Katarina B. Greer

Association of insulin and insulin-like growth factors with Barrett's oesophagus

Background It is postulated that high serum levels of insulin and insulin growth factor 1 (IGF-1) mediate obesity-associated carcinogenesis. The relationship of insulin, IGF-1 and IGF binding proteins (IGFBP) with Barretts oesophagus (BO) has not been well examined. Methods Serum levels of insulin and IGFBPs in patients with BO were compared with two separate control groups: subjects with gastro-oesophageal reflux disease (GORD) and screening colonoscopy controls. Fasting insulin, IGF-1 and IGFBPs were assayed in the serum of BO cases (n=135), GORD (n=135) and screening colonoscopy (n=932) controls recruited prospectively at two academic hospitals. Logistic regression was used to estimate the risk of BO. Results Patients in the highest tertile of serum insulin levels had an increased risk of BO compared with colonoscopy controls (adjusted OR 2.02, 95% CI 1.15 to 3.54) but not compared with GORD controls (adjusted OR 1.55, 95% CI 0.76 to 3.15). Serum IGF-1 levels in the highest tertile were associated with an increased risk of BO (adjusted OR 4.05, 95% CI 2.01 to 8.17) compared with the screening colonoscopy control group but were not significantly different from the GORD control group (adjusted OR 0.57, 95% CI 0.27 to 1.17). IGFBP-1 levels in the highest tertile were inversely associated with a risk of BO in comparison with the screening colonoscopy controls (adjusted OR 0.11, 95% CI 0.05 to 0.24) but were not significantly different from the GORD control group (adjusted OR 1.04, 95% CI 0.49 to 2.16). IGFBP-3 levels in the highest tertile were inversely associated with the risk of BO compared with the GORD controls (OR 0.36, 95% CI 0.16 to 0.81) and also when compared with the colonoscopy controls (OR 0.40, 95% CI 0.20 to 0.79). Conclusions These results provide support for the hypothesis that the insulin/IGF signalling pathways have a role in the development of BO.

Development of a Program to Train Physician Extenders to Perform Transnasal Esophagoscopy and Screen for Barrett's Esophagus

BACKGROUND & AIMS Screening for Barretts esophagus (BE) and esophageal adenocarcinoma is not recommended because it was not found to be cost effective. However, physician extenders (PEs) are able to perform unsedated procedures; their involvement might reduce the costs of BE screening. We examined the feasibility of training PEs to independently perform transnasal esophagoscopy (TNE) and screen patients for BE and measured their learning curve. METHODS Two PEs at a Veterans Affairs (VA) medical center underwent a structured didactic training program and observed nasopharyngoscopies before performing TNE under the supervision of attending endoscopists. Individual technical and cognitive components of TNE were rated on a 9-point structured scale. Learning curves were constructed using cumulative summation. Once the PEs were judged to be technically competent, each PE performed 10 independent videotaped TNEs, which were graded. RESULTS Both PEs identified anatomic landmarks after 18 consecutive procedures. PE1 and PE2 performed satisfactory nasal intubations after 20 and 25 procedures and esophageal intubations after 29 and 35 procedures, respectively. They acquired overall competence after supervised training on 43 and 47 procedures, respectively. CONCLUSIONS We developed a program at a VA medical center to train PEs to perform TNE to screen for BE. The PEs were able to perform TNE and recognize esophageal landmarks independently after a modest number of supervised procedures.

