Fontan-Associated Liver Disease: A Review.

Fontan-associated liver disease (FALD) is a chronic complication of the Fontan procedure, a palliative surgery for patients with congenital heart disease that results in a single-ventricle circulation. The success of the Fontan procedure has led to a growing population of post-Fontan patients living well into adulthood. For this population, FALD is a major cause of morbidity and mortality. It encompasses a spectrum of hepatic abnormalities, ranging from mild fibrosis to cirrhosis and hepatocellular carcinoma. The pathophysiology of FALD is multifactorial, involving hemodynamic and inflammatory factors. The diagnosis and monitoring of FALD present many challenges. Conventional noninvasive tests that use liver stiffness as a surrogate marker of fibrosis are unreliable in FALD, where liver stiffness is also a result of congestion due to the Fontan circulation. Even invasive tissue sampling is inconsistent due to the patchy distribution of fibrosis. FALD is also associated with both benign and malignant liver lesions, which may exhibit similar imaging features. There is therefore a need for validated diagnostic and surveillance protocols to address these challenges. The definitive treatment of end-stage FALD is also a subject of controversy. Both isolated heart transplantation and combined heart-liver transplantation have been employed, with the latter becoming increasingly preferred in the US. This article reviews the current literature on the epidemiology, pathophysiology, diagnosis, and management of FALD, and highlights knowledge gaps that require further research.

Part 2: Disease of the Heart and Liver: A Relationship That Cuts Both Ways.

Diseases known to affect both the heart and liver include a variety of infectious, autoimmune, and metabolic disorders, as well as toxins: most commonly alcohol. As damage to both the heart and liver progresses, transplantation is a reasonable therapeutic option. Heart failure patients with underlying congestive hepatopathy receiving cardiac transplant have demonstrated improved liver enzyme levels posttransplant. Patients with severe end-stage liver disease requiring a liver transplant must undergo careful preoperative evaluation as surgical stress exposes the myocardium to high levels of catecholamines. Clinicians must consider both cardiac and hepatic complications when evaluating heart failure, cirrhosis, and nonalcoholic fatty liver disease. In Part 2 of this review, we discuss new noninvasive techniques for assessing liver fibrosis in the preoperative stage. Both serum and radiologic studies, such as transient elastography, have begun to take the place of liver biopsy due to their decreased morbidity. Last, we explore the current research examining the benefit of combined heart-liver transplant, although more longitudinal outcome studies are needed.

Part 1: Disease of the Heart and Liver: A Relationship That Cuts Both Ways.

The heart and the liver display multifaceted, complex interactions that can be divided into cardiac effects of liver disease, hepatic effects of heart disease, and disease processes affecting both organs. In part 1 of this 2 part series, we discuss how acute and chronic heart failure can have devastating effects on the liver, such as acute cardiogenic liver injury and congestive hepatopathy. On the other hand, primary liver disease, such as cirrhosis, can lead to a plethora of cardiac insults representative in cirrhotic cardiomyopathy as systolic dysfunction, diastolic dysfunction, and electrophysiological disturbances. Nonalcoholic fatty liver disease has long been associated with cardiovascular events that increase mortality. The management of both disease processes changes when the other organ system becomes involved. This consideration is important with regard to a variety of interventions, most notably transplantation of either organ, as risk of complications dramatically rises in the setting of both heart and liver disease (discussed in part 2). As our understanding of the intricate communication between the heart and liver continues to expand so does our management.

Performance evaluation of stool DNA methylation tests in colorectal cancer screening: a systematic review and meta-analysis.

AIM: There is not sufficient evidence about whether stool DNA methylation tests allow prioritizing patients to colonoscopy. Due to the COVID-19 pandemic, there will be a wait-list for rescheduling colonoscopies once the mitigation is lifted. The aim of this meta-analysis was to evaluate the accuracy of stool DNA methylation tests in detecting colorectal cancer. METHODS: The PubMed, Cochrane Library and MEDLINE via Ovid were searched. Studies reporting the accuracy (Sackett phase 2 or 3) of stool DNA methylation tests to detect sporadic colorectal cancer were included. The DerSimonian-Laird method with random-effects model was utilized for meta-analysis. RESULTS: Forty-six studies totaling 16 149 patients were included in the meta-analysis. The pooled sensitivity and specificity of all single genes and combinations was 62.7% (57.7%, 67.4%) and 91% (89.5%, 92.2%), respectively. Combinations of genes provided higher sensitivity compared to single genes (80.8% [75.1%, 85.4%] vs. 57.8% [52.3%, 63.1%]) with no significant decrease in specificity (87.8% [84.1%, 90.7%] vs. 92.1% [90.4%, 93.5%]). The most accurate single gene was found to be SDC2 with a sensitivity of 83.1% (72.6%, 90.2%) and a specificity of 91.2% (88.6%, 93.2%). CONCLUSIONS: Stool DNA methylation tests have high specificity (92%) with relatively lower sensitivity (81%). Combining genes increases sensitivity compared to single gene tests. The single most accurate gene is SDC2, which should be considered for further research.

