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Abstract

Proper management of inflammatory bowel disease (IBD) in Asia requires knowledge of features unique to their population. These include disease incidence, patient demographics, clinical presentation, and response to therapy. In response to this need, the Asia-Pacific Crohn's and Colitis Epidemiology Study (ACCESS) was initiated in 2011 to prospectively study IBD in Asia (China, Hong Kong, Indonesia, Sri Lanka, Macau, Malaysia, Singapore, Thailand) and Australia. In 2013, ACCESS published in Gastroenterology their initial results describing the incidence of new cases over a 1-year period. They reported a lower overall incidence of IBD in Asia compared to the West, but 52% of Crohn's patients presented with complicated disease characterized by stricturing, penetrating, or perianal disease. In this issue of Gastroenterology, the ACCESS group reports on study patients with follow-up data for ≥6 months between 2011 and 2013. The study included 413 total patients with 330 diagnosed in Asia and 83 in Australia. At the time of diagnosis, stricturing disease was more common in Asia than Australia (18.8% vs 6.1%; P = .035). Those Crohn's disease patients who presented with stricturing or penetrating disease were at high risk for undergoing surgery. The cumulative probability for various medical treatments for Crohn's disease and ulcerative colitis in Asia is shown in Figure 1. Overall, the study revealed that early disease severity, natural history, and clinical outcomes for IBD in Asia were similar to that of the West. An accompanying editorial by Tine Jess and Gilaad Kaplan provides insights into this study. See page 86; editorial on page 24. Increased mortality from hepatic and extrahepatic disease has been shown in patients with chronic hepatitis C virus (HCV) infection. Most, but not all, studies demonstrate increased cardiovascular disease in patients with chronic HCV infection. In this issue of Gastroenterology, Petta et al have performed a metaanalysis of 22 carefully selected studies to assess the risk of HCV infection on cardiovascular disease-related morbidity and mortality. Pooled results of three cohort studies, with a total of >68,000 patients and 735 deaths, demonstrated that mortality from cardiovascular disease was increased in HCV-infected patients (odds ratio [OR], 1.65; 95% CI, 1.07-2.56; Figure 2). Pooled results of 9 case-control studies, with a total of >9000 patients, almost 2000 of whom had carotid plaques, demonstrated an increased risk of carotid atherosclerosis in HCV-infected patients (OR, 2.27; 95% CI, 1.76-2.94). The presence of carotid plaques was directly affected by smoking status. Pooled results of 8 studies (6 cohort and 2 case-control studies), with a total of >390,000 patients and >18,000 events), demonstrated an increased risk of cerebrocardiovascular events, defined as ischemic stroke, myocardial infarction, angina, congestive heart failure, or transient ischemic attack (OR, 1.30; 95% CI, 1.10-1.55). The risk was higher in cohort studies, studies of older patients (age > 50 years) and studies with a higher prevalence of patients with hypertension or diabetes mellitus. This analysis highlights that cardiovascular and cerebrovascular disease, particularly in smokers, and in patients who already have risk factors such as hypertension and diabetes mellitus, can be added to the growing list of extrahepatic manifestations, including type 2 diabetes mellitus, peripheral artery disease, and lymphoproliferative disorders, that contribute to the increased mortality observed in patients with chronic HCV infection. See page 145. Despite major and rapid advances in the development of direct acting antivirals to treat chronic infection with hepatitis C virus (HCV) that hold the promise of cure for most patients, significant barriers to treatment of all affected individuals remain. These barriers have, in part, fueled efforts to develop a vaccine that elicits neutralizing antibodies (nAbs) against HCV. However, vaccine development has been hampered by the ability of HCV to evade humoral immunity. Although the mechanisms by which HCV escapes nAbs are not understood completely, previous studies have suggested the importance of a specific amino acid site on a HCV protein, the association of HCV with triglyceride-rich lipoproteins, and the incorporation of apolipoprotein E (apoE) into the HCV particle as contributing factors mediating this escape. In this issue of Gastroenterology, Fauvelle et al, using cell infection studies and a viral variant (VL), which is refractory to previous immunopreventive approaches and vaccines, further define how HCV avoids neutralization by antibodies. Exposure of virus produced from cells cotransfected with VL:JFH1 HCV RNA, a genotype 1b variant, and a small interfering RNA that reduces apoE expression demonstrated marked sensitivity to nAbs compared with virus produced from control cells with unchanged apoE expression. Similar results were observed using genotype 1a (H77R2a) and 2 (Luc-Jc1) HCV variants (Figure 3). Ectopic apoE expression in apoE knockdown cells restored HCV escape from immunoglobulin G-specific nAbs. As a result of apoE silencing, conformational epitopes of HCV envelope glycoprotein E2 domain B and C were found to be exposed to nAbs and apoE content in immunopurified virions was reduced markedly. Mutations on a specific amino acid site (residue 447) on the periphery of a nonstructured region of the HCV envelope glycoprotein E2 also altered the conformation of the virion–apoE complex without affecting the apoE content. Down-regulation of apoE expression did not, however, affect the association of HCV with