© 2022 The Au ho (s).
Published by S. Ka ge AG, Basel
Single Case
Case Rep Gas oen e ol 2022;16:452–455
Ro o Synd ome P esen ing as
Dubin-Johnson Synd ome
Ma iana Mo ais a Philippe Cou e b, c Isabelle Jé u d, e
Ma iana Ve delho Machado a,
aGas oen e ology Depa men , Faculdade de Medicina da Uni e sidade de Lisboa,
Lisbon, Po ugal; bSe ice de Biochimie Endoc inienne e Oncologique, APHP So bonne
Uni e si é Hôpi al de la Pi ié-Salpê iè e, Pa is, F ance; cUni é de eche che su les
maladies ca dio asculai es e mé aboliques, So bonne Uni e si é-Inse m, Pa is, F ance;
dDépa emen de Géné ique, Hôpi al Pi ié-Salpê iè e, Pa is, F ance; eCen e de Reche che
Sain -An oine (CRSA), So bonne Uni e si é-Inse m, Pa is, F ance; Gas oen e ology
Depa men , Hospi al de Vila F anca de Xi a, Lisbon, Po ugal
Keywo ds
Conjuga ed hype bili ubinemia · Dubin-Johnson synd ome · ABCC2/MRP2 · Ro o synd ome ·
SLCO1B3/OATP1B
Abs ac
A 42-yea -old man wi h no ele an pas medical his o y p esen ed wi h in e mi en mild ic-
e us and no signs o ch onic li e disease. Labo a o y es s we e no able o hype bili ubine-
mia ( o al 7.97 mg/dL, di ec 5.37 mg/dL), bili ubinu ia, no signs o hemolysis, no mal li e es s
and lipids p o ile. Abdominal ul asound was un ema kable. A panel o ch onic li e diseases
was nega i e excep o inc eased se um (147.4 μg/dL) and u ina y (179 μg/24 h) coppe , wi h
no mal ce uloplasmin. No o he Leipzig c i e ia o Wilson’s disease we e ound, including a
nega i e es o ATP7B gene mu a ions (by exome sequencing). To al u ina y cop opo phy in
was no mal wi h p edominance o isome I (86% o o al u ina y cop opo phy in ou pu ).
Clinical and labo a o ial p o ile was compa ible wi h Dubin-Johnson synd ome; howe e ,
exome sequencing and sea ch o dele ions in he ABBC2 gene (encoding MRP2) only ound
a he e ozygous po en ially pa hogenic a ian (c.1483A>G – p.Lys495Glu). Addi ional ex ended
molecula analysis o genes implica ed in bili ubin me abolism ound a homozygous dele ion
o a egion encompassing exons 4–16 o SLCO1B3 gene (encoding OATP1B3) and all SLCO1B1
exons (encoding OATP1B1), he eby es ablishing Ro o synd ome diagnosis. Ro o and Dubin-
Johnson synd omes a e a e au osomal ecessi e li e diseases cha ac e ized by ch onic
conjuga ed hype bili ubinemia, caused by he absence o he hepa ic unc ion OATP1B1/B3
(leading o impai ed hepa ic bili ubin eup ake and s o age) and MRP2 anspo e s (leading
Recei ed: Ap il 15, 2022
Accep ed: June 8, 2022
Published online: Augus 16, 2022
Co espondence o:
Ma iana Mo ais, ma ianamo ais971229 @ gmail.com
www.ka ge .com/c g
This a icle is licensed unde he C ea i e Commons A ibu ion-NonComme cial 4.0 In e na ional License
(CC BY-NC) (h p://www.ka ge .com/Se ices/OpenAccessLicense). Usage and dis ibu ion o comme cial
pu poses equi es w i en pe mission.
DOI: 10.1159/000525517
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453
Case Rep Gas oen e ol 2022;16:452–455
Mo ais e al.: Ro o Synd ome P esen ing as Dubin-Johnson Synd ome
www.ka ge .com/c g
© 2022 The Au ho (s). Published by S. Ka ge AG, Basel
DOI: 10.1159/000525517
o impai ed hepa ic bili ubin exc e ion), espec i ely. We epo a case o compound he edi a y
hype bili ubinemia wi h a misleading p esen a ion wi h special ocus on i s diagnosis, pa -
icula ly he ad an age o ex ensi e unbiased gene ic es ing by dedica ed labo a o ies. Wi h
his case, we aim o highligh he necessi y o es ablishing a diagnosis, eassu ing he pa ien ,
and a oiding unnecessa y in asi e and cos ly diagnos ic p ocedu es.
© 2022 The Au ho (s).
