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BackgroundHepatocellular carcinoma (HCC) is rapidly increasing in the U.S. and is a leading cause of mortality for patients with cirrhosis. Discovering novel biomarkers for risk stratification of HCC is paramount. We examined biomarkers of the gut-liver axis in a prospective multicenter cohort.MethodsPatients with cirrhosis without a history of HCC were recruited between May 2015 and March 2020 and prospectively followed at 3 tertiary care hospitals in Los Angeles. Microbiome analysis was performed on duodenal biopsies and metabolomic analysis was performed on serum samples, collected at the time of enrollment. Optimal microbiome-based survival analysis and Cox proportional hazards regression analysis were used to determine microbiota and metabolite associations with HCC development, respectively.ResultsA total of 227 participants with liver cirrhosis contributed a total of 459.58 person-years of follow-up, with 14 incident HCC diagnoses. Male sex (HR = 7.06, 95% CI = 1.02-54.86) and baseline hepatic encephalopathy (HE, HR = 4.65, 95% CI = 1.60-13.52) were associated with developing HCC over follow-up. Adjusting for age, sex, baseline HE, and alkaline phosphatase, an increased risk of HCC were observed for participants with the highest versus lowest three quartiles for duodenal Alloprevotella (HR = 3.22, 95% CI = 1.06-9.73) and serum taurocholic acid (HR = 6.87, 95% CI = 2.32-20.27), methionine (HR = 9.97, 95% CI = 3.02-32.94), and methioninesulfoxide (HR = 5.60, 95% CI = 1.84-17.10). Being in the highest quartile for Alloprevotella or methionine had a sensitivity and specificity for developing HCC of 85.71% and 60.56%, respectively, with an odds ratio of 10.92 (95% CI = 2.23-53.48).ConclusionAlloprevotella and methionine, methioninesulfoxide, and taurocholic acid predicted future HCC development in a high-risk population of participants with liver cirrhosis.

Background The effect of gender affirming hormone therapy (GAHT) on clinical laboratory parameters, including levels of liver enzymes alanine aminotransferase (ALT) and aspartate transaminase (AST), is an area of uncertainty in transgender health. Aim We sought to estimate the distribution parameters of liver enzyme levels among transmasculine (TM) and transfeminine (TF) persons receiving GAHT relative to the corresponding measures in cisgender reference groups, and to evaluate longitudinal changes in these laboratory measures following GAHT initiation. Methods The data for this longitudinal study included 624 TF and 438 transmasculine (TM) people as well as 4,090 cisgender males and 4,797 cisgender females enrolled in 3 integrated health systems. Time under observation was divided into 2 intervals: from the first blood test to the date of the first filled GAHT prescription and from GAHT initiation to the most recent ALT or AST measurement. Linear mixed models were used to compare changes in log-transformed ALT and AST values among transgender cohort members before and after GAHT initiation, and relative to the reference groups. The results were expressed as relative differences (in %) and the ratios of these differences (ratios-of-ratios) along with the 95% confidence intervals (CIs). Outcomes Changes in ALT and AST levels among transgender people over time and relative to the corresponding changes in cisgender referents. RESULTS Among TM study participants, the post GAHT ratios-of-ratios for AST were 1.61 (95% CI: 1.13, 2.31) and 1.57 (95% CI: 1.06, 2.31) relative to cisgender males and females respectively. For ALT, the corresponding comparisons yielded the ratios-of-ratios (95% CIs) of 2.06 (1.67, 2.54) and 1.90 (1.50, 2.40). No statistically significant changes were observed among TF participants. Other factors associated with higher liver enzyme levels included alcohol use/abuse and obesity. Clinical Implications TM persons may experience modest increases in ALT and AST concentrations following testosterone initiation; however, clinical significance of the observed association remains unclear and requires further investigation. By contrast, feminizing GAHT is unlikely to induce appreciable changes in liver enzyme levels. Strength and Limitations The strengths of this study are the longitudinal design and the ability to assemble an unselected cohort nested within large health systems. The main limitations include the lack of information on hormone levels and the inability to take into account GAHT doses and routes of administration. CONCLUSION The influence of long-term GAHT on ALT and AST levels appears modest and not likely to reflect clinically meaningful changes in liver function.

INTRODUCTION: In hepatitis C (HCV) patients, obesity and/or diabetes may increase the risk of liver-related outcomes. We aimed to determine if diabetes and/or obesity are associated with adverse outcomes in direct acting antiviral (DAA)-treated HCV patients. METHODS: We conducted a retrospective study of 33,003 HCV-infected, DAA-treated Veterans between 2013–2015. Body mass index was used to categorize patients into underweight (35kg/m(2)). Diabetes was defined by ICD-9/10 codes in association with hemoglobin A1c>6.5% or medication prescriptions. Patients were followed from 180 days post-DAA initiation until 2/14/2019 to assess for development of cirrhosis, decompensations, hepatocellular carcinoma (HCC) and death. Multivariable Cox proportional hazards regression models were used to determine the association between diabetes and/or obesity and outcomes. RESULT: During a mean follow-up of 3 years, 10.1% patients died, 5.0% were newly diagnosed with cirrhosis, 4.7% had a decompensation and 4.0% developed HCC. Diabetes was associated with an increased risk of mortality (AHR=1.25, 95%CI 1.10–1.42), cirrhosis (AHR=1.31, 95%CI 1.16–1.48), decompensation (AHR=1.74, 95%CI 1.31–2.31), and HCC (AHR=1.32, 95%CI 1.01–1.72) among patients without baseline cirrhosis. Compared to normal-weight persons, obese persons had a higher risk of cirrhosis, but overweight and obese persons had lower risk of mortality and HCC. CONCLUSION: In this large DAA-treated Veterans cohort, pre-DAA diabetes increases mortality and liver-related events independent of SVR. Continued vigilance is warranted in patients with diabetes despite SVR. Elevated BMI categories appear to have improved outcomes, although further studies are needed to understand those associations.

