S c l e ro s i n g C h o l a n g i t i s in

C h i l d ren an d A d o l e s c e n t s
a, b
Giorgina Mieli-Vergani, MD, PhD, FRCP, FRCPCH *, Diego Vergani, MD, PhD, FRCPath, FRCP

KEYWORDS
 Juvenile sclerosing cholangitis  Primary sclerosing cholangitis
 Autoimmune sclerosing cholangitis  Autoimmune hepatitis
 Inflammatory bowel disease  Liver transplant  Children  Adolescents

KEY POINTS
 Sclerosing cholangitis in pediatric age recognizes different etiologies, management, and
prognosis depending on the underlying cause.
 Sclerosing cholangitis is frequently associated with inflammatory bowel disease (ulcera-
tive colitis, Crohn disease, indeterminate colitis).
 A high proportion of patients with sclerosing cholangitis have autoimmune features similar
to those of autoimmune hepatitis type 1 and respond biochemically to immunosuppres-
sive treatment, but the bile duct disease progresses in half of them leading to liver
transplant.
 Sclerosing cholangitis can recur after liver transplant, particularly in patients with strong
autoimmune features.
 Severity of liver disease and risk of recurrence after transplant are linked to the severity of
the inflammatory bowel disease.

DEFINITION

Sclerosing cholangitis is a chronic disorder characterized by inflammation and pro-

gressive obliterative fibrosis of the intrahepatic and/or extrahepatic bile ducts. It has
long been considered a disease confined to adulthood, but it is now clear that it occurs
in all age groups, with some features being unique to children. Sclerosing cholangitis
progresses slowly to biliary cirrhosis, liver failure, and, particularly in adults, cholangio-
carcinoma (CC).

HISTORIC BACKGROUND

Sclerosing cholangitis was first described in adult patients in 1924 by the Parisian sur-
geon Delbet,1 who reported a patient with “irregular fibrosis and stenosis of the biliary

The authors have nothing to disclose.

a
Paediatric Liver, GI and Nutrition Centre, King’s College Hospital, Denmark Hill, London SE5
9RS, UK; b Institute of Liver Studies, King’s College Hospital, Denmark Hill, London SE5 9RS, UK
* Corresponding author.
E-mail address: giorgina.vergani@kcl.ac.uk

Clin Liver Dis - (2015) -–-

http://dx.doi.org/10.1016/j.cld.2015.08.008 liver.theclinics.com
1089-3261/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
2 Mieli-Vergani & Vergani

tree.” In 1927, Miller2 referred to a similar condition as “benign stricture of common

bile duct.” In 1964,3 the term “primary sclerosing cholangitis” (PSC) was used for
the first time to distinguish sclerosing cholangitis without an obvious etiology from
sclerosing cholangitis secondary to lesions of the bile ducts or systemic disease,
such as primary or secondary immunodeficiencies. Until the advent of endoscopic
retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholan-
giography, recognition was rare, being made at laparotomy in patients with persistent
jaundice. With the availability of ERCP and more recently magnetic resonance cholan-
giopancreatography (MRCP) the reported prevalence of sclerosing cholangitis in
adults and children is increasing. The association of sclerosing cholangitis with inflam-
matory bowel disease (IBD) was first clearly established in 1966,4 although inflamma-
tory involvement of the liver parenchyma in IBD had been described in 1899 by Lister.5

SCLEROSING CHOLANGITIS IN CHILDREN AND ADOLESCENTS

With the growing use of biliary imaging in the form of ERCP and, more recently, nonin-
vasive MRCP, sclerosing cholangitis is diagnosed with increasing frequency also in
pediatric age. It is an important cause of morbidity and mortality, accounting for
some 2% of pediatric liver transplants in the United States between 1988 and 2008
(United Network for Organ Sharing Data Report - October 2009. http://www.unos.
org/data/).
The term PSC, universally used in adult patients, is not accurate to describe pedi-
atric SC: “primary” denotes ignorance about etiology and pathogenesis, whereas in
pediatrics6–10 there are well-defined forms of sclerosing cholangitis. In the neonatal
period, pathologic features of severe sclerosing cholangitis characterize biliary atresia
and neonatal sclerosing cholangitis, a condition inherited in an autosomal-recessive
manner.11 Other inherited diseases, systemic malignancies, and immunologic defects
may produce a clinical picture similar to adult PSC. For example, mild to moderate de-
fects in the ABCB4 (MDR3) gene are a likely cause of several cases of small duct scle-
rosing cholangitis in children and adults.12,13 Sclerosing cholangitis may also
complicate a wide variety of disorders, including primary and secondary immunode-
ficiencies, Langerhans cell histiocytosis (LCH), psoriasis, cystic fibrosis, reticulum
cell sarcoma, and sickle cell anemia. Moreover, an overlap syndrome between auto-
immune hepatitis (AIH) and sclerosing cholangitis (autoimmune sclerosing cholangitis
[ASC]) is significantly more common in children than in adults. Only in those pediatric
patients in whom SC occurs without any of the previously mentioned defining features
should the name of “primary” be used.

