T H E L I V E R IN SE C O N D A R Y S Y P H I L I S
C L I N I C A L , L A B O R A T O R Y A N D H I ST O P A T H O L O G I C A L I N V E ST I G A T I O N O F 2 2 P A T I E N T S W I T H O U T J A U N D I C E . *
H . C. He r cule s, R. F igliu olo, S. F igliu olo
22 pat i ent s wit h a hi st or y of syphi l i t i c cont act , ski n l esions and posit ive
ser ol ogy were eval uat ed by physi cal examinat ion, t iver f unct ion t est s and l íver
bi opsy f or evidence of hepat i c l esions secondar y t o t reponema inf ect ion. Onl y
mi ni mal evidences of hepat i c damage were reveal ed b y cl inicai examinat ion and
liver f unct i on t est s. On bi opsy 21 cases of N SRH were not ed wit h one case of
gr ami oma f ormat ion. No spirochaet es were f ound, so t hese f indings coul d not be
at t r ibut ed t o a dir ect act i on o f t he t reponema.
I N T R O D U C T I O N
M a n y a u t h o r s h ave st u d i e d t h e causai r e l a t i o n sh i p b e t w e e n j a u n d i c e , l iver l e si on s and se c o n d a r y sy p h i l i s b y m e an s o f case r e p o r t s1' 2 ' 1 2 ' 17, 2 ' 2 2 ' 3 0 . Fe w h ave st u d i e d t he l iver in e a r l y sy p h i l i t i c p at i e n t s w i t h o u t j aundi ce. In t h e se st u d i e s som e o f t h e cases ci t ed h ad b e en ad m i t t e d t o t h e w ar d f or r e a so n s o t h e r t h a n su sp e c t e d sy p h i
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l i ver b i o p sy , Ir ga n g9 an d H a h n 8 su gge st e d a n u n d e r l y i n g h e p at i t i s i n se c o n d a r y sy p h i l i s.Fé h e r et a l 6 m ad e a sy st e m a t i c i nve st i - ga t i on o f sy p h i l i t i c p at i e n t s w h o h ad al t er ed l iver f u n c t i o n t e st s b y m e an s o f l iver b i o p sy .
Raj am an d Ra n g i a h 1 9 , M c Cr a c k e n et a l 15 an d n o w Sh e r l o c k 24 sugge st e d a l iver i n ve st i ga t i on b y n eed l e b i o p sy in e ar l y sy p h i l i t i c p at i e n t s w i t h o u t c l i n i c a i n o r l ab o- r a t or y e vi d e n c e o f h e p a t i c l esion.
T h e a u t h o r s st u d i e d 2 2 vo l u n t e e r s w i t h se c o n d a r y sy p h i l i s u si n g l iver f u n c t i o n t e st s an d n ee d l e b i o p sy .
M A T E R I A L A N D M E T H O D S
2 2 p at i e n s w e r e sel ect ed f o r t h i s st u d y . T h e y ali r el at ed a h i st o r y o f sy p h i l i t i c
c o n t ac t an d sh ow e d se c o n d ar y sy p h i l i t i c sk i n l esions* N o n e o f t h e m r el at ed excessi ve u se o f a l c o h o l an d n o n e h ad a n y h ep at i c sy m p t o m a t o l o gy . O f t h e m 12 w er e w om e n . T h e i r ages r an ged b et w e e n 18 an d 4 3 year s. T h e t i m e b e t w e e n on se t o f sy m p t o m s of se c o n d a r y sy p h i l i s an d need l e b i o p sy var ied f r o m 4 t o 9 0 d ays.
Ea c h p at i e n t h ad at l east t w o d i f f e r e nt se r o l o gi c a l l y p osi t i ve t e st s f or sy p h i l i s ( V D R L , Ka h n an d Mal t an e r ) .
T h e l iver f u n c t i o n t e st s p e r f o r m e d w er e: b i l i r u b i n , a l k a l i n e se r u m p h osp h at ase , gl u t am ic p y r u v a t e t r a n sa m i n a se ( SG PT ) , chol es- t e r ol se r u m p r o t e i n s ( t ot al , f r a c t i o n e d and e l e c t r op h or e si s) , f l o c c u l a t i o n r e ac t i on s and p r o t h r o m b i n a c t i v i t y.
A l i p at i e n t s h ad a needl e b i o p sy done, af t er w h i c h t h e y w e r e t r eat ed w i t h peni- ci l l i n .
