M E A S U R E M E N T O F U N C O N J U G A T E D H Y P E R B I L I R U B I N E M I A I N G I L B E R T ' S S Y N D R O M E D U R I N G C O M P U L S O R Y F A S T I N G
S a i l K a p ı c ı o ğ l u / M u s t a f a Ç e t i n e r / A b d u l h a l i m B a l d
M. D., S ub -de pa rtm e nt o f G astroenterology, D e pa rtm e nt o f In te rn a l M edicine, S cho ol o f Medicine, K ara de niz T echnical University, Trabzon, Turkey.
A B S T R A C T
Objective:
W e in v e s tig a te d th e e ffe c t of c o m p u ls o ry fa s tin g on u n c o n ju g a te d h y p e rb iliru b in e m ia in te n a dult p a tie n ts w ith G ilb e rt's s y n d ro m e d u rin g R a m a d a n (a fa s tin g p e rio d o f 30 d a y s ).Methods:
A t 4 a.m . an d 8 p.m . th e y w e re g iv e n m e a ls w h ic h c o n ta in e d a to ta l of a p p ro x im a te ly 2 5 0 0 cal. A fte r th e 4 a.m . b a s e lin e m e a s u re m e n t w a s ta k e n , th e p a tie n ts did n o t e a t o r d rin k a n y th in g fo r 16 hr fo r re lig io u s re a s o n s . T he s e ru m to ta l a n d in d ire c t b iliru b in c o n c e n tra tio n s w e re m e a s u re d e v e ry w e e k d u rin g th is 4 w e e k p e rio d o f c o m p u ls o ry fa s tin g .R e su lts:
P re fa s tin g b a s a l m e a n s e ru m b iliru b in c o n c e n tra tio n s w e re : to ta l b iliru b in 1 .4 ± 0 .0 6 m g/dl, c o n ju g a te d b iliru b in 0 .4 ± 0 .0 3 m g /d l, u n c o n ju g a te d b iliru b in 1 .0 ± 0 .0 5 m g /d l. O n th e firs t d a y a fte r a 16 h fa s tin g th e v a lu e s w e re : to ta l b iliru b in 2 .6 ± 0 .0 6 m g/dl, c o n ju g a te d b iliru b in 0 .4 ± 0 .0 3 m g /d l an d u n c o n ju g a te d b iliru b in 2 .1 1 0 .1 2 m g /d l. In th is p e rio d , c o n ju g a te d b iliru b in re m a in e d u n c h a n g e d w h ile to ta l an d u n c o n ju g a te d b iliru b in s ig n ific a n tly in c re a s e d c o m p a re d to th e b a s a l v a lu e (p < 0 .0 1 3 ). O n th e 7th, 14th, an d 30 th d a y of fa s tin g th e s e ru m to ta l and u n c o n ju g a te d b iliru b in d e c re a s e d to basal va lu e . T he m e a n to ta l b iliru b in le ve l w a s 1 .4 1 0 .0 4 m g/dl, 1.410.11 m g /d l a n d 1 .3 1 0 .0 6 m g /d l on th e 7th, 14th an d 30th d a y re s p e c tiv e ly . T h e m e a n u n c o n ju g a te d b iliru b in le v e l w a s 0 .9 1 0 .0 4 m g /d l, 0 .9 1 0 .0 9 m g /d l a nd 0 .8 1 0 .0 9 m g /d l re s p e c tiv e ly .Conclusion:
C o m p u ls o ry fa s tin g d u rin g R a m a d a n (a p e rio d o f 30 d a y s ) re s u lte d in an in c re a s e in p la s m a u n c o n ju g a te d b iliru b in c o n c e n tra tio n s on th e firs t da y of fa s tin g . T h e n it d e c re a s e d to b asal v a lu e on th e 7th, 14th an d 3 0 th d a y in p a tie n ts w ith G ilb e rt's s y n d ro m e . It is a s s u m e d th a t th e s e re s u lts m a y be im p o rta n t in d ia g n o s in g G ilb e rt's s y n d ro m e an d its c lin ic a l fe a tu re s in th e M u s lim p o p u la tio n .K e y W o r d s : U n c o n ju g a te d h yp e rb iliru b in e m ia , G ilb e rt's s y n d ro m e , C o m p u ls o ry fa s tin g
I N T R O D U C T I O N
