Two Case Reports of Successful

Treatment of Cholestasis With Steroids in

Patients With PFIC-2
Guido Engelmann, MDa, Daniel Wenning, MDb, Diran Herebian, PhDc, Oliver Sander, MDd, Carola Drögee,
Stefanie Kluge, PhDe, Ralf Kubitz, MDe,f

Mutations in the gene encoding the canalicular bile salt export pump (BSEP) can abstract
result in progressive familial intrahepatic cholestasis type 2 (PFIC-2). Treatment
options are limited, and PFIC-2 often necessitates liver transplantation. We report
on a young woman and a boy who clinically presented with PFIC-2 phenotypes
and dramatically improved with steroid treatment. Gene sequencing of ABCB11
encoding for BSEP revealed 2 relevant mutations in both patients. The young
woman was compound heterozygous for p.T919del and p.R1235X. At the age of 5
a
years, partial biliary diversion was performed and rescued liver function but left b
Department of Pediatrics, Lukashospital, Neuss, Germany;
Department of General Pediatrics, University Hospital
serum bile salt levels elevated. At age 23 she developed systemic lupus Heidelberg, Ruprecht-Karls-University, Heidelberg, Germany;
c
erythematosus. Unexpectedly, steroid therapy normalized serum bile salt levels, Departments of General Pediatrics, Neonatology and
d
Pediatric Cardiology, Rheumatology, and
with a strong correlation with the steroid dose. She is currently in clinical e
Gastroenterology, Hepatology and Infectious Diseases,
remission. The boy was compound heterozygous for the ABCB11 mutations University Hospital Düsseldorf, Heinrich-Heine-University,
f
Düsseldorf, Germany; and Medical Clinic I, Bethanien
c.150+3A.C and p.R832C and presented with intractable pruritus. When he Hospital, Moers, Germany
developed colitis, he was treated with steroids. The pruritus completely
Drs Engelmann and Wenning treated one of the
disappeared and relapsed when steroids were withdrawn. To date, with low-dose
patients, conceptualized and designed the
budesonide, the boy has been symptom-free for .3 years. In conclusion, the study, and drafted the initial manuscript; Dr
clinical courses suggest that patients with BSEP deficiency and residual BSEP Herebian carried out biochemical analysis; Dr
Sander treated one of the patients, coordinated
activity may benefit from steroid-based therapy, which represents a new treatment
clinical data collection, and critically reviewed
option. the manuscript; Ms Dröge and Drs Kluge and
Kubitz carried out the biochemical and genetic
analyses, collected clinical data, and reviewed
and revised the manuscript; and all authors
approved the final manuscript as submitted.

Familial intrahepatic cholestasis cirrhosis, often necessitating liver www.pediatrics.org/cgi/doi/10.1542/peds.2014-2376

syndromes comprise a group of liver
diseases that are caused by the failure of
hepatobiliary transporter proteins.
1–
Certain mutations in the ABCB11 gene
3 15% of liver transplantations in children.
lead to deficient expression of the
canalicular bile salt export pump
(BSEP), causing hepatocellular bile salt
(BS) accumulation and subsequent liver
cirrhosis. The residual transport activity
of BSEP inversely correlates with the
severity of the patient’s phenotype.
Complete absence of BSEP activity is
associated with progressive familial
intrahepatic cholestasis type 2 (PFIC-2).
Patients with PFIC-2 suffer from
continuously evolving pruritus, wasting
jaundice, and sequelae of liver
4
transplantation in early childhood. In
large studies, PFIC represented
10% to 15% of causes of childhood
cholestasis and is the reason for up to
Treatment focuses on symptom relief and
normalization of liver function tests. It is
based on ursodeoxycholic acid (UDCA),
with improvement of symptoms in 75%
5,6
of cases, rifampicin, and partial biliary
diversion. We here report on 2 patients
with PFIC-2 phenotypes and sustained
clinical relief of symptoms and
unexpected improvement in
hypercholemia in response to oral
steroids.
DOI: 10.1542/peds.2014-2376
Accepted for publication Feb 4, 2015
Address correspondence to Guido Engelmann,
MD, Lukashospital, Department of Pediatrics,
Preussenstrasse 84, D-41464 Neuss,
Germany. E-mail: engelmann@lukasneuss.de
PEDIATRICS (ISSN Numbers: Print, 0031-
4005; Online, 1098-4275).
Copyright © 2015 by the American
Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have
indicated they have no financial relationships
relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The
authors have indicated they have no
potential conflicts of interest to disclose.

