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Wilson Disease
Pathogenesis and Clinical Considerations in Diagnosis and Treatment

Richard Rosencrantz, M.D.; Michael Schilsky, M.D.

Semin Liver Dis. 2011;31(3):245-259.

Abstract and Introduction

Abstract

Nearly a century after Dr. Samuel Alexander Kinnier Wilson composed his doctoral thesis on the pathologic findings of "lenticular degeneration" in the brain associated with cirrhosis of the liver we know
that the underlying molecular basis for this autosomal recessive inherited disorder that now bears his name is mutation of a copper transporting ATPase, ATP7B, an intracellular copper transporter mainly
expressed in hepatocytes. Loss of ATP7B function is the basis for reduced hepatic biliary copper excretion and reduced incorporation of copper into ceruloplasmin. During the intervening years, there was
recognition of the clinical signs, histologic, biochemical features, and mutation analysis of ATP7B that characterize and enable diagnosis of this disorder. These include the presence of signs of liver or
neurologic disease and detection of Kayser-Fleischer rings, low ceruloplasmin, elevated urine and hepatic copper, and associated histologic changes in the liver. Medical therapies and liver transplantation
can effectively treat patients with this once uniformly fatal disorder. The earlier detection of the disease led to the initiation of treatment to prevent disease progression and reverse pathologic findings if
present, and family screening to detect the disorder in first-degree relatives is warranted. Gene therapy and hepatocyte cell transplantation for Wilson disease has only been tested in animal models but
represent future areas for study. Despite all the advances we still have to consider the diagnosis of Wilson disease to test patients for this disorder and properly establish the diagnosis before committing
to life-long treatment.

History

The disease is named after the American-born British neurologist, Dr. Samuel Alexander Kinnier Wilson who, in 1912, composed his doctoral thesis on the pathologic findings of "lenticular degeneration"
in the brain associated with cirrhosis of the liver.[1] Dr. Wilson's report was preceded almost 30 years earlier by Dr. Carl Westphal's clinical description of what he termed "pseudosclerosis" in patients
suffering from tremors without anatomic findings on autopsy.[2] Dr. Wilson's work built upon the experience in part from a series of patients collected by Sir William Gowers,[3] who similarly identified the
combination of neurologic and liver disease in 1888. Although the medicinal and toxic effects of copper have been known since antiquity,[4] it was A.J. Glazebrook[5] in 1945 and John Cumings[6] in 1948
that linked copper accumulation with the basal ganglia and hepatic pathology. The genetic inheritance was originally proposed by H.C. Hall[7] in 1921 as an autosomal recessive pattern, but subsequently
confirmed by A.G. Bearn[8] in 1953 by genetic ratio analysis calculation. Over 30 years later, its genetic locus was assigned to the long arm of chromosome 13.[9] Ultimately, the genetic basis for Wilson
disease (WD), the ATP7B mutation, was identified and cloned in 1993.[10,11]

The diagnosis of WD first was dependent on recognition of the syndrome of neurologic findings with associated cirrhosis, but this was dramatically changed when Kayser-Fleischer (K-F) rings were
identified as present in clinically affected patients. Diagnostic testing improved further decades later by the routine adoption of testing for liver dysfunction using serum and blood tests and liver biopsy[12]
to evaluate histology, quantify hepatic copper concentration, measure elevated urine copper excretion, and by the recognition that serum or plasma ceruloplasmin concentrations are reduced in most
patients with WD.[13] These findings form the basis for most of the phenotypic characterization of patients that we still use to date. Other adjunctive testing included the use of radiocopper testing for
labeled ceruloplasmin that was useful for identifying the minority of patients with WD with normal levels of ceruloplasmin, but this test is rarely used today. The most recent advance in testing is molecular
genetic testing that has followed the identification of the gene for WD and disease-specific mutations.

We have been able to effectively treat WD for less than a century. Historically, the disease was diagnosed after the development of neurologic symptoms and was invariably fatal. The first treatment
developed was British anti-lewisite (BAL), a compound developed for countering the toxic effects of mustard gas that was found to be a chelator of copper. This parenterally administered medication
resulted in increased copper excretion and reversed neurologic symptoms in many patients.[14] The first oral treatment, d-penicillamine, was developed by John Walshe,[15] who recognized the potential
for this compound to chelate copper and induce cupriuria with high efficiency. He was also instrumental in the development of another chelating agent, trientine,[16] and was the first to use
tetrathiomolybdate in humans,[17] a compound originally used by veterinarians for copper-poisoned sheep. Confirmation of the utility of tetrathiomolybdate has also been performed by Brewer et al.[18]
Schouwink[19] was the first to propose using zinc to block copper absorption to treat WD, and this has been another useful oral therapy currently in use for many patients. A very important historic
milestone with respect to treatment of WD was the recognition that preemptive treatment could prevent the development of disease progression, something that seems almost incontrovertible at this time,
but which was not initially accepted.[20] Liver transplantation is curative and represents a gross form of genetic therapy for WD.