Incidental tracer uptake on DOTATATE PET is increasingly encountered in clinical practice. We describe 3 patients with suspected or known neuroendocrine tumor who were found to have diffuse and intense stomach uptake on DOTATATE PET. All patients underwent esophagogastroduodenoscopy and/or endoscopic ultrasound; the cause of the stomach uptake was attributed to proton-pump inhibitor use, chronic gastritis, and gastrinoma, respectively. These 3 cases highlight that diffuse and intense stomach DOTATATE uptake can be a benign finding probably attributed to proton-pump inhibitor use, chronic gastritis, or gastrinoma.

Background: Worsening glycemic control indicates elevated risk of pancreatic ductal adenocarcinoma (PDAC). We developed prediction models for PDAC among those with worsening glycemic control after diabetes diagnosis. Methods: In 2000–2016 records within the Veterans Affairs Health System (VA), we identified three cohorts with progression of diabetes: (i) insulin initiation (n = 449,685), (ii) initiation of combination oral hypoglycemic medication (n = 414,460), and (iii) hemoglobin A1c (HbA1c) ≥8% with ≥Δ1% within 15 months (n = 593,401). We computed 12-, 36-, and 60-month incidence of PDAC and developed prediction models separately for males and females, with consideration of >30 demographic, behavioral, clinical, and laboratory variables. Models were selected to optimize Akaike's Information Criterion, and performance for predicting 12-, 36-, and 60-month incident PDAC was evaluated by bootstrap. Results: Incidence of PDAC was highest for insulin initiators and greater in males than in females. Optimism-corrected c-indices of the models for predicting 36-month incidence of PDAC in the male population were: (i) 0.72, (ii) 0.70, and (iii) 0.71, respectively. Models performed better for predicting 12-month incident PDAC [c-index (i) 0.78, (ii) 0.73, (iii) 0.76 for males], and worse for predicting 60-month incident PDAC [c-index (i) 0.69, (ii) 0.67, (iii) 0.68 for males]. Model performance was lower among females. For subjects whose model-predicted 36-month PDAC risks were ≥1%, the observed incidences were (i) 1.9%, (ii) 2.2%, and (iii) 1.8%. Conclusions: Sex-specific models for PDAC can estimate risk of PDAC at the time of progression of diabetes. Impact: Our models can identify diabetes patients who would benefit from PDAC screening.

Background: The microbiome has been shown in pre-clinical and epidemiological studies to be important in both the development and treatment of obesity and metabolic associated fatty liver disease (MAFLD). However, few studies have examined the role of the microbiome in the clinical response to calorie restriction. To explore this area, we performed a prospective study examining the association of the intestinal microbiome with weight loss and change in hepatic steatosis on a calorie-restricted diet.Methods: A prospective dietary intervention study of 80 overweight and obese participants was performed at the Greater West Los Angeles Veterans Affair Hospital. Patients were placed on a macronutrient standardized diet for 16 weeks, including 14 weeks of calorie restriction (500 calorie deficit). Body composition analysis by impedance, plasma lipid measurements, and ultrasound elastography to measure hepatic steatosis were performed at baseline and week 16. Intestinal microbiome composition was assessed using 16S rRNA gene sequencing. A per protocol analysis was performed on all subjects completing the trial (n = 46).Results: Study completers showed significant reduction in weight, body mass index, total cholesterol, low density lipoprotein, and triglyceride. Subjects who lost at least 5% of their body weight had significantly greater reduction in serum triglyceride and hepatic steatosis than those with Enterococcus and Klebsiella were reduced at the end of the trial while Coprococcus and Collinsella were increased. There were also significant baseline microbiome differences between patients who had at least 5% weight loss as compared to those that did not. Lachnoclostridium was positively associated with hepatic steatosis and Actinomyces was positively associated with hepatic steatosis and weight. Baseline microbiome profiles were able to predict which patients lost at least 5% of their body weight with an AUROC of 0.80.Conclusion: Calorie restriction alters the intestinal microbiome and improves hepatic steatosis in those who experience significant weight loss. Baseline microbiome differences predict weight loss on a calorie–restricted diet and are associated with improvement in hepatic steatosis, suggesting a role of the gut microbiome in mediating the clinical response to calorie restriction.

AimThe microbiome has been shown to be pivotal in the development of metabolic associated fatty liver disease (MAFLD). Few have examined the relationship of the microbiome specifically with steatosis grade. Therefore, our aim was to characterize the association of the microbiome with MAFLD steatosis severity while adjusting for metabolic comorbidities including diabetes.MethodsWe enrolled patients with MAFLD at the West Los Angeles Veterans Affair Hospital. All patients underwent ultrasound elastography, fasting serum collection, and fecal sampling for 16S sequencing. We examined the associations of microbial diversity and composition with advanced steatosis, defined as a CAP score of ≥ 300 dB/m, with or without the presence of metabolic comorbidities.ResultsSeventy-five patients were enrolled. African American were less likely to have advanced steatosis than either Hispanics or Whites (P = 0.001). Patients with more advanced steatosis had higher fasting serum triglyceride (192.6 ± 157.1 mg/dL vs. 122.5 ± 57.4 mg/dL), HbA1c (6.7% ± 1.4% vs. 6.1% ± 0.8%), transaminases, and were more likely to have metabolic syndrome (52.4% vs. 24.2%, P = 0.02). Advanced steatosis and diabetes were associated with altered microbial composition. Bacteroides was negatively associated with advanced steatosis while Megasphaera was positively associated with steatosis. Akkermansia was negatively associated with diabetes, while Anaerostipes and Parabacteroides were positively associated with diabetes.ConclusionDiabetes and metabolic syndrome are associated with hepatic steatosis severity in MAFLD patients and both advanced steatosis and comorbid diabetes are independently associated with microbiome changes. These results provide insight into the role of the gut microbiome in MAFLD associated with metabolic syndrome.

