Wilson Disease
Thomas W. Faust, M.D.
Professor of Clinical Medicine
The University of Pennsylvania
Wilson Disease
• Clinical spectrum
• Hepatic
• Neuropsychiatric
• Other
• Diagnostic tests
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Blood tests
Urine tests
Liver biopsy
Genetic testing
• Treatment options
• General chelators
• Metallothionein
inducers
• Liver Transplantation
• Follow-up
• Blood tests
• Urine tests
Wilson Disease
Overview
• Autosomal recessive
• Genetic defect: ATP7B
• Encodes metal-transporting ATPase
• Reduced hepatic excretion of copper
• Copper not incorporated into ceruloplasmin
• Systemic accumulation of copper
• Liver, brain, kidneys, cornea, heart,
pancreas, and joints
Wilson Disease
Pathogenesis
test
Wilson Disease
Hepatic Manifestations
• Asymptomatic
hepatomegaly
• Persistently
abnormal AST and
ALT
• Fatty liver
• Cirrhosis
Ferenci P et al. Liver Int 2003;23:139-142.
• Acute hepatitis
• Similar to viral or
autoimmune
etiologies
• Acute liver failure
• Coomb’s negative
hemolytic anemia
• Acute renal failure
Wilson Disease
Fulminant Hepatic Failure
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•
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Coombs-negative hemolytic anemia
Coagulopathy unresponsive to vitamin K
Rapid progression to renal failure
Modest rise in AST/ALT (< 2000 IU/L)
Normal or markedly subnormal alkaline
phosphatase (< 40 IU/L)
• Alkaline Phosphatase:bilirubin ratio is < 2
• Female to male ratio: 2:1
Wilson Disease
Fulminant Hepatic Failure
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Serum ceruloplasmin usually decreased
Serum and urine copper increased
K-F rings may be absent in 50% of patients
Underlying cirrhosis is typically present
Viral infections or drug effects may precipitate
fulminant WD
McCullough AJ, et al, Gastroenterology 1983;84:161-167.
Wilson Disease
Neuropsychiatric Manifestations
• Movement disorders
• Tremors
• Involuntary movements
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Drooling
Dysarthria
Dystonia
Pseudobulbar palsy
Seizures
Ferenci P et al. Liver Int 2003;23:139-142.
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Migraine headaches
Insomnia
Depression
Personality changes
Psychosis
Typically presents later
than liver disease
Wilson Disease
Neuropsychiatric Manifestations
Netter’s Gastroenterology, 2nd ed., Elsevier Inc., 2010, all rights reserved
Wilson Disease
Extrahepatic Manifestations
• Proximal RTA
• Cardiac
• Cardiomyopathy
• Dysrhythmias
• Fanconi’s syndrome
• Distal RTA
• Nephrolithiasis
• Gastrointestinal
• Pancreatitis
• Skeletal
• Osteoporosis
• Arthritis
• Endocrine
Golding DN et al, Ann Rheum Dis 1977; 36:99-111.
Kuan P et al, Chest 1987;91:579-583.
• Hypoparathyroidism
• Menstrual irregularities
• Infertility
Wilson Disease
Kayser-Fleischer Ring
• Copper deposited in Decemet’s membrane
• Slit lamp required in most patients with
suspected Wilson Disease
• 50-62% of patients with liver disease
• 95% of patients with neurologic disease
• Chronic cholestatic diseases associated with KF rings
• WD= K-F rings + low ceruloplasmin
Sternlieb I, Hepatology 1990;12: 1234-1239.
Kayser-Fleischer Rings
Wilson Disease
Ceruloplasmin
• Major carrier protein for copper
• Holoceruloplasmin
• Largest fraction
• 6 copper atoms/molecule of ceruloplasmin
• Apoceruloplasmin
• Smallest fraction
• Copper not bound to protein
Cauza E et al, J Hepatol 1997;27:358-362.
