Degeneração hepatolenticular.

HEPATOLENTICULAR DEGENERATION

H O R A C I O M . C A N E L A S * F R A N C I S C O B . D E JORGE * *

O V I D I O D . E S C A L A N T E * * * E D E R C . R O C H A - Q I N T Ã O * * * *

The history of hepatolenticular degeneration started with the cases of "pseudosclerosis" reported by W e s t p h a l3 3

in 1883 and by Striimpell 4 4 .4 5

in 1898 and 1899. In 1902, K a y s e r 3 0

made the description of a yellow-greenish or brownish ring in the corneal edge, supposedly inborn, in a patient with the diagnosis of "multiple sclerosis". In the following year, F l e i s c h e r1 6 observed a case of "pseudosclerosis" and other of "multiple sclerosis" with a similar ring, advancing the view that it w a s an acquired manifestation. In 1908, S a l u s3 8

reported a case of "multiple sclerosis" with a corneal ring and, in 1909, Fleischer 1 7

published again his two cases, jointly with Kayser*s case, considering the corneal ring a manifestation of a n e w disease process.

In 1911, V o e l s c h5 1

reported the pathological examination of a case of "pseudosclerosis", calling attention to the atrophic nodular cirrhosis of the liver. In 1912, F l e i s c h e r1 8

stressed the lack of hepatic symptomatology in spite of the severe nodular cirrhosis. In the same year Alzheimer found, in a case clinically studied by von Hoesslin 2 1

, extensive lesions in corpora striata, subthalamus, dentate nucleus and pons, characterized by glial hyperplasia; he described then the giant cells of the neuroglia, currently known as Alzheimer's cells.

Still in 1912, in his masterwork, Kinnier W i l s o n 5 4

described the clinical manifestations and the pathological findings, emphasizing the frequently asymptomatic liver cirrhosis, and stressing the familial incidence of the disease; he named it progressive lenticular degeneration. Wilson refuted

P r e s e n t e d t o t h e F i r s t P a n A m e r i c a n C o n g r e s s o f N e u r o l o g y ( L i m a , P e r u , O c t o -b e r 1 9 6 3 ) .

the worth of Alzheimer's histological findings for the characterization of the "pseudosclerosis", considering them as inespecific features. In 1920, S p i e l m e y e r4 2

d r a w the conclusion that, under the pathological viewpoint, Westphal and Strumpell's "pseudosclerosis" and Wilson's disease w e r e t w o forms of the same disease, which H a l l2 5

, in 1921, named hepatolenticular degeneration.

Some conceptions from this period of the history of the disease are still valid: ( a ) presence of the Kayser-Fleischer corneal ring, which is g r a n ­ ted as a truly pathognomonic sign of the disease; ( b ) familial incidence; ( c ) nodular cirrhosis of liver, asymptomatic in most cases; ( d ) lesions of the lenticular nucleus, mainly the putamen, with destruction of the pa­ renchyma, followed by hyperplasia of the neuroglia and then cavitation; multiple nucleated giant astrocytes of Alzheimer m a y also be found.

F r o m 1921 to 1947 many clinical reports of the disease w e r e published. But it w a s not overlooked by the investigators in biochemistry: in 1930, H a u r o w i t zM

, in 1931 L i i t h y3 Z

, and in 1945 G l a z e b r o o k2 1

emphasized the increase of copper content in the liver. Gerlach and R o h r s c h n e i d e r2 0

, in 1934, showed that the corneal ring is made up of copper granules, a fact corroborated in 1936 by Policard et a l .3 4

and later by other investigators. T h e y e a r of 1948 had great significance in the study of Wilson's disease, since its metabolic nature w a s evidenced by w a y of four great investiga­ tions : U z m a n and D e n n y - B r o w n4 9

showed the occurrence of increased ami­ noaciduria, C u m i n g s1 0

irrefutably proved the hepato-cerebral overload of copper, Mandelbrote et a l .3 3

found a permanent increase of the copper excretion in urine, and H o l m b e r g and L a u r e l l2 9

demonstrated the existence, in blood serum, of a cuproprotein bound to the globulin fraction, named ceruloplasmin.

F r o m this y e a r on the studies were directed to the investigation of copper metabolism. In 1952, Scheinberg and G i t l i n3 9

pointed out the l o w blood ceruloplasmin content, in 1953 Zimdahl et a l .5 5

evidenced the increased retention of the ingested copper, and, in 1954, B e a m and K u n k e l4

demons­ trated the l o w blood copper content. Still in 1954 Cartwright et al. 8

evi­ denced an increase of the non ceruloplasmin copper, which reacts directly with diethyldithiocarbamate and is probably bound to the albumin.

I n 1953 B e a m2

showed that the hepatolenticular degeneration is in­ herited in an autosomic recessive w a y .

