Primary billiary cirrhosis (PBC), primary sclerosing cholangitis (PSC), ulcerative colitis (UC) and colorectal cancer (CRC) are common diseases. PBC is marked by the slow progressive destruction of the small bile ducts (bile canaliculi) within the liver. When these ducts are damaged, bile builds up in the liver (cholestasis) and over time damages the tissue. This can lead to scarring, fibrosis and cirrhosis. PSC is a chronic liver disease caused by progressive immune-mediated inflammation and subsequent fibrosis of the bile ducts of the liver with the development of multiple strictures due to an intrinsic liver disease. The underlying cause of the inflammation is believed to be autoimmunity. Both PBC and PSC can be induced by autoimmune reactions. There are multiple similarities between these two diseases that may cause confusion or misdiagnosis, especially at the onset stage, including symptoms of fatigue, abdominal discomfort, pruritus and weight loss. [1] Diagnosis of PBC and PSC needs to be confirmed by liver biopsy.

UC is a chronic inflammatory disease of the colon characterized by intermittent exacerbations and remissions. It may be complicated with colon cancer or autoimmune-related extracolonic problems. It is not rare that PBC can be associated with UC and in such association occurrence of these diseases may not have particular order. [2] [3] Burnevich et al. reported that 24.1% of PBC patients has extrahepatic manifestations including UC. [4] It has also been reported that PBC can happen after proctocolectomy for ulcerative colitis. [2] There are many evidences that UC can be associated with PSC. Approximately, three quarters of patients with PSC have inflammatory bowel disease (IBD), e.g. UC or Crohn's disease [5] and 2–7.5% patients with UC have PSC. [6] [7] [8] [9] It is, generally, accepted that approximately 5% of patients with UC will have the associated PSC.

We describe a complicated case of association of PBC and chronic UC, eventually progressed to PSC and CRC. Some special common mechanisms may be involved in the pathogenesis of these diseases.

A 41-year-old female was admitted with complaint of aggravated abdominal pain and diarrhea for five days accompanied with high fever. The patient was diagnosed with PBC 10 years ago based on pathological examination of liver biopsy. Three years later, a colonoscopy examination proved a diagnosis of UC (Figure 1A). Symptoms including jaundice, pruritus and diarrhea persisted throughout the next seven years during which cholecystolithiasis developed in 2003 and relapsed in 2007. Four months before admission, the patient underwent hysterectomy and resection of right ovarian cyst along with right ovarian appendage in a local hospital. Rectovaginal fistula and rectal stenosis occurred one month later after surgery. A metal stent was placed into the rectum. X-ray exhibited partial intestine dilation with intermediate obstruction (beading). Magnetic resonance cholangiopancreatography (MRCP) showed typical appearance of PSC like diffuse strictures of both intrahepatic and extrahepatic bile ducts with dilation of the intervening areas and multiple bile duct stones in the common bile duct (Figure 1B–C). Severe abdominal pain and increasing skin icterus accompanied with high fever led us to take the patient for surgery. The laboratory test results of the patient are given in Table 1. A total colectomy and ileostomy were performed.

Peroperative findings: During surgery significant adhesions were observed in abdominal and pelvic cavity. Nodular cirrhosis of liver and splenomegaly was found. Biopsy from left external lobe of the liver was taken for pathological examination. Ascending colon, cecum and small intestine were dilated with thickening and swelling of bowel wall. A hard mass of 3x3x3 cm invading the submucosa was found in ascending colon near the hepatic flexure which was causing intestinal obstruction. Distal colon and upper part of rectum were thickened and stiff.