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PEDIATRICS Volume 135, number 5, May 2015 CASE REPORT
PATIENT PRESENTATION
Patient 1
A girl (born 1989) presented with vitamin
K deficiency (8 weeks of age), pruritus (8
months), followed by jaundice (10
months) with a BS concentration of 583
mmol/L (normal: ,8 mmol/L).
Aminotransferases and gamma-glutamyl
transferase were normal. A liver biopsy
revealed severe intrahepatic cholestasis
and PFIC-2 was suspected. UDCA
treatment was started, and a partial
external biliary diversion procedure was
performed at the age of 5 years, which led
to good control of pruritus for 15 years.
Sequencing of ABCB11 (BSEP)
revealed compound heterozygosity for
the deletion of a coding triplet
(c.2756_2758delCCA), resulting in the
loss of a single threonine at amino acid
position 919 (p.T919del, inherited by
the mother) and the non-sense mutation
c.3703C.T/p. R1235X, resulting in a
premature stop-codon at amino acid
position 1235 (inherited by the father)
(Fig 1). The initial liver biopsy revealed
an apparently normal expression of
BSEP (Fig 1). The anti-BSEP antibody,
which was used for
immunofluorescence, was directed
13
against the C-terminal amino acids of
7
BSEP. BSEP immunoreactivity in the
patient’s liver biopsy sample must
therefore have been due to expression
of the allele carrying the T919del
variant, because in the presence of
p.R1235X (premature stop codon) the
86 C-terminal amino acids are lacking.
At the age of 23 years the patient’s
general condition deteriorated, and she
presented with polyarthritis,
polyserositis, splenomegaly, anemia,
leukocytopenia, and pruritus.
Antinuclear antibody titer was .1:
5120, and anti-double-strandedDNA
antibodies were 6738 U/mL (ELISA).
Systemic lupus erythematosus was
diagnosed.
Treatment was started with
prednisolone at a dose of 30 mg/day
followed by complete symptom relief.
Serositis recovered, and the arthritis
improved thereafter. Steroids were
tapered to 7.5 mg/day, with a flare up of
arthritis and increasing anti-double-
strandedDNA antibodies to 4549
U/mL. Prednisolone was increased to
15 mg/day, once again resulting

FIGURE 1
Immunofluorescence of liver tissue and DNA sequencing in patient 1. Liver tissue of patient 1 (taken at the age of 10 months) reveals a
clear canalicular staining pattern for BSEP and MRP2 (scale bar = 10 mm), as visualized by immunofluorescent staining and confocal laser
scanning microscopy. The young woman is compound heterozygous for a triplet deletion in exon 21 c.2756_2758delCCA (p.T919del) and a
non-sense mutation c.3703C.T (p.R1235X) in coding exon 26 of ABCB11. Sequences are shown on the nucleotide and protein level.