other triglyceride-rich lipoproteins or cell-to-cell transmission of HCV, another mechanism to escape nAbs. These novel findings demonstrating that apoE “shielding” of the HCV envelope glycoprotein E2 is a pangenotypic mechanism by which HCV evades nAbs may have significant implications for HCV vaccine design. See page 206. Over the past decade, significant advances have been made in defining the most common mutations in pancreatic cancer. The most common is an activating KRAS mutation that is present in >90% of cases. Less frequent, but still present in the majority of cases, are mutations in p53, p16, and SMAD4 that function in tumor suppression. Mutations in genes that interact with SMAD4-mediated signaling are observed in 100% of pancreatic cancers. SMAD4 serves as a transcription factor that mediates the effects of the transforming growth factor (TGF)-β/activin/bone morphogenetic protein signaling pathways. In addition to the commonly observed deletions of SMAD4, mutations in the receptor, TGFβR2, have also been reported. TGFβR2 mutations were previously found to potentiate the effects of an activating KRASG12D mutation in a murine model for pancreatic cancer. In this issue of Gastroenterology, Qiu et al report on effects of activin signaling in pancreatic cancer. The same group had previously reported the deletion of ACVR1B, the receptor for activin, in human pancreatic cancer. Whether mutations in ACVR1B contribute to pancreatic cancer had not been studied. A conditional mouse model was produced in which the Pdx-1 promoter was employed to express Cre recombinase specifically in the pancreas, which resulted in the disruption of a floxed ACVR1B gene. The result was the development of low-grade intraepithelial pancreatic mucinous neoplasms (IPMN) that represent precursors for cancer. Disruption of ACVR1B alone was associated with the development of acinar to ductal metaplasia and low-grade IPMNs, but without progression to cancer. When the ACVR1B mutant was bred into the mutant KRASG12D animal model, advanced IPMN lesions and ductal pancreatic adenocarcinoma resulted (Figure 4). Survival of the ACVR1B/ KRASG12D double mutant was considerable shorter than mice harboring only the KRASG12D mutation. In addition, mutant ACVR1B/KRASG12D mice favored the development of IPMNs, whereas those with KRASG12D alone were biased toward the development of pancreatic intraepithelial neoplasms. The authors conclude that activin signaling selectively promotes IPMN development. Primary cell lines were established from pancreatic ductal adenocarcinomas harvested from the ACVR1B/KRASG12D mice. Analysis revealed that the tumor suppressor p16 was deleted in all of the tumor cell lines, leading to a conclusion that p16 mutations are a late event in pancreatic ductal adenocarcinoma development in the ACVR1B/ KRASG12D double mutant animal model. See page 218. The Changing Landscape of Inflammatory Bowel Disease: East Meets WestGastroenterologyVol. 150Issue 1PreviewThe inflammatory bowel diseases (IBD) are contemporary diseases of modern societies. Ulcerative colitis emerged in the Western world in the 19th century with “regional ileitis” entering the medical vernacular in the 1930s.1 Throughout the 20th century, the incidence of Crohn’s disease and ulcerative colitis exponentially increased in the Western world including North America, Europe, Australia, and New Zealand, and predominantly, among white individuals of European descent.2 The 21st century ushered in a new era with the advent of IBD in newly industrialized countries throughout the world. Full-Text PDF Early Course of Inflammatory Bowel Disease in a Population-Based Inception Cohort Study From 8 Countries in Asia and AustraliaGastroenterologyVol. 150Issue 1PreviewThe incidence of inflammatory bowel disease (IBD) is increasing in Asia, but little is known about disease progression in this region. The Asia-Pacific Crohn’s and Colitis Epidemiology Study was initiated in 2011, enrolling subjects from 8 countries in Asia (China, Hong Kong, Indonesia, Sri Lanka, Macau, Malaysia, Singapore, and Thailand) and Australia. We present data from this ongoing study. Full-Text PDF Loss of Activin Receptor Type 1B Accelerates Development of Intraductal Papillary Mucinous Neoplasms in Mice With Activated KRASGastroenterologyVol. 150Issue 1PreviewActivin, a member of the transforming growth factor-β (TGFB) family, might be involved in pancreatic tumorigenesis, similar to other members of the TGFB family. Human pancreatic ductal adenocarcinomas contain somatic mutations in the activin A receptor type IB (ACVR1B) gene, indicating that ACVR1B could be a suppressor of pancreatic tumorigenesis. Full-Text PDF Apolipoprotein E Mediates Evasion From Hepatitis C Virus Neutralizing AntibodiesGastroenterologyVol. 150Issue 1PreviewEfforts to develop an effective vaccine against hepatitis C virus (HCV) have been hindered by the propensity of the virus to evade host immune responses. HCV particles in serum and in cell culture associate with lipoproteins, which contribute to viral entry. Lipoprotein association has also been proposed to mediate viral evasion of the humoral immune response, though the mechanisms are poorly defined. Full-Text PDF Hepatitis C Virus Infection Is Associated With Increased Cardiovascular Mortality: A Meta-Analysis of Observational StudiesGastroenterologyVol. 150Issue 1PreviewThere have been many studies of the effects of hepatitis C virus (HCV) infection on cardiovascular risk, but these have produced ambiguous results. We performed a meta-analysis of these studies to systematically assess the risk of HCV infection on cardiovascular disease (CVD)-related morbidity and mortality. Full-Text PDF