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Clinics and Research in Hepatology and Gastroenterology (2018) xxx, xxx—xxx

Available online at

ScienceDirect
www.sciencedirect.com

ORIGINAL ARTICLE

Systematic review of progressive familial

intrahepatic cholestasis
Alastair Baker a, Nanda Kerkar b, Lora Todorova c,
Binita M. Kamath d, Roderick H.J. Houwen e,∗

a
Paediatric Liver Centre, King’s College Hospital, London, UK
b
Division of Gastroenterology, Hepatology and Nutrition, Golisano Children’s Hospital, University of
Rochester Medical Center, Rochester, NY, USA
c
Shire, Zug, Switzerland
d
Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto,
Toronto, ON, Canada
e
Pediatric Gastroenterology, Wilhelmina Children’s Hospital, University Medical Center, Utrecht,
Netherlands

KEYWORDS Abstract
Byler’s disease; Background and aims: Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous
Pruritus; group of rare genetic disorders associated with bile acid secretion or transport defects. This is
Bile secretion; the first systematic review of the epidemiology, natural history and burden of PFIC.
ATP8B1; Methods: MEDLINE and Embase were searched for publications on PFIC prevalence, incidence
ABCB11; or natural history, and the economic burden or health-related quality of life (HRQoL) of patients
ABCB4 with PFIC. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were
followed.
Results: Of 1269 records screened, 20 were eligible (epidemiology, 17; humanistic burden,
5; both, 2). Incidence of intrahepatic cholestasis, including but not limited to PFIC, was 1/18
000 live births in one study that did not use genetic testing. In two studies of infants and
children (2—18 years) with cholestasis, 12—13% had genetically diagnosed PFIC. Of the three
main PFIC subtypes, PFIC2 was the most common (21—91% of patients). Common symptoms
(e.g. pruritus, jaundice, hepatomegaly, splenomegaly) generally appeared at about 3 months

Abbreviations: A1ATD, ␣-1-antitrypsin deficiency; ALGS, Alagille syndrome; ABCB4, ATP binding cassette subfamily B member 4; ABCB11,
ATP binding cassette subfamily B member 11; ATP8B1, ATPase phospholipid transporting 8B1; BSEP, bile salt export pump; GGT, ␥-glutamyl
transferase; HCC, hepatocellular carcinoma; HRQoL, health-related quality of life; LT, liver transplantation; NR, not reported; NS, type of
PFIC diagnosis not specified; PEBD, partial external biliary diversion; PedsQL, Pediatric Quality of Life Inventory; PFIC, progressive familial
intrahepatic cholestasis; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; SD, standard deviation; UDCA,
ursodeoxycholic acid.
∗ Corresponding author: University Medical Center, Heidelberglaan 100, 3584 CX Utrecht, Netherlands.

E-mail address: [email protected] (R.H.J. Houwen).

https://doi.org/10.1016/j.clinre.2018.07.010
2210-7401/© 2018 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Baker A, et al. Systematic review of progressive familial intrahepatic cholestasis. Clin
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of age and tended to emerge earliest in patients with PFIC2. Patients reported that pruritus
was often severe and led to dermal damage and reduced HRQoL. Disease progression led to
complications including liver failure and hepatocellular carcinoma, with 20—83% of patients
requiring liver transplantation. Mortality was 0—87% across 10 studies (treatment varied among
studies), with a median age at death of 4 years in one study.
Conclusions: Patients with PFIC face debilitating symptoms and poor prognosis. Further
research is needed to inform patient management and clinical trial design. Published data
on the epidemiology and socioeconomic burden of PFIC is limited.
© 2018 Elsevier Masson SAS. All rights reserved.

Introduction sion (PEBD) or partial internal biliary diversion (PIBD) may be

needed to lower circulating bile acid concentrations [1,6,7].
Progressive familial intrahepatic cholestasis (PFIC) is a het- Ultimately, liver failure and intractable pruritus may indi-
erogeneous group of rare autosomal recessive liver disorders cate a need for liver transplantation (LT), most often in
of childhood characterized by mutations in genes encoding patients with PFIC2 [8].
proteins involved in the hepatocellular transport system [1]. There is limited information regarding the pathogenesis
Three main subtypes of PFIC (PFIC1, PFIC2, PFIC3) have and burdens of PFIC. Consequently, we have conducted a
been identified [1]. PFIC1, also known as Byler’s disease, is systematic appraisal of the evidence on the epidemiology,
caused by mutations in the ATPase phospholipid transport- clinical presentation, natural history, health-related quality
ing 8B1 gene (ATP8B1), located on chromosome 18, which of life (HRQoL) and the economic burdens of PFIC. Our aim
encodes a phospholipid transporting transmembrane P-type has been to consolidate the data obtained from small studies
adenosine triphosphatase known as FIC1 [1,2]. This ‘flip- and analyses of patient records published over the last 35
pase’ is involved in maintaining an asymmetric distribution years, so that the results can be used to help inform the
of phospholipids across the canalicular membrane bilayer of management of patients with PFIC and the design of future
hepatocytes, thereby protecting the canalicular membrane clinical studies in patients with PFIC.
from hydrophobic bile acids and maintaining its integrity [1].
PFIC2 is caused by mutations in the ATP binding cassette sub- Methods
family B member11 gene (ABCB11), located on chromosome
2, which encodes the bile salt export pump (BSEP), the main Two search strings were devised that used a combination of
transporter of bile acids from hepatocytes to the canalicular free text and Medical Subject Heading terms to explore:
lumen [1,3]. PFIC3 is caused by mutations in the ATP bind-
ing cassette subfamily B member 4 gene (ABCB4), located on • PFIC and epidemiology or natural history;
chromosome 7, which encodes multidrug-resistance protein • PFIC and health-related quality of life (HRQoL) or eco-
3 (MDR3/ABCB4); this protein transports phospholipids into nomic burden (Supplementary Tables S1 and S2).
the canalicular lumen to neutralize bile salts and prevent
injury to biliary epithelia and bile canaliculi [1,4,5].
On May 11—13, 2015, the OvidSP search platform was
The main clinical features of PFIC include cholestasis,
used to carry out searches of the following electronic liter-
jaundice and pruritus, with symptoms typically appearing in
ature databases:
infancy or early childhood [1]. PFIC is associated with a range
of potentially fatal complications of the liver, including por-
• MEDLINE In-Process & Other Non-Indexed Citations and
tal hypertension, liver failure, cirrhosis and hepatocellular
Ovid MEDLINE 1946—present;
carcinoma (HCC; PFIC2), as well as extrahepatic manifes-
• Embase 1974—present.
tations (PFIC1) [1]. The biochemical features of PFIC1 and
PFIC2 are low levels of ␥-glutamyl transferase (GGT) with
elevated serum bile acid and decreased primary bile acid The bibliographic reference lists of the studies subse-
concentrations, while PFIC3 is associated with high levels quently included in the review were also manually searched.
of GGT [1]. Historically, diagnosis of PFIC has been based Proceedings of 11 congresses considered to be most rele-
on a combination of clinical and laboratory or biochemical vant were also searched. The date range for the publication
approaches but, more recently, genetic testing has become database searches was from the start of records to May 2015,
the gold standard. but was restricted to 2012—2015 for conference proceedings
There are no approved pharmacologic treatment options because data before this period were likely to have been
for patients with PFIC that relieve symptoms or pre- published as a journal article. In addition to the major pub-
vent disease progression. Off-label treatments include lication databases, Orphanet, a specialist resource devoted
ursodeoxycholic acid (UDCA), bile acid sequestrants and to rare and orphan diseases, was searched for publications
agents for the symptomatic relief of pruritus, such as anti- on PFIC to ensure comprehensive coverage.
histamines and rifampin (rifampicin) [1,6]. Not all patients Inclusion and exclusion criteria were specified in advance
respond to these approaches, however, and generally only and documented. Identified publications were manually
partial relief from itching is achieved. Accordingly, invasive screened based on the title and abstract in accordance
surgery, such as ileal bypass, partial external biliary diver- with 2009 Preferred Reporting Items for Systematic Reviews