Association of Serum Levels of Adipokines and Insulin With Risk of Barrett's Esophagus: A Systematic Review and Meta-Analysis

BACKGROUND & AIMS Metabolically active visceral fat may be associated with esophageal inflammation, metaplasia, and neoplasia. We performed a meta-analysis to evaluate the association of serum adipokines and insulin with Barretts esophagus (BE). METHODS We performed a systematic search of multiple electronic databases, through April 2015, to identify all studies reporting associations between leptin, adiponectin, insulin, insulin resistance, and risk of BE in adults. Comparing the highest study-specific category with the reference category for each hormone, we estimated the summary adjusted odds ratio (aOR) and 95% confidence intervals (CI), using a random effects model. RESULTS We identified 9 observational studies (10 independent cohorts; 1432 patients with BE total, and 3550 control subjects). Meta-analysis revealed that high serum level of leptin was associated with 2-fold higher risk of BE (BE cases vs population control subjects in 5 studies: aOR, 2.23; 95% CI, 1.31-3.78; I(2), 59%). Total serum level of adiponectin was not associated with BE (BE cases vs population control subjects in 5 studies: aOR, 0.79; 95% CI, 0.46-1.34; I(2), 65%), although 1 study observed decreased risk of BE with increased level of low-molecular-weight adiponectin. High serum level of insulin was associated with increased risk of BE (BE cases vs population control subjects in 3 studies: aOR, 1.74; 95% CI, 1.14-2.65; I(2), 0), whereas insulin resistance was not associated with increased risk of BE (BE cases vs gastroesophageal reflux disease control subjects in 2 studies: aOR, 0.98; 95% CI, 0.42-2.30; I(2), 64%). CONCLUSIONS Increased serum levels of leptin and insulin are associated with increased risk of BE, compared with population control subjects. In contrast, increased total serum levels of adiponectin and insulin do not seem to modify BE risk. Well-designed longitudinal studies of incident BE are needed to clarify existing associations of serum adipokines and insulin with BE.

Associations of Serum Adiponectin and Leptin With Barrett’s Esophagus

BACKGROUND & AIMS Central adiposity is a risk factor for Barretts esophagus (BE). Serum levels of adiponectin and leptin are deregulated in obese states and are implicated as putative mediators in the pathophysiology of esophageal columnar metaplasia. We describe associations between serum adiponectin and leptin levels with BE. METHODS Patients were recruited prospectively for a case-control study. Fasting serum levels of adiponectin and leptin were measured in 135 patients with BE and compared with 2 separate control groups: 133 subjects with gastroesophageal reflux disease (GERD) and 1157 colon screening controls. RESULTS Multivariate analyses adjusted for age, race, and waist-to-hip ratio showed that patients within the highest tertile of serum adiponectin level had decreased odds of BE compared with screening colonoscopy controls (odds ratio [OR], 0.42; 95% confidence interval [CI], 0.22-0.80). This effect was more pronounced in men (OR, 0.35; 95% CI, 0.17-0.74) compared with women (OR, 0.71; 95% CI, 0.17-3.03). In comparisons of BE cases with GERD controls, subjects within the highest tertile of serum adiponectin level showed decreased odds of BE (OR, 0.65; 95% CI, 0.31-1.36), however, this was not statistically significant. Patients in the highest tertile of serum leptin level did not have a significantly increased risk of BE in comparison with GERD (OR, 1.32; 95% CI, 0.61-2.88) or screening colonoscopy controls (OR, 1.57; 95% CI, 0.82-3.04) in analyses including both sexes. Based on sex-specific analyses, sex did not significantly alter the association of leptin with odds of BE. CONCLUSIONS Serum adiponectin was associated inversely with BE and this effect was more pronounced in men, whereas serum leptin showed no evidence of association with BE in comparisons with multiple control groups. The exact mechanism, if any, by which these adipokines promote metaplasia in the esophagus needs to be explored further.

