Presenter: Tyler Reimschisel, MD Preceptor: Harvey Singer, MD


October 07, 2002


Wilson's Disease - Pathophysiology

Wilson's disease is caused by a defect in a copper-transporting ATPase protein expressed in the liver, brain, and placenta. At least 30 distinct mutations can result in the Wilson's disease phenotype. Furthermore, the same mutation can cause predominant liver disease in one person and predominant brain disease in another.

In individuals affected by Wilson's disease, the liver uptake of serum copper is normal, but within the hepatocyte is a defect in the incorporation of copper into ceruloplasmin, and thus biliary excretion of copper bound to ceruloplasmin is reduced. There may also be a defect in the canalicular membrane transport of copper out of the hepatocyte. These defects lead to excess copper in the liver and, secondarily, hepatocyte death. As the hepatocytes die, unbound copper is released into the blood. The circulating copper is then deposited in the brain, kidneys, muscle, bone, and joints. Symptoms develop when this accumulation causes malfunction of these organs. Copper also accumulates in Descemet's membrane in the cornea. These Kayser-Fleischer rings are visualized on ophthalmologic examination, but this accumulation is not associated with any clinical abnormalities.

Clinical Presentation

The 3 basic clinical presentations of Wilson's disease involve hepatic, neurologic, and psychiatric systems. Adolescents typically present with hepatic disease, which can cause jaundice, anorexia, nausea, lassitude, abdominal pain, weight loss, bruising, bleeding, hepatomegaly, splenomegaly, fluid retention, and ascites. Wilson's-related hepatic disease can also cause hemolytic anemia, especially when it begins in childhood. When hemolytic anemia occurs, it is associated with a mortality rate of 60% to 80%. These symptoms can wax and wane. Indeed, hepatic Wilson's disease shows spontaneous remissions and exacerbations. This phenomenon may account for the episodic swelling that occurred in our patient.

The neurologic presentation of Wilson's disease is more prevalent in puberty and accounts for approximately one third of all cases of the disease. Typical symptoms include speech abnormalities (eg, dysarthria), dysphagia, drooling, and virtually any movement disorder, including tremor, ataxia, rigidity, ballismus, dystonia, bradykinesia, and hypokinesia. Our patient's difficulty writing may have been due to dystonia. Furthermore, her swallowing difficulty improved when she put a straw in her mouth or placed a finger on the inside of her cheek. Thus, the swallowing abnormality may have been due to focal dystonia that improved when a trigger point was stimulated.

Psychiatric symptoms comprise the final and least common presentation of Wilson's disease. Patients can manifest mood changes such as depression, behavior changes, and poor performance at work or school relative to baseline. Our patient showed signs of depression, including fatigue, sleep disturbance, flat affect, and restricted mood.

Differential Diagnosis

The differential diagnosis of Wilson's disease includes Huntington's disease, pantothenate kinase-associated neurodegeneration (formerly Hallervorden-Spatz disease), neuroacanthocytosis, infectious hepatitis, alcoholic hepatitis, mitochondrial cytopathy, and a rare familial disorder called aceruloplasminemia.

Diagnostic Tests

The diagnosis relies on a few well-selected tests. Serum copper level is not useful. Ceruloplasmin levels are low in 90% to 95% of individuals with Wilson's disease, but can also be low in asymptomatic carriers. Moreover, ceruloplasmin levels can also be normal in individuals with Wilson's disease because ceruloplasmin is an acute-phase reactant. Thus, it can be "elevated" to the normal range if a person with Wilson's disease has an intercurrent acute infection, inflammatory process, or neoplastic disease, uses oral contraceptives, or is pregnant.

The best confirmatory test for Wilson's disease is the 24-hour urine copper level; if greater than 100 mcg/24 hours, then the patient has Wilson's disease. If the level is less than 50 mcg/24 hours, Wilson's disease can be ruled out.

An ophthalmologic examination can be particularly helpful if Kayser-Fleischer rings are visualized on the slit-lamp examination. The rings can be identified in 50% of those with pure liver disease and in almost 100% of those with neurologic or psychiatric disease.

In equivocal cases, a liver biopsy can be helpful. In affected individuals, the liver copper level is usually greater than 300 mcg/g dry tissue weight. Finally, radioactive copper can be used for direct measurement of incorporation of copper into ceruloplasmin.

For this, a radioactive load of copper is given orally. Patients with Wilson's disease will have diminished production of holoceruloplasmin; therefore, the amount of radiocopper in circulation is reduced. This type of testing is available at only a few institutions.

