medicina

Article
Long-Term Outcome after Liver Transplantation for Progressive
Familial Intrahepatic Cholestasis
Safak Gül-Klein * , Robert Öllinger , Moritz Schmelzle, Johann Pratschke and Wenzel Schöning

Deparment of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum,

Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; [email protected] (R.Ö.);
[email protected] (M.S.); [email protected] (J.P.); [email protected] (W.S.)
* Correspondence: [email protected]; Tel.: +49-1707402409

Abstract: Background and Objectives: Progressive familial intrahepatic cholestasis (PFIC) is a rare auto-
somal recessive inherited disease divided into five types (PFIC 1-5). Characteristic for all types is early
disease onset, which may result clinically in portal hypertension, fibrosis, cirrhosis, hepatocellular
carcinoma (HCC), and extrahepatic manifestations. Liver transplantation (LT) is the only successful
treatment approach. Our aim is to present the good long-term outcomes after liver transplantation
for PFIC1, focusing on liver function as well as the occurrence of extrahepatic manifestation after
liver transplantation. Materials and Methods: A total of seven pediatric patients with PFIC1 under-
went liver transplantation between January 1999 and September 2019 at the Department of Surgery,
Charité Campus Virchow Klinikum and Charité Campus Mitte of Charité-Universitätsmedizin Berlin.
Long-term follow-up data were collected on all patients, specifically considering liver function and
extrahepatic manifestations. Results: Seven (3.2%) recipients were found from a cohort of 219 pediatric



patients. Two of the seven patients had multilocular HCC in cirrhosis. Disease recurrence or graft loss


did not occur in any patient. Two patients (male, siblings) had persistently elevated liver parameters
Citation: Gül-Klein, S.; Öllinger, R.; but showed excellent liver function. Patient and graft survival during long-term follow-up was 100%,
Schmelzle, M.; Pratschke, J.; Schöning, and no severe extrahepatic manifestations requiring hospitalization or surgery occurred. We noted
W. Long-Term Outcome after Liver
a low complication rate during long-term follow-up and excellent patient outcome. Conclusions:
Transplantation for Progressive
PFIC1 long-term follow-up after LT shows promising results for this rare disease. In particular, the
Familial Intrahepatic Cholestasis.
clinical relevance of extrahepatic manifestations seems acceptable, and graft function seems to be
Medicina 2021, 57, 854. https://
barely affected. Further multicenter studies are needed to analyze the clinically inhomogeneous
doi.org/10.3390/medicina57080854
presentation and to better understand the courses after LT.
Academic Editor: Giovanni Tarantino
Keywords: liver transplantation; progressive familial intrahepatic cholestasis; long-term outcome
Received: 29 July 2021
Accepted: 16 August 2021
Published: 22 August 2021
1. Introduction
Publisher’s Note: MDPI stays neutral Persistent neonatal cholestasis can be caused by a manifest liver disease [1,2]. Different
with regard to jurisdictional claims in anomalies of the liver and the bile duct tree, which can be acquired or hereditary, lead
published maps and institutional affil- to disturbances of the bile flow. Progressive familial intrahepatic cholestasis (PFIC), an
iations.
autosomal recessive inherited disease, induces impaired bile formation via mutated genes
responsible for protein transporters. The altered hepatic bile flow subsequently leads, via
severe intrahepatic cholestasis, to progressive chronic liver disease.
PFIC is divided into five types (PFIC1-5), while PFIC1 is the most common disease.
Copyright: © 2021 by the authors. The genetic causes of cholestasis assume an important role in understanding the physiology
Licensee MDPI, Basel, Switzerland. and pathophysiology of the liver. Type 1 (PFIC1) appears to be associated with defective
This article is an open access article bile acid secretion and is defined according to genetic criteria based on recessive mutations
distributed under the terms and in the ATP8B1 gene on chromosome 18q21 [3–8]. The patients are characterized by jaundice
conditions of the Creative Commons
and itching, and the subsequent progression of chronic liver disease [9–11]. Laboratory
Attribution (CC BY) license (https://
characteristics include glutamyl transpeptidase (GGT), whose activity is low for the degree
creativecommons.org/licenses/by/
of hyperbilirubinemia [12]. Bull et al. demonstrated good graft survival for PFIC 1 and
4.0/).

