hepatopancreatobiliary manifestations of inflammatory bowel disease
TRANSCRIPT
CLINICAL REVIEW
Hepatopancreatobiliary manifestations of inflammatorybowel disease
Kazuhiko Nakamura • Tetsuhide Ito • Kazuhiro Kotoh •
Eikichi Ihara • Haruei Ogino • Tsutomu Iwasa •
Yoshimasa Tanaka • Yoichiro Iboshi • Ryoichi Takayanagi
Received: 5 December 2011 / Accepted: 13 December 2011 / Published online: 6 January 2012
� Springer 2011
Abstract Inflammatory bowel disease (IBD) is frequently
associated with extraintestinal manifestations such as
hepatopancreatobiliary manifestations (HPBMs), which
include primary sclerosing cholangitis (PSC), pancreatitis,
and cholelithiasis. PSC is correlated with IBD, particularly
ulcerative colitis (UC); 70–80% of PSC patients in Western
countries and 20–30% in Japan have comorbid UC. There-
fore, patients diagnosed with PSC should be screened for UC
by total colonoscopy. While symptoms of PSC-associated
UC are usually milder than PSC-negative UC, these patients
have a higher risk of colorectal cancer, particularly in the
proximal colon. Therefore, regular colonoscopy surveillance
is required regardless of UC symptoms. Administration of
5-aminosalicylic acid or ursodeoxycholic acid may prevent
colorectal cancer and cholangiocarcinoma. While PSC is
diagnosed by diffuse multifocal strictures on cholangiogra-
phy, it must be carefully differentiated from immunoglobu-
lin G4 (IgG4)-associated cholangitis, which shows a similar
cholangiogram but requires different treatment. When PSC
is suspected despite a normal cholangiogram, the patient
may have small-duct PSC, which requires a liver biopsy. IBD
patients have a high incidence of acute and chronic pancre-
atitis. Most cases are induced by cholelithiasis or medication,
although some patients may have autoimmune pancreatitis
(AIP), most commonly type 2 without elevation of serum
IgG4. AIP should be accurately identified based on charac-
teristic image findings, because AIP responds well to corti-
costeroids. Crohn’s disease is frequently associated with
gallstones, and several risk factors are indicated. HPBMs
may influence the management of IBD, therefore, accurate
diagnosis and an appropriate therapeutic strategy are
important, as treatment depends upon the type of HPBM.
Keywords Inflammatory bowel disease �Ulcerative colitis � Crohn’s disease �Hepatopancreatobiliary manifestation
Introduction
Ulcerative colitis (UC) and Crohn’s disease (CD) are
refractory inflammatory bowel diseases (IBD) characterized
by chronic, persistent intestinal inflammation of unknown
origin. The mechanisms leading to their onset are unknown.
Increased sensitivity to IBD may be conferred by genetic
factors as well as environmental factors, including intestinal
bacteria. For instance, commensal bacteria that usually do
not trigger excessive immune reactions may trigger abnor-
mal immune responses in the intestine of patients with IBD
[1]. IBD patients commonly present with extraintestinal
manifestations in addition to intestinal symptoms, reflecting
an autoimmunological aspect of the disease. These extra-
intestinal manifestations have a 25–40% prevalence and
include musculoskeletal, mucocutaneous, ophthalmologic,
hepatopancreatobiliary, hematologic, bronchopulmonary,
urinary, and metabolic diseases [2, 3]. Hepatopancreatob-
iliary manifestations (HPBMs) are relatively common in
IBD and include primary sclerosing cholangitis (PSC),
pancreatitis, and cholelithiasis. Abnormal hepatic function
test results and elevated pancreatic enzymes are frequently
encountered during IBD examination, and it is important for
physicians to be familiar with the diagnosis and treatment of
HPBMs.
K. Nakamura (&) � T. Ito � K. Kotoh � E. Ihara � H. Ogino �T. Iwasa � Y. Tanaka � Y. Iboshi � R. Takayanagi
Department of Medicine and Bioregulatory Science,
Graduate School of Medical Sciences, Kyushu University,
3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
e-mail: [email protected]
123
Clin J Gastroenterol (2012) 5:1–8
DOI 10.1007/s12328-011-0282-1
Primary sclerosing cholangitis
PSC is the most frequent HPBM in IBD. PSC is a chronic
cholestatic hepatobiliary disease with progressive strictures
in intrahepatic and extrahepatic bile ducts. Based on its
correlation with a specific human leukocyte antigen hap-
lotype, PSC is considered to have an autoimmunological
mechanism [4]. Progressive inflammation and fibrotic
strictures in the intrahepatic and extrahepatic biliary tree
lead to biliary fibrosis and cirrhosis, eventually causing
hepatic failure.
