Chapter 18 –Metabolic Liver Disease - WILSON DISEASE Flashcards
What is Wilson disease?
- autosomal recessive disorder caused by mutation of the ATP7B gene,
- resulting in impaired copper excretion into bile and a failure to incorporate copper into ceruloplasmin. [51]
- This disorder is marked by the accumulation of toxic levels of copper in many tissues and organs, principally the liver, brain, and eye.
What is the normal percentage of copper absorbed in the duodenum and proximal small intestine, and
is transported to the portal circulation complexed with albumin and histidine?
Normally, 40% to 60% of
ingested copper (2 to 5 mg/day) is
Free copper dissociates and is taken up by hepatocytes.
Copper is incorporated into enzymes and also
binds to a α2-globulin (apoceruloplasmin) to form ceruloplasmin, which is secreted into the blood. Excess copper is transported into the bile.
Ceruloplasmin accounts for 90% to 95% of
plasma copper.
Circulating ceruloplasmin is eventually desialylated, endocytosed by the liver, and degraded within lysosomes, after which the released copper is excreted into bile.
This
degradation/excretion pathway is the primary route for copper elimination.
The estimated total
body copper is only 50 to 150 mg.
Discuss the
degradation/excretion pathway which is the primary route for copper elimination.
- Ingested copper is absorbed in the duodenum and proximal small intestine, and is transported to the portal circulation complexed with albumin and histidine
- Free copper dissociates and is taken up by hepatocytes.
- Copper is incorporated into enzymes and also binds to a α2-globulin (apoceruloplasmin) to form ceruloplasmin, which is secreted into the blood.
- Excess copper is transported into the bile.
- Circulating ceruloplasmin is eventually desialylated, endocytosed by the liver, and degraded within lysosomes, after which the released copper is excreted into bile.
What accounts for 90% to 95% of
plasma copper?
Ceruloplasmin
What is the only estimated total
body copper?
50 to 150 mg.
What is ATP7B gene?
The ATP7B gene, located on chromosome 13, _encodes a transmembrane copper-transporting
ATPase_, expressed on the hepatocyte canalicular membrane.
More than 300 mutations in the
ATP7B gene have been identified, but not all genes cause the disease.
The overwhelming
majority of patients are compound heterozygotes containing different mutations on each ATP7B
allele.
The overall frequency of mutated alleles is 1 : 100, and the prevalence of the disease of
approximately 1 : 30,000 to 1 : 50,000 (approximately 9000 patients in the United States).
What is the pathogenesis of Wilson disease?
Deficiency in the ATP7B protein causes a decrease in copper transport into bile, impairs its
incorporation into ceruloplasmin, and inhibits ceruloplasmin secretion into the blood .
These changes cause copper accumulation in the liver and a decrease in circulating ceruloplasmin.
The copper causes toxic liver injury, through the production of ROS by the Fenton reaction (
Chapter 1 ).
WHat is the clinical course of Wilson disease?
Although there is a latent period of variable duration for the disease, once the hepatic capacity for incorporating copper into ceruloplasmin is exceeded, there may be sudden onset of critical systemic illness.
Specifically, non-ceruloplasmin–bound copper spills over from the liver into the circulation, causing hemolysis and pathologic changes at other sites such as the brain, corneas, kidneys, bones, joints, and parathyroids.
Concomitantly, urinary excretion of
copper markedly increases from its normal minuscule levels.
Despite the injury in the liver brought about by Wilson disease, it may also present as what disorder?
The liver often bears the brunt of injury, but the disease may also present as a neurologic disorder.
What are the hepatic changes in Wilson disease?
The hepatic changes are variable, ranging from relatively minor to massive damage.
- Fatty change (steatosis) may be mild to moderate, with vacuolated nuclei (glycogen or water) and occasionally, focal hepatocyte necrosis.
- An acute hepatitis can show features mimicking acute viral hepatitis, except possibly for the accompanying fatty change.
- The chronic hepatitis of Wilson disease exhibits moderate to severe inflammation and hepatocyte necrosis, with the particular features of macrovesicular steatosis, vacuolated hepatocellular nuclei, and Mallory bodies.
- With progression of chronic hepatitis, cirrhosis will develop.
- Massive liver necrosis is a rare manifestation that is indistinguishable from that caused by viruses or drugs.
Excess copper deposition can often be demonstrated by what?
- special stains (rhodamine stain for copper, orcein stain for copper-associated protein).
What is most helpful in the diagnosis of WIlson disease?
Because copper also accumulates in chronic obstructive cholestasis and because histology
cannot reliably distinguish Wilson disease from viral- and drug-induced hepatitis,
demonstration of hepatic copper content in excess of 250 μg per gram dry weight is most
helpful for making a diagnosis.
What toxic injury is primarily affected in the brain of WIlson disease patient?
- basal ganglia, particularly the putamen, which shows atrophy and even cavitation.
What is Kayser-Fleischer rings?
In Wilson Disease nearly all patients with neurologic involvement develop
eye lesions called Kayser-Fleischer rings, green to brown deposits of copper inDesçemet’s membrane in the limbus of the cornea.
What is the age of onset in Wilson disease?
The age at onset and the clinical presentation of Wilson disease are extremely variable
(average age is 11.4 years),but the disorder usually manifests in affected individuals between
6 and 40 years of age.
