Update Update in Gastroenterology and Hepatology: Evidence Published in 2013 Prateek Sharma, MD, and Norton J. Greenberger, MD
T
his update summarizes studies in gastroenterology and hepatology published in 2013 that the authors found important. These studies address descriptions of lower esophageal sphincter augmentation with a novel magnetic device in patients with gastroesophageal reflux disease (GERD) and an elemental diet in adults with eosinophilic esophagitis. Restrictive red blood cell transfusion strategies were shown to improve outcomes in patients with upper gastrointestinal bleeding, whereas newer-generation oral anticoagulants (NOACs) were associated with an increased risk for gastrointestinal bleeding. Rates of antibiotic resistance are increasing, but optimized nonbismuth quadruple therapy cured most patients with Helicobacter pylori infection in geographic areas with high resistance to clarithromycin and metronidazole. In terms of diagnosis of and risk factors for disease, measurement of individual fecal unconjugated bile acids (UBAs) was shown to predict stool characteristics in subgroups of patients with the irritable bowel syndrome (IBS), and constipation and low-fiber diet were determined not to be risk factors for colonic diverticular disease. Finally, a combination of rifaximin and lactulose therapy was more effective than lactulose alone in the treatment of hepatic encephalopathy.
Esophageal Diseases
Decreased Esophageal Acid Exposure and Alleviation of Reflux Symptoms After Lower Esophageal Sphincter Augmentation With a Magnetic Device
sphincter in 100 patients with a 6-month history of GERD, partial response to daily proton-pump inhibitors, and elevated esophageal acid levels confirmed by pH monitoring. The primary outcome was normalization of esophageal acid exposure or a 50% or greater reduction in exposure at 1 year. Secondary outcomes were a 50% or greater improvement in GERD-related quality of life and a 50% or greater reduction in the use of proton-pump inhibitors at 1 year. The authors report 3-year results of a 5-year study. Of 100 study patients (52% men; median age, 53 years; median body mass index, 28 kg/m2), 96 completed pH monitoring. Of these, 61 (64%) had a decrease of at least 50% in esophageal acid exposure and 56 (58%) had normalization of acid exposure. For the secondary outcomes, 93% of patients had a 50% or greater reduction in proton-pump inhibitor use, and quality of life improved in 92% compared with baseline (when they were not receiving proton-pump inhibitors). Dysphagia was the most frequent adverse event (68% of postoperative patients, 11% at 1 year, and 4% at 3 years). Severe adverse events (dysphagia, chest pain, persistent nausea, and vomiting) requiring device removal occurred in 6 patients. Cautions: This study included no comparison group and reported only 3-year outcomes, so long-term risks for foreign body around the esophagus are unknown. Implications: In patients with GERD that is partially responsive to proton-pump inhibitors, augmentation of the lower esophageal sphincter with a magnetic device may be an alternative to surgical interventions.
gastroesophageal reflux disease. N Engl J Med. 2013;368:719-27.
Elemental Diet Induces Substantial Histologic Changes but Does Not Alleviate Symptoms in Adults With Eosinophilic Esophagitis
[PMID: 23425164]
Peterson KA, Byrne KR, Vinson LA, et al. Elemental diet induces
Background: An incompetent lower esophageal sphincter is the basic defect in GERD. Approximately 40% of patients with the disease achieve symptomatic relief with proton-pump inhibitors, the first-line GERD therapy. Antireflux surgical options exist, but acceptance is limited because of potential adverse effects. Less-invasive augmentation of the lower esophageal sphincter with a magnetic device may be an alternative treatment. Findings: This prospective, multicenter (13 centers in the United States and 1 in the Netherlands) study described use of a magnetic device to augment the lower esophageal
histologic response in adult eosinophilic esophagitis. Am J Gastroen-
Ganz RA, Peters JH, Horgan S, et al. Esophageal sphincter device for
Ann Intern Med. 2014;161:205-209. doi:10.7326/M14-0323 For author affiliations, see end of text. This article was published online first at www.annals.org on 10 April 2014.
terol. 2013;108:759-66. [PMID: 23381017]
Background: Eosinophilic esophagitis is diagnosed in about 6% of patients undergoing upper endoscopy and is considered a common cause of dysphagia and food impaction. In a recent study of adults with the condition, a 6-food elimination diet (milk, soy, egg, wheat, peanuts, and shellfish) led to histologic improvement and alleviated symptoms. However, whether an elemental diet could have the same effect in adults with eosinophilic esophagitis is unknown.
Annals of Internal Medicine © 2014 American College of Physicians 205
Downloaded From: http://annals.org/ by a Fudan University User on 12/09/2016
Update
Update in Gastroenterology and Hepatology
Findings: Adults with eosinophilic esophagitis (symptoms and ⱖ15 intraepithelial eosinophils per high-power field on an esophageal biopsy specimen) were enrolled in this prospective study from 2009 to 2011. Symptoms and histologic findings were monitored every 2 weeks. An elemental diet (EleCare Free Amino Acid-Based Medical Food, EleCare, Columbus, Ohio) was given for 4 weeks, or at least 2 weeks if a biopsy specimen showed a complete response (ⱕ2 eosinophils per high-power field). The primary end points were reduction in the number of tissue eosinophils when patients started the elemental diet and how quickly this reduction occurred. The secondary end points were changes in mast cell content or parabasal layer thickening; the tempo of changes in these parameters while patients were on the elemental diet and after they resumed a normal diet; and alleviation of symptoms, measured with the Mayo Dysphagia Questionnaire. Forty-two patients were enrolled in the study, but only 18 completed it (29 met the inclusion criteria, and 11 of them did not adhere to the diet). Of the 18 patients who completed the study (10 men and 8 women; mean age, 34 years), 13 (72%) had a complete or nearly complete response, 4 (22%) had a partial response, and 1 had no response to the elemental diet. After therapy, eosinophil content decreased from 54 to 10 per high-power field (P ⫽ 0.0006). Symptoms and endoscopic fixed strictures showed no improvement. Mast cell content, parabasal layer thickness, endoscopic furrows, and exudates significantly decreased. After normal diet was resumed, eosinophil content increased within 3 to 7 days. Several patients lost significant weight and did not adhere to the diet because they found it unpalatable. Cautions: This study did not include a comparison group. Elemental diets are costly, are not covered by insurance, and seem difficult to adhere to. Although histologic findings showed some improvement, the elemental diet did not alleviate symptoms. Implications: This study documented a histologic response in patients with eosinophilic esophagitis who were on the elemental diet, but adherence was poor and symptoms were not alleviated. These observations, combined with the high cost of an elemental diet, suggest that an elimination diet may be the preferred therapeutic choice.
