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inammatory inltrate is less intense than that found in the lesion of nonsuppurative
destructive cholangitis ofPBC.Concentric layers of brotic tissue surrounding the
bile duct characterize the onionskin lesion classic of PSC; bile ductular proliferation
is also included in this stage. Stage II is characterized by an inammatory inltrate
and brotic changes outside the portal tracts; biliary piecemeal is a feature of this
stage, and ductopenia can also be identied (Fig.5.2). Stage III is characterized by
portal-to-portal brosis. Stage IV is characterized by biliary cirrhosis.
Pseudoxanthomatous changes suggestive of cholestasis are usually found in the last
three stages. PSC can be limited to the smallest branches of the intrahepatic bile
ducts not appreciated in cholangiograms. In these cases, the appearance of the bili-
ary tree on cholangiogram may be normal; thus, only liver histology may be
Fig. 5.1 Magnetic
resonance cholangiogram
in a 59-year-old woman
with primary sclerosing
cholangitis revealing
intrahepatic biliary
strictures (straight arrow)
and dilatations (curved
arrow)
Fig. 5.2 Liver histology in
a patient with primary
sclerosing cholangitis
exhibiting periportal
brosis and absence of bile
duct, replaced by brous
tissue (arrow head).
Another portal tract
exhibits brotic changes
around a bile duct the
lumen of which has been
compromised (arrow)
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consistent with the diagnosis. The lesion that affects the smallest branches of the
intrahepatic bile ducts has been termed small duct PSC; this lesion may represent
the pericholangitis characteristically found in patients with ulcerative colitis and
abnormalities in theserumactivity of liver associated enzymes. Abnormalities of
the pancreatic duct consistent with chronic pancreatitis can also be observed in the
pancreatogram.
Immunology
The mechanisms that mediate the biliary inammation and brosis in PSC are
unknown. In this context, cells of the immune system circulate in the blood to tis-
sues and back into the bloodstream [80]. This characteristic movement allows acti-
vated neutrophils and monocytes to migrate to sites of infection where there is
inammation, naïve T and B lymphocytes into secondary lymphoid tissues, and
effector and memory T cells to sites of infection and tissue injury where they medi-
ate cell-mediated immunity. Recruitment is the process that attracts leukocytes to
tissues from the circulation. It requires the adhesion of leukocytes to the endothe-
lium of postcapillary venules and traversal of the endothelium and basement mem-
brane into extravascular tissue. Adhesion molecules and chemokines are fundamental
components of recruitment [80]. Intercellular adhesion molecule 1, a ligand for the
leukocyte adhesion receptor lymphocyte function-associated antigen 1, was reported
to be expressed by interlobular and proliferating bile ducts in PSC and PBC affected
livers, suggesting a mechanism for the attraction of lymphocytes to the target tis-
sue [81].
A signicant decrease in the number of circulating T cells was reported in
patients with PSC. B cells, in contrast with another study, were signicantly
increased, and a correlation between this change and histologic stage of the disease,
serum gamma globulin, and IgG concentrations, and bilirubin was reported, nd-
ings interpreted to suggest immunological alterations as relevant in the pathogene-
sis of PSC [82]. An immune-mediated pathogenetic component has been indicated
by immunohistochemical studies on explanted livers from patients with PSC that
revealed CD44 positive BEC, which were more preponderant in biliary as opposed
to hepatocellular diseases. The proportion of CD44+ ducts was much higher in bili-
ary disease than in chronic hepatitis. By contrast, the expression of HLA-DR was
detected in a relatively small percentage of bile ducts. CD4+ activated T lympho-
cytes were also reported to be increased in the liver parenchyma; CD8+ T cells were
found in the inammatory inltrate of the biliary epithelium [83]. A small histologi-
cal study from patients with PSC documented CD3+CD45RO+ cells in liver sam-
ples; few cells expressed activation or proliferation markers in the samples that also
included tissues from PBC, another liver disease characterized by inammatory
destruction of BEC.In the PSC material, signicantly more of the inltrative lym-
phocytes were positive for the gut-homing integrin alpha4beta7. There was a vari-
able HLA-DR expression of the biliary epithelium in PSC liver tissues compared to
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the control and disease control livers (i.e., PBC); however, the adhesion molecule
ICAM1 or B7.2 were not detected, suggesting that BEC do not act as antigen-
presenting cells [84].
