Book on hepatitis from page 476 to 487

Book on hepatitis from page 476 to 487

476  Hepatology 2012
this is found in 52% of cases (Tischendorf 2007). Ulcerative colitis is more often
associated (UK 71%, Sweden 72%) than Crohn’s disease. IBD is usually diagnosed
before PSC but owing to the symptomatic latency of both IBD and PSC it can also
be diagnosed at the same time or later than PSC. Most commonly ulcerative colitis
is diagnosed more than a year before PSC (67%). In 22% the diagnoses occurred
within 1 year of each other, and only in 11% the was diagnosis of ulcerative colitis
reached more than 1 year after PSC was established. IBD patients with elevated
liver biochemistry are a risk group and require careful hepatological workup for
PSC. About 5% of all patients with ulcerative colitis have PSC.
PSC as a risk factor for cancer
Apart from the risk of developing portal hypertension and cirrhosis, PSC is a severe
risk factor for cancer, which distinguishes this disease from AIH and PBC (Table 8).
The increased risk of cholangiocarcinoma is well described (Bergquist 2001,
Boberg 2002). The numbers reported vary because explanted livers during liver
transplantation, autopsies and in vivo diagnosed cases are taken into account in
different analyses. The diagnosis of cholangiocarcinoma (CC) in PSC patients
continues to represent a difficult task because stenoses upon cholangiography may
be caused by inflammatory activity as well as tumour, and because biochemical
tests and biopsy procedures have a low sensitivity and specificity. Imaging studies
are equally complicated by a lack of sensitivity since tumours frequently grow
intramurally and are diagnosed in late stages precluding curative therapeutic
approaches. Studies from Sweden show that 54% of CC occur within 1 year of the
diagnosis of PSC and 27% are diagnosed at liver transplantation. Overall 12.2% of
Northern European PSC patients develop CC, which is corroborated by our data
from Hannover (Boberg 2002, Tischendorf 2006). These patients suffer from
jaundice, pruritus and abdominal pains and had a longer IBD history. Male gender
and smoking is also a risk factor (Tischendorf 2006, Weismüller 2008). In a Dutch
study there were similar findings of 18 CC out of 174 patients (10%) (Ponsioen
2002). The CC risk of a PSC patient amounts to 1.5% per year and is 161-fold
higher than in healthy controls. It is also important to realize that the risk for
colorectal cancer (CRC) is elevated 10-fold, in addition to a 14-fold risk of
pancreatic cancer (Bergquist 2002). These data point to the need of yearly
colonoscopies and ultrasound studies after diagnosis of PSC to monitor the high
potential for cancer development.
Table 8. Cancer association of PSC.
Cholangiocarcinoma  10-20% of PSC patients
Yearly risk 1.5%
Frequent within 1 year of diagnosis
Bilirubin, male gender, long-standing ulcerative colitis, abdominal
symptoms, smoking
Colorectal cancer  10-fold risk (PSC and ulcerative colitis)
Yearly colonoscopies in ulcerative colitis
In ulcerative colitis and AP elevation: consider ERC
Pancreatic cancer  14-fold risk in PSC patients
Abdominal ultrasound
Autoimmune Liver Diseases: AIH, PBC and PSC  477
Medical therapy of PSC
Present day data and clinical experience does not suggest that PSC represents a
disease curable by medical therapy (Zein 2010, Wiencke 2011). A cure would
include the improvement or normalization  of abnormal cholestatic biochemical
features but more importantly the improvement of sclerosing changes to the intra-and extrahepatic biliary tree, which ultimately lead to biliary cirrhosis, to episodes
of cholangitis, and, which carry the risk of cholangiocellular carcinoma. The only
available drug that combines a favourable toxicity profile and can lead to a
reduction of cholestatic serum parameters currently is ursodeoxycholic acid
(UDCA). However, controversy surrounds the use of UDCA (Chapman 2010),
which has recently led to guidelines that do not specifically recommend UDCA
treatment in all adult patients (Guidelines 2009, Chapman 2010). In two studies an
improvement was documented using 20 mg/kg body weight, and 25-30 mg/kg body
weight, respectively (Harnois 2001, Mitchell 2001). Both use UDCA doses, which
are considerably higher than those common in the therapy of PBC (15 mg/kg body
weight). From these data a higher dose appeared to be more beneficial in PSC.
However, a study analysing UDCA in bile as a function of oral UDCA dose found
that doses exceeding 25 mg/kg body weight are not likely to be useful since the
maximum transport of UDCA into the bile leveled off at 25 mg/kg with no further
increase (Rost 2004). After these and other initial reports, a meta-analysis was
published in 2002 (Chen 2003), which concluded that UDCA therapy improved
biochemical parameters but that overall beneficial effect in patients with PSC, in
particular survival benefit, was uncertain. A large study appeared to confirm this
view; 219 PSC patients in a placebo-controlled trial (Olsson 2005) received 17-23
mg/kg body weight of UDCA and a trend towards better survival and less need for
transplantation was seen, but did not reach statistical significance. A difference in
the incidence of cholangiocarcinoma was not observed. However, statistical
analyses reported in this study concluded that 346 patients would have been
required to reach statistical significance. Based on the body of literature available, a
positive effect of UDCA at present cannot be excluded, and clearly larger placebo-controlled studies are required. This will only be possible in multicentre trials.
An additional effect of UDCA was reported showing a decrease of the dysplasia
in colon polyps associated with UDCA doses as low as 10-15 mg/kg bodyweight
(Tung 2001, Pardi 2003). Although this requires confirmation in larger studies the
association of PSC with ulcerative colitis in 75% of affected individuals would
make this an interesting ancillary effect of UDCA therapy.