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2 ENGELMANN et al
 At the age of 4.5 years pruritus and
jaundice worsened, with a direct
bilirubin of 230 mmol/L. In addition,
diarrhea and painful bowel movements
developed. Endoscopic retrograde
cholangiography revealed no evidence
of primary sclerosing cholangitis but
showed a secretion of pale-appearing
bile. On colonoscopy,
a left-sided colitis with superficial
granulocyte infiltration of the mucosa
in the proximal parts of the colon was
diagnosed.
Genetic analysis revealed mutations in
the ABCB11 gene. In the 20th coding
exon a heterozygotic missense mutation
c.2494C.T (p.R832C, inherited by the
mother) was detected together with the
heterozygotic splice site mutation
c.150+3A.C distally to exon 3
(inherited by the father). No mutations
of the ATP8B1 gene or
of the JAG1 gene (Alagille syndrome)
were detected. Immunofluorescence
revealed normal distribution of BSEP
and of the bilirubin transporter
multidrug resistance-associated protein
2 (MRP 2) used as a canalicular marker
(Fig 3).
FIGURE 2
Serum BS and bilirubin levels in correlation with steroid therapy in patient 1. Upper panel: (1) The course of the disease was
steroid therapy (30 mg/day) led to normalized BS levels and a decline in bilirubin; (2) dose
progressive, with increasing
reduction to 15 mg/day resulted in slightly increased BSs; (3) further reduction to 7.5 mg/day
entailed a distinct increase in BSs; (4) redoubling the dose led again to a decrease in BSs. Lower hepatomegaly and advancing liver
panel: BSs were measured in serum and bile before (2009) and during (2012) steroid therapy. fibrosis (FibroScan [Echosense, Paris,
Although BS concentration in serum decreased by a factor of 4.5, the concentration in bile France] was 10.4 kPa at the age of
(collected from the biliostoma) increased by a factor of 6.2, from 1.5 to 9.6 mmol/L, suggesting a
strong stimulation of bile acid secretion during steroid therapy.
4.75 years and 14.6 kPa at the age of 5
years). The patient was listed for liver
transplantation and a living
in clinical improvement in arthritis despite adequate therapy with related transplantation was
and pruritus. rifampicin, phenobarbital, and considered.
Serum BS levels normalized during the naloxone; interrupted night sleep; and
fatigue. Blood examinations revealed a The administration of prednisolone led
initial higher dose of systemic steroid to relief of the diarrhea and pruritus.
therapy (Fig 2). Interestingly, total BS mild cholestasis with total bilirubin of
BSs and bilirubin normalized
concentration in bile collected from the 23.4 mmol/L and direct bilirubin of 9
completely (Fig 4). Budesonide had the
partial external biliary diversion mmol/L. Serum BS concentration was
same benefit but without side effects.
increased to 9.56 mmol/L (August 148.6 mmol/L, whereas
Liver stiffness improved to almost
2012) compared with 1.53 mmol/L aminotransferases, gamma-glutamyl- 8
transferase, alkaline phosphatase, and normal values (6.3 kPa, age 7 years).
before steroid treatment (May 2009).
cholesterol were within normal ranges. The patient was taken off the transplant
Three years after the introduction of
PFIC-2 was suspected, and a liver list and is currently free of symptoms
steroids (November 2011), she is still (as of 2014).
free of symptoms of cholestasis. biopsy was obtained. Histology
revealed chronic cholestasis,
disorganization of portal structures, and
Patient 2 degenerative bile duct alterations. DISCUSSION
Patient 2 (born 2004) presented at an Treatment with UDCA and naltrexon We here report on complete symptom
age of 2.5 years with severe pruritus improved pruritus. relief and sustained normalization of

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PEDIATRICS Volume 135, number 5, May 2015 3
FIGURE 3
Immunofluorescence of liver tissue and DNA sequencing in patient 2. BSEP and MRP2 show a clear canalicular and a weak basolateral
hepatocyte staining (scale bar = 10 mm) as uncovered by immunofluorescence and confocal laser scanning microscopy. Patient 2 and his
brother (our patient’s younger brother with the same phenotype but much lesser symptoms has not been treated with steroids so far) are
compound heterozygous for the splice site mutation c.150+3A.C in intervening sequence 4 (IVS4) and the missense mutation c.2494C.T
(p.R832C) in ABCB11 coding exon 20. Sequences are shown on the nucleotide and protein level.

liver function tests in 2 unrelated
patients with PFIC-2 phenotypes. In
most PFIC-2 patients, BSEP
expression is absent or severely
9
reduced in liver tissue. However, our
patients showed clear
immunoreactivity for BSEP in their
livers. Detection of significant
amounts of BSs (between 1.5 and 9.5
mmol/L) in the bile of patient 1
suggests residual BSEP activity, which
may be an important requirement for
successful steroid therapy. It is believed
that the extent of expression inversely
correlates with phenotype severity
(reviewed in ref 10), with some
5 within
exceptions.
In patient 2, the course of liver and
intestinal disease could be positively
influenced by prednisolone. Tapering
of prednisolone was associated with
worsening of cholestasis and intestinal
disease. Eventually, budesonide at a
minimal effective dosage of 3 mg
every second day resulted in complete
clinical and biochemical remission
6 months for .3 years.
The mechanism of action of the
steroids in the context of PFIC-2 is

