Upsala J Med Sci 93: 233-244, 1988 Sequential Changes of the Plasma-protein Pattern in Cases of Hepatitis A Claes-Otto Kindmark,' Carl-Bertil Laurell,2 Sten Iwarson3 and Kennet P e r s o n 4 'Department of Infectious Diseases, University Hospital, Upqsala, 'Department of Clinical Chemistry, University of Lund, Malmo General Hospital, Mulmo, Department of Infectious Diseases, University of Gothenburg, Gothenburg, 4Department of Virology, University of Lund, Malmo General Hospital, Malmo, Sweden ABSTRACT T h e l e v e l o f 21 plasma p r o t e i n s was f o l l o w e d in H e p a t i t i s A f o r t w o m o n t h s a f t e r o n s e t o f i c t e r u s . T h e mean c o n c e n t r a t i o n o f a - a n t i t r y p s i n , orosomucoid, h a p t o g l o b i n , C - r e a c t i v e p r o t e i n ( C R P ) a n d a - a n t i c h y m o t r y p s i n i n c r e a s e d u n i f o r m e l y during t h e f i r s t week o f h e p a t i t i s A. T h u s , t h e y d i f f e r f r o m t h a t o f i n o c u l a t i o n h e p a t i t i s e a r l i e r d e s c r i b e d . T h e mean c u r v e f o r I g M was h i g h e r in h e p a t i t i s A t h a n t h e c o r r e s p o n d i n g r e s u l t s f o r i n o c u l a t i o n h e p a t i t i s during t h e f i r s t week o f illness, but because o f g r e a t i n t e r - i n d i v i d u a l d i f f e r e n c e s in c o n c e n t r a t i o n s I g M d e t e r m i n a t i o n s can n o t b e u s e d t o d i s c r i m i n a t e b e t w e e n t h e t w o diseases in a g i v e n case. I g A l e v e l s w e r e s l i g h t l y i n c r e a s e d e a r l y in h e p a t i t i s A but n o c h a n g e in I g C l e v e l s was o b s e r v e d . P r e a l b u m i n was t h e b e s t m i r r o r o f t h e p a t i e n t s ' r e c o v e r y o r d e t e r i o r a t i o n . 1 1 INTRODUCTION T h e d e t e c t i o n o f plasma p r o t e i n a b n o r m a l i t i e s i s o f v a l u e in t h e d i a g n o s i s a n d f o l l o w - u p of h e p a t i c d i s o r d e r s i n c l u d i n g h e p a t i t i s . A s e a r l y as t h e n i n e t e e n - f o r t i e s , G r a y a n d B a r r o n ( 8 ) showed t h a t h e p a t i t i s i s accompanied by a p o l y - clonal t y p e o f hypergammaglobulininemia a n d t h i s h a s s i n c e b e e n c o n f i r m e d by o t h e r s (3,4,7). Wollheim ( 2 2 ) was t h e f i r s t t o r e c o g n i z e a d i f f e r e n c e b e t w e e n h e p a t i t i s A a n d h e p a t i t i s B, namely, a s u b s t a n t i a l i n c r e a s e o f I g M in most cases of h e p a t i t i s A but in o n l y h a l f o f t h o s e o f h e p a t i t i s B. This d i f f e r e n c e h a s b e e n w i d e l y d i s p u t e d (6,12,14,19). S c a t t e r e d o b s e r v a t i o n s h a v e b e e n r e p o r t e d o n t h e v a r i a t i o n o f some p r o t e i n s during t h e c o u r s e o f h e p a t i t i s . B e l f r a g e ( 3 ) o b s e r v e d a low h a p t o g l o b i n l e v e l in s e r a f r o m p a t i e n t s w i t h h e p a t i t i s B, but n o t in s e r a f r o m t h o s e w i t h hepa- t i t i s A. M u l l e r a n d M u l l e r - v o n V o i g t ( 1 6 ) s t u d i e d t h e v a r i a t i o n s in 16 individ- u a l plasma p r o t e i n s in cases o f l i v e r disease a n d f o u n d a s e r i e s o f s i g n i f i c a n t changes in p a t i e n t s w i t h a c u t e h e p a t i t i s . T h e i r findings r e f e r t o s i n g l e o b s e r v a t i o n s during t h e e a r l y p h a s e of t h e disease. 