How Is Wilson's Disease Diagnosed?

Age of Onset

  • Children younger than 2 years of age and adults older than 70 years have been diagnosed with Wilson’s disease (WD), but the disease is usually diagnosed between the ages of 5 and 35 years1
  • Younger individuals may not show any symptoms, while older people are more likely to have neurological problems, as well as liver defects1

Presentation

  • Clinical presentation of WD varies widely, but the most common clinical manifestations of copper toxicity involve the liver and brain2
  • Signs of liver disease are nonspecific; therefore, any liver disease of unknown origin should include WD as a differential diagnosis2
  • If left untreated, damage to the nervous system, eyes, kidneys, bones, heart, and other systems may occur1
 
 
 

Liver Disease

Some people with WD may be asymptomatic, with biochemical abnormalities.1 Other patients present with evidence of chronic and/or severe liver disease. Symptoms of liver disease include3:
Symptoms of liver disease include3:
  • Weakness
  • Fatigue or feeling tired
  • Loss of appetite
  • Nausea
  • Vomiting
  • Weight loss
  • Pain and bloating from fluid accumulating in the abdomen
  • Edema, usually in the legs, feet, or ankles and less often in the hands or face
  • Itching
  • Angiomas near the surface of the skin
  • Muscle cramps
  • Jaundice
Diagnostic tests may reveal1:
  • Consistently high serum aminotransferase activity (aspartate transaminase, alanine transaminase)
  • Asymptomatic hepatomegaly
  • Isolated splenomegaly
  • Fatty liver
  • Acute hepatitis
  • Signs of autoimmune hepatitis
  • Cirrhosis (compensated or decompensated)
  • Acute liver failure

Neurological Disease

Excess copper can damage the nervous system.1 Neurological symptoms associated with WD typically present later than those of liver disease.3
Neurological symptoms include1,3:
  • Tremors
  • Incoordination
  • Muscle hypertonicity
  • Problems with speech
  • Drooling or difficulty swallowing
  • Migraines
  • Insomnia
  • Seizures

Mental Health Disorders

Altered brain function due to excess copper can also lead to changes in mood or behavior. Mental health symptoms may include1,3:
  • Personality changes
  • Depression
  • Anxiety
  • Psychosis

Other Toxic Effects

Copper buildup in the body may also result in the following1,3:
  • The clinical hallmark of WD is the Kayser-Fleischer ring
    • These are rusty-brown rings around the edge of the iris and in the rim of the cornea
    • These are almost always present in people with neurological WD symptoms, but only about 40%–66% of people with liver symptoms alone have them
    • Kayser-Fleischer rings are the result of copper deposition
  • Anemia
  • Arthritis
  • High levels of amino acids, protein, uric acid, and carbohydrates in the urine
  • Low platelet or white blood cell count
  • Osteoporosis
  • Sunflower cataracts
  • Lunulae ceruleae
  • Cardiovascular problems
  • Pancreatitis
  • Reduced thyroid function
  • Menstrual irregularities, infertility, and multiple miscarriages
WD is diagnosed ideally before any signs or symptoms appear.4 Though you may be able to diagnose WD in advanced cases, based on the presence of signs and symptoms such as Kayser-Fleischer rings, along with liver and neurological disease, usually blood tests and a liver biopsy will be needed to confirm WD.1 These tests might include:
  • Blood and urine tests to measure
    • Urine levels of copper (the amount of copper in the urine is decreased in WD)1
    • Blood levels of ceruloplasmin, the major copper-carrying protein in the blood. It is often low in people with WD, although other conditions can also cause low levels1
    • Liver enzyme activity, which is usually mildly elevated in people with WD1
  • Eye exam to detect Kayser-Fleischer rings1
  • Liver biopsy to
    • Determine the amount of copper in liver tissues; the diagnosis is confirmed if copper levels are >250 μg/g of liver1
    • Detect steatosis1
  • Brain scans such as computed tomography and magnetic resonance imaging to detect brain abnormalities in those with neurological or psychiatric symptoms1
  • Genetic testing to detect mutations of the ATP7B gene; more than 500 mutations have been identified1,4
Genetic testing for ATP7B mutations can be helpful, but costly. Genetic testing is typically reserved to identify family members who might also have WD or be WD carriers.1
If a patient has a family member who is at risk of having WD or is thought to be a carrier, you should consider referring him or her to a hepatologist for a definitive diagnosis and treatment plan. Patients identified through family screening require treatment to prevent disease progression, even if they are asymptomatic.
 