Characteristic features of chronic pancreatitis (CP) may be absent on standard imaging studies. Quantitative Magnetic Resonance Imaging (MRI) techniques such as T(1) mapping, extracellular volume (ECV) fraction, diffusion-weighted imaging (DWI) with apparent diffusion coefficient map (ADC), MR elastography (MRE), and T(1)-weighted signal intensity ratio (SIR) have shown promise for the diagnosis and grading severity of CP. However, radiologists still use the Cambridge classification which is based on traditional ductal imaging alone. There is an urgent need to develop new diagnostic criteria that incorporate both parenchymal and ductal features of CP seen by MRI/MRCP. Designed to fulfill this clinical need, we present the MINIMAP study, which was funded in September 2018 by the National Institutes of Health. This is a comprehensive quantitative MR imaging study which will be performed at multiple institutions in well-phenotyped CP patient cohorts. We hypothesize that quantitative MRI/MRCP features can serve as valuable non-invasive imaging biomarkers to detect and grade CP. We will evaluate the role of T(1) relaxometry, ECV, T(1)-weighted gradient echo SIR, MRE, arteriovenous enhancement ratio, ADC, pancreas volume/atrophy, pancreatic fat fraction, ductal features, and pancreatic exocrine output following secretin stimulation in the assessment of CP. We will attempt to generate a multi-parametric pancreatic tissue fibrosis (PTF) scoring system. We anticipate that a quantitative scoring system may serve as a biomarker of pancreatic fibrosis; hence this imaging technique can be used in clinical practice as well as clinical trials to evaluate the efficacy of agents which may slow the progression or reverse measures of CP.

Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide expressed both centrally and peripherally. CGRP has been shown to be involved in arteriolar dilation, cardiovascular regulation, pain transmission, migraine, and gastrointestinal physiology. Our current research is aimed at analyzing CGRP’s impact on appetite/satiety, body metabolism, and energy homeostasis. Our study investigated the effects of a single-dose intraperitoneal (IP) treatment with CGRP on food and water consumption, energy expenditure, physical activity, respirometry, and a panel of plasma metabolic hormones in C57Bl/6 wild-type (WT) mice. After a CGRP IP injection at a dose of 2 nmol (10 μMCGRP in 200 μl of saline), a significant reduction in food intake and metabolic parameters as RQ, VCO(2), and VO(2) was observed. CGRP-injected mice had also significantly lower total energy expenditure (TEE) with no changes in activity levels compared to vehicle-injected controls. CGRP treatment in mice induced significantly lower plasma levels of glucagon and leptin but higher levels of amylin. Our data show that a single dose of CGRP peptide significantly decreased food consumption and altered calorimetric parameters and plasma metabolic hormone levels, thus confirming that CGRP plays a pivotal role in the regulation of appetite and metabolism. Future studies are necessary to analyze CGRP’s long-term impact on body metabolism and its potential effects on appetite, obesity, and metabolic disorders.

Background/Objectives Alcohol is the most common etiology of recurrent acute pancreatitis and chronic pancreatitis. The extent and timing of drinking that increases the transient risk of acute pancreatitis is yet unknown. Methods We designed a case-crossover study to determine the effective hazard period of drinking in relation to episodes of pancreatitis. We aim to evaluate the dose-response relationship between excess drinking and pancreatitis comparing the extent of drinking during case and control periods from the same individual. We aim to recruit 160 patients hospitalized with acute pancreatitis, whose AUDIT-C score reaches 3 or higher. Interviews of each enrolled patient to define their 15-day history of alcohol consumption employing the timeline follow-back method. Long-term drinking and smoking will be investigated as modifiers of the impact of short-term excess drinking. Patients are followed-up for evaluation of usual alcohol consumption during asymptomatic periods following the index hospitalization. Blood and urine specimens are collected while the patients are hospitalized and during a standard-of-care follow-up visit. Results We have recruited 31 patients to date, with a median age of 33 years. Females and non-White participants make up 26% and 35% of the enrolled population, respectively. Forty-eight % of patients have had a prior history of acute pancreatitis. Conclusions Our study will shed light on the impact of short-term changes in drinking on triggering acute pancreatitis. It will provide data on other covarying factors of drinking and behaviors changes after acute pancreatitis.

Shifts in the microbiome have been correlated with the physiology and pathophysiology of many organ systems both in humans and in mouse models. The gut microbiome has been typically studied through fecal specimen collections. The ease of obtaining fecal samples has resulted in many studies that have revealed information concerning the distal luminal gastrointestinal tract. However, few studies have addressed the importance of the microbiome in the proximal gut. Given that the duodenum is a major site for digestion and absorption, its microbiome is relevant to nutrition and liver disease and warrants further investigation. Here we detail a novel method for sampling the proximal luminal and mucosal gut microbiome in human subjects undergoing upper endoscopy by obtaining duodenal aspirate and biopsies. Specimen procurement is facile and unaffected by artifacts such as patient preparatory adherence, as might be the case in obtaining colonic samples during colonoscopy. The preliminary results show that the luminal and mucosal microbiomes differ significantly, which is likely related to environmental conditions and barrier functions. Therefore, a combination of duodenal aspirate and biopsies reveal a more comprehensive picture of the microbiome in the duodenum. Biopsies are obtained from the descending and horizontal segments of the duodenum, which are anatomically close to the liver and biliary tree. This is important in studying the role of bile acid biology and the gut-liver axis in liver disease. Biopsies and aspirate can be used for 16S ribosomal RNA sequencing, metabolomics, and other similar applications.

Hepatocellular carcinoma (HCC) is a leading cause of cancer‐related death worldwide. Society guidelines recommend surveillance with abdominal ultrasound with or without serum alpha‐fetoprotein every 6 months for adults at increased risk of developing HCC. However, adherence is often suboptimal. We assessed the feasibility of a coordinated telephone outreach program for unscreened patients with cirrhosis within the Veteran’s Affairs (VA) health care system. Using a patient care dashboard of advanced chronic liver disease in the VA Greater Los Angeles Healthcare System, we identified veterans with a diagnosis of cirrhosis, a platelet count ≤ 150,000/uL, and no documented HCC surveillance in the previous 8 months. Eligible veterans received a telephone call from a patient navigator to describe the risks and benefits of HCC surveillance. Orders for an abdominal ultrasound and alpha‐fetoprotein were placed for veterans who agreed to surveillance. Veterans who were not reached by telephone received an informational letter by mail to encourage participation. Of the 129 veterans who met the eligibility criteria, most were male (96.9%). The most common etiology for cirrhosis was hepatitis C (64.3%), and most of the patients had compensated cirrhosis (68.2%). The patient navigators reached 32.5% of patients by phone. Patients in each group were similar across clinical and demographic characteristics. Patients who were called were more likely to undergo surveillance (adjusted odds ratio = 2.56, 95% confidence interval: 1.03‐6.33). Most of the patients (72.1%) completed abdominal imaging when reached by phone. Conclusion: Targeted outreach increased uptake of HCC surveillance among patients with cirrhosis in a large, integrated, VA health care system., HCC surveillance in patients with cirrhosis is recommended by society guidelines, yet suboptimal. In this quality improvement outreach pilot study within a large VA, we demonstrate that HCC surveillance improves by telephone and mail outreach of patients who have confirmed cirrhosis and had not been screened.

