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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.
doi:10.3748/wjg.v21.i19.6001
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.  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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1053/j.gastro.2014.01.045
PMCID: PMC3992177  PMID: 24462733
prognosis; liver cancer; prediction; risk factors
3.  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.
doi:10.1016/S1590-8658(10)60507-5
PMCID: PMC3392755  PMID: 20547305
Cirrhosis; Epidemiology; GLOBOCAN; Hepatitis; Liver cancer
4.  Fat mass by bioelectrical impedance analysis is not associated with increased risk of Barrett's esophagus 
Goal
To evaluate whether the association between obesity and Barrett's esophagus (BE) is due to total body fatness, abdominal obesity, or both.
Background
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.
Study
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.
Results
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.
Conclusion
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.
doi:10.1097/MCG.0b013e31829ae98c
PMCID: PMC3796119  PMID: 23842216
5.  Bundling in Medicare Patients Undergoing Bidirectional Endoscopy. How Often Does it Happen? 
Background
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.
Methods
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).
Results
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.
Conclusions
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.
doi:10.1016/j.cgh.2013.07.021
PMCID: PMC4103975  PMID: 23911874
6.  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.
doi:10.1097/MCG.0b013e3182872f29
PMCID: PMC3683119  PMID: 23632345
Hepatocellular carcinoma; epidemiology; chronic hepatitis B; chronic hepatitis C; prevention
7.  Barrett's Esophagus Suspected at Endoscopy but No Specialized Intestinal Metaplasia on Biopsy, What's Next? 
OBJECTIVES
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.
METHODS
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).
RESULTS
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.
CONCLUSIONS
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.
doi:10.1038/ajg.2013.408
PMCID: PMC4046947  PMID: 24343550
8.  Update on the epidemiology of gastro-oesophageal reflux disease: a systematic review 
Gut  2013;63(6):871-880.
Objective
To update the findings of the 2005 systematic review of population-based studies assessing the epidemiology of gastro-oesophageal reflux disease (GERD).
Design
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.
Results
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.
Conclusions
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%.
doi:10.1136/gutjnl-2012-304269
PMCID: PMC4046948  PMID: 23853213
9.  Oral Bisphosphonates and the Risk of Barrett's Esophagus: Case–Control Analysis of US Veterans 
OBJECTIVES
This study examined Barrett's esophagus (BE) risk factors in veterans to determine the association between risk of BE and use of oral bisphosphonates.
METHODS
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.
RESULTS
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.
CONCLUSIONS
Oral bisphosphonate use may increase the risk for BE, especially among patients with GERD.
doi:10.1038/ajg.2013.222
PMCID: PMC4046950  PMID: 23857477
10.  Age at Onset of GERD Symptoms Predicts Risk of Barrett’s Esophagus 
OBJECTIVES
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.
METHODS
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.
RESULTS
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).
CONCLUSIONS
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.
doi:10.1038/ajg.2013.72
PMCID: PMC3972036  PMID: 23567358
11.  Helicobacter pylori-Negative Gastritis: Prevalence and Risk Factors 
OBJECTIVES
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.
METHODS
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.
RESULTS
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).
CONCLUSIONS
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.
doi:10.1038/ajg.2012.372
PMCID: PMC3984401  PMID: 23147524
12.  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.
Aim
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1111/apt.12268
PMCID: PMC3602156  PMID: 23441936
Epidemiology; H. pylori; Dysphagia; Eosinophilia; Risk Factors
13.  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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.cgh.2011.11.025
PMCID: PMC3311729  PMID: 22155556
biomarker; risk; liver cancer; disease progression
14.  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.
Methods
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.
Results
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.
Conclusions
Serum level of AFP at the time of diagnosis with HCV-related HCC is an independent predictor of mortality.
doi:10.1016/j.cgh.2011.07.026
PMCID: PMC3200479  PMID: 21820396
liver disease; risk; prognosis; epidemiology; blood test
15.  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.
doi:10.1002/hep.24351
PMCID: PMC3125451  PMID: 21488076
16.  Barrett’s esophagus in children and adolescents without neurodevelopmental or tracheoesophageal abnormalities: a prospective study 
Gastrointestinal endoscopy  2011;73(5):875-880.
