Basics
Description
Wilson disease (WD), also known as hepatolenticular degeneration, is an autosomal recessive disorder of copper metabolism affecting several organs, most notably the liver, brain, and cornea.
Epidemiology
Children usually present with hepatic manifestations; adolescents and young adults may present with neurologic symptoms.
- Worldwide carrier rate is 1:100.
- Prevalence is 1:30,000.
- Most cases present between ages 5 and 35 years.
- Worldwide distribution
Risk Factors
Genetics
- Autosomal recessive inheritance with 1 of >500 known defects of the WD gene (ATP7B) on chromosome 13q14.3 membrane (ATPase)
- The affected protein facilitates biliary excretion of excess copper; incorporates copper into apoceruloplasmin for transport
- Heterozygotes are generally asymptomatic.
- Siblings have 25% risk of disease, 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
- Clinical phenotype of WD is modified by mutations in other genes, including MTHFR, COMMD1, ATOX1, and XIAP.
- Use of direct mutational analysis to phenotype WD is limited by the high number of mutations.
Pathophysiology
- Loss of ATP7b function causes; a) impaired biliary copper excretion (the only route for elimination of copper) and b) failure to incorporate copper to apoceruloplasmin during ceruloplasmin biosynthesis, leading to ceruloplasmin deficiency
- Copper accumulates preferentially in the liver, leading to cirrhosis.
- After liver is saturated, copper overflows and settles in the brain (primarily in the basal ganglia leading to impaired motor control), as well as other tissues including kidneys, heart, blood, and cornea.
- Excess copper damages mitochondria, causing oxidative damage to cells. In addition, toxic intracellular copper deposition promotes apoptotic cell death by the inhibition of IAPs (inhibitor of apoptosis proteins).
Diagnosis
History
- Hepatic
- In children, symptoms of hepatic disease predominate, ranging from asymptomatic hepatomegaly and elevated transaminases to chronic hepatitis and even fulminant hepatic failure.
- Mean age for onset of hepatic symptoms ~10 years
- Fulminant liver failure is associated with hemolysis and coagulopathy unresponsive to vitamin K.
- Neurologic
- Neurologic symptoms are rare before age 10 years.
- Neurologic signs in children: behavior change, decline in school performance, poor hand " eye coordination, motor abnormalities " dystonia, tremors, dysphagia, dysarthria, chorea, ataxia, and parkinsonism
- Other manifestations include seizures, myoclonus, and dysautonomia.
- Psychiatric: develop depression, anxiety, psychosis, and/or obsessive-compulsive disorder
- Other: Nonspecific complaints are common " abdominal pain, nausea, anorexia, and fatigue.
- Signs and symptoms:
- 45% of all patients present with liver disease, 35% with neurologic symptoms and 10% psychiatric.
- Remaining 10%: hemolytic anemia, jaundice, cardiomyopathy, other
- Consider WD in all cases of liver abnormality in which viral and autoimmune causes have been excluded.
- Also consider WD in every young patient with unexplained neuropsychiatric symptoms including with a movement disorder.
Physical Exam
- Ophthalmologic
- Kayser-Fleischer (KF) rings: copper deposits on Descemet membrane of cornea (at limbus)
- Not pathognomonic for WD; may be seen in cholestatic liver disease
- May require slit-lamp examination to detect
- 95% with neurologic signs have KF rings.
- 50 " 65% with hepatic presentation has KF rings.
- Cardiovascular: signs of cardiomyopathy, dysrhythmia, congestive heart failure
- Abdominal
- Hepatomegaly, ascites
- Splenomegaly from portal hypertension
- Skin
- Jaundice due to hemolysis
- Bleeding diathesis from liver disease
- Edema
- Neurologic
- Movement disorders
- Neurologic deficits
Diagnostic Tests & Interpretation
Lab
- Serum ceruloplasmin
- An acute-phase reactant; increased with inflammation, infection, or trauma; level may increase to reference range.
- Made mostly in the liver; it is the major carrier of copper in blood.
- Low serum ceruloplasmin can be helpful in diagnosing WD.
- Very low (<50 mg/L): strong evidence for WD
- Low (<200 mg/L) plus symptoms and KF rings: diagnostic of WD
- Ceruloplasmin levels also low in renal or GI protein loss, Menkes disease, and end-stage liver disease
- Serum copper
- Low total serum copper (<80 mcg/dL) in WD
- Level is decreased in proportion to decreased ceruloplasmin in circulation.
- In acute fulminant liver failure, serum copper is increased owing to sudden release of stores (most is not bound to ceruloplasmin).
- Free copper estimation
- Measure of nonceruloplasmin toxic copper in the blood; normal values 1.3 " 1.9 Όmol/L (8 " 12 mcg/dL), in WD >3.9 Όmol/L (25 mcg/dL).