Copper Homeostasis and Pathology of Copper-induced Injury

Copper is a unique essential trace element because it can participate in a wide variety of redox reactions, which allows it to function in numerous biologic processes. Key examples include copper-
dependent enzymes including cytochrome-C oxidase in the mitochondrial electron transport system; Cu/Zn-superoxide dismutase, which is important for free radical detoxification, hephaestin, a
ferroxidase that influences intestinal iron absorption; serum ceruloplasmin that functions as a circulating ferroxidase; protein-lysine-6 oxidase, essential for collagen and elastin crosslinking; and blood
clotting factors V and VIII.[21]

The average adult Western diet contains ~0.6 to 1.6 mg of copper per day, which is in excess of daily needs.[22] In the normal state, copper balance is tightly regulated. Foods containing elevated levels of
copper include shellfish, grains, nuts, mushrooms, legumes, chocolate, and organ meats. Copper is absorbed from the proximal small bowel with an efficiency of ~40–60%. Cu diffuses across intestinal
mucous, is carried across the enterocyte by the copper-transporting enzyme, ATP7A into the portal circulation and is bound mainly by albumin from which it is transported by hepatocytes by the
ubiquitously expressed human copper transporter HCTR1. Once inside the hepatocyte, copper chaperones such as Atox1 and glutathione transfers copper to the trans-Golgi network where ATP7B, a
P-type ATPase transports copper for incorporation into ceruloplasmin and for export to bile.[23] Key elements of copper homeostasis are summarized in Fig. 1.
Figure 1.

Outline of copper homeostasis. Copper absorbed by the proximal small intestine is taken up by the liver that plays a central role in copper homeostasis by utilizing copper for metabolic needs and
excreting excess copper into bile and thereby the gut, or exporting copper as copper containing ceruloplasmin used in iron metabolism and as nonceruloplasmin-bound copper that may be used by or
pathologically accumulated in other tissues or excreted into urine. Treatments for Wilson disease block copper absorption by the gut and increase fecal copper excretion (zinc) or increase urinary copper
excretion (chelating agents D-penicillamine and trientine).

There is some controversy as to whether or not ATP7B is present in vesicles from the trans-Golgi that eventually fuse and pass their contents to the bile canaliculus or whether the protein itself moves to
the apical canalicular membrane and directly transports copper into bile. By whichever mechanism this occurs, this pathway represents the main homeostatic mechanism for copper metabolism. Copper
can transport into bile via its conjugation to glutathione, but this is a relatively low affinity pathway compared with that which is ATP7B dependent. Bile in patients with WD contains only a fraction of the
normal copper content. Therefore, copper accumulates in hepatocytes where due to its highly reactive redox capacity induces cellular damage through oxidative stress.[24] In addition, high intracellular
copper levels lead to a conformational change in the antiapoptotic protein, X-linked inhibitor of apoptosis (XIAP). This change increases its degradation and thereby decreases its ability to inhibit
caspase-3 leading to a lower apoptotic threshold and cell death.[25] The pathogenesis of copper toxicity is outlined in Fig. 2.
Figure 2.

Pathogenesis of copper toxicity. The main pathways of copper overload/toxicity is through both a direct oxidative stress mechanism with lipid peroxidation of membranes, mitochondria, and DNA; and also
from unregulated apoptosis resulting in cell death from copper-induced changes in the anti-apoptotic protein, X-linked inhibitor of apoptosis (XIAP), and its loss of inhibitory control of caspase-3 with
copper accumulation.

Ceruloplasmin is a copper-containing glycoprotein that is synthesized mainly by hepatocytes. Its role is mainly in iron metabolism where it functions as a ferroxidase for mobilization of tissue iron. The
complete loss of production of ceruloplasmin due to defects in the ceruloplasmin gene, or aceruloplasminemia, does not lead to copper accumulation,[26] but in some individuals may lead to tissue iron
accumulation.[27] The loss of some ceruloplasmin activity in patients with WD is not adequate to lead to the same problems seen in aceruloplasminemia with respect to iron metabolism; however,
overtreatment with chelating agents for copper can lead to copper deficiency and loss of ceruloplasmin ferroxidase activity resulting in tissue iron deposition[28]

The copper bound to albumin and peptides not including ceruloplasmin is known as nonceruloplasmin-bound copper or "free copper." This typically amounts to ~10% of the total serum or plasma copper,
the remainder is accounted for by the nonexchangeable copper bound to ceruloplasmin. When copper accumulates in the livers of WD patients or when severe hepatic injury occurs, copper release into
the circulation increases and this fraction of copper is increased relative to the percentage bound to ceruloplasmin. This copper is available for renal excretion, and indeed cupriuria increases significantly
in untreated patients with WD and to a lesser extent in patients with other liver injuries.

