Rare cholestatic childhood diseases
van Wessel, Daan
DOI:
10.33612/diss.133430251
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Publication date:
2020
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van Wessel, D. (2020). Rare cholestatic childhood diseases: Advances in clinical care. University of
Groningen. https://doi.org/10.33612/diss.133430251
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Introduction and outline of thesis
Chapter 1
INTRODUCTION AND OUTLINE OF THESIS
Neonatal cholestasis‘Jaundice’, the yellow discoloration of skin, mucous membranes and bodily fluids,
is observed in up to 80% of new-borns in their first week of life
1,2. While the cause
is physiological, or breastfeeding-associated in the majority of cases, an underlying
disease may be present. Jaundice and elevation of total serum bilirubin can result
from a decrease in bile flow, or ‘cholestasis’, either by impaired secretion by
hepatocytes, or by obstruction of the intra- or extrahepatic bile ducts. Cholestasis
is defined as a conjugated serum bilirubin level >17 μmol/L if the total bilirubin
is <85.5 μmol/L or >20% of the total bilirubin if the total bilirubin is >85.5 μmol/
L
3. Apart from its conjugated form (i.e. water soluble after binding to glucuronic
acid within the hepatocyte), bilirubin exists in an unconjugated form (i.e. a waste
product of haemoglobin, bound to albumin in serum until it reaches the hepatocyte).
While unconjugated hyperbilirubinemia resolves in the majority of cases, either by
phototherapy or spontaneously, conjugated hyperbilirubinemia is never physiological
and should always be evaluated for a hepatobiliary disorder.
Over 100 conditions can lead to neonatal cholestasis, including infections, anatomic
obstruction of the biliary system, genetic and metabolic disorders, endocrinopathies,
toxin or drug exposures and cardiovascular abnormalities
3. Most common are biliary
atresia (BA, 25-40% of cases) and genetic disorders (25% of cases), such as severe
deficiency of the Bile Salt Export Pump (BSEP deficiency) or severe deficiency of the
Familial Intrahepatic Cholestasis protein type 1 (FIC1 deficiency)
4. While a wide variety
of diseases can cause neonatal cholestasis, most of them are individually rare. Rare
diseases are often diagnosed later than necessary and ideal This can be attributed
to the fact that only one in approximately 350 breastfed neonates being evaluated
for neonatal jaundice within primary care, has an underlying disease responsible for
cholestasis
1. Due to the relative rarity of such diseases, especially in the primary care
setting, many providers do not regard fractionating serum bilirubin levels as essential
in these particular patients, despite clear guidelines to do so in any jaundiced child at
the age of 3 weeks
4,5. This prevents them from adequately selecting the neonates in
need of referral to secondary and/or tertiary care, which results in delay and prolonged
exposure to the untreated, underlying disease. An additional disadvantage, from a
more scientific point of view, is that study cohorts in rare disease are generally small
in size. It is often difficult to adequately draw valid conclusions from data derived
from small cohorts due to lack of statistical power. In order to increase the validity
of study data on rare diseases, there has been an increasing incentive over the last
decade to initiate international collaborations to share relevant data of these patients.
This thesis focusses on improving the clinical care for the rare diseases biliary atresia,
severe BSEP defi ciency and severe FIC1 defi ciency, all responsible for neonatal
cholestasis. A more detailed account of these diseases is given in the following
sections.
Biliary atresia
Biliary atresia (BA) is a rare disease of infancy which is characterized by obliteration of
the intra- and extrahepatic bile ducts due to an unknown cause. The incidence of BA
ranges from approximately 1:5000 live births in Asian countries to 1:20,000 live births
in the Western world
6–12. Obliteration of the bile ducts results in cholestasis and, if left
untreated, patients die due to end-stage liver disease within two years
13. BA occurs
in an isolated and syndromal form. There are three anatomical subtypes of isolated
BA, depending on the most proximal location of the biliary obstruction (Figure 1).
