Wilson disease (hepatolenticular degeneration) is an autosomal-recessively
inherited disorder of copper metabolism.16 The
clinical manifestations of Wilson disease result from the excessive
deposition of copper in the liver, brain, kidneys, and eyes. This
excessive accumulation results from disturbed incorporation of copper
into ceruloplasmin and reduced biliary copper excretion.
A single abnormal copy of the Wilson disease gene is found in
up to 1 in 100 people. The disorder occurs in between 1 and 4 per 100,000
The gene for Wilson disease, mapped to the long arm of chromosome
13 and designated ATP7B, encodes a copper-transporting P-type ATPase
expressed predominantly in hepatocytes. Over 400 disease-specific
mutations of ATP7B have now been reported in individuals with Wilson disease.
Genotype/phenotype correlations are complicated by the fact
that many Wilson disease patients are compound heterozygotes. The
ATP7B protein is localized predominantly in the trans-Golgi
network, to a vesicular compartment, and possibly in mitochondria. Ongoing
studies on the structure and function of the ATP7B protein support
its dual synthetic and excretory roles, functioning in the transport
of copper into the trans-Golgi compartment, for incorporation into
the plasma protein ceruloplasmin, and into the bile, for excretion
of excess stores.The mechanism of copper toxicity likely includes
the generation of free radicals, lipid peroxidation of membranes
and DNA, inhibition of protein synthesis, and reduced levels of
cellular antioxidants. Hepatocellular necrosis and apoptosis may
be triggered by copper-induced cellular injury. When the storage
capacity of the liver for copper is exceeded, or when liver-cell
necrosis results in release of cellular copper into the systemic
circulation, the concentration of non-ceruloplasmin-bound copper
in the circulation becomes elevated with resultant extrahepatic
deposition in sites such as the brain.
Wilson disease should be considered in any child with an unexplained
hepatic, neurologic, or psychiatric illness. The natural history
of Wilson disease begins with the asymptomatic accumulation of copper
in hepatocytes. The clinical presentation is highly variable. Although
patients as young as 2 have presented with liver disease, symptoms
are rarely evident before 5 years of age. Younger children, identified
by family screening or after evaluation of abnormal liver biochemical
tests, are often asymptomatic. Patients younger than 20 years of
age tend to present predominantly with hepatic manifestations. Asymptomatic
hepatomegaly or an illness mimicking acute hepatitis may occur.
Hepatic insufficiency associated with cirrhosis may evolve slowly
or be manifest at the time of initial diagnosis with variceal hemorrhage,
ascites, edema, and stigmata of chronic liver disease. A fulminant
form of the disease most often occurs in the second decade of life
with the abrupt onset of liver failure associated with nonimmune hemolytic
anemia. The latter complication likely results from oxidative injury
to red blood cells as massive amounts of copper are released from hepatocytes.
Older patients may present with predominantly neurologic and
psychiatric dysfunction. Findings initially may be quite subtle
and include deterioration in school performance, behavioral changes,
slurred speech, and tremors. If untreated, severe dysarthria and
dystonia result, sometimes leading to psychiatric hospitalization.
Kayser-Fleischer rings, copper deposits on the inner surface of
the Descemet membrane, are invariably found in patients with a neurologic
presentation. They are often absent in younger patients when they
present with only liver disease.
Abnormalities of other organ systems are sometimes present in Wilson
disease. Copper toxicity in the kidney may induce nephrocalcinosis,
hematuria, and aminoaciduria. Arthritis, arthralgias, and premature
osteoarthritis may also occur. Cardiomyopathy and arrhythmias may
result from copper accumulation in the myocardium.
Routine laboratory studies demonstrate variable elevation in
serum aminotransferase values and in the conjugated and unconjugated
serum bilirubin concentrations. Serum alkaline phosphatase levels tend
to be normal or even low. The serum copper concentration is usually
low but may be elevated during episodes of hemolysis. Serum ceruloplasmin,
an α2-globulin involved in copper transport,
is typically low, although this serum protein may also be reduced in
other disorders associated with acute or chronic hepatic insufficiency.