The Inflammatory Relationship Between Hepatitis C Virus With Coronary and Carotid Atherosclerosis.

Hepatitis C virus (HCV), a global health concern, has been linked to various hepatic and extrahepatic deleterious manifestations. Several observational studies have either supported the increased likelihood of coronary and carotid atherosclerosis after infection with HCV or refuted it. To date, there has been no clear consensus to support either train of thought, as randomized, controlled clinical trials have not been completed. In this review, we first discuss articles that support the notion that HCV infection leads to increased plaque formation due to systemic inflammation and then focus on articles that refute this idea. From the literature, we do know that both inflammatory and lipid processes play a role in plaque formation, and thus both components are important in the successful treatment of atherosclerosis. Based on our review of the literature, we do believe that HCV-infected individuals are at an increased risk for more severe coronary artery disease than their healthy counterparts. Although there is no irrefutable evidence that links HCV infection with plaque formation and/or rupture, cardioprotective measures should be taken to reduce poor health outcomes, especially in those individuals who are already at risk of coronary disease.

National Landscape of Unplanned 30-Day Readmission Rates for Acute Non-hemorrhagic Diverticulitis: Insight from National Readmission Database.

BACKGROUND: Early readmissions are an important indicator of the quality of care. Limited data exist describing hospital readmissions in acute diverticulitis. The study aimed to describe unplanned, 30-day readmissions among adult acute diverticulitis patients and to assess readmission predictors. METHODS: We analyzed the 2013 and 2014 United States National Readmission Database and identified acute diverticulitis admissions using administrative codes in adult patients older than 18 years of age. Our primary outcome was a 30-day, unplanned readmission rate. We used Chi-square tests, t tests, and Wilcoxon rank-sum tests for descriptive analyses and survey logistic regression to calculate adjusted odds ratios (aORs) and 95% confidence intervals for associations with readmissions adjusting for confounders. RESULTS: In the cohort of 364,511 hospitalizations with acute diverticulitis, as the primary diagnosis on index admission, 31,420 (8.6%) had at least one unplanned 30-day readmission. Sixty percent of the readmissions occurred within the first 2 weeks of the index admission. The most common reasons for unplanned 30-day readmission were due to diverticulitis of the colon (41.5%), postoperative infection (4.2%), septicemia (3.6%), intestinal infection due to Clostridium difficile (3%), and other digestive system complications such bleeding or fistula (2.8%). Multivariable analysis showed advance age (> 75 years), discharge against medical advice, comorbidities (renal failure, coronary artery disease, atrial fibrillation, congestive heart failure, hypertension, diabetes, obesity, weight loss, chronic lung disease, malignancy), blood transfusion, Medicare and Medicaid insurance, and increased length of stay (> 3 days) were associated with significantly higher odds for readmission. Patients who have undergone abdominal surgery during index admission were 31% less likely to get readmitted. CONCLUSIONS: On a national level, 1 in 11 hospitalizations for acute diverticulitis was followed by unplanned readmission within 30 days with most admissions occurring in the first 2 weeks. Multiple modifiable and non-modifiable factors influencing readmission rates were noted. Further studies should examine if strategies that address these predictors can decrease readmissions.

Prevalence of cannabis use has significantly increased in patients with cyclic vomiting syndrome.

