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1.  Assessment of disease specific knowledge and health-related quality of life among United States military veterans with inflammatory bowel disease 
AIM: To evaluate the association between patient disease knowledge of inflammatory bowel disease (IBD) and health related quality of life (HRQoL) and identify patient and disease related predictors of patient knowledge of IBD.
METHODS: We performed a cross-sectional study of IBD patients with an established diagnosis of IBD longer than 3 mo prior to enrollment. The Crohn’s and colitis knowledge score (CCKNOW) and short inflammatory bowel disease questionnaire (SIBDQ) were self-administered to assess patient knowledge of IBD and HRQoL, respectively. Demographic and disease characteristics were abstracted from the electronic medical record. The correlation between CCKNOW and SIBDQ scores was assessed by a linear regression model. Associations of patient knowledge and the variables of interest were calculated using ANOVA.
RESULTS: A total of 101 patients were recruited. Caucasian race, younger age at diagnosis, and having a college or post-graduate degree were significantly associated with higher CCKNOW scores. Patients with CD had higher CCKNOW scores compared to patients with ulcerative colitis and inflammatory bowel disease type unclassified, P < 0.01. There was no significant correlation between overall CCKNOW and SIBDQ scores (r2 = 0.34, P = 0.13). The knowledge sub-domain of diet in CCKNOW was negatively correlated with HRQoL (r2 = 0.69, P < 0.01).
CONCLUSION: IBD diagnosis at a younger age in addition to Caucasian race and higher education were significantly associated with higher knowledge about IBD. However, patient knowledge of IBD was not correlated with HRQoL. Further studies are required to study the effect of patient knowledge of IBD on other clinical outcomes.
PMCID: PMC4438036  PMID: 26019466
Crohn’s disease; Ulcerative colitis; Crohn’s and Colitis Knowledge Score; Short inflammatory bowel disease questionnaire; Health related quality of life
2.  Personal and family history of cancer and the risk of Barrett’s esophagus in men 
The association between Barrett’s esophagus (BE) and a personal or family history of cancer other than gastroesophageal remains unknown. To evaluate the effect of personal and family history of certain cancers and cancer treatments on the risk of BE, we analyzed data from a Veterans Affairs case-control study that included 264 men with definitive BE (cases) and 1486 men without BE (controls). Patients with history of esophageal or gastric cancer were excluded. Patients underwent elective esophagogastroduodenoscopy (EGD) or a study EGD concurrently with screening colonoscopy to determine BE status. Personal and family history of several types of cancer was obtained from self-reported questionnaires, supplemented and verified by electronic medical-record reviews. We estimated the association between personal and family history of cancer or radiation/chemotherapy, and BE. Personal history of oropharyngeal cancer (1.5% vs. 0.4%) or prostate cancer (7.2% vs. 4.4%) was more frequently present in cases than controls. The association between BE and prostate cancer persisted in multivariable analyses (adjusted OR 1.90; 95% CI 1.07-3.38, P=0.028) while that with oropharyngeal cancer (adjusted OR 3.63; 95% CI 0.92-14.29, P=0.066) was attenuated after adjusting for retained covariates of age, race, GERD, hiatal hernia, and PPI use. Within the subset of patients with cancer, prior treatment with radiation or chemotherapy was not associated with BE. There were no significant differences between cases and controls in the proportions of subjects with several specific malignancies in first- or second-degree relatives. In conclusion, the risk of BE in men may be elevated with prior personal history of oropharyngeal or prostate cancer. However, prior cancer treatments and family history of cancer were not associated with increased risk of BE. Further studies are needed to elucidate if there is a causative relationship or shared risk factors between prostate cancer and BE.
PMCID: PMC4135032  PMID: 24529029
Barrett’s esophagus; Esophageal adenocarcinoma; Prostate cancer; Sex hormones; Radiation-induced esophageal damage
3.  Risk of Upper Gastrointestinal Cancers in Patients with Gastroesophageal Reflux Disease Following a Negative Screening Endoscopy 
Background & Aims
Practice guidelines recommend a 1-time screening endoscopy for patients with gastroesophageal reflux disease (GERD) who are at high risk for Barrett’s esophagus or malignancy. However, little is known about the risk of cancer in patients with negative findings from screening endoscopies.
We conducted a retrospective cohort study using data from 121 Veterans Health Administration facilities nationwide to determine the incidence rate of esophageal adenocarcinoma (EA) separately, as well as any upper gastrointestinal cancers, in patients with an initial negative screening endoscopy (EGD). We included veteran patients with GERD diagnosed between 2004 and 2009 who had a negative screening EGD within 1 year of diagnosis. We estimated the incidence rate of EA, and any upper gastrointestinal cancer, in patients with GERD who had a negative screening EGD. We examined differences in demographic, clinical, and facility factors among patients with and without cancer.
We identified 68,610 patients with GERD and a negative screening EGD (mean age, 55.5 years; 90% men; 67.5% white). During a mean follow up of 3.2 years, 10 patients developed EA and 29 developed any upper gastrointestinal malignancies, including EA. The incidence of subsequent EA in this group was 4.6/100,000 patient-years of follow up, whereas the incidence of any upper gastrointestinal cancers was 13.2/100,000 patient-years of follow up. Patients with a subsequent cancer were significantly older and had higher comorbidity scores than patients without cancer. Other clinical and facility factors did not differ significantly between these 2 groups.