A l i b i o p sy sp e c i m e n s w er e w h o l l y or p ar t i al l y f i x e d in f o r m a l d e h y d e 4 % and p ar af f i n e m b e d d e d . T h e se c t i on s w er e st ai n e d b y r o u t i n e H E, PA S, d e l aye d Zi ehl - Ne e l se n f o r c e r oi d p i gm e n t ( Sc h e u e r , 1968 ) an d a f t e r w a r d s b y t h e W a r t h i n - Fau l k n e r t e c h n i q u e f o r t r e p on e m a d e t e c t i o n 5 . A sp e c i m e n f r o m c o n ge n i t al r enal sy p h i l i s w as i n c l u d e d i n e ach b at t e r y of sl id es as a p osi t i ve r e f e r e n ce r i c h i n t r e p on e m e s.
* H o sp i t a l Esc o la Sã o F r a n c i sc o de A ssi s, De p a r t a m e n t s o f Pa t h o lo gy a n d In t e r n a i M e d i c in e , F a c u lt y o f M e d i ci n e , F e d e r al U n i v e r sit y at R i o de J a n e ir o, Co r r e sp o n d e n c e t o D r . H . C. H e r cu le s, L a b o r a t ó r i o de Pa t o lo gi a , H o sp i t a l U n i v e r sit á r i o, Ilh a d o F u n d ã o , R i o de Jan e ir o.
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F i g . 1 P o r t a l a n d i n t r a l o b u l a r i n f i l t r a t i o n m o st l y F i g . 2 So m e h e p a t o c y t e s w e r e su b st i t u t e d b y
b y m o n o n u c l e a r c e l l s. T h e r e i s K u p f f e r i n f l a m a t o r y c e l l s. C a se B - 4 5 6 1 . H E . O b .
c e l l h y p e r p l a si a . C a se B - 5 4 3 1 H E . O b . 4 0 x .
1 0 x .
Fi g . 3 -i- F o c a l l y l i c n e c i o si s o f so m e h e p a t o c y t e s w i t h e x su d a t i v e t e a c t i o n . So m e t i v e r c e l l s s h o w f a t t y d e g e n e t a t i o n , Sa m e c a se a s f i g. 2 . H E . O b . 4 0 x ,
F i g . 4 ^ N e c r o u c t oüus n e a r c e n t r a l c a n a l . T h e
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18S
O n e sp e c i m e n w a s su b m i t t e d t o sil ver i m p r e gn a t i o n a s d e sc r i b e d b y W i l d e r 28 and st u d i e d f o r t h e p r e se n c e o f H B $A g a c c o r d i n g t o t h e Sh i k a t a m e t h o d 2 5 . Fi v e b i o p si e s w er e se ar ch e d f o r i m m u n o g l o b u l i n s a n d C '3 b y i m m u n o f l u o r e sc e n c e o f d e e p f r o z e n se c t i ons. O n e of t he se f i v e case s w as sear ch ed f o r t r e p o n e m e s a c c o r d i n g t o t h e Le v a d i t i t e c h n i q u e 1 3 .
T h e d i a gn o si s o f n o n sp e c i f i c r eact ive h e p a t i t i s w a s b ase d o n Po p p e r 's c r i t e r i a 1 8 . A c c o r d i n g t o t h e i n t e n si t y o f t h e st r u c t u r al al t e r a t i o n s t h e c ase s w e r e d i v i d e d i n l i gh t , m od e r at e , o r i n t e n se h e p a t i t i s af t er t w o r a n d o m c h e c k s.
T h e l i ver f r a gm e n t s w e r e c l assi f i e d as sm al l ( u n d e r 0 , 5 c m ) , m e d i u m ( 0 , 6 t o 1, 0c m ) , o r b i g ( m or e t h a n 1, 0c m ) in o r d e r t o c h e c k t h e v a l i d i t y o f t h e r esul t s.
R E SU L T S
T h e m o st f r e q u e n t sk i n l e si on s w e r e ge ne r al i zed pa p u l ar sy p h i l i d s. O n e case sh o w e d p a p u l o sq u a m o u s sy p h i l i d s an d a n o t h e r sh o w e d d i sse m i n a t e d al o p e c i a. A l i cases sh o w e d l y m p h gl a n d s e n l ar gm e n t , m o st l y i n t h e c e r vi c al a n d a x i l l a r y r e gi ons. O f 17 p at i e n t s, t h e l iver c o u l d be p al p at ed b u t n o n e w as c o n si d e r e d t o b e i nc r ease d in size. T h r e e p at i e n t s e x p e r i e n c e d p a i n o n p al p at i on . T h e sp l ee n w as p al p at e d in t w o pat ient s»
So m e l iver f u n c t i o n t e st s sh o w e d al t e r a t i o n s (t ab l e I) a n d t h e o t h e r s w er e w i t h i n n o r m a l r ange.