Urinary copper excretion, normally less than 40 to 60 μg
per 24 hours, is usually more than 100 μg per 24
hours in Wilson disease. Urinary copper excretion may be elevated
in other forms of liver disease, such as chronic hepatitis or fulminant
Hepatic copper content remains the gold standard for the diagnosis
of Wilson disease. The typical diagnostic concentration is more
than 250 μg per gram dry weight of liver, commonly
more than 1000 μg per gram. Histologic examination
may show fatty infiltration, glycogen accumulation, glycogenated
nuclei, and enlarged Kupffer cells. However, sometimes there are
findings indistinguishable from those of chronic active hepatitis. Significant
hepatic fibrosis or even cirrhosis may be a presenting feature.
Distinctive mitochondrial changes may be found even at an early
stage of the disease, including enlargement, separation of the inner
and outer membranes, widening of the intercristal spaces, and increased
density and granularity of the matrix or replacement by large vacuoles.
Histochemical stains for copper may be useful when positive but
are not reliable in excluding copper overload.
The most striking neuropathologic changes in Wilson disease are found
in the lenticular nuclei, which may manifest atrophy, cystic degeneration,
and discoloration. The thalamus, the subthalamus, and even the cerebral
cortex may be involved.
Without treatment, Wilson disease is uniformly fatal. The mainstay
of treatment involves chelation therapy with copper-binding agents—D-penicillamine
or trientine. D-penicillamine is administered orally in increasing
doses to approximately 1 g/day in adults and 0.5 to 0.75
g/day for younger children. Chelating agents remove copper
from potentially toxic sites within cells and detoxify the remaining
copper. Urinary copper excretion markedly increases on initiation
of therapy with D-penicillamine. Later, urinary copper excretion
stabilizes, reflecting a new steady state of copper balance. A low-copper
diet must also be instituted to maintain a daily intake below 1
mg per day. Foods containing high amounts of copper, such as liver,
chocolate, nuts, and shellfish, should be avoided. Water sources
should also be assayed for copper content. With effective chelation therapy,
there is usually improvement of hepatic and neurologic function
and regression of Kayser-Fleischer rings. Chelation therapy must be
maintained for life. For patients who are intolerant to D-penicillamine
because of hypersensitivity reactions or bone marrow suppression,
therapy with an alternative chelating agent, trientine, is equally
effective. Tetrathiomolybdate is another chelating agent potentially
useful in patients with neurologic disease in whom D-penicillamine
therapy may be associated with an initial worsening of symptoms.
Several studies have indicated that zinc administration may maintain
a negative copper balance in patients with Wilson disease, but zinc
should be considered as a primary therapy only in patients unable
to tolerate standard chelating agents. Zinc acts to prevent intestinal absorption
of copper, rather than as a chelating agent.
For patients with end-stage liver disease unresponsive to chelation therapy,
and for most patients with the fulminant form of Wilson disease,
liver transplantation may be life saving. Various degrees of regression
of neurologic and psychiatric abnormalities have been described
following liver replacement.
Siblings of patients with Wilson disease should be screened carefully
for the disorder. Zinc has been used successfully in asymptomatic
or presymptomatic affected family members of individuals with Wilson
disease. The abundance of disease-specific mutations and their locations
at multiple sites have limited molecular genetic diagnosis to kindred
of known patients. Thorough evaluation by well-established clinical and
biochemical tests remains essential.
Neonatal Iron Storage
Neonatal iron storage disease, also known as neonatal
hemocromatosis, is a form of neonatal liver failure characterized
by an in utero onset of hepatic and extrahepatic hemosiderosis.18 This
entity is unrelated to hereditary hemochromatosis and does not appear
to be the result of a primary abnormality in fetal iron metabolism.
The rate of occurrence of severe disease in subsequent newborns
after the index case is 60% to 80%.
