GEPATO-TSEREBRALNAYA DYSTROPHY (grech, hepar, hepat[os] liver + lat. cerebrum brain; dystrophy; synonym: hepatolenticular degeneration, Vestfal's pseudosclerosis, Wilson's disease — Konovalova) — the hereditary disease which is characterized by a combination of cirrhosis to dystrophic process in a brain (it is preferential in lentil kernels). The English neurologist S. Wilson in 1912 described typical for G. - c. anatomic changes in a brain, established constant existence of cirrhosis and gave the description of clinic of the new disease called by it a progressive lentikulyarny degeneration (Latin of lenticularis lenticular).
As the main symptoms of a disease the various involuntary movements in extremities and a trunk, the muscular rigidity resulting in constraint a dysphagy and a dysarthtia, affective flashes, sometimes mental disorders were noted, signs of defeat of pyramidal ways were absent. Even earlier K. Vestfal (1883) and A. Shtryumpell (1898) described a disease, a cut on clinical looking alike multiple sclerosis received the name «pseudosclerosis». The disease was characterized by the widespread, wide, rhythmical involuntary movements, increase in a muscle tone, an amimia, a dysarthtia and the expressed mental disturbances up to weak-mindedness. Further it turned out that the progressive lentikulyarny degeneration and a pseudosclerosis are different forms of the same disease, a cut Gall (N. S. of Hall, 1921) called a hepatolenticular degeneration; this name often meets in modern literature. However changes in a brain at it are never limited to lentikulyarny kernels and quite often are even stronger are expressed in other departments of a brain. Therefore N. V. Konovalov in 1960 offered the name «hepatocerebral dystrophy». It considerably expanded ideas of a pathophysiology, a pathogeny and clinic of this disease and allocated its new forms. The clinical form described by Wilson corresponds in general to the second and third forms of Konovalov, and a pseudosclerosis — the fourth form.
G. - c. — the hereditary disease inherited on autosomal recessively type; family and sporadic cases meet approximately equally often. For display of a disease the exogenous influences affecting a liver — intoxications and infections matter. Both floors get sick equally often.
In a brain at G. - c. is noted a softening of lentil kernels, especially shells, with formation of small cysts and wrinkling (fig. 1). Also other educations are surprised: body having a tail, deep layers of bark, gear kernels of a cerebellum, podbugorny kernels; other departments of a brain of change are expressed less. All changes share on angiotoksichesky and cytotoxic (N. V. Konovalov). The first are expressed in an atony of vessels, especially small, and change of their walls. Staza, widespread perivascular hypostasis with an anoxia of nervous tissue and its death result; hemorrhages and their traces in the form of accumulations of hemosiderin are frequent. The cytotoxic component consists in the widespread dystrophic changes of a macroglia and nervous cells which are often coming to an end with their death. Emergence of a glia of Alzheimer is characteristic, edges it is formed of usual astrocytes (tsvetn. fig. 8 — 10); cells with very big body (the first type — fig. 2) and the large deprived naked cytoplasms of a kernel (the second type — fig. 3). Quite often the changed nervous cells very similar to Alzheimer's glia meet; similar cells are found also in a liver and kidneys. These cellular changes the same factor — the same disturbance of cellular exchange probably is the cornerstone of exchange nucleinic to - t. The later the disease begins, the more slowly it flows, especially diffuzna of change in a brain and the more so the cytotoxic component prevails over angiotoksichesky. The liver owing to atrophic cirrhosis is reduced and hilly (fig. 4); sites of normal fabric alternate with sites necrotic, degenerating and with islands of regeneration; the plentiful new growth of vessels leads to emergence of an anastomosis between branches of a portal and lower vena cava.
