Clin J Gastroenterol (2012) 5:1–8 DOI 10.1007/s12328-011-0282-1
CLINICAL REVIEW
Hepatopancreatobiliary manifestations of inflammatory bowel 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 Ó 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. Therefore, 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 cholangiography, it must be carefully differentiated from immunoglobulin 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 pancreatitis. 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 characteristic image findings, because AIP responds well to corticosteroids. Crohn’s disease is frequently associated with
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]
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 abnormal 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 extraintestinal manifestations have a 25–40% prevalence and include musculoskeletal, mucocutaneous, ophthalmologic, hepatopancreatobiliary, hematologic, bronchopulmonary, urinary, and metabolic diseases [2, 3]. Hepatopancreatobiliary 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.
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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 studies, 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 PSCassociated 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].
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 surveillance is required even after surgery.
Natural history
Diagnosis
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.
PSC patients are often asymptomatic at the time of diagnosis but scrutinized by imaging modalities due to abnormal 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. Autoantibodies, 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 cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP) that detects diffuse, multifocal strictures in medium-sized intrahepatic bile ducts or medium- 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
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 haplotype, 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
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
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Fig. 1 Typical ERCP and colonoscopy images of PSC. a Endoscopic retrograde cholangiography revealed diffuse narrowing of intrahepatic and extrahepatic bile ducts with band-like stricture (white arrows), pruned-tree appearance (yellow arrows) and diverticulumlike 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
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 cholangiography. In PSC, band-like strictures, a beaded appearance, a pruned-tree appearance, and diverticulum-like outpouching are frequently observed (Fig. 1). In IAC, segmental strictures, 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 approximately 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 dosages 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 histologic 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
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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 significantly 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.
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are called AIH/PSC overlap syndrome. It has been suggested 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 recommended for screening after diagnosis of PSC whether or not the patient has symptoms of colitis. For this examination, 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 possible involvement of PSC. In the case of a normal cholangiogram, 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 colorectal 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 IgG4-associated cholangitis Epidemiology IAC is characterized by high serum IgG4 levels and intrahepatic 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 therefore an accurate diagnosis is essential.
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 pancreatitis 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.
Autoimmune hepatitis/PSC overlap syndrome
Etiology
Cases with the histologic characteristics of autoimmune hepatitis (AIH) and typical PSC features on cholangiography
The etiology of IBD-associated pancreatitis is wideranging. Cholelithiasis is frequently found in patients
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with CD. Furthermore, pancreatitis may be induced by some of the drugs used to treat IBD, such as azathioprine/6-mercaptopurine, 5-ASA, and corticosteroids [61, 62]. IBD-associated acute pancreatitis may be caused by cholelithiasis or drugs [63], although druginduced 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 (lymphoplasmacytic sclerosing pancreatitis) and type 2 (granulocyte epithelial lesion-associated) [67]. Type 2 is more frequently 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 autoantibody is not related to a history of pancreatitis, lowered pancreatic exocrine function, or abnormal pancreatography [58]. Therefore, its role in pancreatitis has not been demonstrated. Diagnosis Acute pancreatitis is diagnosed when 2 of the following 3 conditions are satisfied: (1) abdominal pain
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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 noncontinuous 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 associated with IBD, and attention is therefore required [68]. Treatment For acute pancreatitis, proteolytic enzyme inhibitors are administered together with sufficient infusion liquid, frequent 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 cholelithiasis 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)
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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 hospitalizations with parenteral nutrition [76, 79]. Diagnosis The diagnostic symptom of gallstones is right hypochondrial pain after a meal, but it is often asymptomatic. The presence of gallstones is checked by ultrasound. Treatment Laparoscopic cholecystectomy or extracorporeal shockwave lithotripsy is performed [82].
Conclusion IBD-associated HPBMs may have complicated pathologies, 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, hepatologist, pancreatologist, and surgeon. Conflict of interest K. Nakamura received a research Grant from Astellas Pharma Inc. and AstraZeneca.