In this other historical period the following concepts w e r e established: ( a ) increased copper content in the tissues, especially in liver and brain; ( b ) abnormally increased absorption ( w i t h retention) of the ingested copper; ( c ) increased aminoaciduria; ( d ) increased excretion of copper in urine; ( e ) lowering of the serum or plasma total copper; ( f ) increase of the direct reacting copper in blood serum; ( g ) l o w blood ceruloplasmin content; ( h ) autosomic recessive heredity.

F r o m 1954 on the researches were aimed at the explanation of the pathogenesis of hepatolenticular degeneration, a goal still not attained.

P o r t e r and F o l c h3 5

im-portance of this protein, which is the only human protein with a loose binding of copper ( H o l m b e r g2 8

) . The studies of Taylor et a l .4 6

on the presence and dynamics of the liver circulation showed that, in hepatolenticular degeneration, an obstruction of the lesser intra-hepatic branches of the vena porta occurs. So, there is a pre-sinusoidal pattern of obstruction, which justifies the absence of changes in the liver function tests of the majority of cases.

T h e investigations of Stein et a l .4 3

and Bickel et a l .6

brought the evidence that the increase of the aminoaciduria is due to the massive in­ crease of glycine, histidine, threonine, cystine, serine, alanin, glutamine, tyrosine, lysine, glutamic acid, leucine and phenylalanin, and to a slight increase of valin. Excretion of taurin is lesser than in normals. T h e authors d r a w the conclusion that the aminoaciduria is secondary and not due to an error of the metabolism of proteins, as U z m a n et a l .4 9

-5 0 had suggested.

The treatment of Wilson's disease aims at the maintenance of a ne­ gative copper balance, and for this purpose the following measures are indicated: ( a ) high protein and low copper diet (about 1 m g of copper a d a y ) ; ( b ) potassium sulfide by oral route (one capsule of 40 mg at each meal) in order to render unsoluble the ingested copper, making it to be excreted in the feces; cation exchanging resins can also be used; ( c ) pe­ nicillamine (jfyg-dimethylcysteine) in daily doses from 500 to 4,800 mg, by mouth 3 1

.

W e have studied 3 cases of Wilson's disease from the clinical, bioche­ mical, and genetic viewpoints. W e consider the results obtained — some of them not yet recorded in the literature — worthy of publication.

C A S E S U M M A R I E S

C A S E 1 — A . O., a 16 year-old girl, B r a z i l i a n , white, register no. HC-641290, admitted to the D e p a r t m e n t of N e u r o l o g y in 11-11-1961. F u l l - t e r m pregnancy, nor­ m a l b i r t h . She frequented p r i m a r y school in a satisfactory w a y . A t the a g e of 10 years, she h a d j a u n d i c e , w h i c h w a n e d spontaneously; she suffered from occa­ sional epistaxes. T h e physical, intellectual a n d g r e g a r i o u s d e v e l o p m e n t w a s n o r m a l until the a g e of 12, w h e n she b e g a n to present s h a k i n g of the four limbs, f o l l o w e d by progressive disturbance of e q u i l i b r i u m a n d speech, as w e l l as m e n t a l impairment. Only 3 menses untill the a g e of 16. She does not k n o w a s i m i l a r disease in her family; she has a n elder brother a n d a y o u n g e r sister, both healthy.

oto-logic e x a m i n a t i o n disclosed a n o r m a l h e a r i n g , uncharacterized provoked nystagmus, and absence of v e r t i g o at the v e s t i b u l a r stimulation. T h e results of l a b o r a t o i y e x a m i n a t i o n a r e s u m m a r i z e d in tables 1 to 4, and the study of copper metabolism in t a b l e 7.

T r e a t m e n t w i t h V e r s e n a t e ( c a l c i u m disodium e t h y l e n e d i a m i n o t e t r a a c e t a t e ) and C a r b o - r e s i n (cation e x c h a n g i n g resin) w a s started, but an infectious picture a p p e a r e d soon after, causing a sudden w o r s e n i n g of the general conditions. In spite of treatment, the patient died in 12-19-1961.

P o s t - m o r t e m e x a m i n a t i o n ( S S 59583/61, D r . O. A . B e h m e r ) —• B i l a t e r a l con­ fluent b r o n c h o p n e u m o n i a . L i v e r w e i g h i n g 920 g, w i t h reduced v o l u m e and in­ creased consistency; e x t e r n a l s u r f a c e w i t h b r o w n i s h nodules 3 to 4 m m w i d e , in­ v o l v e d by fibrous capsule-like tissue (post-necrotic l i v e r c i r r h o s i s ) . A c u t e sple­ nitis. Kidneys w e i g h i n g 90 g each, w i t h n o r m a l shape, size and consistency; the cut surface showed focal a r e a s of steatosis, w i t h slight congestion of cortex a n d m e d u l l a . T h e lenticular (mostly p u t a m e n ) a n d c a u d a t e nuclei evidenced r e t r a c ­ tion, b r o w n i s h pigmentation and a spongy aspect; the histochemical e x a m i n a t i o n s h o w e d the presence of i n t r a c e l l u l a r copper g r a n u l e s . T h e study of copper content of the tissues is s u m m a r i z e d in t a b l e 5.