Gastrointestinal Bleeding and Peptic Ulcer Disease
Restrictive Transfusion Strategies Improved Outcomes in Patients With Upper Gastrointestinal Bleeding
Background: Upper gastrointestinal bleeding is a common indication for red blood cell transfusion. The hemoglobin threshold for safe and effective transfusion strategies in gastrointestinal bleeding is controversial. Although transfusion strategies in critically ill patients have been studied, efficacy and safety of a restrictive transfusion strategy compared with a liberal transfusion strategy in patients with gastrointestinal bleeding is not known. Findings: This randomized, controlled trial assessed the safety and efficacy of a restrictive transfusion strategy (hemoglobin level ⬍7 g/dL) versus a liberal strategy (hemoglobin level ⬍9 g/dL) in 921 consecutive patients hospitalized with severe gastrointestinal bleeding. Randomization was stratified by the presence or absence of cirrhosis. The patients could also receive transfusions if symptoms or signs of anemia developed. Patients were followed until hospital discharge or death. Of 921 patients enrolled in the study, 461 were randomly assigned to restrictive transfusion and 460 were assigned to liberal transfusion. A total of 225 patients (51%) in the restrictive strategy group did not receive transfusion compared with 61 (14%) in the liberal strategy group (P ⬍ 0.001). Patients in the restrictive strategy group had higher probability of survival at 6 weeks (95% vs. 91%; hazard ratio of death with restrictive strategy, 0.55 [P ⫽ 0.02]). In a subgroup analysis of patients with the restrictive strategy, those with peptic ulcer bleeding had statistically insignificantly lower mortality (hazard ratio, 0.70 [95% CI, 0.26 to 1.25]) and those with cirrhosis and Child–Pugh class A or B disease had statistically significantly lower mortality (hazard ratio, 0.30 [CI, 0.11 to 0.85]) than patients with the liberal strategy. No mortality difference was seen in the subgroup of patients with Child–Pugh class C disease (hazard ratio, 1.04 [CI, 0.45 to 2.37]). Rebleeding was seen in 10% of patients in the restrictive strategy group compared with 16% of those in the liberal strategy group (P ⫽ 0.01), and adverse events occurred in 40% and 48%, respectively (P ⫽ 0.02). Significantly higher portal pressures were seen in patients in the liberal strategy group (P ⫽ 0.03). Cautions: Patients with low risk for rebleeding (who may not require transfusion) and those with massive hemorrhage (in whom transfusion may be life-saving) were excluded from the study, which limited the generalizability of the findings. The study was not blinded. Implications: In patients with severe acute upper gastrointestinal bleeding, a restrictive transfusion strategy (hemoglobin threshold of 7 g/dL) improved survival rates and reduced rebleeding, need for rescue therapy, and severe adverse events compared with a liberal transfusion strategy (hemoglobin threshold of 9 g/dL).
Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for
NOACs Are Associated With Increased Risk for Gastrointestinal Bleeding
acute upper gastrointestinal bleeding. N Engl J Med. 2013;368:11-
Holster IL, Valkhoff VE, Kuipers EJ, et al. New oral anticoagulants
21. [PMID: 23281973]
increase risk for gastrointestinal bleeding: a systematic review and
206 5 August 2014 Annals of Internal Medicine Volume 161 • Number 3
Downloaded From: http://annals.org/ by a Fudan University User on 12/09/2016
www.annals.org
Update in Gastroenterology and Hepatology
meta-analysis. Gastroenterology. 2013;145:105-112.e15. [PMID: 23470618]
Background: Gastrointestinal bleeding increases with the use of anticoagulants and is associated with morbidity, mortality, and health care costs. Several NOACs have been developed that are as effective as older-generation anticoagulants in preventing thromboembolism but may be associated with a risk for potentially fatal gastrointestinal bleeding. Findings: In this systematic review and meta-analysis, 2 independent reviewers searched MEDLINE, EMBASE, and the Cochrane Library through July 2012 without language restrictions to identify randomized, controlled trials comparing NOACs with standard treatment. The authors rated study quality according to Cochrane methods and estimated odds ratios (ORs) by using random-effects models. The primary outcome was clinically relevant major or nonmajor gastrointestinal bleeding. The secondary outcome was the risk for clinically relevant bleeding at a critical site (intracranial, intraspinal, intraocular, pericardial, or retroperitoneal), including major and clinically relevant nonmajor bleeding. Among 375 identified studies, 43 randomized, controlled trials (151 578 patients) met inclusion criteria. Although there was an increased risk for gastrointestinal bleeding with NOACs (OR, 1.45 [CI, 1.07 to 1.95]), substantial heterogeneity was noted among these studies. Subgroup analysis showed higher bleeding risk when NOACs were used for treatment of atrial fibrillation (OR, 1.21 [CI, 0.91 to 1.61]), venous thrombosis (OR, 1.59 [CI, 1.03 to 2.44]), and the acute coronary syndrome (OR, 5.21 [CI, 2.58 to 10.53]). Risk for bleeding was lower when NOACs were used for treatment of thromboprophylaxis after orthopedic surgery (OR, 0.78 [CI, 0.31 to 1.96]). Odds ratios were 1.23 (CI, 0.56 to 2.73) for apixaban, 1.58 (CI, 1.29 to 1.93) for dabigatran, 1.48 (CI, 1.21 to 1.82) for rivaroxaban, and 0.31 (CI, 0.01 to 7.69) for edoxaban. The overall risk for clinically relevant bleeding in patients receiving NOACs was borderline statistically significantly higher (OR, 1.16 [CI, 1.00 to 1.34]). Cautions: The included trials were heterogeneous and were not designed to assess gastrointestinal bleeding, and because most did not reliably report on clinically relevant nonmajor gastrointestinal bleeding, they may underestimate the risk for gastrointestinal bleeding. Studies typically enrolled patients at low risk for bleeding, and the findings may not be generalizable to those at higher risk. Implications: The NOACs may increase the risk for gastrointestinal bleeding compared with standard anticoagulation. Studies designed to assess safety are needed to accurately define the risk for gastrointestinal bleeding with these newer agents. www.annals.org
