Aliya Gulamhusein

5-Aminosalicylic Acid Is Not Protective Against Colorectal Cancer in Inflammatory Bowel Disease: A Meta-Analysis of Non-Referral Populations

OBJECTIVES:Some studies have demonstrated that 5-aminosalicylic acid (5-ASA) is associated with a reduced risk of colorectal cancer (CRC) in inflammatory bowel disease (IBD). However, more recent population-based studies suggest no protective association. We conducted a systematic review that focused on non-referral studies to reassess the role of 5-ASA for this indication.METHODS:We searched MEDLINE, EMBASE, and the Cochrane databases for studies of non-referral populations that assessed the association between 5-ASA use for at least 1 year and colorectal neoplasia between 1966 and 2011 and conducted a quantitative meta-analysis.RESULTS:Four observational studies fulfilled inclusion criteria. The pooled adjusted odds ratio (aOR) was 0.95 (95% confidence interval (CI): 0.66–1.38), but there was moderate heterogeneity (I2=58.2%; P=0.07). A sensitivity analysis that included a fifth study in which 5-ASA use was only for a minimum of 3 months yielded a pooled aOR of 0.82 (95% CI: 0.54–1.26). A series of sensitivity analyses in which each of the four studies was excluded one at a time did not show any significant change in the overall pooled OR. We conducted a separate meta-analysis of nine clinic-based studies, which, in contrast, yielded a pooled OR of 0.58 (95% CI: 0.45–0.75).CONCLUSIONS:Our meta-analysis yielded inconsistent results that were dependent on the inclusion of either non-referral or clinic-based populations. Based on non-referral studies, there does not seem to be a protective effect of 5-ASA on CRC in IBD. However, heterogeneity among these studies limits their interpretation.

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.

Genome-Wide Association Studies in Primary Biliary Cirrhosis

Genome-wide association studies (GWASs) have been a significant technological advance in our ability to evaluate the genetic architecture of complex diseases such as primary biliary cirrhosis (PBC). To date, six large-scale studies have been performed that have identified 27 risk loci in addition to human leukocyte antigen (HLA) associated with PBC. The identified risk variants emphasize important disease concepts; namely, that disturbances in immunoregulatory pathways are important in the pathogenesis of PBC and that such perturbations are shared among a diverse number of autoimmune diseases-suggesting the risk architecture may confer a generalized propensity to autoimmunity not necessarily specific to PBC. Furthermore, the impact of non-HLA risk variants, particularly in genes involved with interleukin-12 signaling, and ethnic variation in conferring susceptibility to PBC have been highlighted. Although GWASs have been a critical stepping stone in understanding common genetic variation contributing to PBC, limitations pertaining to power, sample availability, and strong linkage disequilibrium across genes have left us with an incomplete understanding of the genetic underpinnings of disease pathogenesis. Future efforts to gain insight into this missing heritability, the genetic variation that contributes to important disease outcomes, and the functional consequences of associated variants will be critical if practical clinical translation is to be realized.

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.

The utility of screening for asymptomatic lower extremity deep venous thrombosis during inflammatory bowel disease flares: a pilot study.

Background:Asymptomatic deep vein thrombosis (DVT) occurs in up to 11% of medical inpatients. The incidence of asymptomatic DVT among patients with inflammatory bowel disease (IBD) is unknown but may be even higher. D-dimer is effective for DVT screening, but its utility has not been studied in the IBD population. Methods:Hospitalized and ambulatory patients with IBD during flares were recruited between 2009 and 2011. Those with clinical symptoms of venous thromboembolism or previous venous thromboembolism were excluded. We determined the prevalence of DVT among asymptomatic subjects using lower extremity Doppler ultrasound and assessed the performance characteristics of the D-dimer in this high-risk study population. Results:We enrolled 101 hospitalized and 49 ambulatory patients with IBD during active flares. There were no cases of proximal DVT detected by lower extremity Doppler ultrasound. The 95% confidence interval (CI) for the rate of proximal DVT was 0% to 2%. D-dimer was elevated in 60% of subjects without DVT, occurring more frequently among hospitalized than ambulatory subjects [89% versus 65%, P = 0.01; adjusted odds ratio (aOR), 4.16, 95% CI, 1.58–10.9]. Other predictors of elevated D-dimer were incremental decade in age (aOR, 1.97; 95% CI, 1.24–3.14); ulcerative colitis versus Crohn’s disease diagnosis (aOR, 3.38; 95% CI, 1.29–8.84); and every 10-unit increase in C-reactive protein (aOR, 1.33; 95% CI, 1.09–1.62). Conclusion:From this pilot study, there appears to be low prevalence of asymptomatic DVTs among patients with IBD during flares. The high prevalence of elevated D-dimer in DVT-negative patients limits its utility in IBD.

