John E. Eaton

Pathogenesis of Primary Sclerosing Cholangitis and Advances in Diagnosis and Management

Primary sclerosing cholangitis (PSC), first described in the mid-1850s, is a complex liver disease that is heterogeneous in its presentation. PSC is characterized by chronic cholestasis associated with chronic inflammation of the biliary epithelium, resulting in multifocal bile duct strictures that can affect the entire biliary tree. Chronic inflammation leads to fibrosis involving the hepatic parenchyma and biliary tree, which can lead to cirrhosis and malignancy. The etiology of PSC is not fully understood, which in part explains the lack of effective medical therapy for this condition. However, we have begun to better understand the molecular pathogenesis of PSC. The recognition of specific clinical subtypes and their pattern of progression could improve phenotypic and genotypic classification of the disease. We review our current understanding of this enigmatic disorder and discuss important topics for future studies.

High-Dose Ursodeoxycholic Acid Is Associated With the Development of Colorectal Neoplasia in Patients With Ulcerative Colitis and Primary Sclerosing Cholangitis

OBJECTIVES:Some studies have suggested that ursodeoxycholic acid (UDCA) may have a chemopreventive effect on the development of colorectal neoplasia in patients with ulcerative colitis (UC) and primary sclerosing cholangitis (PSC). We examined the effects of high-dose (28–30 mg/kg/day) UDCA on the development of colorectal neoplasia in patients with UC and PSC.METHODS:Patients with UC and PSC enrolled in a prior, multicenter randomized placebo-controlled trial of high-dose UDCA were evaluated for the development of colorectal neoplasia. Patients with UC and PSC who received UDCA were compared with those who received placebo. We reviewed the pathology and colonoscopy reports for the development of low-grade or high-grade dysplasia or colorectal cancer.RESULTS:Fifty-six subjects were followed for a total of 235 patient years. Baseline characteristics (including duration of PSC and UC, medications, patient age, family history of colorectal cancer, and smoking status) were similar for both the groups. Patients who received high-dose UDCA had a significantly higher risk of developing colorectal neoplasia (dysplasia and cancer) during the study compared with those who received placebo (hazard ratio: 4.44, 95% confidence interval: 1.30–20.10, P=0.02).CONCLUSIONS:Long-term use of high-dose UDCA is associated with an increased risk of colorectal neoplasia in patients with UC and PSC.

Accuracy of Spleen Stiffness Measurement in Detection of Esophageal Varices in Patients With Chronic Liver Disease: Systematic Review and Meta-analysis

BACKGROUND & AIMS Spleen stiffness measurement (SSM) is a promising noninvasive alternative to esophagogastroduodenoscopy (EGD) that could be used in the diagnosis of esophageal varices (EV) in patients with cirrhosis. However, its overall diagnostic accuracy in various clinical settings is unknown. We conducted a systematic review and meta-analysis of studies that compared the accuracy of SSM with that of EGD in detecting EV in patients with chronic liver disease. METHODS Through a systematic search of bibliographic databases and conference proceedings, and contact with authors, we identified 12 studies that reported the accuracy of SSM, compared with EGD, in the diagnosis of any and/or clinically significant EV in adults with chronic liver disease. In a meta-analysis, we combined measures of test performance of individual studies. RESULTS Based on pooled estimates, SSM detected the presence of any EV with 78% sensitivity (95% confidence interval [CI], 75%-81%), 76% specificity (95% CI, 72%-79%), a positive likelihood ratio (LR) of 3.4 (95% CI, 2.3-4.9), a negative LR of 0.2 (95% CI, 0.1-0.4), and a diagnostic odds ratio of 19.3 (95% CI, 7.5-49.8). In a meta-analysis of 9 studies, SSM detected the presence of clinically significant EV with 81% sensitivity (95% CI, 76%-86%), 66% specificity (95% CI, 61%-69%), a positive LR of 2.5 (95% CI, 1.7-3.9), a negative LR of 0.2 (95% CI, 0.1-0.5), and a diagnostic odds ratio of 12.6 (95% CI, 5.5-28.7). There was significant heterogeneity among studies owing to differences in elastography techniques and study locations. The included studies that were at risk for spectrum bias, review bias, and disease progression bias. CONCLUSIONS Based on a meta-analysis, current techniques for measuring spleen stiffness are limited in their accuracy of EV diagnosis; these limitations preclude widespread use in clinical practice at this time.

