Wilson-Konovalov's disease

By the nature of the morphological changes pathology is called hepatocerebral dystrophy, according to the authors - Wilson-Konovalov's disease. Another name - hepatolenticular degeneration - specifies and complements the nature of the disease.

Modern studies have made it possible to classify the disease as a congenital metabolic disorder of copper compounds with inheritance transfer. The site of the mutating gene is responsible for it. There is no doubt a link with cirrhosis of the liver. Wilson-Konovalov's disease is characterized by early detection: signs appear in children of school age and younger.

History of the

study Since the end of the 19th century, doctors have been paying attention and describing an unclear disease that was accompanied by involuntary movements in the limbs, in the muscles of the trunk, stiffness, speech impairment, difficulty swallowing food, less often mental disorders with decreased intelligence, dementia development. It resembled multiple sclerosis, therefore it was called "pseudosclerosis."

English doctor neurologist S. Wilson in 1912 for the first time linked the symptoms of the disease with the mandatory presence of cirrhotic changes in the liver, revealed the relationship with the lesion of the lancial nuclei of the brain.

At the same time noted the absence of changes in the pyramidal tract of patients( the so-called group of nuclei and human nerve pathways responsible for movement).A significant contribution to the research on this topic was made by the Russian scientist Academician N.V.Konovalov.

What is known about prevalence?

Statistics show that Wilson-Konovalov's disease is detected in three people per 100,000 population. The indicator is higher in those countries where closely related marriages are possible. According to some authors, men are more likely to get sick, others say that both men and women are equally susceptible.

In families with carriers of the pathological genome, 25% of brothers and sisters fall ill. In this case, parents can be clinically healthy. Symptoms begin to appear on average from 11 to 25 years.

How is the disease inherited?

The type of inheritance of an abnormal disease gene is called autosomal recessive. This means that only children who have received two mutant genes( from mother and father) can get sick. Parents are homozygous carriers.

If a child receives a gene from only one parent, then he does not get sick, but becomes a heterozygous carrier. It may have deviations in the exchange of copper, but weakly expressed. How great is the third generation, depends on the encounter with the similarly altered chromosome structure of the wife or husband.

The disease gene ATP7B is known; it provides the synthesis of the copper transporting protein( ceruloplasmin).It is located on the long shoulder in chromosome 13, on the site with code 13q14-q21.

Mutations associated with the replacement of the amino acid inclusion sequence

Different mutations have been detected in patients in China and Western countries. The causes of violations remain unclear. In 10% of the patients there were no gene changes at all. It was found that in the manifestation of the disease important factors belong to the factors that affect the liver. These include the transferred infectious diseases( viral hepatitis), intoxication.

The role of copper in normal and with hepatolenticular degeneration

A healthy person gets 2 mg of copper daily from food, only 1/3 of them are absorbed, but this is enough to meet the body's needs.

Copper is needed by the liver:

• for the synthesis of proteins and enzymes, which means for growth, physical and mental development;
• formation of hemoglobin, iron transport;
• synthesis of erythrocytes and leukocytes;
• providing elasticity of the walls of the vessels due to participation in the synthesis of collagen;
• stimulation of the hormonal activity of the pituitary and insulin;
• production of immunity cells;
• the formation of antioxidants, preventing early aging.

When they enter the small intestine into the blood, copper molecules are delivered to the hepatic cells via the portal vein. Here, the part binds to the ceruloplasmin protein and returns to the bloodstream, the other( superfluous) - passes into the bile and is removed from the body. One molecule of ceruloplasmin contains 8 copper atoms.

In the pathogenesis of the Wilson-Konovalov disease, both functions are violated. Ceruloplasmin is destroyed. The patient's blood is overflowed with a significant amount of unbound copper. It is deposited in different organs: in the liver, brain, kidneys, the cornea of ​​the eyes, passes into the urine.

In hepatocytes of the liver, as a response to the introduction of copper, inflammation is formed, which translates into nodular cirrhosis. In the kidney tissue, the proximal tubules suffer. Damage to the brain is expressed in the defeat of the basal ganglia, the nuclei of the cerebellum and the black substance.