15-888572 233 We h a v e p r e v i o u s l y r e p o r t e d o n t h e s e q u e n t i a l changes in t h e p a t t e r n o f plasma p r o t e i n s in h e p a t i t i s B 111). O u r findings h a v e b e e n c o n f i r m e d t o a, major e x t e n t (5,15,20.21) t h o u g h r e s u l t s h a v e b e e n i n t e r p r e t e d as a p p l y i n g t o a c u t e v i r a l h e p a t i t i s in g e n e r a l r a t h e r t h a n t o h e p a t i t i s B alone. T h e aim o f t h e p r e s e n t i n v e s t i g a t i o n was t o study t h e s e q u e n t i a l c h a n g e s in plasma p r o t e i n s in p a t i e n t s w i t h h e p a t i t i s A during a n a c u t e epidemic e n a b l i n g t h e c h a n g e s t o b e compared t o t h o s e r e p o r t e d in h e p a t i t i s B ( 1 1 ) . M A T E R I A L A N D METHODS P a t i e n t s : Thirty people a g e d 18-54 (mean 34) y e a r s w e r e i n f e c t e d w i t h h e p a t i t i s A in a f a c t o r y w h e r e a p o i n t - s o u r c e o u t b r e a k o c c u r r e d . Accumulated e v i d e n c e r e p o r t e d e a r l i e r ( 1 8 ) r e v e a l e d t h a t t h e y w e r e i n f e c t e d in t h e f a c t o r y canteen. T h e epidemic was o f s h o r t d u r a t i o n . T h e d i a g n o s i s was based o n epidemiological e v i d e n c e a n d a n t i - H A V d e t e r m i n a t i o n s . None o f t h e p a t i e n t s showed a n y serological e v i d e n c e o f h e p a t i t i s B. T h e c l i n i c a l c o u r s e o f t h e h e p a t i t i s A i n f e c t i o n was u n e v e n t f u l a n d a l l p a t i e n t s h a d normal l e v e l s o f s e r u m bilirubin a n d s e r u m alanine amino t r a n s f e r a s e ( S - A L A T 1 w i t h i n t h r e e m o n t h s o f o n s e t of t h e i r i l l n e s s . Blood sampling: T h e f i r s t b l o o d samples w e r e o b t a i n e d w i t h i n one week of o n s e t o f symptoms. T h e m a j o r i t y o f samples w e r e o f s e r u m w i t h o n l y a f e w plasma samples f r o m t h e f i r s t week o f t h e i l l n e s s . Plasma samples w e r e t h e n t a k e n a t w e e k l y i n t e r v a l s f o r a t least t e n weeks. T h e f o l l o w i n q 21 plasma p r o t e i n s w e r e d e t e r m i n e d : Prealbumin, albumin, orosomucoid, a - l i p o p r o t e i n . a - a n t i t r y p s i n , a - a n t i c h y m o t r y p s i n , ceruloplasrnin, a -macroglobulin, h a p t o g l o b i n , hemopexin, f i b r o n e c t i n ( e a r l i e r w r o n g l y d e s i g n a t e d AHF), t r a n s f e r r i n , C3, C4, plasminogen. p r o t h r o m b i n , p r o p e r d i n . i m m u n o g l o b u l i n C, i m m u n o g l o b u l i n A, i m m u n o g l o b u l i n M a n d C - r e a c t i v e p r o t e i n ( C R P ) . A l l t h e p l a s m a p r o t e i n analyses w e r e p e r f o r m e d by electroimmunoassay ( 1 3 ) w i t h t h e m o d i f i c a t i o n s d e s c r i b e d e a r l i e r (10,171. 1 2 R ESU LTS T h e p r o t e i n p a t t e r n u s u a l l y f o l l o w e d t h e same c o u r s e in a l l p a t i e n t s , t h o u g h it v a r i e d in i n t e n s i t y a n d in t h e d u r a t i o n of abnormal values. T h e r e s u l t s o f t h e d e t e r m i n a t i o n s o f al - a n t i t r y p s i n , orosomucoid a n d h a p t o - g l o b i n a r e summarized in Fig. 1. T h e y a r e p l o t t e d a g a i n s t t h e t i m e a f t e r i c t e r u s was o b s e r v e d . C u r v e s f o r t h e mean v a l u e s a r e g i v e n in t h e f i g u r e s . 234 2 6 0 2 0 0 1 6 0 1 2 0 8 0 LO % 2 00 160 1 2 0 80 LO g/l 2 4 2 0 1 6 1 2 0 8 0 4 Fig. U, A T R > 1 2 3 4 5 6 7 8 9 1 0 11 WEEKS O r o s o H P *I . + 1 2 3 4 5 6 7 8 9 1 0 1 1 W E E K S 1 Acute phase reactants (al-antitrypsin, orosomucoid, hapto- globin) during the course of hepatitis A . The normal (95 per cent) ranges a r e shaded and the mean value lines connected. 