A 15-Year-Old Girl With Elevated Liver Enzymes

Joel A. Friedlander, DO, MBe; Tricia R. Bhatti, MD; Petar Mamula, MD; Kathleen M. Loomes, MD

Disclosures

April 28, 2009

In This Article

Discussion

Wilson disease is a rare autosomal recessive condition that affects between 1/30,000 and 1/100,000 individuals. Kinnear Wilson first described the disorder as hepatolenticular degeneration in 1912. In 1993, the gene associated with the disease was identified as ATP7B, encoding a transmembrane metal transport protein that functions to transport copper from the liver into bile and proteins for excretion. If the gene is absent or does not function properly, the excretion of copper into bile is decreased, and, subsequently, copper levels in the liver and other organs increase.

Clinical Features of Pediatric Wilson Disease

The primary clinical features of Wilson disease include hepatic involvement, neurologic manifestations, psychiatric disorders, and Kayser-Fleischer rings (copper deposition in the cornea). Other less common manifestations include renal involvement, pancreatitis, and cardiomyopathy. The presentation of Wilson disease is quite variable in pediatric patients. However, in general, hepatic symptoms are more common in patients younger than 20 years of age.

The hepatic presentation of Wilson disease can range from asymptomatic to acute liver failure and includes the following:

  • Asymptomatic without elevation of liver enzymes (the classic example of this presentation is that of a screened sibling of a patient confirmed to have Wilson disease);

  • Asymptomatic with elevation of liver enzyme levels;

  • Symptomatic with 1 or more liver disorders including steatosis, chronic hepatitis, cryptogenic cirrhosis, and hepatomegaly or splenomegaly from portal hypertension; and

  • Acute liver failure.

Because of the variation in presentations, the physician should be aware of the importance of recognizing the nonclassical form. As a generalist, the physician should always refer a chronic elevation of aminotransferase levels, hepatomegaly, or splenomegaly for appropriate evaluation and workup.

In addition to hepatic signs and symptoms, other symptoms can be nonspecific indicators of Wilson disease including migraine headaches, Coombs-negative hemolytic anemia, renal Fanconi syndrome (aminoaciduria), arthritis, depression, psychosis, pancreatitis, and cardiomyopathy (Table 1).

Diagnostic Workup of Suspected Wilson Disease

The most common presentation of Wilson disease encountered in an outpatient office is likely to be a child who has hepatitis or asymptomatic elevations in liver enzymes. In such a case, the patient should be evaluated in a manner similar to what has been described to investigate the possible causes of hepatic inflammation. An appropriate workup would include a thorough history, physical examination, and diagnostic testing primarily aimed at infectious, metabolic, oncologic, and autoimmune causes.

If during the workup a low level of serum ceruloplasmin (< 20 mg/dL) is found, the next appropriate test is the measurement of urinary copper excretion rate. Both the ceruloplasmin and copper urinary tests should almost always be performed in cases of possible Wilson disease because neither test is 100% sensitive or specific.

Ceruloplasmin is a copper carrier protein found in the blood, but its values are highly variable. It is an acute phase reactant that may have false elevations and can be low in heterozygote carriers. A normal level of ceruloplasmin does not rule out the disease; conversely, a low level of ceruloplasmin does not establish the diagnosis of Wilson disease. However, a finding of low ceruloplasmin should be followed up with further confirmatory testing if there is high clinical suspicion for Wilson disease.

The 24-hour urinary copper excretion test has higher sensitivity and specificity than the ceruloplasmin test. However, the copper excretion test can produce equivocal values and elevations in urinary copper excretion may be caused by disorders other than Wilson disease. For example, because copper is concentrated in the liver, chronic liver diseases can cause an elevation in urinary copper excretion, just as chronic cholestatic diseases can cause a decrease. The normal values for urinary copper excretion are less than 40 µg/24 hours, and in Wilson disease the value is usually greater than 100 µg/24 hours. However, using this value alone as the confirmatory test for Wilson disease can overlook 16%-23% of patients. To increase the sensitivity of the test, some practitioners advocate the use of a penicillamine challenge. In a penicillamine challenge, 2 doses of pencillamine are given during the 24-hour collection of urine. In a patient with Wilson disease, the urinary copper excretion during a challenge should be greater than 1600 µg/24 hours. This test is not used commonly in children.

Because of the varied sensitivities and specificities of the diagnostic tests, a final confirmatory test should be performed -- namely, a liver biopsy, and a portion of the tissue sample should be sent to a specialized laboratory for quantification of copper content by dry weight. The normal concentration of copper is less than 50 µg/g of dry weight liver, and could be less if the liver is cirrhotic and the sampling poor. Typically, in Wilson disease the hepatic copper concentration is greater than 250 µg/g of dry weight liver. Elevated hepatic copper content is not specific for Wilson disease, and may be present in cholestatic liver disorders, such as primary sclerosing cholangitis and alagille syndrome.

The features of hepatic pathology in Wilson disease include microvesicular and macrovesicular steatosis, glycogenated nuclei, and variable degrees of fibrosis progressing to macronodular cirrhosis. Significant inflammation may be present, sometimes suggesting a diagnosis of autoimmune hepatitis. Copper staining is often done, but testing results are variable (Figure 2).

Confirmatory gene sequencing or haplotyping can be performed and used as a diagnostic tool in first-degree relatives. Kayser-Fleisher rings should be sought by an experienced ophthalmologist, but their absence is not a reliable negative predictor.

Figure 2.

Immunohistologic copper staining (brown pigment) in a liver specimen with Wilson disease.

Rarely, an individual with previously unrecognized Wilson disease may present with acute fulminant hepatic failure. In this clinical setting, with a critically ill patient, definitive diagnosis may be elusive. Factors that increase the likelihood of Wilson disease may include female sex, Coombs-negative hemolytic anemia, normal or low alkaline phosphatase, relatively low elevation in AST and ALT with an increased AST/ALT ratio, coagulopathy that is unresponsive to vitamin K, and rapid progression to renal failure. Patients with an acute fulminant presentation of Wilson disease will not respond to medical therapy and require emergent liver transplantation.

Treatment of Wilson Disease

Medical therapy of Wilson disease includes a copper restricted diet and copper chelation medications to enhance urinary excretion. Copper-rich foods include items such as chocolate, organ meats, nuts, legumes, shellfish, chicken, and dried fruits.

Options for chelation therapy in the United States include penicillamine and trientine. Penicillamine is used less frequently because of its poor tolerability and many side effects. Trientine, which should be taken on an empty stomach, is usually dosed at 20 mg/kg/day to a maximum dose of 750-1500 mg/day. Zinc, which functions to induce metallothionein and block intestinal absorption of copper, may be used as an adjunct to chelation therapy or as monotherapy in an asymptomatic patient who has normal liver enzyme levels. The zinc dose ranges from 75 to 150 mg divided 3 times per day. Some clinicians advocate trientine monotherapy, whereas others advocate zinc and trientine combination therapy. If an affected individual is diagnosed through screening, some clinicians advocate monotherapy with zinc, providing the patient is asymptomatic and has normal ALT/AST levels.

Once the patient's ALT/AST levels have normalized, the urinary copper excretion rate -- while the patient is receiving chelation therapy -- is 200-500 µg/day. Once the hepatic synthetic function normalizes, therapy can be tailored to zinc or trientine monotherapy. Therapy will continue indefinitely and will afford the child a healthy and productive life. If therapy is stopped, a life-threatening decompensation can occur. In cases in which a patient fails to respond to chelation therapy and progressive liver disease develops, liver transplantation may be indicated.

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