INTRODUCTION: Cyclic vomiting syndrome (CVS) is a functional gastrointestinal disorder which leads to multiple hospitalizations and causes significant impairment of quality of life. Cannabis use is common in patients with CVS, and there are limited data on the national trends in the prevalence of its use in the United States. METHODS: We used the National Inpatient Sample (NIS) database from 2005 to 2014 and identified hospitalizations with a primary diagnosis of CVS by utilizing the International Classification of Diseases, 9th revision Clinical Modification (ICD-9 CM) coding system. The primary objective of the study was to analyze the prevalence and trends in cannabis use in CVS patients. We also assessed healthcare resource utilization associated with cannabis use. RESULTS: A total of 129 090 hospitalizations with a primary diagnosis of CVS were identified and included in the study. In the United States, the overall rate of cannabis use among these patients was 104 per 1000 hospitalizations (N = 13 460). Over the last decade, the prevalence of cannabis use increased by 10-fold, from 2.2% in 2005 to 21.2% in 2014. CONCLUSION: Our analysis of the national database suggests that nearly 1 in 5 CVS hospitalizations have concurrent cannabis use. This prevalence is significantly rising over the last decade, perhaps due to changing legislation and increased utilization of cannabis. Age younger than 35, male gender, African American and Native American race, personal history of alcohol abuse and tobacco use were some of the strongest predictors of cannabis use.

A Prospective Multicenter Study Evaluating Endoscopy Competence Among Gastroenterology Trainees in the Era of the Next Accreditation System.

PURPOSE: The Next Accreditation System requires training programs to demonstrate competence among trainees. Within gastroenterology (GI), there are limited data describing learning curves and structured assessment of competence in esophagogastroduodenoscopy (EGD) and colonoscopy. In this study, the authors aimed to demonstrate the feasibility of a centralized feedback system to assess endoscopy learning curves among GI trainees in EGD and colonoscopy. METHOD: During academic year 2016-2017, the authors performed a prospective multicenter cohort study, inviting participants from multiple GI training programs. Trainee technical and cognitive skills were assessed using a validated competence assessment tool. An integrated, comprehensive data collection and reporting system was created to apply cumulative sum analysis to generate learning curves that were shared with program directors and trainees on a quarterly basis. RESULTS: Out of 183 fellowships invited, 129 trainees from 12 GI fellowships participated, with an overall trainee participation rate of 72.1% (93/129); the highest participation level was among first-year trainees (90.9%; 80/88), and the lowest was among third-year trainees (51.2%; 27/53). In all, 1,385 EGDs and 1,293 colonoscopies were assessed. On aggregate learning curve analysis, third-year trainees achieved competence in overall technical and cognitive skills, while first- and second-year trainees demonstrated the need for ongoing supervision and training in the majority of technical and cognitive skills. CONCLUSIONS: This study demonstrated the feasibility of using a centralized feedback system for the evaluation and documentation of trainee performance in EGD and colonoscopy. Furthermore, third-year trainees achieved competence in both endoscopic procedures, validating the effectiveness of current training programs.

Inpatient burden of esophageal varices in the United States: analysis of trends in demographics, cost of care, and outcomes.

BACKGROUND: Esophageal variceal bleeding remains a common reason for hospitalization in the United States. The main objective of this study was to analyze demographic variations and outcomes in hospitalizations related to esophageal varices (EV) in the US. METHODS: We performed a retrospective observational cohort study using National Inpatient Sample (NIS) database for all hospitalizations with discharge diagnoses of EV, with and without hemorrhage from 2001 to 2011. RESULTS: In 2001, there were 19,167 hospitalizations with discharge diagnoses of EV with and without bleeding compared to 45,578 in 2011 (P<0.001). There was a 138% increase in the number of total EV hospitalizations, a 221% increase in hospitalizations with EV without hemorrhage, and a 7% increase in hospitalizations for patients with EV and hemorrhage. Age group 50-64 was the most affected, accounting for 31.4% of EV hospitalizations in 2001 and 46.7% of EV hospitalizations in 2011 (P<0.001). The overall in-hospital mortality rate was 3.4% for patients with EV without hemorrhage and 8.7% for patients with EV with hemorrhage (P=0.0003). CONCLUSIONS: The number of hospitalizations for patients with asymptomatic EV increased significantly between 2001 to 2011, with only a small concurrent increase in the number of hospitalizations for patients with esophageal variceal bleeding.

Opioid use disorder is associated with increased mortality and morbidity in patients with gastroparesis.

