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of Springer Nature 2022
N. V. Bergasa (ed.), Clinical Cases in Hepatology,
https://doi.org/10.1007/978-1-4471-4715-2_5
Chapter 5
Primary Sclerosing Cholangitis
NoraV.Bergasa
A 51-year-old woman presented to the hospital because of abdominal pain and
fever. Her vital signs were notable fora high temperature; she had scleral icterus,
abdominal tenderness on the right upper quadrant without rebound, and legs with
prominent varicose veins. The relevant laboratory tests were leukocytosis, with a
predominance of neutrophils but no bandemia, normal electrolytes, normal coagula-
tion prole, and a serum alkaline phosphatase (AP) of 440IU/L, serum bilirubin of
3mg/dL, and a mild increase of AST and ALT activities to less than 100IU/L.A
right upper quadrant sonogram was normal, but amagnetic resonance cholangio-
pancreatography(MRCP)revealed changes suggestive of primary sclerosing chol-
angitis (PSC) with intrahepatic biliary strictures and sacculations; she did not have
gallstones. Urine and blood cultures were negative for bacterial growth. She was
started on empirical antibiotic therapy for cholangitis in the face of suspected
PSC.She subsequently provided a colonoscopy report from a few years prior to this
presentation, documenting inactive colitis on biopsy. The hepatology service was
consulted and subsequently followed the patient in the clinic with relatively good
liver function but intermittent increases in serum bilirubin. She did not have pruri-
tus. The patient developed episodes of fever and leukocytosis associated with right
upper quadrant discomfort. On one occasion, her blood cultures grew Klebsiella
pneumoniae. She was referred for liver transplant evaluation because of recurrent
cholangitis. After 9years of follow up, she underwent liver transplantation from a
hepatitis B anticore + donor, for which she is on an antiviral. At present, she is doing
relatively well; however, she has an anastomotic stricture. She has had normal sur-
veillance colonoscopies over the years. She regularly goes on vacation, has a good
N. V. Bergasa (*)
Department of Medicine, H+H/Metropolitan, New York, NY, USA
New York Medical College, Valhalla, NY, USA
Hepatology, H+H/Woodhull, Brooklyn, NY, USA
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appetite and energy level, and continues to follow up at our hepatology clinic with
scheduled visits to the transplant center where MRCPs and adjustments of her
immunosuppression are made and where she was started on ursodeoxycholic acid
(UDCA). Her AP activity post-transplantation has been normal, her bilirubin has
been around 3mg/dL, her albumin has been low, without proteinuria, suggestive of
synthetic dysfunction. There are no features of PSC on liver histology and no
inammatory activity, but she has cirrhosis, classied as cryptogenic.
Sclerosing Cholangitis
The patient described in this chapter presented with a picture of cholangitis, associ-
ated with cholestasis, and a magnetic resonance cholangiopancreatography that
revealed intrahepatic biliary strictures [1]. In the absence of prior biliary tract sur-
gery, the ndings are consistent withprimary sclerosing cholangitis (PSC). A colo-
noscopy performed 4years prior to her initial presentation had revealed inactive
colitis. The patient had not had symptoms of inammatory bowel disease, which is
associated with PSC in approximately 70% of the time.
Sclerosing cholangitis is a condition associated with the disappearance of intra-
hepatic and extrahepatic bile ducts secondary to a brosing process that leads to
biliary cirrhosis and liver failure. PSC is the term used when no precipitating factor
is identied; it may or may not be associated with inammatory bowel disease.
Secondary sclerosing cholangitis is the term used when the precipitating factor(s) of
the condition is (are) identied or inferred.
