prednisone can be tapered [4]. In patients with penicillamine-induced granulocytopenia or thrombocytopenia, rechallenge must be started at even lower doses and more gradually, with success reported in only about half of the cases [41. Late reactions to penicillamine may occur in about 3% to 7% of patients and include nephrotic syndrome, a Goodpasture-like syndrome, drug-induced lupus, dysgeusia, cholestasis, myasthenia gravis, depression of serum IgA levels, polymyositis, thrombocytopenia, agranulocytosis, and aplastic anemia. Skin disorders are most common. Hemorrhagic penicillamine dermatopathy results from weakening of the subcutaneous tissues due to penicillamine-induced inhibition of collagen and elastin cross-linking [124]. Similarly, penicillamine may result in impaired wound healing [125,126], and the dose of penicillamine should be reduced to 0.25 to 0.5 g daily during the perioperative period [4]. Other reported skin reactions include elastosis perforans serpiginosa (EPS), pemphigus, lichen planus, and painful aphthous stomatitis. The occurrence of nephrosis, drug-induced lupus, Goodpasture-like syndrome, EPS, or bone marrow suppression usually requires that penicillamine be discontinued indefinitely and that an alternative therapeutic regimen be found. In analyzing their vast clinical experience, Scheinberg and Sternlieb [4] have suggested that only about 2% of WD patients are unable to continue penicillamine therapy due to intolerable adverse reactions, a frequency much lower than that for penicillamine use in patients with primary biliary cirrhosis, progressive systemic sclerosis, and rheumatoid arthritis. (2) Triethylene tetramine dihydrochloride (trientine): Trientine is an alternative chelating agent that may be used in the occasional patient who is intolerant of penicillamine [127] and for initial decoppering [128-1321. Trientine appears to be useful in preventing the rapid clinical deterioration often seen in patients who have discontinued penicillamine therapy [34]. Like penicillamine, trientine acts by chelating Cu and enhancing cupriuresis [133], although the cupriuretic effect of trientine is less than that for penicillamine. Trientine and penicillamine may mobilize Cu from different pools, since, in contrast to penicillamine, trientine causes a rise in the serum free Cu concentration [129]. Trientine is administered by mouth in a dose of 750 mg to 2,000 mg daily in three divided doses. As 650

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for penicillamine, food diminishes the intestinal absorption of trientine, which should also be taken on an empty stomach. Although it appears to be remarkably safe, there is much less clinical experience with trientine than with penicillamine. Lupus nephritis has been reported in two patients, one of whom had this problem with penicillamine [132]. In general, the toxic reactions necessitating a change from penicillamine to trientine subside on trientine, except for penicillamine-induced EPS, which may not improve (and may progress) on trientine [132]. Serum iron concentrations have been noted to decline with longterm trientine therapy but promptly normalize with oral iron supplementation [133]. (3) Zinc: Oral zinc is currently considered a thirdline agent in WD and used only in patients intolerant of both penicillamine and trientine [121,134]. Unlike the chelating agents, zinc promotes fecal Cu excretion. Zinc may directly inhibit intestinal Cu absorption in a competitive fashion [135] or induce the synthesis of metallothionein within enterocytes and possibly hepatocytes [136], or both. Metallothionein is a 61 amino acid polypeptide with a high cysteine content that functions primarily as an intracellular binding ligand. With its high sulfhydryl content, methallothionein binds zinc, cadmium, and Cu to form mercaptides. The metals then may either be transferred into the portal circulation or remain complexed within the cytosolic fraction of the enterocyte to be excreted in the feces with sloughed cells. Although zinc appears to be a more potent stimulus to metallothionein synthesis than Cu, Cu binds more avidly to metallothionein [134,137]. It has been postulated that zinc induces the synthesis of intestinal metallothionein, which subsequently binds Cu in the enterocyte, which is later sloughed. A number of studies have suggested that therapy with oral zinc results in a favorable Cu balance and clinical improvement in patients with WD [138-1431. Elemental zinc 150 mg as the sulfate or acetate administered by mouth in three divided doses and taken 1 hour before or after meals is adequate to achieve Cu balance [142-1441. Although the use of zinc therapy is appealing, most of the published experience with zinc therapy has been in patients who were previously decoppered by a chelating agent. Moreover, in some cases, negative Cu balance was not achieved with zinc, and, in some patients, hepatic Cu concentrations rose during zinc therapy. Although controversy persists [144], currently zinc therapy should be considered only in patients intolerant of both penicillamine and trientine [134,144]. It is possible that in the future zinc wilI play a major role in the treatment of WD.

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The major adverse reaction associated with zinc therapy is gastrointestinal intolerance, specifically epigastric burning, which may be minimized by use of zinc acetate rather than zinc sulfate [140,144]. There has been concern that short-term use of zinc (300 mg/d for 6 weeks) may alter bacterial phagocytosis, chemotaxis, and the lymphocytic response to phytohemagglutinin [145]. Zinc also causes microcytic anemia by interference with iron utilization [146]. In animal studies, zinc excess has been observed to cause bone resorption, hypocalcemia, diarrhea, dehydration, and jaundice [147,148]. (4) Diet: Because of the ubiquity of Cu in our diet, a negative Cu balance cannot be achieved by dietary modification alone. It seems prudent, however, to recommend that early in the course patients with WD avoid foods with a high Cu content, such as shellfish, organ meats (especially liver), nuts, chocolate, and mushrooms. Domestic water softeners dramatically increase the Cu content of water, and distilled water may be preferable for ingestion and cooking.