Hypertension Guideline Adherence Among Nursing Home Patients

BackgroundAdherence to hypertension guidelines in the outpatient setting is low.ObjectiveTo evaluate adherence to JNC VII guidelines in nursing home patients.DesignData were obtained from the 2004 National Nursing Home Survey (NNHS), a nationally representative sample of US nursing homes. Patients with hypertension were identified using ICD-9 codes. Adherence to JNC VII guidelines was defined as the use of a thiazide diuretic in patients without a compelling indication for a different class of antihypertensive medication, such as diabetes, chronic kidney disease, coronary artery disease, congestive heart failure, or a history of stroke.ParticipantsThere were 13,507 patients in the 2004 NNHS survey, of whom 7,129 had hypertension.Main ResultsOf these 7,129 hypertensive patients, only 12.6% were on a thiazide. Out of the 7,129 hypertensive patients, 3,113 did not have diabetes, chronic kidney disease, coronary artery disease, congestive heart failure, or a history of stroke. Of these 3,113 patients, only 13.9% were on a thiazide. After excluding patients with a potential contraindication to a diuretic, such as hospice care or incontinence, only 18% were prescribed a thiazide. Of the 3,113 patients, 1,148 were on a single class of antihypertensive and more were prescribed a beta blocker, ACE inhibitor, calcium channel blocker, loop diuretic, and ARB than a thiazide diuretic.ConclusionsAdherence to hypertension guidelines among nursing home patients is low. The appropriate use of thiazide diuretics could reduce costs and improve blood pressure control and patient outcomes.

Comparative acceptability of transnasal esophagoscopy and esophageal capsule esophagoscopy: a randomized, controlled trial in veterans

BACKGROUND EGD screening for Barretts esophagus (BE) is costly, with insufficient evidence to support its effectiveness. OBJECTIVE To compare acceptance and tolerability of 2 novel, office-based, endoscopic screening techniques done on nonsedated patients. DESIGN Randomized block study design with allocation concealment. SETTING Outpatient clinic setting at a Veterans Affairs medical center. PATIENTS A total of 184 veterans with or without GERD symptoms. INTERVENTIONS Transnasal esophagoscopy (TNE) or esophageal capsule esophagoscopy (ECE). MAIN OUTCOME MEASUREMENTS Acceptance and tolerability of TNE and ECE and effectiveness of BE screening. RESULTS Esophageal screening was accepted by 184 of 1210 (15.2%) veterans. The majority were men (96%) and African American (58%), with a mean (± standard deviation) age of 58.9 (± 8.1) years. Five TNE participants (5%) and 2 ECE participants (2%) refused the assigned procedure after randomization (P = .25). Eleven patients (12.6%) randomized to TNE crossed the minimal clinically important threshold for overall procedure tolerability, as opposed to no patients randomized to ECE (P = .001). Effectiveness of BE screening was not significantly different in both procedures (TNE vs ECE = 3.2% vs 5.4%; P = .47). Overall, BE was present in 8 of 75 white participants (10.6%) and in 0 of 107 African American participants (P < .001). LIMITATIONS The general veteran population may not reflect the screening population for BE. CONCLUSION Despite a small proportion of veterans expressing interest in esophageal screening, both TNE and ECE were feasible in the outpatient clinic setting and were accepted by >95% of participants who did express an interest. Screening was effective only in white participants. Moderate differences in tolerability between TNE and ECE notwithstanding, cost considerations along with availability of equipment and trained personnel should guide the modality to be used for BE screening.

Insulin/Insulin-Like Growth Factor-1 Pathway in Barrett's Carcinogenesis.

