Hepatocerebral dystrophy

Hepatocerebral dystrophy( Wilson-Konovalov's disease) is a disease that develops as a result of excessive accumulation in the body and toxic effects of copper. This pathology is characterized by a combined defeat of internal organs, primarily the liver and brain. Wilson-Konovalov's disease is transmitted according to the autosomal recessive type of inheritance.

The incidence of Wilson-Konovalov disease in the population is 1 to 3 cases per 100 000 population. The disease has uneven geographical and ethnic distribution. More often it occurs in Japan, Italy, India.

The disease is caused by mutations in the 13th chromosome. Due to a genetic defect, the functioning of the system that carries copper transport in the liver cells and the removal of excess copper from bile, as well as its inclusion in the molecule of the protein ceruloplasmin, is disrupted. This leads to an increase in the concentration of "free" copper( not associated with ceruloplasmin) in the blood, its accumulation in various tissues and organs, especially in the liver, brain, kidneys, eyesight, red blood cells, and the development of chronic copper intoxication.

Dystrophic and necrotic changes occur in the liver cells, chronic hepatitis( hepatosis) is formed, followed by a transition to cirrhosis of the liver. Dystrophic changes develop in the kidneys. The brain is damaged nerve cells and blood vessels. The defeat of small vessels and capillaries of the brain leads to insufficient supply of oxygen and nutrients( ischemia) to the brain tissue and destruction( necrosis) with the formation of multiple small cysts( rounded cavities filled with inflammatory fluid) and wrinkling of the brain.

The first signs of the disease occur on 1-3 decades of life.

Three main stages are distinguished during the course of the disease.

Pre-symptomatic stage. There are no manifestations of the disease at this stage, however, when carrying out special laboratory methods of investigation, characteristic metabolic disorders are determined. The most reliable and accurate method for detecting a genetic mutation in the presymptomatic stage is molecular-genetic testing. Identification of individuals homozygous for a mutant gene is necessary primarily among close relatives of a known sick person and is carried out for preventive treatment to prevent disease. Such activities are referred to as secondary, or postnatal prophylaxis.

Visceral( or prenirologic) stage. Characteristics characteristic of this stage, first appear in 1 - 2 decades of life. Their appearance is associated with a variety of violations by internal organs. Excess accumulation of copper in the liver leads to the development of chronic hepatitis( hepatosis) and cirrhosis. The defeat of red blood cells leads to their excessive destruction and the development of anemia. Such changes on the part of the blood are more often observed in childhood. Kidney damage can manifest itself in the form of impurity of blood, the appearance of excessive amounts of protein, leukocytes, there may also be a decrease or increase in the amount of daily urine. In the end, all these changes result in the development of chronic renal failure. The defeat of the heart and joints is expressed in the appearance of pain syndrome. Also, the endocrine system undergoes pathological changes, which is manifested by the underdevelopment of the genital organs and glands, and menstrual flow stops in women. Disorders of internal organs do not have any specific signs, and therefore Wilson-Konovalov's disease at this stage, as a rule, remains unrecognized. Hepatitis can be acute under the guise of infectious hepatitis, more often it develops secretly until the formation of cirrhosis and its complications( portal hypertension, enlarged spleen, hepatic coma).In this case, hepatitis occurs without jaundice and characteristic laboratory signs. However, in this case, a low level of ceruloplasmin protein is detected, which does not occur with hepatitis and liver cirrhosis of another origin. Sometimes hepatitis in childhood and juvenile( youth) age acquires fulminant( fulminant) course with rapid development of hepatic insufficiency and lethal outcome. The variant of the Wilson-Konovalov disease, which proceeds with the primary lesion of the liver, is attributed by NV Konovalov to the abdominal( "abdominal") form. As a result of a violation of the function of the liver, the formation of substances contributing to the coagulation of blood decreases in it. As a result, pathological changes occur on the part of the blood, which is accompanied by an increase in the permeability of the capillaries and leads to the formation of a hemorrhagic syndrome. Hemorrhagic syndrome is characterized by increased bleeding gums, frequent nasal bleeding, groundless( spontaneous) formation of multiple bruises.