- Useful in cases where false elevation of ceruloplasmin is suspected; when a measurement of urinary copper is difficult to obtain, as well to monitor chelators efficacy during maintenance phase of therapy (goal < 25 mcg/dL)
- Calculated by the formula: total serum copper in mcg/mL 100 ’ (ceruloplasmin in mg/dL 3) = free copper
- Urinary copper excretion
- Reflects unbound copper in blood
- Level is high in WD: >100 mcg/24 h in symptomatic patient is diagnostic.
- In equivocal cases, marked increase in urinary copper output after initiation of chelation therapy may help in diagnosis.
- Other:
- Mutational analysis if familial mutation is known
Imaging
- Abdominal ultrasound for liver size and pathology
- MRI of the brain/basal ganglia should be obtained prior to initiation of therapy.
- "Face of the giant panda " sign that is characteristic of Wilson disease (red nuclei, substantia nigra, tegmentum)
Diagnostic Procedures/Other
- Liver biopsy is the definitive procedure for tissue diagnosis and hepatic disease staging.
- Biopsy should be obtained when diagnosis is not straightforward and in younger patients.
- Hepatic parenchymal copper concentration >250 mcg/g dry weight
- Hepatic copper level <50 mcg/g dry weight excludes WD.
Differential Diagnosis
- Liver disease
- Viral hepatitis
- Autoimmune hepatitis/primary biliary cirrhosis
- Menkes disease (low ceruloplasmin)
- Cholestatic disease from parenteral nutrition (KF rings)
- Neurologic disease
- Essential tremor
- Sydenham or Huntington chorea
- Hereditary dystonia
- Other neurodegenerative diseases
- Psychiatric disease: depression, psychoses
- Protein loss from GI or renal abnormalities
Treatment
- Lifetime therapy aimed at treating copper overload
- Consists of two phases
- (1) Removing or detoxifying the tissue copper (achieved by chelators)
- (2) Preventing reaccumulation (low-dose chelators, dosages reduced by about 33% from original induction dose and/or by use of zinc salts)
- Successful therapy is measured in terms of a restoration of normal levels of free serum copper and its excretion in the urine.
Medication (Drugs)
- Penicillamine
- Mode of action (MOA)
- Chelates copper and promotes renal excretion
- Also induces metallothionein (which forms a nontoxic combination with copper)
- Efficacy: Improvement in clinical features noted after 2 " 3 months, continuing over a period of 1 " 2 years.
- Dosages and monitoring:
- Initial dose: 1 " 1.5 g/24 h in 2 " 4 divided doses PO, maximum total daily dose 20 mg/kg, taken 1 or 2 hours after food (absorption decreased by approximately 50% when taken with food).
- May start at a lower dose (250 " 500 mg/day) with gradual escalation over a few weeks
- Monitoring: clinical assessment + hematologic, biochemical (transaminases), and urinary parameters every week for 1 month, then every month for 6 months, and subsequently q6mo.
- While on therapy, 24-hour urine copper exceeds ≥2,000 mcg/day, with gradual decline over 6 " 12 months to values below ≤200 " 500 mcg/day.
- Once this level achieved and free serum copper <15 mcg/dL, the maintenance dose can be lowered to 0.5 " 1 g/24 h in divided doses (usually after 4 " 6 months).
- At this point, a zinc salt could be added to the treatment regimen, preferably before meals to avoid any interaction with penicillamine.
- The goal of treatment is a 24-hour urine copper excretion of 50 " 100 mcg
- Side effects in 20 " 30%
- Acute neurologic deterioration caused by rapid mobilization of hepatic copper stores leading to increased brain copper deposition, or from the development of intracellular copper complexes
- Reduce dose to 250 mg/24 h or switch to trientine or zinc.
- Pyridoxine deficiency, risk factors include intercurrent infection or a growth spurt. B6 supplementation 25 " 50 mg/24 h
- Skin complications due to interference with collagen and elastin formation
- Hypersensitivity reactions (rash, fever, lymphadenopathy), bone marrow suppression, myasthenia gravis, optic neuritis, nephritis, lupuslike syndrome
- Discontinue if the total white blood cell count <3,000 cells per mm3, neutrophils <2,000 cells per mm3, platelets <120,000 per mm3, or if a steady decline over three successive tests even if the values are above the earlier mentioned parameters for discontinuation.
- Discontinue also if >2+ proteinuria on a dipstick, red cell or white casts or >10 red cells seen per high-power field on urine microscopy.
- Trientine
- MOA: chelates copper/promotes renal excretion
- Dosages and monitoring:
- Has become initial drug of choice
- Used in combination with zinc
- Dosages: pediatric dose 20 mg/kg/24 h PO divided 2 " 3 /24 h up to a maximum of 1,500 mg/24 h. Round dose to the nearest 250 mg.