Medicina 2021, 57, 854. https://doi.org/10.3390/medicina57080854 https://www.mdpi.com/journal/medicina

Medicina 2021, 57, 854 2 of 13

PFIC2, consistent with earlier published LT series. Patients with PFIC2, which is based on a
disorder of the bile salt excretion protein (BSEP) caused by a mutation of the ABCB11 gene,
seem to present a slightly better survival rate [7,13]. The occurrence of malignancies for
PFIC, especially that of HCC, is described in the literature [5,14–17]. Here, patients with
missense mutations have been shown to be at lower risk for HCC [5,14,18].
Liver transplantation (LT) is an important therapeutic tool for the management of
PFIC [19,20]. In the course of transplantation, a decrease in cholestasis has been observed,
and the occurrence of PFIC1-specific extrahepatic manifestation was also described in
the literature.
Extrahepatic manifestation post-LT as a potential complication, including pancreatic
disease, is more frequently described after LT in PFIC1 [4,21–24]. Pancreatic disease may
be associated with LT or be due to the progression of extrahepatic disease. In addition,
diarrhea is also frequently described, as PFIC1 is strongly expressed in the small and large
intestine of healthy individuals. Gastrointestinal dysfunction and pancreatic injury may
contribute to diarrhea-associated malnutrition, poor growth, prolonged delay of puberty
and low albumin and hemoglobin levels after LT in PFIC1 [4,23,25].
Histologically, steatosis may occur after LT and be associated with increased transmi-
nase activity, although graft function might not be compromised. The signal transmission
between the hepatic and intestinal tract, which is disturbed in PFIC1 deficiency, seems to
change after LT: post-transplant steatosis may be associated with such a change [4,26].
Follow-up of PFIC1 patients after LT is important for excellent clinical management
and for anticipating results in the long term. Here, multicenter data analysis should provide
more insight. The balancing act between the consequences of a persistent multisystemic
disease with extrahepatic manifestations and graft dysfunction that may affect the LT
outcome of recipients as well as graft survival and the need for LT must be addressed.
We here report long-term results of seven infants with PFIC1 who received LT as their
first line of treatment before the age of two years. The clinical development of infants
into adulthood was studied retrospectively, with special emphasis on the influence of
PFIC1-typical extrahepatic manifestations and liver biopsies.

2. Materials and Methods

2.1. Study Population
A total of 219 patients younger than 18 years of age, who underwent LT from 1 Jan-
uary 2000 to 30 September 2019 at the Department of Surgery, Campus Charité Mitte
and Campus Virchow-Klinikum at Charité-Universitätsmedizin Berlin, Germany, were
retrospectively analyzed. The analysis and reporting of data received institutional review
board approval (EA2/267/20).
Primary endpoints were recurrence of PFIC and/or graft-dysfunction. Secondary
endpoints included 5-, 10-, 15-, and 18-year patient and graft survival as well as occurrence
of extrahepatic manifestations.
Living liver donor transplantations were performed after acceptance by our institu-
tional ethics committee and in accordance with standardized protocols. Liver transplants
from deceased donors were organized by EUROTRANSPLANT within the framework of
an allocation procedure.
For this purpose, demographic data, clinical features (physical development, histolog-
ical examinations) and specific laboratory findings were collected at four different points
in time (pre-transplantation, at the time of transplantation, short-term (first postoperative
90 days), and long-term (from the fourth postoperative month)) during the study period.
This was based on annual check-ups and also on unplanned inpatient stays. Particular
attention was paid to size–weight developments, the clinical course for different features
(occurrence of splenomegaly, development of hearing disorders, complications though
viral or bacterial infections), trough quantities of immunosuppressive drugs, associated
coagulopathies and complications in general, as well as specific histological analysis of
available liver biopsies.
Medicina 2021, 57, 854 3 of 13

Tumor follow-up was performed by means of regular ultrasound examination of the

abdomen over the course of 6 months and AFP controls.
Standard immunosuppression initially was performed with tacrolimus ((tac); 0.1 mg/kg).
Tac trough levels were kept at 10–15 ng/mL during the first month and afterwards at
5–7 ng/mL. Prednisolone tapered to 0.1 mg/kg after 10 days and was discontinued
three months after LT. In the long-term follow-up, immunosuppression was extended to
mycophenolate mofetil (MMF) in one patient and switched to MMF in four recipients.
Patients were followed up until September 2019 for patient and graft survival.