G ilb e rt's s y n d ro m e ha s b een g e n e ra lly d e fin e d as m ild, c h ro n ic , o r in te rm itte n t u n c o n ju g a te d h y p e rb iliru b in e m ia th a t o c c u rs in th e a b s e n c e of ove rt h e m o ly s is an d in trin s ic liv e r d is e a s e (1 ). A lth o u g h this a p p a re n t s y n d ro m e m a y be c a u s e d by m ore th a n one fa cto r, it s e e m s that, in a d d itio n to m ild u n co n ju g a te d h y p e rb iliru b in e m ia , th e m o s t c o n s is te n t bio ch em ica l a b n o rm a lity is p e rs is te n t partial re d u c tio n of hepatic b iliru b in u rid in e d ip h o s p h a te g lu c u ro y ltra n s fe r a s e (U D P G -T ) a c tiv ity (2,3). A lth o u g h th e d ia g n o s is of G ilb e rt’s s y n d ro m e is m o s t o fte n m a d e by e xclu s io n of s tru c tu ra l liv e r a b n o rm a litie s an d h e m o ly s is a nd by the re p e a te d fin d in g o f u n c o n ju g a te d h y p e rb iliru b in e m ia , it is w ell kn o w n th a t G ilb e rt's s y n d ro m e a lso ca n be d ia g n o s e d b y m o re s p e c ific te s ts (4 ). T h e m e a s u re m e n t o f b iliru b in k in e tic s a fte r an in tra v e n o u s in je c tio n o f c o ld c ry s ta llin e p ig m e n t (5 ,6 ) or ra d io la b e lle d b iliru b in (7) o r c o m p u ta tio n by m a th e m a tic a l m e th o d s from s u rviva l of 51C r-la b e lle d e ry th ro c y te s (8) p e rm its th e m o s t re lia b le d o c u m e n ta tio n o f im p a ire d b iliru b in c le a ra n c e . Latent G ilb e rt's s y n d ro m e m a y b e u n m a s k e d by h e m o lytic s tre s s (9) an d th e m e a s u re m e n t o f b iliru b in c le a ra n c e m a y b e in s u ffic ie n tly s e n s itiv e in such in sta n ce s. In the a b s e n c e of s tru c tu ra l liv e r d is e a s e , a re d u ce d he p a tic b iliru b in a c tiv ity U D P G -T is th e m o s t re lia b le m a rk e r for id e n tify in g p e o p le w h o c a rry th e g e n e tic p re d is p o s itio n fo r th is d is o rd e r (1 0 ,1 1 ). In m o s t cases, how ever, n e e d le b io p s y of th e liv e r is not e th ic a lly ju s tifie d in the a b s e n c e o f c lin ic a l an d b io c h e m ic a l signs of liver d is e a s e . T h e m o s t p o p u la r n o n in v a s iv e te s ts used in th e d ia g n o s is o f G ilb e rt's s y n d ro m e are th e ca lo ric re s tric tio n (1 2 -1 4 ) an d th e n ic o tin ic acid te s ts (15,16). In b oth in s ta n c e s th e s e p ro v o c a tiv e te s ts p ro d u c e a s ig n ific a n t in c re a s e (m o re th a n 100% o f b asal values)
(R e c e iv e d 15 J a n u a r y , 19 9 9) M a rm a ra M e d ic a l J o u r n a l 19 9 9 ;1 2 ( 4 ) :1 71 -17 4
Sait Kapicioglu, et al
of serum u n c o n ju g a te d b iliru b in in th e v a s t m a jo rity of G ilb e rt's p a tie n ts .
T h e M u slim c o m m u n ity fo rm s a b o u t o n e th ird o f th e w o rld 's p o p u la tio n . U n c o n ju g a te d b iliru b in m a y be in c re a s e d in p a tie n ts w ith G ilb e rt's s y n d ro m e d u rin g c o m p u ls o ry fa s tin g . T h e re fo re , w e in v e s tig a te d th e e ffe c t o f c o m p u ls o ry fa s tin g on u n c o n ju g a te d h y p e rb iliru b in e m ia in p a tie n ts w ith G ilb e rt's sy n d ro m e .