Although the brain MRI does not confirm a diagnosis of Wilson's disease, it can be helpful in narrowing the differential diagnosis. The MRI is usually abnormal in those with neurologic or psychiatric disease, but may be completely normal in those with pure liver disease. The most common abnormalities reported include symmetrically increased T2-weighted intensities in the caudate, putamen, thalamus, subcortical white matter, and brainstem.

At this time, genetic testing is not available for Wilson's disease. All family members of a proband with Wilson's disease should be screened for the disease.


The treatment for Wilson's disease has 2 phases: the initial, acute therapy and life-long maintenance therapy. Penicillamine, trientine, or ammonium tetrathiomolybdate (TM) can be used for acute therapy. Zinc or penicillamine is used as maintenance therapy.

Acute treatment for Wilson's disease is controversial. In 1999, John Walshe, who has the longest experience treating patients with Wilson's disease, stated in an article in the journal, Movement Disorders (see Bibliography of suggested reading):


The evidence gathered here [in this article] leaves no doubt that penicillamine is a powerful decoppering agent and at present, when used by an experienced physician, can offer patients with Wilson's disease a more reliable prospect of recovery than other therapies.


In an accompanying article, however, George Brewer, another Wilson's disease specialist, wrote:


I feel honored to be asked by the Movement Disorders journal to contribute my thoughts to the controversy on how to treat patients with Wilson's disease, particularly during the initial period. I am doubly honored to cross swords on this topic with Professor John Walshe, who has contributed so much to the treatment of Wilson's disease. As I have said in other settings, a whole generation of patients with Wilson's disease owe their [sic] lives to the pioneering work of Professor Walshe.

But then was then and now is now, and the two are not the same. Drugs that do wonderful things in one era, along with some damage, tend to be replaced by drugs in another era, drugs that still do wonderful things but with much less damage. That is exactly the situation we have at present with penicillamine. Its era is over. It is far too toxic to use when we have drugs that are just as effective and much safer.


Certainly, penicillamine is the oldest medication used to treat Wilson's disease. It chelates copper so that it can be excreted. It also exerts reduction-oxidation properties on free copper. This diminishes the production of free radicals that may cause organ damage. Finally, it induces the production of metallothionein, a protein that binds copper and makes it less toxic.

Penicillamine is clearly efficacious, but it has many potential side effects. It can cause hypersensitivity reactions. It induces the production of autoantibodies, which can ultimately lead to Goodpasture's disease, myasthenia gravis, or lupus. Pyridoxine deficiency can develop with long-term penicillamine use. There are also reports of pancytopenia, proteinuria, and nephrotic syndrome. Fully 27% of patients discontinue penicillamine due to these side effects.

The most worrisome side effect is the precipitant worsening in a patient's neurologic status after initiating penicillamine therapy. According to reports by Brewer, up to 50% of patients with neurologic Wilson's disease have sudden neurologic worsening. Of those, 50% experience permanent disability that is more severe than their clinical status when penicillamine was initiated. The possibility of this serious side effect has prompted many Wilson's disease specialists to use other agents to treat the disease.

TM is a newer, probably less toxic medication that can be used to treat Wilson's disease. Like penicillamine, TM has multiple mechanisms of action. It blocks the intestinal absorption of copper. It also combines with copper bound to albumin or ceruloplasmin and inactivates this complex. It is associated with fewer side effects than penicillamine. TM is used as acute therapy for approximately 8 weeks. Then zinc or trientine is used as maintenance therapy. Unfortunately, TM is not readily available. At this time, only a patient who is enrolled in a clinical trial can receive TM.

Trientine is the best medication for those patients who have pure liver disease. It is not useful for the acute treatment of patients with neurologic symptoms, because it does not mobilize copper from the brain. Trientine competes with albumin for binding copper, and once it binds copper, the trientine-copper complex can be excreted. Trientine also mobilizes copper in the kidney, enhancing excretion of copper. Side effects include abdominal pain, rash, anorexia, anemia, and possibly lupus.

Lastly, zinc can be used to treat patients with Wilson's disease. Because of its slow onset of action, it can only be used as maintenance therapy. Like penicillamine, it induces the synthesis of metallothionein in the intestine. Potential side effects include gastric irritation, increased LDL/HDL ratio, and elevated amylase or lipase. Zinc is also used to treat asymptomatic patients.

Recovery of neurologic symptoms does not usually begin until the patient has received treatment for about 6 months. Recovery occurs over the course of the subsequent 18 months. Any disability that persists 2 years after starting therapy will probably be permanent. However, the brain MRI may continue to show improvement for up to 4 years after therapy is initiated.


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