BACKGROUND: Opioid use disorder (OUD) epidemic has been declared a nationwide public health emergency by the Department of Health and Human Services. There are limited data regarding OUD in patients with gastroparesis. This study aimed to evaluate the impact of OUD on the outcomes in patients hospitalized with gastroparesis and to delineate the trends associated with OUD and gastroparesis using a nationally representative sample. METHODS: We used the National (Nationwide) Inpatient Sample database from 2005-2014 to identify patients hospitalized with a primary diagnosis of gastroparesis (ICD 9 Code: 536.3) and a concurrent diagnosis of OUD. We used Pearson chi-square analysis to compare demographics, the independent samples t-test to assess differences in length of stay and cost of care, and multivariate regression analysis to adjust for confounders. RESULTS: Between 2005 and 2014, a total of 145,700 patients with a primary diagnosis of gastroparesis were hospitalized in the United States, of whom 4519 (3.1%) had a concurrent diagnosis of OUD. The prevalence of OUD in gastroparesis doubled from 2.1% in 2005 to 4.3% in 2014. After adjusting for confounders, patients with OUD had greater in-hospital mortality (adjusted odds ratio 2.7, 95% confidence interval: 2.1-3.5). Patients with OUD also had significantly longer hospital stays and higher costs. Independent predictors of OUD in patients with gastroparesis were younger age, female sex, alcohol use, depression, and Medicaid insurance. CONCLUSION: OUD in patients with gastroparesis is associated with greater mortality and healthcare resource utilization.

Endoscopy Is Relatively Safe in Patients with Acute Ischemic Stroke and Gastrointestinal Hemorrhage.

BACKGROUND: Gastrointestinal hemorrhage (GIH) is reported to occur in 1-8% of patients admitted with acute ischemic stroke (AIS). AIS is considered to be a relative contraindication to GIE. AIMS: Evaluate the outcomes of gastrointestinal endoscopy (GIE) in patients hospitalized with AIS and GIH. METHODS: Patients hospitalized with AIS and GIH were included from the National Inpatient Sample 2005-2014. Primary outcome measure was in-hospital mortality in patients with AIS and GIH who underwent gastrointestinal endoscopy. Secondary outcomes were (1) resource utilization as measured by length of stay (LOS) and total hospitalization costs and (2) to identify independent predictors of undergoing GIE in patients with AIS and GIH. Confounders were adjusted for by using multivariable regression analysis. RESULTS: A total of 75,756 hospitalizations were included in the analysis. Using a multivariate analysis, the in-hospital mortality was significantly lower in patients who underwent GIE as compared to those who did not [aOR: 0.4, P < 0.001]. Patients who underwent GIE also had significantly shorter adjusted mean LOS [adjusted mean difference in LOS: 0.587 days, P < 0.001]. Patients with AIS and GIH who did not undergo GIE had significantly higher adjusted total hospitalization costs. [Mean adjusted difference in total hospitalization costs was $5801 (P < 0.001).] Independent predictors of undergoing GIE in this population were male gender, age > 65 years, Asian or Pacific race, hypovolemic shock, need for blood transfusion and admission to urban non-teaching hospital. CONCLUSIONS: Gastrointestinal endoscopy can be safely performed in a substantial number of patients with AIS and GIH.

The Predicament of Gastrointestinal Bleeding in Patients With a Continuous-Flow Left Ventricular Assist Device: Pathophysiology, Evaluation, and Management.

Heart failure affects over 5 million Americans, with numbers expected to rise. While heart transplantation is the most effective long-term strategy for end-stage heart failure, there is a limited cardiac donor pool, and these organs are often unavailable at the time of need. Left ventricular assist devices, therefore, continue to be used to bridge this gap. Originally implanted as a bridge to transplant, these devices are now additionally utilized as destination therapy for patients ineligible for transplant. With the widespread applicability of these devices for not just temporary measures, but also for prolonged use, the short- and long-term impact on other organ systems has become more evident. For example, gastrointestinal (GI) bleeding, with an incidence approaching 30%, is one such complication post-continuous-flow left ventricular assist device implantation. This high incidence of GI bleeding is thought to stem from a combination of factors, including the need for concomitant anticoagulant and antiplatelet therapy, and intrinsic device-related properties resulting in acquired Von Willebrand disease and arteriovenous malformations. Due to the significant morbidity associated with these GI bleeding events, a standardized protocol optimizing medical and endoscopic management, alongside close coordination between the gastroenterology and cardiology services, should be advocated for and ultimately employed.

Overview of Link Between Inflammatory Bowel Disease and Cardiovascular Disease.