Epidemiology and Pathogenesis

Wilson disease results from mutations in the ATP7B gene inherited as an autosomal recessive trait on the long arm of chromosome 13. ATP7B encodes a transmembrane copper-dependent P-type
ATPase located intracellularly. ATP7B protein transports copper both into the trans-Golgi network for incorporation into ceruloplasmin and also into the vesicles that merge with the bile canaliculus for
biliary copper excretion. Reduction in ATP7B function results in decreased biliary copper excretion with increased copper accumulation in hepatic and extrahepatic tissues that leads to the clinical features
of WD. This disorder has a global incidence of 1:30,000, and is present in all populations. Over 500 mutations have been identified with specific populations sharing distinct mutations.[29,30] In Caucasian
populations, up to 60% of patients have the point mutation H1069Q in exon 14.[31] In one Central/Eastern European study,[32] mutations in 3402delC, W779X, R778G, and 1340del4 represented more
than 10% of those without H1069Q mutations. In other populations, separate mutations predominate, for example, Arg778Leu and Thr935Met mutations in Chinese populations;[33] Q125R, A1003T, and
I1102T in northwest Indian pedigrees;[34] and Ser744Pro, Gly341Ser, and Glu1399Arg in a Saudi Arabian cohort.[35] Further detail regarding the molecular genetics for WD are discussed in this issue by
Bennett and Hahn.[36]

Other genotypic elements such as modifier genes and gender-related factors may influence the phenotypic expression of hereditary liver disease including genetic hemochromatosis, α-1-antitrypsin
deficiency and WD.[37] For example, MURR1 (aka COMMD1), is thought to adversely interact with the WD gene protein product. In one study including 63 WD patients, 30% had detectable MURR1 gene
changes that were associated with earlier onset of hepatic and neurologic disease.[38] In a Polish cohort of fulminant WD patients, 92% (12 out of 13) were female,[39] which highlights a gender-specific
effect and possibly an associated hormonal influence on clinical phenotype.[40–44]

In another example of the effect of modifier genes, Schiefermeier et al[45] tried to delineate why some patients have later-onset neurologic as well as hepatic symptoms by examining the potential
influence of ApoE genotype in WD patients homozygous for the H1069Q mutation. Though the distribution of ApoE genotypes was similar to known distributions in healthy Europeans, the onset of
symptoms was delayed by ~5 years in patients with the ApoE ε3/3 genotype to 25 years of age at presentation compared with patients with the ApoE ε3/4 genotype. Other phenotypic findings were not
modified. Therefore, it is possible that the presence of ApoE ε3/3 attenuated the clinical manifestations in WD by mechanisms that might involve the antioxidant properties, membrane-stabilizing effects,
and/or astrocyte axonal growth enhancement by the ApoE 3 protein. Few other homogeneous cohorts are available to validate this finding.

Clinical Manifestations

The clinical phenotypes of WD are exceedingly variable ranging from asymptomatic to chronic liver disease to neurologic or psychiatric signs and symptoms and acute liver failure. Each of these is
discussed separately below. Toxic copper accumulation in body tissues, mainly the liver and central nervous system are responsible for the phenotype, with modulation by diet, hormonal influences, and
other extragenic factors as discussed above. Symptoms usually present in the first decades of life, with the majority of cases occurring between the ages of 5 and 35 years old, but there are exceptions.
The youngest patient with cirrhosis was reported to be 3-years-old;[46] and the oldest at time of diagnosis were siblings in their eighth decade of life.[47,48] Typically, hepatic symptoms predominate in
younger patients around their first decade of life; and neurologic symptoms occur in older patients as they approach the third decade of life.

Hepatic Disease

Wilson disease may present with a wide range of liver disease. Some patients with clinically asymptomatic WD are found by family screening or fortuitously identified on routine laboratory tests when
evaluated for other causes. Many may have no signs or stigmata of clinical liver disease and may have abnormalities on liver function tests alone. Some may have a clinical picture of chronic active
hepatitis.[49] At the other end of the spectrum are patients with end-stage liver disease with cirrhosis and portal hypertension or acute liver failure (ALF), often on the background of advanced fibrosis or
cirrhosis. Acute liver failure from WD accounts for ~5% of all ALF and up to 12% in WD cases,[50] with a preponderance in young females[51] often outnumbering males 4:1.

On physical exam, patients early on may have hepatomegaly, and over time may be seen to develop signs of chronic liver injury and cirrhosis with splenomegaly and other stigmata of chronic liver disease
including gynecomastia, fluid retention, jaundice, hemorrhagic diathesis, and hepatic encephalopathy. An acute onset of jaundice occurs in patients with ALF due to WD. These patients may also develop
encephalopathy accompanied by cerebral edema with advancing liver failure. Kayser-Fleischer rings, corneal deposits of copper in Descemet membrane, are present in only 50% of patients with hepatic
presentations. Sunflower cataracts are another rare ophthalmologic finding.

Laboratory testing for the liver most commonly shows persistently elevated serum transaminases. As the disease progresses there is development of synthetic dysfunction with reduced albumin and
elevated international normalized ratio (INR) and loss of transport function with hyperbilirubinemia. For those with acute liver failure, rapid increases in bilirubin, mostly indirectly associated with marked
anemia without evidence of immune-mediated hemolysis (Coombs-negative). Renal insufficiency may also develop in the setting of acute liver injury. Other chronic changes include hypouricemia,
aminoaciduria, and rarely evidence of myositis with elevations in creatine phosphokinase. Urine testing for 24-hour copper collection early on in asymptomatic patients with liver disease may still be
normal (<40 μg/24 h),[52] and typically increases with advancing disease; it is almost invariably elevated above normal in patients symptomatic with neurologic or psychiatric symptoms. There is no longer
a role for penicillamine challenge testing (see discussion below).
Older patients may have either clinically silent liver disease concomitant with neurologic disease that is detectable only biochemically or radiologically. Others have symptomatic liver disease with
symptomatic neurologic or psychiatric symptoms and may require treatment for both as well as the underlying WD. Patients who present solely with liver disease and have been successfully treated may
later develop neurologic symptoms and ALF if medication is stopped or have problems with adherence. Patients with other liver diseases who are found also to have WD often have delays in diagnosis
and may have more advanced liver disease or neurologic and hepatic disease.[53]