The etiology of PSC is unknown [2, 3]. It has been suggested that this liver dis-
ease may have an autoimmune basis. PSC has been diagnosed in association with
retroperitoneal brosis and mediastinal brosis. The syndrome of sclerosing chol-
angitis has been described in patients with histiocytosis X.In contrast to PSC, some
processes lead to secondary sclerosing cholangitis, including hepatic artery infu-
sions of chemotherapeutic agents (e.g., uorodeoxyuridine (FUDR) [4] for treat-
ment of malignancies, the associated coagulative phenomena due to lupus
anticoagulant, infusions of scolicidal solution (formaldehyde, 20% sodium chlo-
ride) directly into hydatid cysts, neoplasms of the biliary tract, bacterial or parasitic
infections of the biliary tree, opportunistic infections in immunocompromised
patients, complications of cholecystectomy, and abdominal trauma [5]. The mecha-
nisms by which these events lead to sclerosing cholangitis are unknown; it has been
speculated that invasion of the biliary tract by pathogens and the effects of inam-
mation lead to cholangitis in the last two conditions. In patients with AIDS, polymi-
crobial cholangitis (e.g., from cryptosporidium, Candida albicans, Klebsiella
pneumoniae, and cytomegalovirus) have been reported. Ischemia has been proposed
in the pathogenesis of sclerosing cholangitis secondary to intraarterial infusions of
FUDR [6]. The instillation of scolicidal solution into intrahepatic Ecchinococcal
cysts communicating with the biliary tree is associated with the rapid development
of sclerosing cholangitis from caustic injury [7]. As PSC is associated with
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inammatory bowel disease (IBD) in 70 to 80 percent of patients, cholestasis in this
patient population suggests the diagnosis of this liver disease [3]; in this regard,
colon neoplasia in patients with IBD in association with PSC tended to be more
frequent than in patients without PSC in one report [8]; in addition, it was docu-
mented that patients with PSC and IBD had more rectal sparing and more involve-
ment of the terminal ileum than patients with PSC.The combination of diseases was
associated with a decreased survival at 5years from the time of presentation [9].
Indeed, PSC associated with IBD has been proposed to differ from that not associ-
ated with IBD, although reports do not seem consistent. In a study from Sweden,
patients with PSC associated with IBD had active inammation documented histo-
logically but not apparent on inspection. The inammation was reported to be prom-
inent or exclusively on the right side of the colon, with rectal sparing and backwash
ileitis. From this study, it has been suggested that the apparent quiescent state of the
colon in patients with IBD may mask active inammatory activity, hence promoting
the development of malignancy [10]. In contrast, in a study from the Netherlands of
patients with PSC in association with IBD, the majority had pancolitis, the rectum
was infrequently spared, and there were few patients with backwash ileitis, in asso-
ciation with ulcerative colitis; in patients with Crohn’s disease, the predominant
nding was colitis [11]. PSC presents alone in a substantial number of patients;
accordingly, it has to be considered in the differential diagnosis of patients who
present with cholestasis regardless of any gastrointestinal comorbidities. It is sig-
nicantly more common in men than in women. It is most commonly diagnosed
around the age of 30years.
Etiology
An autoimmune component in the etiology of PSC has been proposed because of its
association with autoantibodies. Antinuclear antibodies of the homogenous type,
with an approximate prevalence of 35% [12], were reported in PSC.In addition,
anticardiolipin, antithyroperoxidase antibodies, and rheumatoid factor have been
reported in PSC [13]. Antineutrophil nuclear antibody (ANNA), initially reported as
antibodies against a component of the portal tract and subsequently characterized as
ANNA, was reported in the serum of 84% of patients with PSC at a relatively high
titer, and in 86% of patients with IBD [14]. It was demonstrated by an enzyme-
linked immunosorbent assay for immunoglobulin G (IgG) neutrophil antibodies
that neutrophil binding in sera from patients with PSC was signicantly greater than
of patients with other liver diseases, includingprimary biliary cholangitis(PBC)
[15]. Perinuclear immunouorescence was shown by most serum samples from
patients with ulcerative colitis, PSC, and PSC without ulcerative colitis [15]; in one
study, circulating antineutrophil antibodies (ANCA) of the perinuclear type
(p-ANCA) were reported to occur in 87% of patients with PSC with or without
ulcerative colitis, and in 68% of those withulcerative colitis only [13]. Antineutrophil
cytoplasmic antibodies (ANCA) of the IgA class were found in 20% of sera from 35
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patients with PSC and in 50% of 40 patients with autoimmune hepatitis in a small
study. The staining pattern in patients with PSC showed both an atypical perinuclear
staining in PSC and the classical pattern in neutrophils from patients with autoim-
mune hepatitis. The staining pattern for the IgA class of antibody against ANCA
was “classical” and “atypical” in PSC compared to the ndings in autoimmune
hepatitis in which the staining was the classic perinuclear expression. These nd-
ings were interpreted to suggest that there are different target antigens of IgA class
ANCA with distinct subcellular localization [16]. Atypical p-ANCA observed in
patients with PSC, ulcerative colitis, and autoimmune hepatitis was reported to react
with an antigen present in the nuclear lamina of granulocytes [17] that was identi-
ed subsequently as a 50-kilodalton myeloid-specic nuclear envelope protein [18].