In the eye tissues, copper is deposited around the cornea and forms a visible Kaiser-Fleischer ring. The predominant deposition of copper in one of the organs depends on the age. Typically, children suffer from liver damage. After 20 years, major disruptions are localized in the brain.

What changes in the brain cause symptoms of the disease?

Hepatocerebral dystrophy causes softening of several nuclear formations( lenticular, caudate, dentate, podbugornye), cerebellum, deep layers of the cortical layer in the brain tissues. They form small cysts.

Characteristic toxic changes distinguish:

• vascular - atony of small vessels contributes to stagnant blood, edema of surrounding tissue, cell death, haemorrhages with the release of hemosiderin;
• cellular - dystrophy undergoes macroglial neurons, possibly forming Alzheimer's glia, with time cells die.

It is established that cell disorders are more common in the late onset of illness and slow flow. In the liver, the atrophic process leads to the death of hepatocytes, whole lobules with the formation of necrotic nodes. Between them remain pockets of recovery, normal cells.

New vessels form which form the connections between the branches of the portal vein of the liver and the channel of the inferior cavity

How does the disease manifest itself?

For hepatocerebral dystrophy is characterized by initiation in childhood or up to 25 years, further development takes a chronic course with the progression of clinical manifestations. Often before the appearance of neurological symptoms of Wilson-Konovalov's disease, disorders of the functions of the liver and intestine are detected.

Patients experience dull pain in the right upper quadrant, jaundice, diarrhea, or constipation. Less developed hepatolyenal syndrome. Among the neurological signs:

• hyperkinesis( involuntary movements in the arms and legs, tremor), are similar to the killing;
• muscle spasms( stiffness) and convulsions;
• paralysis;
• epileptiform seizures;
• broken speech;
• drooling;
• behavior disorder, psyche.

Among other symptoms of the disease, indicating the defeat of internal organs:

• Kaiser-Fleischer ring - greenish copper deposits around the circumference of the cornea, appear at a late stage of the disease;
• pigmented spots on the skin of the face and trunk of a yellowish-brown color;
• signs of hemorrhagic disorders - frequent nasal bleeding, gum bleeding, marble skin tone, cyanotic lips, fingers;
• joint pain;
• increased brittleness of bone, fractures due to osteoporosis;
• profuse release of sweat.

Symptoms of pathological disorders in the liver are detected in 1/3 of the cases, more often they can be found in blood tests for an increase in the level of transaminases, bilirubin, a drop in platelets and leukocytes, and hemolytic anemia. The liver is significantly enlarged.

Clinical examinations confirm active hepatitis with transition to cirrhosis

Course and forms of the disease

According to the nature of the disease, acute and chronic forms are distinguished. Acute - typical for early childhood, is characterized by lightning development, rapid lethal outcome even in treatment. The chronic form - proceeds slowly with gradual weighting of a neurologic symptomatology.

Depending on the prevailing organ damage, it is common to distinguish five varieties of the disease. Asthmatic-rigid - occurs most often, begins in adolescence, proceeds slowly with remissions and exacerbations.

The condition deteriorates suddenly, the body temperature rises slightly, a combination of muscle rigidity and rhythmic trembling twitches of 2-8 movements per second is determined in the hands. Manifestations intensify with muscle tension, excitement, and in a calm state, in a dream disappear.

Throbbing - occurs by the age of 20, differs by a slow flow. In the clinic, hand trembling prevails. Muscle rigidity appears many years later. Typical loss of facial expressions, slow speech without emotion, sometimes a decrease in muscle tone. The human psyche is severely affected, outbreaks of aggression, epileptiform seizures are possible. Lifespan of patients up to 15 years and over.

Abdominal - the most severe variant of the Wilson-Konovalov disease in children. The defeat of the liver with severe deficiency leads to an early death. Neurological symptoms do not have time to develop. The duration of the disease does not exceed 5 years, the child can die in a few months.

Rigid-arrhythmo-hyperkinetic - another name - early form. It begins in childhood, characterized by a rapidly progressing course. The clinic manifests a significant muscle rigidity with persistent contractures, slowness and difficulty of movement, impaired speech and swallowing, frequent choreoathetoid movements. Intellect decreases moderately. The disease lasts for two to three years before the child dies.