Type 3 is regarded the most extensive atresia and accounts for >90% of cases.
Syndromal BA, more specifi cally the ‘Biliary Atresia Splenic Malformation syndrome’
(BASM)
14,15is observed less frequently. In addition to the phenotype of atretic bile
ducts as in isolated BA, patients with BASM all present with splenic anomalies,
and less often with an absent vena cava (approximately 70% of cases), intestinal
malrotation (approximately 60% of cases) or cardiac anomalies (approximately 45%
of cases, e.g. a ventricular septal defect).
Figure 1. Anatomical subtypes of biliary atresia. 1: left, patent common hepatic ducts. 2: centre, patent
hepatic ducts. 3: right, atresia of all extra-hepatic ducts.
While a signifi cant amount of research has been carried out to understand the
aetiology of BA, the mechanism by which BA originates has still not been conclusively
identifi ed. To date, it is largely accepted that BA is multifactorial in nature. The
most adopted theory is based on a pathogen- or toxin-induced, immune-mediated
destruction of the biliary tree in an individual with genetic susceptibility. This is
supported by evidence of elevated serum levels of Reovirus RNA, Rotavirus DNA,
CMV DNA and IgM in BA patients, as well as the establishment of BA-associated
single nucleotide polymorphisms (SNPs)
14–38. A single viral cause has however not
been found and the aforementioned SNPs have only been found in the minority of
BA patients. If the origin of BA would indeed be (partially) attributed to an infectious
insult, likely occurring between conception and the perinatal period, one would
expect differences in the geographical distribution and a seasonal occurrence of BA
corresponding with the variable occurrence of pathogens. To date, some studies
focusing on the clustering of BA in space and time have been carried out, yet
they provide conflicting results
39–41. Moreover, these studies lack data regarding
environmental factors, such as infectious outbreaks or population density. Studies
describing these factors in relation to the geographical and temporal clustering
of BA are therefore needed, in order to gain further insights in the putative role of
environmental parameters in the pathophysiology of BA.
Some studies have explored the role of the gut microbiome (i.e. the composition of
microorganisms in the gut) in the development of liver disease. A recent study found
that the gut microbiome of BA patients has what is called “decreased richness”
and “structural segregation” compared to healthy individuals
42, which indicates
that the number of observed taxa was decreased and the types of observed taxa
were different, respectively. In addition, a case report describing two BA infants,
one with good and one with poor outcome, observed differences in the microbiota
of these children, which might suggest that the composition of the gut microbiota
is associated with outcome in BA
43. Studies in a variety of (established) adult liver
diseases provided comparable results, i.e. that the gut microbiota of patients with
liver disease differs significantly from that of healthy subjects
44–49. This may be
rather consequence than cause of the liver disease. It might be that changes in
bile composition or the complete absence of bile has a profound impact on the gut
microbiome. Additionally, liver disease and a disruption in the gut microbiome are
associated with increased gut wall permeability, allowing for increased translation
of bacterial products to the liver via the portal vein, potentially provoking constant
hepatocellular damage and/or subclinical inflammation
47,50,51. In BA there is such a
change in bile metabolism, or even a complete absence of bile. While this interplay
between liver, microbiota and gut is an emerging area of research, there is still very
limited data published on the so-called ‘gut-liver axis’ in BA. Studies which assess
this axis in BA are therefore warranted.