Published by S. Ka ge AG, Basel
In oduc ion
Ele a ion o plasma/se um bili ubin concen a ion is o en encoun e ed in e e yday
clinical p ac ice. Unde s anding he ela i e likelihood o di e en disease p ocesses can help
o in es iga e and es ablish he diagnosis app op ia ely. Inhe i ed diso de s o bili ubin
me abolism esul in ei he a educed bili ubin up ake by hepa ocy es, bili ubin conjuga ion,
hepa ocy e s o age, o sec e ion o bili ubin in o bile. Two known inhe i ed diso de s
mani es by isola ed conjuga ed hype bili ubinemia: Dubin-Johnson synd ome (DJS) and
Ro o synd ome (RS). Al hough uncommon, hei diagnosis is c ucial since di e en ia ion
om o he mo e se ious diso de s can p e en hese pa ien s om unnecessa y p ocedu es
and anxie y.
DJS is a a e unde diagnosed diso de , which consis s o he edi a y hype bili ubinemia,
cha ac e ized by mild ele a ion o conjuga ed bili ubin and no o he signs o hepa ic inju y,
due o a de ec on he mul id ug esis ance-associa ed p o ein 2 (MRP2). Li e biopsy in DJS
is cha ac e is ic o he accumula ion o a da k, g anula pigmen in cen ilobula hepa ocy es
in an o he wise no mal li e . RS is a amilial condi ion wi h au osomal ecessi e ansmission,
whe e hepa ic eup ake and s o age a e impai ed due o a de ec in he o ganic anion ans-
po ing polypep ide 1B1 and 1B3 anspo e s (OATP1B1 and OATP1B3, espec i ely) [1].
Biologically, u ina y cop opo phy in exc e ion dis inguishes hem: in RS, o al cop opo -
phy in u ina y exc e ion is inc eased 2- o 5- old being 65% cop opo phy in I, and in DJS,
u ina y cop opo phy in le els a e no mal, bu being o e 80% cop opo phy in I [2]. We
aimed o desc ibe a case o complex he edi a y hype bili ubinemia wi h a misleading p esen-
a ion, highligh ing he necessi y o in-dep h gene ic es ing.
Case Repo
An o he wise heal hy 42-yea -old Caucasian man p esen ed mild in e mi en ic e us
and a igue. He denied abdominal pain, e e , p u i us, cholu ia, acholia, o o he symp oms.
Consump ion o alcohol, obacco, p esc ibed o o e - he-coun e medicines was also excluded.
Apa om scle al ic e us, physical examina ion was un ema kable, wi h no s igma a o
ch onic li e disease. Labo a o y es s we e no able o hype bili ubinemia ( o al 7.97 mg/
dL and di ec 5.37 mg/dL) and bili ubinu ia, no signs o hemolysis, no mal li e es s (AST
21 U/L, ALT 32 U/L, GGT 21 U/L, ALP 74 U/L, albumin 5.3 g/dL, PT 12.5 s) and lipids p o ile.
Abdominal ul asound was un ema kable. A panel o ch onic li e diseases ( i al, au o-
immune, and me abolic) was nega i e excep o inc eased se um (147.4 μg/dL) and u ina y
(179.9 μg/24 h) coppe , wi h no mal ce uloplasmin le els. No o he Leipzig c i e ia o
Wilson’s disease we e ound, including a nega i e gene ic es o ATP7B gene a ian s (by
exome sequencing). Cop opo phy in analysis showed ha o al u ina y cop opo phy in le el
was no mal wi h p edominance o isome I (86% o o al). The clinical and labo a o ial p o ile
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454
Case Rep Gas oen e ol 2022;16:452–455
Mo ais e al.: Ro o Synd ome P esen ing as Dubin-Johnson Synd ome
www.ka ge .com/c g
© 2022 The Au ho (s). Published by S. Ka ge AG, Basel
DOI: 10.1159/000525517
was compa ible wi h DJS; howe e , only a he e ozygous a ian o he ABBC2 gene encoding
MRP2 (c.1483A>G – p.Lys495Glu) was ound. Addi ional molecula s udies e ealed a homo-
zygous dele ion o a genomic egion encompassing exons 4–16 o SLCO1B3 gene (encoding
OATP1B3) and all exons o SLCO1B1 (encoding OATP1B1), consis en wi h RS diagnosis.
Discussion
We p esen a pa ien wi h p edominan ly conjuga ed hype bili ubinemia bu o he wise
no mal li e es s, inc eased u ina y coppe and u ina y cop opo phy in isome I ac ion.