Neurologic and Psychiatric Disease

Neurologic features include tremors, dystonia, Parkinsonian-like cogwheel rigidity, open jaw, drooling and dysarthria. These symptoms are often insidious in onset and progress over the course of months
to years. It is not uncommon for these patients to be treated primarily for their neurologic symptoms prior to the recognition of any liver abnormalities. In some patients, the neurologic symptoms can be
bothersome and disabling. Some may have severe and painful dystonia that can develop into contractures over time. Patients with severe dysphagia are at risk for aspiration.

In addition to other neurologic symptoms, almost one-third of WD patients had abnormal autonomic cardiovascular function tests that were likely due to the involvement of central autonomic neurons,[54]
which appears more commonly in patients with a more advanced neurologic-type presentation of their WD.[55]

Psychiatric symptoms are often underestimated in patients with WD. Young patients may present with subtle psychiatric findings that may include emotional lability and behavioral changes. Clues to their
presence may include social withdrawal and poor school performance. Up to two-thirds of (mostly adult) patients present with psychiatric manifestations such as personality changes, cognitive decline,
behavioral problems, depression, anxiety, affective disorders, and psychosis.[56] A South Indian series[57] showed 24% of patients diagnosed with WD had a psychiatric diagnosis mostly of affective
disorder, major depression, and dysthymia.

Other Organ System Involvement

Other affected organs systems include the kidneys where abnormalities such as aminoaciduria and nephrolithiasis are common; skeletal abnormalities such as osteopenia and arthritis; endocrine
abnormalities such as hypoparathyroidism; reproductive infertility and increased frequency of miscarriage; and ophthalmologic findings such as K-F rings and sunflower cataracts.[42]

Differential Diagnosis

Wilson disease should be considered in young patients with unexplained liver disease and in patients where there is concomitant liver and neurologic or psychiatric illness, and in those with ALF. With
respect to hepatic presentations, there is a great deal of overlap with the presentation of many types of acute or chronic hepatitis. Early on in the natural history, there is overlap with nonalcoholic fatty liver
disease, steatohepatitis, and autoimmune hepatitis with respect to abnormal liver tests and hepatic histology. In young patients, other disorders such as those of fatty acid oxidation metabolism or
mitochondrial disease must also be considered. It is not uncommon for this phase to go unrecognized and patients present with cirrhosis at which time all other etiologies of liver disease must be
considered.

Diagnosis

The diagnosis of WD should be based upon evidence derived from the patient's history, family history, physical exam including neurologic exam, laboratory tests for liver disease, ceruloplasmin and urine
copper, liver biopsy histology (light and sometimes electron microscopy) and copper content determination, radiographic findings, and ultimately molecular genetic testing.[58] The presence of K-F rings
and a low ceruloplasmin; a low ceruloplasmin and elevated hepatic copper above 75 μg/g dry weight and appropriate histology, and molecular genetic testing with evidence of two mutations of ATP7B can
each establish the diagnosis of WD. Diagnostic criteria are summarized in . Even when the diagnosis is established by molecular genetic testing, phenotypic characterization helps the clinician to choose
treatment options and counsel patients about disease prognosis. The individual tests used for evaluating WD are next reviewed below.

Table 1. Summary of Clinical Criteria to Establish a Diagnosis of Wilson Disease

Diagnosis of Wilson Disease (WD) Established

A. B. C.
Molecular (+) K-F rings (+) Cp <20 mg/dL
Plus one or more of the following: and/or
24-hour urine copper >40 μg/24 h
Cp <20 mg/dL Plus:
24-hour urine copper >100 μg/24 h* Liver biopsy >75 μg/g dry weight†
Typical WD neurologic disease
Liver biopsy >75 μg/g dry weight†

Note: Diagnostic testing should meet conditions listed in either column labeled A, B, or C. Diagnostic tests: (A) molecular testing; or (B) slit lamp examination, serum ceruloplasmin (CP), and 24-hour urine
copper; and (C) liver biopsy for copper quantification (if needed).
*24-hour urine copper >40 μg/24 h may be used if one other criteria present.
†>75 μg/g dry weight with appropriate histology and electron microscopy findings, otherwise the standard >250 μg/g dry weight is required.

Kayser-Fleischer (K-F) Rings

Classically, the K-F ring is the hallmark of WD. In fact, evidence of K-F rings in combination with a serum low ceruloplasmin or typical WD neurologic manifestations is diagnostic.[59] Corneal copper
deposits within Descemet membrane appear as granular golden-greenish layer that is best seen by slit-lamp observation (Fig. 3). Although K-F rings are commonly present in up to 98% of patients with
neurologic and psychiatric disease,[60] they are found in only 40 to 66% of patients with hepatic presentation and are uncommonly seen in young, asymptomatic patients.[61] However, similar corneal
findings may rarely be found in other chronic cholestatic syndromes including primary biliary cirrhosis, cryptogenic cirrhosis, chronic active hepatitis, and neonatal hepatitis.[62,63]

Figure 3.

