Home
 

WD requires lifelong treatment, generally using drugs to remove excess copper from the body and to prevent it from re-accumulating.  Zinc salt, which blocks the absorption of copper in the stomach and causes no serious side effects, is often considered the treatment of choice. Penicillamine and trientine increase urinary excretion of copper; however, both drugs can cause serious side effects.  Tetrathiomolybdate is an investigational drug with a lower toxic profile, but it has not been approved by the Food and Drug Administration for the treatment of WD and its long-term safety and effectiveness aren??t known.  A low-copper diet may also be recommended, which involves avoiding mushrooms, nuts, chocolate, dried fruit, liver, and shellfish.  In rare cases where there is severe liver disease, a liver transplant may be needed.  Symptomatic treatment for symptoms of muscle spasm, stiffness, and tremor may include anticholinergics, tizanidine, baclofen, levodopa, or clonazepam. 

Medical Care:
  • Medical therapy for Wilson disease is still controversial.
    • In 1999, Walshe recommended D-penicillamine as the initial therapy of choice, and Brewer stated that D-penicillamine should not be used in Wilson disease at all.
    • In 2005, Brewer recommended TM with zinc for 8-16 weeks and zinc or trientine if TM is not available.
    • Although initial use of D-penicillamine can worsen neurologic symptoms, Czlonkowska et al (2005) did not note any difference in mortality for 164 patients treated with D-penicillamine or zinc sulphate as initial therapy.
    • Pranshanth et al recommend a start-low, go-slow approach if penicillamine is used.

    • Both D-penicillamine and zinc can reverse liver fibrosis.
  • Zinc is the recommended therapy during pregnancy because D-penicillamine and trientine are both teratogenic in animals and because D-penicillamine is teratogenic in humans.

    • Zinc therapy reduces copper accumulation in the LEC rat.

    • In 2005, Carelli reported zinc use with 10 year follow up in children. Zinc was given to individuals younger than 6 years without an adverse effect on growth. Dosages were 25 mg of elemental zinc twice a day to age 6 years, 25 mg 3 times a day to age 16 years or 125 lb, and 50 mg 3 times a day after that.

Surgical Care: Liver transplantation is indicated for patients with acute hepatic insufficiency; it also can be considered in patients whose disease does not respond to medical therapy. Whether liver transplantation is indicated in patients with neurologic or psychiatric disease without liver insufficiency is debatable; however, liver transplantation provides neurologic and psychiatric improvement.

Diet: A low copper diet, with 1 mg/d at first (0.5 mg/d for children), is recommended. Dietary copper intake can be increased to 1-1.5 mg/d after good control is established; however, average diets usually contain 1 mg/d. Foods high in copper content include shellfish, liver, mushrooms, broccoli, chocolate, and nuts.

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Drug Category: Chelating agents -- These agents were initially developed to prevent intoxication resulting from drug overdose. Dimercaptopropanol (or British anti-Lewisite [BAL]) was the first therapy used in Wilson disease. It has 2 sulfhydryl groups that form a 5-member ring with copper. BAL can cross the blood-brain barrier. It must be administered intramuscularly and is known to cause tachyphylaxis, probably secondary to induction of liver enzymes. Dimercaptopropane sulphonate (Unithiol) is an orally active derivative of BAL. The agents listed below are those most widely used today.
Drug Name Penicillamine (Cuprimine) -- Metal chelator used to treat copper poisoning; forms soluble complexes with metals excreted in urine. First used in 1955. Can reverse neurologic deficits, neuroimaging abnormalities, KF rings, and sunflower cataracts. Psychiatric symptoms, aminoaciduria, peptiduria, and hepatic disease improve. Monitor nonceruloplasmin copper value or urinary excretion of copper.
Adult Dose 250 mg PO qid, 500 mg PO bid, or 15-25 mg/kg/d; can be decreased to 10-15 mg/kg/d once patient reaches basal copper excretion of 50-70 mcg/d; must be taken with empty stomach
Pediatric Dose Not established
Contraindications Documented hypersensitivity; renal insufficiency; previous penicillamine-related aplastic anemia
Interactions Increases effects of immunosuppressants, phenylbutazone, and antimalarials; decreases digoxin effects; zinc salts, antacids, and iron may decrease effects
Pregnancy D - Unsafe in pregnancy
Precautions Risk of hypersensitivity reaction at start or other adverse effects 20-30% (can be treated with steroids or by lowering dose or temporarily stopping); can suppress bone marrow and proteinuria; other adverse effects are systemic lupus and immune complex nephritis (?Ь5%); other less common adverse effects are Goodpasture syndrome, epidermolysis bullosa, myasthenia gravis, urticaria, connective tissue changes, and altered immune function; may be associated with neurologic deterioration within 2-6 weeks of start (may be permanent [Brewer]); worsening may be due to increased brain copper levels during start or shifts in intraneuronal copper level; in animal studies, damaged collagen and elastin; D-penicillamine teratogenic in humans and animals
Drug Name Zinc acetate -- Schouwink first used in 1961; approved in 1997. In intestinal cells, induces synthesis of metallothionein, which has high affinity for copper and prevents absorption of endogenously secreted and dietary copper. Copper excreted in stool with sloughed intestinal cells.