After the obliteration of the biliary tree due to (a) so far unknown event(s), patients
typically present several weeks after birth with jaundice and pale stools. An early
diagnosis in BA is essential start treatment timely and limit the exposure of the liver
to cholestasis. Yet, this is hindered by the vast differential diagnosis underlying
neonatal cholestasis
4. Usually BA is diagnosed by a combination of laboratory,
imaging and pathological studies. Ultrasound is used as first line imaging
52, followed
by liver biopsy. The histological presence of portal fibrosis, ductular reaction or
proliferation, oedema and bile plugs are indicative of BA
53. If BA is suspected,
clinicians proceed to laparotomy during which the diagnosis is classically based on
intra-operative cholangiography showing discontinuity of the biliary tree between the
liver and the intestine. Upon making the diagnosis, the Kasai portoenterostomy (KPE)
is performed, usually in the same session as the cholangiography was performed
4
. This surgical procedure, first described in 1959 by Morio Kasai
54, aims to
re-establish bile flow from remaining microscopic intrahepatic ductules towards the gut,
by anastomosing a jejunal ‘Roux-en-y’ conduit to the porta hepatis (Figure 2). The
KPE is deemed therapeutically successful if clearance of jaundice (COJ) is achieved,
which is defined as a total serum bilirubin <20umol/L within six months after KPE. A
surgically well performed procedure does not guarantee COJ, since the restoration of
bile flow is dependent on patent microscopic ductules in the porta hepatis. Patients
without COJ usually require a liver transplantation (LTx) within the first year of life. The
liver graft used to be routinely become available from a deceased donor, but over
the last decade living related LTx is being increasingly performed as an alternative,
to overcome wait-list mortality due to donor organ shortage. In living related LTx,
the partial donor organ is obtained via a surgical procedure on a relative (frequently
one of the parents) or someone else.
Figure 2. Kasai portoenterostomy as performed in biliary atresia patients. A jejunal conduit is
anasto-mosed to the porta hepatis (‘roux-eny’) in order to re-establish bile fl ow towards the intestine, depending on patent microscopic ductules. Picture taken from 143, illustrated by Holden Groves.
The vast majority (>80%) of BA patients require an LTx during their life time due
to the direct or indirect consequences of end-stage liver disease, even when COJ
had initially been achieved. Therefore, BA is the main indication for paediatric
LTx, accounting for approximately 50% of the transplantations performed during
childhood in the Western world
13,55,56.
The prognosis of BA has been found to strongly correlate with timely surgical
management by means of KPE, in order to minimize exposure to untreated disease.
It has become generally accepted that the earlier the KPE, the better the outcome.
More specifi cally: a KPE performed before the age of 60 days results in prolonged
native liver survival (NLS, i.e. the time between birth and LTx, death or last follow-up)
as opposed to an age at KPE above 60 days
11,57–61. Several studies also suggest that
in the post-KPE prognosis remains controversial. It is believed that steroids might
have an anti-inflammatory effect, either in the liver or locally on the anastomosis,
which both are believed to improve bile flow. Whilst two studies found that
post-operative administration of steroids improved COJ-rates, a profound effect on 1- and
4-year NLS was not established
66,67. The largest randomized controlled trial to date
by Bezerra et al. did not show a positive effect of steroids on COJ, and NLS did
not significantly improve after a 13-week steroid regimen
68. Concerningly, an earlier
onset of serious adverse events was observed in the steroid group. In an ancillary
study it was observed that the steroid-use in the specific study was associated with
impaired growth
69.
The prognosis of BA may also be affected by other factors. For example, preterm
birth has been reported as a risk factor for BA
40,70,71, while BA might also be
considered a risk factor for preterm birth. To what extent prematurity influences the
prognosis of BA remains largely unknown. The diagnosis of BA in the preterm born
population is even more difficult than in the general population, largely due to the
frequent multifactorial origin of cholestasis in this patient group (e.g. prematurity of
the enterohepatic circulation, sepsis, prolonged total parenteral nutrition
72,73. These
diagnostic difficulties may result in delayed referral to the treatment centre, to later
treatment and subsequently, to worse outcome. There is a need for establishing
the natural history of BA in preterm infants, in order to be able to optimize care and
awareness for this vulnerable subgroup of BA patients.