Downloaded From: http://annals.org/ by a Fudan University User on 12/09/2016
Update
In Geographic Areas With High Resistance to Clarithromycin and Metronidazole, Optimized Nonbismuth Quadruple Therapy Cured Most Patients With Helicobacter pylori Infection Molina-Infante J, Romano M, Fernandez-Bermejo M, et al. Optimized nonbismuth quadruple therapies cure most patients with Helicobacter pylori infection in populations with high rates of antibiotic resistance. Gastroenterology. 2013;145:121-128.e1. [PMID: 23562754]
Background: Triple antibiotic therapy remains the most common treatment for H. pylori infection, but because of emerging antibiotic resistance, a bismuth-containing quadruple regimen (either sequentially or concomitantly) has been proposed as the first-line therapy in areas with high antibiotic resistance. However, such therapy is not widely available. Findings: This multicenter trial investigated the effectiveness of nonbismuth quadruple therapy in Italy and Spain (areas with clarithromycin resistance rates of approximately 20%). Consecutive adult patients with H. pylori infection who were not treated previously were enrolled in the study and randomly assigned to receive either hybrid therapy (40 mg of omeprazole and 1 g of amoxicillin [both twice daily] for 14 days, with 500 mg of clarithromycin and 500 mg of nitroimidazole [both twice daily] added for the final 7 days) or concomitant therapy (same 4 drugs taken concurrently [twice daily] for 14 days). The primary outcome was H. pylori eradication. Secondary end points were to address the influence of antimicrobial resistance on the outcome of eradication treatments, the incidence of adverse effects, and adherence rates with both therapies. A total of 343 patients participated in the study. Sex, age, and smoking status were similar among the patients in the hybrid treatment (n ⫽ 171) and concomitant therapy (n ⫽ 172) groups. Helicobacter pylori eradication rates were 90% (CI, 86% to 93%) and 91.7% (CI, 87% to 95%), respectively, in the intention-to-treat analysis (P ⫽ 0.35) and 92% (CI, 87% to 95%) and 96.1% (CI, 93% to 99%), respectively, in the per-protocol analysis (P ⫽ 0.07). The clarithromycin resistance rate was 23.5% (26% in Italy and 34% in Spain), the metronidazole resistance rate was 33% (33% in Italy and 34% in Spain), and 8.8% of patients were resistant to both strains. Mild adverse effects were reported in both groups. Adherence rates were 98.8% in the hybrid therapy group and 95.2% in the concomitant therapy group (P ⫽ 0.05). Cautions: Helicobacter pylori infection was confirmed by endoscopy in only 66% of patients, and the urea breath test was used to diagnose infection in the remaining patients, so patients with false-positive test results may have been included in the study. The E-test, which tends to overestimate resistance, was used to determine metronidazole resistance. No antibiotic susceptibility tests were done for H. pylori. 5 August 2014 Annals of Internal Medicine Volume 161 • Number 3 207
Update
Update in Gastroenterology and Hepatology
Implications: In a sample of Spanish and Italian patients with high rates of antibiotic-resistant H. pylori infection, both hybrid and concomitant nonbismuth quadruple therapy were effective. Hybrid therapy may be the preferred therapeutic option because of higher adherence rates and shorter duration (12 vs. 14 days). Lower Gastrointestinal Disorders Measurement of Individual Fecal UBAs Can Predict Stool Characteristics and Identify Subgroups of Patients With IBS Shin A, Camilleri M, Vijayvargiya P, et al. Bowel functions, fecal unconjugated primary and secondary bile acids, and colonic transit in patients with irritable bowel syndrome. Clin Gastroenterol Hepatol. 2013;11:1270-1275.e1. [PMID: 23639599]
Background: Several factors have been shown to play an important role in the pathophysiology of IBS. Two phenotypes are known: IBS with predominant diarrhea (IBS-D) and IBS with predominant constipation (IBS-C). Bile acids are known to induce changes in the colonic mucosal, motor, and sensory functions. Total bile acid secretion has been shown to be significantly higher in patients with IBS-D. However, the relationship among total, primary, and secondary fecal UBAs and the interrelationships among total bile acids, UBAs, and IBS phenotypes are unknown. Findings: This study prospectively enrolled healthy volunteers and patients with IBS. All participants completed a validated bowel disease questionnaire and the Hospital Anxiety and Depression Scale. They followed a diet of 100 g of fat per day for 4 days before measurement of fecal fat and fecal UBAs. The researchers aimed to measure total bile acids and UBAs and to assess the relationship among total bile acids, UBA profile, IBS phenotype, colonic transit time, and stool characteristics. Ninety-one participants were enrolled, including 30 healthy volunteers (22 women; mean age, 40 years), 30 patients with IBS-D (all women; mean age, 48 years), and 31 patients with IBS-C (all women; mean age, 36 years). Compared with the control group, levels of fecal primary UBAs were significantly higher in the IBS-D group (P ⬍ 0.01), whereas fecal secretory UBAs were higher in the IBS-C group (P ⫽ 0.02). Significant associations were also found among stool number and form and total fecal UBA, fecal fat, and colonic transit times at 24 and 48 hours after meals. Bile acids were associated with colonic transit time. Cautions: Adherence to high-fat diets may not be feasible in practice, and such diets may not be given to all patients, especially those with coronary artery disease or pancreatitis. Collection of stool samples at 24 and 48 hours is tedious. This study did not examine the effect of these findings on subsequent therapy or patient outcomes. Implications: Measurement of total bile acids and fecal UBAs can help identify subgroups of patients with IBS, which could help in the appropriate management of IBS symptoms. 208 5 August 2014 Annals of Internal Medicine Volume 161 • Number 3