Likelihood of Malignancy in Gallbladder Polyps and Outcomes Following Cholecystectomy in Primary Sclerosing Cholangitis

OBJECTIVES:Patients with primary sclerosing cholangitis (PSC) have an increased risk for gallbladder cancer. We aimed to define the postoperative outcomes in PSC patients after cholecystectomy and determine if size of a gallbladder lesion on imaging predicts the presence of neoplasia.METHODS:We conducted a retrospective review of patients with PSC who underwent cholecystectomy at Mayo Clinic between 1 January 1995 and 31 December 2008. Patients with a prior history of a liver transplant or cholangiocarcinoma were excluded.RESULTS:A total of 57 patients were included in our primary analysis during the early postoperative period. The most common indication for undergoing a cholecystectomy was the presence of a gallbladder polyp or mass. The sensitivity and specificity of a gallbladder lesion of 0.80 cm and the presence of gallbladder neoplasia was 100% (95% confidence interval (CI) 77–100%) and 70% (95% CI 35–93%), respectively. Of the patients, 23 (40%) had an early postoperative complication. The Child-Pugh score was the only predictor of postoperative outcomes in the multivariate model (odds ratio 1.78, 95% CI 1.11–3.12, P=0.02).CONCLUSIONS:Cholecystectomy in patients with PSC is associated with a high morbidity. Gallbladder polyps <0.80 cm are unlikely to be malignant and observation of these small polyps should be considered. A higher Child-Pugh score was associated with early postoperative complications.

Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (rG) between PSC and ulcerative colitis (UC) (rG = 0.29) was significantly greater than that between PSC and Crohns disease (CD) (rG = 0.04) (P = 2.55 × 10−15). UC and CD were genetically more similar to each other (rG = 0.56) than either was to PSC (P < 1.0 × 10−15). Our study represents a substantial advance in understanding of the genetics of PSC.

Primary Sclerosing Cholangitis as a Premalignant Biliary Tract Disease: Surveillance and Management

Primary sclerosing cholangitis (PSC) is a premalignant biliary tract disease that confers a significant risk for the development of cholangiocarcinoma (CCA). The chronic biliary tract inflammation of PSC promotes pro-oncogenic processes such as cellular proliferation, induction of DNA damage, alterations of the extracellular matrix, and cholestasis. The diagnosis of malignancy in PSC can be challenging because inflammation-related changes in PSC may produce dominant biliary tract strictures mimicking CCA. Biomarkers such as detection of methylated genes in biliary specimens represent noninvasive techniques that may discriminate malignant biliary ductal changes from PSC strictures. However, conventional cytology and advanced cytologic techniques such as fluorescence in situ hybridization for polysomy remain the practice standard for diagnosing CCA in PSC. Curative treatment options of malignancy arising in PSC are limited. For a subset of patients selected by using stringent criteria, liver transplantation after neoadjuvant chemoradiation is a potential curative therapy. However, most patients have advanced malignancy at the time of diagnosis. Advances directed at identifying high-risk patients, early cancer detection, and development of chemopreventive strategies will be essential to better manage the cancer risk in this premalignant disease. A better understanding of dysplasia definition and especially its natural history is also needed in this disease. Herein, we review recent developments in our understanding of the risk factors, pathogenic mechanisms of PSC associated with CCA, as well as advances in early detection and therapies.

Prospective Clinical Trial of Rifaximin Therapy for Patients With Primary Sclerosing Cholangitis.

Primary sclerosing cholangitis (PSC) is a rare, chronic, cholestatic liver disease in which emerging data suggest that oral antibiotics may offer therapeutic effects. We enrolled patients with PSC in a 12-week, open-label pilot study to investigate the efficacy and safety of 550 mg of oral rifaximin twice daily. The primary end point was serum alkaline phosphatase (ALK) at 12 weeks. Secondary end points included (1) serum bilirubin, gamma-glutamyl transpeptidase, and Mayo PSC risk score; (2) fatigue impact scale, chronic liver disease questionnaire, and short form health survey (SF-36) scores; and (3) adverse effects (AEs). Analyses were performed with nonparametric tests. Sixteen patients were enrolled, among whom the median age was 40 years; 13 (81%) were male, 13 had inflammatory bowel disease, and baseline ALK was 342 IU/mL (interquartile range, 275–520 IU/mL). After 12 weeks of treatment, there were no significant changes in ALK (median increase of 0.9% to 345 IU/mL; P = 0.47) or any of the secondary biochemical end points (all P > 0.05). Similarly, there were no significant changes in fatigue impact scale, chronic liver disease questionnaire, or SF-36 scores (all P > 0.05). Three patients withdrew from the study due to AEs; 4 others reported mild AEs but completed the study. In conclusion, although some antibiotics may have promise in treating PSC, oral rifaximin, based on the results herein, seems inefficacious for this indication. Future studies are needed to understand how the antimicrobial spectra and other properties of antibiotics might determine their utility in treating PSC.