Objective
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.
Design
A prospective cross-sectional study
Setting
Three pediatric GI Centers in Houston, TX, Phoenix AZ, and Portland ME between February, 2006 and December, 2007.
Patients
Children and adolescents consecutively presenting for elective upper endoscopy. Patients with neurodevelopmental and tracheoesophageal disorders were excluded.
Interventions
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.
Results
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.
Limitations
The accuracy of BE prevalence estimates is limited by the small number of cases.
Conclusions
BE is rare in children without neurodevelopmental delay or tracheoesophageal anomalies presenting for elective upper endoscopy.
doi:10.1016/j.gie.2011.01.017
PMCID: PMC3083476  PMID: 21354565
17.  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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1053/j.gastro.2010.02.045
PMCID: PMC2883678  PMID: 20188100
epidemiology; chemoprevention; GERD; VA; Medicare
18.  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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1007/s10620-010-1174-9
PMCID: PMC2864330  PMID: 20238248
19.  The Epidemiology of Obesity 
doi:10.1016/j.gtc.2009.12.014
PMCID: PMC2833287  PMID: 20202574
obesity; epidemiology of obesity; complications of obesity
20.  Irritable Bowel Syndrome and Dyspepsia among Women Veterans: Prevalence and Association with Psychological Distress 
Background
The burden of functional GI disorders and their associations with psychological distress in women veterans is unclear.
Aim
To examine one-year prevalence of IBS and dyspepsia symptoms and their associations with anxiety, depression and PTSD among women veterans receiving primary care at a Veteran Affairs Medical Center Women’s Clinic.
Methods
IBS, dyspepsia and psychological distress were assessed using the validated self-administered Bowel Disorder Questionnaire, the Beck Depression and Anxiety Inventories, as well as the Mississippi Scale for Combat-Related posttraumatic stress disorder (PTSD) questionnaire.
Results
We enrolled 248 women (84% participation rate). Ninety-three (38%) reported IBS and 51 (21%) dyspepsia symptoms. Women with IBS and dyspepsia reported higher mean scores of anxiety (IBS: 24 vs. 12, p<.0005 and dyspepsia: 26 vs. 12, p <.0005), depression (IBS: 22 vs. 11, p=.0005 and dyspepsia: 23 vs. 11, p <.0005), and PTSD (IBS: 87 vs. 69, P<.001 and dyspepsia: 86 vs. 69, p <.0005). Age- and ethnicity-adjusted logistic regression analyses showed a 3- to 46-fold increase in odds of IBS and dyspepsia among women with anxiety, depression, or PTSD.
Conclusions
Women veterans have high prevalence of IBS and dyspepsia symptoms, both of which are highly associated with presence of depression, anxiety and PTSD.
doi:10.1111/j.1365-2036.2008.03847.x
PMCID: PMC2939246  PMID: 18785989
21.  Obesity increases oesophageal acid exposure 
Gut  2006;56(6):749-755.
Background
Obesity has been associated with gastro‐oesophageal reflux disease (GERD); however, the mechanism by which obesity may cause GERD is unclear.
Aim
To examine the association between oesophageal acid exposure and total body or abdominal anthropometric measures.
Methods
A cross‐sectional study of consecutive patients undergoing 24 h pH‐metry was conducted. Standardised measurements of body weight and height as well as waist and hip circumference were obtained. The association between several parameters of oesophageal acid exposures and anthropometric measures were examined in univariate and multivariate analyses.