References
  1. Roberts EA, Schilsky ML. AASLD Practice Guidelines. Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008;47(6):2089-2111.
  2. European Association for Study of Liver. EASL Clinical Practice Guidelines: Wilson’s disease. J Hepatol. 2012;56(3):671-685.
  3. National Institute of Diabetes and Digestive and Kidney Diseases. Wilson disease. http://www.niddk.nih.gov/health-information/health-topics/digestive-diseases/wilson-disease/Pages/facts.aspx#sec10. Accessed May 25, 2016.
  4. Rodriguez-Castro KI, Hevia-Urrutia FJ, Sturniolo GC. Wilson’s disease: a review of what we have learned. World J Hepatol. 2015;7(29):2859-2870.
Physicians planning to use penicillamine should thoroughly familiarize themselves with its toxicity, special dosage considerations, and therapeutic benefits. Penicillamine should never be used casually. Each patient should remain constantly under the close supervision of the physician. Patients should be warned to report promptly any symptoms suggesting toxicity.

INDICATION

CUPRIMINE® (Penicillamine) is indicated in the treatment of Wilson's disease, cystinuria, and in patients with severe, active rheumatoid arthritis who have failed to respond to an adequate trial of conventional therapy. Available evidence suggests that CUPRIMINE® is not of value in ankylosing spondylitis.

