AMBER TRESCA

THE CASE:The parents of a 16-year-old girl report that during the past several months, she has exhibited behavioral changes, irritability, increased anger, depression, and anxiety. The girl had previously been healthy, and there has been no recent illness or trauma.

On examination, the patient's vital signs are normal. She is alert but somewhat irritable. Physical examination also reveals hepatomegaly, mild lower extremity edema, and a greenish gold ring on the outer edge of the cornea bilaterally.

What is the most likely cause of the patient's symptoms?

•Primary biliary cirrhosis

•Wilson disease

•Primary sclerosing cholangitis

•Arcus senilis

(Answer and discussion begin on the next page.)

DISCUSSION: In a patient with neurologic abnormalities, peripheral corneal rings (Kayser-Fleischer rings) are pathognomonic for Wilson disease, an autosomal recessive disorder that results in the accumulation of abnormal levels of copper in the liver and eventually other areas of the body, including the brain, kidneys, and corneas. Kayser-Fleischer rings are found in the Descemet membrane and are usually greenish brown to gold. They initially appear as superior crescentsand ultimately become circumferential. Slit lamp examination is required to detect rings early in their formation. Patients may also exhibit "sunflower" cataracts from copper accumulation in the lens.

Wilson disease results from mutations in both alleles of the ATP7B gene. The major function of the protein generated by this gene is excretion of hepatic copper. Wilson disease occurs in approximately 1 in 30,000 to 40,000 live births annually. The prevalence of heterozygous gene carriers is 1 in 90. The risk of disease is higher in populations with consanguineous mating.

The clinical features of Wilson disease include liver and renal disease, neurologic and skeletal abnormalities, psychiatric illness, and hemolytic anemia. Manifestations of liver disease range from abnormal laboratory findings in asymptomatic patients to chronic active hepatitis, cirrhosis, or fulminant hepatic failure; cirrhosis is the usual initial presentation. Liver disease typically appears earlier than neurologic signs, which often begin as subtle behavioral changes and deterioration of fine motor skills. Patients may present with tremor, lack of motor coordination, drooling, dysarthria, dystonia, or spasticity. Psychiatric manifestations include depression, anxiety, and psychosis. Kayser-Fleischer rings are found in nearly all patients with a neurologic presentation and in slightly more than half of those presenting with liver disease.

The diagnosis of Wilson disease is generally established through laboratory investigation, including tests of liver function; levels of ceruloplasmin, serum copper, and urinary amino acids; and urinary copper excretion. Typical findings include ceruloplasmin levels lower than 20 mg/dL (normal range, 25 to 63 mg/dL), an increased rate of urinary copper excretion, and an elevated hepatic copper concentration.

Suspect Wilson disease in any patient between the ages of 3 and 45 years who has liver abnormalities of unknown cause, particularly in association with neuropsychiatric manifestations. Perform a slit lamp examination for Kayser-Fleischer rings in these patients.

Penicillamine, a chelating agent that binds copper, is the recommended initial treatment for symptomatic patients. A small number of patients experience adverse effects, including nephrotoxicity, hematologic abnormalities, or rash. Trientine was developed especially for these patients and is now used as primary therapy. Zinc has also been used alone or in combination with a chelating agent. Liver transplantation is reserved for severe or refractory cases.

Kayser-Fleischer rings and sunflower cataracts gradually disappear after liver transplantation or effective medical treatment. The presence of either of these signs in a patient who is receiving pharmacologic therapy suggests noncompliance.

Primary sclerosing cholangitis (PSC), a chronic progressive disorder of the intrahepatic and extrahepatic biliary tree, is characterized by inflammation, fibrosis, and stricturing of medium and large bile ducts. The cause is unknown, although most patients have underlying ulcerative colitis. Destruction of bile ducts leads to end-stage liver disease, portal hypertension, and cholestasis.

Patients commonly present with fatigue and pruritus that may be accompanied by fevers, chills, night sweats, and right upper quadrant pain. Laboratory investigation usually shows elevated serum alkaline phosphatase and bilirubin levels. Atypical perinuclear antineutrophil cytoplasmic antibodies and other antibodies may be present. In most patients, hepatic and urinary copper levels are elevated and serum ceruloplasmin levels are decreased. Copper accumulation increases as the disease progresses and sometimes produces Kayser-Fleischer rings.

Median survival after diagnosis in patients who do not undergo liver transplantation is approximately 12 years. Management options include balloon dilation or stenting of dominant strictures; many patients require repeated treatments. Prophylactic antibiotic therapy, particularly ciprofloxacin, has been advocated for the prophylaxis and treatment of bacterial cholangitis. Patients with PSC who have not undergone liver transplantation have a 10% to 15% risk of cholangiocarcinoma, an end-stage manifestation.

About 95% of patients who have primary biliary cirrhosis (PBC), an autoimmune disease of the liver, are women. Onset is usually between the ages of 30 and 65 years; children are never affected. Clinical manifestations include fatigue, pruritus, hyperpigmentation, and hepatomegaly with a cholestatic pattern on liver function tests. Musculoskeletal complaints, including rheumatoid arthritis, symptoms of Sjögren syndrome, and scleroderma, are seen in approximately 40% of patients. Physical features may be absent, or patients may manifest with hyperpigmentation caused by melanin deposition; hepatomegaly; and signs of cirrhosis (spider nevi, ascites, and edema). Kayser-Fleischer rings are found rarely.

Antimitochondrial antibodies are the serologic hallmark of PBC. Antinuclear antibodies are found in up to 70% of patients. Other laboratory abnormalities include dramatically elevated serum alkaline phosphatase levels and associated elevations of 59-nucleotidase and g-glutamyl transpeptidase. Liver enzyme levels may be normal or slightly elevated. Serum bilirubin levels are elevated late in the disease course and are a poor prognostic sign. Patients with PBC typically have increased levels of ceruloplasmin.

Agents used to slow the rate of disease progression include ursodeoxycholic acid and immunosuppressive agents. Pruritus is typically the most severe symptom; it may be controlled with antihistamines or cholestyramine, but it is often refractory. Liver transplantation is the only definitive treatment.

Arcus senilis is an arc-shaped gray, white, or yellowish deposit often seen in the cornea of elderly persons. This finding is secondary to deposition of cholesterol and other lipids in the peripheral cornea, which may occur despite normal serum cholesterol levels; the immediate perilimbal area is spared. A workup for familial hypercholesterolemia is recommended in persons younger than 40 years who have arcus senilis.

References:

FOR MORE INFORMATION:

• Ala A, Schilsky ML. Wilson disease: pathophysiology, diagnosis, treatment, and screening. Clin Liver Dis. 2004;8:787-805.
• Kaler SG. Wilson's disease. In: Cecil RL, Goldman L, Bennett JC, eds. Cecil Textbook of Medicine. 22nd ed. Philadelphia: WB Saunders Co; 2004:1301-1305.
• Kaplan MM. Clinical manifestations, diagnosis, and natural history of primary biliary cirrhosis. UpToDate. April 2005. Available at: http://patients.uptodate.com/ topic.asp?file=hep_dis/8639&title=Primary+Biliary+cirrhosis.
• Roberts EA, Schilsky ML; Division of Gastroenterology and Nutrition, Hospital for Sick Children, Toronto, Ontario, Canada. A practice guideline on Wilson disease. Hepatology. 2003;37:1475-1492.
• Tung BY, Kowdley KV. Clinical manifestations and diagnosis of primary sclerosing cholangitis. UpToDate. March 2004. Available at: http://patients. uptodate.com/topic.asp?file=biliaryt/4959&title=Primary+Sclerosing+cholangitis.