Wilson-Konovalov disease: pathogenesis

With Wilson-Konovalov's disease, there is a genetic defect in the synthesis of ceruloplasmin (copper-oxidase) in the liver, related to a2-globulins. The meaning of ceruloplasmin lies in the fact that it keeps copper in the blood in a bound state. With food, the body receives about 2-3 mg of copper per day in the intestine, about half of this amount is absorbed, enters the blood, binds to ceruloplasmin, is delivered to the tissues and is incorporated into specific apoenzymes.

Copper is involved in hematopoiesis, bone formation. A small amount of copper is in the blood in ionized form and excreted in the urine.

If there is a violation of the synthesis of ceruloplasmin, the content of copper not connected with ceruloplasmin increases in the blood and it begins to be deposited in organs and tissues - liver, kidneys, brain, pancreas, etc. This is facilitated by an increase in copper absorption in the intestine, which is also observed in this disease . 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 by autosomal recessive type. Its prevalence is approximately 1:30 000, and the frequency of carriage of the defective gene is 1:90. The Wilson disease gene is located on the long arm of chromosome 13, it is cloned and studied. The gene encodes a copper-transferring ATPase, to which 6 copper atoms bind. The location in the cell and the exact function of this vector are unclear. Perhaps he is involved in the excretion of copper with bile or in transferring it to ceruloplasmin. Currently, with Wilson's disease, more than 25 different mutations of the gene have been identified. Most of them lead to changes in the functional domain of ATPase rather than in areas connecting copper. In many patients, the mutation can not be identified. There is an assumption that with mutations leading to a functional domain, the disease manifests itself at an earlier age. In most patients, the mutations on each chromosome are different, which makes it difficult to establish a correspondence between the phenotype and the genotype. The variety of mutations makes their study in separate patients with the aim of establishing a diagnosis impractical.

Haplotype analysis, which is the study of 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 cloning the defective gene, this analysis has not lost its significance and is used to exclude Wilson's disease in the brothers and sisters of the patient or to establish their homo- or heterozygosity by a defective gene or norm.

This is important, because the disease does not develop in heterozygous carriers. There is a link between the haplotype and some mutations, which can help in identifying new mutations.

LEC line rats (Long-Evans Cinnamon) are a natural model for studying Wilson's disease. They have during the first few months of life a significant accumulation of copper in the liver, a low level of ceruloplasmin in the serum and the development of acute and, later, chronic hepatitis. These changes can be prevented by administration of penicillamine. The genetic defect in these inbred rats is based on the deletion of the copper transfer gene ATPase, which is homologous to the Wilson disease gene.

Reducing the excretion of copper with bile in Wilson's disease, as well as in an experiment on animals, leads to the accumulation of toxic amounts of copper in the liver and in other tissues. As a result of lipid peroxidation, damage to the mitochondria occurs, which in the experiment can be reduced with the help of vitamin E.

Normally, newborns significantly increased the copper content in the liver and reduced the level of ceruloplasmin in the serum. In newborn guinea pigs, the copper content in the tissues and the level of copper-binding protein in the plasma soon become the same as in adult individuals. It remains unclear whether this process is associated with a change in the activity of the Wilson disease gene.

Pathomorphology

Liver

The degree of changes in liver tissue can be different - from periportal fibrosis to submissive necrosis and severe coarse nodular cirrhosis.

Histological examination reveals balloon dystrophy and polynuclear liver cells, glycogen accumulations and glycogen vacuolation of hepatocyte nuclei. Characteristic fatty infiltration of hepatocytes. Kuffffer cells are usually enlarged in size. In some patients, these changes are particularly pronounced; the Mallory calf is revealed, which resembles the morphological picture of acute alcoholic hepatitis. Some of the patients experience changes in the liver that are characteristic of chronic hepatitis. Histological changes in the liver with Wilson's disease are not diagnostic, however, the detection of the changes described above in young patients with cirrhosis of the liver can be suspected of this disease.

The method of detecting copper by staining with rubaic acid or rhodamine is unreliable, since copper is distributed unevenly and there is no regeneration at the sites. Accumulation of copper usually occurs in periportal hepatocytes and is accompanied by the appearance of atypical deposits of lipofuscin.

Electron microscopy

Even in the asymptomatic course of the disease, autophagic vacuoles and large altered mitochondria are revealed. Fat infiltration can be associated with damage to the mitochondria. You can see the infiltration of the intercellular space with collagen fibers, as well as light and dark cells of the liver.

The defeat of other organs

In the kidneys, fatty and hydropic changes are detected, copper deposition in the proximal convoluted tubules.

The Kaiser-Fleischer ring is formed by depositing a copper-containing pigment in the descemet shell around the periphery of the posterior surface of the cornea.