IMPORTANT SAFETY INFORMATION

  • Except for the treatment of Wilson's disease or certain patients with cystinuria, use of penicillamine during pregnancy is contraindicated. Mothers on therapy with penicillamine should not nurse their infants.
  • Patients with a history of penicillamine-related aplastic anemia or agranulocytosis should not be restarted on penicillamine. Because of its potential for causing renal damage, penicillamine should not be administered to rheumatoid arthritis patients with a history or other evidence of renal insufficiency.
  • The use of penicillamine has been associated with fatalities due to certain diseases such as aplastic anemia, agranulocytosis, thrombocytopenia, Goodpasture's syndrome, and myasthenia gravis.
  • Routine urinalysis, white and differential blood cell count, hemoglobin determination, direct platelet count, together with monitoring of the patient's skin, lymph nodes and body temperature, must be done twice weekly for five months and monthly thereafter. Patients should be instructed to report promptly the development of signs and symptoms of granulocytopenia and/or thrombocytopenia such as fever, sore throat, chills, bruising or bleeding.
  • A reduction in WBC count below 3500/mm3 requires discontinuation. Platelet count below 100,000/mm3 even in absence of clinical bleeding; or a progressive fall in either platelet or WBC count in three successive determinations requires at least temporary cessation of therapy.
  • Proteinuria and/or hematuria may develop during therapy and may be warning signs of membranous glomerulopathy which can progress to a nephrotic syndrome.
  • Because of rare reports of intrahepatic cholestasis and toxic hepatitis, liver function tests are recommended every six months for the duration of therapy. In Wilson's disease, these are recommended every three months, at least during the first year of treatment.
  • Onset of new or worsening of existing neurological symptoms has been reported during initiation of therapy with CUPRIMINE®.
  • When pemphigus is suspected, CUPRIMINE® should be discontinued.
  • Pregnancy Category D - Penicillamine can cause fetal harm when administered to a pregnant woman. Penicillamine should not be administered to pregnant women with cystinuria or rheumatoid arthritis and should be discontinued promptly in patients in whom pregnancy is suspected or diagnosed. Penicillamine has been shown to be teratogenic in rats when given doses 6 times higher than the highest dose recommended for humans.
  • Penicillamine for Wilson’s disease should be used in women of childbearing potential only when the expected benefits outweigh the possible hazards. Reported experience shows that continued treatment with penicillamine throughout pregnancy protects the mother against relapse of the Wilson's disease, and discontinuation of penicillamine has deleterious effects on the mother, which may be fatal.
  • Some patients may experience drug fever with or without macular cutaneous eruptions. Penicillamine should be temporarily discontinued in these patients if being treated for Wilson's disease or cystinuria until the reaction subsides. In the case of drug fever in rheumatoid arthritis patients, because other treatments are available, penicillamine should be discontinued.
  • The skin and mucous membranes should be observed for allergic reactions. Early and late rashes have occurred. Less commonly, a late rash may be seen, usually after six months or more of treatment, and requires discontinuation of penicillamine.
  • The appearance of a drug eruption accompanied by fever, arthralgia, lymphadenopathy or other allergic manifestations usually requires discontinuation of penicillamine.
  • Penicillamine should not be used in patients who are receiving concurrently gold therapy, antimalarial or cytotoxic drugs, oxyphenbutazone or phenylbutazone because these drugs are also associated with similar serious hematologic and renal adverse reactions. Patients who have had gold salt therapy discontinued due to a major toxic reaction may be at greater risk of serious adverse reactions with penicillamine but not necessarily of the same type.
  • Patients who are allergic to penicillin may theoretically have cross-sensitivity to penicillamine.
  • Patients with Wilson's disease or cystinuria should be given 25 mg/day of pyridoxine during therapy, since penicillamine increases the requirement for this vitamin. Patients also may receive benefit from a multivitamin preparation. In Wilson's disease, multivitamin preparations must be copper-free. Rheumatoid arthritis patients whose nutrition is impaired should also be given a daily supplement of pyridoxine. Mineral supplements should not be given, since they may block the response to penicillamine.
  • Penicillamine is a drug with a high incidence of untoward reactions, some of which are potentially fatal.
  • Reported incidences for the most commonly occurring adverse reactions in rheumatoid arthritis patients based on 17 representative clinical trials reported in the literature (1270 patients) include events related to Allergy: pruritis, rashes, pemphigus; Gastrointestinal: anorexia, epigastric pain, nausea, vomiting, or occasional diarrhea, hepatic dysfunction, effect on taste perception and oral ulcerations; Hematological: leukopenia, thrombocytopenia leading to fatalities; Renal: proteinuria and/or hematuria progressing to nephrotic syndrome, renal failure; Central Nervous System: tinnitus, optic neuritis, peripheral sensory and motor neuropathies, muscular weakness, visual and psychic disturbances, mental disorders, and agitation and anxiety; Neuromuscular: myasthenia gravis, dystonia. Other: Adverse reactions reported rarely include thrombophlebitis, hyperpyrexia, alopecia, lichen planus, polymyositis, dermatomyositis, mammary hyperplasia, elastosis perforans serpiginosa, toxic epidermal necrolysis, anetoderma, and Goodpasture's syndrome. Vasculitis, including fatal renal vasculitis, allergic alveolitis, obliterative bronchiolitis, interstitial pneumonitis, pulmonary fibrosis, and bronchial asthma also has been reported.
Please click here to see full Prescribing Information for CUPRIMINE® capsules.

©2016 Valeant Pharmaceuticals North America LLC. All Rights Reserved. CUP.0031.USA.16

 

INDICATIONS

Cuprimine® (Penicillamine) is indicated in the treatment of Wilson's disease, cystinuria, and in patients with severe, active rheumatoid arthritis who have failed to respond to an adequate trial of conventional therapy. Available evidence suggests that Cuprimine is not of value in ankylosing spondylitis.

