Wilson Disease
Wilson Disease: Excerpt from The 5-Minute Pediatric Consult
Molly E. Rideout, MD
Wilson Disease - BASICS
Wilson Disease - description
Wilson disease (WD), also known as hepatolenticular degeneration, is an autosomal recessive disorder of copper metabolism affecting the liver and brain.
Wilson Disease - epidemiology
Children usually present with hepatic manifestations; adolescents and young adults may present with neurologic symptoms.
Wilson Disease - incidence
- Incidence is 15–25 per million.
- Worldwide carrier rate is 1:100.
Wilson Disease - prevalence
- Prevalence is 1:30,000.
- Most cases present between ages 5 and 35.
- Worldwide distribution
Wilson Disease - risk factors
Wilson Disease - genetics
- Autosomal-recessive inheritance with one of >200 known defects of the WD gene (ATP7B) on chromosome 13q14.3, which produces a membrane P-type adenosine triphosphatase (ATPase) protein
- The affected protein facilitates biliary excretion of excess copper. It also incorporates copper into apoceruloplasmin for transport to other sites.
- Heterozygotes are generally asymptomatic.
- Future siblings have 25% risk of disease.
- Direct mutational analysis is limited due to the high number of mutations, except in isolated populations.
Wilson Disease - pathophysiology
- Loss of ATP7b function causes impaired biliary copper excretion (the only route for elimination of copper) and ceruloplasmin biosynthesis.
- Copper accumulates 1st in the liver, leading to cirrhosis.
- After liver is saturated, copper overflows and settles in the brain and other tissues.
- In the brain, copper collects primarily in the basal ganglia, leading to impaired motor control.
- Other tissues affected by copper accumulation are kidneys, heart, blood, and cornea.
- Failure to incorporate copper during ceruloplasmin biosynthesis produces an apoprotein that is rapidly degraded.
Wilson Disease - associated conditions
- Renal: Copper accumulation leads to Fanconi syndrome with tubular dysfunction, causing glycosuria, hypophosphatemia, and low uric acid.
- Hematologic: Hemolytic anemia develops from release of copper into plasma during liver failure, with disruption of RBC membrane. Coagulopathy results from liver failure.
- Cardiac: Cardiomyopathy and dysrhythmias develop from copper deposits.
Wilson Disease - DIAGNOSIS
Wilson Disease - signs & symptoms
- 45% of all patients present with liver disease, 35% with neurologic symptoms, 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.
- WD accounts for 8–10% of all chronic active hepatitis in children.
- Also consider WD in patient with unexplained neuropsychiatric symptoms.
Wilson Disease - history
- Hepatic:
- In children, symptoms of hepatic disease predominate, ranging in severity from asymptomatic hepatomegaly or elevated transaminases to chronic hepatitis to fulminant hepatic failure.
- Average age for onset hepatic symptoms ~10.
- Fulminant liver failure is twice as common in women than in men, is common in adolescents, and is associated with hemolysis and coagulopathy unresponsive to vitamin K.
- Neurologic:
- Neurologic symptoms are rare before age 10.
- Neurologic signs in children may include behavior change, a decline in school performance, poor hand–eye coordination, and motor abnormalities such as dystonia, tremors, dysphagia, dysarthria.
- Psychiatric: Patients may present with or develop depression, anxiety, psychosis, and/or obsessive–compulsive disorder.
- Other:
- Nonspecific complaints are common, such as abdominal pain, nausea, anorexia, and fatigue.
- Family history of liver disease may be present.
Wilson Disease - physical exam
- Ophthalmologic:
- Kayser–Fleischer (KF) rings: Copper deposits on Decemet’s membrane of cornea (at limbus)
- May require slit-lamp examination to see
- 95% with neurologic signs have KF rings
- 50–65% hepatic presentation have KF rings
- KF rings not pathognomonic for WD; may be seen in cholestatic liver disease
- Sunflower cataracts are copper deposits on the anterior lens: Greenish-gray in color
- 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
Wilson Disease - tests
Wilson Disease - lab
- Serum ceruloplasmin:
- Low sensitivity and specificity
- Usually low; however, up to 1/3 of patients have normal values
- An acute phase reactant; during inflammation, infection, or trauma, level may increase to reference range
- Made mostly in the liver, it is the major carrier of copper in blood.
- 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 due to sudden release of stores (most is not bound to ceruloplasmin).
- Urinary copper excretion:
- Reflects unbound copper in blood
- Level is high in WD: >100 mcg/24 hours in symptomatic patient is diagnostic.
- May be increased in other chronic liver diseases, so cannot be used alone to diagnose
- In equivocal cases, marked increase in urinary copper output after initiation of chelation therapy may help in diagnosis.
- Other:
- Liver function tests: Mild to moderate elevations of serum aminotransferase levels
- Mutational analysis: No single available test, but useful for screening familial mutation is known
Wilson Disease - imaging
- Abdominal ultrasound for liver size and pathology
- If neurologic symptoms present, an MRI of the brain with focus on basal ganglia should be obtained prior to initiation of therapy.
- Brain MRI may show atrophy of basal ganglia, midbrain, pons, white matter changes
Wilson Disease - diag proced-surgery
- 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 is the best biochemical evidence for WD (normal level <50 mcg/g).
- High levels may also be seen in chronic cholestasis and idiopathic copper toxicosis syndrome, but levels are usually <250 mcg/g.
- Hepatic copper level <50 excludes WD.