Results
206 patients (63% women) with a mean age of 51.4 years who were not on acid‐suppressing drugs were enrolled. A body mass index (BMI) of >30 kg/m2 (compared with BMI<25 kg/m2) was associated with a significant increase in acid reflux episodes, long reflux episodes (>5 min), time with pH<4, and a calculated summary score. These significant associations have affected total, postprandial, upright and supine pH measurements. Waist circumference was also associated with oesophageal acid exposure, but was not as significant or consistent as BMI. When adjusted for waist circumference by including it in the same model, the association between BMI>30 kg/m2 and measures of oesophageal acid exposure became attenuated for all, and not significant for some, thus indicating that waist circumference may mediate a large part of the effect of obesity on oesophageal acid exposure.
Conclusions
Obesity increases the risk of GERD, at least partly, by increasing oesophageal acid exposure. Waist circumference partly explains the association between obesity and oesophageal acid exposure.
doi:10.1136/gut.2006.100263
PMCID: PMC1954847  PMID: 17127706
22.  Statins Are Associated with a Reduced Risk of Hepatocellular Carcinoma in a Large Cohort of Patients with Diabetes 
Gastroenterology  2009;136(5):1601-1608.
Background
Experimental studies indicate a potential cancer prevention effect for statins. Given the increasing prevalence of statin use, and the rising incidence of hepatocellular carcinoma (HCC), the potential association between statins and HCC is an important issue to examine.
Methods
We conducted a matched case-control study nested within a cohort of patients with diabetes. Cases comprised incident HCC as defined by those occurring at least 6 months following entry in the cohort. Controls were identified by incidence density sampling from patients who remained at risk at the date of the HCC diagnosis matched on age and gender. We identified filled statin prescriptions as well as several potential confounding conditions, medications as well as propensity score to use statins. Odds ratios (OR) as estimates of the relative risk for HCC associated with statin use and 95% CIs were obtained using conditional logistic regression.
Results
We examined 1303 cases and 5212 controls. The mean age was 72 years and 99% were men. A significantly smaller proportion of cases (34.3%) had at least one filled prescriptions for statins than controls (53.1%). There were no significant associations between HCC and non statin cholesterol or triglyceride lowering medications. The unadjusted OR for any statin prescription was 0.46 (95% CI: 0.40–0.517) and the adjusted OR was 0.74 (0.64, 0.87). To reduce the potential confounding effect of existing liver disease, we ran the analyses in a subgroup of patients without recorded liver disease; the ORs were slightly attenuated but remained highly significant both for any statin prescription (0.63 (0.50–0.78).
Conclusions
Statin use is associated with a significant reduction in the risk of hepatocellular carcinoma among patients with diabetes.
doi:10.1053/j.gastro.2009.01.053
PMCID: PMC2677134  PMID: 19208359
23.  Gene Expression in Barrett's Esophagus: Laser Capture vs. Whole tissue 
Background
Diagnosis of Barrett's esophagus (BE) is typically done through morphologic analysis of esophageal tissue biopsy. Such samples contain several cell types. Laser capture microdissection (LCM) allows the isolation of specific cells from heterogeneous cell populations. The purpose of this study was to determine the degree of overlap of the two sample types and to define a set of genes that may serve as biochemical markers for BE.
Methods
We obtained biopsies from regions of the glandular tissue of BE and normal esophagus from 9 subjects with BE. Samples from 5 subjects were examined as whole tissue (BE [whole]; E [whole]), and in 4 subjects the glandular epithelium of BE was isolated using LCM (BE [LCM]) and compared to the averaged values (E [LCM]) for both basal cell (B [LCM]) and squamous cell (S [LCM]) epithelium.
Results
Gene expression revealed 1797 probesets between BE [whole] and E [whole] (fold change > 2.0; p<0.001). Most (74%) were also differentially expressed between BE [LCM] and E [LCM], showing that there was high concordance between the two sampling methods. LCM provided a great deal of additional information (2113 genes) about the alterations in gene expression that may represent the BE phenotype.
