Chapter 18: Biliary complications of liver transplantation 303
5. Biliary complications may present with the following signs and
symptoms, except
a. abnormal laboratory values
b. acute rejection
c. abdominal pain
d. nausea and vomiting
e. fever
f. sepsis
6. The advantages of magnetic resonance cholangiography
(MRC) in evaluation of suspected biliary complications
include
a. noninvasive and therapeutic modality
b. high sensitivity and specificity for biliary complications
c. visualization of the biliary system above and below a biliary
stricture
d. ideal for identifying biliary leaks
e. b and c
f. all of the above
7. Complications of percutaneous transhepatic cholangiography
(PTC) include
a. hemobilia
b. cholangitis
c. acute rejection
d. a and b
e. a, b, and c
8. What is the most appropriate diagnostic and therapeutic
modality used to evaluate a suspected biliary complication
following living donor liver transplantation with CDJ
reconstruction?
a. endoscopic retrograde cholangiography (ERC)

b. PTC
c. MRC
d. ultrasound
e. radionuclide scan
9. All of the following are cited complications of ERC, except
a. cholangitis
b. pancreatitis
c. gastrointestinal bleeding
d. acute rejection
e. bowel perforation
10. All of the following are possible etiologies of nonanastomotic
strictures, except
a. hepatic artery thrombosis (HAT)
b. chronic rejection
c. portal vein thrombosis
d. cytomegalovirus infection
e. all are associated with nonanastomotic strictures
11. What is the anatomic structure most important in preventing
postoperative cholangitis?
a. recipient bile duct
b. donor bile duct
c. sphincter of Oddi
d. hepatic veins
e. portal vein
12. Cystic duct mucocoeles
a. commonly occur but rarely cause complications
b. require operative resection and drainage if biliary flow is
compromised by the anatomic location of the mucocoele
c. usually occur in the early postoperative period
d. almost always require conversion to CDJ

13. Clinical questions
—
a 55-year-old male patient, status post
living donor liver transplantation with CDCD reconstruction
2 months prior, presents with fever, chills, malaise, and right
upper quadrant abdominal pain. The patient has jaundice,
leukocytosis, elevated total bilirubin, and mildly elevated
transaminases (aspartate aminotransferase 50 U/L, alanine
aminotransferase 65 U/L).
13.1 What is the next appropriate diagnostic tool?
a. CT scan
b. ERC
c. ultrasound
d. a or c
e. a, b, or c
13.2 Further investigations reveal an anastomotic stricture. What is
the most appropriate initial treatment option?
a. balloon dilation and biliary stent or drainage tube placement
b. immediate operative revision
c. supportive care and antibiotics
d. a and c
e. all
13.3 A balloon dilation is performed and a biliary stent placed
across the anastomosis. The patient’s fever and leukocytosis
resolve and his total bilirubin returns to normal. What is the
appropriate management strategy for the biliary stent?
a. remove the stent prior to discharge from the hospital
b. repeat ERC at follow-up and if stricture resolves, remove the
biliary stent
c. leave the stent in place indefinitely

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CHAPTER 19
Primary sclerosing cholangitis
Robert Enns
19
OBJECTIVES
• By providing an understanding of the pathophysiology of primary sclerosing cholangitis (PSC), the progression of disease
and eventual outcomes become logical
• To present the various options of therapy
—
their advantages, limitations, complications, and clinical outcomes
• To provide a thorough understanding of the trials that have been performed in PSC, their limitations and where further
study is required
Primary sclerosing cholangitis (PSC) is a chronic, cholestatic

liver disease of unknown etiology, characterized by infl am-
mation, destruction, and eventual fibrosis of intrahepatic
and extrahepatic bile ducts.
Focal strictures of the biliary tree lead to cholestasis and a
characteristic beaded appearance on cholangiography [1–4].
The disease may progress silently, or with recurrent episodes
of cholangitis characterized by right upper quadrant pain,
fever, and jaundice. Insidious, but continuous, progression to
cirrhosis with concomitant portal hypertension and liver
failure is typical [5–7]. PSC is much less common than alco-
holic liver disease; nonetheless, because it often affects oth-
erwise healthy young people, it is the fourth most common
indication for liver transplantation in the United States
[5,8].
Although Delbet first described the syndrome of PSC in
1924, the disease was considered a rare medical curiosity
with fewer than 100 cases reported up until 1970 [9,10]. With
the advent improved imaging techniques, particularly endo-
scopic retrograde cholangiography (ERC) in 1974, the num-
bers of cases diagnosed in most major centers increased.
Subsequent reviews from the Mayo Clinic and Royal Free
Hospital in London spurred further interest in the disease as
it was quickly realized that the disorder had an association
with infl ammatory bowel disease (IBD), more often affect-
ing young males with ulcerative colitis [4,11].
The epidemiology of PSC in regards to the incidence and
prevalence of disease in North America was not known until
recently. There are no studies involving whole or multiple
different states; however, there are at least some regional
studies that characterize the epidemiological characteristics

of this disorder. A study in Rochester, Minnesota using a
medical records linkage system in Olmsted County, Minne-
306
sota has resulted in the soundest, objective data in this re-
gard. Between the years 1976 and 2000 the incidence of PSC
in men (1.25/100,000 person-years) was twice that of women
(0.54/100,000 person-years). The prevalence of PSC, during
the same time period, was three times greater in men
(20.9/100,000 versus 6.3/100,000) than women. The same
study confirmed the findings that 73% of cases have IBD,
most of them ulcerative colitis [12].
One of the reasons why the prevalence of this disease ap-
pears to be increasing is that the availability of diagnostic
tests has increased. Many patients may simply have mildly
increased liver enzymes and through thorough investiga-
tions be found to have PSC. The widespread implementation
of ERCP and MRCP has likely led to a greater number of pa-
tients being diagnosed at an earlier stage of the disease, which
has also contributed to an improved understanding of the
disorder’s classifi cation, pathogenesis, natural history and
the clinical, radiographic, and therapeutic modalities deemed
appropriate.
Classification
The early classifi cations of PSC were very rigid and excluded
patients with gallstones, previous biliary tract surgery, in-
fl ammatory bowel disease, and retroperitoneal fibrosis. Ad-
ditionally, progression of disease over a 2-year time period
was mandatory prior to the diagnosis [13]. These strict crite-
ria seem unjustified and present classifi cation schemes
divide sclerosing cholangitis into primary (of unknown

etiology) and secondary (with a known or suspected under-
lying cause). Present criteria for the diagnosis of PSC are
shown in Table 19.1 [7]. Since the majority of patients with
PSC have IBD, patients can be further classifi ed as those with
Diseases of the Gallbladder and Bile Ducts: Diagnosis and Treatment, Second Edition
Edited By Pierre-Alain Clavien, John Baillie
Copyright © 2006 by Blackwell Publishing Ltd
Chapter 19: Primary sclerosing cholangitis 307
associated infl ammatory bowel disease and those without
[14].
The most common secondary causes of sclerosing cholan-
gitis include ischemia (arising from operative trauma, hep-
atic arterial infusion of floxuridine, allograft rejection),
recurrent biliary sepsis, multifocal cholangiocarcinoma,
AIDS, and toxic agents (formaldehyde, absolute alcohol)
[15–24]. Radiographically, secondary causes of sclerosing
cholangitis simulate PSC but the clinical course and thera-
peutic options may differ considerably.
There are several other classifi cation schemes that are ac-
cepted and used by various interest groups. Caroli and Rosner
developed an anatomical classifi cation in which the condi-
tion is divided according to whether involvement of the bili-
ary tree is diffuse or segmental [25]. Segmental involvement
could further be divided into disease that affects the hepatic
duct junction, the common hepatic duct, or the common bile
duct. Another classifi cation (Table 19.2), devised by Long-
mire [26,27], is based on the disease’s clinical course as well
as the operative, radiological, and pathological findings in 37
patients at the UCLA Medical Center. Four distinct groups
were identified, of which the most common were diffuse PSC

associated with IBD (Type 3) or without IBD (Type 4). PSC
can also be classified according to other cholangiographic
fi ndings (Table 19.3), which have been reported to predict
clinical outcomes [28].
Typically, liver biopsy reveals only a paucity of normal bile
ducts with nonspecific fibrosis and infl ammation of the por-
tal tracts [5,11,29]. The classic onion-skin lesions (Fig. 19.1)
are rarely seen on percutaneous biopsy of the liver; therefore,
the diagnosis has usually been made through cholangiogra-
phy. At least some investigators have suggested that a liver
biopsy rarely adds information that changes the clinical
management of the patient [30]. Histologically, PSC tends to
gradually progress through four reasonably well-character-
ized stages [4,31]. Stage 1 is the earliest, characterized by
degeneration of epithelial cells in the bile duct and an
infl ammatory infiltrate localized to the portal triads. In stage
2, fibrosis and infl ammation infiltrate the hepatic parenchy-
ma with subsequent destruction of periportal hepatocytes
resu lt i ng i n p ieceme a l nec r o s i s a nd lo s s of b i le duc ts . I n s t age
3, cholestasis becomes more prominent and portal-to-portal
fibrotic septa are characteristic. In stage 4, frank cirrhosis
develops, with histological features similar to other causes of
cirrhosis. In some patients, the findings of large duct obstruc-
tion with proliferation and dilatation of interlobular bile
ducts may dominate the histological picture.
PSC has been noted to be associated with a host of other
disorders (Table 19.4). The most common association is with
infl ammatory bowel disease, which affects up to 75% of pa-
tients with PSC. Of these patients, over 80% have ulcerative
colitis (UC) and less than 20% have Crohn’s disease. Con-