SCREENING Once a diagnosis of WD is made, it is of paramount importance that family members at risk be screened, since treatment of asymptomatic homozygotes will prevent the evolution of disease manifestations [67,107-112,149]. Consistent with autosomal recessive transmission, the disease is found frequently in siblings of affected persons. Parents, first-degree relatives, and, if there is a history of consanguinity, other close relatives should also be screened [150]. Because the biochemical Cu profile of a normal neonate mimics that seen in WD and clinical manifestations of WD are rarely seen before age 6, screening of potentially affected children should begin no earlier than age 3 to 4 [150]. Screening should include a careful history and physical examination, routine liver biochemical tests, a slitlamp evaluation, and a serum ceruloplasmin level. Liver biopsy with quantitative hepatic Cu determination and radiocopper incorporation studies should be reserved for diagnostic uncertainties. Subjecting an unaffected person to life-long therapy unnecessarily may be as tragic as missing an opportunity to treat a patient with this readily treatable disease.

PREGNANCY Women with cirrhosis of any cause are at increased risk for spontaneous abortion, stillbirth, and premature delivery. Patients with untreated WD may experience primary or secondary amenorrhea due to hepatic or ovarian disturbances [67-69]; they are also prone to spontaneous abortions [68,151]. As some intrauterine devices are thought to produce contraception by increasing local Cu concentrations [152], it has

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been postulated that excessive free intrauterine Cu, derived from plasma, may be responsible for the repeated spontaneous abortions commonly seen in women with WD [Xl]. This concept is supported by reports of successful pregnancies within weeks of instituting chelation therapy in women with WD and a history of repeated miscarriages [153]. Whereas successful pregnancy is rare in women with untreated symptomatic WD, successful treatment can be expected to result in a normal reproductive life [151]. Although pregnancy does not appear to have a deleterious effect on treated WD, certain precautions should be considered. First, there is probably an increased risk of bleeding from gastroesophageal varices in cirrhotics during pregnancy [154]. Unfortunately, the occurrence of massive variceal hemorrhage cannot be predicted and may occur at any time during pregnancy [155]. Second, discontinuation of chelation therapy during pregnancy has been associated with clinical deterioration (as in nonpregnant patients) [4]. Both penicillamine and trientine appear to be safe for mother and fetus [151,153,156-1581. Although both chelating agents have been reported to be teratogenic in rats, the teratogenicity is believed to result from Cu deficiency [159,160], which has never been observed in penicillamine-treated WD patients or their infants. In contrast, Cu deficiency may occur in patients treated with penicillamine for disorders not characterized by Cu overload (such as rheumatoid arthritis and cystinuria), and the safety of chelating agents in these settings cannot necessarily be extrapolated from experience in WD [159,160]. To date, there has been only one case of transient, reversible cutis laxa in an infant born to a patient with WD treated with penicillamine (1.5 g/d) during pregnancy [161]. In general, because discontinuing chelation therapy during pregnancy may be harmful to the mother and because continued administration appears to be without appreciable risk to the infant, maintenance doses of penicillamine (or trientine) should be continued throughout pregnancy. If cesarean section is anticipated, the doses may be reduced to 0.25 g/d about 6 weeks before delivery [151] to attempt to avoid impaired wound healing. Although there are no published data to support its use during pregnancy, oral zinc therapy may be an attractive alternative approach in patients who have previously been decoppered.

LIVERTRANSPLANTATION Despite the effectiveness of pharmacotherapy in the vast majority of patients with WD, occasional patients with WD require liver transplantation [162]. When indicated, liver transplantation is actually an attractive treatment option for WD, because June

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it corrects the metabolic defect localized in the liver. Patients with WD who have undergone liver transplantation no longer require specific medical treatment for WD. Indications for transplantation in WD include FHF; decompensated cirrhosis with refractory coagulopathy, ascites, encephalopathy, and jaundice despite an adequate trial of chelation therapy; and progressive hepatic insufficiency after inadvertent discontinuation of chelation therapy [36]. Currently, neurologic manifestations of WD unresponsive to treatment are not an indication for liver transplantation in the absence of hepatic failure. In Wilsonian FHF, a prognostic index utilizing the serum aspartate aminotransferase and bilirubin levels and the prothrombin time has been formulated to predict a fatal outcome and select patients for liver transplantation [163]. However, the value of the index in predicting clinical outcome has been questioned [164]. Other novel treatments used in Wilsonian FHF as “bridges” to orthotopic liver transplantation have included postdilution hemofiltration [ 165,166] and heterotopic liver transplantation [ 1671.

CONCLUSION WD is a disorder of hepatobiliary Cu excretion manifested predominantly by hepatic and neurologic Cu toxicosis and inherited in an autosomal recessive pattern. Although the specific underlying biochemical defect remains to be defined, specific therapy with chelating agents is generally successful. Liver transplantation is an option for chelation therapy failures or patients presenting with Wilsonian FHF. Maintaining a high index of suspicion is critical in diagnosing this readily treatable disease.

ACKNOWLEDGMENT We thank Carol A. Miller and Marie Albert0 for their patient and expert secretarial assistance.

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