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Figure 1 PRISMA flow diagram for systematic review of (a) epidemiology and natural history (b) HRQoL and economic burden.

and Meta-Analyses (PRISMA) guidelines [9]. Abstracts were 18 000 live births [10]. However, molecular genetic diagnos-
screened for inclusion by two independent reviewers and, tics for PFIC were not available at the time of data collection
in the case of uncertainty, by a third reviewer. Data were (1955—1974). A later study that analyzed death registers
extracted manually. Case studies were ineligible. Studies and case records from two hospitals in Greenland for the
reporting only clinical outcomes, treatment preferences, period 1943—2002 reported 46 cases of PFIC1 diagnosed by
epidemiology estimates or risk factors were ineligible. See liver biopsy, biochemistry and/or molecular genetic testing
Supplementary Tables S3—S5 for full eligibility criteria. (ATP8B1) [11]. In this study, many cases occurred in patients
originating from indigenous populations described by the
Results authors as ‘‘highly inbred’’. The overall study population
size and incidence were not reported [11].
Six publications reported the prevalence of PFIC among
The searches yielded 1269 publications for screening. The
patients with liver-related disease (Table 1) [12—17]. Of
numbers of included and excluded publications are shown
these, three studies used genetic testing for PFIC diagno-
in Fig. 1a (epidemiology and natural history) and Fig. 1b
sis: a multicenter study from North America in children with
(HRQoL and economic burden). Of the 20 publications
intrahepatic cholestasis [17], a Swedish tertiary referral
that met the eligibility criteria for inclusion in the review
center study that included infants with neonatal cholestasis
(Table 1), 17 publications reported the epidemiology or
with an onset in the first 6 months of life [14], and a world-
natural history of PFIC (summarized in Tables 2—4) and 5
wide multicenter study in infants with cholestasis, acute
publications assessed the HRQoL in patients with PFIC (sum-
liver failure or splenomegaly [16]. In these three studies,
marized in Table 5); 2 publications were identified in both
the proportions of cases of PFIC among the study populations
searches. No publications that addressed the economic bur-
were 11.7% [17], 12.9% [14], and 9.0% [16], respectively.
den of PFIC were identified.
In the remaining three studies the basis of PFIC diagnosis
was either clinical, biochemical and histological [13,15], or
Epidemiology was not reported [12]. A study from India assessed children
with encephalopathy, acute liver failure, cholestasis, hep-
Two publications reported population-level epidemiology atomegaly or chronic liver disease [12]; a study from Tunisia
data for PFIC (Table 1) [10,11]. A retrospective study assessed children with cirrhosis [13]; and a study from Iran
assessed 124 infants admitted to hospitals in Norway with assessed children referred for liver needle biopsy [15]. In
cholestatic jaundice during the first 3 months of life between these three studies, the proportions of cases of PFIC among
1955 and 1974, of whom 60 had intrahepatic cholestasis. the study populations were 2.4% [12], 12.7% [13], and 5.0%
These figures result in an incidence of intrahepatic cholesta- [15], respectively.
sis, including but not limited to PFIC, of approximately 1 per

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Table 1 Summary of included publications.

Reference Study design Study population n Patients with Genetic Country/region Study period Reported data
PFIC, n diagnosis
PFIC PFIC At pre- At Mortality HRQoL and/or
epidemiology subtype sentation follow-up pruritus
Henriksen et al., Retrospective Infants with 124 60 No Norway 1955—1974 Incidence: NS Yes Yes 43% No
1981 [10] chart review cholestatic jaundice (follow-up in 1/18,000 live
1978) births
Whitington et Retrospective Patients with PFIC 33 33 No North America 1978—1991 No NS Yes Yes 21% No
al., 1994 [26] chart review (with chronic
cholestasis but
excluding other
chronic cholestatic
conditions)
Fischler et al., Retrospective Infants with neonatal 85 11 Yes Sweden 1988—1995 Prevalence: PFIC2: No No No No
2001 [14] chart review cholestasis 12.9% 91%
Others:

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NS
Nielsen and Retrospective Patients with PFIC1 46 46 Yesa Greenland 1943—2002 No PFIC1:100%Yes No 87% No
Eiberg, 2004 review of death
[11] register and
hospital records
Wanty et al., Retrospective Patients with PFIC 49 49 Yesb Belgium NR No PFIC1/2: Yes Yes 8% No
2004 [24] chart review (based on chronic 61%
cholestasis) PFIC3:
39%
Chaabouni et Retrospective Children with cirrhosis 71 9 No Tunisia 1990—2004 Prevalence: NS No No 33% No
al., 2007 [13] review of 12.7%
hospital records
Englert et al., Retrospective Patients with PFIC 42 42 Yes Germany NR No PFIC2: Yes Yes 0% No
2007 [20] chart review treated with UDCA 62%
plus PEBD and/or LT PFIC3:
38%
Monajemzadet Cross-sectional, Children referred for 321 20 No Iran 2004—2006 5.0% NS No No No No
et al., 2009 diagnostic liver needle biopsy
[15] excluding those with
thalassemia
Lee et al., 2009 Case series Infants with PFIC 5 5 No Malaysia 1996—2004 No PFIC1/2: Yes Yes 80% Pruritus scores
[23] (based on chronic 80%
cholestasis) PFIC3:
20%
Yang et al., 2009 Retrospective Children with PFIC 11 11 Partial Netherlands 2000—2005 No PFIC2: No No No HRQoL
[30] chart review who underwent PEBD 73%
Others:
NS
Miyagawa- Retrospective Children who 725 14 Yes Japan 1990—2008 No PFIC1: No Yes 21.4% No
Hayashino et chart review underwent LT 78.6%
al., 2009 and PFIC2:

A. Baker et al.
Hori et al., 21.4%
2011 [22,25] c
Lind et al., 2010 Prospective Children/adolescents 8 8 NS NR NR No No No No No Yes
[29] PFIC/ALGS with PFIC/ALGS who
database underwent PEBD
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Table 1 (Continued)
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Reference Study design Study population n Patients with Genetic Country/region Study period Reported data
PFIC, n diagnosis
PFIC PFIC At pre- At Mortality HRQoL and/or
epidemiology subtype sentation follow-up pruritus
Davit-Spraul et Retrospective Children with 62 62 Yes France 1978—2007 No PFIC1: Yes Yes 10% No
al., 2010 [8] chart review hepatocellular 21%d
cholestasis, pruritus, PFIC2:
elevated serum bile 63%d
acid, and normal Others:
serum GGT activity NSd
Schukfeh et al., Retrospective Children with PFIC 24 24 Partial Germany 1994—2008 No NS No No No Pruritus scores
2012 [27] chart review who underwent PEBD
Alam et al., 2013 Protocol-based Children with 288 7 NS India NR Prevalence: 2.4% PFIC2: No No No No
[12] screening study encephalopathy, acute 100%
liver failure,
cholestasis,

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hepatomegaly, or
chronic liver disease
Al Mehaidib et Retrospective Patients with 68 48 Yes Saudi Arabia 2002—2012 No PFIC1: Yes Yes 6% No
al., 2013 [19] chart review cholestasis and 10.4%
suspected PFIC PFIC2:
56.3%
PFIC3:
33.3%
Gray et al., 2013 Prospective, Infants < 2 years of age 87 8 Yes Int. (13 centres) NR No PFIC1: No No No No
[21] genetic with cholestasis, acute 37.5%e
liver failure, or PFIC2:
splenomegaly and with 37.5%e
DNA sequencing data PFIC3:
37.5%e
Ruth et al., 2014 Prospective, Infants < 2 years of age 238 NRf Yes International (13 NR Prevalence: 9% NS No No No No
[16] genetic with cholestasis, acute centres)
liver failure, or
splenomegaly
Vasishta et al., Retrospective, Children with hepatic 181 NRf NS North India NR Prevalence: 0.6% NS No No No No
2015 [18] postmortem disease
Kamath et al., Cross-sectional Children with chronic 214 25 Yes North America NR Prevalence: PFIC1: No No No HRQoL
2015 [17] sub-study intrahepatic (16 centres) 11.7% 24.0%
cholestasis PFIC2:
48.0%
PFIC3:
28.0%
A1ATD: ␣-1-antitrypsin deficiency; ALGS: Alagille syndrome; BSEP: bile salt export pump; GGT: ␥-glutamyl transferase; HRQoL: health-related quality of life; Int: international; LT:
liver transplantation; NR: not reported; NS: type of PFIC diagnosis not specified; PEBD: partial external biliary diversion; PFIC: progressive familial intrahepatic cholestasis; UDCA:
ursodeoxycholic acid.
a PFIC diagnosed by molecular testing, liver biopsy, and/or biochemistry.
b Genetic analysis was performed where possible only for PFIC2 mutations.
c Miyagawa-Hayashino et al. (journal article) and Hori et al. (subsequent congress abstract) reported on the same study population. Hori et al. included one additional patient (who

had PFIC2 and survived); and reported death of one more of the original patients (who had PFIC1).
d PFIC subtype remained unknown in 10 patients (16%).
e There were 3/8 patients with each subtype; one patient had both PFIC1 and PFIC3.
f Proportion, but not number, of cases reported.

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Table 2 Clinical presentation of patients with PFIC.

Reference Age at onset of PFIC/first Clinical features, n/N (%) in patients with PFIC
symptoms

PFIC1/PFIC2/PFIC3
Henriksen et al., First 3 months of life Cholestasis: 60/60 (100)
1981 [10] Jaundice with hepatomegaly and/or splenomegaly: 60/60
(100)
Pale stools and dark-colored urine: 60/60 (100)
Whitington et al., 3.1 ± 3.0 months (mean ± SD)a Pruritus: 32/33 (97); 25/33 (76) with pruritus grade ≥ 3+
1994 [26] [constant itching with significant excoriations], based on
Whitington scale
Hepatomegaly: 32/33 (97)
Rickets: 25/33 (76)
Recurrent and severe epistaxis (no coagulopathy or
thrombocytopenia): 17/33 (52)
Vitamin E deficiency: 17/33 (52)
Persistent vitamin E neuropathy (mild-to-severe): 13/33 (39)
Wheezing and cough: 10/33 (30)
Cholelithiasis: 9/33 (27)
Bleeding diathesis: 8/33 (24)
Severe osteopenia: 2/33 (6)
Sensorineural hearing loss: 2/33 (6)
Mild mental retardation: 1/33 (3)
PFIC1/PFIC2
Schukfeh et al., Age at diagnosis: 21 months [4 Chronic cholestatic liver disease: 24/24 (100)
2012 [27] months—17 years] Jaundice: 13/24 (54)
Elevated serum bile acids: 24/24 (100)
Normal GGT: 23/24 (96)
Pruritus: 18/24 (75)
Lee et al., 2009 3—4 days Moderate-to-severe neonatal cholestatic jaundice: 4/4 (100)
[23] Hepatomegaly: 4/4 (100)
Slightly pigmented or pale stools: 4/4 (100)
Pruritus: 4/4 (100); 3/4 (75) with pruritus grade ≥ 3+, based on
Whitington scale
Splenomegaly: at least 2/4 (50)b
Wanty et al., 2004 2 months [0—58] (mean Pruritus: 23/24(96)c
[24] [range]) Hepatomegaly:19/21 (90)c
Cholestasis: 20/25 (80)c
Jaundice: 19/27 (70)c
PFIC1
Al Mehaidib et al., < 18 months Jaundice: 5/5 (100)
2013 [19] Hepatomegaly: 5/5 (100)
Poor growth: 5/5 (100)
Diarrhea: 4/5 (80)
Splenomegaly: 3/5 (60)
Davit-Spraul et al., 2 months [1—5] (median Jaundice, discolored stools, and/or hepatomegaly at ≤ 1
2010 [8] [range]) month: 2/13 (15)
Jaundice, discolored stools, hepatomegaly, and/or pruritus
at ≤ 3 months: 8/13 (61)
Diarrhea: 8/13 (61)
Elevated sweat chloride levels: 2/13 (15)
Pancreatitis: 1/13 (8)
Nielsen and Eiberg, 1—2 months Jaundice with protuberant abdomend
2004 [11] Hepatomegalyd
Itchingd
Bleeding episodesd
Failure to thrived
Ricketsd