versely, on ly 2 .5 to 7.5% of pat ients w ith UC have or will de-
velop PSC [2–4,29,32–34]. The true prevalence is likely much
higher, but because many patients with UC are asymptomatic
Table 19.1 Criteria for the diagnosis of primary sclerosing cholangitis.
Source: Porayko et al. [7].
1. Presence of typical cholangiographic abnormalities of PSC (involving
bile ducts segmentally or extensively)
2. Compatible clinical, biochemical, and hepatic histologic findings
(recognizing that they are nonspecific)
3. Exclude the following in most instances
a. Biliary calculi (unless related to stasis)
b. Biliary tract surgery (other than simple cholecystectomy)
c. Congenital abnormalities of the biliary tract
d. AIDS-associated cholangiopathy
e. Ischemic strictures
f. Bile duct neoplasms (unless PSC previously established)
g. Exposure to irritant chemicals (fl oxuridine, formalin)
h. Evidence of another type of liver disease, such as primary biliary
cirrhosis or chonic active hepatitis
Table 19.2 Longmire’s classification of primary sclerosing cholangitis.
Source: Longmire [26,27].
Type Frequency Clinical/radiological features
(%)
1 5–10 Affecting primarily distal common bile duct
2 5–10 Occurring soon after attack of acute necrotizing
cholangitis
3 40–50 Chronic diffuse
4 40–50 Chronic diffuse associated with inflammatory
bowel disease
Table 19.3 Classification of cholangiographic findings in primary

sclerosing cholangitis. Source: Majoie [28].
Type of duct/ Cholangiographic appearance
classification
Intrahepatic
I Multiple strictures, normal caliber of bile ducts
II Multiple strictures, saccular dilations, decreased
arborization
III Only central branches filled, severe pruning
Extrahepatic
I Slight irregularity of duct contour, no stricture
II Segmental stricture
III Stricture of almost the entire length of the duct
IV Extremely irregular margin, diverticulum
outpouchings
308 Section 3: Specific conditions
and show only minimal elevation in liver enzymes, cholan-
giography is not performed and they may remain undiag-
nosed. This may not be an inappropriate practice since early
intervention in the disorder has not been demonstrated to
improve clinical outcomes.
In a recent study from Sweden, the prevalence of UC was
170 /100,00 0 ; of these, 3.7% had PSC . Th is y ield s prevalence
for PSC of 6.3 per 100,000 inhabitants [35]. This is similar, al-
though not as robust, as the data found in Olmsted County in
the United States [12]. A subsequent Swedish study demon-
strated that 72% of PSC patients had UC, yielding a total
prevalence for PSC of 8 per 100,000 inhabitants [36]. In con-
trast to these fi gures are data from Japan, where only 18% of
patients with PSC have IBD [37]. Many other disorders, par-
ticularly infl ammatory disorders, show an association with

PSC.Theseinclude hypereosinophilic syndrome [21,38–40],
Sjögren’s syndrome [41], systemic sclerosis [21,42], celiac
disease [21,43,44], pancreatitis [45,46], Behçet’s syndrome
[47], histiocytosis X, sarcoidosis [48–50], sicca complex [51],
rheumatoid arthritis [52], systemic mastocytosis [53],
histiocytosis X [54,55], and Reidel’s thyroiditis [56,57].
Figure 19.1 Concentric peribiliary fibrosis and inflammation characteristic of early bile duct damage is typical of primary sclerosing cholangitis. It is
not usually seen on liver biopsy specimens because it is has a “patchy” distribution with the highest concentration occurring in the hilum (from where
biopsies are not usually obtained).
Table 19.4 Disease associations with primary sclerosing cholangitis.
Inflammatory bowel disease
Pancreatitis
Diabetes mellitus
Retroperitoneal fibrosis
Sarcoid
Histiocytosis X
Hypereosinophilic syndrome
Sjögren’s syndrome
Reidel’s thyroiditis
Sicca complex
Celiac disease
Rheumatoid arthritis
Chapter 19: Primary sclerosing cholangitis 309
All methods of classifi cation attempt to organize the dis-
ease process in the hope of determining which subtypes
(particularly predominant common bile duct strictures)
may be amenable to radiological, endoscopic, and surgical
intervention, in contrast with diffuse disease, which may be
amenable only to liver transplantation. Classifi cation, par-
ticularly histological, also allows prognostication, which

may help identify future transplantation requirements in a
timely manner.
Etiology
Although the etiology of PSC is unknown, several mecha-
nisms related to immunological, genetic, toxic, and infec-
tious abnormalities have been proposed as contributing
factors (Table 19.5).
Given the close association of PSC with ulcerative colitis,
early investigators postulated that recurrent portal bactere-
mia might be an important factor in the development of the
disorder. Recurrent portal infection could lead to chronic bil-
iary tract infection, infl ammation, and subsequent fibrosis
and classical stricture formation [58]. One study even found
that portal bacteremia was present in patients who had co-
lonic surgery [59]. Subsequent studies, however, could not
confirm the findings of portal vein phlebitis [31,58]. Fur-
thermore, if recurrent colitis leads to portal vein phlebitis,
colectomy (or at least controlled colonic disease) should have
a protective effect. This has not been demonstrated to be true
[60]. Additionally, hepatic histology does not support portal
venous infection since the hallmark of this disorder, portal
phlebitis, is mild or absent in most patients with PSC [31].
Thus, there is little evidence to support the colonic-bacterial
infection hypothesis.
If portal bacteremia from a colonic source is not a critical
factor, then toxins that might be released from a diseased
colon could be suspect. Theoretically, toxic bile acids such as
lithocholic acid, which arise from bacterial activity within
the colon, can be absorbed through a diseased colon with its
increased mucosal permeability [61]. Lithocholic acid is

formed from chenodeoxycholic acid by bacterial 7-α-
dehydroxylation in the colon, and it has even been shown to
be hepatotoxic in animals. Unfortunately, abnormalities in
bile acid metabolism in PSC or UC patients have not been
demonstrated. Furthermore, in human tissue, lithocholic
acid is rapidly sulfated and rendered nontoxic, a process
which does not occur in animal models [62,63].
Other toxic substances that have been considered more re-
cently are N-formylated chemotactic peptides, produced by
enteric flora, which have been shown in animal studies to in-
duce fibrosis and damage to major bile ducts through colonic
absorption and enterohepatic circulation. Increased biliary
excretion of these peptides has been shown in experimen-
tally induced colitis in animal models [64,65]. Further inves-
tigation to delineate the role of these peptides in the etiology
of PSC is required.
The major criticism of the theories of colonic toxins caus-
ing PSC comes from studies looking at the natural history of
the disorder. It has been demonstrated that the severity of the
colitis bears little relation to the development or severity of
PSC [32]. Furthermore, patients who have a colectomy show
no change in their PSC natural history. Some patients devel-
op PSC years after a colectomy or even prior to the onset of
their colitis [60]. Some patients who develop PSC never even
have infl ammatory bowel disease. Antibiotics (which could,
theoretically, alter the colonic flora) appear to have little
effect on the natural history of PSC [66]. Because of these
findings, colonic toxins are likely to play only a minor role, if
any, in the overall etiology of PSC.
The association of appendectomy with IBD is an interest-

ing one. Appendectomy has been demonstrated to have some
interesting associations with UC and UC-associated PSC. In a
case–control study in Australia, patients with PSC/UC, PSC
alone, and UC were matched to controls in regards to the
effects of appendectomy and smoking, and PSC in regards to
disease onset, severity, and extent. Appendectomy rates in
PSC patients were no different from controls; however, the
appendectomy rates in those with UC were four times less
than controls, suggesting a protective effect of appendectomy
in this patient population. Additionally, those patients with
appendectomy in both PSC and UC groups resulted in a 5-
year delay in onset of either intestinal or biliary symptoms.
The factors responsible for this are not understood; however,
infectious or toxic etiologies have again been hypothesized
[67].
Abnormalities of copper metabolism have also been impli-
cated in the pathogenesis of PSC. Several authors have noted
that liver samples from patients with PSC show an excess of
hepatic copper, which is known to be hepatotoxic [27,68].
However,unlike other disorders with excessive copper depo-
sition, treatment with chelating agents (penicillamine), has
not been shown to have any benefit [69]. Likely, as with
many cholestatic disorders, copper accumulation is the result
of poor biliary excretion, rather than a primary inciting event
critical to the pathogenesis of the disorder [70].
Table 19.5 Possible etiologies of primary sclerosing cholangitis.
Genetic predisposition
Autoimmune
Portal infection (bacteremia)
Viral infection

Colonic toxins
Copper toxicity
Ischemic injury
310 Section 3: Specific conditions
Chronic infection of the biliary tree has been implicated in
the pathogenesis of PSC through several observations. Long-
mire, who noted that some patients appear to develop PSC
after an initial episode of acute necrotizing cholangitis, clas-
sified this group as a separate category (type 2) of PSC [26,27].
Patients with acquired immunodeficiency syndrome (AIDS)
have been noted to have a s c lero s i ng chola ng i t i s t hat i s felt to
be caused by opportunistic infection (i.e. cytomegalovirus,
cryptosporidium). Unfortunately,an extensive investigation
of 37 PSC patients showed evidence of cytomegalovirus
(polymerase chain reaction (PCR) testing of liver tissue) in
only one patient [71]. Although reversibility of sclerosing
disease in an infectious environment has been demonstrated
in immunocompromised patients who have the underly-
ing infection treated [72,73], this has not been demonstrated
in normal hosts who have a fully functional immune
system.
Perhaps the infectious organism is difficult to find. Experi-
mental cholangitis and biliary atresia can be induced in ani-
mal models through infection with Reovirus type 3. Early
reports suggested that patients with PSC had a signifi cant in-
crease in antibody titers to this virus compared to controls.
M o r e r e ce n t d a t a , howe v e r , show n o d i f f e ren c e i n p r eva le n c e
or titers of Reovirus between controls and PSC patients [74].
Rubella can also cause an obliterative cholangitis of the in-
trahepatic ducts in the fetus, although the histological pic-