The presence of advanced fibrosis is an important measure of the severity of chronic liver disease. Prior works that have examined the gut microbiome as a novel biomarker for advanced fibrosis have only examined patients with nonalcoholic fatty liver disease. Therefore, our goal was to examine the gut microbiome across varying etiologies of liver disease to create a predictive model for liver fibrosis based upon a microbial signature. Stool samples were obtained from patients with chronic liver disease (n = 50) undergoing FibroScan (ultrasound elastography) at the VA Greater Los Angeles Healthcare System. Healthy control patients (n = 25) were also recruited as a reference population. Fecal samples underwent 16S ribosomal RNA sequencing. Using differentially abundant microbes, a random forest classifier model was created to distinguish advanced fibrosis from mild/moderate fibrosis. The findings were then validated in a separate cohort of chronic liver disease patients (n = 37). Etiologies for liver disease included non-alcoholic liver disease (58.0%), hepatitis C (26.0%), hepatitis B (10.0%), and alcohol (6.0%). Microbiome composition was distinct in liver patients with advanced fibrosis compared to those with minimal fibrosis and healthy controls (p = 0.003). In multivariate negative binomial modeling, 26 bacterial taxa were differentially abundant in patients with advanced fibrosis as compared to those with minimal/moderate fibrosis (q-value Prevotella copri, which was enriched in patients with advanced fibrosis, was the most strongly predictive microbe in the classifier. The classifier had an AUROC of 0.82 for advanced fibrosis in the validation cohort and Prevotella copri remained the strongest predictive microbe for advanced fibrosis. There is a distinct microbial signature for patients with advanced fibrosis independent of liver disease etiology and other comorbidities. These results suggest that microbial profiles can be used as a non-invasive marker for advanced fibrosis and support the hypothesis that microbes and their metabolites contribute to hepatic fibrosis.

Background: There is conflicting evidence regarding prevalence and incidence of atherosclerotic cardiovascular disease (ASCVD) in patients with liver cirrhosis. The risk factors associated with ASCVD within this group of patients have not been investigated previously. Methods and Results: This is a retrospective longitudinal study utilizing the Veterans Affairs (VA) Greater Los Angeles Electronic Medical Record of 623 patients with diagnosis of liver disease. We investigated the incidence of ASCVD events and risk factors associated with ASCVD in these patients. We observed an increase in prevalence of ASCVD events in patients with cirrhosis compared to liver disease patients without cirrhosis (19.12% vs 2.46%). Although the cirrhosis group patients were older but, in our Cox-regression model, after adjusting for traditional ASCVD risk factors especially age, cirrhosis remained a major risk factor for ASCVD events with a hazard ratio (HR) of 5.73 (CI: 2.74-12.72). In the subgroup analysis of cirrhosis group, transferrin saturation greater or equal to 40% had 4.27 times higher risk of ASCVD events than lower transferrin saturation. Conclusion: We propose that the liver damage and subsequent decrease in hepcidin production in patients with cirrhosis would cause a major increase in Non-Transferrin-Bound Iron (NTBI) in circulation. Circula-ting NTBI promotes endothelial dysfunction, produces reactive oxygen species (ROS), and exposes important biomolecules, like low density lipoprotein (LDL), to oxidative stress to facilitate atherosclerosis. Accordingly, these epidemiological results provide evidence for further translational investigations to identify factors to mitigate the development of ASCVD.

AIM Cirrhosis is a leading cause of death worldwide, yet there are no well-established risk stratifying tools for lethal complications, including hepatocellular carcinoma (HCC). Patients with liver cirrhosis undergo routine endoscopic surveillance, providing ready access to duodenal aspirate samples that could be a source for identifying novel biomarkers. The aim of this study was to characterize the microbiome and bile acid profiles in duodenal aspirates from patients with liver cirrhosis to assess the feasibility of developing biomarkers for HCC risk stratification. METHODS Thirty patients with liver cirrhosis were enrolled in the Microbiome, Microbial Markers, and Liver Disease study between May 2015 and March 2017. Detailed clinical and epidemiological data were collected at baseline and at 6-monthly follow-up visits. Duodenal aspirate fluid was collected at baseline for microbial characterization using 16S ribosomal RNA sequencing and bile acid quantification using mass spectroscopy. RESULTS Alcohol-related cirrhosis was associated with reductions in the Bacteroidetes phylum, particularly Prevotella (13-fold reduction), and expansion of Staphylococcus (13-fold increase), compared to hepatitis C virus-related cirrhosis. Participants with hepatic encephalopathy (HE) had less microbial diversity compared to patients without HE (P

Secukinumab is an interleukin-17 inhibitor used for the treatment of ankylosing spondylitis (AS), psoriasis, and psoriatic arthritis. The risk of exacerbating underlying inflammatory bowel disease (IBD) in patients being treated with secukinumab for other conditions is controversial. We document a patient with AS and previously undiagnosed IBD, found to be in a severe ulcerative colitis flare shortly after receiving the loading dose of secukinumab. There are no guidelines regarding biologic salvage therapy for IBD in the setting of active treatment with another biologic agent. After waiting one half-life of secukinumab, our patient had an excellent response to initiation of infliximab.

Hereditary hemorrhagic telangiectasia (HHT), also called Osler-Weber-Rendu syndrome, is an autosomal dominant genetic disease that affects the vasculature of numerous organs. The prevalence of HHT is estimated to be between 1.5 and 2 persons per 10,000. While there is still much to learn about this condition, there is an increasing understanding its underlying pathophysiology, genetic basis, presentations, and management. Recognizing that the clinical manifestations of HHT can involve a number of organ systems will provide clinicians with a higher index of suspicion for the disease. This early diagnosis and genotyping can greatly reduce mortality for a patient with HHT through appropriate screening for complications. This review will focus on the gastrointestinal manifestations of HHT and how these can dictate treatment and prognosis.