The neurological stage of is characterized by the fact that the disorders of the nervous system( brain) come to the fore in the form of a combination of the three main symptom complexes:

1) the extrapyramidal symptom complex is represented by two different variants:

a) the akinetic-rigid syndrome is characterized by an increase in the volume and number of involuntary movements, which are irregular;also this syndrome can be manifested by trembling of the extremities( tremor);

b) widespread large-amplitude jitter( against a background of reduced or unchanged muscle tone).The trembling is more pronounced in the hands and resembles the "waving of the wings of a bird", it can grow with any attempt of active movement to the degree of a motor storm;

2) pseudobulbar symptom complex is manifested by a disorder of voice, speech, swallowing, the appearance on the face of a forced smile or involuntary crying;

3) psycho-organic syndrome with the disorder of intellect, memory, speech, thinking, disturbance of the emotional sphere and behavior. In addition, there may be psychotic episodes.

According to NV Konovalov, the following forms of the disease are distinguished:

1) rigidly-arrhythmo-hyperkinetic( the first manifestations occur in 7-15 years);

2) rigid-trembling( the first manifestations occur in 15-25 years);

3) trembling( the first manifestations occur in 20-25 years and later);

4) extrapyramidal-cortical( can develop in any of the forms of the disease with the adherence to it of paralysis of one half of the body, epileptic seizures and rapidly progressing mental disorders).

The diagnosis of Wilson-Konovalov's disease is fully confirmed if the following characteristics are present in the person:

1) autosomal recessive type of disease transmission, which is determined when conducting a family survey in genetic centers;

2) appearance of the first signs of the disease in 1-3 decades of life;

3) simultaneous defeat of many organs and systems;

4) appearance of signs of chronic hepatitis( hepatosis) and cirrhosis of the liver;

5) extrapyramidal disorders( increase in the volume and number of involuntary movements that are irregular, widespread large-amplitude jittering against a background of reduced or unchanged muscle tone) in combination with mental disorders;

6) decrease in the content, in the blood of the ceruloplasmin protein, urinary excretion of a large amount of copper, an increase in the concentration of copper in the liver tissue( determined by the biopsy method, that is, the lifelong taking of a piece of organ tissue followed by its examination);

7) continuously progressing course of the disease;

8) positive results in DNA testing.

Treatment. During the life of a person suffering from Wilson-Konovalov's disease, it is necessary to carry out treatment with drugs that remove copper from the body. The main drug with this effect is D-penicillamine( kurenyl, metalcapase, artamine, etc.).Treatment begins with taking 1 capsule( 0.15 or 0.25 g) daily or every other day with a gradual increase in the dose every 1-2 weeks for 1 capsule. Such an increase in the dose should be carried out before reaching a daily dose of 1-1.5 g. Later, after 1-2 years, go to supportive treatment. In this case, the daily dose of the drug should be 0.45-1 g. In 1982, for the treatment of Wilson-Konovalov's disease, a less toxic drug was extracted that removes copper from the body-trientine. The recommended dose for the treatment of this disease is 400-800 mg 3 times a day. Tetrathiomolybdate is a new promising tool. Zinc preparations( zinc sulfate, zinc acetate) are taken every 4 hours between meals and at bedtime. These medicines reduce the absorption of copper, are somewhat weaker and slower, but have less toxicity and are recommended in the initial stages of the disease, as well as for preventive treatment in the initial stage of the disease. Persons with Wilson-Konovalov's disease should follow a diet that spares the liver. This diet should exclude products rich in copper( legumes, mushrooms, nuts, chocolate, liver, shrimp).In addition, regular courses of vitamin therapy are a prerequisite for achieving positive results. In this case, vitamins of group B, especially B6, vitamin E, ascorbic acid should be used. A good effect is the preparation Essentiale. In severe disease with signs of liver failure, a liver transplant is performed.