A cDNA library from normal human common bile duct cells was constructed
and was screened with sera from patients with PSC.From these experiments, the
immunoreactivity against PDZ domain containing 1 (PDZK1), identied as a can-
didate antigen in patients’ sera but not in control sera, was detected in cytoplasmatic
granules and apical cell membranes of BEC in a small group of patients with PSC
(9% of 35 patients). However, it was not unique to PSC, as it was found in 18% of
patients with Grave’s disease and a small percentage of patients with IBD and auto-
immune hepatitis [85]. The integrin alpha4beta7 and mucosal addressin cell adhe-
sion molecule-1 (MAdCAM-1) participate in the trafcking of lymphocytes
between blood and tissues. MAdCAM-1 is expressed in the liver of patients with
portal inammation; its expression correlated with the degree of inammation in
chronic hepatitis C; however, it was not detected in fetal or normal adult liver. These
ndings have suggested that MAdCAM-1 may contribute to the recruitment of
inammatory cells to the liver [86], an idea that is further supported by the strong
expression of MAdCAM-1in the endothelium of the inamed portal vein and sinu-
soids from patients with autoimmune-mediated liver diseases, shown to support the
adhesion of gut-derived alpha4beta7+ T lymphocytes from patients with IBD and
PSC in an experimental assay [87]. The mechanism by which PSC develops in asso-
ciation with IBD in the absence of active colon inammation was proposed to relate
to the presence of memory T cells stimulated in the gut. These memory T cells reach
the liver by the enterohepatic circulation, where, in a permissive environment, lym-
phocyte recruitment mediates the inammatory process of PSC [88]. C-C chemo-
kine receptor type 9 (CCR9) or cluster of differentiation w199 (CDw199) is the
receptor for CCl25 [89]. CCR9 is expressed by a subset of circulatory memory
α4β7high CD4+ and CD8+ lymphocytes [90]; the α4β7 integrin is expressed on gut
trafcking T lymphocytes, which has suggested that this subset of cells is relevant
in immune-mediated processes in the intestines [90, 91]. Mucosal vascular addressin
cell adhesion molecule 1 (MAdCAM-1), found in the endothelium of venules, inter-
acts preferentially with α4β7. Chemokine (C-C motif) ligand 25 (CCL25) is a cyto-
kine that is chemotactic for thymocytes, macrophages, and dendritic cells; CCl25 is
also found in the small intestine where it is produced by intestinal epithelium and
where it mediates homing of effector CD8+ T cells [92]. The expression of the che-
mokine CCL25 was reported in the liver sinusoids of patients with PSC, in associa-
tion with interface hepatitis, and macrophages and dendritic cells in portal tracts;
this nding is in contrast to the absence of CCL25 expression in the liver of patients
with other liver diseases including PBC. Quantication of mRNA conrmed a
marked increase in CCL25in the liver tissues from patients with PSC compared to
livers from disease controls and control tissue. Liver inltrating lymphocytes had a
substantial increase in adhesion of MAdCAM-1 in association with CCL25, as
compared to control lymphocytes, an effect that was blocked by anti-α4β7 antibod-
ies. These results have suggested that the aberrant expression of CCL25 provides
the environment necessary for effective recruitment of gut-stimulated lymphocytes,
which contribute to PSC development in dormant IBD, or after colectomy [93].
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Indeed, it has been suggested that the inammatory process that triggers or perpetu-
ates IBD or both are also involved in the pathogenesis of the associated liver dis-
ease. In this regard, the expression of MAdCAM-1in the mucosal endothelium of
the gut may be a factor in the pathogenesis of IBD.MAdCAM-1 is also detected on
the liver vessels of patients with IBD and liver disease, which is suggested to recruit
effector cells from the gut, where they were initially activated, to the liver.