21 b i o p sy f r a gm e n t s sh ow e d a n o n sp e c i f i c r e ac t ive he pat i t is. T h e b i g g e r sp e c i m e n s ( 10 in al i ) r eveal ed m o r e i n f l a m m a t i o n an d n e c r ot i c f o c i t h a n t h e sm al l er o n e s ( 5 o u t o f 21 ) . Si n c e i n f i l t r a t i o n o f var ie d i n t e n si t y w a s e n c ou n t e r e d in t h e p o r t al t r a c t s an d less p r o n o u n c e d i n t h e si n u so i d s t h e d i f f u se c h ar ac t e r o f t h e i n f l a m m a t i o n w as assu m e d (f ig. 1). In f i l t r a t i o n i n t he p or t al t r a c t s w a s t he o n l y f i n d i n g in som e cases. T h e i n f i l t r a t i o n w a s m o st l y b y m o n o n u c l e a r c e l l s an d t o a l esser e x t e n t b y n e u t r o p h i l s. Ku p f f e r cel l s a l w a y s w e r e f o u n d in c r e ase d in n u m b e r an d size, so m e t i m e s l oad e d w i t h c e r oi d p i gm e nt .
In 13, i n f l a m m a t o r y c e l l s su b st i t u t i n g h e p a t o c y t e s w e r e n ot e d (f ig. 2) . A l i t he se cases sh o w e d so m e w h a t d i f f e r e n t asp e c t s r e se m b l i n g t h e e v ol u t i ve st age s o f t h e h e p a t i c f o c a l l e si on . Le ss ad van c e d l e si o n s
sh ow e d o n e t o t h r e e h e p at oc yt e s w i t h sh r u n k e n a n d a c i d o p h i l i c c y t o p l a sm and t h e p r esen ce o f h y st i o c y t e s an d l ym p h oc y t e s. I n m od e r a t e l y a d va n c e d l e si o n s t hese hepa t o c y t e s d i sap p e a r e d an d w e r e su bst i t u t e d b y h y st i o c y t e s, l y m p h o c y t e s an d som e t i m e s b y n e u t r o p h i l s (f ig. 3) . Ad v a n c e d l e si on s t ended t o f o r m gr a n u l o m a (f ig. 4 e 5) w i t h o u t a n y p r e f e r en t i al l o c a l i za t i o n in t h e h epat i c l ob ul e. H e p a t o c y t e s at a d i st a n c e f r o m t hese l e si on s d i d n o t sh o w m u c h e vi de nce of al t e r at i on. So m e o f t h e m w er e vac u ol i ze d w i t h so m e d egr ee of b a l l o o n i n g b u t t her e w as n o m o d i f i c a t i o n in t he n or m a l an at om i c st r u c t ur e.
O n e sp e c i m e n sh ow e d an area of int ense i n t r al o b u l a r i n f i l t r a t i o n w i t h m o st l y n e u t r o p h i l s (f ig. 6) . A n o t h e r r eveal ed ve r y sm al l a c i d o p h i l i c i n c l u si o n s in t h e c y t o p l a sm of t he h e p a t oc y t e s. In o n e case b i o p si e d 30 d a y s af t er on se t o f t he d i sease an i nt ense e n l ar gm e n t o f t h e p or t ai t r ac t s b y m o n o n u c l e ar i n f i l t r a t i o n an d p iece-m eal n e c r osi s c o u l d b e ob se r ve d (f ig. 7 e 8) . T h e h e p a t o c y t e s seem ed m o r e sw o l l e n t h a n in t he ot h er cases, b u t H B j A g c o u l d n ot be t r aced b y t h e Sh i k a t a m e t h od . N o f oc al l e si on s w er e e n c o u n t e r e d i n t h i s case.
T r e p o n e m e s w er e n ot t r aced b y ei t her t he W a r t h i n - Fa u l k n e r o r Le vad i t i t e c h ni q u es, a l t h o u gh ali r e f er en ce sl id e s sh ow e d p l e nt y of t r e p o n e m e s.
N o i m m u n o gl o b u l i n s or C '3 c ou l d be t r aced b y i m m u n o f l u or e sc e n c e .