Wilson Disease
Ceruloplasmin
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Values < 20 mg/dL suggestive of WD
Values < 5 mg/dL highly suggestive of WD
Normal values do not exclude the diagnosis
Low values can be seen in other diseases
Wilson Disease
Serum Copper
• Total serum copper decreased in proportion to
fall in ceruloplasmin
• FHF: total serum copper may be normal or
increased due to increased free copper
• Non-ceruloplasmin bound copper
• Untreated patients: > 25 g/dL (nl: < 15 g/dL)
• Cu2+ bound to ceruloplasmin: 3.15 g/mg CP
• Free Cu2+ = total Cu2+ (g/dL) - 3x CP (mg/dL)
Gaffney D et al, J Clin Pathol 2000;53:807-812.
Wilson Disease
Urinary Copper
• Helps for diagnosing WD and monitoring
therapy
• Reflects amount of non-ceruloplasmin bound
copper in circulation
• Diagnostic of WD: > 100 g/24 Hr.
• Values > 40 g/24 Hr. warrant investigation
• May be elevated in other liver diseases
Gow PJ et al, Gut 2000;46:415-419.
Wilson Disease
Hepatic Copper Concentration
• Diagnostic of WD: > 250g/g dry liver wt. (nl.
< 50 g/g)
• May be elevated in other liver diseases
• Chronic cholestatic disorders
• Indian childhood cirrhosis
• Heterogeneous distribution
• Obtained when diagnosis not clear
Merle U et al, Gut 2007;56:115-120.
Wilson Disease
Liver Biopsy
• Early disease
• Micro and macrovesicular steatosis
• Glycogenated nuclei in hepatocytes
• Focal hepatocellular necrosis or “chronic active
hepatitis”
• Fulminant hepatic failure
• Parenchymal collapse + cirrhosis
• Advanced disease
• Fibrosis and cirrhosis (macro or micronodular)
Wilson Disease
Histopathology
Chronic hepatitis
Fatty infiltration
Cirrhosis
Apoptosis
Wilson Disease
Genetic Analysis
• Pedigree analysis using haplotypes based on
polymorphisms surrounding WD gene
• Identification of proband required
• After mutation identified, DNA from first
degree relatives can be screened
• Utility limited
• Most patients are compound heterozygotes
• Over 200 mutations of ATP7B gene
Thomas GR et al, Am J Hum Genet 1995;56:1315-1319.
Wilson Disease
Diagnostic Testing
Roberts EA et al, Hepatology, 2008:47, 2089-2111
Wilson Disease
Diagnosis Established
I
Molecular +
II
III
K-F rings +
Plus one or more of
following:
Ceruloplasmin < 20 mg/dL
and/or
Ceruloplasmin < 20 mg/dL
24 hr urine Cu > 40 μg
24 hr urine Cu > 100 μg
Plus:
Typical neurologic
manifestations
Liver bx > 75 μg/gm dry wt.
Liver bx > 75 μg/gm dry wt.
Rosencrantz R et al, Sem. Liv. Dis. 2011;31: 245-259
Wilson Disease
Family Screening
• Candidates
• First degree relatives of
newly diagnosed
patients with WD
• Preliminary lab tests
• Serum copper, CBC,
ceruloplasmin, LCTs
• 24 hour urinary copper
• Liver biopsy
• Pts without K-F rings+
low ceruloplasmin
• Above with abnl LCTs
• Genetic studies
• Haplotype analysis after
identification of proband
• Opthalmology
• Slit lamp exam
Thomas GR et al, Am J Hum Genet 1995;56:1315-1319.
Wilson Disease
Screening
Roberts EA et al, Hepatology, 2008:47, 2089-2111
Wilson Disease
Treatment Options
• Medical
• Chelators
• Penicillamine, trientine
• Metallothionein inducers
• Zinc
• Surgical
• Liver transplantation
Wilson Disease
Chelating Agents
• Initial approach to symptomatic patients
and those with active disease
• Penicillamine
• Largest experience worldwide
• Worsening of neurologic symptoms reported
• Trientine
• Viable option as primary therapy
• Effective for hepatic or neurologic disease
Walshe JM. Q J Med 1973;42:441-452.
Scheinberg IH, et al, N Engl J Med 1987;317:209-213.