- Maintenance therapy: 750 " 1,000 mg/24 2 " 3 /day, avoid taking with food.
- Monitoring: same as penicillamine
- Side effects: fewer than penicillamine
- Risk of sideroblastic anemia (drug 's effects on mitochondrial iron metabolism), hemorrhagic gastritis, nephritis, arthritis, worsened neurologic signs
- Serum copper increases during treatment.
- Also chelates iron, creating toxic complex; do not give supplemental Fe (if iron supplementation required, administer Fe in short courses, separated by trientine by at least 2 hours).
- Zinc
- Routinely combined with trientine
- Also used alone as maintenance therapy
- Used successfully in asymptomatic or presymptomatic affected family members of individuals with Wilson disease
- MOA
- Interferes with absorption from GI tract by inducing metallothionein in enterocytes, which chelates metals. Copper is bound within the enterocyte and not absorbed into the portal circulation. It is shed in stool along with normal shedding of enterocytes.
- Also induces copper-binding metallothionein in the liver
- May create a negative copper balance, removing all extra copper stores, resulting in improvement of hepatic and brain function, and loss of KF rings
- Dosage: 50 mg t.i.d. PO, empty stomach
- Side effects:
- Few side effects: gastric irritation, nausea
- Overtreatment may result in anemia, decreased wound healing, or neuromyelopathy from copper deficiency.
- No altered dose needed for surgery.
- Compliance with overall therapy monitored by urine zinc levels, which should be above 2 mg
- After chelation for 4 " 6 months, with normal labs, usually OK to change to zinc for maintenance
- Ammonium tetrathiomolybdate
- Not FDA-approved
- Complex with copper in the intestinal tract, preventing absorption.
- Absorbed drug forms a complex with copper and albumin in blood, which is metabolized by liver and excreted in bile.
- Particularly suited for treatment of neurologic manifestation in Wilson disease, as it is not associated with exacerbation on initiation of treatment.
- S/E: bone marrow suppression, elevated aminotransferases
- Antioxidants and experimental therapies
- Antioxidants (vitamin E/N-acetylcysteine) may protect against oxidative damage.
Additional Therapies
General Measures
- Immunize for hepatitis A, B.
- Avoid excess alcohol.
- Well water or water via copper pipes needs to be tested: If >0.1 ppm Cu, find alternative source.
Surgery/Other Procedures
- Orthotopic liver transplant required for fulminant liver failure or end-stage liver cirrhosis, which is resistant to chelation therapy.
- Uncertain indication for therapy-resistant neurologic symptoms. Several case reports suggest improved neurologic symptoms after transplantation.
- 5% with WD need liver transplants.
Ongoing Care
Follow-up Recommendations
Patient Monitoring
- Patients require lifelong dietary copper restriction and chelation therapy.
- Continual monitoring for compliance and side effects of medications is crucial.
- Sudden discontinuation of therapy may precipitate fulminant hepatic failure.
- 1st-degree relatives >age 3 years should be screened with history, physical exam, LFTs, CBC, serum ceruloplasmin, 24-hour urine copper, and ophthalmologic examination for KF rings.
- Reproductive and genetic counseling for carriers should be offered. Prenatal testing
Diet
Low-copper diet for life: Avoid liver and other organ meats, shellfish, nuts, mushrooms, and chocolate.
Complications
- Renal: Copper accumulation leads to Fanconi syndrome (tubular dysfunction, glycosuria, hypophosphatemia, and low uric acid).
- Hematologic: Coombs-negative hemolytic anemia, coagulopathy from liver failure
- Cardiac: cardiomyopathy/dysrhythmias
- Rare associations include renal stones, gallstones, osteomalacia, osteoporosis, arthralgias, pancreatitis, hypoparathyroidism, skin pigmentation, and a bluish discoloration at the base of the fingernails (azure lunulae)
Prognosis
- If WD is recognized early and treated, most patients experience complete recovery.
- Progression to hepatocellular carcinoma is rare, unlike hemochromatosis.
Additional Reading
- Ala A, Walker P, Ashkan K, et al. Wilson 's disease. Lancet. 2007;369(9559):397 " 408. [View Abstract]
- Brewer GJ, Askari F, Dick Rb, et al. Treatment of Wilson 's disease with tetrathiomolybdate: V. Control of free copper by tetrathiomolybdate and comparison with trientine. Transl Res. 2009;154(2):70 " 77. [View Abstract]
- Das SK, Ray K. Wilson 's disease: an update. Nat Clin Pract Neurol. 2006;2(9):482 " 493. [View Abstract]
- European Association for Study of Liver. EASL clinical practice guidelines: Wilson 's disease. J Hepatol. 2012;56(3):671. [View Abstract]
Codes
ICD09
- 275.1 Disorders of copper metabolism
ICD10
SNOMED
- 88518009 Wilson 's disease (disorder)