C A S E 2 — J. S., a 22-year-old industrial w o r k e r , white, male, B r a z i l i a n from Y u g o s l a v ascent, reg. HC-638026, admitted to the emergency w a r d of the "Hospital das Clinicas de S γ o P a u l o " in 11-24-1961, in state of unconsciousness. His relatives informed that the patient w a s in good h e a l t h untill the middle of 1959, w h e n he suffered a fall o w i n g to a transient lack of consciousness. Soon a f t e r w a r d s he began to display speech disorders, lack of interest for his customary activities, and crises of excitation. H e w a s admitted to a n inland hospital, w h e r e he stayed for 45 days in drowsiness. W h e n his conditions did further deteriorate, he w a s removed to the emergency w a r d of o u r hospital, a n d admitted to the N e u r o l o g i c D e p a r t m e n t 5 days later. T h e familial history could not be ascertained.

Good physical development; slight j a u n d i c e ; liver and spleen not p a l p a b l e . The patient w a s unconscious, r e a c t i n g only to painful stimuli. H e exhibited spon­ taneous a n d pain-induced movements. W a x y stiffness w i t h the c o g - w h e e l pheno­ menon in the four extremities. T h e deep reflexes of the limbs w e r e absent, w h i l e the orbicularis oris a n d n a s o - p a l p e b r a l reflexes w e r e hyperactive; the B a b i n s k i sign w a s present firstly on the left a n d l a t e r on the right too; the a b d o m i n a l reflexes w e r e absent; the cough, s w a l l o w i n g , and c o r n e o - p a l p e b r a l reflexes w e r e present. T h e patient had a t r e m o r w i t h a parkinsonian rhythm, but w i t h g r e a t e r a m p l i t u d e , in the left limbs, especially in the upper left extremity. B i l a t e r a l K a y s e r - F l e i s c h e r corneal rings. T h e results of l a b o r a t o r y e x a m i n a t i o n s a r e s u m ­ m a r i z e d in tables 1 to 4, a n d the study of copper metabolism in t a b l e 7. Soon a f t e r admission h y p e r t h e r m i a a p p e a r e d and the general conditions w e n t w o r s e . I n 12-1-1961 h e m a t u r i a and tracheobronchial oversecretion w e r e noted, the patient d y i n g in 12-3-1961.

P o s t - m o r t e m e x a m i n a t i o n (SS-59422/61, D r . J. T. W a i n m a n ) — B r o n c h o p n e u ­ m o n i a a n d p u l m o n a r y emphysema. L i v e r w e i g h i n g 1,150 g, w i t h a globoid shape and a reduced v o l u m e ; at the external s u r f a c e nodules 10 to 20 m m w i d e w e r e noted; in the cut s u r f a c e greenish a n d y e l l o w i s h nodules w e r e seen (post-necrotic liver c i r r h o s i s ) . S p l e n o m e g a l y and h y p e r p l a s i a of the splenic red p u l p . H o r s e ­ shoe kidneys, o t h e r w i s e n o r m a l . B r a i n w i t h n o r m a l shape and consistency, reduced sulci a n d congested blood vessels. T h e lenticular nuclei, mostly the p u t a m e n , s h o w e d reduced consistency a n d a b r o w n i s h tinge; slight and proportioned d i l a ­ tation of the l a t e r a l ventricles. T h e histochemical e x a m i n a t i o n showed the pre­ sence of i n t r a c e l l u l a r copper g r a n u l e s . T h e study of copper content of the tissues is summarized in t a b l e 5.

he started to abuse of alcoholic drinks, only stopping it w h e n the first symptoms of the disease a p p e a r e d . H e w a s in good h e a l t h untill 1962, w h e n he noted that the right fingers w e r e loosing their agility and strength, a n d started to present rapid and i r r e g u l a r i n v o l u n t a r y movements; the disorder did a g g r a v a t e especially w h e n he attempted to observe the phenomenon, w h e n he tried to stop it or if someone called his attention for it. Soon a f t e r w a r d s he noted difficulty to w a l k , caused by stiffness and a slight and continuous t r e m o r of the legs. T h e shaking of the right upper limb got so severe that he could not g r a s p the objects any more. A t the same time the speech became slurred. Some days prior to the admission a tremor a p p e a r e d in the left hand.

The patient's mother died at the a g e of 56 years, from a r t e r i a l hypertension; his father is obese a n d hypertensive. T h e patient has 9 brothers a n d 2 y o u n g children. I n one of his sisters the slitlamp e x a m i n a t i o n disclosed a K a y s e r F l e i s -cher corneal ring; she suffered f r o m sporadic a n d transient episodes of slight j a u n d i c e but the n e u r o l o g i c a l e x a m i n a t i o n w a s n o r m a l ( f o r m o r e details, see the genetic study a n d f i g u r e 1 ) .