Low incidence of primary biliary cirrhosis (PBC) in the first‐degree relatives of PBC probands after 8 years of follow‐up

Primary biliary cirrhosis (PBC) is characterized by chronic cholestasis and disease‐specific antimitochondrial antibodies (AMA). A high prevalence of AMAs in first‐degree relatives (FDRs) of PBC probands has been reported, although the natural history of such patients has not been described. We aimed to assess the risk of developing PBC in AMA+ FDRs of patients with PBC.

Neutralization of IL-15 abrogates experimental immune-mediated cholangitis in diet-induced obese mice

Obesity is a global epidemic affecting chronic inflammatory diseases. Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease that can occur as an extraintestinal manifestation of inflammatory bowel disease (IBD). Previously we reported that patients with PSC who are obese have a higher risk of advanced liver disease. Currently it is unknown how obesity accelerates or worsens PSC. We evaluated the progression of PSC in an antigen-driven cholangitis mouse model of diet-induced obesity. Obesity was induced in our murine model of immune-mediated cholangitis (OVAbil). OVAbil mice were fed standard chow or high-fat/sucrose diet for twelve weeks followed by induction of biliary inflammation by OVA-specific T cell transfer. Histopathological damage in portal tracts was scored and serum collected. Neutralizing antibodies against IL-15 were administered daily until study termination. Obese mice developed exacerbated liver inflammation and damage. Immune cell phenotyping in liver revealed greater numbers of neutrophils and CD8+ T cells in obese mice. Higher levels of cytokines and chemokines were found in obese mice with cholangitis. Immuno-neutralizing antibodies against IL-15 greatly attenuated cholangitis in obese mice. Obesity exacerbated experimental PSC in part by overproduction of IL-15. Timely targeting of IL-15 may slow the progression of PSC.

External validation of the United Kingdom‐primary biliary cholangitis risk scores of patients with primary biliary cholangitis treated with ursodeoxycholic acid

The United Kingdom‐Primary Biliary Cholangitis (UK‐PBC) risk scores are a set of prognostic models that estimate the risk of end‐stage liver disease in patients with PBC at 5‐, 10‐ and 15‐year intervals. They have not been externally validated outside the United Kingdom. In this retrospective, external validation study, data were abstracted from outpatient charts and discrimination and calibration of the UK‐PBC risk scores were assessed. A total of 464 patients with PBC treated with ursodeoxycholic acid were included. The median diagnosis age was 52.4 years, and 88% were female patients. The cumulative incidence of events was 6%, 9%, and 15% at 5, 10, and 15 years, respectively. Concordance (c‐statistic) was 0.88, 0.85, and 0.84 using the 5‐, 10‐ and 15‐year risk scores, respectively, which was slightly lower than values observed in the United Kingdom validation cohort. Using the 5‐year risk score, more events were observed than predicted (25 versus 16.8; P = 0.046); using the 10‐year risk score, there was no difference between the observed and predicted number of events (35 versus 44.9; P = 0.14); conversely, using the 15‐year risk score, fewer events were observed than predicted (46 versus 67.5; P = 0.009). Limiting evaluation by the 15‐year UK‐PBC risk score to those with >10 years of follow‐up demonstrated no difference between observed and predicted events. Using the 5‐year risk score, patients within the highest quartile had statistically significant worse event‐free survival compared to the rest of the cohort: 82% versus 98% at 5 years, 73% versus 97% at 10 years, and 58% versus 93% at 15 years. Conclusion: In patients assessed at a North American tertiary medical center, the UK‐PBC risk score had excellent discrimination and was reasonably calibrated both in the short and long term. (Hepatology Communications 2018;2:676‐682)