Wilson Disease
Penicillamine and Trientene Monitoring
• Overall goals of monitoring
• Assess efficacy of treatment
• Assure compliance on therapy
• 24-hour urinary copper excretion
• Goal: 200-500 g/d
• Non-ceruloplasmin bound copper
• Normalization with effective Rx (< 15 g/dL)
Wilson Disease
Zinc
• Presymptomatic disease
• Can be used as first line therapy
• As effective as penicillamine and trientine
• Symptomatic disease
• Combination therapy with chelating agents
probably no better than chelating agents alone
• Used as maintenance therapy after chelation with
either penicillamine or trientine
Wilson Disease
Zinc Monitoring
• 24-hour urinary copper excretion
• < 75 g/d on stable dose
• Non-ceruloplasmin bound copper
• Normalization with effective Rx (< 15 g/dL)
Wilson Disease
Diet
• Not recommended as sole therapy
• Avoid foods with high copper content
• Shellfish, nuts, chocolate, mushrooms, organ
meats
• Check household water supplies
Brewer GJ, et al, J Am Coll Nutr 1993;12:527- 530.
Wilson Disease
Maintenance Therapy
• Assure stabilization of WD with a chelator
• Conversion from a chelator to zinc
• Clinical remission and normal LCTs
• Non-ceruloplasmin bound copper < 15 g/dL
• 24-hour urinary copper between 200-500 g/d
• Treatment must be lifelong regardless of
choice of therapy
Walshe JM, et al, Lancet 1986;1:845-847.
Wilson Disease
Fulminant Hepatic Failure
• Chelating agents and zinc are not effective
therapies for fulminant WD
• OLT is the only effective treatment for FHF
• Bilirubin, AST, and PT are prognostically important
• Preservation of renal function
• Plasmapheresis and exchange transfusions
• Hemofiltration or dialysis
Sokol RJ, et al, J Pe- diatr 1985;107:549-552.
Wilson Disease
Pregnancy
• Treatment of WD must continue throughout
pregnancy
• Penicillamine, trientine, and zinc are safe
• Penicillamine and trientine reduced by 25-50%
of pre-pregnancy dose to promote better
wound healing in cesarean cases
Morimoto I, et al, Jpn J Med 1986; 25:59-62.
Devesa R, et al, J Pediatr Gastroenterol Nutr 1995;20:102-103.
Wilson Disease
Liver Transplantation
• Decompensated liver disease
• Refractory to chelating agents
• Complications of portal hypertension
• Hepatocellular carcinoma (rare)
• Fulminant hepatic failure
• Uniformly fatal without OLT
• OLT is curative
• 1 year survival: 79-87%
Eghtesad B, et al, Liver Transpl Surg 1999;5:467-474.
Wilson Disease
Treatment
Established Wilson
disease diagnosis:
liver disease ±
neuropsychiatric
symptoms
Confirmed Wilson
disease diagnosis:
asymptomatic or family
screening
Maintenance dose
therapy
Liver transplantation
Treatment dose
therapy
Clinical improvement: urine Cu
200-500 μg/24h on chelation,
urine Cu 30-100 μg/24h on
zinc, non-ceruloplasmin Cu <
10 μg/dL
Maintenance dose
therapy
Rosencrantz R et al, 2011;31: 245-259
WD acute liver failure
Clinical deterioration
Liver transplantation
Wilson Disease
Take Home Points
• Autosomal recessive disorder of copper metabolism
• Patients can be asymptomatic or present with a variety
of hepatic and extrahepatic manifestations
• Diagnosis based upon clinical exam, LFTs,
ceruloplasmin, serum and urine copper studies, and
liver biopsy
• Treatment includes chelators, metallothionein
inducers, dietary modification, and liver
transplantation
• After proband identified, family members should be
screened
Wilson Disease
Question 1
• A 25 yr old woman is referred to you by her psychiatrist
because of abnormal LFTs. She has been exhibiting bizarre
behavior for several months, complaining of difficulty
speaking and swallowing, and has recently lost her job as
an accountant because of inattentiveness. Routine
screening labs revealed AST 150 U/L, ALT 110 U/L, alkaline
phosphatase 20 U/L, albumin 3 gm/dl, and total bilirubin
1.5 mg/dl. She was previously healthy, not obese, and
denies alcohol use. She is an only child and reports no
family history of liver disease. Tests for HBV and HCV are
negative. Physical exam reveals a hard liver edge and a
palpable spleen tip. Based upon the above, you suspect
Wilson Disease. All of the following would support the
diagnosis except:
DDSEP 6, AGA Press, 2011.