Downloaded From: http://annals.org/ by a Fudan University User on 12/09/2016
Higher Prevalence of Diverticulosis Was Found in a Sample of Patients With High-Fiber Diet Intake Peery AF, Sandler RS, Ahnen DJ, et al. Constipation and a low-fiber diet are not associated with diverticulosis. Clin Gastroenterol Hepatol. 2013;11:1622-7. [PMID: 23891924]
Background: About one third of adults older than 60 years are known to have asymptomatic diverticulosis. A large percentage of these individuals develop complications, with associated morbidity, mortality, and health care costs. Low-fiber diet has traditionally been believed to be associated with the development of diverticulosis, but highquality evidence to support this hypothesis is lacking. Findings: This cross-sectional study analyzed data from patients participating in the Diet and Health Studies, a study of the relationship of environmental and lifestyle changes with colorectal adenomas. Recruited patients had outpatient colonoscopy for colon cancer screening, and presence of diverticula was assessed. Patients were interviewed via telephone within 12 weeks of colonoscopy by a trained research assistant blinded to the colonoscopy results. Information on bowel habits, physical activity, eating habits, age, sex, race, smoking history, alcohol use, nonsteroidal anti-inflammatory drug use, laxative use, and comorbid conditions was collected. Among 2104 participants (878 patients with diverticulosis and 1226 without), a dose-dependent increase in the prevalence of diverticulosis was seen in quartiles with highfiber dietary intake compared with the lowest quartile (prevalence ratio, 1.30 [CI, 1.13 to 1.50]; P for trend ⫽ 0.004) after adjustment for such confounders as age, race, and body mass index. Participants with more than 15 bowel movements per week were determined to be at a significantly higher risk for diverticulosis than those with fewer than 7 bowel movements per week (prevalence ratio, 1.70 [CI, 1.24 to 2.34]). Physical activity and red meat consumption were not associated with increased risk for the condition. Cautions: Dietary histories were obtained only for the past year. A relationship between long-term dietary patterns and diverticulosis could not be determined from these data. Implications: This study suggests that individuals currently consuming a high-fiber diet and having frequent bowel movements are at greater risk for diverticulosis. Long-term prospective studies are needed to show the role of dietary fiber in the development of diverticulosis.
Liver Disease Combination Therapy With Rifaximin and Lactulose Is More Effective Than Lactulose Alone in Treatment of Hepatic Encephalopathy and Decreases In-Hospital Mortality Rate and Length of Hospital Stay Sharma BC, Sharma P, Lunia MK, et al. A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose www.annals.org
Update in Gastroenterology and Hepatology
alone in treatment of overt hepatic encephalopathy. Am J Gastroenterol. 2013;108:1458-63. [PMID: 23877348]
Background: Hepatic encephalopathy is a common, serious, and reversible complication of cirrhosis. Lactulose has been the primary treatment for the disorder, but rifaximin has been shown to be an alternative therapeutic and prophylactic option. The effectiveness of combination therapy with lactulose and rifaximin in the treatment of overt hepatic encephalopathy has not been studied. Findings: This double-blind trial randomly assigned patients with cirrhosis and overt hepatic encephalopathy to rifaximin, 1200 mg/d, plus lactulose, 30 to 60 mL 3 times daily, or lactulose plus placebo. The primary end point was complete reversal of hepatic encephalopathy, and secondary end points included death and length of hospital stay. Of 120 patients randomly assigned (89 men and 31 women; mean age, 39 years; mean Child–Turcotte–Pugh score, 9.7; mean Model for End-Stage Liver Disease score, 24.6), a significantly higher number of patients randomly assigned to combination therapy (46 [76%]) had complete reversal of hepatic encephalopathy compared with those randomly assigned to lactulose plus placebo (29 [50.8%]) (P ⫽ 0.004). The combination therapy group also had a significantly lower overall mortality rate (23.8%) than the control group (49.1%) (P ⫽ 0.03). More deaths due to sepsis were seen in patients receiving lactulose alone versus
Update
combination therapy (17 vs. 7 [P ⫽ 0.01]). Patients receiving combination therapy had a shorter hospital stay (5.8 vs. 8.2 days [P ⫽ 0.001]). No difference in gastrointestinal bleeding or hepatorenal syndrome was seen between the groups. Cautions: Longer-term trials are needed to determine whether combination therapy decreases mortality rates and prevents hepatic encephalopathy in patients with cirrhosis. Future studies should include patients with transjugular intrahepatic portosystemic shunt. Implications: A combination of lactulose and rifaximin is more effective in the treatment of overt hepatic encephalopathy than lactulose plus placebo and seems to reduce short-term mortality and duration of hospitalization. From Veterans Affairs Medical Center, Kansas City, Missouri, and Brigham and Women’s Hospital, Boston, Massachusetts. Disclosures: None disclosed. Forms can be viewed at www
.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum ⫽M14-0323. Requests for Single Reprints: Prateek Sharma, MD, Veterans Affairs Medical Center, 4801 East Linwood Boulevard, Kansas City, MO 64128; e-mail, [email protected].