235 D u r i n g t h e f i r s t 2-3 weeks a u n i f o r m r i s e o f t h e s e t h r e e acute-phase r e a c t - a n t s i s noted. T h e n a g r a d u a l decrease o f t h e mean c o n c e n t r a t i o n s o f these, t h r e e acute-phase r e a c t a n t s o c c u r s o v e r a p e r i o d o f 5 weeks. H a v i n g r e t u r n e d t o t h e normal r a n g e t h e mean f o r a l - a n t i t r y p s i n , orosomucoid a n d h a p t o g l o b i n remained normal during t h e r e s t o f t h e p e r i o d o f o b s e r v a t i o n . a - a n t i c h y m o t r y p s i n - n o t s h o w n in a n y f i g u r e - followed t h e p a t t e r n o f orosomucoid v e r y closely. D e t e r m i n a t i o n s o f C - r e a c t i v e p r o t e i n (Fig. 2 w e r e i n i t i a l l y s l i g h t l y t o m o d e r a t e l y i n c r e a s e d but decreased c o n s i d e r a b l y a f t e r t h e f i r s t t w o weeks. 1 C R P 1 2 3 4 5 6 7 8 9 1 0 11 W E E K S F i g . 2 C - r e a c t i v e protein ( C R P ) d u r i n g t h e course of tiepatitis A . S e v e r a l p r o t e i n s showed a n i n i t i a l f a l l in c o n c e n t r a t i o n w i t h t h e lowest v a l u e a r o u n d t h e 10-14 d a y o f i l l n e s s f o l l o w e d by a g r a d u a l r e t u r n t o w a r d s normal values. P r e a l b u m i n ( F i g . 31, albumin, hemopexin a n d a - l i p o p r o t e i n demon- s t r a t e t h i s p a t t e r n . S t a r t i n g f r o m t h e normal r a n g e i n i t i a l l y t h e mean s e r u m a l b u m i n v a l u e r e a c h e d i t s lowest p o i n t ( 3 6 g / l ) during t h e second week a n d r e t u r n e d t o t h e normal r a n g e a f t e r one m o n t h . T h e mean c u r v e f o r hemopexin i n d i c a t e s v a l u e s well below t h e normal r a n g e by t h e time t h e p a t i e n t was h o s p i t a l i z e d ( 7 8 % o f t h e normal mean). T h e mean c u r v e r e a c h e d i t s lowest p o i n t (63% o f t h e normal mean) t e n d a y s a f t e r o n s e t o f t h e i l l n e s s a n d r e - t u r n e d t o i t s s t a r t i n g l e v e l in t h e third week. T h e mean c u r v e c o n t i n u e d t o i n c r e a s e g r a d u a l l y a n d r e a c h e d i t s h i g h e s t v a l u e s ( 8 7 % o f normal mean) a f t e r 7 weeks a n d remained a t t h a t l e v e l during t h e r e s t o f t h e p e r i o d o f o b s e r v a - t i o n . 236 P r e a l b 140 % I 1 2 0 1 0 0 80 60 2 o t I 9 1 2 3 4 5 6 7 8 9 10 11 W E E K S Fig. 3 Prealbumin during the course of hepatitis A . Too f e w plasma samples w e r e a v a i l a b l e f r o m t h e f i r s t week of i l l n e s s t o allow a n y d e f i n i t e c o n c l u s i o n s t o b e d r a w n a b o u t changes in p r o t h r o m b i n l e v e l s during t h i s p e r i o d . T h e mean c o n c e n t r a t i o n o f p r o t h r o m b i n in plasma samples a r o u n d d a y 10 was 80% of t h e normal mean. T h e r e a f t e r t h e mean p r o t h r o m b i n l e v e l r e m a i n e d normal. A third g r o u p o f p r o t e i n s i n c l u d i n g t r a n s f e r r i n (Fig. 4 ) . a2-macroglobulin ( F i g . 4 ) , ceruloplasmin a n d p r o p e r d i n showed o n l y m i n o r changes a n d t h e mean c u r v e remained e s s e n t i a l y c o n s t a n t w i t h i n t h e normal r a n g e during t h e whole t i m e of o b s e r v a t i o n . T h e same appears t r u e f o r plasminogen, f i b r o - nectin, C 3 a n d C4, p r o v i d e d allowances a r e made f o r t h e p a u c i t y o f plasma samples c o l l e c t e d during t h e f i r s t week of t h e i l l n e s s . 