In this regards to the etiology of IBD and PSC, it was reported that the deamina-
tion of methylamine (MA) by vascular adhesion protein-1 (VAP-1) in the presence
of tumor necrosis factor (TNF)-alpha results in the expression of MAdCAM-1in
hepatic endothelial cells, which is associated with increased adhesion of lympho-
cytes from patients with PSC to hepatic vessels. In laboratory animals, feeding
methylamine, which is found in food and cigarette smoke, and in the portal blood,
was associated with VAP-1/SSAO-dependent MAdCAM-1 expression in mucosal
vessels invivo. These ndings have identied a potential mechanism in the patho-
genesis of liver diseases, including PSC, in patients with IBD, and perhaps, poten-
tial environmental factors that may be involved in the triggering of this type of liver
disease [94].
Altered regulation of toll-like receptors (TLR), which are present in BEC, in
response to the stimulation of intracellular signaling by cytokines andpathogen-
associated molecular patterns (PAMPs) may be relevant in the pathogenesis of bili-
ary diseases [95]. BEC isolated from PSC liver explants revealed a reversible
increase in TLR and nucleotide binding oligomerization domain (NOD) protein
expression and activation of the myeloid differentiation primary response gene
(MYD88)/interleukin (IL)-1 receptor-associated kinase 1 (IRAK1) pathway [96].
This pathway is associated with a stimulated interleukin-1 receptor and induction of
nuclear factor-kappaB (NF kappa B), a rapid-acting transcription factor that partici-
pates in cellular responses to numerous stimuli, including regulating genes that play
a role in innate and adaptive immune response [97]. In an in vitro study, the immune
response to endotoxin was altered, and tolerance was not developed after repeated
exposure to it [96]. This nding was interpreted to result from the stimulatory effect
of interferon-gamma and TNF-alpha, which were strongly expressed in the liver of
patients with PSC, and which might have led to an increase in the incorporation of
endotoxin from the stimulation of TLR-4-mediated signaling in BEC, and to an
impaired inactivation of the TLR-4 signaling cascade [96]. This hyper- responsiveness
and lack of tolerance to intestinal endotoxin were interpreted as potential perpetua-
tors of the cholangitis of PSC [96].
Cellular Pathogenesis
Cellular senescence is a cell state implicated in various physiological processes and
a broad spectrum of age-related diseases [98]. It is characterized by a cycle arrest of
formerly replicating competent cells induced by stress, which usually is triggered
by persistent DNA damage response (DDR) or stress signaling, and executed by
constitutive activation of the p16
INK4a
-RB or p53 pathways, or both [99]. Senescent
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cells exhibit increased expression of the products of the CDKN2a locus, p16INK4a,
and ARF, tend to express an increased lysosomal β-galactosidase activity, and to
secrete cytokines, composite that has been labeled as senescence-associated secre-
tory phenotype (SASP) [100]. Although senescent cells are in a low hyporeplicative
state, they are metabolically active and often can perform functions typical of the
cells from which they originate [101]. A pathogenic effect of senescent cells is the
formation of lesions that can lead to impaired physiology, e.g., atherosclerotic
plaque in blood ow, the grouping of these cells that obstruct tissue homeostasis,
and the production of paracrine and endocrine proinammatory products that pro-
mote tissue dysfunction at all levels of the economy.