T h e patient h a d a good physical constitution. H y p e r c h r o m i c spots w e r e seen in the right interscapular and l u m b a r regions. L i v e r a n d spleen not p a l p a b l e . N o a p p a r e n t psychic disorder. N o r m a l l a n g u a g e and p r a x i a . W i l s o n i a n facies. W h e n lying, the patient preferred the r i g h t l a t e r a l decubitus, the left h a n d holding the right a g a i n s t the bed; trunk and limbs s h o w i n g a contracture-like aspect. W h e n seated, he held w i t h both hands te bed's borders and bent the t r u n k f o r w a r d ; the neck shaked continuously; the legs w e r e crossed and flexed. W h e n he stood up, the a r m s w e r e kept behind the body, the base w a s broadened, a n d he assumed a rigid attitude w i t h the head s h a k i n g t o - a n d - f r o . T h e gait w a s rigid. V o l u n ­ tary movements w e r e satisfactory. T h e finger-to-nose test w a s hindered by a tremor w h i c h g r e a t l y increased at the end of the m o v e m e n t ; t h o u g h the heel-to-knee-to-toe test w a s also hindered by the t r e m o r and stiffness, errors in direction were not noted even after closing the eyes. T h e tests for synergy w e r e e m b a r ­ rassed by the rigidity. T h e s w a l l o w i n g w a s n o r m a l . T h e speech w a s s l u r r e d . In the limbs, neck a n d in the protruded t o n g u e there w a s a continuous a l t e r n a t i n g tremor w i t h v a r i a b l e intensity. T h e right a r m and especially the right hand shook violently in a w i n g - f l a p p i n g w a y . T h e deep reflexes w e r e hypoactive; the n a s o - p a l p e b r a l , orbicularis oris, a b d o m i n a l and cremasteric reflexes w e r e n o r m a l ; the p l a n t a r response w a s v a r i a b l e , more frequently in flexion. M o d e r a t e w a x y stiffness of the neck, t r u n k and extremities; the cog-wheel phenomenon w a s not present. T h e sensation and the cranial nerves w e r e n o r m a l . T h e eyes sometimes showed transient and short l a t e r a l jerks. K a y s e r - F l e i s c h e r rings in both eyes, confirmed a t the slit-lamp e x a m i n a t i o n .

T h e e l e c t r o e n c e p h a l o g r a m w a s n o r m a l . T h e skull X - r a y s disclosed a slight degree of b a s i l a r impression; the hands and feet showed diffuse decalcification, but the joint spaces w e r e preserved and no sign of f r a c t u r e w a s seen; h a l l u x v a l g u s . T h e excretion u r o g r a p h y a n d the e l e c t r o c a r d i o g r a m w e r e n o r m a l . T h e needle biopsy of the kidney w a s n o r m a l . T h e liver biopsy revealed postnecrotic cirrhosis. T h e results of the l a b o r a t o r y e x a m i n a t i o n a r e summarized in tables 1 to 4, the study of copper content of tissues in t a b l e 5, the metabolic b a l a n c e of copper in t a b l e 6 and f i g u r e 3, and the study of copper m e t a b o l i s m in table 7 a n d f i g u r e 4.

T r e a t m e n t w i t h l o w copper diet ( 1 . 2 5 m g each d a y ) w a s associated w i t h B A L (200 m g daily, by i n t r a m u s c u l a r r o u t e ) , and later w i t h D - p e n i c i l l a m i n *

( d a i l y doses r a n g i n g f r o m 1 to 2 g ) . C a r b o - r e s i n or potassium sulfide w a s also used. T w o months after the use of D - p e n i c i l l a m i n and especially after estrogens (diethylstilbestrol 15 m g / d a y ) w e r e associated, a moderate i m p r o v e m e n t in tremor a n d rigidity w a s noted; the biochemical results w e r e definitely good.

D I S C U S S I O N

T h e neurologic manifestations in our cases molded to the classic picture of Wilson's disease. A l l the patients showed a combination of static and kinetic tremor, which had a wing-flapping pattern ("Fliigelschlagen") in two. W a x y stiffness of limbs w a s noted in cases 2 and 3, whereas case 1 showed a marked spasticity in flexion, especially in the lower limbs. In case 1 the tendon reflexes w e r e hyperactive; in case 2 the Babinski sign w a s present and the abdominal reflexes w e r e absent. Case 1 showed also cerebellar signs. Mental disorders w e r e evident in cases 1 and 2.

In cases 2 and 3 the short course of the disease is striking. The patient J. S. (case 2) w a s admitted in coma at the emergency w a r d of the hospital.

T h e Kayser-Fleischer corneal ring w a s always complete and bilateral, being visible at naked eye; its presence was confirmed at the slit-lamp examination, which disclosed no "sunflower cataract" in any case.