DIAGNOSIS

The diagnosis of sclerosing cholangitis is usually based on the demonstration of radio-

logic evidence of bile duct disease, with or without biliary features on liver histology.
More recently, a condition called small-duct PSC has been described, whereby
chronic cholestasis and hepatic histology compatible with sclerosing cholangitis are
associated with normal cholangiography.14 In pediatrics, all disorders described pre-
viously that can be associated with sclerosing cholangitis should be excluded.
Several papers have compared the accuracy of MRCP with that of ERCP in the
diagnosis of sclerosing cholangitis in adults and children. With the availability of
more advanced magnetic resonance instrumentation and matching software, coupled
with increased radiologic expertise, the sensitivity and specificity of MRCP ranks in the
high 80s and is comparable with that of ERCP,15,16 although ERCP may still be more
accurate in the diagnosis of early changes17 and allows therapeutic interventions in
 Sclerosing Cholangitis in Children and Adolescents 3

the case of strictures.18 MRCP is reported to be 84% sensitive and accurate in the
diagnosis of pediatric sclerosing cholangitis.8,19
The classic histologic feature of adult PSC, periductular onion skin fibrosis, is rare, a
high proportion of pediatric patients having variable degrees of interface hepatitis at
diagnosis.6,20 In view of the presence of interface hepatitis on liver biopsy and the
frequent positivity for circulating autoantibodies,6,10,20 the differential diagnosis be-
tween AIH and ASC relies on the demonstration of bile duct damage at presentation.
Neither the original nor the simplified International Autoimmune Hepatitis Group
scoring systems devised for the diagnosis of AIH21–23 are suitable to discriminate be-
tween AIH and ASC6,9,10,24,25 because they do not include cholangiographic studies at
disease onset.

EPIDEMIOLOGY

The reported incidence and prevalence of PSC in adults range from 0 to 1.3 and from
0 to 16.2 per 100,000, respectively.26 Little is known about the epidemiology of pedi-
atric sclerosing cholangitis, probably because of its rarity and heterogeneous etiology.
The incidence of PSC was estimated to be 0.23 per 100,000 children in Calgary27 and
0.2 per 100,000 children in Utah.28 In the latter study, the prevalence of pediatric PSC
was 1.5 per 100,000,28 whereas the incidence and prevalence of ASC per 100,000
were 0.1 and 0.6, respectively.28

GENETIC FEATURES

ASC and adult-type PSC are complex trait diseases (ie, conditions not inherited in a
mendelian autosomal-dominant, autosomal-recessive, or sex-linked fashion). The
mode of inheritance of a complex trait disorder is unknown and involves one or
more genes operating alone or in concert to increase or reduce the risk of the trait,
and interacting with environmental factors.
Susceptibility to juvenile ASC is associated with possession of the HLA haplotype
DRB1*13 (DR13).1,29 Susceptibility to PSC in adults is associated with two main HLA
haplotypes, DRB1*0301-DQA1*0501-DQB1*0201 (referred to as DR3) and HLA-
DRB1*1301-DQA1*0103-DQB1*0603 (referred to as DR6).30 The role of additional
genes encoded within or without the HLA region has been investigated in patient co-
horts mainly comprising adults, but also including children. The main contribution of
genetic susceptibility to PSC comes from the Oslo group,30–34 which follows a
particularly well-characterized patient population. Through the use of seven micro-
satellite markers, Wiencke and colleagues30 have shown that a gene in linkage
disequilibrium with microsatellite D6S265 contributes to PSC susceptibility in indi-
viduals carrying the DR6 haplotype. They also show that the PSC-associated DR3
haplotype extends more telomerically than previously reported and that DR11
may have a protective effect on the development of PSC. Karlsen and colleagues33
have reported that the frequency of HLA-Bw4 and-C2, ligands for the inhibitory re-
ceptors on natural killer cells KIRs 3DL1 and 2DL1, is significantly reduced in pa-
tients with PSC exerting a protective role. In two further papers Karlsen and
colleagues32 dissociate susceptibility to PSC from that to IBD. In the first report
they show that associations with HLA class II genes are different in the two condi-
tions; similarly, in the second paper31 they show that IBD-associated polymor-
phisms do not play a major predisposing role to PSC. The same group has
reported that polymorphisms in the steroid and xenobiotic receptor gene influence
survival in PSC, with median survival being significantly reduced in patients homo-
zygous for an allele in this region.22,34
4 Mieli-Vergani & Vergani