ture differs from that of PSC [75]. Despite these negative
studies, an infectious etiological agent that alters antigenic
determinants has yet to be excluded in PSC.
Prompted by the observation of familial aggregates of
PSC, genetic predisposition has been increasingly reported
[76,77]. Several human leukocyte antigens (HLA) mole-
cules, including HLA-B8, HLA-DR2, HLA-DR3, and HLA-
DRw52 A h ave b e e n fou nd to be ass o c ia ted w it h P SC [ 78 ,79 ] .
Interestingly, HLA-B8 and HLA-DR3 are also known to be
associated with other autoimmune diseases, which (as noted
below) may play an etiological role in PSC. The DRB3*0101
allele, which encodes HLA-DRw52A, has also been most
strongly associated with PSC; it is present in 55% of PSC pa-
tients compared to 22% of control subjects. Unfortunately,
the finding of HLA-DRw52A in 100% of Caucasian North
Americans has not been substantiated in European studies
[80–84]. Therefore, conflicting data still exist and further re-
search is required to identify possible genetic contributions to
the etiology of PSC.
There is a novel model of PSC in mice using multi-drug-
resistance gene (Mdr2) (Abcb4) knockout mice (Mdr2(−/−))
which may have application when it comes to the etiology of
disease in PSC [85]. Bile ducts of these mice showed disrupt-
ed tight junctions and basement membranes with subsequent
bile acid leakage into portal tracts and subsequent induction
of a portal infl ammatory infiltrate. Activation of proinfl am-
matory and profibrogenic cytokines occurs, leading to the
characteristic periductal fibrosis. Sclerosing cholangitis in
Mdr2(−/−) mice, therefore, is from a “leaky duct” permeabil-
ity issue that results in periductal fibrosis and finally oblitera-

tive cholangitis [85].
A second novel, organ-specific model, in rats, in which
PSC is induced by intrabiliary administration of 2,4,6-
trinitrobenzenesulfonic acid (TNBS) has some signifi cant
similarities to human PSC [86]. Unfortunately, when mild
stenosis of t he c om mon bi le duc t wa s ach ie ved by s ubtot a l l i-
gation and cholangitis induced by TNBS injection no evi-
dence of cholangitis, assessed by serum chemistry, histology,
or retrograde cholangiography of TNBS-treated rats, oc-
curred during long-term follow-up of the rats. Although an-
tineutrophil cytoplasmic antibodies were positive in 75% of
animals, they were not predictive of liver damage. The au-
thors concluded that a single, initial insult is not sufficient to
trigger chronic progressive infl ammation and that other fac-
tors must be employed to replicate the human disease.
Ischemic arteriolar injury, as can occur with patients who
receive intra-arterial infusions of floxuridine, can result in
diffuse and focal strictures of the intra- and extrahepatic bile
ducts similar to PSC, secondary to obliterative thromboen-
darteritis [87]. Similar findings can be found in polyarteritis
nodosa and in those with hepatic artery thrombosis after
liver transplantation [88,89]. Although ischemia can cause a
biliary disorder typical of PSC, no specific vascular pathology
is found in most patients with PSC [90].
Histiocytosis X has been shown in several patients to be as-
sociated with PSC. In three patients reported by Thompson et
al., both disorders were demonstrated by pathological evalu-
ations to occur in the same patient. The authors suggested
that, since the natural history of histiocytosis X is to progress
from a proliferative to a fibrous stage, it is a cause of PSC and

the two disorders may have a similar pathogenesis.
Despite the absence of antimitochondrial, smooth muscle,
and nuclear antibodies, accumulating evidence suggests that
immune system abnormalities may contribute to the patho-
genesis of PSC. The disorder is immune-mediated as opposed
to being a classical autoimmune disease. There are a number
of immune abnormalities in PSC, including a range of auto-
antibodies, portal tract infiltration of T cells, and aberrant
expression of HLA molecules on biliary epithelial cells [91].
Initial support for an immune etiology arose from observa-
tions that the disorder occurred in concert with other
autoimmune diseases, such as ulcerative colitis, Reidel’s
thyroiditis, rheumatoid arthritis, and sicca complex. The as-
sociation of PSC with HLA-B8 and HLA-DR3, which are typi-
cally linked with autoimmune disorders, also supports an
autoimmune pathogenesis. Autoantibodies interacting with
nuclei of cells infiltrating the portal tract have been charac-
terized by Chapman et al. [1,83,92,93]. They have described
anticolon and antiportal tract antibodies, of which the latter
is more commonly associated with HLA-B8 and, therefore,
more specific for patients with PSC. The antigen in obstruct-
ed portal ducts was localized to the nuclei of neutrophils and
Chapter 19: Primary sclerosing cholangitis 311
since the reactivity of the antibody was primarily perinucle-
ar, the antibody was called pANCA. This antibody has been
reported in up to 83% of patients with ulcerative colitis and
27% of those with Crohn’s disease. The same pattern has
been demonstrated in up to 88% of patients with chronic ul-
cerative colitis and PSC [94,95]. The etiological role of pANCA
is unclear, but presumably a shared, aberrantly expressed

antigenic determinant exists between the biliary tree and
the colon that underlies the pathogenesis of the colitis and
sclerosis [54].
Further support for an immunological pathogenesis of PSC
comes from abnormalities noted in both immune complexes
and cellular immunity. Most patients with PSC show in-
creased levels of circulating immune complexes, likely re-
fl ecting activation of complement through the classic pathway
in the serum [96,97]. Abnormalities of cellular immunity
have also been observed in patients with PSC. In particular,
increased expression of intercellular adhesion molecule-1
(ICAM-1) on biliary epithelium has been noted. ICAM-1
may allow activated T cells to interact with major histocom-
patibility complex antigens expressed on biliary epithelium,
subsequently leading to infl ammation and fibrosis. In PSC
there is an increase in activated T lymphocytes of CD3++HLA
DR+ phenotype as compared to healthy subjects (7.9 versus
2.7%, p < 0.01) and also NK cells (12.6 versus 10.3%, respec-
tively, p < 0.05) that would support this theory of immune
and genetic interplay in the pathogenesis of the disorder [98].
An increased CD4/CD8 ratio within the biliary tree has been
noted and this increased proportion of CD8 cells has been
found specifi cally in areas of bile duct proliferation, further
supporting an immune role for PSC [99–101].
Intercellular adhesion molecule-1 (ICAM-1, CD54) gene
polymorphisms have been demonstrated to increase suscep-
tibility to IBD and PSC. ICAM-1 is expressed on proliferating
bile ducts and interlobular bile ducts and when analyzed in
patients for PSC, the E469E homozygote status for ICAM-1 is
associated with protection against PSC [102]. Along a similar

vein, the recent finding that MadCAM-1 and CCL25 are up-
regulated within the liver and not just restricted to the gas-
trointestinal tract helps explain why patients may develop
PSC many years after a colectomy. In theory, memory lym-
phocytes may be present in the liver for many years and re-
quire activation by some, as yet unknown, antigen, resulting
in up-regulation of the “homing receptors” that activate the
infl ammatory cascade [103].
Clinical manifestations
PSC predominantly affects males, with a median onset of 40
years of age but a wide range of 1 to 90 years [4]. Pediatric
cases show an increased association with immunodeficiency
states (10%) and histiocytosis X (15%), and a lesser associa-
tion with infl ammatory bowel disease (47%) [104–106]. The
male predominance occurs primarily in patients with both
PSC and ulcerative colitis. In patients with appendectomy,
UC appears to be increased; however, in contrast, appendec-
tomy does not seem to be associated with higher PSC rates.
PSC is essentially a disease of nonsmokers (decreased risk)
whereas ulcerative colitis has an increased risk in smokers
[107]. Additionally, the colitis in PSC tends to be milder, for
unknown reasons [67]. PSC has been reported in all races
[29]. The disorder tends to develop insidiously, with symp-
toms present in one study for a mean of 52 months (range 0–
451 months) prior to diagnosis [36]. Symptoms of PSC are
often nonspecific initially, but jaundice, right upper quad-
rant pain, pruritis, fever, weight loss, and fatigue subse-
quently develop (Table 19.6). Atypical presentations of fever
of unknown origin or acute supportive cholangitis have been
reported. Periodic exacerbations and remissions are typical

of the disorder. Exacerbations may be precipitated by gall-
stones, which form in a strictured biliary tree where normal
flow is impeded [108,109]. Depending on the location of the
stones and the strictures, endoscopic or percutaneous treat-
ment can be useful in removing a nidus of recurrent infec-
tion. Unfortunately, many strictures and stones develop in
the proximal biliary tree, which may be less amenable to
mechanical intervention.
An association with other autoimmune disorders has been
noted in patients with PSC. More recently, an association
with celiac disease has also been documented [110,111].
With the increased awareness of PSC, availability of ERCP,
and use of laboratory screening, more patients who have as-
ymptomatic elevations in liver enzymes are being diagnosed
with this disorder, particularly if they have underlying ulcer-
ative colitis. In particular, asymptomatic elevations of alka-
line phosphatase in the setting of chronic ulcerative colitis
should raise the suspicion of sclerosing cholangitis and trig-
ger further investigation. Early in the course of PSC, the
physical examination is normal. As the disease progresses,
physical stigmata of chronic liver disease (spider angioma,
jaundice, palmar erythema) and hepatosplenomegaly may
Table 19.6 Clinical presentation of primary sclerosing cholangitis.
Source: Ludwig et al. [31].
Symptom Percent of presentation
Jaundice 75–80
Right upper quadrant pain 50–55
Pruritus 30–35
Fever 20–25
Weight loss 15–20

Fatigue 10–15
Asymptomatic 5–10
312 Section 3: Specific conditions
become apparent, as well as the development of portal hyper-
tension, resulting in ascites and varices.
Laboratory evaluations
Elevation of cholestatic liver enzymes is typical of this dis-
ease. Up to 98% of patients will have an increase in the alka-
l i ne phosph ata se level, a lt hough nor ma l a l ka li ne phos phat ase
levels have occasionally been recorded, even in symptomatic
patients [112]. Most often, the serum alkaline phosphatase is
at least twice the upper limit of normal, out of proportion to
that of the serum bilirubin. Serum bilirubin levels are also
variable (especially early in the course of the disease) but in-
evitably, as the disease progresses, elevations occur in con-
junction with a gradual decline in serum albumin. Caution
must be used in interpreting isolated findings of low albumin
as a negative prognostic factor in PSC, as it may also be de-
creased by active infl ammatory bowel disease in many pa-
tients [5]. Transient worsening of serum transaminases and
bilirubin often occurs during exacerbations of the disease.
These will often return to near normal when the episode of
fever, chills, or right upper quadrant pain has resolved.
Serum antinuclear, antismooth muscle, and antimito-
chondrial antibodies are negative in over 90% of patients
[11,52]. One exception may be an uncommon variant of PSC
termed “small duct PSC” (where cholangiography is normal),
in which there may be an overlap with autoimmune hepatitis
[113,114]. In this disorder, which accounts for only 5% of
PSC patients, autoimmune markers may be positive.

