Wilson disease: Clinical manifestations, diagnosis, and treatment

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Abbreviations

ALF

acute liver failure

INR

international normalized ratio

KF

Kayser—Fleischer

LT

liver transplantation

WD

Wilson disease

Wilson disease (WD) is an autosomal recessive inherited disorder caused by dysfunction of the copper transporter ATP7B, which is expressed mainly in hepatocytes and is critical for hepatic copper homeostasis.1, 2, 3 Defective ATP7B function causes impaired biliary copper excretion and pathological accumulation of copper in the liver and central nervous system. WD has a prevalence of approximately 1 in 30,000 live births. Most patients present with symptoms in their first or second decades of life, with 5% developing acute liver failure (Fig. 1); in rare cases, however, symptoms occur up to and including the eighth decade of life.4 The natural history of untreated WD is disease progression. Patients presenting with liver disease may subsequently develop neurologic or psychiatric symptoms, and conversely, liver failure may develop in patients presenting with neurologic or psychiatric symptoms. Medical therapy can treat disease or prevent its development, and liver transplantation can be curative.

Figure 1.

Schema for WD hepatic presentations.

Clinical Manifestations

Clinical manifestations of WD vary widely but are predominantly hepatic in the first and second decades, and neurologic and psychiatric thereafter.2, 3, 5 Many patients have a combination of symptoms. WD often presents in children as chronic liver disease with abnormal liver tests. Liver pathology ranges widely, from hepatic steatosis to acute and chronic hepatitis to cirrhosis. As WD progresses, many patients develop complications of portal hypertension and liver failure (Fig. 2). Acute liver failure (ALF) due to WD develops in about 5% of patients.6

Figure 2.

Pathogenesis of hepatic WD and chronic liver injury.

Patients with WD are more likely to present with neurologic or psychiatric manifestations in their second or third decade of life. Some patients have symptoms of liver disease as well. Neurologic symptoms may be subtle or rapidly progressive, leading to severe disability over weeks to months. In patients with cirrhosis, neurologic manifestations may be mistaken for or exacerbated by hepatic encephalopathy. Some common neurologic manifestations of WD include tremor, gait abnormalities and dyscoordination, dystonia, Parkinsonism, choreiform movements, drooling, dysphonia, dysarthria or anarthria, and dysphagia. Dysautonomia may also occur, typically in patients with other neurological findings.

Behavioral and psychiatric symptoms are more common in patients with neurologic involvement than in patients with isolated hepatic involvement. However, psychiatric symptoms may precede the recognition of hepatic or neurological WD by a significant period. Behavioral and psychiatric manifestations of WD include depression, altered behavior and personality, impulsiveness and labile mood, sexual exhibitionism, and frank psychosis.7 When neurologic or psychiatric manifestations precede clinical liver disease, the diagnosis of WD is often delayed by 1 to 2 years.

Diagnosis

The diagnosis of WD starts with recognition of the clinical features suggestive of the disease or identification of family members who require screening. WD should be considered in patients with unexplained liver or acute liver failure, in patients those with neurologic or psychiatric abnormalities and liver disease, or in first‐degree relatives of WD patients. WD should also be considered in pediatric patients (and, less commonly, adults) with clinical and biochemical features suggestive of autoimmune hepatitis with no or inadequate response to steroids, as there have been rare instances of concurrent WD and autoimmune hepatitis. To aid clinicians, a scoring system was developed at an international meeting in Leipzig that includes clinical and laboratory testing and yields three categories of patients; those in whom another diagnosis should be considered, those in whom further diagnostic testing is needed, and those in whom WD is likely present.8 This scoring system has recently been incorporated into the diagnostic algorithm for WD in the European Association for Study of Liver Diseases guidelines for the diagnosis and treatment of WD.

Testing of a new patient begins with serologic testing (liver biochemical tests, complete blood count, international normalized ratio [INR], serum copper and ceruloplasmin levels) and an ocular slit‐lamp examination and 24‐hour urinary copper excretion (Table 1). Corneal Kayser–Fleischer (KF) rings are visible in only 50% of patients presenting with hepatic disease but are present in over 95% of those with neurological or psychiatric features of WD. In common with other patients with liver disease, WD patients may have jaundice, hepatomegaly, splenomegaly, ascites, esophageal or gastric varices, or hepatic encephalopathy. Abnormal laboratory testing includes elevated aminotransferase levels, decreased serum ceruloplasmin levels (in ∼95% with chronic presentations), decreased serum copper levels, elevated 24‐hour urine copper excretion (which is higher in symptomatic patients), and hypouricemia. With advanced liver disease thrombocytopenia, coagulopathy, hypoalbuminemia, and hyperbilirubinemia may be seen.