Pathological results and final diagnosis: Histopathological examination of colon showed mucosal atrophy with loss of crypts and distortion of the mucosal architecture. Some of the crypts were shortened and branching. Transmucosal inflammation with basal plasmacytosis, lymphocytosis and eosinophilia were evidenced by the presence of neutrophils infiltrating the wall of some crypts. Thickening of mucosal muscularis layer and hyperplasia of fibrotic and fatty tissue in the submucosal layer indicated late stage of ulcerative colitis (Figure 2A). Grade II cololic adenocarcinoma was found which was invading all the layers of colon from epithelium to serosa to the surrounding connective tissue (Figure 2B). Lymph nodes metastasis was found positive in one out of 10 lymph nodes. The final diagnosis was UC concomitant with PSC complicated by colonic adenocarcinoma, liver cirrhosis, hypersplenism, post-cholecystectomy, post-hysterectomy, and post-unilateral adnexectomy. The patient was regularly followed-up so far and was given Pentasa, 1 g, qid, po; UDCA 25o mg, bid po. and UDCA without discomfort.

This case was a complicated, multi-disease long-duration clinical manifestation. Although certain diseases discussed here may be an isolated event, most of the diagnoses reported in literature have shown a pattern of more or less interconnection with a common mechanism for disease progression.

Liver biopsy clearly indicated that the onset of all symptoms in this case started from PBC and progressed to UC and further to PSC. It is unclear whether PBC can directly progress to PSC. Not many cases about PBC progression to PSC have been reported. Jeevagan et al. report one case recently that PBC and PSC were diagnosed in the same patient but failed to clarify whether it is just an overlapping phenomenon or progression of one disease to another. [10] In a large study in Sweden with 1500 UC patients, it was found that 5% patients had increased serum alkaline phosphatase and 3.7% had evidence of PSC. [11] The same study showed that 95% patients who had PSC were found to have UC. In another study, 14% (48/336) patients with UC had evidence of hepatobiliary pathology and 4% patients with UC had PSC. [12] In our case, the patient received ERCP twice for removing stones in bile duct. It is reported that cholecystolithiasis was found in 23/41 (56%) UC patients, of which 7/23 (30%) were missed on cholangiography and detected only by cholangioscopy. [13] Major investigations for stone detection include CT scan, sonography and cholangiogram. Endoscopic therapy can provide drainage of bile ducts, removal of stones and/or temporary relief from obstruction. [14]

After the prolonged duration of UC, the possibility of CRC should be highly suspected. The patient was found to have CRC during the surgical operation, which has already invaded through the whole layer including serosa with lymph node metastasis.

UC-PSC shows unique colonoscopy features and is associated with more frequent colorectal neoplasm development and poor prognosis. [15] The overlap of UC and PSC constitutes a higher risk of developing colorectal dysplasia/carcinoma than UC patients without PSC. Prolonged disease duration of IBD is another important risk factor for CRC. [16] Eaden's meta-analysis has shown that the risk for CRC in UC patients is 2% at 10 years, 8% at 20 years and 18% at 30 years of disease duration. [17] The onset of CRC was significantly younger in patients with IBD and PSC. [7] Terg R et al. once analyzed the prevalence of PSC in 1,333 patients with UC and the risk for developing colon cancer. Seven (18%) out of 39 patients with PSC developed colorectal carcinoma compared with 2 out of 78 (2.6%) in the control group (p=0.006). The cumulative risk of colorectal carcinoma was 11% and 18% after 10 and 20 years in the PSC group compared with 2% and 7% in the control group, respectively (p=0.002). [9] It is highly recommended to have early and/or regular colonoscopy screening for IBD patients with or without PSC.

Prolonged IBD accompanied with PSC is not an uncommon disease that has high risk of CRC. Close follow-up of patient with regular colonoscopy for neoplasm detection will help in the early diagnosis and extension of life span. Additional research studies such as prospective studies that might be pursued to gain insight into the disease evolution and relationship between IBD, PBC, PSC and CRC. Additionally, exploring when CRC screening should begin in IBD and PSC patients would be an interesting topic.

The research was supported by the Science Foundation of Nanjing Science & Technology Bureau of China (Grant. No. 2010ZD220) and the National Natural Science Foundation of China (Grant No. 81101800/H1617).

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