Wilson Disease Clinical Presentation

Wilson disease has a range of clinical manifestations, from an asymptomatic state to fulminant hepatic failure, chronic liver disease with or without cirrhosis, neurologic, and psychiatric manifestations. ^[2]

Consider hepatic Wilson disease in the differential diagnosis of any unexplained chronic liver disease, especially in individuals younger than 40 years. ^[12] The condition may also manifest as acute hepatitis. Hepatic dysfunction is the presenting feature in more than half of patients. The three major patterns of hepatic involvement are as follows: (1) chronic active hepatitis, (2) cirrhosis, and (3) fulminant hepatic failure. The most common initial presentation is cirrhosis.

Neuropsychiatric symptoms

An estimated 50% of patients with Wilson disease have neurologic or psychiatric symptoms. ^[13] Most patients who present with neuropsychiatric manifestations have cirrhosis. The most common presenting neurologic feature is asymmetrical tremor, occurring in approximately half of individuals with Wilson disease. The character of the tremor is variable and may be predominantly resting, postural, or kinetic. Kayser-Fleischer rings are seen in at least 98% of patients with neurological Wilson disease who have not received chelation therapy.

Frequent early symptoms include difficulty speaking, excessive salivation, ataxia, masklike facies, clumsiness with the hands, and personality changes.

Late manifestations (now rare because of earlier diagnosis and treatment) include dystonia, spasticity, grand mal seizures, rigidity, and flexion contractures.

One study described four distinct diagnostic categories based on patients' major neurologic findings, as follows ^[14] :

• Patients in the parkinsonian group (45%) - Distinguished by paucity of expression and movement

• Patients in the pseudosclerotic group (24%) - Had tremor resembling multiple sclerosis

• Patients in the dystonic group (15%) - Characterized by hypertonicity associated with abnormal limb movements.

• Patients in the choreic group (11%) - Predominantly characterized by choreoathetoid abnormal movements associated with dystonia

Psychiatric features include emotional lability, impulsiveness, disinhibition, and self-injurious behavior. The reported percentage of patients with psychiatric symptoms as the presenting clinical feature is 10%-20%. The range of psychiatric abnormalities associated with Wilson disease has been divided into four basic categories, as follows:

• Behavioral

• Affective

• Schizophrenic-like

• Cognitive

Musculoskeletal symptoms

Skeletal involvement is a common feature of Wilson disease, with more than half of patients exhibiting osteopenia on conventional radiologic examination.

The arthropathy of Wilson disease is a degenerative process that resembles premature osteoarthritis. Symptomatic joint disease, which occurs in 20%-50% of patients, usually arises late in the course of the disease, frequently after age 20 years. The arthropathy generally involves the spine and large appendicular joints, such as knees, wrists, and hips. Osteochondritis dissecans, chondromalacia patellae, and chondrocalcinosis have also been described.

Hematologic symptoms

Hemolytic anemia is a recognized, but rare (10%-15%), complication of the disease. Coombs-negative acute intravascular hemolysis most often occurs as a consequence of oxidative damage to the erythrocytes by the higher copper concentration. Any patient in whom acute hepatic failure occurs with a Coombs-negative intravascular hemolysis, modest elevations in serum aminotransferases, and a low serum alkaline phosphatase or ratio of alkaline phosphatase to bilirubin of less than 2 must be considered for a diagnosis of Wilson disease.

Renal symptoms

The Wilson disease gene is expressed in kidney tissue; therefore, any renal manifestations may be primary or secondary to release of copper from the liver.

Clinically, patients may resemble those with Fanconi syndrome, demonstrating defective renal acidification and excess renal losses of amino acids, glucose, fructose, galactose, pentose, uric acid, phosphate, and calcium. The frequency of renal manifestations is variable.

Urolithiasis, found in up to 16% of patients with Wilson disease, may be the result of hypercalciuria or poor acidification.

Hematuria and nephrocalcinosis are reported, and proteinuria and peptiduria can occur before treatment as part of the disease process and after therapy as adverse effects of D-penicillamine. ^[15]

Fulminant Wilson disease

Although no individual clinical or laboratory finding is definitively diagnostic for fulminant Wilson disease, the combination of low serum transaminases, low serum alkaline phosphatase, hemolysis, and evidence of renal Fanconi syndrome is characteristics of a fulminant presentation of Wilson disease. Critically important is early recognition.

Hepatic symptoms

Hepatic insufficiency and cirrhosis may slowly develop and can result in signs of fulminant hepatic failure, including the following:

• Ascites and prominent abdominal veins

• Spider nevi

• Palmar erythema

• Digital clubbing

• Hematemesis

• Jaundice

Neurologic symptoms

Central nervous system (CNS) pathology in patients with Wilson disease results from copper deposition in the basal ganglia. The resulting signs include the following:

• Drooling

• Dysphagia

• Dystonia

• Incoordination

• Difficulty with fine motor tasks

• Masklike facies

• Gait disturbance

Ophthalmologic symptoms

Kayser-Fleischer rings are formed by the deposition of copper in the Descemet membrane in the limbus of the cornea. The color may range from greenish gold to brown; when well developed, rings may be readily visible to the naked eye or with an ophthalmoscope set at +40. When not visible to the unaided eye, the rings may be identified using slit-lamp examination or gonioscopy.

Kayser-Fleischer rings are observed in up to 90% of individuals with symptomatic Wilson disease and are almost invariably present in those with neurologic manifestations.

Although Kayser-Fleischer rings are a useful diagnostic sign, they are no longer considered pathognomonic of Wilson disease unless accompanied by neurologic manifestations. They may also be observed in patients with chronic cholestatic disorders, such as partial biliary atresia, primary biliary cirrhosis, primary sclerosing cholangitis, and cryptogenic cirrhosis.

Kayser-Fleischer rings consist of electron-dense granules rich in copper and sulfur. The rings form bilaterally, initially appearing at the superior pole of the cornea, then the inferior pole, and, ultimately, circumferentially.

Sunflower cataract appears to be a rare and reversible ophthalmologic finding in Wilson disease. ^[16] This finding may occur only at the time of diagnosis of Wilson disease and is thus not a pathognomonic sign.

Additional symptoms

Skeletal abnormalities in patients with Wilson disease widely vary and include osteoporosis, osteomalacia, rickets, spontaneous fractures, and polyarthritis.

Cardiac manifestations, such as rhythm abnormalities and increased autonomic tone, have been described in patients with Wilson disease. Autopsy findings have included hypertrophy, small vessel disease, and focal inflammation. ^[17]

Patients with Wilson disease exhibit signs of anemia, presumably due to oxidative injury of the cell membrane caused by excess copper. Skin pigmentation and a bluish discoloration at the base of the fingernails (azure lunulae) have been described in patients with Wilson disease.