2.2. Data Collection

Anonymous donor data were retrieved from the Eurotransplant Network Information
System (ENIS), and additionally all available records of recipient data were collected
from the hospital information system (SAP® SE, Walldorf, Germany) and from archived
patient files. Demographic and clinical characteristics of patients included gender, recipient
and donor age at time of LT, PELD score prior to transplantation. In addition, previous
abdominal and other disease-associated surgeries prior to LT, transplant types (living liver
donation, deceased donor liver (split-graft, full-size organs), median surgery duration
(min), and total hospital duration were also determined.

2.3. Statistical Analysis

Due to the limited sample size, the statistical analysis was performed in a purely
descriptive manner without any testing. Calculations were performed using IBM SPSS
Statistics, version 25 (IBM Corporation, Armonk, NY, USA).

3. Results
3.1. Characteristics Pre-Transplantation
A total of seven PFIC children out of 219 pediatric patients analyzed after LT were
eligible for this analysis.
All infants suffered from PFIC1 (n = 7) and developed progressive cirrhosis (n = 7).
The mean age at the time of LT was 9 months (range 7–23). All patients presented jaun-
dice before liver transplantation, which regressed post-LT. In the long-term course, only
one patient presented recurrent episodes of diarrhea, with no pancreatitis. No patient
developed portal hypertension post-LT. Two patients had need of endoscopic retrograde
cholangiopancreaticography (ERCP) due to biliary complications (biliary anastomosis
stenosis and cholangitis). The patient with cholangitis showed no complications in the
long-term follow-up after single ERCP and endoscopic papillotomy. The patient with
biliary anastomosis stenosis showed a complication-free course after repeated ERCP and a
Yamaka dilatation program over the last 12 years.
Among the seven patients, two pairs of siblings were detected (Table 1) and two
patients developed multilocular HCC (Table 2). None of the patients had abdominal
surgery prior to LT.

Table 1. Patient characteristics and demographic features.

* C/Affected Premature Age: Onset of Initial Age at LT ** Indications Time of HCC Follow-Up
Pat. Gender HCC ∞ Outcome
Siblings Birth (Weeks) Symptoms ** (Months) for LT Diagnosis (Years)

1 f no/no no since birth j/c/p 8 LF no - 18 Disease-free

2 f no/yes ** - since birth j/c/p 9 LF no - 18 Disease-free
3 m no/yes ** yes three months j/c/p 20 SC, LF yes incidental 10 Disease-free
4 m yes/yes ** - since birth j/c/p 7 LF no - 17 Disease-free
5 m yes/yes ** yes since birth j/c 8 LF no - 14 Disease-free
6 m no/no no since birth j/c/p/d 18 HCC yes prior LT 6 Disease-free
7 w no/no no since birth j/c 23 LF no - 20 Disease-free

* Consanguinity: 2 and 3, and 4 and 5 are siblings; ** jaundice (j), pruritus (p), cholestasis (c), diarrhea; severe cholestasis (SC), liver failure
(LF), HCC; ∞ outcome: including PFIC1 recurrence as well as HCC recurrence.

Different graft types were used for the LT, such as left-sided liver lobes from living
donors (n = 3; mother, aunt, uncle), left-sided lobe split-grafts (n = 2) and full-size grafts
(n = 2) from deceased donors (Table 3).
Medicina 2021, 57, 854 4 of 13

Table 2. HCC characteristics.

Histological Number Localisation Max. Diameter AFP Pre-LT//

Pat. Cirrhosis Type N V G
Type of Nodules of Nodules (mm) Last Follow-Up
1 solid trabecular micronodular >3 bilobular 20 no 1 2 19,536//1.3
2 solid trabeculat micro-, macronod. 3 bilobular 11 no no 2 32,779//2.7

Table 3. Donor characteristics, perioperative parameters.