While factors predicting the prognosis in the first years after KPE have been studied
extensively, conclusive data regarding factors associated with long-term follow-up
are still scarce. As stated before, approximately half of the patients with BA need an
LTx before the age of two years. It thus seems that reaching the age of two years
with the native liver seems favourable in the prognosis BA. However, little is known
regarding the long-term outcome of BA patients with at least two years of NLS. Also,
factors associated with prolonged survival with native liver after two years of age
have not been established to date. This information, however, can be very helpful
for counselling parents and making treatment decisions.
Severe Bile Salt Export Pump deficiency
Severe deficiency of the Bile Salt Export Pump (BSEP) belongs to the heterogeneous
group of autosomal recessive cholestatic disorders termed ‘Progressive Familial
Intrahepatic Cholestasis’ (PFIC)
74–78. The most severe form of BSEP deficiency has
been labelled ‘PFIC2’. BSEP belongs to the ATP-binding cassette (ABC) superfamily
and P-glycoprotein / Multidrug resistance (ABCB/MDR) subfamily of transporters
75,79
. BSEP, among other transporters, is localized at the canalicular membrane of the
liver parenchymal cells (“hepatocytes”) where it facilitates the transport of conjugated
bile acids into the biliary system, against up to 1000-fold concentration gradients
(Figure 3). Severe BSEP deficiency is a rare disease with an estimated incidence of
1:50.000 to 1:100.000 live births
80–82in the Western world. Higher incidences have
been reported in the Middle East (1:7200)
83. Sexes seem to be equally affected.
Severe BSEP deficiency results from mutations in the ABCB11 gene which in
humans is localized on chromosome 2 (2q24)
84,85. Decreased trafficking of BSEP
from the Golgi system towards the canalicular membrane and/or decreased transport
capacity of BSEP
80,84,86–92, the transport of bile acids from the hepatocyte towards
the canaliculus is impaired. As a result, bile acids accumulate within the hepatocyte
and the systemic circulation and inflict hepatocellular damage, leading to liver fibrosis
and cirrhosis.
Patients typically present within the first months of life with a phenotype
consisting of jaundice, high serum bile acids and transaminases, normal gamma
glutamyltransferase (GGT) levels, malabsorption, fat soluble vitamin deficiencies
and pruritus
81,93. Some patients present with a relatively milder form of disease,
which is termed ‘Benign Recurrent Intrahepatic Cholestasis type 2’ (BRIC2). This
phenotype is characterized by episodic cholestasis with transient hepatocellular
damage
91,94,95. BRIC2 might, however, progress to severe BSEP deficiency and
end-stage liver disease at later age, sometimes as late as age 30 years. Liver
histology at presentation in severe BSEP deficiency is characterized by canalicular
cholestasis, hepatocellular necrosis and giant cell transformation
80,96. Upon
immunohistochemistry, BSEP antibody staining is abnormal or absent in at least
90% of severe cases
80.
Final diagnosis is preferably made by DNA genotyping techniques, such as whole
exome sequencing. Access to such sequencing facilities might however be limited
in some parts of the world. There, the diagnosis of severe BSEP deficiency still relies
on clinical features and histology, which might lead to delayed diagnosis and even
misdiagnosis. It is therefore important – especially for a rare disease such as severe
BSEP deficiency – to connect various regions of the world through international
networks (e.g. European Reference Networks
97. Such networks will increase the
exchange of knowledge and facilities, ultimately benefiting patients suffering severe
BSEP deficiency.
Figure 3. Transporters located at or near the canalicular membrane. The familial intrahepatic
choles-tatis protein type 1 (FIC1) transports aminophospholipids (i.e. phosphatidylcholine, PC) from the outer to the inner leafl et of the canalicular membrane, to maintain an aminophospholipid asymmetry. The bile salt export pump (BSEP) transports bile acids (BAs) from the hepatocyte towards the canaliculus. The func-tionality of these two proteins is impaired in severe FIC1 defi ciency (or progressive familial intrahepatic cholestatis type 1, PFIC1) or severe BSEP defi ciency (or progressive familial intrahepatic cholestasis type 2, PFIC2), respectively.