Epidemiology
PSC frequently occurs in people in their 30s to 50s, and the
male to female ratio is 2:1 [5]. In Western countries, IBD is
reported to develop concurrently in 70–80% of all PSC
patients [6]. Meanwhile, PSC is found in only 2.4–7.5% of
IBD patients [6]. There may be an ethnic difference in the
prevalence of IBD among PSC patients. In Japanese stud-
ies, IBD was found to be present in 21–32% of PSC
patients [7, 8], indicating a lower prevalence in Japan than
in Western countries. UC represents 85–90% of PSC-
associated IBD [9], but CD and indeterminate colitis may
also occur [10]. The prevalence of PSC depends on the
form of UC; it is as high as 5.5% in patients with pancolitis
and as low as 0.5% in patients with distal colitis [9]. UC
may develop before or after PSC. UC may occur even after
liver transplantation (LT) for treatment of PSC, or PSC
may occur after complete removal of the large intestine for
treatment of UC [11].
Natural history
Although PSC is initially asymptomatic, symptoms develop
with progression of hepatic dysfunction and include pruritus,
jaundice, right upper quadrant pain, fatigue, and weight
loss. Biliary fibrosis gradually progresses to cirrhosis
and finally to hepatic failure with a lowered hepatic reserve.
PSC is characterized by repeated onset of cholangitis.
Portal hypertension may cause esophageal varices, ascites,
and hepatic encephalopathy. Without transplantation, the
median survival period from diagnosis, symptom onset, or
abnormal hepatic function tests is 12–18 years [12–14].
Cholangiocarcinoma (CCC) is a complication of PSC that
carries a poor prognosis and has an annual prevalence of
0.6–1.2% [15, 16]. Furthermore, the risk of concurrent
colorectal cancer or pancreatic cancer is also high.
Characteristics of PSC-associated UC
Pancolitis is the most frequent form of PSC-associated UC
[17, 18]. Features of UC associated with PSC can be seen
in the affected area of the large intestine. In PSC-associated
UC, rectal-sparing, which indicates milder inflammation in
the rectum than in the proximal colon, and backwash ileitis
which indicates inflammation in the terminal ileum, are
more prevalent than in PSC-negative UC [19]. It was
suggested that right-sided colitis is frequently found in
patients with PSC-associated UC [20, 21] (Fig. 1).
Compared with PSC-negative UC, PSC-associated UC
has lower levels of clinical activity and histologic severity
[11, 22]. Colonoscopies of PSC patients without UC-related
symptoms frequently uncover UC [23, 24]. However, the
risk of colitis-associated neoplasia is higher in patients with
PSC-associated UC than in those with PSC-negative UC
[25, 26]. Specifically, proximal colorectal cancer is more
common in patients with PSC-associated UC than those with
PSC-negative UC [27, 28], reflecting the finding that
inflammation occurs predominantly in the right-side of the
colon in patients with PSC-associated UC [20, 21]. Dysplasia
and other neoplastic changes may develop at the subclinical
stage in PSC patients without UC symptoms [24]. Therefore,
even in PSC patients without symptoms of colitis, regular
total colonoscopies are recommended for surveillance
starting from the time of diagnosis. The risk of colorectal
cancer is high even after LT for treatment of PSC [29];
therefore, endoscopy for surveillance should be continued.
Patients with PSC-associated UC have a high risk of
developing pouchitis after total colectomy and ileal
pouch-anal anastomosis [30]. Furthermore, they have a
high risk of developing dysplasia in the pouch after ileal
pouch-anal anastomosis [31], and therefore regular sur-
veillance is required even after surgery.
Diagnosis
PSC patients are often asymptomatic at the time of diag-
nosis but scrutinized by imaging modalities due to abnor-
mal hepatic function test results. As the disease progresses,
the patients eventually show symptoms, including pruritus,
jaundice, right upper quadrant pain, fatigue, and weight
loss. Hepatic enzyme tests usually show increased alkaline
phosphatase (ALP) and other biliary enzymes. Autoanti-
bodies, such as anti-nuclear antibody, anti-smooth muscle
antibody, and perinuclear anti-neutrophil cytoplasmic
antibody, are frequently detected [32], but there is no
specific autoantibody to PSC.