237 T 140 1 2 0 100 a o 60 40 2 0 YO 2 40 2 00 1 6 0 1 2 0 80 40 Fig. t 8 I 8 T f 1 2 3 4 5 6 7 8 9 10 11 W E E K S a 2 M a k r o 8 4 Transferrin and a2macroglobulin during the course of hepatitis A . T h e I g M v a l u e s v a r i e d g r e a t l y between t h e d i f f e r e n t p a t i e n t s a l t h o u g h t h e i n d i v i d u a l v a l u e s f o l l o w e d t h e mean c u r v e (Fig. 5 ) . Most p a t i e n t s a l r e a d y h a d peak l e v e l s of I g M o n admission, c o - i n c i d i n g w i t h t h e appearance o f jaundice. T h e v a l u e s g r a d u a l l y r e t u r n e d t o normal during t h e f o l l o w i n g months. T h e mean c u r v e s o f l e v e l s o f I g C a n d I g A w e r e b o t h w i t h i n t h e normal r a n g e during t h e whole p e r i o d of o b s e r v a t i o n . A s l i g h t i n c r e a s e in I g A l e v e l s ( F i g . 5 ) was, however, o b s e r v e d during t h e f i r s t t w o weeks o f illness. 238 . . 4 8 1 2 3 4 5 6 7 8 9 1 0 1 1 WEEKS . 7 1 2 3 4 5 6 7 8 9 1 0 1 1 W E E K S Fig. 5 Immunoglobulin M and A during hepatitis A . DISCUSSION T h e d a t a p r e s e n t e d a r e based o n samples d r a w n f r o m p a t i e n t s s u f f e r i n g f r o m h e p a t i t i s A . None o f t h e p a t i e n t s showed a n y serological e v i d e n c e o f h e p a t i t i s B. Thus, t h e d a t a o b t a i n e d m e r i t a comparison o f t h e s e q u e n t i a l c h a n g e s in p a t t e r n of plasma p r o t e i n s in h e p a t i t i s A w i t h t h o s e r e p o r t e d e a r l i e r f o r h e p a t i t i s B ( 1 1 1 . Since t h e p r e s e n t a t i o n o f t h e h e p a t i t i s B s e r i e s t h o s e s e r a h a v e b e e n c h e c k e d f o r a n t i b o d i e s t o h e p a t i t i s A as t h i s t e s t became available. No e v i d e n c e o f h e p a t i t i s A was f o u n d in t h o s e sera. 239 M u c h a t t e n t i o n h a s b e e n p a i d t o t h e changes in t h e s e r u m i m m u n o g l o b u l i n c o n c e n t e r a t i o n in cases o f h e p a t i t i s A a n d B . T h e I g M l e v e l s in h e p a t i t i s A r e p o r t e d h e r e showed t h a t t h e mean c u r v e f o r I g M r e a c h e d m u c h h i g h e r ’ v a l u e s t h a n t h e c o r r e s p o n d i n g c u r v e f o r h e p a t i t i s B. This is e v i d e n t f r o m t h e o n s e t o f t h e i l l n e s s w h e n t h e mean c u r v e f o r I g M s t a r t s a t 3.2 g / l compared t o 1 g / l f o r h e p a t i t i s B ( 1 1 ) . S u b s t a n t i a l i n t e r i n d i v i d u a l c h a n g e s w e r e seen in h e p a t i t i s A, i.e. t h e r e w e r e just as many p a t i e n t s s u f f e r i n g f r o m h e p a t i t i s A w i t h a n I g M v a l u e well a b o v e 4 g / l during t h e f i r s t week o f i l l n e s s as t h e r e w e r e p a t i e n t s w i t h a n I g M v a l u e below 2 g/l. Thus, I g M v a l u e s a f f o r d t h e c l i n i c i a n l i t t l e , if any, d i a g n o s t i c g u i d a n c e in a n y g i v e n case. In t h e c o u r s e o f h e p a t i t i s A we did n o t o b s e r v e a n y c h a n g e in I g C c o n c e n t r a - t i o n s . T h u s , o u r r e s u l t s c o n f i r m e d t h o s e r e p o r t e d by K r u g m a n , Giles a n d Hammond ( 1 2 ) a n d by C i l e s a n d K r u g m a n (6) but n o t t h o s e of Lo Grippo, H a y a s h i a n d S h a r p l e s s ( 1 4 ) . Bevan, Taswell a n d C l e i