Ursodeoxycholic acid has been prescribed as treatment for severe BSEP defi ciency,
yet conclusive data regarding its long-term effi cacy have not been established. In
selected cases however, improvements such as de novo or retargeted canalicular
expression of BSEP have been described
81,98. Some patients may benefi t from
surgery aimed at interrupting the enterohepatic circulation, termed surgical biliary
diversion (SBD). The Partial External Biliary Diversion is most commonly performed
surgical interruption of the enterohepatic circulation, during which an anastomosis
is created between the gallbladder and the skin by means of a short bowel segment
(Figure 4). It aims to divert bile out of the body, thereby decreasing the bile acid pool
which is available for reuptake in the terminal ileum.
SBD has been associated with a decrease in pruritus and might postpone or even
avert liver transplantation (LTx) in selected patients
99–107. Not all patients respond
to treatment and even after an initial response, many cases progress into end-stage
liver disease within the fi rst years of life. Some patients receive LTx before reaching
this stage due refractory pruritus. Even though BSEP is expressed exclusively
in liver tissue, LTx is not a defi nitive treatment in some cases. Studies report
development of alloantibodies against BSEP in the graft, resulting in a severe BSEP
defi ciency phenotype, even after LTx
108–111. Alternative treatments for severe BSEP
defi ciency are currently being developed and studied, such as medical interruption
of the enterohepatic circulation by means of apical sodium-dependent bile acid
transporter (ASBT) inhibitors or organic solute transporter (OST) inhibitors
112–114, as
well as targeted pharmacotherapy such as chaperone drugs
115–117. Mainly due to its
rarity, it so far remains unclear to what extend therapy, especially SBD, impacts the
natural history of severe BSEP defi ciency. Perhaps more importantly, it is yet to be
determined which subgroup(s) of patients will likely benefi t from therapy and which
not. Establishing this would allow for improved personalized clinical care for these
patients, as well as better targeting of novel therapeutic strategies. Large multicentre
studies are needed to address such topics.
Figure 4. Schematic overview of a partial external biliary diversion. A jejunal conduit is anastomosed
to the gallbladder and skin in order to divert bile out of the body. Illustrated by Antonia Felzen, with special
Figure 5. Medical interruption of the enterohepatic circulation by means of inhibition of the apical sodium bile acid transporter (ASBT, blue channel) in the ileum. Inhibition of the ASBT aims to decrease
the amount of bile acids available for reuptake in the liver, thereby limiting the hepatocellular damage.
While it has been established by a variety of studies to what extent mutations
impact BSEP traffi cking or its transport function, it has been diffi cult to establish
associations between the genotype and prognosis; ‘genotype-phenotype
relationships’. Mutations leading to a truncated or otherwise non-functional BSEP
protein, such as insertions, deletions, nonsense and splicing mutations, have been
associated with a severe phenotype in relatively small cohorts
80,92. In addition,
missense mutations may affect protein traffi cking or processing or lead to a disrupted
protein structure
88,89,118,119often resulting in a milder phenotype than the complete
abrogation or truncation of protein synthesis. Two examples are common European
missense mutations (c.890A>G; p.E297G and c.1445A>G; p.D482G) which result
in some residual function of BSEP and seem to respond better to some therapies
81,91,99,119
. While the fi ndings above provide some insight in genotype-phenotype
relations, such relations have so far never been established in large, multicentre
studies with genetically defi ned cohorts. This has prevented researchers and
clinicians to provide proper understanding and characterization of severe BSEP
deficiency, which in turn would allow for improved personalized clinical care.