Pat. Donor Type Operation Time (min) ∞ Re-Operation Post-LT Other Perioperative Complications
1 Aunt LDLT 245 no no
2 Mother LDLT 198 no no
3 deceased Full-size 289 no no
4 deceased split graft 242 no no
5 deceased split graft 349 yes * no
6 Uncle LDLT 340 yes ** no
8 deceased Full-size 210 no no
∞ Re-operation: within short-term, first 90 days post-LT; * reason: removal intraabdominal hematoma, familial APC-Resistency; ** calculated
staged abdominal-wall closure.

3.2. Short-Term Follow- and Long-Term Follow-Up

One patient developed acute rejection. One patient with known coagulopathy had
a hematoma post-LT as a major complication according to Clavien–Dindo (>II), so that
relaparotomy was required. No unplanned hospitalizations were detected during the
short-term follow-up.
All patients showed a disease-free outcome (median; range 6 to 18 years) during the
17-year follow-up. Especially complications specific for LT, such as bile leakage or need for
re-transplantation did not occur in any of the different donor types (LDLT, deceased organ
transplantation, such as full-size and left-lateral split-grafts).
During this long observation period, the overall survival rate of all patients and grafts
was 100%. None of the seven patients developed a PFIC1 relapse (Table 4). Both infants
with multilocular HCC are disease-free up to now post-LT.

Table 4. Histological findings and immunosuppression for short- and long-term follow-up.

Short-Term Follow-Up Long-Term Follow-Up

Liver-Biopsies # 2/7 4/7
Fibrosis 0/2 2/4
Cirrhosis 0/2 0/4
Steatohepatitis 0/2 3/4
ACR * 1/2 0/4
Tac 7/7 0/7
MMF 0/7 7/7
Liver function:
Dysfunction ** 0/7 1/7
Renal function:
Dysfunction 0/7 0/7
# = in the short-term available for only two patients; in the long-term available for four patients. * ACR = histolog-
ical proven acute cellular rejection; ** = elevated liver enzymes, hyperbilirubinemia, reduced INR.

Patients showed varying degrees of extrahepatic manifestations, including intermit-

tent mild diarrhea in one patient. Events of pancreatitis or persistent severe diarrhea were
not detected in our patient cohort. In addition, hearing loss (n = 4) and growth failure
(n = 2) were observed over the long-term course.
Medicina 2021, 57, 854 5 of 13

However, with regard to graft function, liver biopsies were performed in two male
patients (siblings) with persistently elevated liver enzymes, resulting in steatohepatitis
(Table 4). Histologically, steatohepatitis was described as mild and was associated with
mild dysfunction due to slightly reduced levels of coagulation (INR) in one of the siblings
(No. 4). Both HCC patients have demonstrated tumor-free follow-up. One patient with
HCC received everolimus.
The consideration of general complications in long-term aftercare presented one
patient (no. 2) with stenosis of the bile duct anastomosis and consecutive cholestasis
6.5 years after LT. Endoscopic interventions, such as repetitive dilatations (Yamakawa) were
needed for one year. Currently, eleven years after the last endoscopic treatment, the patient
is free of complaints and intervention. A second patient (no. 7) developed stenosis of the
biliary anastomosis and of the bile duct, with consecutive cholangitis 6 years after LT, which
was well-treated with endoscopic dilatation and papillotomy. Nevertheless, this patient
received in consequence 10 years post-LT re-operation with biliodigestive anastomosis and
is presently in good general condition. Another patient (no. 1) underwent partial lung
resection 7 years after LT in recurrent pneumonia due to a middle lobe atelectasis.