Henckaerts and colleagues35 hypothesize that CC-type chemokine receptor 5

(CCR5) would be an interesting candidate gene for susceptibility to PSC because of
its chromosomal location within the IBD susceptibility region. They found that the fre-
quency of the CCR5-D32 mutation in PSC is significantly lower than in patients with
IBD and healthy control subjects, suggesting a protective effect of this mutation for
PSC.
Bergquist and colleagues36 have shown that first-degree relatives of patients with
PSC have an increased risk of PSC, indicating the importance of genetic factors in
the cause of this condition. Moreover, first-degree relatives of patients with PSC
without IBD have an increased risk of developing ulcerative colitis (UC), suggesting
a shared genetic susceptibility between UC and PSC.
Two studies have focused on cystic fibrosis transmembrane conductance regulator
in PSC. Pall and colleagues37 found that the chloride channel function is markedly
decreased in patients with PSC, whereas Henckaerts and colleagues38 reported
that cystic fibrosis transmembrane conductance regulator variants affecting the func-
tional properties of the cystic fibrosis transmembrane conductance regulator protein
offer protection against the development of PSC.

PEDIATRIC SERIES

There is a limited number of published series of pediatric sclerosing cholangitis.6–10,28

In these reports the incidence of the various clinical forms of sclerosing cholangitis dif-
fers depending on the year of publication and the center where the study was con-
ducted, reflecting different study designs, pattern of referral, and diagnostic
protocols. Most of these series are retrospective and cholangiographic studies, per-
formed by ERCP, percutaneous cholangiography, or more recently MRCP, were
prompted by biochemical and/or histologic features of cholestatic disease.7–10,28
Only one study, published in 2001, differs from all the other series, because it was pro-
spective and aimed at establishing the relative incidence of AIH and ASC among chil-
dren presenting with liver disease and positive autoimmune serology (autoantibodies;
increased levels of IgG), by performing cholangiograms at disease onset, irrespective
of biochemical or histologic evidence of cholestatic disease.6 Other forms of scle-
rosing cholangitis seen over the same period of observation were excluded from
this prospective study.
In all published series, boys are more affected than girls; 20% to 40% of patients
have intrahepatic cholangiopathy with normal extrahepatic bile ducts; and IBD is
strongly associated with the diagnosis of sclerosing cholangitis, being found in 60%
to 90% of cases according to study design.6–10,28 More than two-thirds of the cases
have UC, and the others have Crohn disease or indeterminate colitis. IBD can precede
the diagnosis of liver disease by many years, be diagnosed at the same time, or
develop during follow-up. The prevalence of IBD is higher in those centers where sur-
veillance enteroscopy is performed even in the absence of clinical symptoms of IBD.6
It is advisable to consider surveillance colonoscopy in all children who are newly diag-
nosed with sclerosing cholangitis and to have a low threshold for performing this pro-
cedure in those who have symptoms consistent with IBD (eg, diarrhea, growth failure,
anemia).