In patients with clearly defined autoimmune hepatitis,
there is also a clear overlap with those with PSC and some of
these patients have been characterized. In patients with di-
agnosed autoimmune hepatitis, overlap syndrome with PSC
should be suspected if patients are male, of young age (<35
years), present with cholestasis, have negative antinuclear
antibodies, and have a suboptimal response to immune sup-
pression [115].
Hypergammaglobulinemia is found in about 30% of pa-
tients and increased IgM levels in 40 to 50% [4,52]. Approxi-
mately 65% of patients will have a positive pANCA with
HLA-DRw52a (DRB3*0101 allele). pANCA is reported to be
higher in patients who have both PSC and UC (68 to 83%)
than in patients with PSC and Crohn’s disease (13 to 27%).
Similar to Wilson’s disease and primary biliary cirrhosis,
hepatic and urinary copper levels are elevated in PSC [68].
The levels appear to correlate with the histological stage of
the disorder, thereby providing prognostic information.
Serum copper and ceruloplasmin levels are also elevated in
49 and 71% of patients, respectively [27,69,70].
Natural history
PSC is a progressive disorder with a variable rate of progres-
sion. Progression to cirrhosis has occurred as quickly as 8
months, yet other patients have been symptom free after
more than 21 years [81]. The variability in the progression of
the disorder has led to the development of staging systems to
provide prognostic information to patients and to allow
ample time for arrangements for those who are suitable for
liver transplantation. Three large, retrospective series have
confirmed a median survival (or time to transplantation) of

12 years from the time of diagnosis [2,36,116]. The increased
use of laboratory screening of patients with IBD for PSC (with
liver enzymes) and increased availability of ERCP likely will
lead to detection of the disease at an earlier stage and thus the
duration of survival may statistically increase.
A subgroup of patients who had no symptoms at the time of
diagnosis has also been evaluated. Forty-fi ve patients with
no hepatic-related symptoms were followed by the Mayo
Clinic for a mean of 6.25 years. Interestingly, 76% demon-
strated progression of their liver disease and 31% developed
hepatic failure [6]. Other studies have found PSC to be more
benign; a Norwegian study showed a mean survival of 17
years after initial diagnosis [117,118]. Although some of the
data conflict, it is clear that for most patients, PSC is a progres-
sive disorder that within 10 years will signifi cantly affect
their health and, eventually, will lead to hepatic failure and
death or require liver transplantation.
Cox multivariate regression analyses have been performed
to determine which factors are important in predicting the
prognosis for individual patients with PSC. In a Swedish se-
ries of 305 patients, age at diagnosis, histological stage, and
serum bilirubin were applied as individual variables to ob-
tain a prognostic index [36]. Another regression analysis was
performed by the Mayo Clinic: in this analysis, 21 prognostic
variables were analyzed individually (in 174 patients with
PSC) as predictors in a univariate Cox regression analysis [2].
Of these, five variables were determined to be important pre-
dictors of survival: age, bilirubin, hemoglobin, presence or
absence of IBD, and hepatic histological stage.
In a third retrospective analysis, a multicenter study

evaluated 426 patients with PSC and identified four
variables
—
bilirubin, histological stage, age, and splenomeg-
aly
—
as independent variables of prognosis [116,119]. A rela-
tively cumbersome mathematical model to predict survival
(relative risk) included these variables:
R = (0.535 × log bilirubin in mg/dL)
+ (0.486 × histological stage) + (0.041 × age in years)
+ 0.705 (if spenomegaly was present)
The survival for 1 and 5 years for low-risk patients (R = 2.35 −
2.46) was 0.98 to 0.92. The 1 and 5-year survival for high-risk
patients (5.23–5.42) was 0.68 to 0.73 and 0.15 to 0.21
respectively.
Modifi cations of this formula have also been devised for
liver transplantation and shown to be accurate in studies by
Kim et al. [120]. In this abstract, a modified Mayo score was
devised using the formula:
Chapter 19: Primary sclerosing cholangitis 313
Risk = 0.0295 × age in years + 0.5373 × log bilirubin in
mg/dL − 0.8389 × albumen + 0.5380 × log aspartate
transaminase (IU/L) + 1.2426 × variceal bleeding
Although somewhat cumbersome, this formula proved par-
ticularly important in assessing patients for liver transplan-
tation, as those with low Mayo scores (<4.4) tended to have
signifi cantly improved survival following liver transplanta-
tion than those with higher scores (>5.3). Furthermore,
these same prognostic formulations have also been used to

demonstrate that liver transplantation improves overall sur-
vival (when compared to predicted survival through the
models) [120].
Recently, a comparison between the Mayo Clinic model
and age-adjusted Child–Pugh classifi cation has also been
performed. This demonstrated that the age-adjusted Child–
Pugh score does provide similar accuracy to the Mayo Clinic
model. Since it involves less statistical manipulation, it may
be easier to use and may help minimize listing criteria for
liver transplantation listing selection [121].
With the different prognostic models available it has be-
come clear that other methods for assessing these patients
may be beneficial. Genetic assessment has recently been en-
couraging in this area. In an evaluation of 265 PSC patients
from five European countries, HLA associations were stud-
ied. Although the data were not convincing, statistically sig-
nifi cant findings were obtained. The primary endpoints for
the study included death (n = 38) or liver transplantation (n =
52). The DR3,DQ2 heterozygous genotype was associated
with an increased risk of death or liver transplantation
(hazard ratio = 1.63; 95% CI 1.06–2.52). The presence of a
DQ6 encoding haplotype (DQB1*0603 or DQB1*0602) in
DR3,DQ2 negative individuals resulted in a reduced risk of
death or liver transplantation (hazard ratio = 0.57; 95% CI =
0.36 − 0.88) [122].
Although prognostic models are important and generally
help predict the prognosis for individual patients, it is impor-
tant to recognize that some patients have specific strictures
(particularly hilar) that are difficult to drain adequately
using percutaneous, radiological, or surgical methods. Usu-

ally their serological laboratory markers elevate them to a
high-risk category. Some of these patients may have low-
grade histology with no evidence of jaundice but, instead,
have increasing episodes of sepsis. These patients may be ide-
ally suited for transplantation despite the fact that their Mayo
risk score or Child–Pugh score is not markedly elevated.
Therefore, despite the use of a very good predictive system,
each candidate for transplantation must still be assessed on
an individual basis.
Diagnosis
Because histological findings are not diagnostic in the major-
ity of PSC patients, the gold standard for diagnosis is cholan-
giography. In the early 1970s, operative cholangiography
was the primary diagnostic modality; however, between
1974 and 2000, ERC or percutaneous transhepatic cholangi-
ography (PTC) have been the preferred methods. Since PTC
may be difficult to perform in a nondilated biliary system,
with particular difficulty in opacifying small biliary radicals,
ERC has been the gold standard for diagnosis. Typically, this
is performed on a patient with known infl ammatory bowel
disease and cholestatic enzyme elevation (particularly of al-
kaline phosphatase) (Figs 19.2 and 19.3). Usually, the patient
has had an abdominal ultrasound, which occasionally dem-
onstrates areas of focal biliary dilation.
An ERC in patients with PSC is not without risk; a compli-
cation rate of up to 14% has been documented [123]. In par-
ticular, cholangitis can occur, presumably because focal
areas of the biliary tree are poorly drained, resulting in bili-
ary stasis. Since an ERC catheter is not sterile, infection of the
biliary tree following an ERC is not uncommon. To decrease

this risk, all patients with suspected PSC should receive
broad-spectrum antibiotics prior to the procedure. Those
who have been demonstrated at ERC to have PSC should re-
ceive several days of antibiotics postprocedure. Since most
ERCs are done as daycare procedures, an oral antibiotic is
preferable, although parenteral antibiotics can easily be ad-
ministered prior to the procedure. Ciprofloxacin is effective
against most of the typical biliary pathogens (Gram-negative
Figure 19.2 Typical intrahepatic strictures in a patient with elevated
liver enzymes and known ulcerative colitis.
314 Section 3: Specific conditions
bacilli), is well absorbed, and achieves high levels within the
biliary tree, so is likely the oral antibiotic of choice. A combi-
nation of ampicillin and an aminoglycoside or a third-
generation cephalosporin can be used if intravenous
antibiotics are required.
ERC demonstrates diffuse disease in the majority of PSC
patients, with only rare patients having disease limited to the
intra- or extrahepatic ducts. Only 1 out of 86 patients re-
ported by MacCarty et al. at the Mayo Clinic had disease lim-
ited to the intrahepatic ducts [124]. Lee et al. noted that only
11% of 100 patients with PSC had involvement limited to the
intrahepatic ducts and only 2% limited to the extrahepatic
ducts [5]. In 20% of patients, however, disease is limited to
the intrahepaticand proximal biliary tree, typically not ame-
nable to endoscopic intervention. Diverticular outpouchings
of the common bile duct, once considered diagnostic of the
disorder, are seen in 25% of patients with PSC [124]. In a
more recent report by Cameron et al., 24/36 patients with
PSC had extensive involvement of the bifurcation making

endoscopic treatment more challenging as well as creating
considerable confusion regarding the possibility of cholan-
giocarcinoma [125].
A small proportion of patients with IBD have biochemical
and histological findings consistent with PSC but no evidence
of typical radiologic abnormalities. This entity, previously
known as pericholangitis, is more accurately described as
“small-duct PSC” and comprises fewer than 5% of PSC cases
overall [113]. These patients likely have a more favorable
long-term prognosis in terms of survival with low rates of
progression to large duct PSC [126]. PSC has also been de-
scribed as an “overlap” syndrome with autoimmune hepati-
tis [115,127,128].
Pancreatograms have been noted to be abnormal in up to
10% of PSC patients. Stricturing or tapering of the pancreatic
duct was noted in 3/40 patients with PSC in the Mayo series
[124]. In a series of 20 PSC patients published by Muller et al.,
two patients had abnormalities of the choledochopancreatic
duct junction, which has been implicated in other biliary dis-
orders such as choledochcal cysts and biliary atresia. An un-
usual amount of pancreatic duct refl ux was noted in 43% of
patients and overall pancreatic duct abnormalities in up to
50% of patients [129].
To complicate the issue, the disorder of sclerosing pancre-
atitis (a specific entity) is associated with bile duct lesions and
has been termed sclerosing pancreatitis-associated scleros-
ing cholangitis. Histologically, the bile ducts in these cases
showed extensive and dense fibrosis with marked lympho-
plasmacytic infiltration, many eosinophils, and obliterative
phlebitis which occur less frequently in PSC. Immunohisto-