Diagnosis is made by endoscopic retrograde cholangio-
pancreatography (ERCP) or magnetic resonance cholangi-
opancreatography (MRCP) that detects diffuse, multifocal
strictures in medium-sized intrahepatic bile ducts or med-
ium- to large-sized extrahepatic bile ducts. ERCP is the gold
standard for PSC diagnosis and is also used for its treatment,
although it may have serious complications, including
pancreatitis. MRCP is slightly less sensitive, specific, and
2 Clin J Gastroenterol (2012) 5:1–8
123
accurate than ERCP but is less invasive [33, 34] and is often
used prior to ERCP. Biliary strictures similar to those caused
by PSC are also found in autoimmune pancreatitis
(AIP)-associated cholangitis and immunoglobulin G4
(IgG4)-associated cholangitis (IAC), as discussed below. In
AIP-associated cholangitis, diffuse strictures are found in the
main pancreatic duct and can be differentiated from PSC
using a pancreatogram. While the cholangiogram of IAC is
basically identical to that of AIP-associated cholangitis, the
pancreatogram is normal in IAC. IAC is differentiated from
PSC on the basis of a high level of serum IgG4 and the
cholangiogram. Whereas bile duct strictures are found both
in PSC and IAC (as well as AIP-associated cholangitis),
there are slight differences in the findings of cholangiogra-
phy. In PSC, band-like strictures, a beaded appearance, a
pruned-tree appearance, and diverticulum-like outpouching
are frequently observed (Fig. 1). In IAC, segmental stric-
tures, dilatation after confluent strictures, and strictures of
the lower common bile duct are often found [35].
Liver biopsy shows specific findings of fibro-obliterative
cholangitis (‘onion-skinning fibrosis’) only in approxi-
mately 13% of PSC cases and therefore may not be a
diagnostic requirement, considering the possibilities of
serious complications of this procedure [36]. However,
for IBD patients with high ALP levels despite normal
cholangiograms, liver biopsies should be performed due to
the possibility of small-duct PSC.
CCC occurs in 0.6–1.2% of PSC patients every year
[15, 16]. CCC carries a poor prognosis, and therefore annual
follow-up examinations are recommended using serum
CA19-9, ultrasound, computed tomography (CT), magnetic
resonance imaging, and other imaging diagnostic tests [16].
Treatment
Ursodeoxycholic acid (UDCA) is widely used for treating
PSC. Previous randomized controlled trials used the dos-
ages of 13–15, 17–23, and 28–30 mg/kg per day. While
UDCA improved hepatic function test data, there were no
clinical benefits, including survival rate, LT rate and his-
tologic progression [37–39]. Meanwhile, UDCA-untreated
PSC was reported to be a risk factor for hepatobiliary
malignancy [40]. In addition, UDCA has an inhibitive
effect on colorectal neoplasia in patients with UC and PSC
[41], indicating that UDCA is a useful chemopreventive
agent for patients with PSC. Steroids and infliximab [42]
are not effective in the treatment of PSC.
When dominant strictures are observed in the common
bile duct, common hepatic duct, or right and left hepatic
duct in the extrahepatic biliary tree, the stricture is
Fig. 1 Typical ERCP and colonoscopy images of PSC. a Endoscopic
retrograde cholangiography revealed diffuse narrowing of intrahe-
patic and extrahepatic bile ducts with band-like stricture (whitearrows), pruned-tree appearance (yellow arrows) and diverticulum-
like outpouching (blue arrow), which are typical findings of PSC.
b Endoscopic retrograde pancreatography showed no abnormality in
the main pancreatic duct. c, d Colonoscopy revealed diffuse, marked
granularity of the mucosa with edema, redness and small erosions,
which are compatible with active phase of UC, in the proximal colon.
The findings of active inflammation were not observed in the distal
colon. These are the findings of right-sided colitis, which is relatively
frequent in the patients of UC-associated PSC
Clin J Gastroenterol (2012) 5:1–8 3
123
expanded with a dilator or pneumatic balloon under ERCP.
Dominant strictures are found in approximately 20% of
patients with PSC [43]. Endoscopic treatment not only
alleviates the symptoms on a short-term basis, but also
improves survival and long-term prognosis [44, 45].
LT is the only therapeutic option for end-stage PSC. Its
therapeutic results are excellent, with 85–89% of patients
surviving for 5 years after transplantation [46] and 70%
surviving for 10 years after transplantation [47]. While
20% of patients have recurrent PSC in the graft after
transplantation [48], it is not considered to have a major
impact on prognosis. It is difficult to determine when LT
should be performed in patients with PSC. The model for
end-stage liver disease score, which has been widely used
in predicting the prognosis of end-stage liver insufficiency,
does not necessarily apply to PSC [49].