At present there is no universally accepted classification for gastritis. The first successful classification (The Sydney System) that is still commonly used by medical professionals was first introduced by Misiewicz et al in Sydney in 1990. In fact, it was the first detailed classification after the discovery of Helicobacter pylori by Warren and Marshall in 1982. In 1994, the Updated Sydney System was proposed during the International Workshop on the Histopathology of Gastritis followed by the publication in The American Journal of Surgical Pathology by Dixon et al. Using the new classification, distinction between atrophic and nonatrophic gastritis was revised, and the visual scale grading was incorporated. According to the Updated Sydney System Classification, atrophic gastritis is categorized into multifocal (H. pylori, environmental factors, specific diet) and corpus-predominant (autoimmune). Since metaplasia is a key histological characteristic in patients with atrophic gastritis, it has been recommended to use the word "metaplastic" in both variants of atrophic gastritis: autoimmune metaplastic atrophic gastritis (AMAG) and environmental metaplastic atrophic gastritis. Although there are many overlaps in the course of the disease and distinction between those two entities may be challenging, the aim of this review article was to describe the etiology, epidemiology, pathogenesis, diagnosis, clinical manifestations and treatment in patients with AMAG. However, it is important to mention that H. pylori is the most common etiologic factor for the development of gastritis in the world.

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Background: People with new-onset diabetes face higher risk of pancreatic cancer (PC). However, data on PC risk in people with more advanced stages of diabetes are lacking. We aimed to identify factors associated with PC among people with progressing diabetes. Methods: We conducted a retrospective cohort study on veterans aged ≥50, who were treated with either combination oral hypoglycemic therapy (n=578,543) or insulin (n=609,687) at the VA in 2000-2016. Incident PC was determined through the electronic health records and cancer registries. We examined the association of multiple risk factors with PC using Cox regression analyses. Results: In both people initiating combination therapy and in those initiating insulin, increasing age, male sex, non-Hispanic ancestry, current smoking, acute and chronic pancreatitis, abdominal pain, alcoholism, increase in A1c, and decrease in weight were associated with increased risk of PC (Table). Based on the multivariable model, we can identify sub-populations with ≥5% risk of PC, such as ≥75 year-old non-Hispanic white males initiating insulin who have a history of alcoholism, and who show ≥2% increase in A1c and ≥15% decrease in weight prior to insulin initiation. Conclusion: We identified risk factors associated with PC among people initiating combination oral hypoglycemics or insulin, which may be useful for stratifying people who may benefit from screening for PC. Disclosure C.Y. Jeon: None. M.O. Goodarzi: None. Y. Lin: None. S. Kim: None. T. Moin: None. J.R. Pisegna: None. Funding National Cancer Institute (R21CA220073)

BACKGROUND: Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are a group of cytoplasmic sensors that survey danger signals released by invading pathogens or damaged tissue. Mutations in the NLRP subfamily affect pro-inflammatory mediators and cause nonspecific systemic symptoms. AIMS: We sought to identify a potential genetic etiology of an inflammatory syndrome in a patient that presented with an atypical multisystem illness with carcinoid syndrome as well as atopic and autoimmune features. METHODS: Exome sequencing was performed using the Agilent SureSelect Clinical Research Exome XT kit on an Illumina HiSeq 2500. Longitudinal monitoring of pro-inflammatory cytokines was performed. RESULTS: We identified a novel variant (heterozygous c.536C > T [p.Thr179Ile]) in the NLRP12 gene in a 63-year-old woman and her daughter, who presented with an unusual clinical syndrome that differs from autoinflammatory disorders previously reported in association with the NLRP subfamily gene mutations. This NLRP12 variant was predicted to be pathogenic by functional analysis through Hidden Markov Models (FATHMM). Both the mother and the daughter had episodes of abdominal pain, fever, diarrhea, skin rash, hypothyroidism, and elevated urine 5-hydroxyindoleacetic acid (5-HIAA) levels. The proband also had elevated serum levels of pro-inflammatory (IL-1β, IL-6, IL-12, and TNF-α), Th1 (IL-2, IFN-γ), and Th2 (IL-4, IL-5, IL-13) cytokines, but not of Th17 (IL-17) and IL-10. CONCLUSION: This report adds to the expanding spectrum of clinical manifestations attributed to the NLRP subfamily gene variants and suggests a role of NLRP12 in the regulation of multiple cytokines.

Author(s): Baecker, Aileen; Kim, Sungjin; Risch, Harvey A; Nuckols, Teryl K; Wu, Bechien U; Hendifar, Andrew E; Pandol, Stephen J; Pisegna, Joseph R; Jeon, Christie Y | Abstract: Background and objectiveEarly detection methods for pancreatic cancer are lacking. We aimed to develop a prediction model for pancreatic cancer based on changes in health captured by healthcare claims data.MethodsWe conducted a case-control study on 29,646 Medicare-enrolled patients aged 68 years and above with pancreatic ductal adenocarcinoma (PDAC) reported to the Surveillance Epidemiology an End Results (SEER) tumor registries program in 2004-2011 and 88,938 age and sex-matched controls. We developed a prediction model using multivariable logistic regression on Medicare claims for 16 risk factors and pre-diagnostic symptoms of PDAC present within 15 months prior to PDAC diagnosis. Claims within 3 months of PDAC diagnosis were excluded in sensitivity analyses. We evaluated the discriminatory power of the model with the area under the receiver operating curve (AUC) and performed cross-validation by bootstrapping.ResultsThe prediction model on all cases and controls reached AUC of 0.68. Excluding the final 3 months of claims lowered the AUC to 0.58. Among new-onset diabetes patients, the prediction model reached AUC of 0.73, which decreased to 0.63 when claims from the final 3 months were excluded. Performance measures of the prediction models was confirmed by internal validation using the bootstrap method.ConclusionModels based on healthcare claims for clinical risk factors, symptoms and signs of pancreatic cancer are limited in classifying those who go on to diagnosis of pancreatic cancer and those who do not, especially when excluding claims that immediately precede the diagnosis of PDAC.