F r o m the clinical point of view it must b e emphasized that the func­ tional impairment of liver w a s mild, despite the severeness of the damage seen at the histologic examination, thus confirming a rule of the literature. A s table 2 shows, there is no agreement between the severeness of the neurologic picture and the functional state of liver, at least when it is esteemed through the tests currently used. Such disagreement occurs in spite of the fact that the histologic involvement of liver is a rule in Wilson's disease 4 8

.

This is more striking in case 1, where the usual protein function tests and particularly the bromsulphalein test w e r e normal. However, in case 2 the liver damage, at least according to the results of the flocculation tests, w a s parallel to the nervous damage; taking account of his excellent physical constitution and the good nutritional state, the low plasma albumin, leading to a positive flocculation test, must be ascribed to the liver damage 4 1

.

According to the absolute figures of the electrophoresis (table 2 ) , the plasma proteins fit the normality r a n g e in case 3, and are obviously asso­ ciated with the normality of the protein function tests, in spite of a slight increase of the transaminases. H o w e v e r , the wilsonian cirrhosis being post­ necrotic 1

, such disagreement may occur in much the same w a y as it is seen in the evolution of functional tests in the cirrhosis in g e n e r a l4 0

.

Regarding the renal function, the hyperphosphaturia, described by B e a m et a l .5

in 1957, w a s inconstant in case 3, and the metabolic balance trended to be negative. T h e finding of reducing substances in the urine of cases 1 and 2 was occasional; however, other tests for confirmation of tubular glycosuria, also described by B e a m et a l .5

, were not performed.

In hepatolenticular degeneration, the kidney damage is secondary to the disordered copper m e t a b o l i s m6

in such a w a y that the increased ami­ noaciduria of cases 1 and 3, associated with normal or low blood aminoacid content, and thus allowing an increase of its clearance to be foreseen, is a clear-cut example of true renal aminoaciduria. Moreover, the slow and progressive impairment of the renal function 7

The finding of changes in the urine sediment of two cases, including proteinuria, does not permit other conclusions, because the patients were submitted to drainage of the urinary bladder for several days, and a secondary infection of kidney could not be discarded.

The patient J. S. had a blood urea content of 140 mg/100 ml when he was dehydrated, just before the death.

T h e blood sialic acid concentration w a s increased in case 3 (table 1 ) .

Confirming the references of the literature, we found low blood uric acid content and high aminoacid concentration in urine (cases 1 and 3 ) . W e found no reference to the low blood phosphorus and the high blood magnesium contents noted in our cases.

The routine examination of the cerebrospinal fluid gave normal results. T h e electrophoresis of the proteins (table 4) showed absence of prealbumin in case 1 and 3, low anda, globulins in two cases, reversal of the « , /

Copper contents in the tissues — T h e samples w e r e removed either

at the post mortem examination (cases 1 and 2) or by needle biopsy (case 3 ) .

In all the examined tissues the copper levels were increased (table 5 ) . Other authors have already evidenced this copper overload in pancreas ° .8

, k i d n e y s6

.8 -4 7

, adrenal g l a n d s6 .8

, liver 8 . 1 0

. 2 1 > 2 4

.2 6 >4 7

, white matter of brain «, 8

, 2 4

, gray matter of brain 8 . 2 4

, lenticular and caudate nuclei °. 2 4

, thala­ mus 2 4

, cerebellar c o r t e x6 -8

- 2 4

. In brain, greater copper levels w e r e found in the white and gray matter of the temporal lobe, and in the thalamus (table 5 ) . N o reference in the literature was found concerning the copper contents of the red nucleus and substantia nigra in hepatolenticular dege­ neration; in cases 1 and 2 the copper levels w e r e markedly increased in these mesencephalic nuclei.

N o reference w a s found in the literature regarding the copper contents of the submaxillary glands and cerumen in this disease; in our cases the levels were increased as compared to normals 1 2

> 1 4

. I n hairs the copper content w a s low, a finding already observed by Rice and G o l d s t e i n3 7

, w h o stressed the absence of correlation between the copper concentration in hairs and the severeness of the disease. In nails the copper content fell in the normal range, thus confirming the results of Rice and Goldstein : i 7

.

Copper metabolism and metabolic balances — L o w blood copper and

ceruloplasmin contents and increased copper concentration in urine and saliva w e r e found in the three cases of Wilson's disease (table 7 ) . Blood direct reacting copper w a s determined only in case 3 and showed a moderate increase. Cerebrospinal fluid copper content w a s found to be within the normal r a n g e1 3

, the total levels being close to the concentration of direct reacting copper. In A and C-bile the copper content was low, while in B-bile it w a s normal; in the mixture of the three fractions the copper level was low (table 7 ) .

A f t e r administration of Versenate (case 1 ) , dimercaprol ( B A D and especially yg^dimethylcysteine (D-penicillamine) in case 3, a marked rise of copper excretion through urine was evidenced (table 6, figs. 3 and 4 ) .