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Table 2 (Continued)

Reference Age at onset of PFIC/first Clinical features, n/N (%) in patients with PFIC
symptoms

PFIC2
Al Mehaidib et al., ≤ 2 years Jaundice: 22/27 (81)
2013 [19] Rickets: 6/27 (22)
Pruritus: 3/27 (11)
Davit-Spraul et al., 2 months [1—60] (median Jaundice, discolored stools, and/or hepatomegaly at ≤ 1
2010 [8] [range]) month: 16/36 (44)
Jaundice, discolored stools, hepatomegaly, and/or pruritus
(≤ 3 months): 26/36 (72)
Cholelithiasis: 10/36 (28)
Vitamin K deficiency (bleeding): 3/36 (8)
Cirrhosis:1/21 (5)c,e
HCC:1/21 (5)c,e
Vitamin D deficiency (rickets): 1/36 (3)
PFIC3
Englert et al., 2007 3.2 [2 months—10 years] (mean Pruritus: 18/26 (69)
[20] [range]) Cholestasis: 15/26 (58)
Liver cirrhosis: 12/26 (46)
Growth retardation: 10/26 (38)
Al Mehaidib et al., ≥ 2 years Jaundice: 5/16 (31)
2013 [19] Pruritus: 4/16 (25)
Rickets: 1/16 (6)
Wanty et al., 2004 3 months [0—36] (median Jaundice:14/17 (82)c
[24] [range]) Hepatomegaly: 13/17 (76)c
Cholestasis: 8/14 (57)c
Pruritus: 7/17 (41)c
Lee et al., 2009 3—4 days Neonatal jaundice within first week: 1/1 (100)
[23] (3 days in 4 patients and 4 days Hepatomegaly: 1/1 (100)
in 1 patient) Pale stools: 1/1 (100)
Pruritus: 1/1 (100); grade ≥ 4+ [cutaneous mutilation
hemorrhage and scarring evident], based on Whitington scale
Possible splenomegalyb
GGT: ␥-glutamyl transferase; HCC: hepatocellular carcinoma; PFIC: progressive familial intrahepatic cholestasis; SD: standard deviation.
a One patient with clinical presentation at 17 years was excluded from this calculation.
b Three patients with PFIC of unspecified subtype had splenomegaly.
c Among patients with available data.
d n/N not reported.
e At diagnosis or before age 1 year.

One postmortem study in India carried out autopsies on [22]. One publication identified a patient with both PFIC1-
children (aged 0—14 years) with signs and symptoms of hep- and PFIC3-causing mutations [21]. In another study exploring
atic diseases and reported a 0.6% prevalence of PFIC [18]. PFIC1 and PFIC2 genotypes, 18 different mutations in ATP8B1
and 41 mutations in ABCB11, respectively, were identified
[8]. In the three studies that reported values for all three
Distribution and biochemical characteristics of main PFIC subtypes, the relative incidences of PFIC1, PFIC2
main PFIC subtypes and PFIC3 were 10.4%, 56.3% and 33.3% [19]; 37.5%, 37.5%
and 37.5% [21]; and 24%, 48% and 28% [17], respectively
Nine studies reported the distribution of subtypes among (Table 1).
patients with PFIC [8,14,17,19—25]. PFIC2 was generally the Serum GGT levels were normal or minimally elevated
most common subtype among patients diagnosed via genetic in patients with PFIC1 or PFIC2 [8,19,23], but significantly
testing: PFIC2 was detected in 37.5—90.9% of patients elevated in patients with PFIC3 [19,23]. PFIC2 was asso-
[8,14,17,19,21], while PFIC1 and PFIC3 were detected in ciated with elevated serum alanine aminotransferase and
10.4—37.5% [8,14,17,19,21] and 28.0—37.5% of patients ␣-fetoprotein levels, low biliary bile acid concentrations,
[17,19,21], respectively. In contrast, a study in Japanese severe lobular lesions with giant hepatocytes and negative
patients with PFIC who had undergone LT reported a higher BSEP canalicular staining [8].
frequency of PFIC1 (11/14, 78.6%) than PFIC2 (3/14, 21.4%)

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Table 3 Disease progression in patients with PFIC.

Reference Study period Clinical features at follow-up, Liver transplantation (LT)

n/N (%) in patients with PFIC
Patients, n/N (%) Indications, n/N Age at LT Clinical
(%) features/outcome
post-LT, n/N (%)

PFIC1/PFIC2/PFIC3
Henriksen 1955—1974 Hepatomegaly: 6/32 (19)a 0/32 (0) NR NR NR
et al., 1981 [10] (follow-up in 1978) Splenomegaly: 4/32 (13)a
Idiopathic neonatal cholestasis:
8/32 (25)a

ARTICLE IN PRESS
Cholestasis with lymphedema:
5/32 (16)a
Other familial cholestases: 4/32
(13)a
Septicemia: 3/32 (9)a
Inspissated bile syndrome: 1/32
(3)a
Mucopolysaccharidosis:1/32 (3)a
Subpopulation biopsied (n = 7):
cirrhosis: 2/7 (29)b ; fibrosis: 1/7
(14)b ; bile duct hypoplasia: 1/7
(14)b
Lee et al., 2009 1996—2004 Giant cell hepatitis: 4/5 (80) 1/5 (20) NR 22 months Death post-LT (sepsis):
[23] Developmental delay: 1/5 (20) 1/1 (100)
Severe pruritus (grade ≥ 3+ based
on Whitington scale): 4/5 (80)
Failure to thrive: 5/5 (100)
Cirrhosis: 4/5 (80)
Schukfeh et al., 1994—2008 PEBD without LT after 1 year: 9/24 (37) Liver cirrhosis: 7/9 24 months [4 NR
2012 [27] (median follow-up 21/24 (88): normalisation of (78) months to 4.4
9.8 years serum bile acid levels: 13/21 (62); PEDB failure: 6/9 years] (median
[1.6—14.3]) signs of improved liver function (67) [range])
and reduced liver damage: 13/21
(62); pruritus score ≤ 3: 13/21
(62); PEBD failure: 8/21 (38)

A. Baker et al.
LT within 1 year after PEBD: 3/24
(12.5)
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Table 3 (Continued)

Reference Study period Clinical features at follow-up, Liver transplantation (LT)

n/N (%) in patients with PFIC
Patients, n/N (%) Indications, n/N Age at LT Clinical
(%) features/outcome
post-LT, n/N (%)

Wanty et al., The 15 years Treatment with UCDA: 20/49 (41): 38/49 (78) NR PFIC1/PFIC2: 50 Death post-LT: 3/38 (8)
2004 [24] before publication favourable liver enzyme response months [19—189] (1 sepsis following
and reduced pruritus: 10/20 (50); PFIC3: 63 months surgery, 1 post-LT
partial response in liver enzymes [17—129] (median hepatitis C, 1 unknown
and persisting pruritus: 10/20 [range]) cause)
(50); untreated patients: 29/49:

ARTICLE IN PRESS
NR
Whitington 1987—1991 Pruritus and other symptoms 14/33 (42) Decompensated 6.2 years [8 Death post-LT: 3/14 (21)
et al., 1994 [26] persistently severe despite cirrhosis: 13/14 months—11 years] (All due to complications
treatment with medication(s), (93): unsuccessful (mean [range]) of LT)
33/33 (100) biliary diversion:
Partial ileal bypass, 2/33 (6): 4/14 (29)
reversal of cholestasis, 2/2 (100) Mutilating
Partial cutaneous biliary pruritus: 1/14 (7)
diversion: 14/33 (42): adequate
response: 13/14 (93); complete
relief of cholestasis: 9/14 (64);
partial relief of cholestasis: 1/14
(7); death 1/14 (7); secondary LT:
4/14 (29)
Death at follow-up: 7/33 (21):
liver failure: 2/7 (29);
hepatocellular carcinoma: 2/7
(29); LT complications: 3/7 (43)
PFIC2/PFIC3
Englert et al., NR Pruritus: 32/42 (76) 35/42 (83) Severe pruritus, NR Death post-LT: 0/33 (0)
2007 [20] Cholestasis: 27/42 (64) (2/35 awaiting LT) NR Significant catch-up of
Liver cirrhosis: 25/42 (60) Growth growth retardation: 8/19
Successful treatment with retardation, NR (83)
medication: 2/42 (5) Liver cirrhosis, NR
Growth retardation: 19/42 (45) Cholangitis and
Biliary diversion: 17/42 (40): pruritis, NR
successful: 5/17 (29); referred for
secondary LT: 12/17 (59)

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Table 3 (Continued)

Reference Study period Clinical features at follow-up, Liver transplantation (LT)

n/N (%) in patients with PFIC
Patients, n/N (%) Indications, n/N Age at LT Clinical
(%) features/outcome
post-LT, n/N (%)

ARTICLE IN PRESS
PFIC1
Al Mehaidib 2002—2012 NR 2/5 (40) NR NR NR
et al., 2013 [19]
Davit-Spraul 1978—2007 Recurrent or permanent jaundice: 6/13 (46) Severe cholestasis 4 years [1.5—7.5] Diarrhea: 5/6 (83)
et al., 2010 [8] 13/13 (100) with no liver (median [range]) Liver steatosis: 3/6 (50)
Cirrhosis: 2/5 (40)c,d failure or HCC: Growth retardation: 4/6
Pruritus: 13/13 (100) 6/6 (100) (67)
Hepatomegaly: 13/13 (100) Deafness: 2/6 (33)
Splenomegaly: 4/13 (31) Pancreatitis: 2/6 (33)
Positive response to UDCA: 5/13 Liver failure requiring
(38) second LT: 2/6 (33)
Successful biliary diversion: 1/1 Death post-LT: 2/6 (33)
(100)
Miyagawa- 1990—2008 Severe cholestasis with cirrhosis, 11/11f End-stage liver 4 years [1—18] Steatosis: 8/11 (73)
Hayashino et (follow-up for undergoing LT: 11/11 (100) disease, severe (median [range]) Steatohepatitis: 7/11
al., 2009 [25] e 4.2—16.5 years) pruritus, (64): bridging fibrosis:
Hori et al., 2011 2011 update significant growth 4/7 (57)b ; cirrhosis: 2/7
[22] e failure: 11/11 (29)b
(100) Diarrhea: 7/11 (64)
Chronic pancreatitis:
2/11 (18)
Deaths post-LT: 3/11
(18)c

A. Baker et al.
 Management of HCV and end-stage kidney disease

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Table 3 (Continued)

Reference Study period Clinical features at follow-up, Liver transplantation (LT)

n/N (%) in patients with PFIC
Patients, n/N (%) Indications, n/N Age at LT Clinical
(%) features/outcome
post-LT, n/N (%)

PFIC2
Al Mehaidib 2002—2012 NR 15/27 (56) NR NR NR
et al., 2013 [19] Death awaiting LT:
3/27 (11)

ARTICLE IN PRESS
Davit-Spraul 1978—2007 Recurrent/permanent jaundice: 19/36 (53) Severe cholestasis: NR Deaths during/post-LT:
et al., 2010 [8] 29/36 (81) (4/19 awaiting LT) 8/19 (42) 4/19 (21)
Cirrhosis: 15/26 (58)c,d Severe cholestasis No extrahepatic
Pruritis: 36/36 (100) and liver failure: manifestations in
Hepatomegaly: 35/36 (97) 6/19 (32) patients surviving LT:
Splenomegaly: 15/36 (42) Severe cholestasis, 14/19 (74)
HCC: 3/26 (12)c,d liver failure and
Positive response to UDCA: 9/29 HCC: 5/19 (26)
(31)
Successful biliary diversion: 1/9
(11)
Hori et al., 2011 1990—2011 Severe cholestasis with cirrhosis, 3/3 (100)f End-stage liver NR No steatosis, fibrosis or
[22] f undergoing LT: 3/3 (100) disease, severe deaths post-LT, 3/3 (100)
pruritus,
significant growth
failure: 3/3 (100)
PFIC3
Al Mehaidib 2002—2012 NR 1/16 (6) NR NR NR
et al., 2013 [19]
HCC: hepatocellular carcinoma; LT: liver transplantation; NR: not reported; PEBD: partial external biliary diversion; PFIC: progressive familial intrahepatic cholestasis; UCDA:
ursodesoxycholic acid.
a Among patients who were alive at follow-up and had a follow-up examination.
b Among patients who were alive at follow-up and had a liver biopsy.
c Among patients with available data.
d After 1 year of age.
e Miyagawa-Hiyashino et al. (journal article) and Hori et al. (subsequent congress abstract) reported on the same study population. One additional patient with PFIC1 died according

to Hori et al.
f Miyagawa-Hiyashino et al. did not report on patients with PFIC2 (n = 2) in the cohort; Hori et al. reported on one additional patient with PFIC2 (total n = 3).

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Table 4 Mortality in patients with PFIC.