IMPORTANT SAFETY INFORMATION

Physicians planning to use penicillamine should thoroughly familiarize themselves with its toxicity, special dosage considerations, and therapeutic benefits. Penicillamine should never be used casually. Each patient should remain constantly under the close supervision of the physician. Patients should be warned to report promptly any symptoms suggesting toxicity.

  • Except for the treatment of Wilson's disease or certain patients with cystinuria, use of penicillamine during pregnancy is contraindicated. Mothers on therapy with penicillamine should not nurse their infants.
  • Patients with a history of penicillamine-related aplastic anemia or agranulocytosis should not be restarted on penicillamine. Because of its potential for causing renal damage, penicillamine should not be administered to rheumatoid arthritis patients with a history or other evidence of renal insufficiency.
  • The use of penicillamine has been associated with fatalities due to certain diseases such as aplastic anemia, agranulocytosis, thrombocytopenia, Goodpasture's syndrome, and myasthenia gravis.
  • Routine urinalysis, white and differential blood cell count, hemoglobin determination, direct platelet count, together with monitoring of the patient's skin, lymph nodes and body temperature, must be done twice weekly for five months and monthly thereafter. Patients should be instructed to report promptly the development of signs and symptoms of granulocytopenia and/or thrombocytopenia such as fever, sore throat, chills, bruising or bleeding.
  • A reduction in WBC count below 3500/mm3 requires discontinuation. Platelet count below 100,000/mm3 even in absence of clinical bleeding; or a progressive fall in either platelet or WBC count in three successive determinations requires at least temporary cessation of therapy.
  • Proteinuria and/or hematuria may develop during therapy and may be warning signs of membranous glomerulopathy which can progress to a nephrotic syndrome.
  • Because of rare reports of intrahepatic cholestasis and toxic hepatitis, liver function tests are recommended every six months for the duration of therapy. In Wilson's disease, these are recommended every three months, at least during the first year of treatment.
  • Onset of new or worsening of existing neurological symptoms has been reported during initiation of therapy with Cuprimine.
  • When pemphigus is suspected, Cuprimine should be discontinued.
  • Pregnancy Category D - Penicillamine can cause fetal harm when administered to a pregnant woman. Penicillamine should not be administered to pregnant women with cystinuria or rheumatoid arthritis and should be discontinued promptly in patients in whom pregnancy is suspected or diagnosed. Penicillamine has been shown to be teratogenic in rats when given doses 6 times higher than the highest dose recommended for humans. enicillamine for Wilson’s disease should be used in women of childbearing potential only when the expected benefits outweigh the possible hazards. Reported experience shows that continued treatment with penicillamine throughout pregnancy protects the mother against relapse of the Wilson's disease, and discontinuation of penicillamine has deleterious effects on the mother, which may be fatal.
  • Some patients may experience drug fever with or without macular cutaneous eruptions. Penicillamine should be temporarily discontinued in these patients if being treated for Wilson's disease or cystinuria until the reaction subsides. In the case of drug fever in rheumatoid arthritis patients, because other treatments are available, penicillamine should be discontinued.
  • The skin and mucous membranes should be observed for allergic reactions. Early and late rashes have occurred. Less commonly, a late rash may be seen, usually after six months or more of treatment, and requires discontinuation of penicillamine.
  • The appearance of a drug eruption accompanied by fever, arthralgia, lymphadenopathy or other allergic manifestations usually requires discontinuation of penicillamine.
  • Penicillamine should not be used in patients who are receiving concurrently gold therapy, antimalarial or cytotoxic drugs, oxyphenbutazone or phenylbutazone because these drugs are also associated with similar serious hematologic and renal adverse reactions. Patients who have had gold salt therapy discontinued due to a major toxic reaction may be at greater risk of serious adverse reactions with penicillamine but not necessarily of the same type.
  • Patients who are allergic to penicillin may theoretically have cross-sensitivity to penicillamine.
  • Patients with Wilson's disease or cystinuria should be given 25 mg/day of pyridoxine during therapy, since penicillamine increases the requirement for this vitamin. Patients also may receive benefit from a multivitamin preparation. In Wilson's disease, multivitamin preparations must be copper-free. Rheumatoid arthritis patients whose nutrition is impaired should also be given a daily supplement of pyridoxine. Mineral supplements should not be given, since they may block the response to penicillamine.
  • Penicillamine is a drug with a high incidence of untoward reactions, some of which are potentially fatal.
  • Reported incidences for the most commonly occurring adverse reactions in rheumatoid arthritis patients based on 17 representative clinical trials reported in the literature (1270 patients) include events related to Allergy: pruritis, rashes, pemphigus; Gastrointestinal: anorexia, epigastric pain, nausea, vomiting, or occasional diarrhea, hepatic dysfunction, effect on taste perception and oral ulcerations; Hematological: leukopenia, thrombocytopenia leading to fatalities; Renal: proteinuria and/or hematuria progressing to nephrotic syndrome, renal failure; Central Nervous System: tinnitus, optic neuritis, peripheral sensory and motor neuropathies, muscular weakness, visual and psychic disturbances, mental disorders, and agitation and anxiety; Neuromuscular: myasthenia gravis, dystonia. Other: Adverse reactions reported rarely include thrombophlebitis, hyperpyrexia, alopecia, lichen planus, polymyositis, dermatomyositis, mammary hyperplasia, elastosis perforans serpiginosa, toxic epidermal necrolysis, anetoderma, and Goodpasture's syndrome. Vasculitis, including fatal renal vasculitis, allergic alveolitis, obliterative bronchiolitis, interstitial pneumonitis, pulmonary fibrosis, and bronchial asthma also has been reported.
Please click here to see full Prescribing Information for Cuprimine capsules.
 

