Wilson s Disease Case and Review Tom Orli MD April 19, 200

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Wilsons Disease

• Case and Review
• Tom Orli MD
• April 19, 2005

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HPI

• 21 y/o WM college student. Problems with
  fatigue, depression, difficulty concentrating and
  poor sleeping habits. Doing poorly at school.
  Denies neurological complaints. Binge drinking
  history. Found to have elevated transaminases on
  multiple occasions which have persisted despite
  several months off ETOH. Low serum copper and
  ceruloplasmin. Viral, autoimmune metabolic
  work-up normal.

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• 21 yo WM
• CC fatigue, depression, difficulty concentrating
  and poor sleeping habits, doing poorly at school
• PMH jaundice as baby
• Meds none
• FH healthy younger sister, no liver disease
• SH no tob or drugs

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HP

• PMH jaundice as baby
• Meds MVI, SSRI in past
• FH healthy younger sister, no liver disease
• SH no tob or drugs

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HP cont..

• Vitals normal
• Gen Thin well developed, blunted affect but
  appropriate. Mom does most talking.
• HEENT Non-icteric, no obvious KF rings
• CV RRR
• Lungs CTA
• Abd NT, ND, BS, no organomegaly
• Skin Normal
• Neuro Normal gait, no tremor, no deficits

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• Vitals normal
• Gen Thin well developed, blunted affect but
  appropriate. Mom does most talking.

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Labs

• AST - 59
• ALT - 97
• ALP, Bili, Albumin, CBC, BMP all WNL
• Viral, Fe studies, ANA, ASMA, AAT all WNL
• Ceruloplasmin 14, 14, 18 mg/dl (normal gt 20)
• Serum copper 0.68 ug/dl (low)

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Next ?
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AASLD Guidelines
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24 hr urine copper normal Ophthalmology thinks
they see KF rings.
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History

• 1912 - Dr. Kinnear Wilson describes a
  progressive lenticular degeneration in the
  journal Brain.
• Kayser and Fleischer link WD with corneal
  deposits.
• 1951 - First available treatment
  dimercaptopropanol introduced, given IM.
• 1956 - D-penicillamine, oral chelator.

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Genetics

• Autosomal recessive.
• Prevalence of disease 130,000 with 190 carrier.
• Gene on C13 discovered in 1993.
• The gene ATP7b encodes the ATP7B protein.

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ATP7B Protein

• Intracellular, transmembrane protein.
• Localized to the Golgi within the hepatocyte.
• Central role in copper transport.
• Exact mechanism of action unclear.

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ATP7B Processing
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Copper MetabolismBig Picture
Dietary Copper
Gut Absorption
Liver
Ceruloplasmin
Bile
Reduced in Wilson's
Feces
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Cellular Copper Metabolism
WD
WD
Not decreased In Wilson's
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Presentation

• Variable including hepatic, neurologic and
  psychiatric symptoms. Less commonly only
  hemolytic anemia.
• Age range 5-40 yr, but two cases recently
  diagnosed in eighth decade.
• Hepatic presentation typically earlier, i.e.
  first two decades of life with neuropsych
  symptoms occurring later.

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Gow et al.Gut 2000

• 30 patients with WD seen from 1971 1998.
• 50 male.
• Age from 7 58, mean 21.
• 22 liver (8 FHF, 12 chronic), 3 neurologic, 1
  hemolysis, and 4 asymptomatic siblings

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Gow cont..Results from the 22 non-FHF

• 14 had KF rings.
• 16 had low ceruloplasmin.
• 12 had both KF rings and low ceruloplasmin.
• 13 had elevated 24 hr urine copper.
• 21 had elevated liver copper, 1 had been on
  penicillamine for 6 years.
• 2 had no evidence of copper metabolism
  abnormality, but had elevated liver copper.

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Gow cont..Results from 8 with FHF

• 6 with KF rings.
• 7 with low ceruloplasmin.
• 5 had both.
• 4 had elevated urine copper, 4 anuric.
• 5 of 6 tested had elevated free copper.
• ALT 26-384, ALP 16-130
• 6 had hemolysis.

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Liver Manifestations

• The liver manifestations of Wilson disease may be
  of almost any variety and severity.
• Has to be suspected in young patients.
• Acute hepatitis which appears to resolve, but
  without viral etiology.
• Chronic hepatitis with ongoing LFT abnormalities
  clinically indistinguishable from an autoimmune
  hepatitis, usually without elevated globulins and
  auto-antibodies.
• Decompensated cirrhosis.
• Fulminant liver failure (FHF).

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FHF

• Mortality near 100 without transplant.
• 31 female to male ratio.
• Cirrhosis common but liver disease often not
  suspected.
• Coombs (-) hemolysis
• Coagulopathy
• Renal failure
• Only modest transaminase elevations which may be
  falsely reassuring.
• Low ALP and ALP to total bili ratio of lt 2.