The metal binding agents promote this cupriuretic response in subjects with diseases other than hepatolenticular degeneration, and even in nor­ m a l s2 3

and ceruloplasmin contents and no Kayser-Fleischer ring, this effect of B A L was also marked (table 8 ) .

In case 3, the copper balance was positive in the control periods, becoming markedly negative after the use of metal binding agents, espe­ cially D-penicillamine; the association of estrogens evoked a new and strong negativation of the copper balance (table 6, fig. 3 ) . A s Goldstein et a l .2 3

already mentioned, the excretion of copper in urine is very pro­ nounced at the onset of the treatment, but later it gradually falls, approach­ ing the pretreatment range approximately one year afterwards, despite the continued use of the drug. In case 3 this fall of cupriuresis is also evident (fig. 4 ) .

Regarding phosphorus balance, it w a s found that it w a s slightly negative in the control periods, becoming markedly negative 10 days after the onset of the treatment with penicillamine; this finding lead us to administer, during the subsequent treatment, a formula containing dibasic sodium phosphate.

In spite of the still short therapeutic course with D-penicillamine, the benefits of which usually became apparent only months or years after its

onset 2 3 >3 1

, the partial failure noted in our case could be explained by the findings of Duckett et a l .1 3

; these authors, after determining the copper concentration in the tissues of a patient with Wilson's disease unsuccessfully submitted to treatment with penicillamine, d r a w the con­ clusion that the greatest copper depletion occurred in liver.

S U M M A R Y

A f t e r a r e v i e w of the fundamental steps in the history of

hepatolenti-cular d e g e n e r a t i o n , the authors r e p o r t 3 cases o f the disease. T w o patients died, t h e p o s t m o r t e m e x a m i n a t i o n h a v i n g c o n f i r m e d the clinical and l a b o

-r a t o -r i a l diagnosis.

A m o n g the n e u r o l o g i c p a r t i c u l a r i t i e s t h e presence, in one case, of flexion spasticity and c e r e b e l l a r signs, besides t h e usual p i c t u r e of W i l s o n ' s disease, is stressed. T h e K a y s e r F l e i s c h e r corneal r i n g w a s a l w a y s c o m -p l e t e and b i l a t e r a l . A m o n g the unsteady features of the -p r o t e i n o g r a m

of the cerebrospinal fluid, absence of pre-albumin, a n d l o w e r i n g o f 1 and

2 globulins w e r e m o r e f r e q u e n t l y found. L o w blood phosphorus and m a g

-nesium contents w e r e found in our cases, s e e m i n g l y f o r the first t i m e in the l i t e r a t u r e .

S p e c i a l a t t e n t i o n w a s dedicated t o the study of l i v e r and kidney func-tions t h r o u g h t h e p r o p e r functional tests. T h e i m p a i r m e n t of l i v e r function w a s mild, in a s t r i k i n g d i s a g r e e m e n t w i t h the d e g r e e of t h e histologic p i c t u r e of post-necrotic cirrhosis. R e g a r d i n g the kidney, in t w o cases increased

urinary e x c r e t i o n of aminoacids w a s found, associated w i t h a s l i g h t l y l o w e -red t u b u l a r e x c r e t i o n in o n e of t h e m .

T h e g e n e t i c study could b e m o r e detailed in one of the cases, and in-cluded the search f o r K a y s e r - F l e i s c h e r c o r n e a l ring, the d e t e r m i n a t i o n of copper in blood and urine, and of b l o o d ceruloplasmin in the r e l a t i v e s , besides

t h e c y t o g e n e t i c study of the patient. K a y s e r - F l e i s c h e r r i n g w a s found in an o t h e r w i s e a s y m p t o m a t i c sister, and disorders of copper m e t a b o l i s m w e r e evidenced in her and some o t h e r r e l a t i v e s .

T h e study of copper contents in the tissues c o n f i r m e d the data of the

l i t e r a t u r e r e g a r d i n g the o v e r l o a d in pancreas, kidneys, adrenal glands, l i v e r , w h i t e and g r a y m a t t e r o f the brain, thalamus, c e r e b e l l a r c o r t e x , and in t h e l e n t i c u l a r and caudate nuclei, as w e l l as n o r m a l l e v e l s in the nails and l o w contents in the hairs. P r e s u m a b l y f o r the first t i m e , an increase o f copper c o n c e n t r a t i o n in t h e substantia n i g r a and r e d nucleus, as w e l l as

L o w blood copper and ceruloplasmin contents and increased copper concentration in urine and saliva w e r e found in t h e t h r e e cases. B l o o d d i r e c t r e a c t i n g copper w a s d e t e r m i n e d only in one case and showed a m o d e r a t e increase.

T h e study of the m e t a b o l i c balance s h o w e d a positive result f o r copper in the control periods, and a slight n e g a t i v e result f o r phosphorus. A f t e r the use of B A L , and especially o f D-penicillamine, the copper balance b e c a m e n e g a t i v e and the phosphorus balance turned out m a r k e d l y n e g a t i v e .

