What is Wilson-Konovalov Disease (Hepatocerebral Dystrophy)?
Wilson-Konovalov disease or hepatocerebral dystrophy or hepatolentic degeneration or Westphal-Wilson-Konovalov disease is a congenital disorder of copper metabolism, leading to severe hereditary diseases of the central nervous system and internal organs.
It is diagnosed in 5-10% of patients with cirrhosis of the liver of preschool and school age. The disease is transmitted by an autosomal recessive type, due to low or abnormal synthesis of ceruloplasmin – a protein that transports copper. The ATP7B gene, the mutations of which cause the disease, is located on chromosome 13 (segment 13q14-q21).
Hepato-cerebral dystrophy, syn .: hepato-lenticular degeneration, Westfal pseudosclerosis, Wilson-Konovalov disease is a hereditary disease characterized by a combination of liver cirrhosis with a dystrophic process in the brain (mainly in lentils).
English neurologist Wilson (S. Wilson) in 1912 described typical changes in the brain for hepato-cerebral dystrophy, established the constant presence of cirrhosis of the liver and described the clinic of a new disease, which he called progressive lenticular degeneration (from Latin lenticular).
The main symptoms of the disease were various involuntary movements in the limbs and trunk, muscular rigidity leading to stiffness, dysphagia and dysarthria, affective outbreaks, and sometimes mental disorders, but there were no signs of damage to the pyramidal pathways. Earlier, K. Westfalem (1883) and A. Strumpell (1898) described a disease which, due to its clinical similarity to multiple sclerosis, was called “pseudosclerosis”. The disease was characterized by widespread, sweeping, rhythmic involuntary movements, increased muscle tone, amimia, dysarthria and severe mental disorders up to such an intellectual disorder as dementia.
Later it turned out that progressive lenticular degeneration and pseudosclerosis are different forms of the same disease, which Gall (1921) called hepatolenticular degeneration. However, changes in the brain with it are never limited to lenticular nuclei and are often even more pronounced in other parts of the brain. Therefore, N. V. Konovalov in 1960 proposed the name “hepato-cerebral dystrophy”. He significantly expanded his understanding of the pathophysiology, pathogenesis and clinic of this disease and highlighted its new forms.
Causes of Wilson-Konovalov Disease (Hepatocerebral Dystrophy)
An autosomal recessive type of transmission is observed, the pathological gene is located in the long arm of chromosome 13. Occurs on average in a population of 3: 100,000. The prevalence is higher among ethnic groups where closely related marriages are common. More often men are ill, the average debut age is 11-25 years. For the manifestation of the disease are important exogenous effects affecting the liver – intoxication and infection.
Pathogenesis during Wilson-Konovalov Disease (Hepatocerebral Dystrophy)
In the brain, in hepatocerebral dystrophy, the lenticular nucleus, especially the shell, softens to form small cysts. Other formations are also affected: the caudate nucleus, the deep layers of the cortex, the cerebellum, in particular the dentate nuclei, the hypollar nuclei; in other parts of the brain, changes are less pronounced.
All changes are divided into angiotoxic and cytotoxic. The first are expressed in the atony of blood vessels, especially small ones, and the change in their walls. As a result, stasis occurs, common perivascular edema with anoxia of the nervous tissue and its death; hemorrhages and their traces in the form of hemosiderin accumulations are frequent.
The cytotoxic component is a common dystrophic changes in the macroglia of nerve cells, often resulting in their death. The appearance of Alzheimer’s glia, which is formed from ordinary astrocytes, is characteristic. Often there are altered nerve cells, very similar to Alzheimer’s glia; similar cells are also found in the liver and kidneys. The basis of these cellular changes is one and the same factor – a similar violation of cellular metabolism, probably of nucleic acid metabolism.
The later the disease begins, the slower it proceeds, the more diffuse changes in the brain and the more cytotoxic component prevails over the angiotoxic one. The liver due to atrophic cirrhosis is reduced and lumpy; patches of normal tissue alternate with patches of necrotic, degenerating and regenerative islets; abundant neoplasm of blood vessels leads to the appearance of anastomoses between the branches of the portal and inferior vena cava.
The main role in the pathogenesis is played by a violation of the exchange of copper, its accumulation in the nervous (especially the basal ganglia are affected), renal, hepatic tissue and cornea, as well as toxic damage to these organs by copper. Violation of metabolism is expressed in violation of the synthesis and decrease in blood concentration of ceruloplasmin. Ceruloplasmin is involved in the process of removing copper from the body. High-grade or mixed cirrhosis is formed in the liver. In the kidneys, proximal tubules are primarily affected. In the brain, the basal ganglia, the dentate nucleus of the cerebellum and the substantia nigra are affected. The deposition of copper in the Descemet’s membrane of the eye leads to the formation of a Kaiser-Fleischer ring.
Symptoms of Wilson-Konovalov Disease (Hepatocerebral Dystrophy)
Hepato-cerebral dystrophy begins in childhood or at a young age and has a chronic progressive course. In many cases, the appearance of symptoms of damage to the nervous system is preceded by visceral disorders in the form of disorders of the liver and gastrointestinal disorders (jaundice, pain in the right hypochondrium, dyspeptic phenomena). Sometimes develops pronounced hepato-lienal syndrome.