M A T E R I A L S A N D M E T H O D S
T h e s u b je c ts o f th is s tu d y w e re te n a d u lts w ith m ild, c h ro n ic o r re c u rre n t, u n c o n ju g a te d h y p e rb iliru b in e m ia in w h o m h e m o ly s is w a s not e v id e n t and th e u su a l te s ts o f liv e r fu n c tio n w e re w ith in no rm a l lim its. O v e rt h e m o ly s is w a s e x c lu d e d by th e a b s e n c e o f a n e m ia and re tic u lo c y to s is . T h e s e ru m b iliru b in c o n c e n tra tio n w as e s tim a te d by th e M a llo ry -E v e ly n m o d ific a tio n of th e V an de n B erg re a c tio n (17). S erial d e te rm in a tio n of fra c tio n a l s e ru m b iliru b in w e re o b ta in e d th ro u g h o u t th e R a m a d a n (a p e rio d o f 30 d a ys). A t 4 a.m . a nd 8 p.m . th e y w e re g iv e n m e a ls w h ic h c o n ta in e d a to ta l of a p p ro x im a te ly 2 5 0 0 c a l (a p p r o x im a te ly 3 0 g r o f c a rb o n h y d ra te , 20 g p ro te in and 10 gr o f fa t). A fte r th e 4 a.m . b a s e lin e m e a s u re m e n t w a s ta k e n , th e p a tie n ts did not e a t o r d rin k a n y th in g fo r 16 h fo r re lig io u s reasons.
T h e s e ru m to ta l a n d in d ire c t re a c tin g b iliru b in c o n c e n tra tio n s w e re m e a s u re d e v e ry w e e k d u rin g th is m onth of c o m p u ls o ry fa s tin g . S tu d e n t’s t-te s t w a s used fo r sta tis tic a l a n a ly s is (18).
R E S U L T S
T h e re s u lts a re s u m m a riz e d in fig. 1. T h e p re fa s tin g b a s a l m e a n s e ru m b iliru b in c o n c e n tra tio n w a s : to ta l b iliru b in 1 .4 ± 0 .0 6 m g /d l, c o n ju g a te d b iliru b in 0 .4 ± 0 .0 3 m g/dl, u n c o n ju g a te d b iliru b in 1 .0 ± 0 .0 5 m g/dl. O n th e firs t d a y a fte r a 16 h fa s tin g th e v a lu e s w e re : to ta l b iliru b in 2 .6 ± 0 .0 6 m g /d l, c o n ju g a te d b iliru b in 0 .4 + 0 .0 3 m g /d l a nd u n c o n ju g a te d b iliru b in 2 .1 1 0 .1 2 m g /d l. In th is p e rio d c o n ju g a te d b iliru b in re m a in e d u n c h a n g e d w h ile to ta l and u n c o n ju g a te d b iliru b in s ig n ific a n tly in c re a s e d c o m p a re d to th e b a s a l v a lu e (p < 0 .0 1 3 ). O n th e 7 th , 14th a n d 30 th d a y o f fa s tin g th e s e ru m total an d u n c o n ju g a te d b iliru b in d e c re a s e d to b a sa l va lu e . T h e m e a n to ta l b iliru b in le v e ls w e re 1 .4 1 0 .0 4 m g/dl, 1.410.11 m g/dl an d 1 .3 1 0 .0 6 m g /d l on th e 7th, 14th a nd 30 th d a y re s p e c tiv e ly . T h e m e a n u n c o n ju g a te d b iliru b in le v e ls w e re 0 .9 1 0 .0 4 m g /d l, 0 .9 1 0 .0 9 m g/dl an d 0 .8 + 0 .0 9 m g /d l re s p e c tiv e ly . D I S C U S S I O N T h is s tu d y in d ic a te s a re c ip ro c a l re la tio n s h ip b e tw e e n c o m p u ls o ry fa s tin g a n d th e d e g re e o f h y p e rb iliru b in e m ia in G ilb e rt's s y n d ro m e . T h e s e ru m b iliru b in c o n c e n tra tio n in c re a s e s a fte r a b rie f fa s tin g in all p a tie n ts w ith G ilb e rt's s y n d ro m e . In c o n tra s t, the m e a n s e ru m b iliru b in c o n c e n tra tio n did n o t c h a n g e d u rin g th e s e c o n d an d th ird an d fo u rth w e e k of c o m p u ls o ry fa s tin g . It is im p o rta n t to re c o g n iz e th a t th e ra te o f e le v a tio n in G ilb e rt's s y n d ro m e is v e ry rapid, m a x im u m v a lu e s re a c h e d w ith in 2 4 to 4 8 h o u rs (19). T h is im m e d ia te e ffe c t o f fa s tin g o n s e ru m
Baseline Day
1
Day7
Day14
j Total —» —Conjugate
—
àc—
UnconjugateFig-1 : Level of serum bilirubin value in patients with Gilbert's syndrome during compulsory fasting (X±SEM ) (*p<0.05 difference from basal level)
Gilbert’s syndrome and compulsory fasting
u n c o n ju g a te d b iliru b in c o n c e n tra tio n in p a tie n ts w ith G ilb e rt's s y n d ro m e c o n tr a s ts s h a rp ly w ith th e a p p a re n tly p ro lo n g e d p e rio d o f fa s tin g re q u ire d to in d u c e a s ig n ific a n t in c re a s e in p la s m a b ro m s u lfa le in re te n tio n re p o rte d fo r o b e s e s u b je c ts (19). It is w ell k n o w th a t re d u c tio n o f c a lo ric in ta k e c a u s e s a m uch g re a te r a b s o lu te ris e in s e ru m b iliru b in c o n c e n tra tio n in p a tie n ts w ith G ilb e rt's s y n d ro m e c o m p a re d to n o rm a l p e o p le (12). A lm o s t 70 y e a rs a go, G ilb e rt an d H e rs c h e r (20) re p o rte d th a t the s e ru m b iliru b in c o n c e n tra tio n in 3 no rm a l a d u lts w a s m a x im a l a fte r an o v e rn ig h t fa s tin g . M o re s u b s ta n tia l s tu d ie s s h o w e d th a t th e s e ru m b iliru b in level in c re a s e d slig h tly , b u t re m a in e d w ith in the n o rm a l ra n g e in h e a lth y in d iv id u a ls a fte r a b rie f fa s tin g (2 0 ,2 1 ).