L o w copper diet, cation e x c h a n g i n g resins or potassium sulphide w e r e associated w i t h the m e t a l binding agents in d i f f e r e n t t h e r a p e u t i c schemes. T h e clinical i m p r o v e m e n t , although noticeable in case 3 a f t e r the use of D - p e n i c i l l a m i n e and estrogens, did not a g r e e w i t h the g r a t i f y i n g b i o c h e m i c a l results.

A C K N O W L E D G E M E N T S

W e w i s h t o e x p r e s s o u r t h a n k s to D r . F e r n a n d o T e i x e i r a M e n d e s and D r . F r a n -cisco D i G r a d o f o r t h e c y t o g e n e t i c s t u d y o f case 3.

R E S U M O

Degeneraηγo hepatolenticular: estudo clνnico e bioquνmico de trκs casos. 

A p ó s r e v e r e m os marcos fundamentais da história da moléstia de W i l s o n , os autores r e l a t a m 3 casos desta a f e c ç ã o . D o i s pacientes f a l e c e -ram, tendo o e x a m e necroscópico c o n f i r m a d o o diagnóstico clínico-labora¬ torial.

E n t r e as particularidades do q u a d r o neurológico, sobressaía, e m um caso, a existência de espasticidade e m f l e x ã o e de sinais c e r e b e l a r e s . O anel corneano de K a y s e r F l e i s c h e r apresentouse s e m p r e c o m p l e t o e b i l a t e -ral. E n t r e os c a r a c t e r e s inconstantes d o p r o t e i n o g r a m a do líquido cefalor-raqueano são salientadas a ausência de pré-albumina e os baixos níveis de globulinas 1 e 2. P r o v à v e l m e n t e pela p r i m e i r a v e z , foi o b s e r v a d a r e d u ç ã o

dos v a l ô r e s de fósforo e m a g n é s i o no sôro sangüíneo.

O estudo das funções hepática e renal foi r e a l i z a d o por m e i o dos testes convencionais, tendo-se v e r i f i c a d o que o c o m p r o m e t i m e n t o do f í g a d o era discreto, e m nítida desproporção c o m o g r a u d e l e s ã o histológica do ó r g ã o ( c i r r o s e p ó s - n e c r ó t i c a ) . E m r e l a ç ã o aos rins, foi c o m p r o v a d a hipera¬ minacidúria e m dois casos, associada a discreta diminuição da e x c r e ç ã o tu-bular, e m u m deles.

O estudo do conteúdo de cobre nos tecidos confirmou os dados da l i -t e r a -t u r a quan-to ao acúmulo desse m e -t a l no pancreas, rins, supra-renais, f í g a d o , substâncias branca e cinzenta do c é r e b r o , t á l a m o , c ó r t e x c e r e b e l a r

e núcleo lentículo-caudado, assim c o m o níveis normais nas unhas e baixos nos cabelos. V e r i f i c a ç ã o p r o v à v e l m e n t e inédita foi o achado de acúmulo de cobre na substância negra e núcleo rubro, assim c o m o nas glândulas submandibulares e no c e r u m e . N o líquido c e f a l o r r a q u e a n o os v a l ô r e s do c o b r e t o t a l se e n c o n t r a v a m dentro dos l i m i t e s n o r m a i s e m u i t o p r ó x i m o s

dos do cobre de r e a ç ã o direta. N a bile, d e a c o r d o c o m as r e f e r ê n c i a s da l i t e r a t u r a , o b s e r v a m o s c o n c e n t r a ç ã o de c o b r e n o r m a l na bile t o t a l e na f r a ç ã o B, e v a l ô r e s diminuídos nas biles A e C.

E m todos os casos verificou-se diminuição da c o n c e n t r a ç ã o de cobre e

ceruloplasmina no sangue e e l e v a ç ã o dos v a l o r e s na urina e saliva. O cobre de r e a ç ã o direta d o soro, d e t e r m i n a d o e m um caso, mostrou-se e m nível r e l a t i v a m e n t e a l t o .

O estudo dos balanços m e t a b ó l i c o s demonstrou positividade para o cobre nos períodos de contrôle, e discreta n e g a t i v i d a d e do b a l a n ç o do fósforo. A p ó s

o e m p r e g o do B A L , e p a r t i c u l a r m e n t e da D-penicilamina, o balanço do cobre se n e g a t i v o u e o do f ó s f o r o tornou-se mais a c e n t u a d a m e n t e n e g a t i v o .

D i e t a hipocúprica, resinas p e r m u t a d o r a s de cations ou sulfeto de potássio f o r a m associados aos a g e n t e s c o m p l e x a n t e s . A m e l h o r a clínica, e m -bora nítida no caso 3 após o uso de D-penicilamina e estrógenos, n ã o

cor-respondeu ao e x c e l e n t e resultado b i o q u í m i c o .