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Berman et al.Gastroenterology 1991

• FHF caused by Wilson's disease (n 6) from other
  etiologies (n 43).
• lt 2.0 for the ALP/Bili-total ratio and gt 4.0 for
  the AST/ALT ratio were associated with a
  diagnosis of fulminant hepatic failure caused by
  Wilson's disease only (P lt 0.001).
• The 2.0 for the ALP/Bili-total ratio provided
  100 sensitivity and specificity in identifying
  fulminant hepatic failure caused by Wilson's
  disease from other types of fulminant hepatic
  failure.

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Steindl et al.Gastroenterology 1997

• 55 pts diagnosed with WD between 1967-1995
• Diagnosis of WD made in pts with two of the
  following KF rings, low ceruloplasmin and
  typical neurologic symptoms.
• 43 had liver biopsy sent for copper content, with
  39 having gt250 ug/g

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Steindl et al.Gastroenterology 1997
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Psychiatric Manifestations

• Psychiatric disorders are quite variable.
• Depression is common.
• Phobias neurotic, compulsive , and anti-social
  behavior.
• Cognitive deterioration may occur with worsening
  school performance and shortened attention span.
• Poor sleep habits.
• Frank psychosis is uncommon.

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Neurological Manifestations

• Diverse and may present as movement disorders
  which can be quite difficult to differentiate
  from other neurological disorders.
• Dystonia and dysarthia
• Ataxic syndrome with postural and intentional
  tremor. Gait disturbances.
• Parkinsonian symptoms

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Evaluation

• Ceruloplasmin
• KF rings
• 24 urine copper
• D-penicillamine challenge
• Serum copper
• Liver biopsy
• Neuroimaging
• Genetic testing

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Ceruloplasmin

• 132 kd protein predominately of hepatic origin.
• Acute phase reactant.
• Major carrier of copper, 6 atoms per molecule.
• Exists as apoceruloplasmin (less stable) and
  holoceruloplasmin.
• Antibody dependent (UAB Lab) or copper dependent
  oxidase assays use to measure.

• Normal levels are gt20mg/dL
• Low during first 6 months of life and elevated
  early childhood.
• Low in WD but also in 20 heterozygotes, in
  protein losing states (gut or renal), cirrhosis
  and rare diseases such as Menkes and
  aceruloplasminemia.
• Elevated in acute inflammation, pregnancy, or
  estrogen therapy.

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Ceruloplasmin cont.

• As a screening test.
• Significance of low value?
• Reassurance of normal value?

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Cauza et alJ of Hepatology 1997

• Screening for WD in patients with liver diseases
  by serum ceruloplasmin
• 2867 pts evaluated for a liver disease
• Ceruloplasmin determined by immunodiffusion,
  normal 20-60mg/dL.
• 17 pts had level lt20 mg/dL, 1 had WD.
• PPV 6 (Probability that pt with low
  ceruloplasmin has WD)

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Steindl et al.Gastroenterology 1997

• Data on 55 pts with WD reviewed to identify
  algorithm for diagnosis.
• 15 pts had normal ceruloplasmin levels.
• 12 pts had neither KF rings or low ceruloplasmin,
  however they all had other characteristics which
  led to high suspicion for WD.

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Steindl et al.
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Steindl et al.
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Ceruloplasmin cont.

• Significance of low value?
• Not diagnostic, but definitely keep looking.
• Reassurance of normal value?
• Some, however WD not excluded. Must consider
  entire presentation.

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Kayser-Fleischer Rings

• Corneal copper deposition.
• Slit-Lamp exam
• 50 in isolated liver disease presentation
• 95 pts with neuro symptoms.
• Absence does not exclude WD even with neuro
  symptoms.
• Disappear with therapy

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Sunflower Cataract

• Copper deposition in lens.
• Slit-lamp exam
• Usually do not interfere with vision.
• Will also regress with therapy.

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Urine Copper

• Measured as 24 hr collection and is a reflection
  of NCbCu.
• Needs to be collected in copper free container.
• 100 ug/24hr or greater typical of WD but not
  universal therefore levels gt 40 ug/24hr (normal
  for most labs) need further investigation.
• Overlap occurs in other liver diseases i.e. AH.
• Penicillamine challenge may be helpful but only
  evaluated in children.

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Claudia et al.Hepatology 1992

• Retrospective analysis of 75 children referred to
  pediatric liver service to investigate value of
  penicillamine challenge.
• Penicillamine challenge 500 mg before start
  24hr collection and again at 12hrs.
• Compared with 24 hr urine copper at baseline,
  CPL, serum copper, free copper and liver copper
  to distinguish WD from other liver conditions in
  children.

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Claudia et al.

• 43F, 32M ages 2-18 yr
• 12 with WD and 13 with other LD had biopsy data
• 17 diagnosed with WD
• 22 CAH
• 6 PSC
• 4 Cryptogenic LF
• 18 other LD
• 8 no LD

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Claudia et al.
1 umol 67 ug
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Claudia et al.