Although hepatocellular carcinoma (HCC) is rare in young children, research has
demonstrated that patients with severe BSEP deficiency are at a considerable risk
to develop such carcinomas. Up to 15% of patients are diagnosed with HCC, of
which the majority before the age of five years, either clinically diagnosed or for the
first time observed in the explanted organ at the time of transplantation
92. Based on
anticipated severity, it can be hypothesized that patients with truncating mutations
have a higher chance to develop HCC and possibly at an earlier age as opposed
to patients with milder mutations, e.g. missense mutations. This hypothesis was,
to a certain extent, supported by previously published case series
80,92, yet an
in-depth analysis of large cohorts of genetically defined patients is lacking. Such data
is essential in targeting those patients in need for early-life screening for HCC and
possibly early referral for liver transplantation.
Severe Familial Intrahepatic Cholestasis protein type 1 deficiency
Severe deficiency of the Familial Intrahepatic Cholestasis protein type 1 (FIC1) results
from mutations in the ATP8B1 gene which in humans is localized on chromosome 18
(18q21). Just as severe BSEP deficiency, it belongs to the heterogeneous group of
autosomal recessive cholestatic disorders termed ‘Progressive Familial Intrahepatic
Cholestasis’
74–78. The disease was first described as ‘Byler disease’ in the Amish
kindred by Clayton et al
120. The most severe form of FIC1 deficiency was previously
known as Progressive Familial Intrahepatic Cholestasis type 1 (PFIC1). FIC1 is a
member of ATP-dependent membrane transporters known as phospholipid flippases,
which maintain a phospholipid asymmetry across phospholipid bilayers, such as the
canalicular membrane
84,121. FIC1 is also expressed in e.g. pancreas, kidney, small
intestine and inner ear. The incidence and prevalence of severe FIC1 deficiency are
estimated to be even lower than the estimate of 1:50.000 to 1:100.000 for severe
BSEP deficiency. So far, a gender predisposition has not been established.
Mutations in ATP8B1 indirectly impair biliary bile salt excretion, although the
exact mechanism by which this occurs remains elusive. It has been suggested
that cholestasis might result from a disturbed phospholipid asymmetry across the
phospholipid bilayer. This asymmetry maintains a protective barrier against the high
bile acid concentration in the canaliculus, and therefore a disruption might enable
bile acids to damage the canalicular membrane, which in turn is believed to inhibit
the functionality of other canalicular membrane transport proteins (e.g. BSEP or the
Multidrug Resistant Protein 3)
121–123. It has, however, been suggested that the role
of FIC1 in apical membrane organization may be unrelated to its aminophospholipid
translocase activity
124.
Due to impaired bile salt excretion, patients with severe FIC1 deficiency typically
present with jaundice and pruritus in early childhood. Due to the expression of
FIC1 in other tissues, patients may also present themselves with concurrent
symptoms such as diarrhoea, pancreatitis, pneumonia, hearing loss, resistance
to parathyroid hormone, kidney stones and, as a result of malabsorption, severe
growth retardation
81,84,93,124–129. As in severe BSEP deficiency, patients may
initially present with milder, episodic disease which is termed ‘Benign recurrent
intrahepatic cholestasis type 1’ (BRIC1). BRIC1 might evolve into severe FIC1
deficiency at later age
95. At presentation, patients have elevated serum bile acids,
total serum bilirubin and transaminases, and normal GGT levels. The elevation of
the transaminases may be less pronounced than in patients with BSEP deficiency.
Additionally, liver histology at presentation usually shows intracanalicular cholestasis,
yet no or merely mild portal and lobular fibrosis
81. Over time, inflammation, bile
duct proliferation and cirrhosis might develop. The final diagnosis is preferably
made by genotyping. As addressed earlier, sequencing techniques are not readily
available in all parts of the world, which hinders adequate diagnosis. International
networks to ensure the exchange of knowledge and resources are therefore needed.
Currently, treatment for the hepatic phenotype of severe FIC1 deficiency consists
of medical symptomatic treatment, surgical biliary diversion (SBD) and LTx.