Retrospective Studies
The first relatively large retrospective series of children with sclerosing cholangitis was
published in 1994.7 It comprised 56 children with a variety of underlying pathologies,
including immunodeficiencies, LCH, neonatal sclerosing cholangitis, and psoriasis.
 Sclerosing Cholangitis in Children and Adolescents 5

Eight children had associated autoimmune features, including six with IBD, and two
with AIH/sclerosing cholangitis overlap syndrome, one of whom had IBD. Ten children
had no associated disease. Patients with autoimmune features received immunosup-
pressive treatment of IBD and had an overall better outcome than the other disease
groups, with an estimated 10-year survival rate of 86%. The 10 with no associated
conditions had a particularly poor prognosis, three dying and four requiring liver trans-
plantation during a mean of 7  4.3 years of follow-up.
In 1995 Wilschanski and colleagues8 described 32 children with sclerosing chol-
angitis. Excluding two with associated immunodeficiencies, 30 children were diag-
nosed as having PSC. Interestingly, at presentation half of the children had normal
levels of alkaline phosphatase (g-glutamyl transpeptidase [GGT] levels were not
measured). Prognosis at a mean follow-up of 3.8 years was poor for nine patients
with evidence of overlap between AIH and sclerosing cholangitis (six with IBD), five
requiring liver transplantation, and for four patients with incidental finding of ab-
dominal organomegly (one with IBD), two needing transplant. Prognosis in 17
further patients (one with IBD) presenting with chronic liver disease and prominent
features of cholestasis, similar to adult PSC, was better, with only three developing
end-stage liver disease requiring grafting. In this series the prognosis of AIH/PSC
overlap syndrome was particularly severe and not ameliorated by immunosuppres-
sive treatment, although no information is provided regarding the timing of treat-
ment implementation during the course of the disease or the immunosuppressive
drugs used.
A report by Feldstein and colleagues9 describes 55 patients with sclerosing cholan-
gitis. Seventy-two percent were positive for antineutrophil cytoplasmic antibody, 68%
for antinuclear (ANA) and/or anti-smooth muscle (SMA) antibodies, and 70% had high
levels of IgG. IBD was present in 81%. Based on the presence of interface hepatitis on
liver biopsy, 14 patients were labeled as AIH/PSC overlap, whereas 38 children were
diagnosed as PSC. Forty-one of the 55 children were treated either with ursodeoxy-
cholic acid (UDCA) alone, with immunosuppressive drugs (corticosteroids with or
without azathioprine) alone, or a combination of UDCA and immunosuppression,
with variable response. The overall outcome was poor, with 11 patients requiring liver
transplantation over a mean of 6.6  4.4 years of follow-up, the median (50%) survival
free of liver transplantation being 12.7 years. The prognosis of children with PSC or
AIH/PSC was similar and was not ultimately affected by treatment. Three of 11
(27%) transplanted children had recurrence of PSC in the graft within 6 years from
surgery.
Miloh and colleagues10 describe 47 patients with sclerosing cholangitis. Based on
absence or presence of interface hepatitis on liver biopsy, 35 were diagnosed as hav-
ing PSC and 12 as having AIH/PSC overlap syndrome. All patients with overlap syn-
drome had positive ANA and/or SMA and/or increased IgG levels. Autoantibodies
were present also in 32% of patients with PSC. In this series, where cholangiographic
studies were mainly performed by MRCP, no radiologic biliary involvement was
detected despite histologic evidence of sclerosing cholangitis in an unusually high
proportion (36%) of patients. These patients were diagnosed as having small-duct
PSC.14 Whether this is caused by the lower sensitivity of the MRCP compared with
the ERCP in detecting biliary changes remains to be verified. Patients with AIH/PSC
overlap syndrome were treated with UDCA and immunosuppression, whereas those
with PSC with UDCA alone, with amelioration of biochemical parameters in both
groups. After a median of 6.5 years, however, nine children required liver transplanta-
tion, one experiencing disease recurrence 10 years later. Transplant-free survival was
marginally better in patients with small-duct PSC than in the others.
6 Mieli-Vergani & Vergani

Deneau and colleagues28 performed a large pediatric population–based study in

Utah between 1986 and 2011. They identified 29 children with PSC (96.6% with
IBD) and 12 with overlap syndrome (ASC, 75% with IBD). After a mean follow-up of
5.9 years, their outcome was compared with that of 44 children diagnosed with AIH
over the same time period. Although no information is provided regarding treatment,
it is interesting that survival with native liver was marginally better in ASC and AIH
compared with PSC, the probability of developing complicated liver disease within
5 years from diagnosis being 37% for PSC, 25% for ASC, and 15% for AIH. Also of
interest is that this is the only study reporting the development of CC in 2 of 29 patients
with PSC, both with UC, one of whom died, whereas the other was alive 3 years after
chemotherapy, radiation, and liver transplant.