Small-duct PSC
Some patients show normal cholangiograms, despite
increased ALP and other histologic findings indicative of
PSC. These patients are considered to have a subtype of PSC,
called small-duct PSC, where the small biliary ducts are the
only affected sites. There are no differences in age of onset or
the male/female ratio between small-duct PSC and classical
PSC, and IBD is involved in 80% of patients with small-duct
PSC. In one study, compared with classical PSC, the LT-free
survival time of patients with small-duct PSC was signifi-
cantly longer, and 23% moved into a classical PSC stage
during the observation period [50]. Therefore, in IBD
patients with high ALP levels and normal cholangiograms
under MRCP or ERCP, small-duct PSC should be suspected,
and a liver biopsy should be performed.
IgG4-associated cholangitis
IAC is characterized by high serum IgG4 levels and intra-
hepatic or extrahepatic biliary strictures. The disease was
first thought to be AIP associated with PSC-like cholangitis
(AIP-associated cholangitis), but it was later revealed that
AIP-negative IAC cases exist. Histologically, IgG4-positive
plasma cell infiltrate near the bile duct lesion [51]. Despite
the similarity with PSC by cholangiogram, there are slight
differences [35]. It was reported that 9% of PSC patients had
high serum IgG4 levels [52]. Investigation will be needed to
determine whether IAC is included in these patients. Unlike
PSC, IAC responds well to corticosteroids [51], and there-
fore an accurate diagnosis is essential.
Autoimmune hepatitis/PSC overlap syndrome
Cases with the histologic characteristics of autoimmune
hepatitis (AIH) and typical PSC features on cholangiography
are called AIH/PSC overlap syndrome. It has been sug-
gested that AIH/PSC overlap syndrome is associated with
UC. In a prospective study, 7 of 41 PSC patients had AIH
overlap, and 2 of them had UC [53]. The prognosis of AIH/
PSC overlap syndrome is better than that of classical PSC,
and treatment with immunosuppressive agents and UDCA
is considered beneficial [53].
Important points in the management
of PSC-associated UC
In order to detect UC, colonoscopy is highly recom-
mended for screening after diagnosis of PSC whether or
not the patient has symptoms of colitis. For this exami-
nation, total colonoscopy should be performed instead of
sigmoidoscopy, since the proximal colitis is more often
observed in PSC-associated UC. Conversely, MRCP
should be performed when a UC patient shows an
increase in ALP or other biliary enzymes, due to a pos-
sible involvement of PSC. In the case of a normal chol-
angiogram, a liver biopsy is recommended. Patients with
PSC-associated UC often have no symptoms or mild
symptoms, but attention should be paid to the high risk of
colorectal neoplasia. Even in cases of asymptomatic UC,
5-aminosalicylic acid (5-ASA) agents [54] and/or UDCA
should be considered for chemoprevention against colo-
rectal neoplasia. A total colonoscopy should be conducted
annually for regular surveillance. Colorectal cancer may
develop even after LT for treatment of PSC, and therefore
surveillance colonoscopy should be performed on a
regular basis.
Pancreatitis
Epidemiology
IBD patients have a high risk of acute pancreatitis or
chronic pancreatitis [55–57], which is a significant HPBM
with potentially serious outcomes. Clinically evident pan-
creatitis is comorbid in approximately 2% of IBD patients
[58]. The incidence of hyperamylasemia is as high as
5.8–15.8% in patients with IBD [59]; pancreatic exocrine
ability is lowered in 30–40% of patients with IBD [58, 60],
and abnormal pancreatograms are detected by ERCP or
MRCP in 8.4–10.6% of patients with IBD [58, 59]. As
such, subclinical pancreatitis is thought to be frequently
associated with IBD.