Severe FIC1 deficiency and even BRIC1 have been largely refractory to medical
treatment; data regarding the symptomatic effect as well as the effect on
long-term outcome are inconclusive
74,81,99,126,130. SBD procedures, such as the Partial
External Biliary Diversion or Ileal Exclusion, have been successful in decreasing
pruritus and slowing hepatic fibrosis, yet these data are derived from studies with
a proportion of genetically undefined patients
99,105,131–134. Those patients that do
not (sufficiently) respond to medical treatment or SBD are candidates for LTx.
Since FIC1 is expressed in a variety of tissues, LTx is no definitive treatment for the
disease and complications after LTx have been reported, which will be discussed
below. Despite this, LTx may prolong overall survival. As in severe BSEP deficiency,
there is a – perhaps even larger – paucity of data regarding the symptomatic effect
of medical and surgical treatment strategies, as well as their effect on long-term
outcome. To be able to select those patients that will benefit from either of these
treatments, studies with relatively large, genetically defined cohorts are needed.
Such studies have so far not been published. FIC1 is a rare disease, therefore the
natural history and genotype-phenotype relationships are not very well established.
Genotype/phenotype associations might actually be difficult to assess in severe
FIC1 deficiency; even within one family with a specific mutation, a wide variability in
phenotype can exists
95,135. The nature of the mutation might to a certain extent predict
the phenotype. Patients with missense mutations may have milder disease than
patients with truncating mutations
135. On the other side of the spectrum are patients
harbouring nonsense or frameshift mutations or large deletions, which are expected
to result in a severe phenotype. One variant, p.Ile661Thr, is of European descent
and has been described in mild phenotypes. However, compound heterozygous
patients with this mutation can have severe disease
135. Interestingly, HCC has never
been described in severe FIC1 deficiency, whilst up to 15% of patients with severe
BSEP deficiency are diagnosed with HCC. Obviously, absence of HCC in severe
FIC1 deficiency patients have precluded and association with severe mutations, in
contrast to BSEP deficiency patients.
The prognosis of severe FIC1 deficiency after LTx is unpredictable and might be even
worse than before transplantation, especially in terms of quality of life. In several
patients with severe FIC1 deficiency, diarrhoea might worsen after LTx and fluid
resuscitation might be needed
132,136. Bile chelators or clonidine may milden diarrhoea
in selected patients
137. Some patients develop post-LTx pancreatitis. Additionally,
development of steatohepatitis is a worrisome complication; it might necessitate
re-LTx. Performing a total biliary diversion (sometimes performed already at the
transplant itself) may reduce liver graft steatosis
99,136,138–142.
So far, there has been no detailed investigation of the natural history or prognosis
in FIC1 deficiency, especially not in large samples of genetically defined patients.
Healthcare is increasingly moving towards patient tailored approaches, yet such
approaches are so far not been possible to patients with severe FIC1 deficiency (or
severe BSEP deficiency), because of lack of relevant natural history data. To provide
for this need, large study cohorts of severe FIC1 patients are needed to properly
address genotype/phenotype associations, in order to gain detailed insight in the
natural history and prognosis of this disease.
Outline
The aim of this study was to improve the clinical care for patients with the rare,
cholestatic childhood diseases biliary atresia (BA), severe BSEP deficiency
and severe FIC1 deficiency. Patients with BA undergo Kasai portoenterostomy,
preferably in the first weeks of life, to re-establish bile flow towards the intestine.
Unfortunately, the majority of patients require liver transplantation (LTx) before
the age of two. LTx after the age of two is relatively uncommon in BA and one
might therefore hypothesize that reaching the age of two with a native liver seems
rather favourable. While prognostic factors within the first two years have been
studied extensively, neither the native liver survival (NLS) beyond the age of two
years, nor the factors associated with it have however been characterized in detail.