Transepithelial/transendothelial electrical resistance (TEER) is a quantitative
technique to measure the integrity of tight junction dynamics in cell culture models
of endothelial and epithelial monolayers [102]. Characterization of cultured biliary
BEC isolated from livers of patients with PSC documented a signicantly lower
proliferation rate and TEER versus those of control BEC; in addition, the amount
and expression of IL-6 and IL-8 mRNAs and their translated proteins, and
senescence- associated β-galactosidase were signicantly higher in PSC-BEC than
in the control cells [103]. PSE-BEC invivo and experimentally induced senescence
of BEC was associated with activationof N-Ras, a known inducer of senescence,
which was inhibited by the inactivation of Ras, suggesting a mechanistic involve-
ment of the gene in the senescence process. Studies documented an increase in the
expression of the senescence-related p16(INK4a) and γH2A.x compared to normal
and disease control cells and exhibited the proinammatory senescence-associated
secretory phenotype (SASP) that includes the expression of IL-6, IL-8, CCL2, and
PAI-1. The investigators suggested that the use of drugs that inhibit N-RAS activa-
tion may provide a pathway to the treatment of PSC [104]. Further involvement of
N-Ras was suggested in an in vitro experiment that documented an increase of BEC
proliferation by LPS, which was inhibited by the inactivation of the gene; in addi-
tion, the blocking of IL-6 by a specic antibody prevented the proliferation of BEC
induced by stimulation of TLRs. These ndings were interpreted to suggest that
LPS, which is produced by commensal intestinal bacteria, may contribute to the
inammatory response caused by microbes on the BECs [105].
Dysbiosis
Dysbiosis is dened as an imbalance in the composition and function of intestinal
microbes [106]. Characterization of gut microbiota from stool samples from patients
with PSC revealed markedly decreased bacterial diversity as compared to that from
the healthy control group, and a different composition from that of patients with
ulcerative colitis, and from the healthy control pool. The microbiota from patients
with PSC with or without associated IBD were similar. Eleven genera were reduced
from the twelve that separated PSC samples from healthy controls, with the
Veillonella genus being signicantly increased in the PSC samples versus those
from the healthy control and ulcerative colitis groups, a nding that allowed for the
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separation of PSC from the healthy control group, with an area under the curve of
0.64, and 0.78 when all the genera from the PSC samples were combined [107].
Anaerobic species, including Veillonella, were isolated from sputum samples from
patients with cystic brosis [108], which indeed has a brosis component including
biliary strictures [109, 110]; however, the connection between this nding and the
gut microbiota is unknown [111]. Altered biodiversity was conrmed in another
study that explored the characteristics of the microbiota in PSC and which expanded
the ndings to include documentation of fungal dysbiosis that had an increase in the
representation of Exophiala and a decrease in Saccharomyces cerevisiae as com-
pared to samples from healthy controls and patients with IBD [112]; the idea of
altered interkingdom cross talk in patients with PSC was proposed based on the
disruption in bacteria–fungi correlation network [112]. A case of systemic infection
in an immunocompetent subject with Exophiala dermatitidis has been reported in
association with hepatobiliary ndings that mimicked PSC [113], and a fatal case of
a child with systemic disease complicated by cholestasis and intrahepatic biliary
dilatation has also been reported [114]. The pathogenesis of PSC in the context of
perturbation of intestinal dysbiosis is a subject of research interest.
Histology
The lesion of intrahepatic bile ducts of PSC is characterized by concentric brosis;
nger-like projections or ne undulations of the basal free surfaces with duplicated
basal lamina have been documented. The lamina is surrounded by elongated bro-
blasts and thickened bundles of collagen bers outwards. Severe periductal brosis
was associated with the disappearance of bile ducts, interpreted to suggest that the
communication between bile ducts and peribliary plexus through which the ducts
are nourished was interrupted. Lymphocytes inltrating BEC were observed [115].
Inammatory lymphoplasmacytic inltration and brosis were reported in peribili-
ary glands, suggesting that these structures are also affected by thePSC’s disease
process [116]. In vitro, the activation of hepatic stellate cells, which express stem
cell factor, attracted mast cells, an effect that was inhibited, in part, by antibodies to
that cytokine [117]. Mast cells that expressed c-kit, broblast growth factor, tumor
necrosis factor-alpha, or both were identied in the periductal and ductal brotic
changes around the intrahepatic large bile ducts and around proliferative peribiliary
glands. Stem cell factor, which binds to c-kit, was also expressed on the BEC epi-
thelium of dilated and stenotic bile ducts that showed periductal brosis and inam-
mation, and by proliferating bile ducts and peribiliary glands in PSC and
hepatolithiasis but not in spared bile ducts. These ndings were interpreted to sug-
gest that stem cell factor may contribute to the pathogenesis of PSC by stimulating
mast cells by the c-kit receptor and inducing the expression of brogenic fac-
tors [118].