The risk of cancer is low, over a mean 3-year period, for patients with GERD who had a negative screening endoscopy. These findings justify recommendations for a 1-time screening endoscopy for patients with GERD.
PMCID: PMC4284151  PMID: 25004461
GERD; Endoscopy; Cancer; Incidence
4.  Practice patterns of surveillance endoscopy in Veterans’ Affairs database of 29,504 patients with Barrett's esophagus 
Gastrointestinal endoscopy  2012;76(4):743-755.
Practice guidelines recommend surveillance endoscopy every 2–3 years among patients with Barrett's esophagus (BE) to detect early neoplastic lesions. Although surveys report that > 95% of gastroenterologists recommend or practice BE surveillance, the extent and patterns of surveillance in clinical practice are unknown.
Identify the extent and determinants of endoscopic surveillance among BE patients.
Retrospective cohort study
121 VA facilities nationwide
Veteran patients with BE diagnosed during 2003–2009 with follow-up through September 30, 2010.
Not an interventional study
Main Outcome Measurements
The proportions of patients with BE who received any EGD after the index BE EGD date. In the subgroup of patients with at least 6 years of follow-up, we also calculated proportions for regular (EGD during both 3-year intervals), irregular (EGD in only 1 interval), and no surveillance. We examined differences in demographics, clinical and facility factors among these groups in unadjusted and adjusted analyses.
We identified 29,504 patients with BE; 97% were men, 83% white, and their mean age was 61.8 years. During a 3.8 years median follow-up period, 45.4% of BE patients received at least one EGD. Among the subgroup of 4,499 BE patients who had at least 6 years of follow-up, 23.0% had regular surveillance and 26.7% had irregular surveillance. There was considerable facility-level variation in percentages with surveillance EGD across the 112 facilities and by geographic region of these facilities. Demographic and clinical factors did not explain these variations. Patients with at least one EGD were significantly more likely to be white, younger than 65 with low comorbidity, to have GERD, obesity, dysphagia or esophageal strictures, to have more outpatient visits and to be seen in smaller hospitals (<87 beds) than those without any EGD.
Possibility of misclassification of BE and surveillance EGD. Lack of pathology data on dysplasia, which dictates surveillance intervals.
Endoscopic surveillance for BE is considerably less commonly practiced in VA than self-reported by physicians. Although several clinical factors are associated with variations in surveillance, facility-level factors play a large role. The comparative effectiveness of the different practice based surveillance patterns needs to be examined.
PMCID: PMC4689298  PMID: 22985642
VA; epidemiology; risk factors; GERD
5.  Clinical Outcomes of Hepatitis B Virus Co-infection in a United States Cohort of Hepatitis C Virus-infected Patients 
Hepatology (Baltimore, Md.)  2014;60(6):1871-1878.
The effect of hepatitis B virus (HBV) co-infection in patients with hepatitis C virus (HCV) remains unclear. We used the National Veterans Affairs HCV Clinical Case Registry to identify patients with confirmed HCV viremia during 1997–2005. We defined HBV co-infection as a positive test for hepatitis B surface antigen, HBV DNA, or hepatitis B e antigen. We defined cirrhosis and HCC based on the validated ICD9 codes and determined mortality through the end of 2009. We performed Cox proportional hazard regression analyses to examine the effect of HBV co-infection stratified by HBV DNA status (positive or negative) on the risk of cirrhosis, HCC, and death adjusting for patients’ age, gender, race, HIV infection, alcohol or drug use, Deyo Score, and antiviral treatment. Among 99,548 patients with HCV infection, 1370 patients (1.4%) had HBV co-infection. Of the co-infected patients, 677 (49.4%) patients had at-least 1 HBV DNA test done and 303 patients (44.7%) tested positive for HBV DNA. The incidence rates of cirrhosis, HCC, and death were significantly higher in patients with HBV co-infection and detectable HBV DNA compared to HCV mono-infection (36.8, 6.9, and 41.7 versus 17.4, 3.6, and 31.4 per 1,000 person-years, respectively; p<0.05 for all comparisons). After adjustment for demographic, clinical, and treatment factors, patients with detectable HBV DNA had a significantly higher risk for cirrhosis, (hazard ratio [HR] =1.89 95% CI=1.46–2.45), HCC (HR=2.12, 95%CI=1.26–3.60), and death (HR=1.62, 95%CI=1.33–1.99), respectively, compared to HCV mono-infected patients. There were no differences in the risk of cirrhosis, HCC, or overall mortality between co-infected patients with undetectable HBV DNA and those with HCV mono-infection (HRs=1.18, 95% CI=0.90–1.55; 1.54, 95% CI=0.93–2.56; 1.08, 95% CI=0.88–1.33, respectively). In conclusion, we found that while only a small number of HCV patients were co-infected with HBV, patients with documented HBV viremia were at a significantly higher risk for cirrhosis, HCC, and overall death than HCV mono-infected patients. Absence of HBV replication was associated with a clinical course similar to that of HCV mono-infected patients.