No mal se um hap oglobin and blood ilm excluded hemolysis; clinical and imaging in es i-
ga ions did no show any signs o bilia y obs uc ion. Howe e , speci ic bilia y imaging such
as MRCP was no pe o med which migh be poin ed ou as a limi a ion o his epo as well
as he lack o a his ological analysis o p omp ly exclude DJS. Conside ing he p esen ed da a,
a e inhe i ed diso de s o bili ubin me abolism we e hypo hesized, DJS being he mos likely
diagnosis since an in e ed a io o u ina y exc e ed cop opo phy in isome s I and III was
ound. Unde no mal ci cums ances, cop opo phy in I is p e e en ially exc e ed in bile
(accoun ing o 65% o bilia y cop opo phy in), whe eas cop opo phy in III isome is p e -
e en ially elimina ed in u ine (accoun ing o 75% o u ina y cop opo phy in). Se e al hepa-
obilia y diso de s, including choles asis, p esen inc eased o al u ina y cop opo phy in,
e lec ing he di e sion in o u ine o ma e ial no mally exc e ed in o bile, wi h an inc ease in
he u ina y p opo ion o isome I, which is almos always below 65% o o al. In DJS, o al
u ina y cop opo phy in exc e ion is no mal bu o e 80% is exc e ed as cop opo phy in I,
due o an inc eased e lux o isome I back in o he sinusoid [3]. The ini ial gene ic app oach
consis ed o exome sequencing and dele ion sea ch on ABCC2 gene, inding only a he e o-
zygous a ian , which could no con i m he clinical suspicion o DJS, an au osomal ecessi e
condi ion. A e wa d, a mul igene panel e alua ion unexpec edly ound a newly epo ed
dele ion encompassing SLCO1B1 whole-gene and exons 4–16 o SLCO1B3, which esul s in
comple e OATP1B1 and OATP1B3 de iciency, and con i med he diagnosis o RS. U ina y
exc e ion o cop opo phy ins is he mos impo an diagnos ic ool o di e en ia e DJS om
RS. Con a y o DJS, in RS, o al cop opo phy in exc e ion in u ine is inc eased and isome I
is usually <75–80%, in line wi h he in e ac ion o se e al po phy ins wi h OATP1B1 [4]. The
pheno ypical pa e n showed in his RS case migh be due o modula ion o po phy in
exc e ion by he he e ozygous a ian o ABCC2 (c.1483A>G). Addi ionally, he deg ee o
cup u ia obse ed in his case makes i a unique p esen a ion o RS. Wilson’s disease was
ex ensi ely excluded, no ul illing Leipzig c i e ia and a e nega i e gene ic es ing o ATP7b
gene mu a ions. One explana ion o cup u ia in his pa ien could be he he e ozygous
mu a ion o ABCC gene, which migh p eclude he al e na i e bilia y exc e ion pa hway o
coppe [5] coupled wi h he eup ake de ec om RS esul ing in coppe accumula ion in
ci cula ing plasma and subsequen inc eased u ina y exc e ion. Al hough benign and a e,
es ablishing RS o DJS diagnosis is c ucial o eassu e he pa ien , a oid unnecessa y in asi e
and cos ly diagnos ic p ocedu es, and o p e en decompensa ion du ing in e cu en illness,
p egnancy, o d ug oxici y isks.
S a emen o E hics
E hical app o al is no equi ed o his s udy in acco dance wi h local and/o na ional
guidelines. W i en in o med consen was ob ained om he pa ien o publica ion o he
de ails o hei medical case.
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455
Case Rep Gas oen e ol 2022;16:452–455
Mo ais e al.: Ro o Synd ome P esen ing as Dubin-Johnson Synd ome
www.ka ge .com/c g
© 2022 The Au ho (s). Published by S. Ka ge AG, Basel
DOI: 10.1159/000525517
Con lic o In e es S a emen
The au ho s ha e no con lic s o in e es o decla e.
Funding Sou ces
None unding sou ces o epo .
Au ho Con ibu ions
Ma iana Mo ais w o e he manusc ip . Philippe Cou e pe o med gene ic analysis and
e ised he manusc ip . Isabelle Jé u and Ma iana Ve delho Machado e ised he manusc ip .
Da a A ailabili y S a emen
All da a analyzed du ing his s udy a e included in his a icle. Fu he inqui ies can be
di ec ed o he co esponding au ho .
Re e ences
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2 Van De S eeg E, S ánecký V, Ha manno á H, Nosko á L, H ebicek M, Wagenaa E, e al. Comple e OATP1B1
and OATP1B3 de iciency causes human o o synd ome by in e up ing conjuga ed bili ubin eup ake in o
he li e . J Clin In es . 2012; 122(2): 519–28.
3 F ank M, Doss MO. Rele ance o u ina y cop opo phy in isome s in he edi a y hype bili ubinemias. Clin
Biochem. 1989; 22(3): 221–2.
4 Campbell SD, Lau WF, Xu JJ. In e ac ion o po phy ins wi h human o ganic anion anspo ing polypep ide
1B1. Chem Biol In e ac . 2009; 182(1): 45–51.
5 Robe s EA, Sa ka B. Li e as a key o gan in he supply, s o age, and exc e ion o coppe . Am J Clin Nu . 2008;
88(3): 851–4.
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