Current author addresses and author contributions are available at www.annals.org.
READERS’ COMMENTS Readers may comment on published articles at www.annals.org. While this service is free to Annals subscribers, readers without subscriptions who wish to comment on articles may purchase temporary access.
www.annals.org
Downloaded From: http://annals.org/ by a Fudan University User on 12/09/2016
5 August 2014 Annals of Internal Medicine Volume 161 • Number 3 209
Annals of Internal Medicine Current Author Addresses: Dr. Sharma: Veterans Affairs Medical Cen-
ter, 4801 East Linwood Boulevard, Kansas City, MO 64128. Dr. Greenberger: Gastroenterology Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115.
Author Contributions: Conception and design: P. Sharma, N.J. Greenberger. Analysis and interpretation of the data: P. Sharma, N.J. Greenberger. Drafting of the article: P. Sharma, N.J. Greenberger. Critical revision of the article for important intellectual content: P. Sharma, N.J. Greenberger. Final approval of the article: P. Sharma, N.J. Greenberger. Administrative, technical, or logistic support: P. Sharma, N.J. Greenberger. Collection and assembly of data: P. Sharma, N.J. Greenberger.
© 2014 American College of Physicians W-3231
Downloaded From: http://annals.org/ by a Fudan University User on 12/09/2016
T
his update summarizes studies in gastroenterology and hepatology published in 2013 that the authors found important. These studies address descriptions of lower esophageal sphincter augmentation with a novel magnetic device in patients with gastroesophageal reflux disease (GERD) and an elemental diet in adults with eosinophilic esophagitis. Restrictive red blood cell transfusion strategies were shown to improve outcomes in patients with upper gastrointestinal bleeding, whereas newer-generation oral anticoagulants (NOACs) were associated with an increased risk for gastrointestinal bleeding. Rates of antibiotic resistance are increasing, but optimized nonbismuth quadruple therapy cured most patients with Helicobacter pylori infection in geographic areas with high resistance to clarithromycin and metronidazole. In terms of diagnosis of and risk factors for disease, measurement of individual fecal unconjugated bile acids (UBAs) was shown to predict stool characteristics in subgroups of patients with the irritable bowel syndrome (IBS), and constipation and low-fiber diet were determined not to be risk factors for colonic diverticular disease. Finally, a combination of rifaximin and lactulose therapy was more effective than lactulose alone in the treatment of hepatic encephalopathy.
Esophageal Diseases
Decreased Esophageal Acid Exposure and Alleviation of Reflux Symptoms After Lower Esophageal Sphincter Augmentation With a Magnetic Device
sphincter in 100 patients with a 6-month history of GERD, partial response to daily proton-pump inhibitors, and elevated esophageal acid levels confirmed by pH monitoring. The primary outcome was normalization of esophageal acid exposure or a 50% or greater reduction in exposure at 1 year. Secondary outcomes were a 50% or greater improvement in GERD-related quality of life and a 50% or greater reduction in the use of proton-pump inhibitors at 1 year. The authors report 3-year results of a 5-year study. Of 100 study patients (52% men; median age, 53 years; median body mass index, 28 kg/m2), 96 completed pH monitoring. Of these, 61 (64%) had a decrease of at least 50% in esophageal acid exposure and 56 (58%) had normalization of acid exposure. For the secondary outcomes, 93% of patients had a 50% or greater reduction in proton-pump inhibitor use, and quality of life improved in 92% compared with baseline (when they were not receiving proton-pump inhibitors). Dysphagia was the most frequent adverse event (68% of postoperative patients, 11% at 1 year, and 4% at 3 years). Severe adverse events (dysphagia, chest pain, persistent nausea, and vomiting) requiring device removal occurred in 6 patients. Cautions: This study included no comparison group and reported only 3-year outcomes, so long-term risks for foreign body around the esophagus are unknown. Implications: In patients with GERD that is partially responsive to proton-pump inhibitors, augmentation of the lower esophageal sphincter with a magnetic device may be an alternative to surgical interventions.
gastroesophageal reflux disease. N Engl J Med. 2013;368:719-27.
Elemental Diet Induces Substantial Histologic Changes but Does Not Alleviate Symptoms in Adults With Eosinophilic Esophagitis
[PMID: 23425164]
Peterson KA, Byrne KR, Vinson LA, et al. Elemental diet induces
Background: An incompetent lower esophageal sphincter is the basic defect in GERD. Approximately 40% of patients with the disease achieve symptomatic relief with proton-pump inhibitors, the first-line GERD therapy. Antireflux surgical options exist, but acceptance is limited because of potential adverse effects. Less-invasive augmentation of the lower esophageal sphincter with a magnetic device may be an alternative treatment. Findings: This prospective, multicenter (13 centers in the United States and 1 in the Netherlands) study described use of a magnetic device to augment the lower esophageal
histologic response in adult eosinophilic esophagitis. Am J Gastroen-
Ganz RA, Peters JH, Horgan S, et al. Esophageal sphincter device for
Ann Intern Med. 2014;161:205-209. doi:10.7326/M14-0323 For author affiliations, see end of text. This article was published online first at www.annals.org on 10 April 2014.
terol. 2013;108:759-66. [PMID: 23381017]
Background: Eosinophilic esophagitis is diagnosed in about 6% of patients undergoing upper endoscopy and is considered a common cause of dysphagia and food impaction. In a recent study of adults with the condition, a 6-food elimination diet (milk, soy, egg, wheat, peanuts, and shellfish) led to histologic improvement and alleviated symptoms. However, whether an elemental diet could have the same effect in adults with eosinophilic esophagitis is unknown.