INDICATIONS

Cuprimine® (Penicillamine) is indicated in the treatment of Wilson's disease, cystinuria, and in patients with severe, active rheumatoid arthritis who have failed to respond to an adequate trial of conventional therapy. Available evidence suggests that Cuprimine is not of value in ankylosing spondylitis.

IMPORTANT SAFETY INFORMATION

Physicians planning to use penicillamine should thoroughly familiarize themselves with its toxicity, special dosage considerations, and therapeutic benefits. Penicillamine should never be used casually. Each patient should remain constantly under the close supervision of the physician. Patients should be warned to report promptly any symptoms suggesting toxicity.

  • Except for the treatment of Wilson's disease or certain patients with cystinuria, use of penicillamine during pregnancy is contraindicated. Mothers on therapy with penicillamine should not nurse their infants.
  • Patients with a history of penicillamine-related aplastic anemia or agranulocytosis should not be restarted on penicillamine. Because of its potential for causing renal damage, penicillamine should not be administered to rheumatoid arthritis patients with a history or other evidence of renal insufficiency.
  • The use of penicillamine has been associated with fatalities due to certain diseases such as aplastic anemia, agranulocytosis, thrombocytopenia, Goodpasture's syndrome, and myasthenia gravis.
  • Routine urinalysis, white and differential blood cell count, hemoglobin determination, direct platelet count, together with monitoring of the patient's skin, lymph nodes and body temperature, must be done twice weekly for five months and monthly thereafter. Patients should be instructed to report promptly the development of signs and symptoms of granulocytopenia and/or thrombocytopenia such as fever, sore throat, chills, bruising or bleeding.
  • A reduction in WBC count below 3500/mm3 requires discontinuation. Platelet count below 100,000/mm3 even in absence of clinical bleeding; or a progressive fall in either platelet or WBC count in three successive determinations requires at least temporary cessation of therapy.
  • Proteinuria and/or hematuria may develop during therapy and may be warning signs of membranous glomerulopathy which can progress to a nephrotic syndrome.
  • Because of rare reports of intrahepatic cholestasis and toxic hepatitis, liver function tests are recommended every six months for the duration of therapy. In Wilson's disease, these are recommended every three months, at least during the first year of treatment.
  • Onset of new or worsening of existing neurological symptoms has been reported during initiation of therapy with Cuprimine.
  • When pemphigus is suspected, Cuprimine should be discontinued.
  • Pregnancy Category D - Penicillamine can cause fetal harm when administered to a pregnant woman. Penicillamine should not be administered to pregnant women with cystinuria or rheumatoid arthritis and should be discontinued promptly in patients in whom pregnancy is suspected or diagnosed. Penicillamine has been shown to be teratogenic in rats when given doses 6 times higher than the highest dose recommended for humans. enicillamine for Wilson’s disease should be used in women of childbearing potential only when the expected benefits outweigh the possible hazards. Reported experience shows that continued treatment with penicillamine throughout pregnancy protects the mother against relapse of the Wilson's disease, and discontinuation of penicillamine has deleterious effects on the mother, which may be fatal.