Reference Mortality, n/N (%) Reasons for death, n/N Age of death Treatment, n/N (%)a

Al Mehaidib et al., 2013 [19] 3/48 (6) NR NR Awaiting LT: 3/48 (6)
LT: 18/48 (38)
Davit-Spraul et al., 2010 [8] 6/62 (10) Post-LT: 3/6 PFIC1: 15 years [7—23] UDCA: 53/62 (85)
During LT: 1/6 PFIC2: 1 year [3—4] PEBD: 15/62 (24)
Liver failure: 1/6 PFIC NS: 3.2 years LT: 25/62 (40)
Cerebral bleeding: 1/6 (median [range])
Englert et al., 2007 [20] 0/42 (0) NA NA UDCA: 42/42 (100)
PEBD: 17/42 (40)b
LT: 35/42 (83)b
Henriksen et al., 1981 [10] 26/60 (43) Acute complications secondary to NR NR

ARTICLE IN PRESS
cholestasis (infection, dehydration, GI
bleeding): 16/26
HCC secondary to cholestasis: 3/26
Other: 7/26
Miyagawa-Hayashino et al., 3/14 (21) Rupture of splenic artery aneurysm post-LT: 13.8 years; 5.5 years; NR LT: 14/14 (100)d
2009 [25] c 1/3
Hori et al., 2011 [22] c Chronic rejection post-LT: 1/3
NR: 1/3
Lee et al., 2009 [23] 4/5 (80) Cirrhosis with liver failure: 2/4 9—51 months UDCA: 5/5 (100)
Coagulopathy, massive upper GI bleed: 1/4 Rifampin: 4/5 (80)
Sepsis after LT: 1/4 LT: 1/5 (20)
Nielsen and Eiberg, 2004 40/46 (87) Infectionse NR NR
[11] Bleeding episodese
Liver failuree
Wanty et al., 2004 [24] 4/49 (8) Sepsis and massive fluid loss post-PEBD: 1/4 NR UDCA: 20/49 (41)
Sepsis post-LT: 1/4 PEBD: 5/49 (10)
Chronic aggressive hepatitis C post-LT: 1/4 LT: 38/49 (78)
Unknown cause post-LT: 1/4
Whitington et al., 1994 [26] 7/33 (21) Liver failure: 2/7 3.9 ± 2.4 years UDCA: 6/33 (18)
HCC: 2/7 (mean ± SD) PEBD: 18/33 (55)f
LT-related complications: 3/7 LT: 14/33 (42)
GI: gastrointestinal; HCC: hepatocellular carcinoma; LT: liver transplantation; NA: not applicable; NR: not reported; PEBD: partial external biliary diversion; PFIC: progressive familial
intrahepatic cholestasis; SD: standard deviation; UDCA: ursodeoxycholic acid.
a More than one treatment possible.
b LT or PEBD was an inclusion criterion. LT includes 2/35 awaiting surgery.
c Miyagawa-Hiyashino et al. (journal article) and Hori et al. (subsequent congress abstract) reported on the same study population. Hori et al. included one additional patient (who

A. Baker et al.
had PFIC2 and survived); and reported death of one more of the original patients (who had PFIC1).
d LT was an inclusion criterion.
e n/N not reported.
f Includes four unsuccessful PEBDs.
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Table 5 Summary of studies exploring health-related quality of life and pruritus in patients with PFIC.

Reference Cohort characteristics Results

Kamath et al., 2015 [17] 49 children aged 5—18 years with chronic Children with IHC had lower total PedsQL
intrahepatic cholestasis (non-ALGS or A1ATD); self-report scores than healthy peers (73 vs.
25 with genetic diagnosis (PFIC1, 6; PFIC2, 12; 84; effect size, 0.87)
PFIC3, 7)
Lee et al., 2009 [23] 5 infants with PFIC (based on chronic Pruritus severity score based on Whitington
unremitting infantile cholestasis and scale (0—4): 1 patient with pruritus grade 1+
biomarkers typical of cholestasis [including (rubbing or mild scratching when not
increased levels of conjugated bilirubin and distracted); 3 patients with pruritus grade 3+
alkaline phosphatase with low-to-normal levels (abrasions evident); 1 patient with pruritus
of serum GGT]) grade 4+ (cutaneous mutilation, hemorrhage,
and scarring evident)
Lind et al., 2010 [29] 8 children with PFIC or ALGS who had Self-reported and parent-proxy PedsQL overall
undergone PEBD (median age, 9.2 years; HRQoL, Physical Health, and Psychosocial
range, 6.3—14.5 years) Health summary scores were lower in patients
with PFIC/ALGS than in healthy peers
Median score for severity of pruritus in patients
with PFIC/ALGS: 2.5 (Infant Dermatitis Scale:
1 = none; 5 = severe); significantly correlated
with overall HRQoL (r = 0.74)
Schukfeh et al., 2012 [27] 24 children (16 boys and 8 girls) with PFIC Overall, the median preoperative Kardoff
undergoing PEBD in a medical school in pruritus score was 3 (range, 0—5)
Germany, 1994—2008 In patients in whom PEBD surgery was
successful, postoperative pruritus severity
scores were significantly lower than
preoperative scores: preoperative median
pruritus score: 3 (range, 0—5); postoperative
median pruritus score: 0 (range, 0—3)
Pruritus scores were unchanged in patients in
whom surgery was unsuccessful: preoperative
median pruritus score: 2 (range, 0—4);
postoperative median pruritus score: 2 (range,
0—4)
Yang et al., 2009 [30] 11 children with PFIC undergoing PEBD at a Median follow-up: 3.1 years (range, 2.0—5.7)
university medical center in the Netherlands, 2 years after PEBD, 5/11 children (45%) did not
2002—2005; diagnosis primarily on clinical experience pruritus, 3/11 (27%) had mild
grounds, laboratory parameters, and liver pruritus, and 3/11 (27%) continued to
biopsy; 8 with genetically confirmed PFIC2 experience severe pruritus with significant
scratch marks
Sleep of patients and parents improved, and
all patients resumed their school activities,
contributing to improved HRQoL
A1ATD: ␣-1-antitrypsin deficiency; ALGS: Alagille syndrome; GGT: gamma-glutamyl transferase; HRQoL: health-related quality of
life; IHC: intrahepatic chronic cholestasis; PEBD: partial external biliary diversion; PedsQL: Pediatric Quality of Life Inventory; PFIC:
progressive familial intrahepatic cholestasis.