Annals of Internal Medicine © 2014 American College of Physicians 205
Downloaded From: http://annals.org/ by a Fudan University User on 12/09/2016
Update
Update in Gastroenterology and Hepatology
Findings: Adults with eosinophilic esophagitis (symptoms and ⱖ15 intraepithelial eosinophils per high-power field on an esophageal biopsy specimen) were enrolled in this prospective study from 2009 to 2011. Symptoms and histologic findings were monitored every 2 weeks. An elemental diet (EleCare Free Amino Acid-Based Medical Food, EleCare, Columbus, Ohio) was given for 4 weeks, or at least 2 weeks if a biopsy specimen showed a complete response (ⱕ2 eosinophils per high-power field). The primary end points were reduction in the number of tissue eosinophils when patients started the elemental diet and how quickly this reduction occurred. The secondary end points were changes in mast cell content or parabasal layer thickening; the tempo of changes in these parameters while patients were on the elemental diet and after they resumed a normal diet; and alleviation of symptoms, measured with the Mayo Dysphagia Questionnaire. Forty-two patients were enrolled in the study, but only 18 completed it (29 met the inclusion criteria, and 11 of them did not adhere to the diet). Of the 18 patients who completed the study (10 men and 8 women; mean age, 34 years), 13 (72%) had a complete or nearly complete response, 4 (22%) had a partial response, and 1 had no response to the elemental diet. After therapy, eosinophil content decreased from 54 to 10 per high-power field (P ⫽ 0.0006). Symptoms and endoscopic fixed strictures showed no improvement. Mast cell content, parabasal layer thickness, endoscopic furrows, and exudates significantly decreased. After normal diet was resumed, eosinophil content increased within 3 to 7 days. Several patients lost significant weight and did not adhere to the diet because they found it unpalatable. Cautions: This study did not include a comparison group. Elemental diets are costly, are not covered by insurance, and seem difficult to adhere to. Although histologic findings showed some improvement, the elemental diet did not alleviate symptoms. Implications: This study documented a histologic response in patients with eosinophilic esophagitis who were on the elemental diet, but adherence was poor and symptoms were not alleviated. These observations, combined with the high cost of an elemental diet, suggest that an elimination diet may be the preferred therapeutic choice.
Gastrointestinal Bleeding and Peptic Ulcer Disease
Restrictive Transfusion Strategies Improved Outcomes in Patients With Upper Gastrointestinal Bleeding
Background: Upper gastrointestinal bleeding is a common indication for red blood cell transfusion. The hemoglobin threshold for safe and effective transfusion strategies in gastrointestinal bleeding is controversial. Although transfusion strategies in critically ill patients have been studied, efficacy and safety of a restrictive transfusion strategy compared with a liberal transfusion strategy in patients with gastrointestinal bleeding is not known. Findings: This randomized, controlled trial assessed the safety and efficacy of a restrictive transfusion strategy (hemoglobin level ⬍7 g/dL) versus a liberal strategy (hemoglobin level ⬍9 g/dL) in 921 consecutive patients hospitalized with severe gastrointestinal bleeding. Randomization was stratified by the presence or absence of cirrhosis. The patients could also receive transfusions if symptoms or signs of anemia developed. Patients were followed until hospital discharge or death. Of 921 patients enrolled in the study, 461 were randomly assigned to restrictive transfusion and 460 were assigned to liberal transfusion. A total of 225 patients (51%) in the restrictive strategy group did not receive transfusion compared with 61 (14%) in the liberal strategy group (P ⬍ 0.001). Patients in the restrictive strategy group had higher probability of survival at 6 weeks (95% vs. 91%; hazard ratio of death with restrictive strategy, 0.55 [P ⫽ 0.02]). In a subgroup analysis of patients with the restrictive strategy, those with peptic ulcer bleeding had statistically insignificantly lower mortality (hazard ratio, 0.70 [95% CI, 0.26 to 1.25]) and those with cirrhosis and Child–Pugh class A or B disease had statistically significantly lower mortality (hazard ratio, 0.30 [CI, 0.11 to 0.85]) than patients with the liberal strategy. No mortality difference was seen in the subgroup of patients with Child–Pugh class C disease (hazard ratio, 1.04 [CI, 0.45 to 2.37]). Rebleeding was seen in 10% of patients in the restrictive strategy group compared with 16% of those in the liberal strategy group (P ⫽ 0.01), and adverse events occurred in 40% and 48%, respectively (P ⫽ 0.02). Significantly higher portal pressures were seen in patients in the liberal strategy group (P ⫽ 0.03). Cautions: Patients with low risk for rebleeding (who may not require transfusion) and those with massive hemorrhage (in whom transfusion may be life-saving) were excluded from the study, which limited the generalizability of the findings. The study was not blinded. Implications: In patients with severe acute upper gastrointestinal bleeding, a restrictive transfusion strategy (hemoglobin threshold of 7 g/dL) improved survival rates and reduced rebleeding, need for rescue therapy, and severe adverse events compared with a liberal transfusion strategy (hemoglobin threshold of 9 g/dL).
Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for
NOACs Are Associated With Increased Risk for Gastrointestinal Bleeding
acute upper gastrointestinal bleeding. N Engl J Med. 2013;368:11-
Holster IL, Valkhoff VE, Kuipers EJ, et al. New oral anticoagulants
21. [PMID: 23281973]
increase risk for gastrointestinal bleeding: a systematic review and
206 5 August 2014 Annals of Internal Medicine Volume 161 • Number 3
Downloaded From: http://annals.org/ by a Fudan University User on 12/09/2016
www.annals.org
Update in Gastroenterology and Hepatology
meta-analysis. Gastroenterology. 2013;145:105-112.e15. [PMID: 23470618]
Background: Gastrointestinal bleeding increases with the use of anticoagulants and is associated with morbidity, mortality, and health care costs. Several NOACs have been developed that are as effective as older-generation anticoagulants in preventing thromboembolism but may be associated with a risk for potentially fatal gastrointestinal bleeding. Findings: In this systematic review and meta-analysis, 2 independent reviewers searched MEDLINE, EMBASE, and the Cochrane Library through July 2012 without language restrictions to identify randomized, controlled trials comparing NOACs with standard treatment. The authors rated study quality according to Cochrane methods and estimated odds ratios (ORs) by using random-effects models. The primary outcome was clinically relevant major or nonmajor gastrointestinal bleeding. The secondary outcome was the risk for clinically relevant bleeding at a critical site (intracranial, intraspinal, intraocular, pericardial, or retroperitoneal), including major and clinically relevant nonmajor bleeding. Among 375 identified studies, 43 randomized, controlled trials (151 578 patients) met inclusion criteria. Although there was an increased risk for gastrointestinal bleeding with NOACs (OR, 1.45 [CI, 1.07 to 1.95]), substantial heterogeneity was noted among these studies. Subgroup analysis showed higher bleeding risk when NOACs were used for treatment of atrial fibrillation (OR, 1.21 [CI, 0.91 to 1.61]), venous thrombosis (OR, 1.59 [CI, 1.03 to 2.44]), and the acute coronary syndrome (OR, 5.21 [CI, 2.58 to 10.53]). Risk for bleeding was lower when NOACs were used for treatment of thromboprophylaxis after orthopedic surgery (OR, 0.78 [CI, 0.31 to 1.96]). Odds ratios were 1.23 (CI, 0.56 to 2.73) for apixaban, 1.58 (CI, 1.29 to 1.93) for dabigatran, 1.48 (CI, 1.21 to 1.82) for rivaroxaban, and 0.31 (CI, 0.01 to 7.69) for edoxaban. The overall risk for clinically relevant bleeding in patients receiving NOACs was borderline statistically significantly higher (OR, 1.16 [CI, 1.00 to 1.34]). Cautions: The included trials were heterogeneous and were not designed to assess gastrointestinal bleeding, and because most did not reliably report on clinically relevant nonmajor gastrointestinal bleeding, they may underestimate the risk for gastrointestinal bleeding. Studies typically enrolled patients at low risk for bleeding, and the findings may not be generalizable to those at higher risk. Implications: The NOACs may increase the risk for gastrointestinal bleeding compared with standard anticoagulation. Studies designed to assess safety are needed to accurately define the risk for gastrointestinal bleeding with these newer agents. www.annals.org
Downloaded From: http://annals.org/ by a Fudan University User on 12/09/2016
Update
In Geographic Areas With High Resistance to Clarithromycin and Metronidazole, Optimized Nonbismuth Quadruple Therapy Cured Most Patients With Helicobacter pylori Infection Molina-Infante J, Romano M, Fernandez-Bermejo M, et al. Optimized nonbismuth quadruple therapies cure most patients with Helicobacter pylori infection in populations with high rates of antibiotic resistance. Gastroenterology. 2013;145:121-128.e1. [PMID: 23562754]
Background: Triple antibiotic therapy remains the most common treatment for H. pylori infection, but because of emerging antibiotic resistance, a bismuth-containing quadruple regimen (either sequentially or concomitantly) has been proposed as the first-line therapy in areas with high antibiotic resistance. However, such therapy is not widely available. Findings: This multicenter trial investigated the effectiveness of nonbismuth quadruple therapy in Italy and Spain (areas with clarithromycin resistance rates of approximately 20%). Consecutive adult patients with H. pylori infection who were not treated previously were enrolled in the study and randomly assigned to receive either hybrid therapy (40 mg of omeprazole and 1 g of amoxicillin [both twice daily] for 14 days, with 500 mg of clarithromycin and 500 mg of nitroimidazole [both twice daily] added for the final 7 days) or concomitant therapy (same 4 drugs taken concurrently [twice daily] for 14 days). The primary outcome was H. pylori eradication. Secondary end points were to address the influence of antimicrobial resistance on the outcome of eradication treatments, the incidence of adverse effects, and adherence rates with both therapies. A total of 343 patients participated in the study. Sex, age, and smoking status were similar among the patients in the hybrid treatment (n ⫽ 171) and concomitant therapy (n ⫽ 172) groups. Helicobacter pylori eradication rates were 90% (CI, 86% to 93%) and 91.7% (CI, 87% to 95%), respectively, in the intention-to-treat analysis (P ⫽ 0.35) and 92% (CI, 87% to 95%) and 96.1% (CI, 93% to 99%), respectively, in the per-protocol analysis (P ⫽ 0.07). The clarithromycin resistance rate was 23.5% (26% in Italy and 34% in Spain), the metronidazole resistance rate was 33% (33% in Italy and 34% in Spain), and 8.8% of patients were resistant to both strains. Mild adverse effects were reported in both groups. Adherence rates were 98.8% in the hybrid therapy group and 95.2% in the concomitant therapy group (P ⫽ 0.05). Cautions: Helicobacter pylori infection was confirmed by endoscopy in only 66% of patients, and the urea breath test was used to diagnose infection in the remaining patients, so patients with false-positive test results may have been included in the study. The E-test, which tends to overestimate resistance, was used to determine metronidazole resistance. No antibiotic susceptibility tests were done for H. pylori. 5 August 2014 Annals of Internal Medicine Volume 161 • Number 3 207
Update
Update in Gastroenterology and Hepatology