Inflammation has been shown to play an increasingly important role in the pathogenesis of atherosclerosis and in precipitating thrombotic events. Inflammatory bowel disease (IBD) is a systemic inflammatory disorder with a wide range of extraintestinal manifestations including a clinically significant increase in the risk of venous thromboembolism compared to matched controls in several studies. The data for the association between IBD and ischemic heart disease are less clear; multiple population-based studies have shown both positive and negative associations between the 2 conditions. While the systemic inflammation should theoretically increase the risk for cardiovascular disease, inflammatory bowel also potentially provides a cardioprotective effect in several ways. Patients with IBD typically enter the healthcare system at an earlier age and experience a lower incidence of obesity, hypercholesterolemia, and hyperlipidemia. Given the complex interplay among the proatherogenic, prothrombogenic, and cardioprotective effects, IBD should be taken into consideration as a nontraditional risk factor for cardiovascular disease in specific subsets of patients.

Development of NASH in Obese Mice is Confounded by Adipose Tissue Increase in Inflammatory NOV and Oxidative Stress.

AIM: Nonalcoholic steatohepatitis (NASH) is the consequence of insulin resistance, fatty acid accumulation, oxidative stress, and lipotoxicity. We hypothesize that an increase in the inflammatory adipokine NOV decreases antioxidant Heme Oxygenase 1 (HO-1) levels in adipose and hepatic tissue, resulting in the development of NASH in obese mice. METHODS: Mice were fed a high fat diet (HFD) and obese animals were administered an HO-1 inducer with or without an inhibitor of HO activity to examine levels of adipose-derived NOV and possible links between increased synthesis of inflammatory adipokines and hepatic pathology. RESULTS: NASH mice displayed decreased HO-1 levels and HO activity, increased levels of hepatic heme, NOV, MMP2, hepcidin, and increased NAS scores and hepatic fibrosis. Increased HO-1 levels are associated with a decrease in NOV, improved hepatic NAS score, ameliorated fibrosis, and increases in mitochondrial integrity and insulin receptor phosphorylation. Adipose tissue function is disrupted in obesity as evidenced by an increase in proinflammatory molecules such as NOV and a decrease in adiponectin. Importantly, increased HO-1 levels are associated with a decrease of NOV, increased adiponectin levels, and increased levels of thermogenic and mitochondrial signaling associated genes in adipose tissue. CONCLUSIONS: These results suggest that the metabolic abnormalities in NASH are driven by decreased levels of hepatic HO-1 that is associated with an increase in the adipose-derived proinflammatory adipokine NOV in our obese mouse model of NASH. Concurrently, induction of HO-1 provides protection against insulin resistance as seen by increased insulin receptor phosphorylation. Pharmacological increases in HO-1 associated with decreases in NOV may offer a potential therapeutic approach in preventing fibrosis, mitochondrial dysfunction, and the development of NASH.

Novel Oral Anticoagulants in the Peri-Endoscopic Period.

Millions of patients in the United States are currently prescribed some form of anticoagulation therapy. Recently, novel oral anticoagulants (NOACs), including direct thrombin inhibitors and direct factor Xa inhibitors, have begun to replace warfarin as the drugs of choice for anticoagulation. As the use of these medications becomes more widespread, it is increasingly important for gastroenterologists to understand the risks associated with performing endoscopic procedures on patients who are taking NOACs. In this review, we provide an overview of the NOACs and current guidelines from international societies regarding the management of patients scheduled to undergo endoscopic procedures who are prescribed these medications. Finally, we offer a perspective on future studies required to adequately investigate and characterize the effects that these drugs have on a patient's risk for bleeding in the peri- and/or postprocedural timeframes.

Hepatitis C Virus and Nonliver Solid Cancers: Is There an Association between HCV and Cancers of the Pancreas, Thyroid, Kidney, Oral Cavity, Breast, Lung, and Gastrointestinal Tract?

Hepatitis C virus (HCV) is known for its oncogenic potential and has been found to be associated with hepatocellular carcinoma (HCC) and non-Hodgkin lymphoma. It has also been postulated that HCV may play a role in the development of other extrahepatic solid tumors of other organs of the body since it has been isolated from the vessel wall, kidney, and oral mucosa. In this article, we have reviewed epidemiological studies that have been done to look into the relationship of HCV with nonliver solid cancers of the pancreas, thyroid, renal, oral cavity, breast, and lung and nonpancreatic gastrointestinal cancers. Based on this review, HCV might be associated with an increased risk of renal cell and lung cancers.