Table 1.

Testing for Wilson Disease

Slit lamp examination for KF rings

Serum ceruloplasmin

Serum copper

24‐hour urine copper

Liver biopsy: histology, histochemistry, copper quantitation

Magnetic resonance imaging or computed tomography of brain

ATP7B mutation analysis

Liver biopsy is examined for histology to determine the stage of liver disease, to look for other abnormalities such as steatosis, and for histochemistry for copper. Importantly, even if histochemical copper is negative, copper quantitation must be performed. Copper quantitation can be performed in a dried liver specimen (>250 μg copper/g dry weight liver is diagnostic) or can be retrospectively obtained from a paraffin‐embedded specimen. A minority of WD patients have hepatic copper content below 250 μg/g and as low as 75 μg (normal: <40 μg). Lowering the cutoff increases the sensitivity for a diagnosis of WD, but reduces specificity due to overlap with unaffected heterozygotes. WD should not be excluded only on the basis of this one test unless liver copper is truly in the normal range.

For patients with neurological symptoms, magnetic resonance imaging (MRI) or computed tomography of the brain may reveal abnormalities in the basal ganglia, such as increased density on computed tomography scans and hyperintensity on T2‐weighted magnetic resonance images. Other findings include hyperintensities in the tectal plate and central pons or simultaneous involvement of the basal ganglia, thalamus, and brainstem that is highly suggestive of WD.

Molecular Diagnostic Testing for ATP7B Mutations

Testing for ATP7B mutations is commercially available. Over 500 disease‐specific mutations of ATP7B have been described, and in most populations patients have two different mutations on each allele (compound heterozygotes). Mutation analysis of the WD gene, ATP7B, is now the first‐line test for siblings if the proband has been tested and two mutations have been found.2, 3 If mutation analysis cannot be performed, routine clinical and biochemical testing should be performed on first‐degree relatives. ATP7B mutation analysis is also useful in patients in whom the diagnosis is indeterminate. If molecular genetic testing is performed, family counseling about the results is required. If needed, a formal consultation with a genetic counselor should be offered.

Acute Liver Failure

Approximately 5% of WD patients present with ALF. Features that distinguish these patients include a Coombs‐negative hemolytic anemia, relatively lower levels of serum aminotransferases with an aspartate aminotransferase to alanine aminotransferase ratio >2, a normal or low level of serum alkaline phosphatase with alkaline phosphatase (IU/L) to total bilirubin (mg/dL) ratio <4, rapidly progressive renal failure, and a high female‐to‐male ratio of >2‐4:1.6 Levels of ceruloplasmin are unreliable for diagnosing ALF due to WD, but serum copper and urine copper levels are markedly elevated. Identifying WD as the etiology of ALF permits initiation of disease‐specific therapy to lower serum copper levels, prepares the patient for possible liver transplantation, and informs of the need for family screening (see Fig. 3 for pathogenesis).

Figure 3.

Acute liver failure in WD, pathogenesis of injury cycle.

Treatment

Life‐long medical therapy is required in patients with WD. Treatment should be considered in two phases: removing or detoxifying the tissue copper that has accumulated, and preventing its reaccumulation.2, 3, 9 Copper removal is achieved by the administration of potent chelators. The primary chelator that has been used is d‐penicillamine; however, ∼30% of patients do not tolerate long‐term therapy because of side effects, and some with neurologic symptoms may develop worsening and irreversible changes. Trientine, an alternative chelator introduced as a second‐line agent for those intolerant of d‐penicillamine, is a reasonable option for primary therapy because of its lower incidence of side effects. No head‐to‐head studies of these agents have been conducted, thus recommendations for their use are based mainly on observational data, clinical experience, and clinician preference. A newer chelating agent, tetrathiomolybdate, is still being evaluated. In a prospective trial, tetrathiomolybdate has been shown to be effective treatment for patients presenting with neurological signs and symptoms.10

Discontinuation of therapy can lead to the appearance of neurological or psychiatric symptoms or the development of ALF. Monitoring of therapy is critical to detect nonadherence or treatment failure.

The second phase of treatment, prevention of reaccumulation, or maintenance therapy can be achieved with chelators or by use of zinc salts. Typically, maintenance dosages of chelation are decreased by 25%‐33% from initial treatment dosages. Oral zinc acts by preventing intestinal copper absorption but also increases metallothionein, an endogenous metal chelator, in the liver.

Pregnant WD patients must continue treatment during pregnancy, but for those on chelation, there should be dosage reductions by ∼50% and increased monitoring before conception if possible, and during the pregnancy. No adjustments in zinc dosing are necessary. Successful pregnancies have been accomplished on chelating agents and on zinc therapy.