Kayser-Flescher ring in a 40-year-old male with Wilson disease.

Serum Ceruloplasmin
Circulating levels of ceruloplasmin are reduced in ~95% of patients presenting with WD. This is measured in the serum or plasma by immunologic methods or by testing for oxidase activity against specific
substrates. Testing for oxidase activity is now less frequently used due to the efficiency of immunologic testing, but may be slightly more sensitive for the diagnosis of WD due to its detection of only the
copper containing active protein. Ceruloplasmin may be in the normal range in some patients with WD, but is also influenced by inflammation as this protein is an acute-phase reactant, and is increased
by estrogens that may be present in oral contraceptives or in pregnancy. Other causes of a reduced ceruloplasmin include the rare disorder of aceruloplasminemia, severe copper deficiency, severe
hepatic insufficiency, and severe nephrosis with protein loss (where all serum proteins are reduced). Testing for a reduced ceruloplasmin, while useful for identifying patients with chronic presentations of
WD, is less sensitive or specific in the setting of ALF where serum copper may be more useful.[64]

Urine Copper

The excretion of copper in the urine of untreated symptomatic patients is elevated above normal values up to 40 μg/24 h. Using this threshold value instead of the prior 100 μg/24 h value increases
sensitivity for the diagnosis, but reduces specificity. However, the results of testing in a pediatric population showed that the lower threshold value was equivalent to testing patients using a penicillamine
challenge. It should be noted that though urine copper is markedly elevated in patients with acute liver failure due to WD,[64] it is less reliably elevated in liver patients who are asymptomatic.[60]

Hepatic Histology, Ultrastructure, and Copper Content

Histologic findings on liver biopsy vary with the stage of the disease; this subject is reviewed in this issue by Johncilla and Mitchell.[36] Briefly, early on there is hepatic steatosis and subsequently
advancing fibrosis. During the phase of steatosis, ultrastructural features in hepatocyte mitochondria include crystalline deposits and dilated cristae.[65] As further copper accumulates, one may see dense
lysosomal deposits of copper and copper metallothionein. Advanced fibrosis and cirrhosis is common with later recognition of the disease, but can be present even in young patients. Marked
hepatocellular disruption with apoptotic as well as necrotic injury on the background of advanced fibrosis is found in ALF due to WD. Hepatic copper content determination has been extremely useful for
disease diagnosis. The initial value of 250 μg/g dry weight liver for copper content was better for distinguishing between patients and nonaffected individuals; however, data from Ferenci et al[66] suggests
that lowering the threshold to 75 μg/g increases the test's sensitivity by 13.2% and would identify more patients. With a lower threshold, the histology and molecular genetic testing is critical in establishing
the diagnosis of WD and excluding other liver disorders.

Investigating for hepatic copper by standard histochemistry is useful only when positive. Stains for sulfhydryl compounds such as the Timm stain are more sensitive than rhodanine or rubeanic acid stains,
which detect aggregates of copper-binding protein, but are rarely used. Standard histochemical staining for copper may reveal a copper-staining positive nodule with nearby copper-staining absent
regenerative areas. In severe cholestatic disorders, however, copper is typically present only in a periportal distribution, which helps to distinguish this from WD.

MRI/CT Brain for Patients With Central Nervous System Disease

Magnetic resonance imaging (MRI) and computed tomography (CT) of the brain may detect changes in the basal ganglia and other regions such as the pons or thalamus suggestive of WD,[67] but copper,
unlike iron, cannot be detected directly on imaging. When neurologic signs or symptoms are present, patients should undergo brain imaging for baseline study purposes. Changes in the basal ganglia due
to hypermanganism may also be present in some patients with WD with portal hypertension and portosystemic shunting, but can be distinguished from changes due to WD based on MRI T1 imaging that
can reliably detect manganese.

Laboratory Testing in Acute Liver Failure

Biochemical features include depressed levels of serum alkaline phosphatase for the degree of jaundice;[68] alkaline phosphatase to total bilirubin level of <2. The diagnosis of WD can be established with
almost complete certainty in acute liver failure when the combined measurements of an alkaline phosphatase to total bilirubin level yield a ratio of <4 and the aspartate aminotransferase (AST) to alanine
aminotransferase (ALT) ratio is >2.2.[64] An elevated serum copper above 200 μg/dL is also helpful, but not readily measurable on presentation in most sites, and urine copper is also elevated. A low-
serum ceruloplasmin is less specific in this setting compared with chronic disease presentations.

Scoring System to Aid Diagnosis

To aid in helping determine the need for clinicians to pursue a diagnosis of WD, a scoring system for the diagnosis of WD was developed by international consensus in Leipzig, Germany based on
phenotypic, hematologic, biochemical, tissue, and genetic criteria.[52] In a recent study, 28 of 30 asymptomatic children with WD scored in the "highly likely" diagnostic category suggesting that scores
above 4 appear to be validated.[61]

Other Liver Disease and WD

Patients with WD who concurrently have other liver diseases, particularly hepatitis C viral infection, hemochromatosis, hemochromatosis heterozygote, primary biliary cirrhosis, or primary sclerosing
cholangitis may present with more severe hepatic injury and show greater mortality.[53] Often the disease diagnosis is delayed in these individuals as other disease entities are considered first.