Prospective Study
Progression from AIH to sclerosing cholangitis has been reported in children and
adults.40–43 However, in these reports no cholangiographic studies were performed
at disease presentation, challenging the concept of progression from one disease
to the other. To establish the relative prevalence, the response to treatment, and
the outcome of AIH versus ASC, a prospective study was initiated at the King’s Col-
lege Hospital tertiary referral center in 1984 and patients were recruited over a period
of 16 years.6 Interim results were published in 2001,6 and the patient cohort is being
followed up to date. In this study, all children with serologic (ie, positive autoanti-
bodies, high IgG levels) and histologic (ie, interface hepatitis; Fig. 1) features of auto-
immune liver disease underwent a cholangiogram at the time of presentation,
independently of the presence of biochemical or histologic evidence of cholestasis.
Surveillance enteroscopy to investigate for possible IBD was performed in all cases,
independently of symptoms. Approximately 50% of the patients enrolled in this pro-
spective study had alterations of the bile ducts characteristic of sclerosing cholangitis,
although they were generally less advanced than those observed in adult-type PSC
(Fig. 2) and were diagnosed as having ASC. A quarter of the children with ASC, despite
abnormal cholangiograms, had no histologic features that suggested bile duct
involvement, and the diagnosis of sclerosing cholangitis was only possible because

Fig. 1. Dense portal tract inflammatory infiltrate comprising lymphocyte and plasma cells
and invading the surrounding parenchyma (interface hepatitis) in a child with autoimmune
sclerosing cholangitis. The arrows show bile duct damage (hematoxylin-eosin, original
magnification  40).
 Sclerosing Cholangitis in Children and Adolescents 7

Fig. 2. Magnetic resonance cholangiography (A) and endoscopic retrograde cholangiog-

raphy (B) of a child with autoimmune sclerosing cholangitis showing a diffuse cholangiop-
athy with ductal changes in both lobes. The extrahepatic bile ducts have normal
appearance.

of the cholangiographic studies. Virtually all patients with ASC were seropositive for
ANA and/or SMA, antibodies typical of AIH type 1, only one patient being positive
for anti–liver kidney microsomal type 1 (anti-LKM1), the antibody characterizing AIH
type 2. In contrast to AIH, which had a clear female preponderance, ASC was diag-
nosed in a similar proportion of boys and girls. The mode of presentation of ASC
was similar to that of AIH type 1 (Table 1). IBD was present in 45% of children with
ASC compared with 20% of those with typical AIH type 1, and 90% of children with
ASC had greatly increased serum IgG levels. At the time of presentation, standard liver
function tests, including alkaline phosphatase and GGT levels, did not help in discrim-
inating between AIH and ASC, although the alkaline phosphatase/aspartate amino
transferase ratio was significantly higher in ASC (Table 2). Atypical perinuclear anti-
neutrophil cytoplasmic antibodies, whose target is located within the nuclear mem-
brane leading to the name of perinuclear antineutrophil nuclear antibody (pANNA),
were present in 74% of patients with ASC compared with 45% of patients with AIH
type 1 and 11% of those with AIH type 2. Antisoluble liver antigen antibodies were
found in some 50% of patients with ASC, defining a more severe disease course.44
Evolution from AIH to ASC was documented in one patient during the published pro-
spective series6 and has been observed in two further patients during follow-up,45
suggesting that AIH and ASC may be part of the same pathogenic process. During
the same observation period of the prospective study, nine children with cholangio-
graphic evidence of bile duct disease, but no positivity for ANA, SMA, or anti-LKM1
at the time of presentation, were diagnosed as having PSC. Three had UC treated
with immunosuppressive drugs at the time of referral, one had thyroiditis, three a fam-
ily history of autoimmune disorders, and four were pANNA positive. After an observa-
tion period of 6 years, six of the nine children were alive and stable, four on treatment
with UDCA alone and two on UDCA plus immunosuppressive drugs for IBD, one had
died of ischemic hepatitis, and two were lost to follow-up.
Currently, in our center imaging of the biliary system by MRCP, followed by ERCP if
MRCP is not informative, and colonoscopy is part of the evaluation of all children with
liver disease associated with autoimmune features.
8 Mieli-Vergani & Vergani