chemically, many IgG4-positive plasma cells are found in the
bile duct of the sclerosing pancreatitits patients, possibly al-
lowing separation of these cases from standard PSC patients
[130]. Additionally, the IgG4-positive patients with scleros-
ing pancreatitis may be responsive to steroid therapy result-
ing in a clear differentiation from those PSC patients
[131,132]. A mass lesion in the head of the pancreas that re-
solves with medical therapy has been considered a pancreatic
pseudotumor (a possible characteristic of autoimmune pan-
creatitis) by some and typically is associated with other ab-
normalities, including salivary gland fibrosis, fibromuscular
Figure 19.3 Intrahepatic ducts strictures occurring
in a young male with known acquired
immunodeficiency syndrome (AIDS). The
cholangiographic picture is similar to primary
sclerosing cholangitis (AIDS cholangiopathy).
Chapter 19: Primary sclerosing cholangitis 315
dysplasia, and retroperitoneal fibrosis. Pancreatic pseudotu-
mor with sclerosing pancreatocholangitis may be a manifes-
tation of a systemic disease characterized by nonmalignant
strictures and multifocal fibroinfl ammatory processes, un-
like classical PSC. The overlap or differentiation between
these disorders is difficult and requires further characteriza-
tion for clinical differentiation; however it appears clear that
there is a group of patients with mass-like lesions with pan-
creatic disease predominating that respond to corticosteroid
therapy [133].
Recently, the advent of magnetic resonance imaging (MRI)
has brought a noninvasive testing modality into the diagnos-
tic armamentarium of the gastroenterologist [134]. Several

studies have demonstrated the usefulness of magnetic reso-
nance cholangiograms (MRC) for evaluating the biliary tree
for stones, strictures, and other abnormalities [134–141].
Single-breath hold sequences with rapid scanning have im-
proved imaging and most strictures, particularly involving
the common bile duct and hilum, can be visualized. If dilata-
tion of the biliary tree is present, imaging sensitivity is im-
proved, but in those patients with a nondilated biliary tree,
diagnostic accuracy is still limited. For those with advanced
disease, dilated ducts, and stones, the sensitivity of MRC is
likely still high [142–147]. Unfortunately, many of these pa-
tients still require ERC for therapeutic intervention (stone
extraction and stricture dilation) as well as biliary tissue
sampling (i.e. cytology brushings) to exclude malignancy,
thereby negating some of the benefit of an MRC prior to ERC.
If MRC can accurately diagnose patients with mild disease
(who do not require therapeutic intervention and in whom
malignancy is not a concern) then it would become a very
useful diagnostic test. Unfortunately, patients with mild dis-
ease typically have diffuse mild intrahepatic duct strictur-
ing, which can be very difficult to diagnose with the present
MRC techniques. Attempts to stimulate the biliary tree to
enhance dilation of the ducts through the use of cholecysto-
kinin may improve the diagnostic sensitivity of MRC but fur-
ther studies are required to draw concrete conclusions. In
general, despite the limitations of MRC, since it is noninva-
sive without risk and may characterize the biliary tree well,
its use prior to ERCP should always be considered.
The issues of cost are important when comparing MRC and
ERC in the diagnosis of PSC. If the patient does not require a

therapeutic procedure (and the MRC has appropriate sensi-
tivity and specificity), because the complication rate of ERC is
clearly greater than that of MRC, the added expenditures to
treat these may result in increased cost for ERC. This has been
demonstrated in a cost-minimization study by Talwalker et
al. where MRC was clearly less costly (partially secondary to
increased costs related to the treatment of complications with
ERC). In this study, for an ERC to be an optimal initial test
strategy, a prevalence rate of PSC greater than 45%, MRC
specificity less than 85%, or reduction in the average cost per
diagnosis to US $538.30 would be required. Although this
may be true for “strict” diagnosis of the disease, since ERC has
other important benefits (i.e. obtaining brushings, thera-
peutic intervention) the two tests should likely be considered
complementary as opposed to competitive. For a diagnostic
study however, it would seem prudent to consider a noninva-
sive test prior to ERC [148].
Liver biopsies have been used to stage disease and exclude
coexisting liver disease, however their value is often limited
with specificity lacking. In a comparative study between PSC
patients with and without a biopsy, the biopsy did not appear
to affect management in 78/79 patients (one patient diag-
nosed with autoimmune hepatitis). Liver biopsies, therefore,
are not routinely recommended following a diagnostic chol-
angiogram [30].
Therapy
Although a variety of antifibrotic, anti-infl ammatory, and
immunosuppressive medications have been used to treat PSC
(Table 19.7), none of them has demonstrated effectiveness in
altering the natural history of the disease. Of critical impor-

tance is understanding a fundamental difference between
sclerotic biliary tract disorders and disorders of a hepatocel-
lular nature. Hepatocytes have a remarkable ability to regen-
erate, and, when the inciting agent (i.e. fulminant viral
hepatitis) is removed, treated, or spontaneously disappears,
patients can fully recover despite a major insult. On the other
hand, when patients with PSC (or other sclerotic biliary dis-
orders) scar their biliary tree, this results in a permanent loss
of function with limited ability for regeneration. Once the
serum bilirubin starts to rise, a seemingly irreversible, medi-
cally untreatable disorder is present and liver transplantation
is the only viable, long-term alternative. Ideally, medical
therapy should be directed at the underlying cause of PSC
(but this is unknown) and administered early in the course
of the disease when the patient is asymptomatic, which is not
always practical [5,149]. Medical therapy, even when insti-
tuted later, is difficult to evaluate since the disease has a slow
Table 19.7 Medical treatments evaluated in primary sclerosing
cholangitis.
Ursodeoxycholic acid (UDCA)
Methotrexate
Azathioprine
Cyclosporine
Corticosteroids
Colchicine
Cholestyramine
Antibiotics
316 Section 3: Specific conditions
progression with spontaneous fluctuations in severity. This
means that large, lengthy, multicenter, randomized, con-

trolled trials are required for accurate assessment of response
to therapy. These studies are difficult to perform since sham
controls would characteristically be used as a comparator
group.
Treatment of the disorder is therefore divided into medical
therapy for PSC, symptom control, complication therapy,
and monitoring for malignancy.
Since PSC is presumed to have an autoimmune etiology, it
wou ld be log ic al to ex pec t that steroids wou ld have a benefi -
cial effect. Only uncontrolled trials are available to assess the
effectiveness of corticosteroids. Sivak et al. treated 10 patients
with early PSC with prednisone without signifi cant bio-
chemical improvement [150]. Burgert et al. found conflict-
ing data, with some improvement in biochemical testing in
10 patients with documented PSC [151]. Although some of
these uncontrolled trials have suggested improvement in
biochemical parameters of PSC in those who took corticoste-
roids, there is little support for their routine use. PSC devel-
ops in some patients who have been exposed to, or are taking,
corticosteroids (for infl ammatory bowel disease), thereby
suggesting its lack of benefit. Furthermore, steroids enhance
osteoporosis, for which these patients are already at risk.
Lastly, in another, more recent, combined trial of prednisone
(10 mg daily) and colchicine (0.6 mg b.i.d.), when compared
to a historical control group, improvement in biochemical
tests results and alteration in the progression of the disease
could not be demonstrated [152]. For these reasons, cortico-
steroids,outsideofa clinical trial, cannot be recommended as
therapy for PSC. Their lack of benefit may be secondary to de-
creased glucocorticoid receptor expression found on hepatic

T lymphocytes that likely are responsible for the progression
of this infl ammatory disease process [153]. The only excep-
tion to this would be in patients with a suspected overlap
syndrome with autoimmune hepatitis where, typically,
transaminases are signifi cantly elevated. In this setting a
biochemical response to corticosteroids is typical.
Given early evidence of its possible benefit in hepatic fibro-
sis and cirrhosis, colchicine has been used in several studies
[154–156]. Unfortunately, in studies by Lindor et al. (when it
was used in combination with prednisone) and in other case
reports, colchicine has not been shown to be useful [152].
This has been confirmed in a randomized trial from Sweden
where colchicine (1 mg/day) was compared with placebo in
84 patients w ith PSC. At 3-yea r follow-up t here were no d i f-
ferences in clinical symptoms, serum biochemistry, liver his-
tology, or survival between the two groups.
Local therapy in the form of topical corticosteroids has
been administered through a nasobiliary drain inserted dur-
ing ERC. Three anecdotal studies have demonstrated benefit
[157–159], but the only controlled trial, from the Royal Free
Hospital, London, showed no benefit when compared to a
placebo group [160]. Furthermore, the bile of treated patients
rapidly became colonized with enteric flora and they had a
higher incidence of bacterial cholangitis. Therefore, topical
steroids are not recommended.
Methotrexate yielded promising results in an uncontrolled
trial of 10 PSC patients [161]. Unfortunately, when the au-
thors performed a prospective double-blind randomized
control trial (methotrexate 15 mg/week versus placebo) in 24
patients with PSC, the only signifi cant change was a fall