To further prevent accumulation of copper, WD patients should also be maintained on a low copper diet, avoiding copper‐rich foods such as liver, kidney, shellfish, nuts, dried fruits or beans, peas, unprocessed wheat, chocolate, cocoa, and mushrooms.

In appropriate patients, pharmacologic or interventional treatment of complications of portal hypertension in those with ascites or esophageal or gastric varices and treatment of hepatic encephalopathy is needed. Additional treatment of neurological symptoms such as tremor or Parkinsonism and psychiatric symptoms independent of primary therapy for WD may improve quality of life and should be considered in appropriate patients.

Treatment Monitoring

An important part of monitoring treatment is clinical observation of patients to ensure they have not developed (a) signs or symptoms if they were asymptomatic or (b) disease progression or new signs and symptoms on treatment. Over time, KF rings, if present at the onset of treatment, will diminish and become absent. Liver tests should improve and inflammation should decrease within months, and synthetic function should be measured by INR. Albumin should demonstrate improvement over 6‐12 months and may improve further with time. For patients on chelation, urine copper is extremely elevated at the start of treatment, and reduces markedly with time. The amount of urine copper at any given time for those on chelation is dependent on the stage of copper accumulation (highest early on, less later after effective treatment) and the dosage of the chelator used, but very general goals are at or below 250 μg/24 hours. For patients on zinc therapy, urine 24‐hour copper excretion is typically below 100 μg. Urine zinc can be measured to look for adherence as well. Serum “free” or nonceruloplasmin copper (calculated indirectly by subtracting ceruloplasmin copper from the total serum copper or by newer direct ultrafiltration techniques to isolate low molecular weight fractions of copper) are often >25 μg/dL at the outset, and should reduce to between 5 and 15 μg/dL. Signs of nonadherence to treatment include changes in and worsening of clinical symptoms, reappearance or increase in size of KF rings, elevation of aminotransferase levels and decreased synthetic function, an increase in urinary copper levels and an increase in circulating nonceruloplasmin‐bound copper. Signs of overtreatment include marrow suppression, especially neutropenia and a sideroblastic anemia; iron accumulation in liver (indirectly seen with rising ferritin or directly by histochemically detectable iron overload in hepatocytes); and low urine copper levels (for chelation therapy, <100 μg/24 hours; for zinc, <20 μg/24 hours). Neurological toxicity may develop with severe copper depletion.

The frequency of monitoring should be the greatest at the start of therapy for symptomatic patients and should be individualized based on symptoms and disease severity, but for those who are successfully treated and are on maintenance therapy, examinations and testing should be performed twice a year to detect nonadherence or failure of treatment.

Liver Transplantation

Patients presenting with ALF due to WD require urgent evaluation for liver transplantation (LT). Plasmapheresis, exchange transfusion, hemofiltration, molecular adsorbent recirculating system (MARS) or albumin dialysis may be performed while LT is being awaited. Recovery with supportive therapy has been described, but these cases are exceedingly rare.

LT is also indicated for patients with decompensated liver disease unresponsive to medical therapy. A prognostic scoring system was developed for children with WD presenting with failure. The revised system (based on an index of serum bilirubin, the prothrombin time INR, aspartate aminotransferase level, and white blood cell count) is useful for predicting death with medical therapy alone.11 This scoring system was validated in pediatric and in adult patients.

LT is curative for WD, and patients do not require treatment for WD following transplantation. Options for LT for donor organs include standard cadaveric grafts and also partial grafts from unaffected or even heterozygous carriers, the latter enabling successful living donor transplantations from heterozygous parents or siblings of patients. Auxiliary transplantations wherein the native liver is left in situ also can be performed for WD. Outcomes for graft and patient survival for WD are excellent for patients who undergo transplantation for acute liver failure or for liver failure from chronic liver disease.12 Whether LT is indicated in patients with predominantly neurologic manifestations is controversial. This is due to the unpredictability of resolution of neurologic manifestations posttransplantation in LT recipients with neurologic manifestations and data suggesting that posttransplantation survival is worse in patients with neurologic involvement, as well as the scarcity of donor organs.

Prognosis

The prognosis for WD is excellent in all but those with advanced liver or neurological disease at presentation.2, 3, 5 The neurologic, psychiatric, and hepatic abnormalities may gradually improve with medical treatment or following LT in most patients, but currently LT is mainly recommended for WD patients with hepatic failure. A multidisciplinary team approach to diagnosis and treatment at experienced centers and longitudinal monitoring of treatment and adherence improves outcomes for these individuals.