PMCID: PMC4245372  PMID: 25065513
HBV; HCV; Viral hepatitis; Cirrhosis; HCC
7.  Nonsteroidal Anti-Inflammatory Drugs and the Risk of Barrett’s Esophagus 
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been suggested to protect against esophageal adenocarcinoma (EAC). This study examined the effect of NSAIDs on the risk of developing Barett’s esophagus (BE), the precursor lesion to EAC.
We conducted a case-control study among eligible patients scheduled for either elective esophagogastroduodenoscopy (EGD) or recruited from primary care clinics to undergo a study EGD. We compared 323 patients with BE (296 nondysplastic and 27 dysplastic) with 2 separate control groups: 1347 patients from the elective EGD group ("endoscopy controls") and 502 patients from the primary care group ("primary care controls") with no endoscopic or histopathologic BE. Use of aspirin products and 23 nonaspirin NSAIDs was ascertained from detailed, self-reported questionnaires. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable logistic-regression models.
There were no significant differences in self-reported NSAID use between all BE cases and all controls (58.2% vs. 54.6%, P=0.33); this was seen for aspirin products (43.0% vs. 37.4%, P=0.08) and nonaspirin NSAIDs (7.7% vs. 8.9%, P=0.46). These findings persisted in the multivariable model for any NSAIDs (adjusted OR 0.89; 95% CI 0.75–1.28), aspirin (adjusted OR 1.16; 95% CI 0.90–1.51), and nonaspirin NSAIDs (adjusted OR 0.88; 95% CI 0.55–1.39). Use of a combination of aspirin and nonaspirin NSAIDs was reported in 7.4% cases and 8.3% controls, and a non-significant inverse association with BE was seen (adjusted OR 0.70; 95% CI 0.44–1.11). There was no significant association between BE and daily NSAID use (adjusted OR 1.03; 95% CI 0.78–1.37). Similar findings were observed for comparisons involving nondysplastic or dysplastic BE cases, and endoscopy or primary care control groups separately or combined.
The use of NSAIDs was not associated with a reduced risk of BE. It is likely that the protective mechanism of NSAIDs on EAC occurs subsequent to the development of BE.
PMCID: PMC4214884  PMID: 24793026
8.  The changing pattern of epidemiology in hepatocellular carcinoma 
Digestive and Liver Disease  2010;42(Suppl 3):S206-S214.
Primary liver cancer (PLC) represents approximately 4% of all new cancer cases diagnosed worldwide. The purpose of this review is to describe some of the latest international patterns in PLC incidence and mortality, as well as to give an overview of the main etiological factors. We used two databases, GLOBOCAN 2002 and the World Health Organization (WHO) mortality database to analyze the incidence and mortality rates for PLC in several regions around the world. The highest age adjusted incidence rates (>20 per 100,000) were reported from countries in Southeast Asia and sub-Saharan Africa that are endemic for HBV infection. Countries in Southern Europe have medium-high incidence rates, while low-incidence areas (<5 per 100,000) include South and Central America, and the rest of Europe.
Cirrhosis is present in about 80–90% of HCC patients and is thereby the largest single risk factor. Main risk factors include HBV, HCV, aflatoxin and possibly obesity and diabetes. Together HBV and HCV account for 80–90% of all HCC worldwide. HBV continues to be the major HCC risk factor worldwide, although its importance will most likely decrease during the coming decades due to the widespread use of the HBV vaccine in the newborns. HCV has been the dominant viral cause in HCC in North America, some Western countries and Japan. Obesity and diabetes are increasing at a fast pace throughout the world, and if they are proven to be HCC risk factors, they would account for more HCC cases in the future.
PMCID: PMC3392755  PMID: 20547305
Cirrhosis; Epidemiology; GLOBOCAN; Hepatitis; Liver cancer
9.  A New Laboratory Based Algorithm to Predict Development of Hepatocellular Carcinoma in Patients with Hepatitis C and Cirrhosis 
Gastroenterology  2014;146(5):1249-1255.e1.
Background & Aims
Serum levels of α-fetoprotein (AFP) are influenced not only by the presence of hepatocellular carcinoma (HCC) but also by underlying severity and activity of liver disease, which is reflected by liver function tests. We constructed an AFP-based algorithm that included these factors to identify patients at risk for HCC, and tested its predictive ability in a large set of patients with cirrhosis.
We used the national Veterans Administration hepatitis C virus (HCV) clinical case registry to identify patients with cirrhosis, results from at least 1 AFP test, and 6 months of follow up. Our algorithm included data on age; levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total bilirubin, albumin, creatinine, and hemoglobin; prothrombin time; and numbers of platelets and white cells. We examined the operating characteristics (calibration, discrimination, predictive values) of several different algorithms for identification of patients who would develop HCC within 6 months of the AFP test. We assessed our final model in the development and validation subsets.