Monitor compliance and efficacy with 24-hour urinary zinc (should be ?Э2 mg) and copper (should be <125 mcg) levels; can be done q6mo then annually. May also check nonceruloplasmin copper level (plasma copper level - 3X ceruloplasmin level); should be <25.

Acute hepatic copper crisis can occur if patient not at steady state stops taking drug for few weeks. May be treatment of choice for presymptomatic patients; not teratogenic.

Adult Dose 37.5 mg PO bid; Brewer recommends 50 mg PO tid as standard dose; Shimizu (1999) recommends 5-7.5 mg/kg/d; must be taken 1 h before or 2 h after meals
Pediatric Dose <1 year: Not recommended 1-5 years: 25 mg PO bid (recommended by Brewer) 6-16 years: 25 mg PO tid >16 years: 50 mg PO tid
Contraindications Documented hypersensitivity
Interactions May reduce penicillamine and tetracycline effects
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Main adverse affect is gastric intolerance; patients may have progression of disease for 4-6 mo after starting therapy
Drug Name Trientine (Syprine) -- Tetramine hydrochloride; chelates copper and increases its urinary excretion. May monitor urinary copper excretion or nonceruloplasmin copper level; useful in patients unable to tolerate penicillamine.
Adult Dose 250 mg PO qid, 500 mg PO bid, or 40-50 mg/kg/d; should be taken on empty stomach
Pediatric Dose Not established
Contraindications Documented hypersensitivity; biliary cirrhosis; rheumatoid arthritis; cystinuria
Interactions Iron or other mineral supplements decrease effects
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Can cause bone marrow suppression and proteinuria; at start, obtain CBCs weekly; reported to induce neurologic worsening; teratogenic in animals
Drug Name TM -- Harper and Walshe first used in 1984. Binds tissue copper, rendering it metabolically inert, and blocks intestinal copper absorption. May monitor by measuring molybdenum and nonceruloplasmin copper levels. When levels equal, all copper in blood complexed. Takes 3-15 d to reach equilibrium. Given with meals, prevents intestinal absorption of copper; given between meals, absorbed into body and forms complex with albumin and copper.
Adult Dose 20 mg PO q4h for 8 wk followed by zinc acetate maintenance therapy; improved neurologic function in 53 of 55 patients
Pediatric Dose Not established
Contraindications Documented hypersensitivity
Interactions None reported
Pregnancy D - Unsafe in pregnancy
Precautions Ammonium TM causes reversible anemia when patients overtreated; copper essential for hemoglobin synthesis and cellular development

What is the prognosis?

Early onset of the disease is worse than late onset in terms of prognosis.  If the disorder is detected early and treated appropriately, an individual with WD can usually enjoy normal health and a normal lifespan.  If not treated, WD can cause severe brain damage, liver failure, and death.  The disease requires lifelong treatment.