Primary Care Perspectives on Hepatitis C Virus Screening, Diagnosis and Linking Patients to Appropriate Care.

Enormous progress has been made in recent years toward effectively treating and curing patients with chronic hepatitis C (CHC). However, at least half of the possible 7 million individuals infected with hepatitis C virus (HCV) in the US remain undiagnosed. The formidable task of increasing the number of patients diagnosed, and subsequently linked to appropriate care has fallen to primary care clinicians, who are mandated by some US States to offer screening to individuals born between 1945 and 1965 (the Baby Boomer Generation). This peer-reviewed video roundtable discussion http://hepcresource.amjmed.com/Content/jplayer/video_roundtable.html#video0 addresses the challenges encountered by primary care clinicians faced with the increasing societal need to screen for HCV, make appropriate diagnoses, and subsequently link infected patients to appropriate care. Discussion in this roundtable initially focuses on the offering of HCV screening to patients in primary care settings. Roundtable participants discuss the need for primary care clinicians to ask appropriate risk factor-based questions of their patients, especially if the ongoing HCV epidemic is to be curtailed. The participants note, however, that the majority of patients currently infected with HCV in the US are Baby Boomers, and USPTF guidelines require this population to be tested for HCV regardless of any past risk-taking behaviors. So while asking the right questions is important, the failure of a Baby Boomer to recall risk-taking behavior does not preclude HCV screening. In fact, clinicians should proactively screen all persons in this birth cohort, and be more sensitive and open to screening requests from these individuals. Roundtable participants also discuss how HCV screening results should be communicated to patients, and how physicians can keep patients engaged and not lost to follow-up after an initial positive HCV antibody test. Patients screened and found to be HCV antibody positive require a follow-up HCV RNA test, and every effort must be made to overcome the challenge of losing patients between these two steps. Good communication between the physician, the physician's office staff, and the patient is necessary. In addition, point-of-care tests and PCR reflex testing can alleviate the need for HCV antibody positive patients to arrange subsequent office visits to undergo confirmatory HCV RNA testing. Physician and patient perspectives are presented throughout this roundtable discussion to obtain a complete picture of the management barriers encountered prior to initiation of therapy. Physician perspectives are provided by Edward Lebovics, the Upham Professor of Gastroenterology and Director of the Sarah C. Upham Division of Gastroenterology and Hepatobiliary Diseases at New York Medical College and Westchester Medical Center in Valhalla, New York, and Richard Torres, Chief Medical Officer at Optimus Health Care and an Associate Professor of Medicine at Yale School of Medicine. Torres has been a primary care provider for 29 years, working at the largest federally qualified community health center in Southwestern CT, which provides over 240,000 patient visits annually primarily to populations that are underserved and suffering from healthcare disparities. Patient perspectives in this roundtable are provided by Lucinda K. Porter, RN, who is the author of two books for hepatitis C patients, and is a former hepatology nurse and hepatitis C patient. She has been advocating for others since 1997, and writes for the HCV Advocate. Lucinda is a contributing editor of HEP magazine, and she blogs at www.LucindaPorterRN.com. The overall goal of this video roundtable discussion is to demonstrate that when provided with appropriate clinical knowledge, and aided by supportive collaborations with appropriate specialists, primary care clinicians should be able to effectively screen, diagnose, and link patients with hepatitis C to appropriate care. While patients need to be educated on the possible outcomes of a positive HCV antibody test, the significance of a positive HCV RNA test, and how to prevent further transmission, they should also be assured that currently available therapies have dramatically increased the chances of being cured. Appropriate education and the availability of excellent treatment options will hopefully quell fears and increase the morale of patients as they navigate the process of HCV screening and diagnosis.

Fructose Mediated Non-Alcoholic Fatty Liver Is Attenuated by HO-1-SIRT1 Module in Murine Hepatocytes and Mice Fed a High Fructose Diet.