We identified 11,721 patients with HCV-related cirrhosis in whom 35,494 AFP tests were performed, and 987 patients developed HCC. A predictive model that included data on levels of AFP, ALT, and platelets, along with age at time of AFP test (and interaction terms between AFP and ALT, and AFP and platelets), best discriminated between patients who did and did not develop HCC. Using this AFP-adjusted model, the predictive accuracy increased at different AFP cutoffs, compared with AFP alone. At any given AFP value, low numbers of platelets and ALT and older age were associated with increased risk of HCC, whereas high levels of ALT and normal/high numbers of platelets were associated with low risk for HCC. For example, the probabilities of HCC, based only on 20 ng/ml and 120 ng/ml AFP, were 3.5% and 11.4%, respectively. However patients with the same AFP values (20 ng/ml and 120 ng/ml) who were 70 y old, with ALT levels of 40 IU/ml and platelet counts of 100,000, had probabilities of developing HCC of 8.1% and 29.0%, respectively.
We developed and validated an algorithm based on levels of AFP, platelets, and ALT, along with age, which increased the predictive value for identifying patients with HCV-associated cirrhosis likely to develop HCC within 6 months. If validated in other patient groups, this model would have immediate clinical applicability.
PMCID: PMC3992177  PMID: 24462733
prognosis; liver cancer; prediction; risk factors
10.  Fat mass by bioelectrical impedance analysis is not associated with increased risk of Barrett's esophagus 
To evaluate whether the association between obesity and Barrett's esophagus (BE) is due to total body fatness, abdominal obesity, or both.
BE risk appears more strongly related to central obesity than total obesity. However, no studies have investigated the association between total obesity and BE using direct measures of total body fatness.
We conducted a case-control study among patients scheduled for elective esophagogastroduodenoscopy (EGD), and a sample of patients eligible for screening colonoscopy recruited from primary care clinics. BE cases were patients with specialized intestinal metaplasia; while controls had no endoscopic or histopathologic BE. All patients underwent a study EGD and had body measurements taken. Fat mass and fat-free mass were estimated from bioelectrical impedance analysis (BIA). We calculated odds ratios (OR) and 95% confidence intervals (95%CI) using multivariable logistic regression.
There were 70 BO cases, 229 endoscopy controls and 118 primary care controls. BMI and BIA derived fat mass were highly correlated; however we found no association between BMI, fat mass and BE (vs. all controls: BMI, OR per 1 standard deviation [s.d.] = 1.01, 95%CI 0.76–1.34; fat mass, OR=1.02, 95%CI 0.77–1.36). WHR was significantly associated with increased BE risk (vs. all controls: OR=1.45, 95%CI 1.03–2.04). We found similar results when we analyzed the control groups separately.
WHR, but not fat mass or BMI, was associated with increased BE risk. This study provides strong evidence that BE is related to body size and composition via central adiposity and not via total body fatness.
PMCID: PMC3796119  PMID: 23842216
11.  Bundling in Medicare Patients Undergoing Bidirectional Endoscopy. How Often Does it Happen? 
In patients with appropriate indications, performance of both colonoscopy and esophagogastroduodonscopy (EGD) at the same time (bundling) is convenient for patients, efficient for providers, and cost saving for the healthcare system. However, Medicare reimbursement for bundled procedures is at a rate that is less than the sum of the two procedures when charged separately; this may create a disincentive to bundle. The practice patterns of bundling are unknown at a US population-based level.
We examined 2007 to 2009 Medicare claims from the Carrier file in a national, random sample of fee-for-service beneficiaries aged 66 and older. We identified patients who had both a colonoscopy and EGD performed within 180 days of each other and calculated the proportions of patients with both procedures bundled on the same date, within 1 to 30 days, and within 31 to180 days of each other. We compared patients in these 3 groups for demographics and clinical indications for the procedures (bleeding, lower or upper gastrointestinal [GI] symptoms, surveillance, and screening).
We identified 12,982 Medicare-enrolled individuals who had a colonoscopy and an EGD performed within 180 days of each other. Approximately 35% of procedures were not bundled on the same day; and, of these, 2,359 (18%) were performed within 30 days of each other; and 2,219 (17%) were performed within 31 to180 days of each other. There were marked geographic differences in the percentage of bundling, with the lowest in the Northeast and the highest in the West. Patients with bundled procedures were more likely to have GI bleeding and less likely to have screening or surveillance indications.
Although same-day bundling of endoscopic procedures offers a number of advantages, it is not practiced in more than one third of cases in a national sample of Medicare beneficiaries.
PMCID: PMC4103975  PMID: 23911874
12.  Epidemiology of HCC: Consider the Population 
Hepatocellular carcinoma (HCC) is increasing in incidence and has a very high fatality rate. Cirrhosis due to chronic hepatitis B or hepatitis C is the leading risk factor for HCC. Global epidemiology of HCC is determined by prevalence of dominant viral hepatitis and the age it is acquired in the underlying population. Upcoming risk factors include obesity, diabetes and related non-alcoholic fatty liver disease. This review discusses the latest trends of HCC globally and in the United States. It also provides an evidence-based commentary on the risk factors and lists some preventive measures to reduce the incidence of HCC.