OBJECTIVES:Obesity-associated carcinogenesis is postulated to be mediated through the proliferative actions of insulin and the insulin-like growth factor (IGF) family. The aim of this study was to determine whether the insulin/IGF-1 pathway is involved in the sequential progression from metaplastic Barrett’s esophagus (BE) to dysplasia to esophageal adenocarcinoma (EAC).METHODS:Fasting serum levels of insulin, glucose, IGF-1, insulin growth factor binding protein-1 (IGFBP1), and IGFBP3 were measured in 44 non-dysplastic, 9 low-grade dysplasia (LGD), 12 high-grade dysplasia (HGD), and 10 EAC subjects. Immunohistochemistry was performed on paraffin-embedded tissue derived from BE cases using rabbit monoclonal antibodies to p-mammalian target of rapamycin (mTOR) and p-AKT, mouse monoclonal antibody to Ki-67, and rabbit polyclonal antibody to p-insulin receptor substrate 1 (IRS1).RESULTS:Nineteen of 44 (43.2%) BE, 5/9 (55%) LGD, 8/12 (66.7%) HGD and EAC 7/10 (70%) cases showed strong staining for p-IRS1. A significantly higher proportion of HGD/EAC subjects showed p-IRS1 staining when compared with BE/LGD subjects, 63.6% vs. 41.5%, P<0.05. p-IRS1 immunostaining was moderately correlated with strong immunostaining of the downstream mediators p-AKT and p-mTOR (Spearman correlation coefficient=0.167 and 0.27 for p-IRS1/p-AKT and for p-IRS1/p-mTOR, respectively) and the proliferation marker Ki-67 (Spearman correlation coefficient=0.20, P=0.09). However, systemic levels of insulin, IGF-1, or IGF-2 were not associated with tissue immunostaining of p-IRS1.CONCLUSIONS:Activation of the insulin/IGF-1 pathway in BE may be associated with cellular proliferation and appears to have a role in the progression from metaplasia to cancer. The activation of the insulin/IGF-1 pathway at the tissue level is likely complex and does not have a simple association with systemic measures of insulin or IGF-1.

American Gastroenterological Association Institute Guideline on the Medical Management of Opioid-Induced Constipation

Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina; Division of Gastroenterology and Liver Disease, University Hospitals Cleveland Medical Center, Cleveland, Ohio; Departments of Family Medicine and Urology, University of Michigan Medical School, Ann Arbor, Michigan; Division of Gastroenterology, Case Western Reserve University and Louis Stokes Veterans Affairs Medical Center, Cleveland, Ohio; and Division of Gastroenterology, University of Minnesota and Minneapolis Veterans Affairs Health Care System, Minneapolis, Minnesota

Red Meat Intake is Associated With Increased Risk of Barrett's Esophagus

Background: GEJ biopsies that contain inflamed squamous and columnar epithelium may represent distal esophageal columnar metaplasia or proximal gastritis (“carditis”). Pathologically, differentiation of these two disorders is difficult regardless of the presence or absence of goblet cells (GC). The aim of this study was to evaluate a wide variety of histologic features in GEJ biopsies, from a large prospective cohort of GERD patients, in order to determine their utility in predicting the presence of columnar-lined esophagus (CLE). Design: 2208 mucosal biopsies of the GEJ, from 552 GERD patients (M/F ratio: 305/247, mean age: 51 years), all of whom were endoscoped and interviewed prospectively as part of a large community clinic-based study of GERD patients in Washington state, were evaluated blindly for a wide variety of histologic features, such as mucosal and submucosal glands/ducts, multilayered epithelium (ME), type of glands (mucous, oxyntic, mixed), squamous islands, and buried columnar epithelium and correlated with the endoscopic evidence of, and length, of CLE, and with the presence of GC. The findings were also correlated with patients clinical risk factors for BE, such as gender, race, waist:hip ratio, smoking history, and body mass index (BMI). Results: Overall, 56% of patients revealed CLE. The prevalence rates of relevant histologic features in GEJ biopsies were as follows: submucosal glands (0.6%), ducts (4%), ME (17%), GC (26%), mucous glands only (20%), oxyntic glands only (25%), mixed mucous/oxyntic glands (52%), squamous islands (15%), buried columnar epithelium (19%). The presence of ME (p=0.03), GC (p=0.001), pure mucous glands (p= 25, at least weekly heartburn, and increased waist:hip ratio (male≥0.9, female≥0.8) were all associated with CLE. Conclusion: Certain histologic features, such as submucosal glands and/or ducts, ME, pure mucous glands, squamous islands, and buried columnar epithelium, when detected in GEJ biopsies of GERD patients, are indicative of the presence of CLE at endoscopy. Any of these findings, even in the absence of GC, should warrant clinical suspicion for CLE in endoscopically ambiguous cases.