A study examined the status of canalicular transporters in PSC. ATP-binding cas-
sette (ABC) transporters are located in the hepatocyte’s canalicular side and trans-
port compounds from the hepatocyte into the bile, including organic anions, bile
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acids, and phospholipids; they play a pivotal role in bile formation and detoxica-
tion. Malfunction of the transporters can lead to cholestasis [119]. A study explored
the expression of ABCB11, the bile salt efux pump of hepatocytes that coordinates
cellular excretion of conjugated bile acids into the bile canaliculi, and of ABCB4,
andATP-dependent ippasethattranslocates phosphatidylcholine from the inner to
the outer leaet of the bile canalicular membrane. In the liver of patients with PSC,
the expression of ABCB11 and ABCB4 mRNAs and proteins were signicantly
increased, exhibiting a correlation with disease stage. These ndings tend to suggest
that the upregulation of these canalicular transporters is a cellular effort to protect
the liver from the toxic effects of substances, including bile acids, that accumulate
in the organ as a result of cholestasis [120].
Three conditions that affect the biliary tree have been described in the last decade,
IgG-4-related sclerosing cholangitis, follicular cholangitis, and sclerosing cholangi-
tis with granulocytic epithelial lesion. The diagnosis of these conditions requires
histology, in contrast to PSC, for which MRCP is the preferred diagnostic test [1],
as this modality does not require manipulation of the biliary tree. IgG4+ related
cholangitis is characterized by a transmural inammatory inltrate composed of
lymphocytes and plasma cells. In general, IgG4 cholangiopathy is associated with
autoimmune pancreatitis type I, whereas the others present as isolated cholangitis
[121]. An aggressive phenotype, however, has been reported in association with
IgG4 and classic cholangitis; in a study from the United States that examined stored
materials from 98 patients with PSC [122], 23% of liver samples had periductal
inltration with IgG4+ plasma cells, and 22% had elevated serum IgG4 levels,
including eight without tissue IgG4 positivity. Dense periductal brosis was reported
in all cases. There was a strong correlation between IgG4 positivity in the liver and
moderate-to-marked periductal lymphoplasmacytic inammation. The expression
of IgG in the liver correlated with shorter disease duration prior to liver transplant
and recurrence of disease in the graft compared to serum IgG4. A substantial num-
ber of liver samplesfrom patients with PSC had increased IgG4+ periductal plasma
cell inltrates and high IgG4 serum concentration [122]. These ndings seem to
suggest some relevance of IgG4in the pathogenesis of classic PSC.In a study from
the United Kingdom, however, 95% of 41 explants from patients with PSC had
minimal inltration of IgG4+ plasma cells, and only two cases had a high number
of this type of cells, which were present in areas of xanthogranulomatous tissue
within large bile ducts; there were no signicant ndings in common with IgG4+
sclerosing cholangitis identied [123].
Epidemiology
A literature review on PSC reported an incidence rate of 1.3 per 100,000 subjects
per year and a prevalence rate of 0–16.2 per 100,000 [124], and both are likely to
vary among different geographical areas. From a pooled analysis of eight studies,
the incidence rate ratio for men compared to women was 1.70 (1.34–2.07) [125].
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An increase in the incidence of PSC in Scandinavia has been reported. From
1986 to 1995, from a hospital in Oslo, Norway, 70 patients with PSC were regis-
tered, with a calculated point prevalence of 8.5 [126]. In a study from southern
Sweden, 199 patients with PSC were identied in a retrospective review from 1992
to 2005; the point prevalence of PSC on the last day of 2005 was 16.2 per 100,000
inhabitants, with that for men being 23.7 per 100,000 persons, and for women, 8.9.