PMCID: PMC3683119  PMID: 23632345
Hepatocellular carcinoma; epidemiology; chronic hepatitis B; chronic hepatitis C; prevention
13.  Barrett's Esophagus Suspected at Endoscopy but No Specialized Intestinal Metaplasia on Biopsy, What's Next? 
There are no guidelines regarding the best practice for when Barrett's esophagus (BE) is suspected but not confirmed by histology. The aim of this study was to examine the value of endoscopic follow-up for individuals with endoscopic only BE at index endoscopy.
We performed a longitudinal study of patients diagnosed with suspected columnar lined esophagus (CLE) (suspected BE in the absence of histological confirmation of specialized intestinal metaplasia (IM)). We examined three possible outcomes (definite BE defined as CLE plus IM in targeted biopsies, suspected CLE, or no suspected CLE) on repeat endoscopy within 2 years after the index endoscopy and their predictors (clinical, demographic as well as endoscopists' identity).
A total of 107 of 1,844 patients had suspected CLE (101 were <3 cm), and 80 underwent a repeat endoscopy within 2 years. Approximately, 71% (95% confidence interval (CI) 61.1–80.9%) had suspected CLE confirmed at repeat endoscopy and only 29% (95% CI 19.1–38.9%) had IM. The length of CLE on the index esophagogastroduodenoscopies was slightly longer among patients with definite BE on repeat endoscopy than those with suspected CLE and no IM or no CLE (1.6 cm (s.d. 1.3) vs. 1.5 cm (s.d. 1.4), and 1.4 cm (s.d. 1.2), respectively P>0.1). Patient demographics, body mass index, gastro-esophageal reflux disease symptoms, hiatal hernia, and endoscopists' identity were not significantly associated with the outcome on the repeat endoscopy.
Most (71%) patients with suspected CLE remain negative for IM in the 2 years following the index endoscopy. The findings support withholding BE diagnosis for individuals with suspected CLE.
PMCID: PMC4046947  PMID: 24343550
14.  Update on the epidemiology of gastro-oesophageal reflux disease: a systematic review 
Gut  2013;63(6):871-880.
To update the findings of the 2005 systematic review of population-based studies assessing the epidemiology of gastro-oesophageal reflux disease (GERD).
PubMed and Embase were screened for new references using the original search strings. Studies were required to be population-based, to include ≥200 individuals, to have response rates ≥50% and recall periods <12 months. GERD was defined as heartburn and/or regurgitation on at least 1 day a week, or according to the Montreal definition, or diagnosed by a clinician. Temporal and geographic trends in disease prevalence were examined using a Poisson regression model.
16 studies of GERD epidemiology published since the original review were found to be suitable for inclusion (15 reporting prevalence and one reporting incidence), and were added to the 13 prevalence and two incidence studies found previously. The range of GERD prevalence estimates was 18.1%–27.8% in North America, 8.8%–25.9% in Europe, 2.5%–7.8% in East Asia, 8.7%–33.1% in the Middle East, 11.6% in Australia and 23.0% in South America. Incidence per 1000 person-years was approximately 5 in the overall UK and US populations, and 0.84 in paediatric patients aged 1– 17 years in the UK. Evidence suggests an increase in GERD prevalence since 1995 (p<0.0001), particularly in North America and East Asia.
GERD is prevalent worldwide, and disease burden may be increasing. Prevalence estimates show considerable geographic variation, but only East Asia shows estimates consistently lower than 10%.
PMCID: PMC4046948  PMID: 23853213
15.  Oral Bisphosphonates and the Risk of Barrett's Esophagus: Case–Control Analysis of US Veterans 
This study examined Barrett's esophagus (BE) risk factors in veterans to determine the association between risk of BE and use of oral bisphosphonates.
We conducted a case – control study among eligible patients scheduled for an elective esophagogastroduodenoscopy (EGD) and a sample of patients eligible for screening colonoscopy recruited from primary care clinics from a single VA Medical Center. Cases with definitive BE were compared with controls; all underwent study EGD. Use of oral bisphosphonates was ascertained by reviewing filled prescriptions in electronic pharmacy records. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs), using multivariate logistic regression modeling while adjusting for sex, age, race, proton-pump inhibitor use, hiatal hernia, waist-to-hip ratio, Helicobacter pylori infection, and gastroesophageal reflux disorder (GERD) symptoms.
There were 285 BE cases, 1,122 endoscopy controls, and 496 primary care controls. Alendronate and risedronate were the only oral bisphosphonates prescribed. The proportion of BE cases with filled prescription of oral bisphosphonates (4.6%) was greater than in endoscopy controls (1.6%) or primary care controls (2.9%). In the adjusted analysis, oral bisphosphonate use was significantly associated with BE risk (OR = 2.33; 95% CI: 1.11 – 4.88) compared with the combined control groups. This association remained significant when BE cases were compared with endoscopy controls only (OR = 2.74; 95% CI: 1.28 – 5.87) but was attenuated when compared with primary care controls only (OR = 2.60; 95% CI: 0.99 – 6.84). The association was observed in patients with GERD symptoms (OR = 3.29; 95% CI: 1.36 – 7.97) but not in those without GERD symptoms.
Oral bisphosphonate use may increase the risk for BE, especially among patients with GERD.