Background: High protein calorie restriction diets have shown clinical efficacy for obesity, but the mechanisms are not fully known. The intestinal microbiome is a mediator of obesity and preclinical data support an effect of high protein diet (HPD) on the gut microbiome of obesity, but there are few studies in humans. Methods: To address this, we conducted a dietary intervention trial of 80 overweight and obese subjects who were randomized to a calorie-restricted high protein diet (HPD) (30% calorie intake) or calorie-restricted normal protein diet (NPD) (15%) for 8 weeks. Baseline dietary intake patterns were assessed by the Diet History Questionnaire III. Longitudinal fecal sampling was performed at baseline, week 1, week 2, week 4, week 6, and week 8, for a total of 365 samples. Intestinal microbiome composition was assessed by 16S rRNA gene sequencing. Results: At baseline, microbial composition was associated with fiber and protein intake. Subjects on the HPD showed a significant increase in microbial diversity as measured by the Shannon index compared to those on the NPD. The HPD was also associated with significant differences in microbial composition after treatment compared to the NPD. Both diets induced taxonomic shifts compared to baseline, including enrichment of Akkermansia spp. and Bifidobacterium spp. and depletion of Prevotella spp. Conclusion: These findings provide evidence that weight loss diets alter the gut microbiome in obesity and suggest differential effects of HPDs compared to NPDs which may influence the clinical response to HPD.

PurposeMen with alcohol-related chronic pancreatitis (ARCP) resulting in type 3c diabetes mellitus (DM) are at a uniquely elevated risk of adverse ischemic events given the role of inflammation in both the underlying disease processes and atherosclerosis.We hypothesized that their panoramic images would show a prevalence of calcified carotid artery atheromas (calcified carotid artery plaques [CCAPs]) significantly more often than a general population of similarly aged men.Patients and methodsWe implemented a retrospective observational study. The sample was composed of male patients older than 30years having panoramic images.The predictor variable was a diagnosis of ARCP-DM, and the outcome variable was the prevalence rate of CCAPs. The prevalence of CCAPs among the patients with ARCP-DM was then compared with that of a historical general population composed of similarly aged men. Descriptive and bivariate statistics were computed, and the P value was set at .05.ResultsOf the 32 men (mean age, 61.7±11.2years) with ARCP-DM, 8 (25%) (mean age, 63.3±4.80years) had atheromas (CCAPs). There was a statistically significant (P&nbsp

AIM To determine whether successful treatment with directacting antivirals (DAA) is associated with improvements in hemoglobin A1c (HbA1c) and if type 2 diabetes mellitus (T2DM) or metabolic syndrome affects sustained virologic response (SVR). METHODS We performed a retrospective analysis of all hepatitis C virus (HCV) patients at the VA Greater Los Angeles Healthcare System treated with varying DAA therapy between 2014-2016. Separate multivariable logistic regression was performed to determine predictors of HbA1c decrease ≥ 0.5 after DAA treatment and predictors of SVR 12-wk post treatment (SVR12). RESULTS A total of 1068 patients were treated with DAA therapy between 2014-2016. The presence of T2DM or metabolic syndrome did not adversely affect SVR12. 106 patients had both HCV and T2DM. Within that cohort, patients who achieved SVR12 had lower mean HbA1c pre treatment (7.35 vs 8.60, P = 0.02), and lower mean HbA1c post-treatment compared to non-responders (6.55 vs 8.61, P = 0.01). The mean reduction in HbA1c after treatment was greater for those who achieved SVR12 than for non-responders (0.79 vs 0.01, P = 0.03). In adjusted models, patients that achieved SVR12 were more likely to have a HbA1c decrease of ≥ 0.5 than those that did not achieve SVR12 (adjusted OR = 7.24, 95%CI: 1.22-42.94). CONCLUSION In HCV patients with T2DM, successful treatment with DAA was associated with a significant reduction in HbA1c suggesting that DAA may have a role in improving insulin sensitivity. Furthermore, the presence of T2DM or metabolic syndrome does not adversely affect SVR12 rates in patients treated with DAA.

BackgroundPatients with early-stage pancreatic neuroendocrine tumors (PNETs) may develop metastatic recurrences despite undergoing potentially curative pancreas resections. We sought to identify factors predictive of metastatic recurrences and develop a prognostication strategy to predict recurrence-free survival (RFS) in resected PNETs.MethodsPatients with localized PNETs undergoing surgical resection between 1989 and 2015 were identified. Univariate and multivariate analysis were used to identify potential predictors of post-resection metastasis. A score-based prognostication system was devised using the identified factors. The bootstrap model validation methodology was utilized to estimate the external validity of the proposed prognostication strategy.ResultsOf the 140 patients with completely resected early-stage PNETs, overall 5- and 10-year RFS were 84.6% and 67.1%, respectively. The median follow-up was 56months. Multivariate analysis identified tumor size > 5cm, Ki-67 index 8-20%, lymph node involvement, and high histologic grade (G3, or Ki-67 > 20%) as independent predictors of post-resection metastatic recurrence. A scoring system based on these factors stratified patients into three prognostic categories with distinct 5-year RFS: 96.9%, 54.8%, and 33.3% (P

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease. HCV cure has been linked to improved patient outcomes. In the era of direct-acting antivirals (DAAs), HCV cure has become the goal, as defined by sustained virological response 12weeks (SVR12) after completion of therapy. Historically, African-Americans have had lower SVR12 rates compared to White people in the interferon era, which had been attributed to the high prevalence of non-CC interleukin 28B (IL28B) type. Less is known about the association between race/ethnicity and SVR12 in DAA-treated era. The aim of the study is to evaluate the predictors of SVR12 in a diverse, single-center Veterans Affairs population. We conducted a retrospective study of patients undergoing HCV therapy with DAAs from 2014 to 2016 at the VA Greater Los Angeles Healthcare System. We performed a multivariable logistic regression analysis to determine predictors of SVR12, adjusting for age, HCV genotype, DAA regimen and duration, human immunodeficiency virus (HIV) status, fibrosis, nonalcoholic fatty liver disease (NAFLD) fibrosis score, homelessness, mental health, and adherence. Our cohort included 1068 patients, out of which 401 (37.5%) were White people and 400 (37.5%) were African-American. Genotype 1 was the most common genotype (83.9%, N=896). In the adjusted models, race/ethnicity and thepresence of fibrosis were statistically significant predictors of non-SVR. African-Americans had 57% lower odds for reaching SVR12 (adj.OR=0.43, 95% CI=1.5-4.1) compared to White people. Advanced fibrosis (adj.OR=0.40, 95% CI=0.26-0.68) was also a significant predictor of non-SVR. In a single-center VA population on DAAs, African-Americans were less likely than White people to reach SVR12 when adjusting for covariates.