The annual incidence was calculated as 1.22 per 100,000 inhabitants; for men, it
was 1.78 per 100,000 and for women 0.69. The overall incidence rate of PSC
increased signicantly over the years that comprised the study, with an average
annual percent change of 3.06 (95% CI 0.01–6.20). The incidence of inammatory
bowel disease associated with PSC increased at an average annual rate of 7.01 (95%
CI 0.24–14.24). The average annual percent change for classic PSC in women was
6.32 (95% CI 0.03–13.02), and for PSC without IBD, the average annual rate was
9.69 (95% CI 0.82–19.33), and for small duct PSC, it was 17.88 (95% CI 0.95–40.25)
in men [127].
From a large database of ethnically diverse subjects from Northern California in
the United States, 169 patients, 59.7% of whom were male, were identied as hav-
ing PSC from 2000 to 2006. The age-adjusted point prevalence was 4.15 per
100,000in 2005. The age-adjusted incidence per 100,000 person-years was 0.45
(95% CI 0.33–0.61) in men and 0.37 (95% CI 0.26–0.51)in women. PSC was asso-
ciated with IBD in 64.5% of the subjects; 73.3% of men had both conditions, in
contrast to women, in whom both conditions existed in 51.5%. The cumulative aver-
age mortality rate per year was 1.9% [128].
In a study from Switzerland composed of 950 patients with inammatory dis-
ease, PSC was found in 1% of those with Crohn’s disease and 4% of those with
ulcerative colitis [129].
Natural History
The natural history of PSC is variable. It seems to differ depending on the country
where the patients reside [130]. However, it is a rare disease, and robust information
on its natural history is lacking. The reported period to death or liver transplantation
has ranged between 4 and 18 years [124, 131, 132]. In patients from Europe, a
median survival rate of approximately 12years from the time of diagnosis was
reported in a group of 305 patients from Sweden [131]; in a group of 28 patients
from Italy, the estimated survival rate was 65% at 10years [133]; in The Netherlands,
the estimated median survival in a group of 174 patients diagnosed and followed for
almost three decades starting in 1970 was 18years from the time of diagnosis to
death from liver disease or to liver transplantation [132]; from France, survival
without liver transplantation was reported to be 4years in 79% of 150 patients over
a period that ranged from 0.1 to 7.2years [134]; from the United States, the survival
rate from a group of 174 was reported to be 11.9years [135]. Patients without symp-
toms from PSC were reported to have signicantly higher survival than those with
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symptoms [131]. The Kaplan-Meier curve in adults shows a 65% rate of survival at
10years. A serum bilirubin concentration four times the upper limit of normal was
reective of advanced disease in one study [130]. Hepatomegaly and a serum bili-
rubin concentration greater than 1.5mg/dL at the time of diagnosis were associated
with poor prognosis [136]. The importance of bilirubin has been conrmed by a
report indicating that a persistent increase in serum bilirubin concentration for lon-
ger than 3months from the time of diagnosis correlated with poor prognosis [137].
The outcome for secondary sclerosing cholangitis has been reported to be worse
than that of PSC [138].
Liver Transplantation
PSC recurs after liver transplantation in 20% to 25% of subjects [139]. Referral for
liver transplant evaluation is recommended when the Model for End-Stage Liver
Disease (MELD) score is 15 or when complications specic to PSC such as recur-
rent cholangitis arise. A study that included 150 patients transplanted at one institu-
tion with the provision of 174 liver grafts and who were followed for a mean of
55months reported the actuarial patient survival at 1, 2, 5, and 10years of 93.7%,
92.2%, 86.4%, and 69.8%, respectively, and graft survival as 83.4%, 83.4%, 79.0%,
and 60.5%, respectively. The main indication for retransplantation was hepatic
artery thrombosis and the most common cause of death severe infection. The pro-
portion of patients developing acute cellular and chronic ductopenic rejection was
higher in patients with PSC thanin those with other liver diseases. Frequent compli-
cations of biliary strictures, anastomotic, and nonanastomotic were reported in 16.2
and 27.2% of patients, respectively, with disease recurring in 20%; however, these
complications were not reported to decrease survival. Four percent of the patients
transplanted had cholangiocarcinoma, which was associated with mortality in a
patient in whom cancer recurred. Seventy-eight percent of patients had associated
IBD, with ulcerative colitis being the most common type, and which did not inu-
ence the outcome of transplantation. Colectomy post-transplant was required in
some patients because of IBD-related complications [140].