PMCID: PMC4046950  PMID: 23857477
16.  Age at Onset of GERD Symptoms Predicts Risk of Barrett’s Esophagus 
Symptoms of gastroesophageal reflux disease (GERD) are the primary risk factor for Barrett’s esophagus (BE). However, the significance of age at symptom onset is unknown. We examined the effects of multiple dimensions of GERD exposure on BE risk and whether these associations are modified by other risk factors for BE.
Data were from a cross-sectional study of 683 Veterans Affairs patients undergoing an elective esophagogastroduodenoscopy (EGD) or a study EGD concurrently with colonoscopy from primary care clinics. We compared 236 patients with both endoscopically suspected and histologically confirmed BE to 447 primary-care patients (“primary-care controls”) without endoscopically suspected BE on their study EGD. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariate logistic regression.
Age at onset <30 years of frequent (at least weekly) GERD symptoms was associated with highest risk of BE (OR = 15.1, 95% CI 7.91–28.8), and risk increased linearly with earlier age at onset of symptoms (P-trend = 0.001). This association was independent of cumulative GERD symptom duration. People with early onset GERD symptoms who reported ever using proton pump inhibitors were at especially high risk of BE (OR = 31.1, 95% CI 13.9–69.7). In people with frequent GERD symptoms, BE risk was almost 80% lower among Helicobacter pylori-positive patients (OR = 2.60, 95% CI 1.26–5.40) than those negative for H. pylori (OR = 8.24, 95% CI 5.00–13.6).
Risk of BE increased linearly with earlier age at onset of frequent GERD symptoms. Age at symptom onset may help practitioners decide which patients with GERD symptoms to refer for endoscopic screening for BE.
PMCID: PMC3972036  PMID: 23567358
17.  Helicobacter pylori-Negative Gastritis: Prevalence and Risk Factors 
Recent studies using histology alone in select patients have suggested that Helicobacter pylori-negative gastritis may be common. The objective of this study was to investigate the prevalence of H. pylori among individuals with histologic gastritis.
Subjects between 40 and 80 years underwent elective esophagogastroduodenoscopy at a VA Medical Center. Gastric biopsies were mapped from seven prespecified sites (two antrum, four corpus, and one cardia) and graded by two gastrointestinal pathologists, using the Updated Sydney System. H. pylori-negative required four criteria: negative triple staining at all seven gastric sites, negative H. pylori culture, negative IgG H. pylori serology, and no previous treatment for H. pylori. Data regarding tobacco smoking, alcohol drinking, nonsteroidal anti-inflammatory drug, and proton pump inhibitor (PPI) use were obtained by questionnaire.
Of the 491 individuals enrolled, 40.7% (200) had gastritis of at least grade 2 in at least one biopsy site or grade 1 in at least two sites. Forty-one (20.5%) had H. pylori-negative gastritis; most (30 or 73.2%) had chronic gastritis, five (12.2%) had active gastritis, and six (14.6%) had both. H. pylori-negative gastritis was approximately equally distributed in the antrum, corpus, and both antrum and corpus. Past and current PPI use was more frequent in H. pylori-negative vs. H. pylori-positive gastritis (68.2% and 53.8%; P = 0.06).
We used multiple methods to define non-H. pylori gastritis and found it in 21% of patients with histologic gastritis. While PPI use is a potential risk factor, the cause or implications of this entity are not known.
PMCID: PMC3984401  PMID: 23147524
18.  Prevalence of oesophageal eosinophilia and eosinophilic oesophagitis: a prospective study in unselected patients presenting to endoscopy 
Oesophageal eosinophilia (EE) is encountered in clinical practice as oesophageal biopsies are being obtained in patients with GI symptoms other than classical symptoms of eosinophilic oesophagitis (EoE). The prevalence, determinants and clinical relevance of EE identified irrespective of symptoms are unclear.
To determine the prevalence and risk factors of EE with or without EoE in a non-selected group of patients undergoing endoscopy and in primary care patients.
A cross-sectional study in a single VA center in which we obtained at least one oesophageal biopsy from patients presenting to elective endoscopy, as well as a sample of patients eligible for screening colonoscopy recruited from primary care clinics. EE was defined by > 15 eosinophils in a single HPF; and EoE was defined as definite, probable or none depending on the presence of EE, acid-suppressive therapy and oesophageal symptoms.
EE was identified in 33 of 1357 patients (2.4%, 95% CI: 1.7–3.4); of whom 9 had definite EoE (0.66%, 95% CI: 0.23–1.10), 17 had probable EoE (1.25%), and the only 7 patients had EE without EoE. The prevalence of EE was 2.3% among patients undergoing elective endoscopy and 0.1% among patients eligible for screening colonoscopy. Seasonal allergies (adjusted OR: 2.78; 95%CI 1.26 – 6.11) and oesophageal strictures (4.50; 0.90 – 22.40) were associated with EE.
The prevalence of EE was 2.3% among unselected patients presenting to endoscopy most of whom have EoE. EE was present in 0.1% in primary care patients none of whom had EoE.