(31%) in the serum alkaline phosphatase in those receiving
methotrexate. There was no improvement in symptoms, his-
tology, serum albumin, bilirubin, or transaminases. Compli-
cations of methotrexate were minimal, with only a single
episode reported of Campylobacter enterocolitis and one leu-
kopenic episode related to bacterial cholangitis. Since many
patients in this study had advanced disease (7/12 receiving
methotrexate had cirrhosis), it is possible that a positive ef-
fect in early-stage PSC could have been missed [162]. A larger
trial in early stage PSC is required to definitively determine
the role of methotrexate in this disease. Unfortunately, given
its toxicity and the lack of benefit of methotrexate added to
ursodeoxycholic acid (UDCA) in 19 patients with PSC by Lin-
dor et al., it is unlikely that a larger trial can be justified [163].
Since hepatic copper levels are increased in all patients
with cholestatic liver disorders, penicillamine was tested in a
well-designed, randomized, placebo-controlled trial of 70
patients at the Mayo Clinic. As expected, urinary excretion
of copper increased with concomitant reduction in hepatic
copper concentrations; however, after 3 years there were no
beneficial effects on symptoms, biochemical results, liver
histology, disease progression, or survival. In addition, sig-
nifi cant toxicity, such as proteinuria and pancytopenia, lead-
ing to permanent discontinuation of penicillamine, was
noted in 21% of patients, thereby discouraging any further
use of this agent in PSC [69].
Enthusiasm for the use of UDCA stems from the theory
that replacing toxic bile acids, such as lithocholic acid, with
UDCA may decrease hepatic damage. Although the standard
dosages of UDCA (10 to 15 mg/kg) have been used in most

studies, if biliary enrichment of UDCA represents the deci-
sive factor for its clinical effect, it seems likely that UDCA
doses of up to 22 to 25 mg/kg may be more effective than
lower doses [164]. UDCA may have an immunologic effect by
decreasing the expression of Class 1 antigens, and a choleret-
ic effect by increasing bile flow [165]. Numerous uncontrolled
trials demonstrated a beneficial effect (primarily biochemi-
cally with improvement of alkaline phosphatase). Symptom
improvement was variable and liver histology usually not
available [163,166,167]. In controlled studies (Table 19.8),
typically between 13 mg/kg and 15 mg/kg of UDCA were
used. Study duration varied, but ranged from 12 to 30 months.
In the first randomized, double-blind, controlled trial of
U DC A i n PSC , Beuers et a l. placed si x pat ients on U D C A and
eight on placebo for a period of 12 months [168]. After 6
months there was an improvement in serum alkaline phos-
Chapter 19: Primary sclerosing cholangitis 317
phatase and aminotransferases in the treatment group, but it
took up to 12 months to demonstrate an improvement in the
serum bilirubin. Hepatic histology improved, particularly
of portal and parenchymal infl ammation. Unfortunately,
symptoms did not improve. Similar results were seen by
Stiehl et al., who had to terminate the placebo-controlled
arm since the majority of patients experienced a twofold rise
in aminotransferases after 3 months. Improvement with
UDCA was documented in biochemical and histologic analy-
sis but not with symptoms [169–173].
In a larger trial by Lindor et al. of 105 patients randomized
to treatment or placebo, the follow-up was for up to 6 years
[174]. T reat ment w it h U DC A had no ef fec t on t i me to tra ns-

plantation, death, or evolution of cirrhosis. Although there
was signifi cant improvement in liver biochemistry, this
was not reflected by improvement in liver histology or
symptoms.
In a more recently presented abstract, the combination of
UDCA with metronidazole in a randomized sample of 80 pa-
tients resulted in improved histology and New Mayo Risk
Scores in patients in the combined group over a period of 3
years. The theory in this study is that the antibiotic may have
activity against anaerobes and thereby decrease anaerobic
bacteria within the biliary tree [175].
From these studies, it can be concluded that there is a bene-
ficial effect of UDCA on serum transaminases and alkaline
phosphatase; unfortunately, it does not appear to improve
hepatic histology or symptoms or prolong survival, evolution
of cirrhosis, or time to transplantation. A recent Cochrane
analysis has concluded “Ursodeoxycholic acid leads to a sig-
nifi cant improvement in liver biochemistry, but there is in-
sufficient evidence to either support or refute its clinical
effects in patients with primary sclerosing cholangitis. Large
scale, high-quality randomized clinical trials are needed”
[176]. On the other hand, when UDCA is combined with ag-
gressive endoscopic intervention (dilation of amenable bili-
ary strictures), actual survival rates have been longer than
predicted [168,177].
Only long-term, high quality, randomized studies will de-
termine whether the biochemical improvement produced by
UDCA results in improved outcome and survival. UDCA may
have other benefi ts (other than hepatobiliary) that enhance
its attractiveness; in particular its benefit on colorectal neo-

plasia. Recently, a study of 52 PSC/UC patients were followed-
up for a total of 355 person-years [178]. Those assigned to
UDCA had a relative risk of 0.26 for developing colorectal
dysplasia or cancer (95% confidence interval, 0.06–0.92; P =
0.034) versus a control group. UDCA therefore, signifi cantly
decreases the risk for developing colorectal dysplasia or can-
cer in patients with UC and PSC. Although this data is en-
couraging and UDCA has minimal side-effects, the current
lack of clinical benefit demonstrated by multiple studies sug-
gests that it cannot be regarded as routine effective clinical
treatment for PSC.
Other immunosuppressive drugs have been tried in a num-
ber of studies. No controlled trials are available for azathio-
prine but in one uncontrolled study two patients improved
[179], while in the other case report the patient deteriorated
[180]. Cyclosporine has been used in a randomized clinical
trial involving 34 patients with PSC, most with coexisting ul-
cerative colitis. After 2 years of therapy, the ulcerative colitis
had improved but there was no beneficial effect demonstr-
ated on serum hepatic biochemistry. Regarding histology,
there was progression of disease in 9 out of 10 patients on pla-
cebo and but in only 11 out of 20 on therapy. The incidence
of side-effects was relatively low and included paresthesias
and hypertrichosis, but no serious renal toxicity was noted
[181,182].
Table 19.8 Placebo controlled trials of ursodeoxycholic acid in primary sclerosing cholangitis.
Reference Number of Study Alk Phos Bilirubin Symptom Histology Percentage
Patients duration improved improved improved improved with early
(months) disease
Beuers [168] 14 12 Yes Yes No Yes 57

Lo [249] 23 24 Trend No No No 74
Lindor [174] 105 35 Yes Yes No No N/A
Farkkila
a
(with 80 36 – – – Yes –
metronidazole) [175]
De Maria [250] 59 24
Mitchell [251] 20 24 Yes No No Yes N/A
Stiehl [171] 20 36 Yes Yes No N/A N/A
a
Randomized study combining UDCA with metronidazole in one group. Outcome was specifically to evaluate histology and Mayo Risk Score at 36
months, both of which improved.
318 Section 3: Specific conditions
Tacrolimus (FK-506) has been used in one open study in 10
patients with PSC. After 360 days, there was evidence of bio-
chemical improvement in all patients [183]. A randomized
controlled clinical trial is required to confirm these results.
Etanercept (25 mg subcutaneously twice weekly) has also
been used in a pilot study of 10 patients with symptomatic
PSC. Although there was some improvement in pruritis,
there was no improvement in biochemical parameters [184].
Mycophenolate mofetil (MMF) is a new immunosuppress-
sive medication that inhibits proliferation of B and T lympho-
cytes. Recently, 30 patients underwent a 1-year trial with
mycophenolate mofetil with no significant clinical or bio-
chemical improvements [185].
In summary, numerous medical therapies have been used
for PSC and, although several treatment modalities appar-
ently result in biochemical improvement, there appears to be
no convincing evidence that these medications yield a sus-

tained clinical benefit. Therefore, outside of a clinical trial,
their use is not recommended.
Management of complications of PSC
Associated complications of PSC include fatigue, pruritus,
steatorrhea, fat soluble vitamin deficiency and its complica-
tions, including osteoporosis. Fatigue often parallels progres-
sion of disease and can be disabling; however, no medical
treatment has been demonstrated to be effective in amelio-
rating this symptom.
Pruritus can be intense, leading to a diminished quality of
life as well as skin and systemic infections arising from exco-
riations. The pathogenesis of itching may be related to the in-
creased availability of endogenous opiate ligands at central
receptors. Although therapy for pruritus associated with
cholestatic liver diseases typically is initiated with cholestyr-
amine, other medical therapies include activated charcoal,
rifampicin, phenobarbitol, plasmapheresis, and opiate an-
tagonists (naloxone, nalmefene) (Table 19.9). Cholestyr-
amine is a nonabsorbable resin that binds bile acids and
therefore results in increased fecal excretion of bile by inhib-
iting enterohepatic circulation. The dose is typically 12 to
24 g/day, but since over 50% of patients receiving the drug
are troubled by constipation and nausea, compliance is often
poor. In primary biliary cirrhosis, rifampicin has been dem-
onstrated to be more effective in reducing pruritus than phe-
nobarbital. Unfortunately, up to 10% of patients develop
drug-induced hepatitis from rifampicin, necessitating dis-
continuation of this medication [186–188]. Opiate antago-
nists such as naloxone are occasionally useful in ameliorating
pruritus but they are awkward to use and can be expensive. A

more recent attempt at extracorporeal albumin dialysis in a
single case was met with some improvement in biochemical
pa r a me ter s as wel l a s pr u r it i s [189 ] .
Cholestasis eventually results in signifi cant changes in fat
malabsorption. Although chronic pancreatitis and celiac dis-
ease have been associated with PSC and can contribute to fat
malabsorption, most patients with PSC have steatorrhea sec-
ondary to decreased bile acid concentrations within the small
intestine. Fat-soluble vitamins (A, D, E, and K) are typically
malabsorbed and patients can occasionally develop night
blindness, osteomalacia, and coagulopathy. Patients should
be screened for these deficiencies and supplemental therapy
supplied as required [190].
Osteoporosis is a common problem in cholestatic liver dis-
ease. In 50% of PSC patients undergoing transplantation, the
bone density levels are below the fracture threshold. One-
third of liver transplant patients with PSC will develop verte-
bral compression fractures. Bone mineral densities do not
correlate with serum bilirubin (or the severity of liver disease
[191]) or 25-hydroxyvitamin D, fecal fat, or the presence or
absence of ulcerative colitis. As in primary biliary cirrhosis
(PBC), the etiology of the osteoporosis is unknown and ther-
apy has not been fully evaluated [166,192]. Dual-energy X-
ray absorptiometry and dual-photon absorptiometry are
noninvasive techniques that provide an excellent quantifi ca-
tion of the bone mass. Antiresorptive agents such as the bi-
phosphonates (etidronate, pamidronate, alendronate) may
avoid the osteopenic complications but further clinical trials
in this area are necessary.
The end stages of PSC are often associated with portal hy-

pertension resulting in esophageal varices, ascites, and en-
cephalopathy. These complications can be managed in the
usual fashion for patients with end-stage liver disease, with a
few exceptions. It has been demonstrated that 36% of pa-
tients with PSC will have esophageal varices and that a sup-
pressed platelet count, advanced histological stage, and low
albumin levels are all predictors of the presence of esopha-
geal varices [193]. These patients should be targeted for endo-
scopic variceal screening protocols.
Particular caution should be maintained in patients being
considered for systemic surgical shunting for difficult to
Table 19.9 Treatments used for pruritus.
Resins
Cholestyramine
Cholestipol
Antibiotics
Rifampicin
Metronidazole
Enzyme inducers
Rifampicin
Phenobarbitone
Antihistamines
Opiate antagonists
Naloxone
Anabolic steroids
Stanozolol
Other
Primrose oil
Phototherapy
Plasmapheresis

