Title: Wilson s Disease Case and Review Tom Orli MD April 19, 200
1Wilsons Disease
- Case and Review
- Tom Orli MD
- April 19, 2005
2HPI
- 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.
3- 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
4HP
- PMH jaundice as baby
- Meds MVI, SSRI in past
- FH healthy younger sister, no liver disease
- SH no tob or drugs
5HP 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
6- Vitals normal
- Gen Thin well developed, blunted affect but
appropriate. Mom does most talking.
7Labs
- 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)
8Next ?
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10AASLD Guidelines
1124 hr urine copper normal Ophthalmology thinks
they see KF rings.
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13History
- 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.
14Genetics
- Autosomal recessive.
- Prevalence of disease 130,000 with 190 carrier.
- Gene on C13 discovered in 1993.
- The gene ATP7b encodes the ATP7B protein.
15ATP7B Protein
- Intracellular, transmembrane protein.
- Localized to the Golgi within the hepatocyte.
- Central role in copper transport.
- Exact mechanism of action unclear.
16ATP7B Processing
17Copper MetabolismBig Picture
Dietary Copper
Gut Absorption
Liver
Ceruloplasmin
Bile
Reduced in Wilson's
Feces
18Cellular Copper Metabolism
WD
WD
Not decreased In Wilson's
19Presentation
- 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.
20Gow 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
21Gow 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.
22Gow 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.
23Liver 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).
24FHF
- 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.
25Berman 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.
26Steindl 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
27Steindl et al.Gastroenterology 1997
28Psychiatric 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.
29Neurological 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
30Evaluation
- Ceruloplasmin
- KF rings
- 24 urine copper
- D-penicillamine challenge
- Serum copper
- Liver biopsy
- Neuroimaging
- Genetic testing
31Ceruloplasmin
- 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.
32Ceruloplasmin cont.
- As a screening test.
- Significance of low value?
- Reassurance of normal value?
33Cauza 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)
34Steindl 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.
35Steindl et al.
36Steindl et al.
37Ceruloplasmin cont.
- Significance of low value?
- Not diagnostic, but definitely keep looking.
- Reassurance of normal value?
- Some, however WD not excluded. Must consider
entire presentation.
38Kayser-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
39Sunflower Cataract
- Copper deposition in lens.
- Slit-lamp exam
- Usually do not interfere with vision.
- Will also regress with therapy.
40Urine 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.
41Claudia 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.
42Claudia 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
43Claudia et al.
1 umol 67 ug
44Claudia et al.
- Determined that gt 25 umol(1600 ug)/24hr was most
discriminating biochemical test to diagnose WD.
45Serum 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.
46Biopsy
- 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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48Neuro-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.
49Face of Giant Panda
50Giant and Baby Cub Panda
51Genetic 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.
52Family 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.
53Treatment
- Chelation with D-penicillamine and trientine.
Tetrathiomolybdate is currently experimental. - Absorption blocking with zinc.
- Liver transplant.
54D-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
55Trientine
- 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.
56Zinc
- 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
57Transplant
- 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.
58Schilsky 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.
59AASLD 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.
60Conclusions
- Rare.
- Potentially difficult to diagnose.
- Needs to be considered in the young.
- Failure to diagnose/treat bad.
- Good therapies which effectively manage illness.
61MRI of Mid-Brain and Thalmus Before and After Tx