BACKGROUND: Oxidative stress underlies the etiopathogenesis of nonalcoholic fatty liver disease (NAFLD), obesity and cardiovascular disease (CVD). Heme Oxygenase-1 (HO-1) is a potent endogenous antioxidant gene that plays a key role in decreasing oxidative stress. Sirtuin1 (SIRT1) belongs to the family of NAD-dependent de-acyetylases and is modulated by cellular redox. HYPOTHESIS: We hypothesize that fructose-induced obesity creates an inflammatory and oxidative environment conducive to the development of NAFLD and metabolic syndrome. The aim of this study is to determine whether HO-1 acts through SIRT1 to form a functional module within hepatocytes to attenuate steatohepatitis, hepatic fibrosis and cardiovascular dysfunction. METHODS AND RESULTS: We examined the effect of fructose, on hepatocyte lipid accumulation and fibrosis in murine hepatocytes and in mice fed a high fructose diet in the presence and absence of CoPP, an inducer of HO-1, and SnMP, an inhibitor of HO activity. Fructose increased oxidative stress markers and decreased HO-1 and SIRT1 levels in hepatocytes (p<0.05). Further fructose supplementation increased FAS, PPARα, pAMPK and triglycerides levels; CoPP negated this increase. Concurrent treatment with CoPP and SIRT1 siRNA in hepatocytes increased FAS, PPARα, pAMPK and triglycerides levels suggesting that HO-1 is upstream of SIRT1 and suppression of SIRT1 attenuates the beneficial effects of HO-1. A high fructose diet increased insulin resistance, blood pressure, markers of oxidative stress and lipogenesis along with fibrotic markers in mice (p<0.05). Increased levels of HO-1 increased SIRT1 levels and ameliorated fructose-mediated lipid accumulation and fibrosis in liver along with decreasing vascular dysfunction (p<0.05 vs. fructose). These beneficial effects of CoPP were reversed by SnMP. CONCLUSION: Taken together, our study demonstrates, for the first time, that HO-1 induction attenuates fructose-induced hepatic lipid deposition, prevents the development of hepatic fibrosis and abates NAFLD-associated vascular dysfunction; effects that are mediated by activation of SIRT1 gene expression.

Screening, diagnosis, treatment, and management of hepatitis C: a novel, comprehensive, online resource center for primary care providers and specialists.

Current initiatives focusing on hepatitis C (HCV) screening and diagnosis, together with the advent of oral interferon (IFN)-free treatment regimens have prompted Elsevier Multimedia Publishing and the American Journal of Medicine (AJM) to develop a novel, comprehensive, online Resource Center dedicated to providing both primary care providers and specialists with the latest information on the screening, diagnosis, treatment, and management of HCV. To date, only 25% of infected patients have been diagnosed and only 5% cured. With the Centers for Disease Control and Prevention (CDC) and the US Prevention Services Task Force (USPSTF) recommendation of one-time screening for all individuals born between 1945 and 1965, and the availability of safe and effective therapy, it is anticipated that primary care providers and community practices will become increasingly responsible for the screening, diagnosis, and management of infected patients, as well as providing access to care by specialists when needed. The AJM Hepatitis C Resource Center site will have two major channels; one channel tailored to specifically address the needs of internal medicine physicians and other primary care providers, and one channel tailored to address the needs of specialists including hepatologists, gastroenterologists, and infectious disease specialists. Systematic surveys of these clinician audiences are being conducted by Elsevier to assess educational gaps, and ensure that the content of each channel of the Resource Center satisfies the needs of the intended audiences. In a recent Elsevier survey of primary care physicians (PCPs) who had screened and/or participated in the care of patients with HCV within 6 months of participating in the survey, 60% of PCPs stated that they were not very confident or only somewhat confident about screening patients for chronic HCV infection. A recent Elsevier survey of specialists revealed low levels of satisfaction with the treatment options available in 2013, with "no therapy" being selected for up to 38% of patients. This survey also showed that experience with newly-approved options for HCV including IFN-free regimens is currently limited, but the likelihood that a variety of patient types will be treated with these options is high. This provides an impetus for educational opportunities focusing on optimizing treatments for the different HCV genotypes and for patients with comorbidities. Further results of the PCP and specialist surveys will be published on the Resource Center. Each channel of the Resource Center will be comprised of a variety of specific communication elements, which are open to sponsorship, and include roundtable panel discussions, case studies, and direct links to relevant original research, review articles, and guidelines. All Resource Center components are peer-reviewed for publication on the Resource Center by the AJM Editorial Office and the Resource Center Guest Editor, Edward Lebovics, MD. The AJM Hepatitis C Resource Center will be accessible from the AJM online home page (http://www.amjmed.com) and will be launched immediately prior to the American Association for the Study of Liver Diseases (AASLD) Liver Meeting to be held from November 7 to 11, 2014 in Boston, Massachusetts.