The 50-kDa ANCA autoantigen has been reported to be β-tubulin isotype 5 (TBB-5).
In experiments that included sera from patients with autoimmune hepatitis, and with
PSCalone orin association with IBD, p-ANCA recognized human β-tubulin iso-
type 5 (TBB5) and cross-reacted with lamenting temperature-sensitive mutant Z
(FtsZ), its evolutionary bacterial precursor protein. FtsZ is a tubulin homolog and
the major cytoskeletal protein in bacterial cell division, during which it is the rst
protein to move to the division site from where it recruits other proteins that produce
a new cell wall between the dividing cells [19]. These results have suggested that the
reaction of p-ANCAs against human TBB-5 and their cross reactivity with FtsZ
reects an abnormal immune response to intestinal microorganisms in individuals
vulnerable to develop these types of diseases, including PSC [20]. The association
of some autoimmune diseases with PSC has been interpreted to suggest an autoim-
mune component in the pathogenesis of the latter [21].
The high frequency of autoantibodies that bind biliary epithelial cells (BEC) was
documented in patients with PSC compared to control and disease control sera. Anti
biliary epithelial cellantibodies were reported to induce IL-6 production by BEC
from patients with PSC (and PBC); however, IgM and IgG immunoglobulin frac-
tions only from PSC sera signicantly induced the expression of CD44, an adhesion
molecule [22], which suggested a potential function of biliary epithelial cellanti-
bodies in BEC injury in PSC (and PBC).
Genetics
Associations with the human leukocyte antigen (HLA) complex located in chromo-
some 6p21 have been consistently documented in patients with PSC from distinct
geographical areas [23–25]. The occurrence of PSC in members of the same family
also has suggested its genetic predisposition. The frequency of HLA-DR2 and the
haplotype A1 B8 DR3 was increased in patients with the disease, whereas a decrease
was documented in the B44 and DR4 haplotype in a study of 81 patients [26].
Another study documented that HLA DR3, DR52a, DR2, and Dw2 were signi-
cantly more frequent in the disease group than in the control group [27]. It was also
documented that HLA DR4 was associated with rapid disease progression [27], in
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contrast with a prior study in which no associations with disease progression and
HLA alleles were found [26]. In Northern Italy, the frequency of HLA-C2 killer-
immunoglobulin receptor (KIR) ligand was signicantly decreased in patients with
PSC compared tothe control group; homozygosity of HLA-C1 was documented in
association with an increased risk for PSC.In contrast to the population of Northern
Europe in which DRB1*03, *04, or *1301 alleles have been identied as prevalent,
no such nding was conrmed in a study from Northern Italy; the association with
DRB1*15 and DRB1*07, however, was also detected [25]. By the use of genome-
wide association studies (GWAS) in a study of patients from Norway, strong asso-
ciations were identied in chromosome 6p21 near HLA-B and in chromosomes
13q31 and 2q35 and 3p21, both of which have been identied as susceptibility loci
for ulcerative colitis [24]. Other associations outside the HLA complex have been
found by the use of GWAS in PSC for a total of 16 risk loci for PSC specically.
Although the association with IBD was found in 72% of the patients studied, 6 of
the 12 loci had a stronger association with PSC alone than with IBD, which sug-
gested that although there is overlap in the risk for both, there are genetic distinc-
tions between the two conditions. Association statistics from seven diseases that
occur in patients with PSC, i.e., Crohn’s disease, celiac disease, psoriasis, rheuma-
toid arthritis, sarcoidosis, type 1 diabetes, and ulcerative colitis, documented 33
additional pleiotropic risk loci [28].
Most killer immunoglobulin-like receptors (KIRs) are inhibitory [29]. The
decrease in natural killer (NK) cells inhibition by a combination of killer
immunoglobulin- like receptors (KIRs) and HLA class I ligands have been reported
as a risk for the development of autoimmune disease [30]. In a study from
Scandinavia, the gene frequency of KIR was not different in patients with PSC than
from the control group; however, it was reported that the frequency of HLA-Bw4
and –C2, ligands at the inhibitory KIRs3DL1 and 2DL1, respectively, was signi-
cantly reduced in PSC patients as compared with controls. The 5.1 variant of the
major HLA class I chain-related A (MICA), which has been documented to inu-
ence the predisposition to develop PSC, was prevalent in the patients. In contrast,
the DRB1*0301 or DRB1*1501 alleles were absent. These ndings have suggested
that variants of ligands for NK cell receptors encoded by different genes in the HLA
complex may contribute to the genetic predisposition to develop PSC [31].