The issue of immunosuppression in PSC is controversial and the majority of
centres and publications do not recommend the routine administration of
corticosteroids and other immunosuppressants (van Hoogstraten 2000, LaRusso
2006). In PSC one of the most feared and unpredictable complicating factors is
bacterial cholangitis and cholangiosepsis (Negm 2011). Immunosuppression would
be expected to aggravate this complication. In rare instances such as overlapping
features  of PSC and autoimmune hepatitis (AIH) (Boberg 2011),
immunosuppression may be of benefit but this requires rigorous documentation of
AIH, which includes biopsies, autoimmune serology and suggestive biochemistry
(Boberg 1996, Beuers 2005).
478  Hepatology 2012
Therapy of IBD in PSC
Many PSC patients suffer from a milder course of IBD. Ulcerative colitis  is
frequently characterized by pancolitis without severe symptoms, rectal sparing or
backwash ileitis. Nevertheless the risk of dysplasia and CRC remains significantly
higher in PSC patients with ulcerative colitis. Therapeutic intervention is no
different that that for IBD without PSC. In this context UDCA appears to provide a
beneficial effect for dysplasia development. In a study with 59 PSC patients with
ulcerative colitis, UDCA reduced the risk of colonic dysplasia (Tung 2001, Serfaty
2003). UDCA may therefore contribute to the positive modulation of CRC risk in
PSC.
Endoscopic therapy
The most important factor determining the course of PSC is the development of
biliary strictures, which carry and increase the risk of septic cholangitis driving
biliary fibrosis (Figures 4 and 5). Endoscopic dilatation can improve cholestasis, in
some cases biliary stenting (Weismüller 2008), which is not recommended by all
gastroenterologists. The combination of endoscopic intervention and UDCA therapy
appears to lead to a significant prolongation of transplant-free survival. UDCA
alone does not lead to this effect.
Figure 5. Management of PSC by dilatation of a dominant stricture of the common bile
duct (arrows) and subsequent short-term stenting with a plastic stent. In this particular
case it turned out that the biliary biopsy revealed cholangiocarcinoma.
Liver transplantation in PSC (OLT)
In PSC patients survival has been shown to be reduced both in symptomatic and in
asymptomatic patients (Kim 2000, LaRusso 2006), which is in part attributable to
the inherent risk of cholangiocarcinoma affecting 10-20% of these patients, and
renders decision-making for liver transplantation a formidable challenge. In
addition, PSC patients with advanced destructive cholangiopathy frequently exhibit
only mild signs of liver failure based upon coagulation abnormalities,
Autoimmune Liver Diseases: AIH, PBC and PSC  479
hypoalbuminemia, or complications of portal hypertension (Tischendorf 2007,
Strassburg 2009). The course of deterioration to liver failure is often observed after
long periods of clinical stability, and frequently proceeds rapidly following septic
biliary complications. This is not well predicted by the aforementioned PSC scores,
which is also true for the model of end stage liver disease (MELD), the measure for
organ allocation in the US and the Eurotransplant member countries.
Two major problems define the challenges involved in the indication for liver
transplantation in PSC. First, timing is difficult (Wiesner 1992). PSC patients are
young and preemptive liver transplantation carries a higher short-term risk of OLT
itself than the most likely short-term natural course of the disease. On the other
hand, patients that urgently require OLT because of advanced biliary destruction
frequently do not meet priority criteria calculated by the MELD system. Second, the
161-fold increase of cholangiocarcinoma risk (Bergquist 2002) is a risk that may
eliminate the option of liver transplantation altogether when evidence of
cholangiocarcinoma is detected by diagnostic imaging procedures. The diagnosis of
early cholangiocarcinoma is difficult and presently no single diagnostic procedure
with high sensitivity and specificity is available (Tischendorf 2006). Moreover, the
patients at risk cannot be reliably identified.
In terms of practical management the first point can only be addressed by careful
clinical monitoring of PSC patients in experienced hepatological transplant centers,
where the likelihood of early complication diagnosis and management, as well as
the individualized timing of wait-listing for OLT is higher (Tischendorf 2007). The
second point has been addressed in two centres by establishing specific protocols
for the management of hilar cholangiocarcinoma and OLT (Sudan 2002, Rea 2005).
A rigorous algorithm for non-resectable hilar cholangiocarcinoma patients, that
were carefully selected and capable of surviving chemotherapy, radiation therapy
and surgery was reported. A multimodal approach including neoadjuvant chemo-/radiation therapy, brachytherapy, chemotherapy, laparotomy and OLT was
employed resulting in a 5-year survival of 82%, which did not differ from results in
PSC patients  without cholangiocarcinoma (Rea 2005). However, although
attractive, these interdisciplinary strategies are best limited to studies and
experienced hepatological transplant centers.
Overall the results of liver transplantation in PSC are good, leading to 10-year
survival rates of around 70% (Graziadei 1999). In our centre the median survival of
PSC patients with cholangiocarcinoma was 12.7 months, and all PSC patients,
irrespective of OLT, had a mean survival of 112 months (Tischendorf 2006).
Recurrence after OLT is difficult to diagnose but appears to occur in up to 25% of
patients (Graziadei 1999, Rowe 2008). Liver transplantation continues to represent
the only curative option in PSC. Future developments will have to address the
lacking sensitivity and specificity of early cholangiocarcinoma detection, the
clinical prediction of the disease course and consequently, specific allocation
criteria for patients with PSC.
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