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4 ENGELMANN et al
FIGURE 4
Progression of serum BS concentrations in patient 2. Prednisolone (Pred) administration was started at 2 mg/kg per day. Decreasing dosages of
prednisolone led to an increase in BS concentrations. Repetitive prednisolone treatment improved serum BS concentrations. Treatment with
azathioprine (Aza; 2 mg/kg) and methotrexate (MTX; 15 mg/m ) were inefficient. Budesonide (Bud; 6 mg/day) induced a sustained remission.
not yet clear but could possibly involve
upregulation of BSEP transporter
activity, although experimental data are
conflicting. In primary rat hepatocytes,
BSEP-mRNA as well as Mrp2-mRNA
and protein expression were
upregulated by dexamethasone in a
11–13
concentration-dependent manner.
In line with this finding, treatment of
rats with glucocorticoids including
budesonide was associated with the
upregulation of BSEP, Mrp2, and
14
cytochrome P450 oxidase. On the
other hand, Liu
15
et al showed that dexamethasone
administration to neonatal rats
in vivo had a stimulating effect on
Mdr2 (the ortholog to the human
+ sinusoidal membrane of hepatocytes.
MDR3) and Na -taurocholate
cotransporting polypeptide (Ntcp)
gene expression, but decreased the
gene expression of Bsep, Mrp2, and
Fic1, a P-type ATPase protein.
However, most differences were not
significant in that study. The effect of
steroids on canine bile flow has been
demonstrated by Brems
16
et al. Dogs given high dosages of
hydrocortisone at 5 mg/kg per hour
showed a significant increase in bile
flow (from 258 ml/minute to
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PEDIATRICS Volume 135, number 5, May 2015
2
357 mL/minute) independent of BS
concentration.
The ABCB11 splice site mutation
c.150+3A.C results in partial exon
skipping of exon 3 in vivo, and
approximately one-third of mRNA
transcripts are correctly spliced (C.D.,
R.K., D.H., unpublished data).
Therefore, in patient 2, steroids may
upregulate transcription and could
potentially improve correct mRNA
splicing or recover transport activity of
BSEP
R832C
. intestinal reabsorption and a high first-
Another steroid-dependent mechanism
of regulated BS transport may involve
+ may reach the distal colon. In line
Na -dependent cellular bile acid uptake
via NTCP, which is localized at the
17
It has been shown that, under
cholestatic conditions such as biliary
18
atresia, inflammation-induced
19,20
cholestasis, primary biliary
21
cirrhosis, or progressive familial
22
intrahepatic cholestasis, NTCP is
downregulated in human livers. This
downregulation may serve to protect
hepatocytes from toxic BS
concentration but may contribute to the
retention of BSs in the blood
under cholestatic conditions. An
essential glucocorticoid response
element (GRE) has been identified
within the NTCP promoter at
a nucleotide position of 232 to 212
23
relative to the transcription start site.
Therefore, glucocorticoids may
improve transepithelial BS transport by
upregulation of NTCP, providing an
increased gradient for BSEP, thus
counteracting cholestasis.
Budesonide is a steroid with rapid
24,25
pass clearance of ∼90%. Special
formulations of budesonide, however,
26
with this, colitis in patient 2 remained
in remission under alternating dosages
of 3 mg budesonide. It is possible that
cholestasis might be perpetuated due to
extrahepatic inflammation as the
primary insult. On the other hand,
patient 1 had a slight decrease in BS
coincident with active systemic lupus
erythematosus even before initiation of
steroid therapy. It is well known that
lipopolysaccharides induce
27
cholestasis and downregulate BSEP
19
in a model of human liver slices.
However, primary sclerosing
5
cholangitis in the context of ulcerative
colitis in general is not sensitive to
28,29
steroid therapy, a fact that
demonstrates the completely different
pathomechanisms of BSEP deficiency
and primary sclerosing cholangitis.
Clearly, steroid therapy in patients with
PFIC is only indicated if prompt effect
(within 4 weeks) is detected because
the steroid therapy itself has relevant
30
side effects if given for a long time.
To our knowledge, this is the first
clinical report in which, in vivo,
a beneficial effect of steroid
administration on the disease course of
BSEP deficiency/PFIC-2 was shown.
For future patient management it
would be worth further classifying the
PFIC population via genetic analysis,
immunohistochemistry or
immunofluorescence, and clinical
profile to determine those patients who
would benefit from steroid
administration.
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PEDIATRICS Volume 135, number 5, May 2015 7
 Two Case Reports of Successful Treatment of Cholestasis With Steroids in
Patients With PFIC-2
Guido Engelmann, Daniel Wenning, Diran Herebian, Oliver Sander, Carola Dröge,
Stefanie Kluge and Ralf Kubitz
Pediatrics originally published online April 6, 2015;

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 Two Case Reports of Successful Treatment of Cholestasis With Steroids in
Patients With PFIC-2
Guido Engelmann, Daniel Wenning, Diran Herebian, Oliver Sander, Carola Dröge,
Stefanie Kluge and Ralf Kubitz
Pediatrics originally published online April 6, 2015;

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