the Main role in G.'s pathogeny - c. play genetically caused disturbances of exchange of proteins and copper. Disturbance of protein synthesis conducts to a hyper aminoaciduria (see. Aminoatsiduriya ) and hypoproteinemias (see. Proteinemia ); also exchange of nucleoproteids suffers. Reduction of ceruloplasmin — the protein containing copper and having enzymatic properties of an oxidase is of especially great importance (see. Blood , biochemistry). As a result copper is only rykhlo connected with albumine and amino acids of blood, is easily chipped off from them, in a large number is emitted with urine (giperkupruriya) and laid in fabrics, hl. obr. in a liver, a brain (subcrustal nodes) and a cornea. Excess of free copper oppresses activity of oxidizing and some other enzymes that leads to death of cells. Damage of a liver with disintegration of its fabric and decrease in barrier function conducts to an endointoxication the products of a gepatoliz and alien products arriving from intestines (in particular, containing ammonia). As a result of formation of histamine-like and other substances of angiotoksichesky action there come the heavy circulatory disturbances strengthening the available fabric hypoxia. Thereof death of fabric is noted first of all in places where oxygen requirement is especially big, i.e. in a brain, especially in lentil kernels and bark of big hemispheres. Besides, also the cytotoxic substances operating directly on elements of nervous tissue are formed.
A clinical picture
G. - c. begins at children's or young age and has hron, the progressing current. In many cases emergence of symptoms of defeat of a nervous system is preceded by visceral frustration in the form of disturbance of activity of a liver and went. - kish. frustration (jaundice, pains in right hypochondrium, the dispeptic phenomena). Sometimes expressed develops hepatolienal syndrome (see). The stronger the liver suffers, the earlier begins and quicker the disease flows.
From a nervous system into the forefront Extrapyramidal symptoms in the form of muscular rigidity, hyperkinesias (fig. 5) and frustration of mentality act. Pyramidal symptoms can be, but are absent more often. Sensitivity is usually not upset.
Typical symptom of a disease is Kayser's ring — Fleischer — adjournment on the periphery of a cornea of the greenish-brown pigment containing copper (tsvetn. fig. 7); it is more expressed at late forms of a disease. The yellowish-brown xanthopathy of a trunk and person is sometimes noted. The hemorrhagic phenomena (bleeding of gums, nasal bleedings, positive test of a plait), a mramornost of skin, a Crocq's disease are frequent. Kapillyaroskopiya (see) finds an atony of capillaries and a zastoynost of a blood-groove. Joint pains, profuse sweats, osteoporosis, fragility of bones are noted.
Pathology of a liver clinically comes to light approximately at 30% of patients, and in some cases it can be found only by functional trials, napr, test with loading a galactose, a one-stage prothrombin time test, Bergmann's test — Eylbotta, bromsulfoftaleinovy test; the amount of bilirubin in blood and urobilin in urine is usually increased; sedimentary reactions of Takat — Ara and Gray are changed, the leukopenia and thrombocytopenia, hypochromia anemia are usual (see. Bromsulfoftaleinovaya test , Kvika-Pytelya test , Coagulative tests , Liver, methods of a research ).
N. V. Konovalov allocates the following five forms G. - c.
Belly form — the severe damage of a liver leading to death before emergence of symptoms from a nervous system; children get sick. Its duration from several months to 3 — 5 years.
Rigid aritmogiperkineticheskaya, or early, form differs in a rapid current; begins also at children's age. In a clinical picture the muscular rigidity leading to contractures, poverty and slowness of movements, the choreoathetoid or torsion violent movements prevails; the face amimichno, is often distorted by the stiffened grimace (fig. 5). The dysarthtia and a dysphagy, convulsive laughter and crying are characteristic, epileptiform attacks, affective frustration and moderate decrease in intelligence are frequent. The disease lasts 2 — 3 years, comes to an end letalno.