Albumin dialysis
Liver transplantation
Chapter 19: Primary sclerosing cholangitis 319
control esophageal or gastric varices. With the advent of
cyanoacrylate (“glue”) for fundal varices and transjugular
intrahepatic portosystemic shunts, it is uncommon for pa-
tients to require surgical decompression. Some reports have
suggested that if patients have had previous biliary surgery,
future liver transplantation was compromised [125]. Two re-
cent reports have suggested the contrary, that previous bili-
ary surgery was not associated with a decreased survival after
liver transplantation [194,195]. Cirrhotic patients require
careful postoperative management and a combined, multi-
disciplinary team approach. If biliary surgery is required,
consultation with the local liver transplantation team would
be appropriate before it is performed to ensure that future
liver transplantation is not compromised.
A troublesome complication of portal hypertension that
occurs in those patients who have undergone proctocolecto-
my is bleeding from peristomal varices. This bleeding can be
severe with therapy of sclerosants only providing temporary
relief. TIPS or surgical portosystemic shunts can control
bleeding, but since most of these patients have severe portal
hypertension, liver transplantation should always be consid-
ered [196].
A recently recognized complication of PSC patients with a
history of colitis is a substantially increased risk of colon can-
cer. This risk appears to start relatively early in their course
and continues even after liver transplantation (risk of colorec-
tal cancer 10 to 14% at 5 years post-transplant). Aggressive

endoscopic surveillance is recommended [197,198].
Endoscopic management of PSC
Although bacterial cholangitis is an unusual presentation of
PSC, once the biliary tree has been manipulated (either
percutaneously, endoscopically, or surgically) it becomes
colonized, typically with Gram-negative organisms, and
recurrent biliary sepsis is common. If “dominant” strictures
are present, several major endoscopy centers have demon-
strated that endoscopic therapy is successful in relieving sep-
sis and improving biochemical tests (Table 19.10). In 1987,
the Milwaukee group reported on 10 patients with PSC in
whom a total of 19 Gruentzig-type balloon dilations were
performed. In those with high-grade strictures, endopros-
theses were inserted. Strictures treated endoscopically were
typically at the level of the hilum or common bile or hepatic
duct (Fig. 19.4). The number of hospitalizations decreased
from 2.5 to 0.2 per year and over a follow-up period of 19
months both the serum bilirubin and alkaline phosphatase
decreased signifi cantly from 6.9 to 2.7 mg/dL and 959 to
385 IU/L respectively. Three patients died; one from a chol-
angiocarcinoma, one from bleeding peristomal varices, and
the last from an unknown cause. Only one complication of
endoscopic therapy was noted in this series: a single case of
mild pancreatitis [199].
Subsequently, Cotton et al. reported a 32% reduction in
bilirubin levels and 29% reduction in alkaline phosphatase
after a mean follow-up of 6 months in 17 PSC patients treated
with a combination of endoscopic dilation, endoprosthesis,
and biliary sphincterotomy [200]. In 1991, the Milwaukee
group expanded their previous cohort to 35 patients with a

mean follow-up of 24 months. They used a combination of di-
lating catheters and hydrostatic balloon dilators to dilate per-
ceived dominant strictures. In addition, biliary stents were
inserted in 11 patients who could not be adequately dilated.
Typically, the stents were removed in 2 to 3 months and dila-
tion performed during a second ERC. They demonstrated
that the number of hospitalizations, total serum bilirubin,
and average radiological stricture score all decreased signifi -
cantly in patients treated endoscopically [201].
Lee et al. subsequently reviewed the Duke experience by
evaluating the results of 85 ERCPs in 53 patients with PSC
[123]. Overall, 77% of patients had improvement in their
clinical symptoms, liver function tests, or cholangiograms.
From the patients’ point of view, of 50 patients available for
evaluation, 28 felt better, 21 the same, and one felt worse fol-
lowing the therapeutic ERCP. These procedures are done
with broad spectrum antibiotics before the ERC and for a
Table 19.10 Therapeutic endoscopic series in patients with primary sclerosing cholangitis.
Author Number of Use of Nasobiliary Follow-up Mean Mean Radiology Subsequent
Patients tube (months) bilirubin alk phos stricture hospital
decrease decrease score admission
rate
Wagner [206] 12 Yes 23 73% 46% Improved N/A
Johnson [201] 35 No 24 60% 15% Improved Decreased
Gaing [203] 16 Yes 52 60% 35% Improved N/A
Lee [123] 53 Yes (8/53) 31 50% 50% Improved N/A
Van Milligen [252] 25 No 25 80% 50% Improved N/A
320 Section 3: Specific conditions
minimum of 24 hours after the procedure. Dilating balloons
are typically held in position for 30 to 60 seconds until the

constricted “waist” is obliterated [123].
Predicting which patients may benefit from a therapeutic
ERC is always difficult. A single large study to evaluate these
predictors was performed and reviewed all patients at Duke
University undergoing ERC at PSC. It demonstrated that
those patients who underwent therapeutic procedures, had a
dominant stricture (could be assessed pre-ERC with MRC to
localize diseased segments), or were jaundiced had an in-
creased rate of clinical/laboratory improvement following
the procedure [202].
There are several problems with ERC in patients with PSC.
First, as noted by Gaing et al. in 1993, approximately 50% of
patients will have disease that is primarily intrahepatic in na-
ture, thereby making it more difficult to treat endoscopically
[203]. With advancing radiological techniques such as mag-
netic resonance cholangiograms (MRC), it might be reason-
able to consider screening patients with PSC with MRC to
determine if there is disease that is amenable to endoscopic
therapy. Providing that MRC is sensitive and specific for the
location of endoscopically amenable strictures, it could avoid
diagnostic ERCs in selected patients. Conceivably, even if, in
theory, the lesions were amenable to endoscopic therapy the
site and complexity of the procedure could be predicted (i.e.
hilar strictures) and referral to a center with specialized
ERCP expertise considered. Second, the complication rate
following an ERC in a patient with PSC may be as high as
15%. This is primarily accounted for by ascending cholangi-
tis. Pre- and postoperative antibiotic should be administered
in all patients with known and suspected PSC to avoid this
complication. Third, strictures in PSC must always be evalu-

ated for the presence of malignancy. Even with aggressive
brushing sampling, only a 50 to 60% sensitivity is obtained.
Figure 19.4 (A) Distal biliary stricture secondary to primary sclerosing cholangitis with proximal stone formation. (B) The stricture was dilated with
subsequent common bile duct stone extraction.
(A)
(B)
Chapter 19: Primary sclerosing cholangitis 321
A combination of serological tumor markers (e.g. CEA,
CA19-9) with repeated brushings may increase the diagnos-
tic yield of cholangiocarcinoma in this disease. Finally, al-
though there are reports of possible prolongation of survival
with endoscopic therapy [204], convincing evidence of this,
or increased survival or delaying transplantation, has not
been demonstrated in most patients with PSC treated endo-
scopically. Additionally, more recently some authors have
challenged the results of endoscopic series suggesting that at
follow-up after endoscopic treatment of dominant strictures
there is actually very little, if any, alteration in biliary bio-
chemical parameters. Randomized trials have been sug-
gested but are unlikely to be performed as, given that this is a
relatively uncommon condition, a multicenter approach
would be required and patients would be difficult to random-
ize to a “sham” arm of the study [205].
Recent investigators have looked at the use of nasobiliary
lavage following endoscopic therapy. Wagner et al. followed
12 patients with dominant strictures from PSC treated with
hydrostatic balloon dilation and nasobiliary drainage for up
to 50 months. Eight patients demonstrated biochemical im-
provement with only three requiring liver transplantation.
No major complications were reported [206].

Present methods of endoscopic therapy have not been con-
trolled or randomized and clearly have signifi cant bias. How-
ever, the results demonstrated by multiple authors have
proven a major role for ERC in the therapy of PSC by demon-
strating signifi cant biochemical and radiological improve-
ment in selected patients (Table 19.10). Although the
diagnostic potential of MRC may be great, the therapeutic
role of ERC in PSC is unlikely to be replaced in the near fu-
t u re . It m us t b e r eme m b er ed , h o we ve r , t h a t pub l i s he d re su l t s
have been produced by experts at experienced biliary centers
and these results may not be generalizable to smaller
centers.
Cholangiocarcinoma
Up to 15% of patients with PSC may eventually develop chol-
angiocarcinoma [2,36,117,207–209]. The patients at highest
risk have traditionally been reported to be those with long-
standing cirrhosis and ulcerative colitis [210,211]. However,
in a single study by Burak et al. the only clinical risk factor for
cholangiocarcinoma in this patient population was a history
of variceal bleeding (RR 24.2; 95%CI: 3.3–67.1). It would be
logical to theorize that cholangiocarcinoma may be more
common in those patients with dominant biliary strictures
and one recent abstract has demonstrated a 20% malignancy
rate over the 2 years following diagnosis of a dominant bili-
ary stricture in a large series of PSC patients [212]. Bile duct
carcinomas have been difficult to diagnose since no single
test has proven both sensitive and specific for the disorder
[213]. Ultrasound and computed tomography (CT) have a
low sensitivity for the diagnosis of primary bile duct tumors.
The advent of duplex ultrasonography and bolus-enhanced

CT scans may increase sensitivity up to 80% [214,215]. Bili-
ary brushings of the stricture have a variable yield of between
50 and 80% [81,216–221]. In addition to technical factors re-
garding tissue sampling, the yield may be increased by care-
ful attention to cytological classifi cation systems [222].
Tumor markers, such as serum CEA, have not been shown
to be sensitive, with a sensitivity of only 53% being reported
in one group of 15 patients with cholangiocarcinoma (11 oc-
cult tumors) [220]. Serum levels of Ca 19-9 appear to be
slightly more sensitive and specific, although it has not been
found to be predictive of cholangiocarcinoma in patients
with advanced disease (the group thought most likely to de-
velop this tumor) [223,224]. Ramage et al. have shown that
the calculation of a serum tumor index (CEA × 40 +carbohy-
drate antigen (CA) 19-9) was 86% accurate in diagnosing
cholangiocarcinoma in PSC patients and probably is the best
laboratory-based method to raise suspicion of a malignant le-
sion [220]. Biliary CEA, which can be detected through bile
aspirates, also has been suggested as a possible marker for
cholangiocarcinoma [215]. Unfortunately, it is also elevated
in patients with intrahepatic cholelithiasis, which is relative-
ly common in PSC. Biliary CEA is also mildly elevated in PSC
itself making its accuracy in assessing cholangiocarcinoma
in PSC questionable.
More recently, a proteomic study of bile samples from pa-
tients with cholangiocarcinoma has suggested yet another
protein that requires further study. Biliary Mac-2BP levels
were elevated by a factor of approximately three in the biliary
carcinoma group compared with the group of patients who
had PSC or another type of non-neoplastic biliary disease.