Colorectal cancer (CRC) accounts for ~9% of all cancers in the Veteran population, a fact which has focused a great deal of the attention of the VA's research and development efforts. A field-based meeting of CRC experts was convened to discuss both challenges and opportunities in precision medicine for CRC. This group, designated as the VA Colorectal Cancer Cell-genomics Consortium (VA4C), discussed advances in CRC biology, biomarkers, and imaging for early detection and prevention. There was also a discussion of precision treatment involving fluorescence-guided surgery, targeted chemotherapies and immunotherapies, and personalized cancer treatment approaches. The overarching goal was to identify modalities that might ultimately lead to personalized cancer diagnosis and treatment. This review summarizes the findings of this VA field-based meeting, in which much of the current knowledge on CRC prescreening and treatment was discussed. It was concluded that there is a need and an opportunity to identify new targets for both the prevention of CRC and the development of effective therapies for advanced disease. Also, developing methods integrating genomic testing with tumoroid-based clinical drug response might lead to more accurate diagnosis and prognostication and more effective personalized treatment of CRC.

Hypersecretory conditions affecting the stomach account for significant morbidity and mortality manifested in some cases with peptic ulcer, gastrointestinal hemorrhage, and/or gastroesophageal reflux disease (GERD). The diagnosis of gastric acid hypersecretory states can be challenging and relies on the use of quantitative assays to measure gastric acid secretion and serum gastrin. The most common etiology for hypergastrinemia is the use of potent gastric acid inhibitors such as the proton pump inhibitors. The differential diagnosis of this condition is of critical importance, and will dictate management decisions. Conditions such as atrophic gastritis are relatively benign and can lead to hypergastrinemia without the presence of gastric acid hypersecretion. Zollinger-Ellison syndrome, on the other hand, causes hypergastrinemia with profound gastric acid hypersecretion [1]. More common causes of hypergastrinemia include gastric outlet obstruction, ileus, and chronic renal failure [2]. In most cases, proton pump inhibitors will be used to manage these conditions. In some instances, surgical therapy may be required. This chapter will review the important clinical causes of gastric acid hypersecretion and provide insights to the best medical management options to better care for patients with these disorders.

The voltage gated sodium channel SCN4A mutations account for non-dystrophic myotonia and include a heterogeneous group of conditions that include hyperkalemic periodic paralysis, paramyotonica congenita, potassium-aggravated myotonia, and hypokalemic periodic paralysis type 2. This case report proposes that a rare variant p.Pro1629Leu in SCN4A can cause a skeletal muscle deficit with intermittent dysphagia.

Introduction The role of EUS-guided FNA as a highly sensitive modality in the diagnosis of pancreatic adenocarcinoma is well documented. However, there is little published data on the role of EUS-FNA in diagnosing pancreatic neuroendocrine tumors (NETs). Objective The aim of this study is to compare the sensitivity of EUS-FNA to that of CT-FNA for diagnosing pancreatic NETs. Methods This is a single institution retrospective analysis of the operating characteristics of EUS-FNA and CT-FNA in detecting pancreatic NETs. Only patients with a final diagnosis of pancreatic NET were selected for this study. Procedure related data, including tumor size and location, and presence of a cytotechnologist were recorded. The results of each FNA were compared to the final clinico-pathological diagnosis to calculate sensitivity. Results Twenty-eight patients undergoing FNA (19 by EUS, 9 by CT) were analyzed. NETs diagnosed by EUS-FNA were smaller compared with CT-FNA (2.7 ± 0.9cm vs. 6.5 ± 2.1cm, p = 0.009) and were more often found in the pancreatic head (47.4% vs. 11.1%, p = 0.035). There were no significant differences in sensitivity between EUS-FNA and CT-FNA specimens (73.7% vs. 88.9%, p = 0.33). Conclusion EUS-guided FNA is as sensitive as CT-guided FNA in diagnosing pancreatic NETs, but its main advantage is in the diagnosis of smaller pancreatic NETs in the head of the pancreas. It may also be the preferred approach in the diagnosis of multifocal pancreatic NETs in the setting of MEN I Syndrome.

In this prospective referring-physician-based survey, we investigated the definite clinical impact of 68Ga-DOTATATE PET/CT on managing patients with neuroendocrine tumors (NETs). Methods: We prospectively studied 130 patients with 68Ga-DOTATATE PET/CT referred for initial or subsequent management decisions (NCT02174679). Referring physicians completed one questionnaire before the scan (Q1) to indicate the treatment plan without PET/CT information, one immediately after review of the imaging report to denote intended management changes (Q2), and one 6 mo later (Q3) to verify whether intended changes were in fact implemented. To further validate the Q3 responses, a systematic electronic chart review was conducted. Results: All 3 questionnaires were completed by referring physicians for 96 of 130 patients (74%). 68Ga-DOTATATE PET/CT resulted in intended management changes (Q2) in 48 of 96 patients (50%). These changes were finally implemented (Q3) in 36 of 48 patients (75%). Q3 responses were confirmed in all patients with an available electronic chart (36/96; 38%). Conclusion: This prospective study confirmed a significant impact of 68Ga-DOTATATE PET/CT on the intended management of patients with NETs (50% of changes) and notably demonstrated a high implementation rate (75%) of these intended management changes.