PMCID: PMC3602156  PMID: 23441936
Epidemiology; H. pylori; Dysphagia; Eosinophilia; Risk Factors
19.  Determinants of Serum Alpha-Fetoprotein Levels in Hepatitis C Infected Patients 
Background & Aims
Little information is available about what factors determine serum levels of α-fetoprotein (AFP) levels (e.g., demographic, virological, or clinical features) among individuals who do not develop hepatocellular cacrcinoma (HCC). This information might improve AFP-based algorithms for HCC detection.
We examined data from patients in the national Veterans’ Affairs Hepatitis C Virus (HCV) Clinical Case Registry who received at least 1 AFP test (258,275 AFP tests in 76,357 patients; 1.9% developed HCC). We constructed hierarchical multivariate models of AFP levels. Potential predictors of AFP values included patients’ sex, race, cirrhosis status, model for end-stage liver disease (MELD) score, HCV genotype, level of alanine aminotransferase (ALT) within 30 days before the AFP test, time to diagnosis of HCC, and time elapsed from the HCV index date.
Significant determinants for increased levels of AFP included presence of cirrhosis, higher MELD scores and increased levels of ALT. AFP levels were also affected by the interaction between ALT levels and the presence and time to development of HCC. Among patients that did not have HCC, the AFP level increased with the level of ALT; the AFP values in the presence of ALT (37–56 U/L), ALT (57–92 U/L), or ALT > 92 U/L were 16%, 35%, and 68% higher, respectively, than AFP values at ALT (0–36 U/L). However, patients who developed HCC within 30 days of receiving the AFP test had a lower rate of increase in AFP with each higher category of ALT level, with increases of 31%, 39% and 37% for the same respective ALT categories.
In patients with chronic HCV infection, AFP and ALT values correlate; however, among patients with HCC, levels of AFP increase disproportionately to, or unaccompanied by, increases in levels of ALT. The prognostic and diagnostic value of AFP levels might be increased by adjusting for ALT values.
PMCID: PMC3311729  PMID: 22155556
biomarker; risk; liver cancer; disease progression
20.  Level of Alpha-Fetoprotein Predicts Mortality among Patients with Hepatitis C-Related Hepatocellular Carcinoma 
Background & Aims
Hepatocellular carcinoma (HCC) can result from hepatitis C (HCV)-related liver disease and is the fastest-growing cause of cancer-related death in the United States. Alpha-fetoprotein (AFP) has been used as a prognostic factor for HCC, but the value of AFP as a prognostic factor for HCV-related HCC in the United States is unknown. We investigated whether higher levels of AFP at the time of diagnosis are associated with increased mortality of patients with HCV-related HCC.
In a retrospective study, we collected data from a cohort of HCV-infected veterans, identifying incident HCC cases from October 1, 1998 to January 1, 2007 (n=1480 patients). Mean serum levels of AFP, obtained within 60 days before to 30 days after HCC diagnosis, were determined for 1064 patients and categorized as <10 ng/ml (18%), 10–<100 ng/ml (30%), 100–<1000 ng/ml (22%), or ≥1000 ng/ml (29%). Cox proportional hazard models were used to associate serum levels of AFP with mortality, adjusting for demographic features, clinical factors, and treatment.
The median survival times were significantly lower among patients with higher levels of AFP: 709 d for patients with <10 ng/ml, 422 d for 10–<100 ng/ml, 208 d for 100–<1000 ng/ml, and 68 d for ≥1000 ng/ml. In the multivariate analysis, increased levels of AFP (10–<100, 100–<1000, ≥1000) were significantly associated with increased mortality, compared to a serum level of AFP <10; hazard ratios were 1.50, 2.23, and 4.35, respectively.
Serum level of AFP at the time of diagnosis with HCV-related HCC is an independent predictor of mortality.
PMCID: PMC3200479  PMID: 21820396
liver disease; risk; prognosis; epidemiology; blood test
21.  Risk Factors of Cholangiocarcinoma 
Hepatology (Baltimore, Md.)  2011;54(1):173-184.
Cholangiocarcinoma is the second most common primary hepatic malignancy after hepatocellular cancer. It accounts for approximately 10–25% of all hepatobiliary malignancies. There are considerable geographic and demographic variations in the incidence of cholangiocarcinoma. There are several established risk factors for CC including parasitic infections, primary sclerosing cholangitis, biliary-duct cysts, hepatolithiasis, and toxins. Other less-established, potential risk factors include inflammatory bowel disease, hepatitis C virus, hepatitis B virus, cirrhosis, diabetes, obesity, alcohol drinking, tobacco smoking, and host genetic polymorphisms. In studies where the distinction between ICC and ECC was used, some potential risk factors seem to have differential effect on CC depending on site. Therefore, the consistent use of more refined classification would allow better understanding of risk factors for cholangiocarcinoma.
PMCID: PMC3125451  PMID: 21488076
22.  Barrett’s esophagus in children and adolescents without neurodevelopmental or tracheoesophageal abnormalities: a prospective study 
Gastrointestinal endoscopy  2011;73(5):875-880.
There have been no prospective large-scale studies to evaluate the prevalence and determinants of Barrett’s esophagus (BE) in children who are free from neurodevelopmental disorders and tracheoesophageal abnormalities.