Family Counseling

All first-degree relatives of a patient with WD must be screened for the disease. Statistically, siblings have a 1 in 4 chance and children of a parent with WD have a 1 in 180 chance of inheriting WD. The
optimal first-line testing is direct WD mutation analysis; mutation analysis is preferred to screening for polymorphisms around the gene as this is dependent on the diagnosis being firmly established in the
proband. When molecular testing is not feasible, standard testing should include the combinations of liver function tests, serum ceruloplasmin, 24-hour urinary copper, and slit lamp eye examination for
K-F rings

Significant liver injury has been shown to occur in early childhood even in asymptomatic children. In a Greek series,[69] fibrosis was found on liver biopsy in a 4-month old infant and inflammation in
another 23 month old child. Recently, an Italian group reported elevated liver quantitative copper levels >250 μg/g dry weight in all three patients tested under four years of age.[61] Others have described
micronodular cirrhosis in a 3-year-old and ALF occurring in children as young as 5 years of age.[46,69,70] Therefore, testing should be performed at 2 years of age unless any signs or stigmata of liver
disease are found earlier. Repeat clinical and biochemical testing is recommended in 2 to 3 years if the results are normal. Further investigations in larger cohorts are warranted to assess the optimal age
for screening.

Therapy

Treatment strategy with a pharmacologic agent or liver transplantation depends on the phenotypic expression of the disease in a given individual. Medications effective for the treatment of WD include
D-penicillamine, trientine, zinc salts, tetrathiomolybdate, and dimercaprol. Therapy can be divided into initial treatment or maintenance therapy and follows the algorithm illustrated in Fig. 4.
Figure 4.

Treatment algorithm. Patients with a confirmed diagnosis of Wilson disease are divided into three distinct categories, which have different approaches to treatment—both pharmacological and surgical.

The first agents such as BAL, were developed over 60 years ago and were based on copper chelation. Other agents since then have been introduced and have been the mainstay of treatment. These
include penicillamine, trientine, zinc, tetrathiomolybdate, and dimercaprol. Although all patients require lifelong treatment, patients can generally be divided in independent phases: those patients with
asymptomatic liver disease and those treated to steady state who continue on with maintenance therapy; those with symptomatic liver disease only; and those with a combination of symptomatic liver,
neurologic, or psychiatric disease.

Symptomatic Disease

The goal of treatment is to attain a negative copper balance and remove copper from toxic sites within the liver and the central nervous system. Accordingly, patients should be started on chelation therapy
from the outset with first-line agents such as penicillamine (with pyridoxine supplementation) or trientine. Dosages are ramped up slowly and are generally ~30 to 50% higher than maintenance therapy.
Some have advocated the use of combined therapy with zinc to block copper absorption along with chelation, but this does require temporal spacing of medications from food and each other.[71] A
summary of the current pharmacologic regimens are summarized in . Clinical signs of symptomatic liver disease such as portal hypertension; ascites, encephalopathy should be closely followed along with
biochemical monitoring of liver function tests such as bilirubin, serum albumin, and prothrombin time/INR. These values should be checked initially and at periodic intervals dependent on the disease
severity. For those with severe and advanced liver disease, transplant evaluations may need to be considered.

Table 2. Treatment and Follow-Up Management in Wilson Disease Patients: Common Treatment Regimens

Medical
Treatment/Symptomatic Dose Side Effects Monitoring Maintenance Dose
Therapy
Adults: 750–1500 mg divided BID – QID (~20 mg/kg/d Adults and children: 15
Penicillamine Fever Free Cu 5–15 μg/dL
to maximum 2 g/d) mg/kg/d
Children: 20 mg/kg/d divided BD-QID Rash Urine Cu 250–500 μg/24 h
Lupus-like reactions
Bone marrow suppression
Nephrotic syndrome
Colitis (rare)
Note: requires supplemental pyridoxine, and dose
reduction for surgery and pregnancy
Adults and children: 15
Trientene Adults: 750–1500 mg divided TID-QID Sideroblastic anemia Same free Cu as above
mg/kg/d
Children: 20 mg/kg/d divided TID-QID Colitis (rare) Urine Cu 100–500 μg/24 h
Same as above; plus, urine zinc Adults: 75–150 mg
Zinc salts (Dosing is in milligrams of elemental zinc) GI intolerance
>1000 μg/24 h divided TID
Children: 50–75 mg
Adults: 150 mg divided TID Nonpancreatitis elevation of amylase and lipase
divided TID
Children (<50 kg): 75 mg/d divided TID

BD, daily; BID, twice daily; QID, four times daily; TID, three times daily; GI, gastrointestinal.
Adapted from Schilsky ML, Tavil AS. Wilson disease. In: Schiff's Diseases of the Liver. Philadelphia: Lippincott Williams and Wilkins; 2006:1023–1040.
Most practitioners prefer start with trientine. Zinc salt monotherapy or lower dose chelation is preferred for maintenance therapy.

Patients with active neurologic or psychiatric symptoms are considered symptomatic and should be treated similar to those with symptomatic liver disease with attention to their neurologic and psychiatric
condition along with their liver disease. Again, frequent monitoring is needed early on, and combined treatments may be considered as well.

