DEFINITION
Wilson’s disease is an autosomal recessive disorder of copper metabolism, characterized by deposition of this metal in the liver, brain, cornea and other organs. The overload of copper leads to progressive liver and neurological disfunction.
EPIDEMIOLOGY
It’s a rare disease: in Western populations the incidence is around 1 in 30000 individuals, with a male preponderance. A higher prevalence seems to exist in Sardinia, where approximately 10-12 new cases per year are identified.
SYMPTOMS
Mutations that completely destroy gene function are associated with symptoms as early as 5 years of age, mild mutations can manifest themselves as late as 50 years of age. Presentation before 5 years is extremely rare, despite the biochemical defect being present at birth.
Hepatic dysfunction may precede neurologic dysfunction by several years.
Some patients present with fulminant liver failure, but the most common manifastation is chronic active hepatitis, culminating in cirrhosis. Rarely it evolves in hepatocellular carcinoma.
Neurologic and psychiatric symptoms are early dementia, mood disorders or psychosis. Deposition of copper in the basal ganglia (particularly in putamen and globus pallidus) leads to cells death and present with parkinsonism, including ataxia, dyskinesia, tremor and rigidity.
Adjuntive features are
-renale: renal tubular acidosis, kidney store
-ophtalmic: Kaiser-Fleisher rings (brown rings around cornea resulting from copper deposition in Descemet’s membrane), sunflower cataracts
-cardiac: cardiomyopathy, cardiac arrythmias
-dermal: hidradenitis suppurativa
-in severe cases is usually present hemolysis
DIAGNOSIS
- plasma ceruloplasmin levels are less than 30% of normal
- liver biopsy: the concentration of hepatic copper may reach 20 times normal levels
- ncrement in copper levels in urine
- eye exam, to detect Kaiser-Fleisher rings or cataracts
- Brain MRI and CT
PATHOGENESIS
ATP7B, the Wilson's disease gene, is on chromosome 13 and it codes for a protein called copper-transporting ATPase 2 , a new member of the cation-transporting p-type ATPase family.
ATP7B is mainly expressed in the liver, but also in kidney, placenta, heart, brain and lungs.
It mediates both copper secretion into plasma and its excretion into bile.
Within liver cells, copper-transporting ATPase 2 is found in Golgi apparatus, where it supplies copper to a protein called ceruloplasmin which transports it in the blood to other parts of the body. An increase in the intracellular copper level causes ATP7B to move to a cytoplasmic vesicular compartment. As the copper is concentrated into vesicles for excretion from the cell trought the bile, the cytosolic copper concentration decreases and ATP7B returns to the trans-Golgi network
Copper-transporting ATPase2 is a protein with 14 domains:6 copper binding,4 transmembrane, 1 phosphatase, 1 transduction, 1 phosphorilation and 1 ATP binding.
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All copper-transporting ATPases have a histidine residue in the large cytoplasmic loop, adjacent to the ATP-binding domain. The histidine residue is essential for function, and it is the most common mutation in Wilson disease. But several mutations of this gene have been described, causing impairment of its function and, ultimately, copper accumulation.
There is evidence that ceruloplasmin, a copper protein wich oxidizes ferrous iron for subsequent transfer to plasma apotransferrin, plays an important role in its metabolism. Because most patients with Wilson's disease have hypoceruloplasminemia, some could be affected by iron overload.
The excess copper acts as a promoter of free radical formation and causes oxidation of lipids and proteins. In the earliest stages of hepatocellular injury, abnormalities involving the endoplasmic reticulum, mitochondria, peroxisomes, and nuclei have been identified. Initially, the excess copper is stored in the liver and causes damage to the hepatocytes, maybe through activation of acid sphingomyelinase (Asm) and release of ceramide.
Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide. Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
Eventually, as liver copper levels increase, it is released into the circulation and deposited in other organs, including the basal ganglia and the limbus of the cornea.
Some studies were undertaken to understand the relationship between liver copper accumulation and plasma lipid profile, circulating lipoprotein composition, hepatic sterol meabolism and biliary lipid secretion rates. In rats with a genetic defect in ATP7B gene and with the subsequent hepatic copper deposition, it was observed an increase in triglycerides, free cholesterol and cholesterol ester in the liver. Hepatic concentration of an index of lipidic peroxidation (malondialdehide) was also elevated, while microsomal apo B100 and microsomal triglyceride transfer protein were altered.
Hepatic steatosi was associated with hypotriglyceridemia, hipocholesterolemia and abnormalities in both circulating lipoprotein composition and size.
Abnormal hepatobiliary and circulating lipid metabolism in Wilson's disease
Lipid metabolism and cell cycle machinery in Wilson's disease
PATIENT RISK FACTORS
Genetic
TREATMENT
-Zinc acetate, which blocks the absorption of copper in the intestinal tract
-Trientine, which chelates the copper and leads to increased realesed through the urine
-Penicillamine, which also binds copper and leads to increased urinary release of copper (but it can worsen neurological function).
-low copper diet
-In cases where the liver is severely damaged by the disease, liver transplantation might be considered by healthcare providers