Etiology
The etiology of IBD-associated pancreatitis is wide-
ranging. Cholelithiasis is frequently found in patients
4 Clin J Gastroenterol (2012) 5:1–8
123
with CD. Furthermore, pancreatitis may be induced by
some of the drugs used to treat IBD, such as aza-
thioprine/6-mercaptopurine, 5-ASA, and corticosteroids
[61, 62]. IBD-associated acute pancreatitis may be
caused by cholelithiasis or drugs [63], although drug-
induced acute pancreatitis is not strictly considered a
HPBM of IBD. Pancreatitis is also caused by obstruction
of pancreatic fluid outflow due to duodenal lesions of
CD [64]. In 8% of pancreatitis occurring in CD patients,
a cause could not be identified [63], and such cases are
classified as idiopathic pancreatitis. The characteristics of
previously defined idiopathic IBD-related pancreatitis are
similar to those of AIP [56, 58]. At least some cases of
idiopathic IBD-related pancreatitis are considered to be
AIP [65, 66]. AIP is divided into type 1 (lymphoplas-
macytic sclerosing pancreatitis) and type 2 (granulocyte
epithelial lesion-associated) [67]. Type 2 is more fre-
quently associated with IBD [68]. Furthermore, a case of
granulomatous inflammation in the pancreas was reported
to be diagnosed as CD-related pancreatitis [69]. An
autoantibody against a pancreatic antigen was reported in
the serum of 39% of CD patients and 4% of UC patients
[70]. A more recent report found that 32% of CD
patients and 23% of UC patients had the autoantibody
[71]. However, the presence of the pancreatic autoanti-
body is not related to a history of pancreatitis, lowered
pancreatic exocrine function, or abnormal pancreatogra-
phy [58]. Therefore, its role in pancreatitis has not been
demonstrated.
Diagnosis
Acute pancreatitis is diagnosed when 2 of the follow-
ing 3 conditions are satisfied: (1) abdominal pain
characteristic of acute pancreatitis, (2) serum amylase
or lipase concentration 3 times or more above the upper
limit of normal, and (3) characteristic findings of acute
pancreatitis on a CT scan [72]. Chronic pancreatitis is
diagnosed on the basis of manifestation of clinical signs
and symptoms, echo of pancreatolith on ultrasound or
endoscopic ultrasound, intrapancreatic calcification
imaged by CT, irregular dilatation of branch pancreatic
duct imaged by ERCP, and pancreatic parenchyma
decrease or intralobular fibrosis detected by pancreatic
tissue examination [73]. AIP is strongly suspected on
the basis of typical pancreatography (Fig. 2)—the
presence of a long, narrow stricture, lack of upstream
dilatation from the stricture, side branches arising from
the strictured portion of the duct, and multiple non-
continuous strictures—and high serum IgG4 levels; it is
definitively diagnosed upon a good response to steroid
treatment [67, 74]. However, the serum IgG4 level is
not increased in type 2 AIP, which is frequently asso-
ciated with IBD, and attention is therefore required
[68].
Treatment
For acute pancreatitis, proteolytic enzyme inhibitors are
administered together with sufficient infusion liquid, fre-
quent vital sign monitoring, systemic management
according to disease severity, and intravenous narcotic
medication for pain relief. Additionally, the drug thought to
have induced pancreatitis is to be stopped. When choleli-
thiasis is observed, endoscopic or surgical treatment should
be performed at an appropriate time. Treatment with oral
prednisolone at 30–40 mg/day should be started in patients
with suspected AIP [75].
Fig. 2 Typical CT and ERCP images of AIP. a CT scan revealed a ‘sausage-like appearance’ with diffuse swelling of pancreas head, body and
tail. b ERCP showed diffuse narrowing of the main pancreatic duct with irregular walls (arrows)
Clin J Gastroenterol (2012) 5:1–8 5
123
Cholelithiasis
Epidemiology
Gallstones are found in 11–34% of patients with CD; there is
a significantly higher prevalence in patients with CD than in
the general population or in patients with UC [76–78].
Similarly, a large case–control study found that the incidence
of gallstones in CD patients was higher than that in the
control or UC groups [79]. However, the risk of gallstones in
patients with UC is controversial; while some reports have
found that the risk is higher in patients with UC [80], others
have found no difference [79, 81]. The following are
considered risk factors for gallstones in patients with CD:
ileo-colonic distribution, disease duration of C15 years, C3
recurrences, C2 past surgeries, ileocecal resection, C30 cm
ileectomy, C3 hospitalizations, and C2 long-term hospital-
izations with parenteral nutrition [76, 79].
Diagnosis
The diagnostic symptom of gallstones is right hypo-
chondrial pain after a meal, but it is often asymptomatic.
The presence of gallstones is checked by ultrasound.
Treatment
Laparoscopic cholecystectomy or extracorporeal shock-
wave lithotripsy is performed [82].
Conclusion
IBD-associated HPBMs may have complicated patholo-
gies, serious progression, and impact IBD management.
Differential diagnosis is important in some cases due to
similar image findings. Therefore, careful attention is
needed. Because the therapeutic strategy and prognosis
largely depend upon diagnosis, diagnostic accuracy is of
utmost importance. Appropriate treatment is required with
close coordination between the gastroenterologist, hepa-
tologist, pancreatologist, and surgeon.
Conflict of interest K. Nakamura received a research Grant from
Astellas Pharma Inc. and AstraZeneca.
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