In a study from Norway, strong associations were identied in chromosome
6p21 near HLA-B and in chromosomes 12q31 and 2q35 and 3p21 by the use of
GWAS in patients with PSC.These chromosomes have been identied as suscepti-
bility loci for ulcerative colitis [24]. A relatively large study from Sweden reported
that the risk of PSC was signicantly higher in rst-degree relatives of patients with
PSC than in the rst-degree relatives of a control group subjects. The hazard ratio
and 95% condence interval (CI) for offsprings were reported as 11.5 (1.6–84.4),
for siblings 11.1 (CI=3.3–37.8), and for parents 2.3 (CI=0.9–6.1) [32]. Through
GWAS, several susceptibility loci carrying SNP in genes, the product of which may
reveal their relevance in the pathogenesis of PSC.In a study from Norway, strong
associations were identied in chromosome 6p21 near HLA-B and in chromosomes
12q31, and 2q35 and 3p21, identied as susceptibility loci for ulcerative colitis [24].
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HLA-B8 was reported in association with PSC in patients identied as European
Americans, African Americans, and Hispanic from the United States Organ Sharing
database listed for liver transplantation. In contrast, HLA-DR3, which is in linkage
disequilibrium with HLA-B8, was found only in European Americans and Hispanic
subjects; however, this association was absent from the African American patients,
which has suggested an area of further study as a difference among the groups was
revealed [33].
SNP rs 9524260 in chromosome 13q31, where glypican 6 is encoded, was also
signicantly more prevalent in samples from patients with PSC than in those in the
control group. Downregulation and upregulation of hundreds of genes were docu-
mented in association with silencing of glypican 6in in vitro studies in a cell line of
BEC; among the genes that were upregulated were: (i) LIPOCALIN-2, which
encodes lipocalin-2, a protein involved in iron delivery to the cell [34] and relevant
in the immune response to bacterial infections [35] and in cell growth [36], (ii)
NR1H4, which encodes the farsenoid receptor X, a nuclear receptor that induces the
expression of the small heterodimer partner (SHP), which inhibits the transcription
of the CYP7A1 gene encoding CYP7A1, the rate-limiting enzyme in the synthesis
of bile acids from cholesterol, (iii) the CXCL3 and CXCL5, encoding chemokine
ligand 3 (CXCL3), and CXCL5, respectively, involved in cell adhesion processes
[37, 38], (iv) MCPT8, which encodes mast cell protease 8 which,as other products
of mast cells, participates in inammatory processes and regulation of immunity
[39, 40], and (v) TIMP3, encoding tissue inhibitor of matrix metalloproteinase 3,
which inhibits, as other members of this group of proteins, matrix metalloprotein-
ases, a group of peptidases that participate in the degradation of extracellular matrix
[41]. These ndings have suggested that genes that participate in the regulation of
bile acid production and the inammatory response contribute to the genetic sus-
ceptibility to develop PSC [24]. Additional GWAS have identied other loci in asso-
ciation with PSC, including: (i) IL-2RA located in chromosome 10p15 encoding
interleukin-2 receptor A [42], an inducible growth factor that mediates immune
function through its effects on the development and activity of T and B lympho-
cytes, natural killer cells, and lymphokine-activated killer cells, and that is located
on the surface of activated T lymphocytes [43], (ii) MST1 located in chromosome
3p21, encoding macrophage stimulating 1 (MST1) [42, 44]. The deduced amino
acid sequence of MST1 is homologous to hepatocyte growth factor [45, 46]; it is
proteolytically activated by caspases during apoptosis, and its biological processes
include positive regulation of apoptosis and negative regulation of cell proliferation
[47], (iii) IL-2/IL-21 loci in chromosome 4q27 [42]; Il-21 has a role in proliferation
and maturation of natural killer cells and proliferation of some stimulated B and T
cells [48]; IL-2 is pivotal in the pathway that leads T cells to become effector cells
[49], (iv) MMEL1 and TNFRSF14 in chromosome 1p36 [50]; membrane
metalloendopeptidase- like 1 (MMEL1) is a metalloprotease that participates in
early embryonic development and sperm function, and that degrades a broad variety