BACKGROUND: This study evaluated the effects of intravenous pantoprazole on gastric volume and acid output in elective-surgical patients. METHODS: This is a multicenter, randomized, pilot study of adult patients receiving intravenous pantoprazole: 40 mg every 24 h, 40 mg every 12 h (q12h) or 80 mg q12h. The first dose was administered 1 h before general anesthesia for surgery. All gastric fluid was aspirated through a nasogastric tube 1 h before dosing and through the postoperative period. Aspirate volume was recorded; pH and H(+) concentrations were measured. RESULT: Twenty-six patients were enrolled and 21 were evaluable. Pantoprazole was well tolerated. All regimens decreased gastric acid output and volume, and increased pH within 1 h of dosing. Effects were sustained for up to 12 h following single-dose administration. CONCLUSIONS: Intravenous pantoprazole administered prior to anesthesia induction may be efficacious for the reduction of gastric volume and acid output, and for pulmonary aspiration prophylaxis in surgical patients.

Nocturnal reflux is a largely undiagnosed and unmanaged condition predisposing to multiple esophageal complications. We evaluated the effects of rabeprazole and pantoprazole on nocturnal intragastric pH and gastric acid output during Day 1 of therapy following the consumption of standard meals.The study had a double-blinded, randomized, two-way crossover design, and involved 15 patients with a history of mild reflux. Following an overnight fast, patients were given either rabeprazole (20 mg) or pantoprazole (40 mg) prior to the first of three standard Western meals. They then underwent overnight continuous intragastric pH monitoring and gastric acid output measurement. The drug effect was analyzed using a two-treatment, two-period crossover mixed model.The percentage of time during which the mean intragastric pH was greater than 4.0 and gastric acid output was less than 2.0 was higher for oral rabeprazole (p0.05). The inhibition of acid output was greater for rabeprazole at almost all time points. Furthermore, the mean time-matched pH values differed significantly over the first 8.3 hours (p0.05).On day 1, oral rabeprazole inhibited acid output to a greater extent and for a longer period than pantoprazole, and the intragastric pH was significantly higher for rabeprazole than for pantoprazole over the first 8.3 hours.

Summary Background Intravenous (IV) formulations of proton pump inhibitors are effective for patients in whom oral therapy is not appropriate. Aim To compare IV esomeprazole and IV lansoprazole for the control of intragastric pH. Methods In this open-label crossover study, healthy, Helicobacter pylori-negative adults were randomized to one of two treatment sequences, each consisting of two 5-day dosing periods of IV esomeprazole 40 mg or IV lansoprazole 30 mg. Twenty-four-hour intragastric pH monitoring was conducted on days 1 and 5 of each dosing period. Results On days 1 and 5, intragastric pH was >4.0 significantly longer with esomeprazole than lansoprazole (least-squares means: day 1, 40.0% vs. 33.6%; day 5, 61.9% vs. 45.4%; both P 4.0 significantly longer on days 1 and 5 with esomeprazole than lansoprazole (P 4.0 were 4.92 for esomeprazole and 5.75 for lansoprazole (P = 0.0014 for test on Gehan scores). Conclusion In healthy adults, IV esomeprazole 40 mg controlled intragastric acidity faster and more effectively than IV lansoprazole 30 mg.

To evaluate the efficacy and safety of oral esomeprazole in the control of gastric acid hypersecretion in patients with hypersecretory states.In this 12-month, open-label, multicenter study, acid output (AO) was evaluated at baseline, day 10, and months 3, 6, and 12. The starting dose of esomeprazole was 40 mg or 80 mg twice daily. On day 10, patients with controlled AO were maintained on the same dose, while those with uncontrolled AO had their doses increased (maximum dose 240 mg/day) until control was attained. Esophagogastroduodenoscopy (EGD) was performed at baseline and at 6 and 12 months. Safety and tolerability were assessed throughout the study by EGD, gastric analysis, and adverse events.Twenty-one patients (19 with Zollinger-Ellison syndrome [ZES], 2 with idiopathic gastric acid hypersecretion [IGH]) completed the study. Of the 20 patients with controlled AO at day 10, 18 (90%) had sustained AO control for the rest of the study. At 12 months, AO was controlled in 14 of 16 patients receiving esomeprazole 40 mg twice daily, in all 4 patients receiving esomeprazole 80 mg twice daily, and in the 1 patient receiving esomeprazole 80 mg 3 times daily. At 6 and 12 months, no patient had endoscopic evidence of mucosal disease. Esomeprazole was well tolerated; 1 patient had a serious adverse event (hypomagnesemia) attributed to treatment that resolved with magnesium supplementation during continued treatment.Esomeprazole in appropriately titrated doses controls AO over 12 months in patients with hypersecretory states and is well tolerated.

SUMMARY A long-term cure is now possible in more than 30% of selected patients with Zollinger–Ellison syndrome who undergo gastrinoma resection. The need, however, for continued gastric acid antisecretory therapy in these patients remains controversial. The current study was designed to determine whether post-operative antisecretory therapy is needed in patients who have undergone successful gastrinoma resection and, if so, to attempt to define criteria with which to identify patients who require therapy. Twenty-eight consecutive patients who had previously undergone curative gastrinoma resection were prospectively studied. When antisecretory therapy was discontinued, 43% (12/28) of these patients developed gastro-oesophageal reflux, diarrhoea, acid–peptic symptoms or endoscopic evidence of acid-peptic disease within 2 weeks and were deemed to have failed a trial of antisecretory drug withdrawal. The remaining 57% (16/28) of patients who successfully discontinued antisecretory therapy were followed for a mean time of 31 months after withdrawal of therapy. Analysis of acid output studies pre-operatively, as well as at the time of drug withdrawal, demonstrated that patients who were unable to discontinue antisecretory therapy exhibited higher pre-operative maximal acid output values and higher basal acid output values at the time of attempted drug withdrawal than patients who were able to discontinue therapy. Despite these findings, there was significant overlap in acid output values between groups so that it was not possible to define specific acid output criteria for successful drug withdrawal. Pre-operative clinical characteristics, such as the presence or absence of gastro-esophageal reflux or acid-peptic disease, or post-operative laboratory values, such as the fasting serum gastrin level, did not correlate with the ability to discontinue antisecretory therapy. We conclude that following successful curative gastrinoma resection, 40% of patients still require antisecretory therapy and that both symptom evaluation as well as upper endoscopy should be used to guide attempted drug withdrawal. Although patients who are not able to discontinue therapy have significantly higher acid output measurements than those who are able to discontinue therapy, neither acid output criteria nor any other laboratory or clinical characteristics are able to predict the need for continued antisecretory therapy in these patients.