4. Discussion
Progression of PFIC may temporarily present a clinical and laboratory improvement
through drug therapies (rifampicin, ursodeoxycholic acid, cholestyramine, phenobarbital)
or through biliary diversion (BD) in the absence of liver cirrhosis [27–29]. Even if there
is no full manifestation of liver cirrhosis, liver transplantation (LT), especially for PFIC1,
might also be the therapy of choice, since the PFIC-specific itching and jaundice can lead
to serious developmental disorders, accompanied by retarded growth, severe rickets and
reduction in quality of life [1–3,12,19,30–34]. LT for PFIC1 proves to be feasible regardless of
donor type and reduces failure to thrive and permanent itching [19,30,35,36]. The analysis
of our patient cohort showed an excellent course for all transplant types. Crucial remains
the appropriate aftercare care depending on the underlying disease, regarding the different
PFIC types [37–40].
We herein present long-term outcomes of 6 to 18 years for seven infants with PFIC1
undergoing LT at our surgical department. The seven infants (<2 years of age) in our analy-
sis presented cirrhosis, with two patients exhibiting HCC (Table 2), and most were affected
from birth with itching, pruritus and jaundice. At the timepoint of LT, the patients presented
a median age of 9 months and had an inconspicuous course peri- and postoperatively.
Although the procedure of LT in infants has entered clinical routine with good results,
regarding long-term follow-up, we must take into account late complications for patient-
and graft-survival. In this context, for PFIC1, special attention must be given to extrahepatic
manifestations occurring and exacerbating post-LT and the process of steatohepatitis [4].
Regarding extrahepatic manifestations, not only their occurrence but also their man-
agement play an important role in the routine follow-up. Since the gene for PFIC1 is
mainly expressed in the intestine and pancreas, PFIC1 disease also plays a crucial role
in extrahepatic tissues [8]. There are reports of severe clinical courses after LT [21,24].
Following this, PFIC1 patients after LT may develop persistent diarrhea and loose stools.
This may explain a possible influence of PFIC1 on the intestinal absorption of bile acids, as
patients with benign recurrent intrahepatic cholestasis (BRIC) have increased fecal bile acid
loss and reduced bile acid reservoirs [41]. Furthermore, Pawlikowska et al. demonstrated
in a multicenter analysis of 145 patients prior to surgical intervention in a comparative
analysis between PFIC1 (n = 61) and BSEP (n = 84) that PFIC1 patients were more likely to
have extrahepatic disease (16), whereas Walkowiak et al. showed that pancreatic secretion
was normal in patients with PFIC1 both without and after LT for a prolonged period of
time. They observed that steatorrhea was not associated with pancreatic insufficiency [22].
No pancreatitis was observed in our patient cohort. With regard to the often described
diarrhea, only one patient in the retrospective study showed intermittent diarrhea, with no
Medicina 2021, 57, 854 6 of 13

