Page 237 - The Netter Collection of Medical Illustrations - Integumentary System_ Volume 4 ( PDFDrive )

Plate 8-14 Nutritional and Metabolic Diseases

WILSON’S DISEASE

Wilson’s disease, also known as hepatolenticular degen-
eration, is a disorder caused by a defect in copper metab-
olism. The disease is rare, with a worldwide incidence Kayser-
of approximately 1 in 18,000. It is an autosomal reces- Fleischer
sive condition that is caused by a defect in the ATP7B ring
gene, which is located on the long arm of chromosome
13. The product of this gene is responsible for the
proper transport of copper. The main clinical findings
relate to nervous system involvement and liver disease.
Wilson’s disease has a variable phenotype depending on
the specific genetic mutation. Cutaneous disease and
ophthalmological disease are frequently seen.
Clinical Findings: Wilson’s disease equally affects
males and females, and its incidence varies among pop-
ulations. The usual age at onset is in the first 2 decades
of life. Liver disease and central nervous system (CNS)
disease are often the first signs. Patients may present Degenerative changes Adolescents more likely
have generalized dystonia
with unexplained hepatomegaly, cirrhosis, and end- in lenticular nuclei with neck (torticollis) and
stage liver disease. The CNS findings can manifest in face (grimacing) effects,
various patterns. Mild to severe psychiatric symptoms occasionally focal;
of depression and mood lability are common; the mani- hypertonicity and
festations in some patients may approach the diagnosis choreoathetosis may coexist
of schizophrenia. Impaired cognition and memory are
frequently seen and may lead to early dementia. Extra- Adults more likely have
coarse, proximal “wing
pyramidal features are always present and include beating” or “chest beating”
tremor and rigidity. The tremor has been described as tremor, masked facies,
a “wing-beating” tremor of the shoulder girdle. Brady- and dysarthric speech
kinesia is invariably a part of the disease. Ataxia and
chorea, along with dysfunction of normal motor coor-
dination, are evident as time progresses.
The cutaneous findings, when present in conjunction
with liver and CNS disease, can make the diagnosis.
Patients have varying amounts of pretibial hyperpig-
mentation, the cause of which is poorly understood.
Rarely, patients present with a blue discoloration to the
lunula of the nail. The most pathognomonic sign is the
presence of Kayser-Fleischer rings on the cornea. A
Kayser-Fleischer ring is a yellow to orange-brown ring
around the iris. It represents an abnormal accumulation
of copper in Descemet’s membrane of the cornea. A
slit-lamp examination is required to appreciate this
clinical finding, which is unique to Wilson’s disease.
Laboratory testing is required to confirm the diag-
nosis. A hallmark is a decreased ceruloplasmin level.
The actual ceruloplasmin protein is not defective in any
manner. Urinary copper excretion is elevated to more
than 100 µg/day.
Pathogenesis: The ATP7B gene is mutated in Wil-
son’s disease, and this leads to the systemic and cutane-
ous manifestations of the disease. The ATP7B gene
encodes the P-type adenosine triphosphatase (ATPase)
that serves as a metal-binding and metal-carrying Postnecrotic
protein. This P-type ATPase is primarily responsible type of cirrhosis
for the transport of copper. When it is defective, copper
builds up to abnormal levels in the liver, in the CNS,
and to a lesser extent, in the cornea. Many different
mutations have been discovered in the ATP7B gene and
are responsible for the different phenotypes seen.
Homozygous patients and compound heterozygotes
have completely different phenotypes with some over- cirrhosis. Hydropic degeneration of individual hepato- normal. CNS symptoms, if present at the time of trans-
lapping features. Certain mutations lead to liver and cytes is seen to a varying degree, depending on the plantation, typically persist with minimal improvement
CNS disease or to a predominance of one over the other. timing of the biopsy. Special staining methods can high- over time. While awaiting liver transplantation, patients
The large number of mutations and the large size of the light the elevated copper within the hepatocytes. are usually treated with a combination of a low-copper
gene make it difficult to analyze. The prevalence of the Treatment: The only cure for the disease is liver diet, oral zinc supplementation, and D-penicillamine.
different genetic mutations varies among populations. transplantation. This procedure is becoming more Zinc competes with copper for absorption and decreases
Histology: Skin biopsies are not helpful in the diag- common and has led to excellent therapeutic responses. the amount of copper absorbed from the gastrointesti-
nosis. Biopsies of the liver show varying degrees The transplanted normal liver produces adequate levels nal tract. D-Penicillamine is a copper-chelating agent
of portal inflammation and fibrosis with eventual of the P-type ATPase to bring the copper levels to that helps to lower serum and tissue copper levels.

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 223