Serum levels of Mac-2BP levels were not elevated in those pa-
tients with biliary tract cancers. According to the immuno-
histochemical analysis, Mac-2BP was expressed in 34 of 36
patients (94.4%) with biliary tract carcinoma. As a diagnos-
tic marker for biliary carcinoma, Mac-2BP levels were as ac-
curate as biliary CA19-9 levels; however, the use of both of
these bile markers in combination led to signifi cantly better
diagnostic accuracy compared with the accuracy achieved
using CA19-9 alone (area under the curre, 0.75; P < 0.001). It
appears from this study that biliary Mac-2BP levels show
promise as a novel diagnostic marker for biliary tract carcino-
ma [225].
The prognosis for cholangiocarcinoma in the setting of PSC
is poor, with a reported survival of less than 12 months
[207,226]. However, in patients with the incidental finding
of cholangiocarcinoma in the explanted liver (with regional
lymph nodes clear of disease), long-term survival similar to
those undergoing transplant without cholangiocarcinoma
has been reported. Therefore, those patients who are diag-
nosed with cholangiocarcinoma preoperatively may be ex-
p e c t e d t o h a v e a p o o r p r o g n o s i s ; h o w e v e r , i t h a s b e e n r e p o r t e d
322 Section 3: Specific conditions
that those with cholangiocarcinoma discovered incidentally
may have a long survival [194,227]. In other studies, how-
ever, even those with cholangiocarcinoma discovered inci-
dentally have been demonstrated to do poorly with liver
transplantation, typically dying of metastatic disease, lead-
ing most transplant centers to “steer clear” of suspected ma-
lignant biliary trees [228].
Some authors have suggested that early transplantation

(pre-emptive transplant) to decrease the risk of cholangio-
carcinoma may be considered [229]. One argument against
this approach is that retransplantation rates appear to be
higher with graft survival slightly shorter than other com-
monly transplanted disorders (i.e. PBC) and therefore PSC
would not be an ideal setting to initiate early transplantation
[230].
Liver transplantation
Despite limitations, the treatment of choice for end-stage PSC
is liver transplantation (Fig. 19.5). The reported 1- and 3-year
survival rates are 85 and 75% respectively [194,228,231,232].
Patients with PSC undergoing liver transplantation have sig-
nifi cantly improved survival when compared to patients un-
dergoing liver transplantation for most other indications
(Fig. 19.6) [165]. One of the challenges facing today’s hepa-
tologists is not only the timing of the transplant, but deter-
mining when patients should be referred to transplant centers
to optimize the results and minimize resource utilization.
Although results with liver transplantation are improved,
there is a shortage of donor livers for transplant and actual
survival from the time of listing to transplant is much shorter
than the results demonstrated after transplantation. In a re-
cent Nordic study the 5- and 10-year survival from the time of
listing for transplant was evaluated and demonstrated to be
68% and 58% respectively [233]. Additionally, resource uti-
lization is a clear concern and overall expenditures for PSC
patients in liver transplantation have been demonstrated to
be more favorable than those patients with alcoholic liver dis-
ease, which clearly is more common [234]. Additionally, in
the same study the cost per quality-adjusted life-year from

time of listing for PBC was greater (29,000 pounds) than PSC
(21,000 pounds). In conclusion, liver transplantation in-
creases the survival and health-related quality of life of pa-
tients with each of three end-stage liver diseases; however,
when evaluating cost issues, PSC is very favorable. Anther
disease-specific complication that occurs in PSC transplan-
tation is a recurrence of the underlying disease, which does
occur pathologically in up to 30% of patients [235].
Clearly, transplantation may be required for the usual
complications of cirrhosis, such as recurrent variceal bleed-
ing, diuretic-resistant ascites, and hepatic encephalopathy.
Unlike other causes of cirrhosis, however, symptoms par-
ticular to PSC such as wasting, fatigue, pruritus, recurrent
bacterial cholangitis, and jaundice without evidence of chol-
angiocarcinoma often prompt referral to transplant centers.
In an era where organs such as livers are in short supply, it is
often difficult to accommodate potential recipients (even if
they are excellent candidates) and various strategies for
transplant assessment are used.
Rarely, other types of surgical procedures, such as he-
paticojejunostomy or partial hepatectomy, can be consid-
ered. These types of procedures need to be performed with
consultation of transplant orientated surgeons to ensure
that they don’t preclude the patient from subsequent liver
Figure 19.5 Estimated survival after liver
transplantation (based on Kaplan–Meier analysis) in
patients with primary sclerosing cholangitis compared
with estimates of survival without liver
transplantation. Liver transplantation increases
survival significantly. (Reproduced from Abu-Elmagd

KM, Malinchoc M, Dickson ER, et al. Efficacy of hepatic
transplantation in patients with primary sclerosing
cholangitis. Surg Gynecol Obstetrics 1993;177:335–
44, with permission.)
Chapter 19: Primary sclerosing cholangitis 323
transplantation. In rare, selective cases long-term symptom
relief may be obtained with selective surgical intervention
[236].
A number of complications particular to PSC patients do
occur post-transplant. PSC patients seem to have a higher in-
cidence of chronic ductopenic rejection post-liver transplant
compared with PBC [194,232]. In addition, colon cancer in
patients with PSC and ulcerative colitis represents a signifi -
cant cause of late mortality after liver transplantation; there-
fore, surveillance every 6 to 12 months by colonoscopy
is recommended [237–243]. Nonanastomotic biliary stric-
tures, not associated with recurrent PSC, post-liver trans-
plantation have been reported with increasing frequency
and can be difficult to manage [244]. Although definitive
criteria for the diagnosis of PSC recurrence have not been es-
tablished post-liver transplantation, some patients appear to
develop a similar syndrome postoperatively. Males and an
intact colon prior to transplant have been shown to have a
higher risk of recurrent PSC in one pathological study of 152
transplanted PSC patients of whom 52 had recurrent PSC
[245]. Other conditions such as ischemia, cytomegalovirus
infection, and chronic ductopenic rejection must also be con-
sidered in the differential diagnosis of post-transplant PSC
[5,246–248].
Summary

Primary sclerosing cholangitis is a chronic cholestatic disor-
der of unknown etiology, commonly associated with infl am-
matory bowel disease, characterized by destruction of both
intra- and/or extrahepatic biliary ducts. The disease tends to
present with abdominal pain, elevated liver enzymes, jaun-
dice, and cholangitis. The diagnosis relies upon a cholangio-
gram which can be obtained through ERC or MRC. The
noninvasive nature of MRC is attractive, and may help delin-
eate the biliary tree to avoid unnecessary manipulation at
ERC. The risks of ERC in this patient population are increased
over standard cases and caution prior to invasive endoscopic
procedures is recommended.
Although its natural history is variable from patient to
patient, several models have been developed to help predict
survival and enable timely arrangements for liver transplan-
tation. No medical therapies have demonstrated prolonged
survival or duration until transplantation. Several studies
have demonstrated that endoscopic therapy can be very suc-
cessful, especially if dominant strictures occur within the
distal biliary tree. In some patients, endoscopic therapy may
decrease future need for hospitalization from cholangitis.
Many of the diffi culties with the interpretation of data from
endoscopic treatments has to do with the fact that large series
tend to be published from expert centers. Additionally, un-
like studies with medical therapy, these endoscopic studies
tend to be nonrandomized with considerable selection bias
predominating. Ideally, randomized sham studies would be
performed but, given that this is a relatively uncommon dis-
order, the feasibility of this is unclear.
The complication of cholangiocarcinoma must always be

considered when dealing with a dominant biliary stricture.
Brushings at the time of endoscopy and tumor marker evalu-
ation are critical to making an early diagnosis of these mitotic
lesions, which are often difficult to find. Other complica-
tions, such as osteoporosis, vitamin deficiencies, and those
related to portal hypertension, should be treated aggressively
to minimize future morbidity and mortality. Ultimately,
most patients will require liver transplantation for which
survival rates are excellent.
Figure 19.6 Survival in patients undergoing liver
transplantation for primary sclerosing cholangitis in
comparison to overall survival for all indications of
orthotopic liver transplantation. Patients
undergoing liver transplantation for primary
sclerosing cholangitis have significantly improved
survival. (Reproduced from Wiesner RH. Managing
complications of PSC and monitoring disease
progression. Contemp Intern Med 1994;6:37–46.)
324 Section 3: Specific conditions
Questions
1. Which of the following has been documented to result in
sclerosing cholangitis?
a. advanced HIV disease
b. abdominal radiation
c. ischemia
d. all of the above
2. In patients with suspected sclerosing cholangitis, following a
normal abdominal ultrasound, with mild elevation in liver
enzymes the first modality of investigation should be
a. liver biopsy

b. endoscopic retrograde cholaniography
c. percutaneous cholangiogram
d. magnetic resonance cholangiogram
3. The median time to transplantation from diagnosis is
approximately
a. 1 year
b. 3 years
c. 6 years
d. 12 years
e. 20 years
4. Which of the following parameters are important in assessing
the severity and predicting survival in PSC patients?
a. age
b. history of variceal bleeding
c. albumen
d. AST (aspartate aminotransferase)
e. all of the above
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