serious findings. Five out of seven children showed an age-appropriate development over
the long term.
Apart from extrahepatic manifestations, liver function is of particular concern in long-
term follow-up. Cuttilo et al. showed that LDLT with donor parents with a heterozygous
PFIC1 status does not increase the risk of liver dysfunction in both the recipient and the
donor [35]. Soubrane et al. described recurrence-free courses for 12 full organ LDLT [30].
However, the possible “recurrence of PFIC” remains a controversial issue. A possible
alloimmunization after LT of the recipient against the BSEP, MDR3 (PFIC3) or FIC1 proteins
of the liver donor remains a theoretical point of controversy. The possible susceptibility
of PFIC patients to the FIC1, BSEP or MDR3 gene products due to a severe mutation is
discussed. Davit-Spraul et al. discussed a rare case with a recurrence of pure hepatocellular
cholestasis similar to PFIC2 in a male patient after cadaveric LT for PFIC2 [34].
Reports of long-term follow-up data with regard to histological findings of the graft
and graft function as well are rare [3]. Only two patients out of the seven attracted attention
with elevated liver enzymes. One of them presented mild steatohepatis.
A further point of our analysis is the first report—so far as we know—of the occurrence
of HCC in two infants with PFIC1, and long-term results are provided, which are rather
scarce [8]. However, our results are favorable, since both patients are disease-free.
Routine follow-up, in particular the closer and targeted oncological follow-up of
HCC patients, includes the monitoring of liver function and the detection of extrahepatic
manifestations. The anticipation of possible complications, based on the evaluations of
long-term monitoring, is of particular importance. Especially from a socio-economic point
of view, patients suffering from this rare multisystemic disease can maximally benefit
from targeted aftercare during puberty into adulthood and be better integrated into social
working life.
Certainly, our study is limited by its retrospective design and a small cohort. Never-
theless, LT for PFIC1 seems to be promising in our analysis in long-term outcome, because
poor prognosis after LT in patients with PFIC1 was reported [26].
Biliary diversion can be successful if there is no fully developed cirrhosis of the liver
and the disease is diagnosed early after the onset of symptoms in infancy [42].
Shiau et al. showed recently (Hepatology Communications) that an increase in
Fibrosis-4 score was associated with 1.36-fold higher odds for LT in PFIC patients. In
addition, the aminotransferase-to-platelet ratio index or Fibrosis-4 score appear to associate
with risk for future LT in children with PFIC [43].
In our patient cohort, the full picture of advanced liver cirrhosis, associated with
severe hypotrophy and developmental delay, was the decisive factor for the need for LT.
Our patients were symptomatic since birth and underwent LT at an age of 9 months
old (median). Two of the patients transplanted at the ages of 18 and 20 months already
had multiple HCC in cirrhosis. Therefore, after confirmation of the diagnosis and in the
presence of advanced fibrosis or liver cirrhosis, liver transplantation should be sought as
soon as possible.
As the urgency of transplantation is not adequately expressed by the labMELD for
this group of patients, these patients should be assigned a matchMELD upon request.
The disease should be listed under the criteria of the standard exceptions according to
the German guideline. The risk of potentially developing HCC should be taken into
account. In view of the often postpartum onset of the disease or early manifestation of
symptoms, suspected HCC should be taken into account regardless of its size and extent,
but after exclusion of distant metastases. As these patients are often infants, histological
confirmation should not be mandatory, but should be supplemented by elevated AFP
values, high-grade suspected imaging and the determination of biomarkers [43].
Finally, regarding the literature (Table 5) multicentric data with large patient cohorts,
comparing PFIC patients of different subtypes after LT, are needed. An analog multi-center
analysis for PFIC1 in comparison with PFIC2 might, facilitate the diagnosis and help to
better differentiate the diseases.
Medicina 2021, 57, 854 7 of 13

Table 5. Review of the included literature specifically for PFIC1 patients after liver transplantation.

Authors PFIC1 PFIC1

Year Age on Onset LT Graft Type Time after LT Survival Outcome Key Findings
(Reference) Specific Patients
Summerskill Recurrent obstructive jaundice, itching; no
1959 no 2 9, 17 no - - -
et al. [13] histological findings
Classification: intrahepatic cholestasis
without any structural abnormalities of the
Ornvold et al.
1989 yes 16 1–3 months no - - 6 alive n. m. bile duct; death in early childhood;
[14]
histological analysis revealing nonspecific
cholestatic features
Question of recurrence remains, longer
Soubrane et al. Neonatal 12 full-size grafts, 2
1990 yes 14 yes 17 months yes Uncomplicated follow-up is necessary; medical therapy
[31] period—5 years reduced-size grafts
ineffective; LT good indication
Only known effective therapy biliary
Whiting et al. 6.2 ± 3.6 months
1994 yes 14 yes n. m. n. m. 11 alive n. m. diversion, LT; Better characterization of
[33] to years
this syndrome is needed
Emond et al. 3.8 years LT should be performed primarily in
1995 yes 11 4 years yes n. m. 8 alive Uncomplicated
[30] (mean) patients who have cirrhosis
Genetic analysis, light microscopy,
transmission electron microscopy may
Bull et al. [9] 1997 yes 9 11 weeks (mean) no - - n. m. n. m. help distinguish PFIC1 from others sorts
of Bylers syndrome; Bylers syndrome is
not a single clinicopathological entity
9 out of 39 In case of failure of UDCA treatment,
Jacquemin et al.
1997 yes not exactly -//- yes n. m. n. m. n. m. n. m. partial external biliary diversion or
[28]
described liver transplantation
Arrese et al. [15] 1998 - - - - - - - - Molecular mechanisms of bile transport
10 months to 19 Patients presenting cirrhosis or ineffective
Ismail et al. [29] 1999 yes 8 out of 46 yes 6 cadaveric, 2 LDLT n. m. 6 alive Uncomplicated
years PEBD should qualify for LT
PFIC is associated with mutations in
Jacquemin et al.
1999 yes - - - - - - - hepatocellular transport system genes
[8]
involved in bile formation
In PFIC-1 LT improves life for the patient,
who no longer is tormented by pruritus,
Knisley et al.
2000 yes - - - - - - - but diarrhea, failure to grow and to enter
[34]
puberty, and pancreatitis may persist
as problems.
Medicina 2021, 57, 854 8 of 13