  • Some patients may experience drug fever with or without macular cutaneous eruptions. Penicillamine should be temporarily discontinued in these patients if being treated for Wilson's disease or cystinuria until the reaction subsides. In the case of drug fever in rheumatoid arthritis patients, because other treatments are available, penicillamine should be discontinued.
  • The skin and mucous membranes should be observed for allergic reactions. Early and late rashes have occurred. Less commonly, a late rash may be seen, usually after six months or more of treatment, and requires discontinuation of penicillamine.
  • The appearance of a drug eruption accompanied by fever, arthralgia, lymphadenopathy or other allergic manifestations usually requires discontinuation of penicillamine.
  • Penicillamine should not be used in patients who are receiving concurrently gold therapy, antimalarial or cytotoxic drugs, oxyphenbutazone or phenylbutazone because these drugs are also associated with similar serious hematologic and renal adverse reactions. Patients who have had gold salt therapy discontinued due to a major toxic reaction may be at greater risk of serious adverse reactions with penicillamine but not necessarily of the same type.
  • Patients who are allergic to penicillin may theoretically have cross-sensitivity to penicillamine.
  • Patients with Wilson's disease or cystinuria should be given 25 mg/day of pyridoxine during therapy, since penicillamine increases the requirement for this vitamin. Patients also may receive benefit from a multivitamin preparation. In Wilson's disease, multivitamin preparations must be copper-free. Rheumatoid arthritis patients whose nutrition is impaired should also be given a daily supplement of pyridoxine. Mineral supplements should not be given, since they may block the response to penicillamine.
  • Penicillamine is a drug with a high incidence of untoward reactions, some of which are potentially fatal.
  • Reported incidences for the most commonly occurring adverse reactions in rheumatoid arthritis patients based on 17 representative clinical trials reported in the literature (1270 patients) include events related to Allergy: pruritis, rashes, pemphigus; Gastrointestinal: anorexia, epigastric pain, nausea, vomiting, or occasional diarrhea, hepatic dysfunction, effect on taste perception and oral ulcerations; Hematological: leukopenia, thrombocytopenia leading to fatalities; Renal: proteinuria and/or hematuria progressing to nephrotic syndrome, renal failure; Central Nervous System: tinnitus, optic neuritis, peripheral sensory and motor neuropathies, muscular weakness, visual and psychic disturbances, mental disorders, and agitation and anxiety; Neuromuscular: myasthenia gravis, dystonia. Other: Adverse reactions reported rarely include thrombophlebitis, hyperpyrexia, alopecia, lichen planus, polymyositis, dermatomyositis, mammary hyperplasia, elastosis perforans serpiginosa, toxic epidermal necrolysis, anetoderma, and Goodpasture's syndrome. Vasculitis, including fatal renal vasculitis, allergic alveolitis, obliterative bronchiolitis, interstitial pneumonitis, pulmonary fibrosis, and bronchial asthma also has been reported.
Please click here to see full Prescribing Information for Cuprimine capsules.