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CLINICAL REVIEW
Hepatopancreatobiliary manifestations of inflammatory bowel 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 Ó 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. Therefore, 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 cholangiography, it must be carefully differentiated from immunoglobulin 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 pancreatitis. 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 characteristic image findings, because AIP responds well to corticosteroids. Crohn’s disease is frequently associated with
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]
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 abnormal 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 extraintestinal manifestations have a 25–40% prevalence and include musculoskeletal, mucocutaneous, ophthalmologic, hepatopancreatobiliary, hematologic, bronchopulmonary, urinary, and metabolic diseases [2, 3]. Hepatopancreatobiliary 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.
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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 studies, 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 PSCassociated 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].
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 surveillance is required even after surgery.
Natural history
Diagnosis
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.
PSC patients are often asymptomatic at the time of diagnosis but scrutinized by imaging modalities due to abnormal 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. Autoantibodies, 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 cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP) that detects diffuse, multifocal strictures in medium-sized intrahepatic bile ducts or medium- 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
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 haplotype, 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
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
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Fig. 1 Typical ERCP and colonoscopy images of PSC. a Endoscopic retrograde cholangiography revealed diffuse narrowing of intrahepatic and extrahepatic bile ducts with band-like stricture (white arrows), pruned-tree appearance (yellow arrows) and diverticulumlike 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
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 cholangiography. In PSC, band-like strictures, a beaded appearance, a pruned-tree appearance, and diverticulum-like outpouching are frequently observed (Fig. 1). In IAC, segmental strictures, 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 approximately 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 dosages 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 histologic 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
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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 significantly 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.
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are called AIH/PSC overlap syndrome. It has been suggested 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 recommended for screening after diagnosis of PSC whether or not the patient has symptoms of colitis. For this examination, 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 possible involvement of PSC. In the case of a normal cholangiogram, 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 colorectal 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 IgG4-associated cholangitis Epidemiology IAC is characterized by high serum IgG4 levels and intrahepatic 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 therefore an accurate diagnosis is essential.
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 pancreatitis 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.
Autoimmune hepatitis/PSC overlap syndrome
Etiology
Cases with the histologic characteristics of autoimmune hepatitis (AIH) and typical PSC features on cholangiography
The etiology of IBD-associated pancreatitis is wideranging. Cholelithiasis is frequently found in patients
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with CD. Furthermore, pancreatitis may be induced by some of the drugs used to treat IBD, such as azathioprine/6-mercaptopurine, 5-ASA, and corticosteroids [61, 62]. IBD-associated acute pancreatitis may be caused by cholelithiasis or drugs [63], although druginduced 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 (lymphoplasmacytic sclerosing pancreatitis) and type 2 (granulocyte epithelial lesion-associated) [67]. Type 2 is more frequently 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 autoantibody is not related to a history of pancreatitis, lowered pancreatic exocrine function, or abnormal pancreatography [58]. Therefore, its role in pancreatitis has not been demonstrated. Diagnosis Acute pancreatitis is diagnosed when 2 of the following 3 conditions are satisfied: (1) abdominal pain
5
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 noncontinuous 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 associated with IBD, and attention is therefore required [68]. Treatment For acute pancreatitis, proteolytic enzyme inhibitors are administered together with sufficient infusion liquid, frequent 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 cholelithiasis 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)
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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 hospitalizations with parenteral nutrition [76, 79]. Diagnosis The diagnostic symptom of gallstones is right hypochondrial pain after a meal, but it is often asymptomatic. The presence of gallstones is checked by ultrasound. Treatment Laparoscopic cholecystectomy or extracorporeal shockwave lithotripsy is performed [82].
Conclusion IBD-associated HPBMs may have complicated pathologies, 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, hepatologist, pancreatologist, and surgeon. Conflict of interest K. Nakamura received a research Grant from Astellas Pharma Inc. and AstraZeneca.
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