of small peptides [51], and tumor necrosis factor receptor superfamily member 14
(TNFRSF14), the receptor for B- and T-lymphocyte attenuator and for tumor necro-
sis factor ligand superfamily member 14. TNFRSF14 is involved in lymphocyte
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activation [52], (v) BCL2L11 in 2q13, encoding Bcl2-interacting protein [44], which
enhances the antiapoptotic effects of BCL-2. Bcl-2 (B-cell lymphoma 2) is the rst
member of the Bcl- 2 family of apoptosis regulator proteins [53], (vi) 2q37.3 GPR35
[54] encoding G protein-coupled receptor 35, the expression of which is detected in
immune cells, in the gastrointestinal tract [55], and gastric cancer [56], in the crypts
of Lieberkühn in rats [57], and expressed in gastric cancer cells and normal intesti-
nal mucosa [56], and (vii) 18q21.2 TCF4 encoding transcription factor 4 or immu-
noglobulin transcription factor 2, which binds to the immunoglobulin enhancer
Mu-E5/KE5-motif, and is involved in neuronal differentiation [58]. It recognizes an
Ephrussi-box (“E-box”) binding site (“CANNTG”) that was rst identied in
immunoglobulin enhancers [59] and is considered important in the development of
the nervous system [60], and (viii) CARD9 [50], in chromosome 9q35, encoding
caspase recruitment domain-containing protein 9 (CARD9), a member of the cas-
pase recruitment domain-containing family, which participates in the regulation of
apoptosis [61].
One of the GWAS reported above [50], which included 715 patients with PSC,
332 from Scandinavia, and 382 from Germany, and a large group of control subjects
from both countries also documented a SNP in the fucosyltransferase 2 gene (FUT2)
in chromosome 19q13, which has suggested some relevance to the susceptibility to
PSC because, although their presence was not sufciently strongfor analysisthere
is a reported association between FUT2 genotypes and infectious diseases [50]. In
this regard, nonsense SNP rs601338 (W(TGC) to * (TAG) encodes a nonfunctional
FUT2 protein, dening a nonsecretor phenotype [62]. The expression of FTU2in
the bile duct epithelium of patients with PSC was sought by the immunostaining of
alpha (1,2) fucose-specic lectin Ulex europaeus agglutinin-1; it was documented
that samples from the subjects with the secretor phenotype expressed alpha (1,2)
fucosylated glycans in bile duct epithelia, in contrast to those with the nonsecretor
phenotype, which did not express the immunostain. Bile samples from several
patients with PSC and that from other species were used for sequencing human
FTU2; from these experiments, differences were documented in the composition of
bile samples from patients with the nonsecretor phenotype, which contained a sig-
nicant increase in the Firmicutes and a decrease in Proteobacteria versus the secre-
tor phenotype [50]. A nonfunctional FUT2 prevents the synthesis of ABH antigens
in intestinal mucosa and their presence in secretions [63]; the phenotype of FTU2
contributes to the susceptibility of infections [64]. The phenotype of FUT2 was also
associated with the community composition of intestinal microbiota [63]. These
ndings suggest a role of FTU2 genotype on how microbiota may contribute to the
pathogenesis of PSC.Interestingly, rs601338 was signicantly more prevalent in
patients with ulcerative colitis than in control subjects, in two minority groups of
China. However, this nding was not reported in a study from the United States,
which documented an association between the nonsecretor phenotype and Crohn’s
disease, but not with ulcerative colitis [65].
SNPs in the matrix metalloproteinase 3 (MMP3) characterized by homozygosity
were identied in patients with PSC and correlated with the risk of progression [66].
The 5A allele in the promoter region of MMT3 is associated with increased
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transcription of the gene product, and it has been found to correlate with disease risk
and possibly disease progression [67]. In this context, patients with PSC and ulcer-
ative colitis also had an increase in the frequency of MMP-3 allele 5A as opposed
to patients with PSC withoutulcerative colitis. In addition, all patients with cholan-
giocarcinoma, to which patients with PSC are predisposed, had the allele 1 G in
MMP-1 compared to patients without cholangiocarcinoma in whom 72% carried
that allele [68].