A study explored the outcomes of 5080 adult patients who had had liver trans-
plantation, had been relisted, and had been retransplanted for PSC from 1987 and
2015 with the United Network for Organ Sharing/Organ Procurement and
Transplantation Network database as source[141]. It was reported that1803 expe-
rienced graft failure; 762 were relisted, and 636 were retransplanted. The most com-
mon types of patients relisted were the young and those with graft failure from
vascular thrombosis and biliary complications, with a signicant decrease in graft
and patient survival at 5years after retransplantation compared to patients trans-
planted once. However, the 5-year survival for graft and patients after retransplanta-
tion for disease recurrence was similar to that of the primary transplantation and
superior to other indications for retransplantation. Features reective of a postop-
erative stormy course, including mechanical ventilation and impaired renal
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function, were associated with inferior outcomes after retransplantation. It was con-
cluded that although retransplantation was associated with a reduced survival versus
one transplantation, retransplantation was a good option for patients with recurrent
disease, as outcomes post retransplantation at 5years were similar to those from the
primary transplantation [141]. These results are encouraging considering the grav-
ity of PSC and the risk for recurrence after a life-changing procedure.
Cholangiocarcinoma
Cholangiocarcinoma usually presents with a relatively sudden increase in serum
bilirubin concentration, which may be associated with a new biliary stricture or
subtle changes in the appearance of the biliary tree on imaging studies, e.g.,
MRCP.It must be suspected in patients with PSC whose liver function deteriorates
itself. The predicted time to develop cholangiocarcinoma was estimated to be 9% at
year 10 after the diagnosis of PSC in a group of 211 patients from The Netherlands
[142]. The annual incidence of cholangiocarcinoma was reported as 1.2% in a study
composed of 230 patients, 23 of whom developed cholangiocarcinoma [143]. Men
and patients with large duct PSC and ulcerative colitis seem to be at a higher risk of
developing cholangiocarcinoma than women and children, and in patients with
small duct PSC or those with associated Crohn’s disease [144]. Antibodies to gly-
coprotein 2, a specic target of pancreatic autoantibodies [PAbs] detected in Crohn’s
disease and involved in gut innate immunity processes, were reported in association
with PSC, correlating with a decrease in transplant-free survival [145]. Antibodies
to glycoprotein 2 (GP2) were documented to exhibit a strong association with bili-
ary tract cancer in a group of patients from Norway, found in over 50% of the
patients in the study [146]; thus, it has been suggested that they may be a useful
marker to detect malignancy in association with PSC.
Cholangiocarcinoma is difcult to differentiate from benign strictures; diagnos-
tic means include cytological analysis of biliary material obtained by brushing sus-
picious areas during endoscopic examination of the biliary tree by ERC, and by
cholangioscopy, and by the measurements of serum markers of biliary tract malig-
nancy. In this regard, the serum concentration of carbohydrate 19-9 (CA 19-9) can
be normal or increased in patients with cholangiocarcinoma. The results of some of
the studies examining CA 19-9in patients with cholangiocarcinoma have included
the following ndings: (i) a serum concentration of CA19-9 > 180U/mL had a sen-
sitivity of 66.7% (95% CI [34.9, 87.7]) and specicity of 97.7% (95% CI [88.2,
99.9]) in a group of 55 patients [147], (ii) serum concentration of CA 19-9 > 100U/
mL had 75% sensitivity and 80% specicity in identifyingpatients withPSC and
cholangiocarcinoma [148], (iii) in fourteen patients, a serum concentration greater
than 129U/mL was associated with a sensitivity of 78.6% and a specicity of 98.5%
for the diagnosis, and an adjusted positive predictive value of 56.6% and a negative
predictive value of 99.4%; in addition, it was reported that in the patients with chol-
angiocarcinoma there was a signicant median change over time of 664U/mL in
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