Duration of Inflammatory Bowel Disease Is Associated With Increased Risk of Cholangiocarcinoma in Patients With Primary Sclerosing Cholangitis and IBD.

OBJECTIVES:Primary sclerosing cholangitis (PSC) often coexists with inflammatory bowel disease (IBD) and can be complicated by cholangiocarcinoma (CCA), a lethal malignancy for which reliable predictors remain unknown. We aimed to characterize the influence of colectomy and IBD duration on risk of CCA in patients with PSC-IBD.METHODS:A retrospective review of patients with PSC-IBD seen at the Mayo Clinic, Rochester, between January 2005 and May 2013 was performed. The primary outcome was time to development of CCA and our goal was to determine whether the risk differed between patients with and without colectomy. Risk factors were assessed using univariable and multivariable Cox proportional hazard models where colectomy, IBD disease duration, and development of advanced liver disease were treated as time-dependent covariates.RESULTS:A total of 399 patients with PSC-IBD were included in the study, of whom 137 had a colectomy and 123 patients developed CCA. Age-adjusted univariate Cox proportional hazard models demonstrated that colectomy (hazard ratio (HR) 1.53, 95% confidence interval (CI) 1.05–2.22, P=0.02) and duration of IBD (HR 1.37, 95% CI 1.15–1.63, P<0.01) were associated with an increased risk of CCA, and colonic neoplasia (HR 1.52, 95% CI 0.97–2.37, P=0.06) and colectomy for colonic neoplasia (HR 1.62, 95% CI 1.01–2.61, P=0.05) approached significance. Among patients with a history of colectomy, colonic neoplasia as the indication for surgery was associated with a particularly increased risk of CCA (HR 2.91, 95% CI 1.24–6.84, P=0.01) compared with medically refractory disease. On multivariate analysis, duration of IBD remained significantly associated with CCA (HR 1.33, 95% CI 1.11–1.60, P<0.01). The influence of IBD duration on CCA risk was not modified after colectomy (P=0.69).CONCLUSIONS:Prolonged duration of IBD is associated with an increased risk of CCA in patients with PSC-IBD, and colectomy itself does not modify this risk. These findings identify a subset of patients who are at high risk of this lethal complication and in need of close surveillance.

Performance of magnetic resonance elastography in primary sclerosing cholangitis

Liver stiffness (LS) measured by magnetic resonance elastography (MRE) is emerging as an important biomarker in chronic liver diseases. We examined the diagnostic performance of MRE, factors associated with an increased LS and the prognostic value of LS as measured by MRE among patients with primary sclerosing cholangitis (PSC).

Biliary Multifocal Chromosomal Polysomy and Cholangiocarcinoma in Primary Sclerosing Cholangitis

Objectives:Polysomy detected by fluorescence in situ hybridization (FISH) is associated with cholangiocarcinoma (CCA) in patients with primary sclerosing cholangitis (PSC). However, a subset of PSC patients with polysomy do not manifest CCA even after long-term follow-up. It is unknown if patients with chromosomal gains detected by FISH in multiple areas of the biliary tree (i.e., multifocal polysomy, MFP) are more likely to be diagnosed with CCA than patients with unifocal polysomy (UFP). Therefore, our aim is to determine whether patients with MFP are more likely to manifest CCA compared with patients with other chromosomal abnormalities including UFP and other FISH subtypes.Methods:We performed a retrospective review of PSC patients without a mass lesion who underwent FISH testing at our institution from 1 January 2005 to 1 July 2013.Results:Three-hundred and seventy-one PSC patients were included. Compared with patients with UFP, those with MFP were more likely to have weight loss (32 vs. 9%), suspicious cytology (45 vs. 13%) and develop serial polysomy (91 vs. 35%). MFP was associated with CCA (hazard ratio (HR), 82.42; 95% confidence interval (CI), 24.50–277.31) and was the strongest predictor of cancer diagnosis. Suspicious cytology (HR, 26.31; 95% CI, 8.63–80.24) and UFP (HR, 13.27; 95% CI, 3.32–53.08) were also predictive of CCA. MFP, UFP and suspicious cytology remained associated with CCA in the multivariable model.Conclusions:Compared with other FISH subtypes, MFP is the strongest predictor of CCA. However, patients with UFP and suspicious cytology (regardless of FISH status) are also at an increased risk for CCA.