D I SC U SSI O N
T h e l iver al t e r a t i on s f o u n d in t h i s st u d y w er e t h o se of n o n sp e c i f i c r eact ive h e p at i t is ( N SRH ) . T h e i n c i d e n c e o f N SR H in t he w h o l e p o p u l a t i o n is n ot w e l l k n o w n . O u t of 3 8 0 0 b i o p si e s, M e i st e r 16 f o u n d 5 5 5 cases and ad d e d t h at N SR H m i gh t o n l y b e an aspect o f h e p at i t i s w i t h a gr a n u l o m a t o u s r eac t ion . He su gge st s t h at t h e need l e m i gh t n o t h ave r each ed t h e gr a n u l om as. T h e use of ser ial se c t i on s m i gh t i m p r o ve t he c h an ce s of f i n d i n g t h e m 4 .
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M a n y a u t h o r s f ai l e d t o f i n d e vi d e n c e o f gr a n u l o m a f o r m a t i o n i n t he, h e p a t i t i s o f s e c o n d a r y s y p h i l i s 1 , 2 ' 4 ' 7’ 1 2 , 1 5 , 1 7 ' 2 0 '
2 2 , 2 3 , 2 6 , 3 0 , 3 1 b u t W a g o n e r 2 7 j n g s e r j e s Q f
1 1 0 0 r a n d o m l iver b i o p si e s f o u n d 5 cases of sy p h i l i s w i t h g r a n u l o m a t o u s l e si o n s o f w h i c h 4 w er e i n t h e e ar l y st age o f t h e d i se ase. O u r st u d y r eveal ed gr a n u l o m a f o r m a t i o n o n l y in on e case. T h i s d o e s n o t e x c l u d e m o r e cases if t he l iver f r a gm e n t s c o u l d have b e e n lar ger.
T h e f i n d i n g o f N SR H i n a l m o st al i o u r cases m i gh t r e p r ese nt o n l y t h e h e p at i c c o m p o n e n t o f a sy st e m i c d i se ase, si n c e in n on e c o u l d t r e p o n e m e s b e f o u n d . T h i s sh o u l d n ot b e d u e t o t e c h n i c al f a i l u r e si n c e t est se c t i on s a l w a y s w e r e f o u n d p osi t i ve. T h e 5 cases st u d i e d b y i m m u n o f l u o r e sc e n c e d i d n o t r eveal a n y Ig. Y o b s29 u si n g a si m i l ar m e t h od d e m o n st r a t e d Ig c a p t u r e d o n t r e p o n e m es in sy p h i l i t i c sk i n l e sions. In an o t h e r st u d y n ot yet p u b l i sh e d 7 o n e of u s al so e x am i n e d liver f r a gm e n t s f r o m 3 i c t e r i c
p at i e n t s w i t h se c o n d a r y sy p h i l i s an d n on e r eveal ed t h e p r ese n c e o f t h e sp i r oc h ae t e s. Fé h e r et a l 6 o n t h e o t h e r h an d e n c o u n t e r e d 7 o u t of 1 5 w i t h t r e p o n e m e s in se c o n d a r y sy p h i l i s. Bi o p si e s d o n e af t er t r e a t m e n t d i d n o t r eveal a n y sp i r oc h a e t e s in t he se p at i en t s. Si n c e w e a n d m a n y o t h e r s a u t h o r s have n ot f o u n d t r e p o n e m e s i n t h e l i ver w e ar e n ot ab l e t o asc r i b e t h e l e si o n s f o u n d i n o u r st u d y t o t h e t r e p on e m e s.
T h i s t y p e o f h e p a t i t i s seem s t o cur e w i t h o u t sequel ae.
In o n e o f o u r cases, b i o p si e d 3 0 d a y s af t er t h e o n se t of sk i n l e si on s, w e f o u n d c h r o n i c h e p a t i t i s w i t h p ie c e- m e al n ec r osis. T h e i m m u n o g l o b u l i n s w er e. n o t al t er ed an d H B sA g w a s n o t e n c o u n t e r e d . Fé h e r et al 6 d e sc r i b e d a si m i l ar case b u t w i t h al t er ed i m m u n o g l o b u l i n s leveis. Fi n a l l y , w e d i d n ot f i n d a n y r e l a t i o n sh i p b e t w e e n t h e i n t e n si t y of t h e l esion s, t h e t i m e o f d i se ase an d t he l i ver f u n c t i o n t est s.
R E F E R E N C E S
1. A L B E R T A Z Z I , F. , ST R A N I , G. F. , & SA R T O R I S, S. L 'e p a t i t i l ue t i ca sec on - d ar i a. Co n si d e r a z i o n i c l i n i c h e e p at oge- n e t ic h e e p r e se n t a zi on e d i u n c aso. G. It al . d e r m at o l . , 4 5 , 4 4 0 - 4 4 5 , 19 7 0 . 2. B A K E R , A . L . , K A P L A N , M. M. ,
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