R E F E R E N C E S

c o b r e . I I : V a l ô r e s n o r m a i s de c o b r e n o s a n g u e , l í q u i d o c e f a l o r r a q u e a n o e u r i n a . R e v . p a u l . M e d . , 62:125-128, 1963. 1 4 . D e J O R G E , F . B . ; C I N T R A , A . B . U . ; P A I V A , L . J.; C O R R Ê A , A . P . ; N O V A , R . — On t h e c h e m i s t r y o f c e r u m e n : ash, v o l a t i l e s u b s t a n c e s , s o d i u m , p o t a s s i u m , c a l c i u m , m a g n e s i u m , p h o s p h o r u s a n d c o p p e r . T o be p u b l i s h e d . 1 5 . D U C K E T T , S.; F R A N C E , N . E.; W A L L I S , P . G. — C l i n i c a l a n d p a t h o l o g i c a l f i n d i n g s in a case o f h e p a t o l e n t i c u l a r d e g e n e r a t i o n t r e a t e d w i t h p e n i c i l l a m i n . J. N e u r o l . N e u r o s u r g . P s y c h i a t . , 25:374-377, 1962. 1 6 . F L E I S C H E R , B . — Z w e i w e i t e r e F ä l l e v o n g r ü n l i c h e r V e r f ä r b u n g d e r K o r n e a . K l i n . M b l . A u g e n h e i l k . , 41:489-491, 1903. 17. F L E I S C H E R , B . — D i e p e r i p h e r e b r a u n - g r ü n ¬ liche H o r n h a u t v e r f ä r b u n g a i s S y m p t o m e i n e r e i g e n a r t i g e n A l l g e m e i n e r k r a n k u n g . M u n c h , m e d . W s c h r . , 56:1120-1123, 1909. 18. F L E I S C H E R , B . — Ü b e r e i n e r d e r " P s e u d o s k l e r o s e " n a h e r s t e h e n d e r b i s h e r u n b e k a n n t e K r a n k h e i t . D t s c h . Z. N e r v e n h e i l k . , 44:179-201, 1912. 1 9 . G E R L A C H , W . — U n t e r s u c h u n g e n ü b e r d e n K u p f e r g e h a l t m e n s c h l i c h e r ( u n d t i e r i e s c h e r ) O r g a n e . V i r c h o w s A r c h . p a t h . A n a t . , 294:171-197, 1934. 2 0 . G E R L A C H , W . ; R O H R S C H N E I D E R , W . — B e s t e h t d a s P i g m e n t des K a y s e r - F l e i s c h e r s c h e n H o r n h a u t r i n g e s aus S i l b e r ? K l i n . W s c h r . , 13:48-49, 1934. 2 1 . G L A Z E B R O O K , A . J. — W i l s o n ' s disease. E d i n b . m e d . J., 52:83-87, 1945. 2 2 . G O L D B L U M , R . W . ; D E R B Y , S.; L E R N E R , A . B . — T h e m e t a l c o n t e n t o f skin, n a i l s a n d h a i r . J. i n v e s t . D e r m . , 20:1318, 1953. 2 3 . G O L D S T E I N , N . P . ; R A N -D A L L , R . N . ; G R O S S , J. B . ; R O S E V E A R , J. W . ; M c G U C K I N , W . F . — T r e a t m e n t o f W i l s o n ' s d i s e a s e ( h e p a t o l e n t i c u l a r d e g e n e r a t i o n ) w i t h D L p e n i c i l l a m i n e . N e u r o -l o g y , 12:231-244, 1962. 2 4 . G R A S H C H E N K O V , N . I . ; H E K H T , B . M . — C o p p e r c o n t e n t o f b r a i n tissues in h e a l t h a n d in c e r t a i n n e r v o u s diseases. E x p . N e u r o l . , 2:573-580, 1960. 2 5 . H A L L , H . C. — L a D é g é n é r e s c e n c e H é p a t o - l e n t i c u l a i r e : Ma¬ l a d i e de W i l s o n - P s e u d o s c l é r o s e . M a s s o n , P a r i s , 1921. 2 6 . H A U R O W I T Z , D . — Ü b e r e i n e A n o m a l i e des K u p f e r s t o f f w e c h s e l s . Z. p h y s i o l . C h e m . , 190:72-74, 1930. 2 7 . v o n H O E S S L I N , C ; A L Z H E I M E R , A . — E i n B e i t r a g z u r K l i n i k und p a t h o l o g i s c h e n A n a t o m i e d e r W e s t p h a l - S t r ü m p e l l s c h e n P s e u d o s k l e r o s e . Z. g e s . N e u r o l . P s y c h i a t . , 8:183-209, 1912. 2 8 . H O L M B E R G , C. G. — D e v e l o p m e n t o f k n o w l e d g e o f c a e r u ¬ l o p l a s m i n . In J. M . W a l s h e •&  J. N . C u m i n g s : W i l s o n ' s D i s e a s e . B l a c k w e l l , O x f o r d ,