From the nervous system, extrapyramidal symptoms in the form of muscular rigidity, hyperkinesis and mental disorders come to the fore. Pyramidal symptoms may be, but more often absent. Sensitivity is usually not upset.
A typical symptom of the disease is the Kaiser-Fleischer ring – the deposition on the periphery of the cornea copper-containing greenish-brown pigment; it is more pronounced in the late forms of the disease. Sometimes there is a yellowish-brown pigmentation of the skin of the trunk and face. Hemorrhagic phenomena (bleeding of the gums, nasal bleeding, positive test of the tourniquet), marbling of the skin, acrocyanosis are frequent. Capillaroscopy detects capillary atony and stagnation of blood flow. Marked joint pain, profuse sweats, osteoporosis, brittle bones. Liver pathology is clinically detected in approximately 30% of patients, and in some cases it can only be detected by functional tests, for example, breakdown with galactose load, Quinquin breakdown, Bergman-Elbott breakdown, bromsulfofftaleiny breakdown; the amount of bilirubin in the blood and urobilin in the urine is usually increased; sedimentary reactions of Takat-Ara and Gray are altered, leukopenia, thrombocytopenia, hypochromic anemia are common.
5 forms of hepato-cerebral dystrophy:
Abdominal form – severe liver damage, leading to death before the onset of symptoms from the nervous system; children get sick. Its duration is from several months to 3-5 years.
Rigid-arrhythmohyperkinetic, or early form is characterized by a rapid course; also begins in childhood. The clinical picture is dominated by muscular rigidity, leading to contractures, poverty and slowness of movements, choreoathetoid or torsional violent movements. Dysarthria and dysphagia, convulsive laughter and crying, affective disorders and a moderate decrease in intelligence are characteristic. The disease lasts 2-3 years, ends lethal.
The trembling-rigid form is more common; begins in adolescence, flows more slowly, sometimes with remissions and sudden deterioration, accompanied by low-grade fever; characterized by the simultaneous development of severe rigidity and tremors, tremors are very rhythmic (2-8 tremors per second), sharply increased with static muscle tension, movement and excitement, at rest and in a dream disappears. Athetoid choreoform violent movements are sometimes found; dysphagia and dysarthria are also observed. The average life expectancy of about six years.
The shivering form begins at the age of 20-30 years, flows rather slowly (10-15 years and more); tremor sharply prevails, rigidity appears only at the end of the disease, and sometimes muscle hypotension is observed; Amymia, slow monotonous speech, severe changes in the psyche are noted, affective flashes are frequent. Epileptiform seizures are observed.
Extrapyramidal cortical form is less common than other forms. Typical disorders of hepato-cerebral dystrophy are further complicated by apoplectic-developing pyramidal paresis, epileptiform seizures and severe dementia (extensive softening is found in the cortex of the big hemispheres). Lasts 6-8 years, ends lethal.
Diagnosis of Wilson-Konovalov Disease (Hepatocerebral Dystrophy)
The basis of the diagnosis is the picture of the disease. The diagnosis of the disease is confirmed:
- The presence of Kaiser-Fleischer rings or his “fragments”
- Decrease in content of copper in serum below 80 mkg on 100 ml
- Reducing the concentration of ceruloplasmin below 20 mg per 100 ml
- Reducing the concentration of ceruloplasmin below 20 mg per 100 ml
For diagnosis use:
- inspection with a slit lamp (Kaiser-Fleischer green ring on the cornea at the limb)
- determining the level of ceruloplasmin (typically decreasing less than 1 µmol / l)
- determination of the level of copper in the serum (decrease less than 9.4 mmol / l)
- determination of copper in daily urine (increased more than 1.6 μmol or 50 μg per day)
Treatment of Wilson-Konovalov Disease (Hepatocerebral Dystrophy)
- Diet number 5 – with the restriction of copper to 1 mg per day – the exception of chocolate, nuts, dried fruits, crayfish, liver, whole wheat
- Diet number 5 – with the restriction of copper to 1 mg per day – the exception of chocolate, nuts, dried fruits, crayfish, liver, whole wheat
- Unithiol
- Vitamin B6
Pathogenetic treatment of hepatolenticular degeneration is aimed at increasing the removal of copper from the body. For this purpose, complexones (thiol compounds) are used. Penicillamine was the most effective. It should be taken continuously for 1.5-2 g orally daily.
Treatment with penicillamine is accompanied by a marked improvement in the condition of patients or even leads to the complete elimination of symptoms. Quite satisfactory results were obtained with the use of unitiol.
Prevention of Wilson-Konovalov Disease (Hepatocerebral Dystrophy)
Prevention is the early detection of the disease. Early diagnosis of the disease is essential for the success of therapy and the prevention of severe damage to the nervous system and liver, characteristic of the advanced stage of Wilson-Konovalov disease.