F lu c tu a tio n in th e level o f s e ru m b iliru b in has b een c o n s id e re d c h a ra c te ris tic in p a tie n ts w ith G ilb e rt's s y n d ro m e (21). V a rio u s fa c to rs h a v e b e e n im p lic a te d to e x p la in th e s e flu c tu a tio n s , a lth o u g h u s u a lly w ith o u t q u a n titiv e e v id e n c e . T h e fa c to rs m o s t c o m m o n ly m e n tio n e d a re p h y s ic a l e x e rtio n , e m o tio n a l upset, in fe c tio n a n d a lc o h o l. In th e lig h t o f c u rr e n t o b s e rv a tio n s , c a lo ric d e p riv a tio n s m a y w e ll a c c o u n t fo r s o m e of th e n a tu ra lly o c c u rrin g flu c tu a tio n s o f s e ru m b iliru b in in p a tie n ts w ith th is d is o rd e r. It is not e x c lu d e d th a t a d d itio n a l fa c to rs , in d e p e n d e n t o f c a lo ric intake, m a y a lso a ffe c t th e le ve l o f s e ru m b iliru b in in th is d is o rd e r. T h e m e c h a n is m o f th e re c ip ro c a l re la tio n b e tw e e n c a lo ric in ta k e a n d th e d e g re e of h y p e rb iliru b in e m ia in G ilb e rt's s y n d ro m e is u n k n o w n . It is kn o w n th a t s ta rv a tio n o f ra ts le a d s to a s ig n ific a n t d e c re a s e in h e p a tic u rid in e d ip h o s p h a te g lu c u ro n y l tra n s fe ra s e a c tiv ity w h ic h is n o t d u e to g e n e ra liz e d c a ta b o lis m o f liv e r p ro te in . T h e s tre s s o f s ta rv a tio n of c o u rs e w a s m u ch m o re s e v e re fo r th e rat th a n re d u c e d c a lo ric in ta k e fo r m a n . It re m a in s a p o s s ib ility th a t th e fa s tin g d o e s in fa c t re d u c e th e c o n ju g a tin g e n zym e , th o u g h it is u n lik e ly to be th e e n tire e x p la n a tio n . T he s tu d y fo u n d th a t d e c re a s e d c le a ra n c e of 3H -b iliru b in on fa s tin g w a s a s s o c ia te d w ith a d e c re a s e d rate- of tr a n s fe r o f b iliru b in in to th e liv e r c e ll. T h is is p re s u m a b ly in d e p e n d e n t o f s u b s e q u e n t c o n ju g a tio n . In o n ly o n e p a tie n t d id in v e s tig a to rs fin d e v id e n c e for d e c re a s e d c o n ju g a tio n (22).
In c o n c lu s io n , c o m p u ls o ry fa s tin g d u rin g R a m a d a n re s u lte d in an in c re a s e in p la s m a u n c o n ju g a te d b iliru b in c o n c e n tra tio n on th e firs t d a y o f fa s tin g . T hen it d e c re a s e d to b a sa l v a lu e s on th e 7th, 14th and 30th d a y in p a tie n ts w ith G ilb e rt's s y n d ro m e . It is a s s u m e d th a t th e s e re s u lts m a y be im p o rta n t in d ia g n o s in g G ilb e rt’s s y n d ro m e a n d its c lin ic a l fe a tu re s in th e M u slim p o p u la tio n .
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