Table 5. Cont.

Authors PFIC1 PFIC1

Year Age on Onset LT Graft Type Time after LT Survival Outcome Key Findings
(Reference) Specific Patients
It is clear that none of the speculative
van Mil et al.
2001 yes - - - - - - - arguments described completely explain
[11]
the etiology of FIC1 disease.
Explanation for diarrhea and growth
Remarkable
retardation after LT and importance of
Egawa et al. [22] 2002 yes 7 3 to 18 years yes LDLT 1 year 7 alive improvements after
early treatment with bile adsorptive resin
LT all patients
for postoperative diarrhea
Complicated: PFIC1 characterized by normal GGT
Lykavieris et al. 2.5 months; 2 Cadaveric whole diarrhea, liver activity and extrahepatic features
2003 yes 2 yes 9.5–11 years 2 alive
[6] months liver steatosis, no catch-up corresponds, which are not corrected or
of stature growth may be aggravated by LT, impairing QoL
Richter et al. Cadaveric whole
2005 yes 1 2 years yes 2 years alive Uncomplicated First report of PFIC and hepatoblastoma
[20] liver
Heterozygote familial donors can be safely
used for LDLT, if evaluation of the donor
Cutillo et al. [36] 2006 yes 7 27 months yes LDLT n. m. alive Uncomplicated
does not reveal any previous history of
even mild liver function defect
PFIC associated with BSEP deficiency
Knisley et al.
2006 yes 11 13–52 months yes LDLT n. m. alive Uncomplicated represents a previously unrecognized risk
[17]
for HCC in young children
18.5 months
Özcay et al. [18] 2006 yes 2 n. m. yes LDLT alive HCC recurrence free LT may offer better survival rates
(median)
knowledge about the function of
Pauli-Magnus hepato-biliary uptake and efflux systems
2006 yes - - - - - - -
et al. [2] and discusses factors that might
predispose to drug-induced cholestasis
No observed
Pancreatic secretion was normal; observed
Walkowiak et al. pancreatic pathology;
2006 yes 3 5–23 years yes n. m. n. m. n. m. steatorrhea not related to
[23] biopsy with normal
pancreatic insufficiency
intestinal mucosa
Good QoL,
disappearance of LT is effective treatment with good
Aydogdu et al. 43.2 ± 27 6 LDLT, 6 deceased
2007 yes 12 yes 1 year 8 alive pruritis, jaundice, outcome, minimal morbidity in PFIC
[26] months donor grafts
improvement of patients with cirrhosis.
nutritional status
Medicina 2021, 57, 854 9 of 13

Table 5. Cont.