Successful treatment will result in improvement in liver tests and clinical signs and symptoms, though there may be a lag time of 3 to 12 months before biochemical studies show a return toward normal. In
some patients with advanced liver disease and portal hypertension, persistent abnormalities in INR and evidence of thrombocytopenia may persist. Once the patient has shown stabilization at 6 to 12
months, then they should transition to maintenance therapy.

Asymptomatic Liver Disease and Maintenance Therapy

This group of patients usually benefit from monotherapy with a chelating agent or with a zinc salt. Options to begin either agent depend on physician or patient preference. Recent data from Austrian and
German cohorts[72] suggest less-frequent late decompensation in patients with initial hepatic presentations on chelation therapy, but successful therapy is achievable for both treatment categories.
Treatment goals for these individuals is to prevent any disease progression, and although monitoring may be less frequent it should include both urine copper excretion on therapy as well as liver tests
and blood counts. Repeat liver biopsy should be reserved for those with possible treatment failure and is not needed for most patients.

Acute Liver Failure

Wilson disease accounts for ~5% of all cases of ALF. The signs and symptoms of ALF are virtually indistinguishable across many etiologies. There are some distinct findings that may heighten suspicion
and aid in the diagnosis of ALF due to WD such as Coombs-negative hemolytic anemia, elevated serum, and 24-hour urine copper and K-F rings. In this setting, serum ceruloplasmin is unreliable as it
may be falsely elevated as an acute-phase reactant in inflammatory conditions. However, the results of 24-hour urine studies will not be immediately available and ~50% of patients with ALF due to WD
will not have K-F rings. Therefore, it is useful to be able to look at parameters that can be easily obtained in a timely fashion. Uniquely, the alkaline phosphatase is inappropriately depressed for the level of
cholestasis. In addition, the ratio of alkaline phosphatase to total bilirubin ratio of <4 and AST:ALT> 2.2 are excellent diagnostic clues.[64]

Patients with ALF due to WD should be evaluated for emergent liver transplant as the mortality rate in this subgroup approaches 100%. In this setting, there is typically massive hemolysis and marked
elevation of circulating copper in addition to other features of WD. Treatment of the patient to reduce the high level of copper in the circulation may help achieve better outcomes. Renal insufficiency is
often present in these patients, and the molecular adsorbents recirculating system (MARS) has shown superiority over continuous veno-venous hemodialysis (CVVHD) for clearing excess copper from the
circulation, but albumin dialysis, exchange transfusion, and plasmapheresis have all been utilized with success with endpoints being reducing hemolysis, and slowing both hepatic and renal injury.[73] Very
rare patients have survived ALF due to WD with intensive medical therapy; however, there are no clear identifiers to predict survival in the face of data that would indicate liver failure.[74–77]

Pregnancy

Therapy for WD should be continued during pregnancy with some modifications.[78,79] Concerns regarding the chelating agents' effect on teratogenicity and postpartum wound healing have been raised.
Hence, dose reduction using these medications has been advised. Recent treatment guidelines recommend that patients reduce the dose to below maintenance dosing (~10 mg/kg/d) before or early on
during their first trimester because this is the highest period of risk for teratogenicity. Patients on zinc monotherapy therapy do not need to change the dose. Alternatively, one can consider switching to a
zinc salt at the onset of pregnancy, if tolerated.

Asymptomatic Children

Zinc therapy is the preferred agent to treat WD in this population because it has an excellent side-effect profile. Asymptomatic children, particularly those who are prepubertal must have adequate copper
for proper bone, connective tissue, and mental development balanced with anticopper therapy to prevent copper toxicity. Close monitoring should include 24-hour urine copper levels maintained in the
high-normal range (40–50 μg/24 h) and complete blood cell count, observing for early signs of overtreatment and copper deficiency such as hypochromic microcytic anemia and leukopenia.[80]

Liver Transplantation

Indications for liver transplantation include end-stage liver disease-related hepatic insufficiency, decompensated cirrhosis that fails to respond to medical therapy, and acute liver failure. Liver transplant for
neurologic WD have given mixed results. Although a German group[81] reported favorable results, others from an Italian group[82] suggest poorer outcomes. In the era of organ shortage, in general, it is
controversial to transplant patients based solely on the presence of neurologic WD because these patients may respond to medical therapy alone.

Neurologic Disease

Liver transplantation may improve survival and quality of life in patients with neurologic disease.[83] Some argue, liver transplantation is indicated in patients with severe motor abnormalities even in those
with normal liver function, however this is not recommended[58] without concurrent liver failure. The neurologic manifestations most commonly identified include tremor, dysarthria, dystonia, sialorrhea,
ataxia, increased muscle tonus, myoclonus, aphasia, and bradykinesia. In one study, all patients with neurologic symptoms prior to liver transplant showed marked neurologic improvement, albeit with
minor residual symptoms in 5.2 years mean follow-up.[81]

Treatment

The initial therapy is with a chelator, either penicillamine or trientine with or without zinc salts. After the initial treatment, monitor for clinical and biochemical improvement, specifically, regression of K-F
rings, hepatosplenomegaly, dysarthria, tremor, hemolysis, and normalization of hepatic function tests.[42] Serum copper may be used as an indicator of degree of chelation (free copper <10 μg/dL). As 24-
hour urine copper levels approach normal levels on chelating medications (200–500 μg/d), symptomatic therapy may be switched to maintenance therapy as once daily dosing.

