Differences in presentation and progression between severe FIC1 and BSEP deficiencies.
OBJECTIVE
Progressive familial intrahepatic cholestasis (PFIC) with normal serum levels of gamma-glutamyltranspeptidase can result from mutations in ATP8B1 (encoding familial intrahepatic cholestasis 1 [FIC1]) or ABCB11 (encoding bile salt export pump [BSEP]). We evaluated clinical and laboratory features of disease in patients diagnosed with PFIC, who carried mutations in ATP8B1 (FIC1 deficiency) or ABCB11 (BSEP deficiency). Our goal was to identify features that distinguish presentation and course of these two disorders, thus facilitating diagnosis and elucidating the differing consequences of ATP8B1 and ABCB11 mutations.


METHODS
A retrospective multi-center study was conducted, using questionnaires and chart review. Available clinical and biochemical data from 145 PFIC patients with mutations in either ATP8B1 (61 "FIC1 patients") or ABCB11 (84 "BSEP patients") were evaluated.


RESULTS
At presentation, serum aminotransferase and bile salt levels were higher in BSEP patients; serum alkaline phosphatase values were higher, and serum albumin values were lower, in FIC1 patients. Elevated white blood cell counts, and giant or multinucleate cells at liver biopsy, were more common in BSEP patients. BSEP patients more often had gallstones and portal hypertension. Diarrhea, pancreatic disease, rickets, pneumonia, abnormal sweat tests, hearing impairment, and poor growth were more common in FIC1 patients. Among BSEP patients, the course of disease was less rapidly progressive in patients bearing the D482G mutation.


CONCLUSIONS
Severe forms of FIC1 and BSEP deficiency differed. BSEP patients manifested more severe hepatobiliary disease, while FIC1 patients showed greater evidence of extrahepatic disease.
Pawlikowska
Ludmila
L
Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA.
Strautnieks
Sandra
S
Jankowska
Irena
I
Czubkowski
Piotr
P
Emerick
Karan
K
Antoniou
Anthony
A
Wanty
Catherine
C
Fischler
Bjorn
B
Jacquemin
Emmanuel
E
Wali
Sami
S
Blanchard
Samra
S
Nielsen
Inge-Merete
IM
Bourke
Billy
B
McQuaid
Shirley
S
Lacaille
Florence
F
Byrne
Jane A
JA
van Eerde
Albertien M
AM
Kolho
Kaija-Leena
KL
Klomp
Leo
L
Houwen
Roderick
R
Bacchetti
Peter
P
Lobritto
Steven
S
Hupertz
Vera
V
McClean
Patricia
P
Mieli-Vergani
Giorgina
G
Shneider
Benjamin
B
Nemeth
Antal
A
Sokal
Etienne
E
Freimer
Nelson B
NB
Knisely
A S
AS
Rosenthal
Philip
P
Whitington
Peter F
PF
Pawlowska
Joanna
J
Thompson
Richard J
RJ
Bull
Laura N
LN
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000172:deficiency* / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001647:Bile Acids and Salts / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002780:Cholestasis, Intrahepatic / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D003937:Diagnosis, Differential; D018450:Disease Progression; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D008297:Male; D009154:Mutation; D010641:Phenotype; D011247:Pregnancy; D012189:Retrospective Studies; D055815:Young Adult; D005723:gamma-Glutamyltransferase / Q000097:blood
C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D005723:gamma-Glutamyltransferase; D000251:Adenosine Triphosphatases; C111067:ATP8B1 protein, human
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