Wilson Disease (hepatolenticular degeneration)
- The incidence is 1/500,000 to 1/100,000 births.
- Abnormal gene 13q14.3).
- This gene encodes a copper transporting P-type
- ATP7B. ATP7B is mainly but not exclusively
expressed in hepatocytes and is thought to be
critical for biliary copper excretion and for copper
incorporation into ceruloplasmin.
- Absence or malfunction of ATP7B results in
decreased biliary copper excretion and diffuse
accumulation of copper in the cytosol of
- When liver cells become overloaded, copper is
redistributed to other tissues including the brain
and kidneys, to which it is toxic, primarily as a
potent inhibitor of enzymatic processes.
- Ionic copper inhibits pyruvate oxidase in brain and
ATPase in membranes, leading to decreased ATP-
phosphocreatine and potassium content of tissue.
- More than 250 mutations, making diagnosis by DNA
mutational analysis a difficult task
- Most patients are compound heterozygotes. raises
presentations are variable, with a tendency to familial patterns. The
younger the patient, the more likely hepatic involvement will be the
Females are three times more likely than males to present with
fulminant hepatic failure. After 20 yr of age, neurologic symptoms
- hepatic disease
o Asymptomatic hepatomegaly (with or without
o subacute or chronic hepatitis, and fulminant
o Cryptogenic cirrhosis, portal hypertension,
o ascites, edema, variceal bleeding,
o hepatic dysfunction
o (Delayed puberty, amenorrhea, and
coagulation defect) can be manifestations of
o insidiously or precipitously
o Intention tremor
o dysarthria, dystonia
o lack of motor coordination
o deterioration in school performance
o behavioral changes.
- Kayser-Fleischer rings
o May be absent in young patients with liver
o Always present in patients CNS.
- Coombs-negative hemolytic anemia: may be an
initial manifestation related to the release of large
amounts of copper from damaged hepatocytes
- Usually fatal without transplantation.
- Urinary copper excretion and serum copper levels
(non-ceruloplasmin-bound) are markedly elevated.
- Fanconi syndrome
o Endocrinopathies (hypoparathyroidism).
All grades of hepatic injury
- Heptocellular ballooning
- Glycogen granules
- Minimal inflammation,
- Enlarged Kupffer cells.
- DD autoimmune hepatitis.
- Fibrosis and cirrhosis
- Ultrastructural changes
o primarily the mitochondria
o increased density of the matrix material,
o inclusions of lipid and granular material,
o increased intracristal space
o Dilatation of the tips of the cristae.
o Liver copper content is elevated.
Wilson disease should be considered in children and teenagers
with unexplained acute or chronic liver disease, neurologic
symptoms of unknown cause, acute hemolysis, psychiatric
illnesses, behavioral changes, Fanconi syndrome, or
unexplained bone disease. The clinical suspicion is confirmed
by study of indices of copper metabolism.
CERULOPLASMIN LEVEL best screening test
- Wilson disease have decreased ceruloplasmin
levels. DUE TO failure of copper to be incorporated
into ceruloplasmin leads to a plasma protein with a
- . FALSE NEGATIVE: elevated in acute inflammation
and in states of elevated estrogen such as
pregnancy, estrogen supplementation, or oral
Serum copper level
may be elevated in early Wilson disease
urinary copper excretion
(usually <40 μg/day) is increased to >100 μg/day and
often up to 1,000 μg or more per day.
In equivocal cases, the response of urinary copper
output to chelation may be of diagnostic help.
During the 24 hr urine collection patients are given
two 500 mg oral doses of D-penicillamine 12 hr apart;
affected patients excrete 1,200–2,000 μg/24 hr.
which may not be present in younger children, requires
a slit-lamp examination by an ophthalmologist.
- Determining the extent and Severity
- Measurement of the hepatic copper content
(normally <10 μg/g dry weight). In Wilson disease,
hepatic copper content exceeds 250 μg/g dry
- In healthy heterozygotes, levels may be
- Family members of patients with proven cases
require screening for presymptomatic
- Determination of the serum ceruloplasmin level
- Urinary copper excretion.
- If these results are abnormal or equivocal, liver
biopsy should be carried out
- linkage analysis
- Direct DNA mutation analysis is possible, especially if the
mutation for the proband case is known or the patient is from an
area where a specific mutation is known (in central and eastern
Europe, the H1069Q mutation is present in 50–80% of
- Restrict copper intake to <1 mg/day. Foods such as
liver, shellfish, nuts, and chocolate should be
- If the copper content of the drinking water exceeds
0.1 mg/L, it may be necessary to demineralize.
- D-penicillamine (β,β-dimethylcysteine)
o Dose: 1 g/day in two doses before meals for
adults and 20 mg/kg/day for pediatric patients.
o In response to penicillamine, urinary copper
excretion markedly increases, and with
continued administration, urinary copper
levels may become normal, with marked
improvement and the disappearance of
o 10–50% of patients initially treated with
penicillamine for neurologic symptoms have a
worsening of their condition.
o Toxic effects of penicillamine 10–20%
(Goodpasture syndrome, systemic lupus
Interaction with collagen and elastin,
deficiency of other elements such as zinc,
and aplastic anemia and nephrosis.
Antimetabolite of vitamin B6, additional
amounts of this vitamin are necessary
triethylene tetramine dihydrochloride (Trien, TETA,
- For patients unable to tolerate penicillamine,
- dose of 0.5–2.0 g/day for adults and 20 mg/kg/day
- Alternate chelating agent under investigation for
patients with neurologic disease
- Dose: 120 mg/day (20 mg between meals tid and 20
mg with meals tid).
- If a nighttime snack is eaten, another 20 mg is given
with the snack.
- Side effects
o Mild elevations of transaminases.
- Used as adjuvant therapy
- Maintenance therapy, or primary therapy in
- Impair the gastrointestinal absorption of copper.
- Zinc acetate dose ; adults at a dose of 25–50 mg of
elemental zinc three times a day, and 25 mg three
times a day in children >5 yr of age.
Untreated patients with Wilson disease die of the
hepatic, neurologic, renal, or hematologic
The prognosis for patients receiving prompt ttt depends
on the time of initiation of and the individual response to
Liver transplantation should be considered for patients
with fulminant liver disease, decompensated cirrhosis,
or progressive neurologic disease; the latter indication
Liver transplantation is curative with a survival rate of
≈85–90%. In asymptomatic siblings of affected patients,
early institution of chelation therapy can prevent
expression of the disease.