Adjunct Therapy With Antioxidants

Vitamin E has been proposed as a potential agent for WD based on decreased circulating serum vitamin E levels and plasma vitamin E/lipid ratios measured in patients with WD when compared with
healthy adult controls.[84,85] Experimentally, incubation of copper-overloaded rat hepatocytes with α-tocopheryl succinate improved both cell viability and completely reduced oxidant injury to that of control
hepatocytes.[86] In addition, curcumin treatment of a transiently transfected cell line with comparable expression and function to WD partially restored protein expression of the ATP7B mutants.[87]

Future Treatments

Proof of principle has demonstrated the feasibility of hepatocyte transplant and gene therapy in successfully treating rodent models of WD.[88] In these animals, both therapies have been shown to
increase biliary copper excretion, and cell transplant therapy has been shown to ameliorate and prevent disease progression.[89] Likely there are too many independent gene mutations leading to WD for
gene therapy to be effective for the population at large. However, in select populations where there is a dominant mutation, this may hold some future promise. Other variations of current treatment involve
combination therapies of a chelation agent plus zinc in a simplified maintenance therapy of once daily chelating dosing.[90]

Prognosis

The prognosis for patients with Wilson disease is excellent. If the disease is diagnosed timely and treatment adhered to, patients die with the disease and not as a result of it. Those asymptomatic at the
time of their diagnosis should remain without symptoms on treatment unless a secondary illness develops or treatment is stopped. For patients with liver disease, even those with active inflammation and
advanced fibrosis, treatment can stabilize disease and even reverse fibrosis with time.[49,71]

Prognostic scoring systems for WD are a useful tool to direct therapy, identify which patients can be treated medically and which have a high likelihood for death and will require liver transplant. A
prognostic index calculated by Nazer et al[91] (score range 0–12) based on serum bilirubin, serum AST, and prolongation in prothrombin time was able to predict response to chelation therapy in newly
diagnosed WD patients who scored 6 or less. An improvement to the Nazer prognostic index score by Dhawan and associates[77] based on serum bilirubin, INR, AST, white blood cell count, and albumin
(score range 0–20) was able to predict favorable response to chelation therapy in newly diagnosed pediatric WD patients who scored 11 and less; and those patients who scored >11 died without
transplantation. Not surprisingly, higher prognostic scores will be found in high MELD (Model for End-Stage Liver Disease) scores because both scores share 2 out of 3 parameters of the MELD score,
which represents a 3-month survival curve for adults and children 12 and older.

For those with neurologic or psychiatric involvement indicating effects on the central nervous system, treatment can also stabilize disease and symptoms regress over time;[92] however disease
progression in a minority may continue despite treatment. Worsening can occur with any of the therapies usually within 4 weeks of starting therapy.[93] Theoretically, this phenomena is attributed to
chelators mobilizing large hepatic copper stores, which may lead to a transient elevation in blood and brain copper levels exacerbating further damage.[94] Adjunctive treatment may help with symptom
management during this time. Significant improvement in psychiatric symptoms, neurologic examination, and speech can occur with chelation and zinc treatment over 3 years and possibly longer.[95]

For those who have undergone liver transplant for WD for liver disease the outcome is excellent with long-term outcomes better than transplant for other etiologies with the exception being WD ALF.[96]
Transplantation for patients with liver and neurologic disease may have less favorable outcomes with a higher incidence of perioperative complications and poorer survival.[97] On one hand, many WD
patients with neurologic signs and symptoms who do undergo liver transplant will have improvement in their disease posttransplant.[49,98] However, on the other hand, if there is severe, long-standing
impairment prior to transplant, deficits are more likely to persist after transplantation.

Conclusion

Our understanding of the molecular etiopathology of WD has greatly advanced since the discovery of the gene for WD, ATP7B, and the elucidation of cellular mechanisms for copper transport. The gene
discovery enabled molecular diagnostics for this disease that have been enhanced by technologic improvements in DNA sequencing, which makes it possible to search for mutations across the entire WD
gene region. This testing is now commercially available for clinical use in approved laboratories, but not all disease-specific alleles can currently be identified. Therefore, there remains a role for
phenotypic diagnosis and patient characterization. Chelation with penicillamine or trientine and zinc salts is the mainstay of therapy that must be lifelong. Tetrathiomolybdate is still experimental and is not
approved in the United States. Liver transplant is effective for those with acute liver failure and end-stage liver disease unresponsive to medical therapy, but remains controversial for primary treatment of
neurologic WD. Gene therapy awaits the development of safe vectors for human use and hepatocyte transplant needs the ability to do without the need for immune suppression. Stem cells, genetically
modified ex vivo and replanted might be a future means to achieve tolerance for transplanted cells to restore function. Despite all the advances, it is still necessary for clinicians to consider a diagnosis of
WD to pursue appropriate diagnostics and treatment.

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Abbreviations
BAL, British anti-lewisite; CP, ceruloplasmin; K-F, Kayser-Fleischer; WD, Wilson disease

Semin Liver Dis. 2011;31(3):245-259. © 2011 Thieme Medical Publishers

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