Although the apparent rate of occurrence of severe disease in
siblings after an index is very high, the inheritance of neonatal
iron storage disease had never been satisfactorily explained. This
led to the hypothesis that neonatal iron storage disease results
from a gestational alloimmune response. Indeed, a recent study has
shown that occurrence of severe neonatal iron storage disease in
at-risk pregnancies can be significantly reduced by treatment with
high-dose intravenous immunoglobulin during gestation. This is a treatment
that has been successfully used to reduce the severity of other
gestational alloimmune diseases.18
The initial clinical presentation of neonatal iron storage disease
can be subtle and can be confused with other pathologic conditions
commonly seen in the newborn. The finding of cholestatic jaundice
with coagulopathy and/or ascites at birth should prompt
diagnostic evaluations for neonatal iron storage disease. Supporting
biochemical features include hypoalbuminemia, hypoglycemia, hyperammonemia,
and high iron saturation and serum ferritin levels.
Diagnosis is dependent on documentation of hepatic insufficiency and
extrahepatic siderosis with no other apparent etiology of the liver failure.
Extrahepatic siderosis can be demonstrated by either biopsy of a
minor salivary gland or magnetic resonance imaging of the pancreas
and/or heart. Analysis of both of these studies requires
assessment by a specialist experienced in these uncommon applications
of the diagnostic tests. Liver histology, when available, reveals
nonspecific findings with evidence of chronic hepatic insufficiency,
well-established fibrosis or cirrhosis, significant hepatocellular
loss, and reactive bile ductular proliferation.
Infants with neonatal hemochromatosis have an expected mortality
of more than 90% unless prompt treatment and/or
liver transplantation is undertaken. Early recognition of neonatal
hemochromatosis is a requisite for successful treatment. Sepsis
often leads to significant morbidity and mortality in these infants
because they are immunocompromised on the basis of both age and
decompensated cirrhotic liver disease. Immediate referral of infants
with neonatal hemochromatosis to a center experienced in liver transplantation
in infants is advised. Medical therapy consists of a combination
of antioxidants (vitamin E in the form of tocopheryl polyethylene
glycol succinate, selenium, and N-acetyl cysteine),
membrane stabilizers (prostaglandin E1), and iron chelators
(deferoxamine). The efficacy of medical therapy alone has been questioned,
but it appears at a minimum to stabilize infants in preparation
for liver transplantation. Liver transplantation has been successfully
utilized in very small infants with neonatal hemochromatosis, but
mortality in these acutely ill babies may still exceed 50%.
Recurrence of the disease posttransplant has not been reported,
although apparent iron toxicity has been observed in an infant who
did not undergo chelation before transplantation. Parents of infants
with neonatal hemochromatosis need to be advised about the risk
of recurrence and referred for therapy to a center experienced with
this disorder in subsequent pregnancies.
Hereditary hemochromatosis is an inherited disorder of iron metabolism
leading to progressive iron loading of parenchymal cells of the
liver, pancreas, and heart.19
The most common form of this disease is caused by homozygosity
for the C282Y mutation in the HFE gene. Not all
patients with this genetic mutation have phenotypic expression.
Other mutations have been described, but their prevalence is low.
Hereditary hemochromatosis is not a disorder of childhood, but iron
studies may be abnormal in children, leading to early diagnosis
of children with affected parents.
A genetically heterogeneous but rare disorder called juvenile
hemochromatosis has been recognized for many years. Owing to the
early and accelerated pace of iron overloading, these patients may
have more prominent cardiac and endocrine dysfunction than severe
liver disease. Mutations in two genes important in regulating iron
homeostasis have been identified: (1) the HAMP gene,
encoding hepcidin, which is essential for inhibiting the release of
iron from enterocytes and macrophages to circulating transferring,
and (2) HFE2, encoding hemojuvelin, a protein that
increases hepcidin expression.
Symptoms of hemochromatosis include nonspecific findings such as
weakness, fatigue, and weight loss. More specific symptoms and signs
include arthralgias, diabetes, hepatomegaly, amenorrhea, and congestive
Once a proband with hereditary hemochromatosis is identified,
family screening is recommended for all first-degree relatives.
In children of an affected parent, it is useful to perform HFE mutation
analysis on the spouse to accurately predict the genotype in the
children. If the spouse has either mutation, then the children will
also need to undergo HFE mutation analysis, although
the value of genetic testing in children is still being evaluated.
In a child at risk, serum iron studies should be periodically evaluated
and therapeutic phlebotomy considered if liver function tests are
elevated and ferritin level is greater than 1000 ng/mL.
This is unlikely until after the second decade of life.