c h ( 4 ) o r Wollheim ( 2 2 ) . T h e s l i g h t i n c r e a s e in t h e I g A l e v e l s during t h e f i r s t t w o weeks o f h e p a t i t i s A r e p o r t e d h e r e was n o t o b s e r v e d f o r h e p a t i t i s B ( 1 1 ) . A f t e r t h e i n i t i a l m i n o r i n c r e a s e t h e mean c u r v e f o r I g A was almost i d e n t i c a l f o r h e p a t i t i s A a n d B . T h i s a g r e e s w i t h d a t a r e p o r t e d by Wollheim ( 2 2 ) . No e x p l a n a t i o n c a n b e o f f e r e d f o r t h e m a r k e d r e a c t i o n o f I g M in m a n y p a t i e n t s in t h e e a r l y phase o f h e p a t i t i s A a t t h e t i m e w h e n o n l y a m i n o r r e a c t i o n is f o u n d in h e p a t i t i s B . P e r h a p s t h e peak in I g M l e v e l s in h e p a t i t i s A may coin- c i d e w i t h t h e peak o f v i r u s s h e d d i n g in this disease t h o u g h it remains t o b e s h o w n t h a t t h e p a t i e n t s w i t h t h e h i g h e s t I g M v a l u e s a r e t h o s e t h a t s h e d t h e g r e a t e s t n u m b e r o f v i r u s p a r t i c l e s . T h e s l i g h t i n c r e a s e in plasma I g A l e v e l s during t h e f i r s t t w o weeks o f i l l n e s s in h e p a t i t i s A but n o t in h e p a t i t i s B remains u n c l e a r . H e p a t i c oedema w i t h c o n s e q u e n t l y i n c r e a s e d p o r t a l venous p r e s s u r e e a r l y in h e p a t i t i s A m i g h t b e a n e x p l a n a t i o n . T h e i n c r e a s e d p r e s s u r e in t h e p o r t a l v e i n a f f e c t s t h e b l o o d f l o w in t h e i n t e s t i n e . T h e I g A p r o d u c e d t h e r e m i g h t t h e r e b y b e f o r c e d b a c k i n t o t h e s y s t e m i c c i r c u l a t i o n . T h e c o n s t a n t r i s e in t h e v a l u e s o f t h e acute-phase r e a c t a n t s (a - a n t i t r y p s i n , orosomucoid, haptoglobin, CRP, a n d al - a n t i c h y m o t r y p s i n 1 w h i c h is c h a r a c t e r - i s t i c o f b a c t e r i a l i n f e c t i o n s , t r a u m a t i c lesions ( 2 ) a n d a s e p t i c n e c r o s i s ( 10) i s also d e m o n s t r a t e d in t h e e a r l y phase o f h e p a t i t i s A, as r e p o r t e d h e r e . This c o n t r a s t s t o t h e f i n d i n g s in h e p a t i t i s B ( 1 1 ) . F u r t h e r m o r e , in h e p a t i t i s A t h e h a r m o n i o u s r i s e o f a l - a n t i t r y p s i n , orosomucoid a n d h a p t o g l o b i n during t h e f i r s t week a f t e r t h e appearance of j a u n d i c e is a r e a c t i o n o f g r e a t r e g u l a r i t y , 1 240 as s h o w n in F i g . 6. In t h i s f i g u r e t h e mean c u r v e s a r e g i v e n f o r t h e s e t h r e e acute-phase r e a c t a n t s during t h e f i r s t week o f i l l n e s s . T h e scales u s e d a r e s u c h t h a t t h e v a l u e s f o r t h e s e t h r e e p r o t e i n s in h e a l t h y i n d i v i d u a l s w i l l b e a r o u n d 100% f o r a - a n t i t r y p s i n a n d orosomucoid a n d 1 g / l f o r h a p t o g l o b i n . T h i s p r o f i l e i s q u i t e d i f f e r e n t f r o m t h e one we h a v e r e p o r t e d f o r h e p a t i t i s B ( 1 1 ) . w h i c h i s i n c l u d e d in f i g u r e 6 f o r r e f e r e n c e . T h u s , t h e r e s p o n s e o f t h e s e a c u t e - p h a s e p r o t e i n s may b e u s e d a s a d i a g n o s t i c t o o l f o r d i f f e r e n t i a t i o n b e t w e e n h e p a t i t i s A a n d B, p a r t i c u l a r l y in t h o s e cases w h e n serological t e s t s in t h e s e diseases h a v e n o t g i v e n u n e q u i v o c a l r e s u l t s . T h e s e f i n d i n g s also s t r e s s t h e f a c t t h a t t h e d e t e r m i n a t i o n o f one acute-phase r e a c t a n t may n o t always s u f f i c e a n d m u c h b e t t e r i n f o r m a t i o n can b e o b t a i n e d if 2 o r 3 acute- phase p r o t e i n s a r e d e t e r m i n e d simultaneously. 