Patients with convulsive crying or laughter

Extrapyramidal-cortical is a rare form of the disease course. Characteristic signs include paresis and paralysis, severe seizures of epilepsy, and the development of complete dementia. In the cerebral cortex of the brain, extensive foci of softening are formed. The average duration is 6-8 years. The death is unavoidable.

The earliest mortality in children with an abdominal form. In half of cases of the disease there is massive liver necrosis, hemolytic disorders, gastrointestinal bleeding( the effects of portal hypertension).From neurological changes, patients without treatment die after 5-15 years.

Diagnosis

Diagnosis is made on the basis of clinical symptoms, information about the incidence in the families of parents, the conclusion of genetic studies. In specialized neurological departments, the following is checked:

• the amount of copper in the blood serum;
• the concentration of ceruloplasmin( both in the disease decline);
• release of copper in urine( growing);
• an ophthalmologist examines the Kaiser-Fleischer rings using a slit lamp, sometimes "debris" is found instead of a full ring.

In the photo of the slit lamp, a greenish ring is clearly visible, it is not present in all

patients. Biochemical liver samples, transaminase, alkaline phosphatase, bilirubin, thymol test, change of protein fractions, revealing reduced coagulability values ​​are important.

For a general blood test, typical reduction of red blood cells and platelets, leukopenia. Renal tubular changes are manifested by the detection in the urine of glucose, salts of phosphoric acid, urates, protein.

Computer and magnetic resonance tomography of the skull reveals brain changes until the appearance of characteristic neurological symptoms: enlargement( expansion) of the ventricles, focal disturbances in the thalamus, shell and pallid sphere. In difficult cases, a liver biopsy is performed, the content of copper in the hepatocytes is determined.

DNA markers are used for genetic studies of Wilson-Konovalov disease, which have high accuracy. In differential diagnosis, it is taken into account that ceruloplasmin decreases with hepatitis, suffering from hunger.

Treatment options for

The indicated life expectancy of patients at the modern level of medicine can be significantly increased by early treatment of Wilson-Konovalov's disease and use of all possible means.

The patient should be fed according to the diet table No.5a( for liver diseases).It excludes all spicy dishes, fried and fatty. At the same time, to restrict the supply of copper from food, categorically prohibited: products and natural products containing chocolate, nuts, coffee, liver meat, crayfish and squid, dried fruits, legumes, whole wheat cereals.

The main direction is to ensure the withdrawal of surplus copper. The main drug is D-penicillamine. The drug is prescribed with a small dose of the scheme, then it increases. It is necessary to consider lifelong reception of a medicine and its negative properties.

Specialists pay attention to the low quality of domestic Penicillamine, its toxicity. In some patients with hepatolenticular degeneration, side effects include dermatitis, anemia.

The drug forms complexes with copper, which pass into the urine and are excreted from the body, in addition, it is able to suppress the activity of intracellular copper.

Another direction is therapy with zinc salts( sulfate, oxide).The use of combinations of D-penicillamine with zinc drugs allows for low-dose therapy and avoiding negative consequences. If the disease is detected before the onset of clinical manifestations, then only zinc preparations are recommended. An addition is the use of Unithiol.

The patient is prescribed hepatoprotective agents: vitamins, Essentiale. To support conduction in nerve fibers, vitamins of group B are needed. A method of bio-hemoperfusion of blood with living isolated cells of the liver and spleen is proposed. The technique is called "auxiliary liver".

It is performed in specialized centers with unsuccessful therapy to support the patient's body before the operation of liver transplantation. Transplanting a healthy donor liver helps to solve a variety of treatment problems.

The operation itself requires the preparation of a patient, taking into account the risks associated with reduced coagulability of blood. This is the most radical method of treating forms of the disease with predominant liver damage.

Magnetic resonance examination is used in the control of treatment

The effectiveness of treatment is significantly improved with early diagnosis. It is possible to achieve a decrease in manifestations. Patients remain socially adapted people: they are able to fully self-service, study, work by profession, create a family. There are observations of young women with Wilson-Konovalov's disease who endured pregnancy and gave birth to healthy children.

Once the effect of treating a disease depends on early detection and onset, then families with a child with hepatolenticular degeneration should examine his brothers and sisters using modern molecular genetic techniques. Knowing the future parents about their carrier will prevent the birth of a sick baby.