The objective in
Chapter 2 was therefore to determine the prognosis of patients
with BA after 2 years of NLS. In addition, we aimed to identify early-life factors
which impacted continued NLS after two years of age. Another factor which might
impact the short- and long-term prognosis of BA is preterm birth. While it is known
that preterm birth is a risk factor for BA (and possibly vice versa), to what extent
prematurity affects the disease course of BA remains largely unknown, especially
in Western countries. In
Chapter 3 we characterized the course of BA in preterm
infants in the Netherlands in terms of clearance of jaundice, NLS and mortality. While
the disease course of BA has been relatively well established, its origin remains
elusive despite extensive scientific effort. A generally accepted theory is that BA
is multifactorial in nature. It is believed that an environmental factor (e.g. viruses,
bacteria or toxins) triggers an exaggerated immune response in an individual with
increased susceptibility for these triggers or their associated pathways. If BA would
indeed be triggered by pathogen, differences in the geographical distribution and
seasonal occurrence should to some extent correspond with abundance of these
pathogens. To provide further support for a pathophysiological role of environmental
factors in BA, we performed an epidemiological study in
Chapter 4. In this study, we
assessed if temporal and geographical clustering of BA existed in the Netherlands,
and if this corresponded with the number of nationwide confirmed infections and
population density. It is increasingly recognized that the gut microbiota is associated
with health and disease. More specifically, the presence and prognosis of several
(adult) liver disease has already been associated with the composition of the gut
microbiota. Data regarding the microbiota and BA are scarce. To establish if in a
BA specific microbiota is present and if the prognosis of BA is associated with
the microbiota in the gut, we performed a prospective cohort study in
Chapter
5. We determined the gut microbiota by means of 16S rRNA sequencing in BA
infants longitudinally, up to six months after Kasai portoenterostomy. Moreover,
we compared the composition of the gut microbiota from that of BA patients to
that of infants undergoing inguinal hernia repair. Severe deficiency of the bile salt
export pump (BSEP) is a rare disease and results from mutations in the ABCB11
gene. Due to its rarity, it has so far been impossible to assess the natural history,
genotype-phenotype associations and the effect of surgical interruption of the
enterohepatic circulation on long-term outcome in large, genetically well-defined
cohorts. In
Chapter 6 we aimed to provide these data and for that we used a
global, multicentre cohort of genetically defined severe BSEP deficiency patients.
Severe BSEP deficiency is mostly recessive in nature, hence it results from two
mutations in ABCB11. Two common European mutations (i.e. c.1445A>G; p.D482G
and c.890A>G; p.E297G) have been associated with residual BSEP functionality and
patients harbouring at least one of these mutations seem to present relatively mild
phenotype. To what extent the mutation other than p.D482G or p.E297G impacts
the phenotype has not been described before. In
Chapter 7 we set out to scrutinize
patients with severe BSEP deficiency that harbour at least one p.D482G or p.E297G
mutation. By subcategorizing patients based on the severity on the second allele
(i.e. the mutation other than p.D482G or p.E297G), we aimed to find
genotype-phenotype associations to be able to address if the combined residual function
of the two mutations in ABCB11 is associated with the severe BSEP deficiency
phenotype. Severe deficiency of the familial intrahepatic cholestasis protein type
1 (FIC1) results from mutations in the ATP8B1 gene. Severe deficiency of FIC1 is a
rare disease, likely even rarer than severe BSEP deficiency. Therefore, the natural
course of disease has not been established in a proper manner. Moreover,
genotype-phenotype associations have not been addressed. Lastly, the effect of interruption of
the enterohepatic circulation on long-term outcome remains unknown. In
Chapter
8 we performed a global, multicentre cohort study to provide these insights.
In
Chapter 9 we discuss the outcomes and clinical implications of the studies
reported in this thesis and future directions for research in neonatal cholestasis as
a whole, and biliary atresia, severe BSEP deficiency and severe FIC1 deficiency
separately.
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