Clinical manifestations of PFIC (Table 2) [8,10,11,19,20,23,24,26,27]. Symptoms of PFIC1

and PFIC2 generally appeared within the first 3 months of
Nine publications described symptoms or other clin- life [8], with a tendency for earlier appearance in patients
ical features of PFIC at presentation (Table 2) with PFIC2 [8,19,20,24]. In one study, symptoms appeared
[8,10,11,19,20,23,24,26,27] and 10 reported on disease in the first month of life in 15% of patients with PFIC1
progression (Table 3) [8,10,19,20,22—27]. and 44% of patients with PFIC2, and by 3 months of age in
Multiple symptoms were reported at presentation, 61% of patients with PFIC1 and 72% of patients with PFIC2
including: jaundice, hepatomegaly, itching/pruritus, pale [8]. No differences between patients with PFIC1 and PFIC2
stools, splenomegaly, diarrhea, discolored stools, failure to were seen in the development of jaundice, pruritus, hep-
thrive, vitamin E deficiency, vitamin D deficiency and pan- atomegaly or splenomegaly over the first few months of life
creatitis, with the last of these being confined to PFIC1 [8] whereas those with PFIC3 may not present with jaun-

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14 A. Baker et al.

dice, hepatomegaly or pruritus until after 2—3 years of age acute infections, dehydration and gastrointestinal bleeding
[19,24]. (Table 4).
Itching or pruritus at presentation were reported in seven
publications (Table 2), with frequencies ranging from 11% Health-related quality of life and pruritus
to 100% of patients [8,11,19,20,23,24,26]. Based on the
Whitington scale (0, none; 1+, rubbing or mild scratching
Five publications evaluated the HRQoL or pruritus associ-
when not distracted; 2+, active scratching without evident
ated with PFIC (Table 5) [17,23,27,29,30]. Of these, only
skin abrasions; 3+, abrasions evident; 4+, cutaneous muti-
two publications assessed the impact of PFIC or pruritus
lation, hemorrhage and scarring evident) [28], pruritus was
on HRQoL [17,29]. Kamath and colleagues assessed HRQoL
reported to be often severe (grade 3+ or more) in 76—80%
in children with chronic intrahepatic cholestasis, including
of patients and was not consistent with the degree of biliru-
those with PFIC [17]. Of 49 patients with chronic intrahep-
bin elevation [23,26]. Pruritus appeared to correlate with a
atic cholestasis, 25 had genetically confirmed PFIC. HRQoL
higher level of serum bile acid in patients with low levels
was assessed using the Pediatric Quality of Life Inventory
of GGT, although this effect was not statistically significant
(PedsQL) Measurement Model; scores range from 0 to 100
[24].
with higher scores indicating better HRQoL. Children with
Some patients with PFIC2 also presented with early signs
chronic intrahepatic cholestasis had lower total PedsQL self-
of vitamin D deficiencies (rickets, 3—22%),vitamin K defi-
reported scores compared with healthy controls (73 vs. 84;
ciencies (bleeding, 8%) or cholelithiasis (28%) [8,19]. Other
effect size, 0.87); parent-reported scores were similar in
extrahepatic manifestations at presentation were evident in
both groups (79 vs. 82) [17]. Lind and colleagues used the
PFIC1 (but not PFIC2), including diarrhea (61%), pancreati-
PedsQL and the Infant Dermatitis Scale to assess HRQoL asso-
tis (8%) and elevated sweat chloride (15%) [8]. PFIC3 was
ciated with pruritus in patients aged 6—18 years with PFIC
also associated with rickets (6%) [19]. None of the identi-
or Alagille syndrome, compared with healthy peers [29].
fied studies reported any other extrahepatic symptoms at
HRQoL, physical health and psychosocial summary scores
presentation.
were lower in patients with pruritus than in healthy peers
At follow-up, symptoms or other clinical features
[29].
reported in patients with PFIC (Table 3) included jaundice,
Three publications identified pruritus as the most
hepatomegaly, pruritus, splenomegaly, diarrhea, failure to
bothersome symptom associated with PFIC [23,27,30]. A
thrive, growth retardation, severe cholestasis and liver fail-
retrospective chart review assessed the severity of pruri-
ure (with possible symptomatic improvement, persistence
tus using the Whitington scale in five Malaysian patients
or recurrence depending on interventions); there were also
with PFIC. Of the five patients, three had moderate pruri-
reports of pancreatitis in patients with PFIC1 and HCC
tus with abrasions; one had severe pruritus with cutaneous
in patients with PFIC2 (Table 3) [8,10,19,20,22—26]. Pru-
mutilation, hemorrhage, and scarring; and one reported
ritus was reported in 76—100% of patients at follow-up
mild scratching and rubbing [23]. A German study in 24
[8,20,23,26,27] and often remained severe despite therapy
patients with PFIC assessed the severity of pruritus using
[23,26].
a 6-point pruritus score; the median was grade 3 (perma-
Progression to severe liver disease was more common and
nent scratch marks) [27]. A Dutch retrospective chart review
occurred earlier in patients with PFIC2 than in those with
of 11 patients with PFIC who had received PEBD identified
PFIC1, occasionally manifesting as early as 7 months of age
the patients’ main complaint as intractable pruritus with
[8]. In patients under the age of 1 year, those with PFIC1 gen-
significant excoriations [30].
erally had no or mild portal and lobular fibrosis, no cirrhosis,
no HCC and no necrosis, whereas those with PFIC2 had mild-
to-severe portal and lobular fibrosis with bridging fibrosis, Discussion
cirrhosis and sometimes necrosis. In patients over 1 year of
age, major portal and lobular fibrosis was observed both in Patients with PFIC experience shortened life expectancy,
children with PFIC1 and those with PFIC2, but lesions were debilitating symptoms and poor HRQoL. This systematic
more pronounced in the latter [8]. Among patients undergo- review consolidates the information available on the epi-
ing LT, liver failure and/or HCC was detectable in about 60% demiology, natural history, and burden of PFIC. Although
of those with PFIC2 but in none of those with PFIC1 [8]. genetic testing now allows definitive diagnosis, we found
significant knowledge gaps in the epidemiology of PFIC and
its subtypes. We also found limited evidence about mortal-
ity, the HRQoL of patients with PFIC, and a lack of published
Mortality information on the economic burden of the disorder.
Published epidemiologic evidence on the global incidence
Ten publications reported PFIC mortality data (Tables 4 and prevalence of PFIC was found to be very limited. It
and 5) [8,10,11,19,20,22—26], with mortality rates ranging was difficult to compare results across studies because of
from 0% to 87% [11,19]. The rates of LT for patients with differences in methods and patient populations, as well as
PFIC1 and PFIC2 (40—100%; Table 3) suggest that the highest the absence of molecular genetic diagnostics to differen-
reported mortality figure (87% [11]) is probably most repre- tiate PFIC from other similar conditions in earlier studies.
sentative of the natural history of untreated PFIC. Reasons When reviewing the literature, numerous authors have indi-
for death included infections, bleeding (cerebral, gastroin- cated that PFIC is estimated to affect 1 in 50,000—100,000
testinal, splenic), liver failure, LT-related complications, births [1,31]. However, the source of this estimate could not
HCC, and complications secondary to cholestasis, including be identified by this systematic literature analysis and this