Primary biliary cholangitis, DNA, and beyond: The Relative contribution of genes

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by immune-mediated damage to biliary epithelial cells resulting in inflammation, progressive fibrosis, cirrhosis, and liver failure. While its precise etiopathogenesis remains unclear, the disease is likely to develop in a genetically susceptible host after exposure to an as yet undefined environmental trigger (Fig. 1). The genetic contribution to PBC risk is highlighted by several lines of evidence that demonstrate a high concordance of disease in monozygotic twins, an increased prevalence in first-degree relatives (FDRs) of affected probands, a sibling relative risk (RR) of 10.5, and a high prevalence of disease-specific antimitochondrial antibodies in FDRs of affected relatives compared to population controls. Furthermore, large-scale genome-wide association studies have identified several single-nucleotide polymorphisms (SNPs) associated with PBC, though the majority of these SNPs are also associated with other autoimmune diseases. In the current issue of HEPATOLOGY, Ornolfsson et al. use a unique Icelandic database to define the familial risk of PBC beyond FDRs. Applying population-level and otherwise unprecedented genealogical data on all living Icelanders and most of their ancestors since the island’s settlement, the authors report the RR of PBC and the average kinship coefficient in first-degree through fifth-degree relatives of PBC patients compared to age, sex, and number of known relative matched controls. A 9.13-fold (95% confidence interval [CI] 4.17-16.76) increased risk of PBC in FDRs was demonstrated, with a lower but still significantly increased risk also noted among seconddegree and third-degree relatives with RRs of 3.61 (95% CI 1.48-8.92) and 2.59 (95% CI 1.35-4.67), respectively. Among fourth-degree and fifth-degree relatives, the increased risk of PBC trended toward significance with RRs of 1.66 (95% CI 1.00-3.02) and 1.42 (95% CI 0.99-2.20), respectively. The kinship coefficient, defined as the probability that two randomly selected autosomal alleles from two individuals are inherited from the same ancestor, was used as a measure of relatedness of PBC patients compared to the general population. Using this metric, PBC patients were shown to be more genetically related than population controls, even after step-wise exclusion of relatives within one to six meiotic distances. The authors rightfully conclude that their data expand on previous reports by describing familial risk of disease well beyond FDRs. Furthermore, they suggest that these findings emphasize the importance of genetic risk in the pathogenesis of PBC and support future investment in understanding the genetic underpinnings of this disease. Do these data demonstrate that genetic susceptibility is acting alone to cause disease? Not necessarily. As with most autoimmune diseases, PBC is complex; and while genetics are important, it is highly likely that individual alleles are not deterministic but rather act by modifying risk through their effect on disease-specific Abbreviations: CI, confidence interval; FDR, first-degree relative; PBC, primary biliary cholangitis; RR, relative risk; SNPs, singlenucleotide polymorphisms.

Liver transplantation in the management of perihilar cholangiocarcinoma

Cholangiocarcinoma (CCA) is the second most common primary hepatic neoplasm and accounts for 10-20% of hepatobiliary cancer-related deaths. The prognosis of patients with CCA is poor with 5-year survival rates of 10%, partially due to the limited effective treatment options that exist for this disease. In this review, we discuss the evolving role of liver transplantation in the management of patients with perihilar CCA (pCCA). We specifically discuss the Mayo Clinic protocol of neoadjuvant chemoradiation followed by liver transplantation in selected patients with pCCA and describe pretransplant, peritransplant, and post-transplant considerations and challenges with this approach. Finally, we review local, national and international outcomes and discuss future directions in optimizing this treatment strategy for patients who otherwise have few therapeutic options and limited survival.