1 100 200 % d, ATR Oroso 1.0 2.0 g / L F i g . 6 Relation b e t w e e n individual values of a - ; l n t i t r y p s i r , orosomucoid and haptoglobin d u r i n g t h e f i r s t week o f hepatitis A . T h e normal ( 9 5 p e r c e n t ) r a n g e s a r e shaded and t h e mean value l i n e s ( x - x) c o n n e c t e d . T h e corresponding mean value lines f o r h e p a t i t i s B ( 0 - - - 0 ) i s g i v e n f o r comparison. ( T h e individual v a l u e obtained f o r h e p a t i t i s B h a v e b e e n r e p o r t e d earlier ( 1 1 ) ) . 1 24 1 T h e c o n c e n t r a t i o n o f C - r e a c t i v e p r o t e i n may also a s s i s t in d i f f e r e n t i a t i o n b e t w e e n h e p a t i t i s A a n d B e a r l y in t h e illness. C o m p a r i n g t h e mean c u r v e o b t a i n e d f o r CRP in h e p a t i t i s A w i t h t h a t of h e p a t i t i s B a r r i v e d a t e a r l i e r ( 1 1 ) s i g n i f i c a n t l y h i g h e r l e v e l s w e r e seen in h e p a t i t i s A t h a n in h e p a t i t i s B, c o n f i r m i n g t h e r e s u l t s o b t a i n e d by H e d l u n d ( 9 ) . T h e d i f f e r e n t r e s u l t s f o r t h e acute-phase r e a c t a n t s r e p o r t e d h e r e compared t o t h o s e r e p o r t e d f o r h e p a t i t i s B e a r l i e r ( 1 1 ) s u g g e s t s t h a t t h e p a t h o l o g y o f t h e 2 t y p e s o f h e p a t i t i s is q u i t e d i f f e r e n t . T h e f i n d i n g s w o u l d b e c o n s i s t e n t w i t h a p r o n o u n c e d c e l l u l a r r e a c t i o n w i t h an i n c r e a s e d a c t i v i t y of g r a n u l o c y t e s o r monocytes in h e p a t i t i s A but n o t in h e p a t i t i s B. When m o n i t o r i n g t h e p a t i e n t s s u f f e r i n g f r o m h e p a t i t i s A it i s h e l p f u l t o h a v e a v z r i a b l e t h a t r e f l e c t s t h e c l i n i c a l c o u r s e of t h e disease. T h e S - A L A T , v e r y o f t e n u s e d in t h i s r e s p e c t , c o u l d p r o v i d e e r r o n e o u s i n f o r m a t i o n as l e v e l s may decrease i n s t e a d o f i n c r e a s e w h e n t h e p a t i e n t i s g r a d u a l l y g e t t i n g c r i t i c a l l y ill. T h e r e s u l t s o f t h i s s t u d y w o u l d seem t o i n d i c a t e t h a t t h e p r e a l b u m i n v a l u e s w e r e t h e b e s t m i r r o r o f t h e p a t i e n t s ' r e c o v e r y o r d e t e r i o r a t i o n during t h e c o u r s e o f h e p a t i t i s A . T h i s i s in agreement w i t h e a r l i e r r e p o r t s (1,11,15,16,20,21). REFER EN C ES 1. A l y , F.W. E Schaup, H.: Eine q u a n t i t a t i v e Bestimmung d e s t r y p t o p h a n - r e i c h e n Serumpraealbumin im A g a r - A g a r . C l i n Chim A c t a 4:88-95, 1959. 2. Aronsen, K . - F . , Ekelund, C., K i n d m a r k , C.-0. E L a u r e l l , C . - B . : S e q u e n t i a l changes of plasma p r o t e i n s a f t e r s u r g i c a l t r a u m a . Scand J C l i n L a b I n v e s t 29, S u p p l . 124:127-136, 1972. 3. B e l f r a g e , S . : Plasma p r o t e i n p a t t e r n in c o u r s e o f a c u t e i n f e c t i o u s disease. A c t a Med Scand, S u p p l . 395, 1963. 4. 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