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Management of HCV and end-stage kidney disease 15

rate is not supported by observational or clinical evidence. tation, and other costly interventions. Furthermore, the
Population epidemiology data identified in the present sys- symptoms of PFIC can be debilitating and, as most patients
tematic review was limited either to an estimate based on are children and infants, there is likely to be an associated
non-genetic diagnoses and average birth rates in Norway economic burden imposed on parents and other caregivers.
[10], or to case reports from a small indigenous population in Further research is needed to quantify the economic burden
Greenland [11]. Confirmation of PFIC diagnosis by molecular of PFIC.
genetic testing allows accurate assessment of its preva-
lence. Among studies assessing children admitted to hospital
with liver-related diseases, publications of studies using
Conclusion
molecular genetic diagnosis reported a prevalence of PFIC
of 12—13% in children with cholestasis and 9% in those with Clinical features and prognosis vary depending on the sub-
cholestasis, acute liver failure, or splenomegaly [14,16,17]. type of PFIC For instance, outcomes after LT can be poor
This suggests that PFIC accounts for a considerable propor- in patients with PFIC1 [25], as the disease is multisystemic
tion of childhood liver disease. Although originally reported and hence the bowel and lung manifestations are not nec-
mostly in Caucasian patients [23], PFIC has also been diag- essarily improved post-LT. These differences underscore the
nosed in individuals from other populations. However, in importance of prompt genetic confirmation of the diagnosis
general, these diagnoses were not based on genetic testing to provide additional guidance to physicians and patients
and the actual prevalence might be higher than reported about the likely disease course. Prenatal genetic diagno-
[12—18,23]. sis could also be considered. PFIC1, PFIC2 and PFIC3 are
Of the three main PFIC subtypes, PFIC2 was generally the main subtypes of PFIC, but genetic testing can also
more common than PFIC1 and PFIC3 in studies conducted in detect other inherited cholestatic liver diseases including
the USA and Europe, but PFIC1 was the most common sub- TJP2 deficiency (encoding tight junction protein 2), which
type in a study conducted in Japan [22]. Further research is sometimes referred to as PFIC4 [33], and cholestasis asso-
is needed for accurate estimates of the prevalence and ciated with genetic defects in MYO5B (encoding myosin VB)
incidence of PFIC and its subtypes, and for improved under- [34]. Next generation sequencing of targeted gene pan-
standing of geographic and ethnic variations. els has proven value in rapidly and reliably discriminating
Pruritus was a primary symptom of PFIC, experienced cholestatic disease of childhood [35].
by 11—100% of patients at presentation and by 76—100% of Current clinical information is variable and based on
patients at follow-up. Pruritus was often severe; was asso- small and often anecdotal studies in a limited number of
ciated with abrasions, cutaneous mutilation, hemorrhage, geographical regions. The increasing availability of molec-
and scarring; and led to significantly diminished HRQoL ular genetic diagnostics, coupled with specific new codes
(assessed using the PedsQL) in patients with PFIC compared in the International Statistical Classification of Diseases
with healthy peers [17]. Symptoms of PFIC also included and Related Health Problems, will allow more accurate
jaundice, hepatomegaly, splenomegaly, diarrhea, and fail- prospective and retrospective assessment of patients with
ure to thrive. These generally appeared by about 3 months PFIC. Creating and unifying patient registries will help to
of age in patients with PFIC1 or PFIC2 [8], whereas patients align all available information on the population of patients
with PFIC3 sometimes did not present with symptoms until with PFIC, including genotyping data. Further studies are
after 2—3 years of age [19,24]. Patients with PFIC2 were required to better characterize the subtypes of PFIC, not
more likely than patients with PFIC1 or PFIC3 to expe- only to improve clinical understanding but also to inform
rience progression to severe liver disease or HCC and to the management of individuals with PFIC and the design of
require LT. Progression to HCC appeared to be a common future therapeutic trials in patients with these genetic con-
and early outcome in patients with PFIC2. Furthermore, an ditions. Evaluation of the economic costs of PFIC and the
immunohistochemical and mutational analysis study of liver HRQoL of patients may help to encourage recognition of the
samples obtained from 10 children with HCC aged 13—52 burden imposed by this debilitating and potentially under-
months showed that the majority had evidence of bile acid diagnosed family of diseases, and to ensure that adequate
transporter deficiencies and mutations in ABCB11 [32]. No attention is paid to patients’ needs.
publications were identified reporting data on PFIC in adults,
indicating the need for further research in this area. Funding
Limited evidence was identified on the HRQoL of patients
with PFIC. Two studies reported that children with PFIC had This work was funded by Shire International GmBH. Shire
lower HRQoL than healthy peers (using the generic PedsQL develops and markets treatments for genetic diseases
questionnaire). HRQoL was also lower in patients with PFIC including progressive familial intrahepatic cholestasis.
or Alagille syndrome than in patients with ␣-1 antitrypsin
deficiency, another chronic liver disease [17]. The develop-
ment of disease-specific instruments may help with future Writing assistance
assessment of the impact of specific symptoms of PFIC (e.g.
pruritus) on HRQoL. Under the direction of the authors, Dr. Obaro Evuarherhe
No publications reporting data on PFIC-related costs, and Dr. Elizabeth Gandhi, employees of Oxford Pharma-
resource utilization, or overall economic burden were Genesis, Oxford, UK, provided writing assistance for this
identified. While rare, PFIC is both severe and life- publication. Editorial assistance in formatting, proofread-
threatening, and management of patients may involve ing, copy editing and fact checking was also provided by
extended and repeated hospitalization, surgery, transplan- Oxford PharmaGenesis. Shire International GmBH provided

Please cite this article in press as: Baker A, et al. Systematic review of progressive familial intrahepatic cholestasis. Clin
Res Hepatol Gastroenterol (2018), https://doi.org/10.1016/j.clinre.2018.07.010
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CLINRE-1154; No. of Pages 17 ARTICLE IN PRESS
16 A. Baker et al.

funding to Oxford PharmaGenesis for support in writing and [10] Henriksen NT, Drablos PA, Aagenaes O. Cholestatic jaundice
editing this manuscript. in infancy. The importance of familial and genetic factors in
aetiology and prognosis. Arch Dis Child 1981;56:622—7.
[11] Nielsen IM, Eiberg H. Cholestasis Familiaris Groenlandica: an
Author contributions epidemiological, clinical and genetic study. Int J Circumpolar
Health 2004;63(Suppl. 2):192—4.
[12] Alam S, et al. Protocol-based management of metabolic liver
All authors were involved in the study concept and design,
disease in children at a tertiary care specialized center. Hepa-
analysis and interpretation of the data, and the drafting and tol Int 2013;7:S112.
critical revision of the manuscript for important intellec- [13] Chaabouni M, et al. Epidemiological, etiological and evolu-
tual content. All authors approved the final version of the tionary aspects of children cirrhosis in a developing country:
manuscript for submission. Experience of the pediatric department of SFAX University hos-
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Please cite this article in press as: Baker A, et al. Systematic review of progressive familial intrahepatic cholestasis. Clin
Res Hepatol Gastroenterol (2018), https://doi.org/10.1016/j.clinre.2018.07.010