Conclusions
There are differences in gene expression profiles depending on whether specimens are whole tissue biopsies or LCM dissected. Whole tissue biopsies should prove satisfactory for diagnostic purposes. Because the data from LCM samples delineated many more Barrett's specific genes, this procedure may provide more information regarding pathogenesis than whole tissue material.
doi:10.1080/00365520902898127
PMCID: PMC2822542  PMID: 19391063
24.  Hepatitis C infection and risk of diabetes: A systematic review and meta-analysis 
Journal of hepatology  2008;49(5):831-844.
Background/aims
Several studies found hepatitis C (HCV) increases risk of Type II diabetes mellitus (DM). However, others found no or only sub-group specific excess risk. We performed meta-analyses to examine whether HCV infection does increase DM risk in comparison to the general population and in other sub-groups with increased liver disease rates including with hepatitis B (HBV).
Methods
We followed standard guidelines for performance of meta-analyses. Two independent investigators identified eligible studies through structured keyword searches in relevant databases including PubMed.
Results
We identified 34 eligible studies. Pooled estimators indicated significant DM risk in HCV-infected cases in comparison to non-infected controls in both retrospective (ORadjusted=1.68, 95 percent CI 1.15–2.20) and prospective studies (HRadjusted=1.67, 95% CI 1.28–2.06). Excess risk was also observed in comparison to HBV-infected controls (ORadjusted=1.80, 95% CI 1.20–1.40) with suggestive excess observed in HCV+/HIV+ cases in comparison to HIV+ controls (ORunadjusted=1.82, 95 percent CI 1.27–2.38).
Conclusions
Our finding of excess DM risk with HCV infection in comparison to non-infected controls is strengthened by consistency of results from both prospective and retrospective studies. The excess risk observed in comparison to HBV-infected controls suggests a potential direct viral role in promoting DM risk, but this needs to be further examined.
doi:10.1016/j.jhep.2008.08.006
PMCID: PMC2642971  PMID: 18814931
hepatitis C; diabetes mellitus, Type 2; meta-analysis; review, systematic; liver diseases; hepatitis B
25.  A Multi-biomarker Risk Score Helps Predict Risk for Barrett’s Esophagus 
Background & Aims
Risk prediction models for Barrett’s esophagus (BE) have been developed using multiple demographic and clinical variables, but their predictive performance has been modest. Adding a multi-biomarker risk score may improve discriminatory ability.
Methods
We used data from 141 patients with definitive BE and 138 controls participating in a case–control study at the Michael E. DeBakey Veterans Affairs Medical Center in Houston, TX (97% male, 65% of controls white, 89% of cases white). We derived and compared 3 prediction models. Model 1 included only GERD frequency and duration; Model 2 included GERD frequency and duration, age, sex, race, waist-to-hip ratio, and Helicobacter pylori status; and Model 3 included the variables in Model 2 as well as a multi-biomarker risk score based on serum levels of interleukin (IL)12p70, IL6, IL8, IL10, and leptin. We assessed their predictive accuracy in terms of discrimination using area under the receiver operating characteristic curve (AUC) and calibration analyses.
Results
The multi-biomarker risk score was significantly associated with risk for BE. Compared to persons with a score of 0, persons with a score of 3 or more had greater than 10-fold increased risk for BE (biomarker risk score ≥3; OR=11.9; 95% confidence interval, 4.06–34.9; P-trend <.001). Risk prediction using the multi-biomarker score in conjunction with demographic and clinical features improved discrimination compared with using only GERD frequency and duration (AUC=0.85 vs 0.74, P=0.01).
Conclusions
Based on data from a case–control study of predominantly white male veterans, a risk prediction model including a multi-biomarker score, derived from serum levels of cytokines and leptin, as well as GERD frequency and duration, age, sex, race, waist-to-hip ratio, and H pylori infection, can more accurately identify persons in this population with BE than previous methods.
doi:10.1016/j.cgh.2013.12.014
PMCID: PMC4063886  PMID: 24362047
Barrett’s esophagus; Biomarkers; Cytokines; Risk prediction

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