A prospective cross-sectional study
Three pediatric GI Centers in Houston, TX, Phoenix AZ, and Portland ME between February, 2006 and December, 2007.
Children and adolescents consecutively presenting for elective upper endoscopy. Patients with neurodevelopmental and tracheoesophageal disorders were excluded.
Endoscopic pictures of all cases with suspected BE were independently reviewed and verified by 2 experienced investigators. Esophageal biopsies were obtained in all patients, and targeted biopsies were also obtained from suspected BE.
Main Outcome Measurements
Endoscopically suspected BE and histologically confirmed BE.
A total of 840 patients (mean age, 9.5 years) were enrolled and had complete questionnaire and endoscopic data. Twelve patients were suspected of having BE (prevalence of 1.43% (95% CI: 0.73–2.45)) and only 1 patient has intestinal metaplasia for a prevalence of 0.12% (95% CI 0–0.65), while the rest had gastric (n=6) or squamous (n=5). Patients with suspected BE had higher mean BMI (23.0 vs. 19.1, p=0.05) and more chest pain (50% vs. 13%, p<0.01) than patients without BE or reflux esophagitis. There was a trend of higher frequency of dysphagia, heartburn and regurgitation in patients with suspected BE.
The accuracy of BE prevalence estimates is limited by the small number of cases.
BE is rare in children without neurodevelopmental delay or tracheoesophageal anomalies presenting for elective upper endoscopy.
PMCID: PMC3083476  PMID: 21354565
23.  Medications (NSAID, Statins, PPI) and the Risk of Esophageal Adenocarcinoma in Patients with Barrett’s Esophagus 
Gastroenterology  2010;138(7):2260-2266.
Background & Aims
Limited evidence suggests that proton pump inhibitors (PPI), non-steroidal anti inflammatory drugs (NSAID)/aspirin and statins may be associated with low risk of esophageal neoplasia. However, the possible effect these medications may have on the risk of esophageal adenocarcinoma (EAC) in patients with existing Barrett’s esophagus (BE) is unclear.
We conducted a nested case-control study in a cohort of patients with BE identified in the national Department of Veterans Affairs (VA) computerized databases. Cases with incident EAC were matched by incidence density sampling to controls with BE who remained without EAC at the date of the EAC diagnosis for the corresponding case. We identified prescriptions for PPI, NSAID/aspirin, and statins that were filled between BE diagnosis and EAC diagnosis. Incidence density ratios were calculated using conditional logistic regression models that adjusted for race, outpatient encounters, a disease comorbidity index, and socio-economic status.
In a cohort of 11,823 patients with first time BE diagnosis, we examined 116 EAC cases and 696 matched controls. Most cases and controls had at least one filled PPI prescription (95% vs. 94%, p=0.5). In this setting of almost universal PPI use, filled NSAID/aspirin prescriptions were associated with a reduced risk of EAC (adjusted incidence density ratio: 0.64; 95% CI, 0.42–0.97). Filled statin prescriptions were also associated with a reduction in EAC risk (0.55; 95% CI, 0.36–0.86), with a significant trend toward greater risk reduction with longer duration of statin use. However, the strong inverse associations with even short periods of use raise concerns of uncontrolled confounding.
This observational study indicates that in patients with Barrett’s esophagus using PPI, NSAID/aspirin or statin therapy might reduce the risk of developing esophageal adenocarcinoma.
PMCID: PMC2883678  PMID: 20188100
epidemiology; chemoprevention; GERD; VA; Medicare
24.  Determinants of Medical System Delay in the Diagnosis of Colorectal Cancer within the Veteran Affairs Health System 
Digestive diseases and sciences  2010;55(5):1434-1441.
Background & Aims
The goals of this study were to evaluate determinants of the time in the medical system until a colorectal cancer diagnosis and to explore characteristics associated with stage at diagnosis.
We examined medical records and survey data for 468 patients with colorectal cancer at 15 Veterans Affairs medical centers. Patients were classified as screen-detected, bleeding-detected, or other (resulting from the evaluation of another medical concern). Patients who presented emergently with obstruction or perforation were excluded. We used Cox proportional hazards models to determine predictors of time in the medical system until diagnosis. Logistic regression models were used to determine predictors of stage at diagnosis.
We excluded 21 subjects who presented emergently leaving 447 subjects; the mean age was 67 years and 98% were male, 66% Caucasian, and 43% stage I or II. Diagnosis was by screening for 39%, bleeding symptoms for 27% and other for 34%. The median times to diagnosis were 73–91 days and not significantly different by diagnostic category. In the multivariable model for time-to-diagnosis, older age, having comorbidities, and Atlantic region were associated with a longer time to diagnosis. In the multivariable model for stage-at-diagnosis only diagnostic category was associated with stage; screen-detected category was associated with decreased risk of late stage cancer.
Our results point to several factors associated with a longer time from the initial clinical event until diagnosis. This increased time in the health care system did not clearly translate into more advanced disease at diagnosis.
PMCID: PMC2864330  PMID: 20238248
25.  The Epidemiology of Obesity 
PMCID: PMC2833287  PMID: 20202574
obesity; epidemiology of obesity; complications of obesity

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