Table 1
Comparison between the clinical presentation of childhood autoimmune hepatitis and
autoimmune sclerosing cholangitis

Parameter AIH Type 1 AIH Type 2 ASC

Median age in years 11 7 12
Mode of presentation (%)
Acute hepatitis 47 40 37
Acute liver failure 3 25 0
Insidious onset 38 25 37
Complication of chronic liver disease 12 10 26
Associated immune diseases (%) 22 20 48
Inflammatory bowel disease (%) 20 12 45
Abnormal cholangiogram (%) 0 0 100
ANA/SMA (%) 100 25 96
Anti-LKM-1 (%) 0 100 4
pANNA (%) 45 11 74
Anti-SLA (%) 58 58 41
Interface hepatitis (%) 92 94 60
Biliary features (%) 28 6 31
Cirrhosis (%) 69 38 15

Abbreviations: AIH, autoimmune hepatitis; ANA, antinuclear antibodies; anti-LKM-1, anti–liver

kidney microsomal type 1 antibody; ASC, autoimmune sclerosing cholangitis; pANNA, peripheral
antinuclear neutrophil antibodies; SLA, soluble liver antigen; SMA, anti–smooth muscle antibodies.
Data from Gregorio GV, Portmann B, Karani, et al. Autoimmune hepatitis/sclerosing cholangitis
overlap syndrome in childhood: a 16-year prospective study. Hepatology 2001;33(3):544–53.

TREATMENT AND PROGNOSIS

Treatment and prognosis of sclerosing cholangitis depend on the underlying pathol-

ogy. Management of sclerosing cholangitis associated with immunodeficiency
syndromes, LCH, or metabolic/genetic disorders is closely related to the ability of

Table 2
Comparison between the biochemical parameters at presentation of childhood autoimmune
hepatitis and autoimmune sclerosing cholangitis

AIH ASC
Bilirubin (nv <20 mmol/L) 35 (4–306) 20 (4–179)
Albumin (nv >35 g/L) 35 (25–47) 39 (27–54)
AST (nv <50 IU/L) 333 (24–4830) 102 (18–1215)
INR (nv <1.2) 1.2 (0.96–2.5) 1.1 (0.9–1.6)
GGT (nv <50 IU/L) 76 (29–383) 129 (13–948)
AP (nv <350 IU/L) 356 (131–878) 303 (104–1710)
AP/AST ratio 1.14 (0.05–14.75) 3.96 (0.20–14.20)

Abbreviations: AIH, autoimmune hepatitis; AP, alkaline phosphatase; ASC, autoimmune sclerosing
cholangitis; AST, aspartate aminotransferase; GGT, g-glutamyl transpeptidase; INR, international
normalized ratio; nv, normal values.
Data from Gregorio GV, Portmann B, Karani, et al. Autoimmune hepatitis/sclerosing cholangitis
overlap syndrome in childhood: a 16-year prospective study. Hepatology 2001;33(3):544–53.
 Sclerosing Cholangitis in Children and Adolescents 9