Wilson Disease
Question 1
• A. Finding of corneal rings on slit lamp
examination
• B. Low serum ceruloplasmin
• C. Low 24 hr. urinary copper excretion
• D. Low serum alkaline phosphatase
• E. Presence of rhodanine positive granules in
hepatocytes on liver biopsy
DDSEP 6, AGA Press, 2011.
Wilson Disease
Question 2
• In the preceding case, having established a
diagnosis of Wilson Disease, you should begin
her immediately on which one of the
following oral mineral supplements?
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A. Iron
B. Selenium
C. Copper
D. Zinc
E. Chromium
DDSEP 6, AGA Press, 2011.
Wilson Disease
Question 3
• In the preceding case, having established a
diagnosis of Wilson Disease in this patient, which
of the following considerations regarding
chelation therapy is true?
• A. Trientene is more toxic than penicillamine
• B. Trientene is more effective than D-penicillamine
• C. Neurologic symptoms often worsen following
initiation of D-penicillamine
• D. Early liver transplantation is usually preferable to
chelation
• E. Treatment benefits of chelation will not become
apparent for several years
DDSEP 6, AGA Press, 2011.
Wilson Disease
Question 4
• Which one of the following statements about Wilson
disease is true?
• A. Autosomal dominant disease of copper metabolism that
invariably leads to progressive copper accumulation in
hepatic and extrahepatic sites.
• B. The disease is associated with acute hepatitis but does
not cause fatty liver or cirrhosis.
• C. The alkaline phosphatase to bilirubin ratio is greater
than 2 in patients with fulminant hepatic failure.
• D. Underlying cirrhosis is usually not present in patients
who present with fulminant hepatic failure.
• E. Serum and urine copper are increased in patients with
fulminant hepatic failure.
Wilson Disease
Question 5
• A 19 yr old female presents with a 4 day history of
anorexia, malaise, and fatigue. According to the family,
her mental status has deteriorated over the past 24
hours. The patient has a sister with Wilson Disease.
Consequently, she was brought to the ED. In the ED,
the patient was stuporous and mildly icteric. Her vital
signs were stable. Pertinent labs are as follows: total
bilirubin 3.4 mg/dl, alkaline phosphatase 23 U/L, AST
340 U/L, ALT 252 U/L, INR 2.3, and albumin of 2.7
gm/dl. You suspect that the patient may have
fulminant Wilson disease. Which of the following
statements is correct?
Wilson Disease
Question 5
• A. Either D-penicillamine or trientene are viable
options as chelators for this patient.
• B. The patient should be given elemental zinc followed
by either D-penicillamine or trientine.
• C. The patient should undergo evaluation and be listed
for liver transplantation.
• D. The patient should be observed and if she does not
improve, begin plasmapheresis as definitive therapy.
• E. The patient should be given N-acetylcysteine and
observed on a medical floor. If she deteriorates further,
she should be transferred to MICU.
Wilson Disease
Question 6
• Which one of the following statements about Wilson
Disease is correct?
• A. Trientine can be discontinued after serum free copper is
determined to be in the normal range.
• B. There is no role for a low copper diet in patients with Wilson
Disease as copper is found in many foods and the diet is too
difficult to maintain.
• C. For pregnant patients undergoing Caesarean section,
trientine and D-penicillamine should be reduced by 25-50% of
pre-pregnancy dose
• D. Kayser-Fleischer rings are pathognomonic for Wilson Disease
• E. Low ceruloplasmin values are pathognomonic for Wilson
Disease
Wilson Disease
Answers to Questions
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1. C
2. D
3. C
4. E
5. C
6. C