• Determined that gt 25 umol(1600 ug)/24hr was most
  discriminating biochemical test to diagnose WD.

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Serum Copper

• Serum copper reflects ceruloplasmin-bound (CbCu)
  and nonceruloplasmin-bound (NCbCu).
• Usually low b/c ceruloplasmin low in WD.
• Can be elevated during FHF, secondary to release
  from hepatocytes.
• Can calculate NCbCu serum Cu 3(ceruloplasmin)
• Normal Serum Cu 70 155 ug/dL
  NCbCu lt15ug/dL, gt25ug/dL in WD
• Limited utility for diagnosis, but useful in
  monitoring treatment.

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Biopsy

• Hepatic copper gt250 ug/g dry weight is gold
  standard.
• Normal is lt50 ug/g and excludes WD, in patients
  w/o cirrhosis.
• Sampling error can occur b/c newly regenerative
  nodules may lack sufficient copper.
• Chronic cholestatic disease can have levels
  gt250ug/g.
• Histology is variable, mild steatosis is earliest
  abnormality seen, but also may have autoimmune
  features, fibrosis and cirrhosis.

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Neuro-imaging

• MRI more sensitive then CT.
• Hyperintensity seen on T2 in basal ganglia
  corresponding to copper deposition.
• Putamen (61)
• Globus pallidus (59)
• Brainstem and cerebellum (34)
• Panda sign in mid-brain.
• MRI and neuro evaluation recommended in patients
  with neurologic symptoms and prior to beginning
  treatment.

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Face of Giant Panda
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Giant and Baby Cub Panda
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Genetic Studies

• Multiple mutations (232 known) make direct
  mutation analysis difficult and not currently
  readily available.
• Patients may be compound heterozygotes with
  differing mutations on each allele.
• Haplotype analysis in families with known proband
  can be done for screening.

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Family Screening

• First degree relatives.
• History of liver or neurologic disease.
• Physical exam including slit-lamp for KF rings
• LFTs
• Serum copper, ceruloplasmin, and 24 hr urine.
• Haplotype analysis based on proband if possible.

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Treatment

• Chelation with D-penicillamine and trientine.
  Tetrathiomolybdate is currently experimental.
• Absorption blocking with zinc.
• Liver transplant.

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D-penicillamine

• First oral agent, available since 1956.
• Breakdown product of penicillin, sulfhydryl group
  which chelates copper.
• Promotes cupriuria.
• Liver function improves after 2-6 months, but
  10-50 may have neurologic decline.

• Many potentially severe side effects. 20-30
  have to discontinue.
• Early reactions 1-3 weeks Cytopenias, skin
  eruptions and proteinuria.
• Late reactions Nephrotoxicity, lupus, aplasia,
  hepatotoxicity

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Trientine

• Available since 1969
• Also copper chelator but chemically different
  from penicillamine.
• Fewer side effects then penicillamine make this a
  more attractive first line agent.
• Should be used first in pts with pre-existing
  renal disease, cytopenias or autoimmune disease.
• Treatment and maintenance dosage similar to
  penicillamine.
• Follow 24hr urine copper levels.

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Zinc

• First used in early 1960s.
• Prevents copper absorption in gut by inducing
  enterocyte metallothionein which bind copper.
  This complex is retained in the enterocyte and
  excreted in stool as cells are shed.
• Copper entering gut from serum also removed
  (negative copper balance).

• GI upset biggest side effect.
• Usually used for maintenance.
• Dose 150 mg/d div tid of elemental zinc.
• Follow 24 hr urine copper (lt75 ug).
• Follow 24 hr urine zinc for compliance, if taking
  should be 3 4mg

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Transplant

• Indications hepatic decompensation despite
  therapy and FHF.
• Possible indication is severe neurologic disease
  but improvement after transplant is variable.
• Transplant is curative.
• Patients who survive first year (79 87) do
  well long term.

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Schilsky et al.Hepatology 1994

• Retrospective review of data from 55 transplants.
• 32 F, 23 M, ages 8 51 yr
• Hepatic insufficiency 32, FHF 21, Intractable
  neurological symptoms 1, GIB 1
• 5 of 8 pts with neuropsych symptoms improved.
• Mean survival 2.5 yr, 1 year survival 79
• 90 survival in FHF as of publication date.

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AASLD Treatment

• Initial treatment for symptomatic pts should
  include chelator.
• Presymptomatic pts or maintenance can be with
  chelator or zinc.
• Treatment needs to be maintained during pregnancy.

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Conclusions

• Rare.
• Potentially difficult to diagnose.
• Needs to be considered in the young.
• Failure to diagnose/treat bad.
• Good therapies which effectively manage illness.

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MRI of Mid-Brain and Thalmus Before and After Tx