Trembling and rigid form meets more often others; begins at youthful age, flows slightly more slowly, sometimes with the remissions and sudden deteriorations which are followed by subfebrile temperature; trembling very typical is characterized by simultaneous development of heavy rigidity and trembling: wide rhythmical (2 — 8 tremblings in 1 sec.), sharply amplifies at a static stress of muscles, the movements and nervousness, at rest and in a dream disappears, takes both extremities, and the head and a trunk. Sometimes the atetoidny and choreiform violent movements are found; also the dysphagy and a dysarthtia are observed. Average life expectancy apprx. 6 years.
Trembling form begins at the age of 20 — 30 years, flows quite slowly (10 — 15 years and more); trembling sharply prevails, rigidity appears only at the end of a disease, and at times hypotonia of muscles is observed; the amimia, a slow plateau speech, heavy changes of mentality are noted, affective flashes are frequent. Epileptiform attacks are observed.
Extrapyramidal and cortical form meets less often than other forms. Typical for G. - c. Extrapyramidal disturbances are complicated further apoplektiformno by the developing pyramidal paresis, epileptiform attacks and heavy weak-mindedness (extensive softenings in bark of big hemispheres are found). 6 — 8 years last, comes to an end letalno. The specified duration of a current of various forms G. - c. to it is established before use of modern methods of treatment which considerably extended life expectancy of patients.
Mental disorders at G. - c. can precede development nevrol, symptoms, but in most cases appear already at the expressed disturbances from a nervous system. Sometimes they arise at temperature increase. Development of the accruing weak-mindedness, on a number of signs coming to weak-mindedness at epid, encephalitis is characteristic. Development of weak-mindedness is preceded by an asthenic state with the expressed mental exhaustion. The focus of interest is narrowed, the affective sphere suffers. Patients become easily excitable, make aggressive acts, their mood finds big instability with frequent transitions from depression to euphoria sometimes having foolish character. The persistent depressions which are noted at some patients, apparently, can be considered as reaction to a disease, hl. obr. on it nevrol, manifestations. Emergence not inherent earlier sick to falsity, tendencies to vagrancy, theft is noted. Further arise intellectual mnesticheskiye frustration with decrease in criticism. Against the background of the progressing weak-mindedness the conditions of the dulled consciousness on delirious and amental type which sometimes are coming to the end with epileptiform motive attacks can develop.
N. V. Konovalov noted a possibility of development of crazy psychoses with the ideas of prosecution and hallucinations. Children can have a fear of darkness, the closed room, fear of death.
the Diagnosis is made on the basis of data of the anamnesis on the hereditary nature of a disease, existence of a corneal ring, instructions on pathology of a liver (the diagnostic puncture of a liver finds cirrhosis and high content of copper), the phenomena of hemorrhagic diathesis and especially a giperkupruriya (allocation during a day of more than 200 mkg of copper) and hyper aminoacidurias (more than 350 mg per day).
in the absence of the specified symptoms early forms of a disease it is difficult to distinguish the differential diagnosis from postencephalitic «vilsonizm», however at the last existence in the anamnesis of the acute period of encephalitis and the subsequent slow progressing of a disease, early forms G. - c is noted. flow quickly enough with tolchkoobrazny deteriorations. In some cases G. - c. should be differentiated with multiple sclerosis (see). Trembling form G. - c. distinguishes lack of pyramidal symptoms, a nystagmus, changes of an eyeground, typical for the last, and also gradual steady development without the considerable remissions characteristic of multiple sclerosis from multiple sclerosis. In sick G.' families - c. are sometimes found in their healthy brothers and sisters unsharply expressed disturbances of copper exchange and pathology of a liver that can indicate a heterozygous state; detection of a ring of Kayser — Fleischer even at absence nevrol, symptoms demonstrates existence of the initial or erased form of a disease, demanding precautionary treatment.
The combination observed in initial stages of a disease intellectual mnesticheskikh frustration, frustration of mood and inclinations demands a differentiation with mental disturbances at endogenous psychoses. Are not inherent to the last characteristic of G. - c. nevrol, frustration, and also disturbances of activity of a liver also went. - kish. path.
