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Wilson-Conovalov disease - Pathogenesis
Last reviewed: 06.07.2025

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Wilson-Konovalov disease is caused by a genetic defect in the synthesis of ceruloplasmin (copper oxidase) in the liver, which is related to a2-globulins. The importance of ceruloplasmin is that it keeps copper in the blood in a bound state. The body receives about 2-3 mg of copper per day with food, about half of this amount is absorbed in the intestine, enters the blood, binds to ceruloplasmin, is delivered to tissues and is included in specific apoenzymes.
Copper is involved in hematopoiesis, bone formation. A small amount of copper is found in the blood in ionized form and is excreted in the urine.
When ceruloplasmin synthesis is disrupted, the blood level of copper not associated with ceruloplasmin increases, and it begins to be deposited in organs and tissues - the liver, kidneys, brain, pancreas, etc. This is facilitated by increased absorption of copper in the intestine, which is also observed in this disease. The accumulation of copper suppresses the activity of sulfhydryl groups of oxidative enzymes, disrupts tissue respiration, glycolysis, and has a toxic effect on the brain.
Molecular genetic mechanisms
The disease is inherited in an autosomal recessive manner. Its prevalence is approximately 1:30,000, and the frequency of carriage of the defective gene is 1:90. The gene for Wilson's disease is located on the long arm of chromosome 13; it has been cloned and studied. The gene encodes copper-transporting ATPase, which binds 6 copper atoms. The location in the cell and the exact function of this carrier are unclear. It may be involved in the excretion of copper with bile or in its transfer to ceruloplasmin. Currently, more than 25 different gene mutations have been identified in Wilson's disease. Most of them lead to changes in the functional domain of ATPase rather than in the copper-binding regions. In many patients, the mutation cannot be identified. There is an assumption that with mutations leading to a violation of the functional domain, the disease manifests itself at an earlier age. In most patients, mutations on each chromosome are different, making it difficult to establish a correspondence between phenotype and genotype. The diversity of mutations makes their study in individual patients in order to establish a diagnosis inappropriate.
Haplotype analysis, which is a study of the alleles of microsatellite markers located near the defective gene on chromosome 13, played an important role in establishing the locus of this gene. However, even after the cloning of the defective gene, this analysis has not lost its significance and is used to exclude Wilson's disease in the patient's brothers and sisters or to establish their homo- or heterozygosity for the defective gene or the norm.
This is important because heterozygous carriers do not develop the disease. There is a link between the haplotype and some mutations, which can help identify new mutations.
LEC (Long-Evans Cinnamon) rats are a natural model for the study of Wilson's disease. They exhibit significant liver copper accumulation, low serum ceruloplasmin levels, and acute and later chronic hepatitis during the first few months of life. These changes can be prevented by penicillamine. The genetic defect in these inbred rats is based on a deletion of the copper-transporting ATPase gene, which is homologous to the Wilson's disease gene.
Reduced copper excretion with bile in Wilson's disease, as well as in animal experiments, leads to the accumulation of toxic amounts of copper in the liver and other tissues. Lipid peroxidation results in mitochondrial damage, which can be reduced in the experiment with vitamin E.
Normally, neonates have significantly elevated liver copper levels and decreased serum ceruloplasmin levels. In neonate guinea pigs, tissue copper levels and plasma copper-binding protein levels soon become similar to those in adults. It is unclear whether this process is related to changes in the activity of the Wilson disease gene.
Pathomorphology
Liver
The degree of changes in liver tissue can vary - from periportal fibrosis to submassive necrosis and severe large-nodular cirrhosis.
Histological examination reveals ballooning degeneration and multinucleated liver cells, glycogen accumulations, and glycogen vacuolization of hepatocyte nuclei. Fatty infiltration of hepatocytes is characteristic. Kupffer cells are usually enlarged. In some patients, these changes are particularly pronounced; Mallory bodies are detected, which resembles the morphological picture of acute alcoholic hepatitis. In some patients, changes in the liver characteristic of chronic hepatitis are observed. Histological changes in the liver in Wilson's disease are not diagnostic, but the detection of the above changes in young patients with liver cirrhosis allows one to suspect this disease.
The method of detecting copper by rubeanic acid or rhodamine staining is unreliable because copper is unevenly distributed and is absent from regenerative nodes. Copper accumulation usually occurs in periportal hepatocytes and is accompanied by the appearance of atypical lipofuscin deposits.
Electron microscopy
Even in asymptomatic cases, autophagic vacuoles and large altered mitochondria are detected. Fatty infiltration may be associated with mitochondrial damage. Infiltration of the intercellular space with collagen fibers, as well as light and dark liver cells, can be seen.
Damage to other organs
In the kidneys, fatty and hydropic changes are detected, as well as copper deposition in the proximal convoluted tubules.
The Kayser-Fleischer ring is formed by the deposition of copper-containing pigment in Descemet's membrane along the periphery of the posterior surface of the cornea.