Clinical Manifestations
The most common clinical manifestations are fatigue, jaundice, pruritus, weight
loss, and right upper quadrant pain; jaundice may manifest itself alone or in combi-
nation with episodic cholangitis, which can be associated with fever and shaking
chills. The symptoms of secondary sclerosing cholangitis are similar to those of
PSC.PSC has been found in association with other diseases, including celiac dis-
ease, Hodgkin’s lymphoma, retroperitoneal, and mediastinal brosis. Accordingly,
the primary clinical manifestations may be those of the associated disease.
As in other diseases characterized by cholestasis, the pruritus of sclerosing chol-
angitis can be mild or severe, with sleep deprivation. Pruritus in patients with PSC
may be secondary to cholangitis, which requires antibiotic therapy, and which can
be associated with relief of the pruritus.
Fatigue is a complex symptom experienced by patients with liver disease and
particularly notable in PBC.PSC can also present with fatigue [69]. Depression and
decrease in general health, as measured by a quality of life tool, predicted the pres-
ence of this symptom, which did not correlate with the severity of disease [70]. This
nding is not supported by another study, in which depression was not a prevalent
symptom in patients with PSC [71]. Health-related quality of life was reported to be
impaired in a group of 182 unselected patients with PSC that resided in England or
Sweden. Pruritus was associated with decreased quality of life; however, fatigue
was not found to be more common in patients with PSC than in the control
group [72].
Differential Diagnosis
The differential diagnosis of sclerosing cholangitis includes all cholestatic syn-
dromes. PSC can present alone or, in a substantial number of patients in association
withIBD, primarily ulcerative colitis, and less commonly, Crohn’s disease. PSC has
been associated with other diseases, including thyroid dysfunction [73, 74], celiac
disease [75, 76], Hodgkin’s [77] and non-Hodgkin’s lymphoma, pulmonary brosis
[78], and systemic sclerosis [79]; accordingly, the dominating clinical presentation
may be those of the associated disease. PSC can also be asymptomatic [5].
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Physical Examination
Physical examination may be normal or suggestive of cirrhosis. Dermatological
manifestations include those suggestive of cirrhosis and portal hypertension, includ-
ing palmar erythema, spider angiomata, and hyperpigmentation. In patients with
ulcerative colitis, erythema gangrenosum and erythema nodosum may be found.
Patients who suffer from pruritus may have cutaneous excoriations and prurigo
nodularis. Also, in patients who have undergone proctocolectomy for ulcerative
colitis, stomal varices secondary to portal hypertension may be appreciated. New
strictures and episodic cholangitis can be associated with jaundice. Hepatomegaly,
not infrequently at the expense of the left lobe of the liver, splenomegaly, and ascites
may be found, as in other liver diseases.
Laboratory Findings
Cholestasis is the dominating serum biochemical feature; thus, increased activity of
AP and gamma-glutamyl transpeptidase (GGTP) are the characteristic laboratory
abnormalities; theserumactivity of 5’nucleotidase, an index of cholestasis, can also
behigh. Modest elevations of the serum activity of transaminases (alanine amino-
transferase and aspartate aminotransferase) are common. Hyperbilirubinemia may
be present from advanced disease, episodic cholangitis, a benign dominant stric-
ture,or cholangiocarcinoma. Hypoalbuminemia and prolonged prothrombin time
suggestive of impaired liver function can be found; because PSC is often associated
with IBD and has been reported in association with celiac disease, these two abnor-
malities can be observed in the context of good liver function but secondary to
severe colitis, and malabsorption. Thrombocytopenia secondary to hypersplenism
from portal hypertension may be found in the hemogram. Normocytic normochro-
mic anemia secondary to cirrhosis may be observed; however, hypochromic micro-
cytic anemia is not uncommon in patients with PSC andIBD because of chronic
fecal blood loss. Eosinophilia has been reported.
Diagnosis
Magnetic resonance cholangiography (MRC) has supplanted the use of endoscopic
retrograde cholangiography (ERC) as the diagnostic test for sclerosing cholangitis,
as the former can reveal the classical radiographic picture suggestive of the disease
(Fig.5.1), and it avoids the manipulation of the biliary tract necessary in endoscopic
procedures. Four histological stages have been described in PSC; stage I is charac-
terized by an inammatory inltrate composed of polymorphonuclear leukocytes
and lymphocytes around the ducts, with vacuolation of the epithelium; however, the
5 Primary Sclerosing Cholangitis
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