At the progressing diseases of a liver as well as sick G. have a c., can arise various psychological frustration from an asthenic state to a delirious and amental syndrome; Extrapyramidal disturbances are frequent. These frustration are designated by N. V. Konovalov as a hepatocerebral syndrome. The changes similar to those which are observed at G. - c are the cornerstone of this syndrome., but less expressed; cytotoxic changes always prevail over angiotoksichesky. At acute toxic dystrophy of a liver find heavy and widespread changes in a brain. Sometimes hron, diseases of a liver cause polyneurites and polyradiculoneurites.
yields the Best results prolonged treatment by alpha Penicillaminum of per os on 0,15 (to 1 — 2 g a day). It is especially effective at late forms of a disease and in many cases leads to total disappearance a wedge, symptoms. The good effect is rendered by the thiol drugs connecting copper and bringing her out of an organism. Unithiolum is applied: intramuscular injections on 5 ml of 5% of solution — 25 — 30 injections; the course can be repeated in 1 — 2 month. It is necessary to appoint a molochnorastitelny diet, carbohydrate-rich and poor in copper.
At development of psychoses drugs of a fenotiazin are used, at psychopatholike and neurotic states — small tranquilizers. Considering damage of a liver, treatment by psychotropic drugs it is necessary to carry out with care.
Surgical treatment (stereotaxic operations with impact on ventrolateralny. the kernel of a thalamus), carried out in the cases which are not giving in to conservative treatment aims to eliminate the heaviest symptoms — tonic disturbances and hyperkinesias.
Before emergence of thiol drugs apprx. 90% of patients died aged up to 30 years. Treatment by thiol drugs considerably improved the forecast.
Bibliography: Vakharlovsky V. G. Clinical displays of a disease of Wilson — Konovalova and modern ideas of its pathogeny, Rubbed. arkh., t. 46, No. 11, page 36, 1974, bibliogr.; Konovalov N. V. Hepatolenticular degeneration (pseudosclerosis, Wilson's disease), liver and brain, M., 1948, bibliogr.; it, Hepatocerebral dystrophy, M., 1960, bibliogr.; Tkachyov R. A. and d river. Principles of pathogenetic therapy of hereditary extrapyramidal diseases, Zhurn, neuropath, and psikhiat., t. 73, No. 4, page 513, 1973, bibliogr.; With and of t w i g h t G. E. a. Lee G. R. The pathogenesis and evolution of Wilson’s disease, Epatologia, v. 20, p. 51, 1974; Goldstein N. P. a. o. Psychiatric aspects of Wilson’s diseases (hepatolenticular degeneration), Amer. J. Psychiat., v. 124, p. 1555, 1968; Gunther K. o. The kinetics of copper uptake by the liver in Wilson's disease studied by a whole-body counter and double labeling technique, Europ. neurol., v. 13, p. 385, 1975, bibliogr.; Sternliebl. ScheinbergI.H. Chronic hepatitis as a first manifestation of Wilson's disease, Ann. intern.’ Med., v. 76, p. 59, 1972, bibliogr.; Strtimpell A. t)ber die Westphalsche Pseudosklerose und tiber diffuse Hirnsklerose, insbesondere bei Kindern, Dtsch. Z. Nervenheilk., Bd 12, S. 115, 1898; Third international symposium on Wilson’s disease, Proc. Mayo Clin., v. 49, p. 361, 1974; West phal C. tiber eine dem Bilde der cerebrospinalen grauen Degeneration Shnliche Erkrankung des centralen Nervensystems ohne anatomischen Befund nebst einigen Bemerkungen liber paradoxe Kontraktion, Arch. Psychiat. Nervenkr. * Bd 14, S. 87, 1883; Wilson S. A. K «Progressive lenticular degeneration, Brain, v. 34, p. 295, 1912.
E. V. Schmidt; D. S. Ozeretskovsky (psikhiat.).