Wilson Disease - differencial diagnosis
- Liver disease:
- Viral hepatitis
- Autoimmune hepatitis/primary biliary cirrhosis
- Menkes disease
- Cholestatic disease from parenteral nutrition
- Neurologic disease:
- Essential tremor
- Sydenham or Huntington’s chorea
- Hereditary dystonia
- Other neurodegenerative diseases
- Psychiatric disease: Depression, psychoses, and neuroses
- KF rings: Seen in other causes cholestatic liver disease
- Low ceruloplasmin:
- End-stage liver disease
- Menkes disease
- Protein loss from GI or renal abnormalities
Wilson Disease - TREATMENT
Early diagnosis is essential to limiting morbidity and mortality.
Wilson Disease - 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.
Wilson Disease - diet
Low-copper diet for life: Avoid liver and other organ meats, shellfish, nuts, mushrooms, and chocolate.
Wilson Disease - special therapy
Patients with fulminant liver failure require liver transplant to survive.
Wilson Disease - medication
- Trientene:
- Has become initial drug of choice
- Used in combination with zinc
- Chelates copper and promotes renal excretion
- Fewer side effects than penicillamine
- Most side effects improve with continued treatment.
- Risk of sideroblastic anemia, hemorrhagic gastritis, nephritis, arthritis, worsened neurologic signs
- Take without food.
- Pediatric dose 20 mg/kg/d divided b.i.d.–t.i.d. to maximum of 750–1,000 mg/d
- Serum copper increases during treatment.
- Also chelates iron, creating toxic complex, so do not give supplemental Fe at the same time
- Penicillamine:
- Chelates copper and promotes renal excretion
- Also induces metallothionein, interferes with collagen cross-linking, immunosuppressant
- Improvement of liver disease takes up to a year.
- Side effects in 20–30%: Fever, neutropenia, thrombocytopenia, hypersensitivity reactions, nephrotoxicity, lupus-like syndrome
- Acute neurologic deterioration in up to 20%
- Also treats cystinosis, rheumatoid arthritis
- Does not contain penicillin
- Monitor CBC, liver function tests (LFTs), urinalysis, urine copper
- Take without food
- Lower dose for surgery, 3rd trimester pregnancy
- Fulminant liver failure seen in patients who discontinue abruptly
- Zinc:
- Routinely combined with trientine for first-line initial treatment
- Also used alone as maintenance therapy
- Interferes with absorption from GI tract by inducing metallothionein in enterocytes, which chelates metals. The copper is bound within the enterocyte and not absorbed into the portal circulation. It is shed in stool as enterocytes are normally shed.
- Few side effects: Gastric irritation, nausea (ameliorated by taking with meat [but no carbohydrates])
- Take without food, except as above
- After chelation 4–6 months, with normal labs, usually OK to change to zinc for maintenance
- May create a negative copper balance, removing all extra copper stores, resulting in improvement of hepatic and brain function, and loss of KF rings
- Overtreatment may result in anemia or decreased wound healing from copper deficiency
- No altered dose needed for surgery
- Compliance with overall therapy monitored by urine zinc levels
Wilson Disease - surgery
- Orthotopic liver transplant required for fulminant liver failure
- Heterozygote can donate liver.
- 5% with WD need liver transplants
Wilson Disease - FOLLOW UP
Wilson Disease - 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.
- Routine monitoring should include serum copper and ceruloplasmin, liver biochemistries, and 24-hour urinary copper excretion.
- First-degree relatives older than age 3 years should be screened with history, physical examination, LFTs, CBC, serum ceruloplasmin, 24-hour urine copper, and ophthalmologic examination for KF rings. In addition, genotype or haplotype testing based on the affected relative’s genetics should be performed.
- Reproductive and genetic counseling for carriers should be offered.
Wilson Disease - prognosis
- If WD is recognized early and treated, most patients experience complete recovery.
- Progression to hepatocellular carcinoma is rare, unlike hemochromatosis.
Wilson Disease - bibliography
- El-Youssef M. Wilson disease. Mayo Clin Proc. 2003;78:1126–1136.
- Gitlin J. Wilson disease. Gastroenterology. 2003;125:1868–1877.
- Roberts E, Schilsky M. A practice guideline on Wilson disease: AASLD practice guidelines. Hepatology. 2003;37:1475–1492.
www.wilsonsdisease.org
Wilson Disease - CODES
Wilson Disease - icd9
- 275.1 Wilson disease or syndrome (hepatolenticular degeneration)
- 275.1 Hepatolenticular degeneration
Wilson Disease - FAQ
- Q: If one child in a family has WD, what is the likelihood that another child with the same parents will develop the disease?
- A: All offspring have a 25% risk of developing the disease.
- Q: Are medications for WD safe during pregnancy?
- A: Women of reproductive age who are treated can have normal pregnancies. Doses of both trientine and penicillamine should be reduced during pregnancy, especially in the 3rd trimester, to promote wound healing in the case of a surgical delivery. Zinc doses can remain unchanged. Interruption of therapy is not recommended during pregnancy.
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Book Source Details
- Book Title: The 5-Minute Pediatric Consult
- Author(s): M. William Schwartz MD; et al.
- Year of Publication: 2008
- Copyright Details: The 5-Minute Pediatric Consult, Copyright © 2008 Lippincott Williams & Wilkins.
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Copyright notice for book excerpts: Copyright © 2008 Lippincott Williams & Wilkins. All rights reserved.
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More About This Book:
Title: The 5-Minute Pediatric Consult
Authors: M. William Schwartz MD; et al.
Publisher: Lippincott Williams & Wilkins
Copyright: 2008
ISBN: 0-7817-7577-9
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