Authors PFIC1 PFIC1

Year Age on Onset LT Graft Type Time after LT Survival Outcome Key Findings
(Reference) Specific Patients
Recognition of post-LT steatohepatitis will
Miyagawa- provide a better understanding of the
8.9 years
Hayashino et al. 2009 yes 11 4 years (median) yes LDLT 8 alive - enterohepatic circulation of bile acids and
(median)
[27] the pathophysiology of
intrahepatic cholestasis
PFIC1 patients present obvious signs of
Davit-Spraul Extrahepatic features
2010 yes 6 4 years (median) yes n. m. n. m. 4 alive extrahepatic disease that do not resolve
et al. [10] were present after LT
after LT.
FIC1 patients showed stronger clinical and
Pawlikowska
2010 yes 61 66 months yes n. m. n. m. - - laboratory evidence of extrahepatic
et al. [16]
disease in comparision to PFIC2 patients
Digestive symptoms;
steatosis and/or LDLT should not be performed in PFIC1
11.9 ± 4.5
Hori et al. [37] 2011 yes 11 - yes LDLT 8 alive fibrosis were found; 3 patients until effective interventions can be
years
dead patients had made to correct the metabolic defects
cirrhotic findings
Complicated: Severe
diarrhea, EBD can avoid organ disfunction and loss
Nicastro et al.
2012 yes 1 5 months yes LDLT 30 months alive protein-losing in post-LT inpatients who develop
[25]
enteropathy, graft steatohepatitis
steatofibrosis
Stricture of native
Steatosis commonly occurs post-LT and
Berumen et al. Reduced size liver bile duct; Persisting
2014 yes 1 8 months yes 2 years alive can progress to fibrosis, cirrhosis with ned
[24] transplant steatosis, severe
for re-transplantation
diarrhea
Mutation of FIC1 protein significantly
impairs bile salt secretion; exact
Mehl et al. [4] 2016 yes - - - - - - - mechanism for how FIC1 deficiency leads
to cholestasis is not fully understood;
varying severities of PFIC1 are noted
LT is currently the only effective treatment
for end-stage liver diseases due to PFIC;
Liu et al. [3] 2018 yes 3 n. m. yes LDLT, DCD 1 year all alive Severe diarrhea
LT for PFIC1 may worsen the
extrahepatic manifestations
Medicina 2021, 57, 854 10 of 13

Table 5. Cont.

Authors PFIC1 PFIC1

Year Age on Onset LT Graft Type Time after LT Survival Outcome Key Findings
(Reference) Specific Patients
Similar results HRQOL for PFIC patients
no specifica- after PEBD and LT; HRQOL in both
Wassmann et al.
2018 yes tion for - - - - - - groups even similar to that of healthy
[42]
PFIC 1 children. PEBD is primary surgical
treatment for PFIC patients with cirrhosis
Clinical features and prognosis vary
depending on the sub-type of PFIC For
instance, outcomes after LT can be poor in
Baker et al. [32] 2019 yes - - - - - - patients with PFIC1, as the disease is
multisystemic, and hence the bowel and
lung manifestations are not necessarily
improved post-LT
ICP: Intrahepatic cholestasis of pregnancy; PEBD: partial external biliary diversion.
Medicina 2021, 57, 854 11 of 13

The analysis and specific mapping of clinical courses and laboratory chemical charac-
teristics in our PFIC1 patient cohort at four different points in time (before LT, at the time
of LT, in the short and long-term follow-up after LT) may be beneficial in treatment before
and after LT as well as for prediction of when transplantation is required.
Our aim was to identify characteristics that have been described so far and to analyze
the patient and graft survival over time. In addition, a specific checklist, which comprehen-
sively records associated symptoms, clinical expression, histological features and targeted
controls in annual controls, could give us information about the prognosis in a multicenter
evaluation [5,7,8,13,18].

5. Conclusions
Our results show that extrahepatic disease manifests only slightly, and that liver
function is very good in the long-term follow-up. With a median follow-up of more
than 14 years, only two patients developed fibrosis. The two patients with hepatocellular
carcinoma continued to be free of recurrence during follow-up. Graft and patient survival
in our cohort is excellent.

Author Contributions: Conceptualization, methodology, software, validation, formal analysis, inves-

tigation, resources, data curation, writing—original draft preparation, writing—review and editing,
S.G.-K.; supervision, M.S., R.Ö., J.P., W.S. All authors have read and agreed to the published version
of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: The study was conducted according to the guidelines of the
Declaration of Helsinki, and approved by the Ethics Committee of Charité—Universitätsmedizin
Berlin (EA2/267/20; 25 March 2021).
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.
Data Availability Statement: The data presented in this study are available on request from the
corresponding author. The data are not publicly available due to the informed consent obtained from
all subjects.
Acknowledgments: We acknowledge support from the German Research Foundation (DFG) and the
Open Access Publication Fund of Charité - Universitätsmedizin Berlin.
Conflicts of Interest: The authors declare no conflict of interest.

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