Wilson disease: Hepatic manifestations

There is a wide variability in the clinical presentation of patients with Wilson Disease (WD). The most common manifestations are due to liver disease. In fact, WD may present with almost any clinical variety of hepatic abnormality. The next most common clinical manifestations are neuropsychiatric.

In patients with WD presenting as an acute hepatitis, aminotransferase elevation, high bilirubin levels, and nonspecific abdominal pain may be noted. An important finding is a low or subnormal alkaline phosphatase levels in patients with WD. Some patients can have a rapidly deteriorating course with progressive hepatic dysfunction including coagulopathy, impaired hepatic synthetic function, and encephalopathy. A coombs negative hemolytic anemia may be noted in patients with WD and acute liver failure.

Additionally, patients with fulminant presentation may develop severe renal insufficiency requiring dialysis.

Chronic hepatitis is a more common presentation of WD patients during adolescence or young adulthood. Such patients may remain asymptomatic and are typically brought to attention during screening tests.

Hepatic fibrosis can be seen in patients with chronic liver disease. They may also have progressive portal hypertension and its sequela of varices, splenomegaly, and ascites. Additionally, as hepatic steatosis is known to occur in patients with WD, some patients being evaluated for fatty liver disease may ultimately be diagnosed with WD.

These manifestations can be subtle and can delay a correct diagnosis for months or years. Most patients with neurologic manifestations have evidence of Kayser-Fleischer rings. Patients can present with depression, declining school/work performance with deterioration in handwriting, schizophrenia, dystonia gait abnormalities, and other movement disorders.

Thus, parental concerns about changes in mood or school performance in a teenager, especially when accompanied by slurring of speech, may be the first subtle clues to the underlying condition. Other clues suggesting WD are: dysarthria, wing-beating tremors (bird flapping its wings), dystonic posture of the stretched arm behind the back, fixed pseudo-smile (risus sardonicus), and postural tremor of the arms.

Acute liver failure, hepatic fibrosis, as well as hepatosplenomegaly, ascites, and cirrhosis can all occur independently as part of other disease processes. Thus viral hepatitis, metabolic liver disease, autoimmune hepatitis, and fatty liver disease could be in the differential diagnosis. Additionally, haematological manifestation, neurological disease, mood disturbances, and features of other pathological processes would be in the differential.

• In WD, also termed hepatolenticular degeneration, there is a defect in hepatic copper metabolism which results in hepatic and systemic copper accumulation and toxicity.

• The liver is both the site of the biochemical defect and the initial target of copper toxicity. Clinical manifestations of WD are therefore rare prior to 5 years of age. Copper progressively accumulates in the liver during childhood. After the liver storage capacity for copper becomes saturated, circulating “free copper” levels rise and copper is redistributed systemically.

• In addition to the findings of liver dysfunction, the diagnosis is suggested by:

  demonstrated hemolysis (Coombs negative hemolytic anemia): low hemoglobin and hematocrit, elevated reticulocyte count,

  a relatively low alkaline phosphatase level,

  elevated urine 24-hour copper excretion above 100 µg/24 hr (normal <40 µg/24 hr),

  an elevated urine copper during a penicillamine challenge,

  a low serum ceruloplasmin level (<20 mg/dL), and

  gene testing for ATP7B mutation can be done.

• Magnetic resonance imaging (MRI) or computed tomography (CT) scans are important diagnostic tools in patients with neurological presentation. Structural changes in the basal ganglia can be seen in patients with WD. Imaging can detect nonspecific changes in the brain such as diffuse brain atrophy and focal abnormalities. These can appear as increased signal activity in lenticular, thalamic, and caudate nuclei as well as in the brain stem, cerebellum, and white matter.

• As WD is relatively rare with estimated 1 in 30,000 prevalence, the clinician must have a high index of suspicion in patients with liver disease and subtle neuropsychiatric signs or symptoms.

• After obtaining the above laboratory studies, a percutaneous liver biopsy should be obtained for light microscopy, electron microscopy, and quantitative copper analysis for confirming the diagnosis. Transjugular liver biopsy may be performed if a significant coagulopathy is present.

• Characteristic histological findings of WD are hepatic steatosis, hepatocellular degeneration, and periportal glycogenated nuclei. The chronic hepatitis lesion exhibits ballooning, erosion of the periportal limiting plate, lymphocytic and plasma cell infiltrates in portal tracts, and periportal fibrosis; and when advanced, combined micronodular and macronodular cirrhosis.

• Slit lamp exam by an ophthalmologist to determine whether the patient has Kayser-Fleischer rings is indicated. The Kayser-Fleischer ring is a gold or gray-brown opacity in the peripheral cornea (Figure 1). It represents copper deposition in the Descemet’s membrane.

• Leipzig scoring system for WD: A scoring system for the diagnosis of WD has been established. A combination of clinical and biochemical tests is assigned a score as shown in Table I. Patients with a total score of at least 4 were diagnosed with WD. Those with a total score of 3 were considered to possibly have WD. The diagnosis of WD was judged to be unlikely for scores below 2.

• A helpful website on WD is found at www.eurowilson.org.

Figure 1.