controlling the primary disease. For sclerosing cholangitis without associated pathol-
ogies, no standard mode of treatment is presently advocated.46 Based on a reported
beneficial effect in adult PSC, UDCA is used also for the treatment of childhood scle-
rosing cholangitis, but whether it is helpful in arresting the progression of the bile duct
disease remains to be established. In adults with PSC high-dose UDCA was initially
reported as more beneficial than standard doses,47 but a randomized double-blind
controlled study from the Mayo Clinic shows that high-dose UDCA has a negative ef-
fect.48 It is prudent, therefore, to use doses not higher than 15 to 20 mg/kg/day.
A beneficial effect of oral vancomycin (50mg/kg per day) has been reported in 14
patients with sclerosing cholangitis and IBD, 12 positive for autoantibodies.49 All
showed a marked improvement in transaminase and GGT levels, erythrocyte sedi-
mentation rate, and clinical symptoms on prolonged oral vancomycin treatment, the
best improvement being observed in patients who were not cirrhotic at treatment
start. Four patients positive for ANA, SMA, and/or perinuclear antineutrophil cyto-
plasmic antibodies became negative after an average of 3 months of vancomycin
treatment. Suspension of treatment was associated with relapse of biochemical ab-
normalities in four patients, who improved again after retreatment. Despite severe
cholangitic changes before treatment, the liver histology of three children rebiopsied
while on vancomycin is reported as normal. Whether these children represent a sub-
group of PSC in whom infectious causes play a major pathogenic role remains to be
clarified. These results await confirmation in a larger number of patients. Whether van-
comycin acts through its antibiotic, immunomodulatory,50 or choleretic51 properties
remains to be elucidated.
The King’s prospective study shows that in ASC treatment with steroids and azathi-
oprine, using the same schedule as in AIH, in association with UDCA, is beneficial in
abating the parenchymal inflammatory lesions, but is less effective in controlling bile
duct damage. Although resolution of liver test abnormalities is seen within a few
months in most patients, the medium- to long-term prognosis of ASC is worse than
that of AIH because of progression of cholangiopathy despite treatment in some
50% of patients, with 20% of them eventually requiring liver transplantation.6,45 Simi-
larly, in the series by Miloh and colleagues,10 although all patients with overlap AIH/
sclerosing cholangitis syndrome were reported to have a favorable biochemical
response to immunosuppression and UDCA treatment, 25% required liver transplan-
tation during the 12-year observation period. Response to immunosuppressive drugs
was less satisfactory in sclerosing cholangitis patients with autoimmune features
described by Wilschanski and colleagues8 and Feldstein and colleagues,9 possibly
because of long-standing liver disease before starting treatment.
It is our experience that reactivation of the liver disease often follows flares of the
intestinal disease in sclerosing cholangitis patients with IBD. In this context, it is of
note that none of the published series of sclerosing cholangitis in pediatric patients
gives details of the severity of the IBD or of the effectiveness of its treatment, informa-
tion that would be important to verify whether ability to control efficiently IBD has a ma-
jor role in preventing liver disease progression.

CHOLANGIOCARCINOMA

In adult patients with PSC the incidence and prevalence of CC are reportedly bet-
ween 5% and 36% and 0.6% per year, respectively.52 In pediatrics, there are
only three cases of CC described in patients with PSC, two by Deneau and col-
leagues28 and one by Ross and colleagues.39 The three patients were 17.9, 18,
and 14 years of age at the time of CC diagnosis; all had UC and developed CC 6
10 Mieli-Vergani & Vergani

years, 4.2 years, and 14 months after the diagnosis of PSC, respectively. None of
the patients with ASC enrolled in the King’s prospective study has developed CC
over an observation period of 30 years. Long-term follow-up of cases identified in
pediatric age is needed to establish the incidence and prevalence of CC in this
group of patients.

LIVER TRANSPLANTATION

Liver transplantation is indicated in patients with sclerosing cholangitis who develop

end-stage liver disease. Approximately 20% to 30% of children with sclerosing chol-
angitis require liver transplantation in the medium term. After transplantation, recur-
rence of disease is reported in 27%9 to 67%45 of patients, the highest risk of
relapse being observed in patients with florid autoimmune features and poorly
controlled IBD.10,45 In these patients it is prudent to continue steroid-based immuno-
suppression at a higher dose than that used for patients not transplanted for autoim-
mune liver disease, because recurrence may occur years after transplantation.
Recurrence of sclerosing cholangitis, which leads to retransplantation in a high pro-
portion of patients, seems to be associated with poorly controlled IBD. In this context
it is of interest that PSC recurrence in adults with IBD can be prevented by pre–liver
transplant colectomy.53–55 A paper focusing on risk factors for recurrence of PSC after
living donor liver transplantation describes disease recurrence in 11 of 20 (55%) pa-
tients.56 Risk factors for recurrence were cytomegalovirus disease within 3 months
posttransplant and grafts from related donors. Multivariate analysis showed that
younger age (<30 years of age, including children and adolescents) was an indepen-
dent risk factor for recurrence.

SUMMARY

In pediatrics, sclerosing cholangitis is the result of several different pathologies. A high

proportion of patients have associated IBD and autoimmune features. Prospective
studies on large cohorts of children with sclerosing cholangitis are needed for a better
understanding of diagnostic pathways and pathogenic mechanisms, including the role
of intestinal inflammation, with the aim of devising more effective treatment to improve
the outcome of this devastating disease.

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of forty-two cases. Am J Surg 1966;111(1):23–38.
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