• Acute liver failure with encephalopathy:

  In addition to the routine management of liver failure, patients may benefit by listing for liver transplantation.

  Medical therapy is directed towards treating the copper overload. This is generally achieved in two phases which are an initial detoxifying phase removing accumulated copper and a subsequent phase to prevent further copper accumulation.

• Broadly, there are three drugs are available to treat WD:

  D-penicillamine, trientine, and zinc (see below).

  Clinicians should be aware that both D-penicillamine and trientine may cause initial deterioration of neurological function upon commencement of treatment.

• D-penicillamine: It is recommended to begin with one-fourth to half of the desired dose and increase the dose slowly over several weeks.

  The dosage for older children and adults is 1-1.5 grams of D-penicillamine orally per day in 2-4 divided doses given at least 30 minutes before, or 2 or more hours after meals.

  In young children, a dosage of 20 mg/kg/day rounded to the nearest multiple of 250 mg is given in 2-3 divided doses.

  D-penicillamine may have an antipyridoxine effect; thus, all treated patients should also receive supplemental pyridoxine daily.

  Uninterrupted lifelong D-penicillamine therapy is generally required. Patients should be reminded of the essential need of medication compliance and adverse or potentially fatal consequences of discontinuing this therapy suddenly.

• Trientine: This medication is generally considered as a second-line drug for patients intolerant of D-penicillamine. It is effective, and some advocate it as an alternative initial copper-chelating drug primarily because of its better safety profile.

• Zinc: Zinc has been proposed as a maintenance or adjunctive therapy for WD. Zinc inhibits intestinal absorption of copper, and possibly increases metallothionein binding of copper in the liver. Because of its slower onset of action, zinc therapy is generally not used as initial therapy for symptomatic patients.

• Diet: A nutritional consultation is helpful. It is recommended that there be restriction of dietary copper for at least the first year of chelation therapy. Patients should particularly avoid chocolate, shellfish, liver, nuts, and mushrooms.

• Psychotherapy and appropriate psychotropic medications may be needed, in addition to copper chelation therapy, in patients with psychiatric disturbances.

D-penicillamine: Toxic effects of D-penicillamine include: skin rash, proteinuria, and bone marrow suppression. A more serious and rare side effect is systemic lupus erythematosus. During initial D-penicillamine therapy, the patient should be monitored at least weekly for fever or rash. Obtaining a complete blood count, platelet count, urinalysis, and renal and liver tests every 1-2 weeks is recommended.

In some patients, neurologic symptoms worsen shortly after D-penicillamine therapy is started. Some investigators propose that there is a transient brain exposure to increased blood copper as the D-penicillamine mobilizes hepatic copper stores. The effect of D-penicillamine therapy on psychiatric disturbances is difficult to predict, although improved school performance is commonly observed in treated children. Liver dysfunction generally improves rapidly with D-penicillamine therapy. There is known cross reactivity to penicillin and thus it should be used with caution in patients with penicillin allergy.

Trientine: The toxicity includes bone marrow suppression (a sideroblastic anemia), nephrotoxicity, and skin and mucosal lesions.

Zinc: Common side effects can include headache and gastrointestinal upset which are generally less common with zinc acetate.

Untreated WD is fatal, and late diagnosis may result in irreversible neurologic sequelae or hepatic damage and the need for liver transplantation. If diagnosed early, WD is treatable with chelators and overall, has a good long term prognosis. Without compliance to lifelong therapy, patients can expect a high likelihood of progression to liver failure or irreversible neurologic damage.

• WD is an autosomal recessive disorder.

• It is caused by gene mutations regulating copper metabolism.

• The prevalence of WD is about 1 in 30,000 live births. WD occurs worldwide.

• The defect has been localized to the ATP7B copper transport protein, resulting in reduced copper excretion into the biliary system causing hepatic and systemic copper accumulation. Such copper accumulation results in end organ injury.

Hepatic: jaundice, fatty liver.

Neuropsychiatric: anxiety, headaches, seizures, ataxia, mood changes, Parkinson’s-like disease.

Ophthalmologic: sunflower cataracts, Kayser-Fleischer rings.

Renal: renal tubular dysfunction, proteinuria, hematuria, aminoaciduria, nephrolithiasis, glycosuria.

Hematologic: thrombocytopenia, coagulopathy.

Orthopedic: rickets, pathologic fractures, osteoporosis.

Cardiac: left ventricular hypertrophy, dysrhythmia.

A penicillamine challenge test can give further information.

Gene testing continues to develop though is not widely available yet.

Younger siblings should be screened for WD. For asymptomatic relatives, screening should begin at an early age. Investigation should include a complete history and physical examination, hepatic panel with PT, INR, ceruloplasmin, slit-lamp examination by a pediatric ophthalmologist, 24-hour urine copper, and consideration for genetic testing.

More information is available at http://www.ncbi.nlm.nih.gov/sites/GeneTests.

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Zinc therapy may play a role in presymptomatic patients or siblings.

New literature points to a dysfunction of hepatic nuclear receptors modulating bile acid metabolism as a contributor to WD pathophysiology. This is possibly due to disruption of ‘Zinc Fingers’ in the receptors with excess copper (Wooton-Kee CR, Jain AK, et al.).

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