Implications: In a sample of Spanish and Italian patients with high rates of antibiotic-resistant H. pylori infection, both hybrid and concomitant nonbismuth quadruple therapy were effective. Hybrid therapy may be the preferred therapeutic option because of higher adherence rates and shorter duration (12 vs. 14 days). Lower Gastrointestinal Disorders Measurement of Individual Fecal UBAs Can Predict Stool Characteristics and Identify Subgroups of Patients With IBS Shin A, Camilleri M, Vijayvargiya P, et al. Bowel functions, fecal unconjugated primary and secondary bile acids, and colonic transit in patients with irritable bowel syndrome. Clin Gastroenterol Hepatol. 2013;11:1270-1275.e1. [PMID: 23639599]
Background: Several factors have been shown to play an important role in the pathophysiology of IBS. Two phenotypes are known: IBS with predominant diarrhea (IBS-D) and IBS with predominant constipation (IBS-C). Bile acids are known to induce changes in the colonic mucosal, motor, and sensory functions. Total bile acid secretion has been shown to be significantly higher in patients with IBS-D. However, the relationship among total, primary, and secondary fecal UBAs and the interrelationships among total bile acids, UBAs, and IBS phenotypes are unknown. Findings: This study prospectively enrolled healthy volunteers and patients with IBS. All participants completed a validated bowel disease questionnaire and the Hospital Anxiety and Depression Scale. They followed a diet of 100 g of fat per day for 4 days before measurement of fecal fat and fecal UBAs. The researchers aimed to measure total bile acids and UBAs and to assess the relationship among total bile acids, UBA profile, IBS phenotype, colonic transit time, and stool characteristics. Ninety-one participants were enrolled, including 30 healthy volunteers (22 women; mean age, 40 years), 30 patients with IBS-D (all women; mean age, 48 years), and 31 patients with IBS-C (all women; mean age, 36 years). Compared with the control group, levels of fecal primary UBAs were significantly higher in the IBS-D group (P ⬍ 0.01), whereas fecal secretory UBAs were higher in the IBS-C group (P ⫽ 0.02). Significant associations were also found among stool number and form and total fecal UBA, fecal fat, and colonic transit times at 24 and 48 hours after meals. Bile acids were associated with colonic transit time. Cautions: Adherence to high-fat diets may not be feasible in practice, and such diets may not be given to all patients, especially those with coronary artery disease or pancreatitis. Collection of stool samples at 24 and 48 hours is tedious. This study did not examine the effect of these findings on subsequent therapy or patient outcomes. Implications: Measurement of total bile acids and fecal UBAs can help identify subgroups of patients with IBS, which could help in the appropriate management of IBS symptoms. 208 5 August 2014 Annals of Internal Medicine Volume 161 • Number 3
Downloaded From: http://annals.org/ by a Fudan University User on 12/09/2016
Higher Prevalence of Diverticulosis Was Found in a Sample of Patients With High-Fiber Diet Intake Peery AF, Sandler RS, Ahnen DJ, et al. Constipation and a low-fiber diet are not associated with diverticulosis. Clin Gastroenterol Hepatol. 2013;11:1622-7. [PMID: 23891924]
Background: About one third of adults older than 60 years are known to have asymptomatic diverticulosis. A large percentage of these individuals develop complications, with associated morbidity, mortality, and health care costs. Low-fiber diet has traditionally been believed to be associated with the development of diverticulosis, but highquality evidence to support this hypothesis is lacking. Findings: This cross-sectional study analyzed data from patients participating in the Diet and Health Studies, a study of the relationship of environmental and lifestyle changes with colorectal adenomas. Recruited patients had outpatient colonoscopy for colon cancer screening, and presence of diverticula was assessed. Patients were interviewed via telephone within 12 weeks of colonoscopy by a trained research assistant blinded to the colonoscopy results. Information on bowel habits, physical activity, eating habits, age, sex, race, smoking history, alcohol use, nonsteroidal anti-inflammatory drug use, laxative use, and comorbid conditions was collected. Among 2104 participants (878 patients with diverticulosis and 1226 without), a dose-dependent increase in the prevalence of diverticulosis was seen in quartiles with highfiber dietary intake compared with the lowest quartile (prevalence ratio, 1.30 [CI, 1.13 to 1.50]; P for trend ⫽ 0.004) after adjustment for such confounders as age, race, and body mass index. Participants with more than 15 bowel movements per week were determined to be at a significantly higher risk for diverticulosis than those with fewer than 7 bowel movements per week (prevalence ratio, 1.70 [CI, 1.24 to 2.34]). Physical activity and red meat consumption were not associated with increased risk for the condition. Cautions: Dietary histories were obtained only for the past year. A relationship between long-term dietary patterns and diverticulosis could not be determined from these data. Implications: This study suggests that individuals currently consuming a high-fiber diet and having frequent bowel movements are at greater risk for diverticulosis. Long-term prospective studies are needed to show the role of dietary fiber in the development of diverticulosis.
Liver Disease Combination Therapy With Rifaximin and Lactulose Is More Effective Than Lactulose Alone in Treatment of Hepatic Encephalopathy and Decreases In-Hospital Mortality Rate and Length of Hospital Stay Sharma BC, Sharma P, Lunia MK, et al. A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose www.annals.org
Update in Gastroenterology and Hepatology
alone in treatment of overt hepatic encephalopathy. Am J Gastroenterol. 2013;108:1458-63. [PMID: 23877348]
Background: Hepatic encephalopathy is a common, serious, and reversible complication of cirrhosis. Lactulose has been the primary treatment for the disorder, but rifaximin has been shown to be an alternative therapeutic and prophylactic option. The effectiveness of combination therapy with lactulose and rifaximin in the treatment of overt hepatic encephalopathy has not been studied. Findings: This double-blind trial randomly assigned patients with cirrhosis and overt hepatic encephalopathy to rifaximin, 1200 mg/d, plus lactulose, 30 to 60 mL 3 times daily, or lactulose plus placebo. The primary end point was complete reversal of hepatic encephalopathy, and secondary end points included death and length of hospital stay. Of 120 patients randomly assigned (89 men and 31 women; mean age, 39 years; mean Child–Turcotte–Pugh score, 9.7; mean Model for End-Stage Liver Disease score, 24.6), a significantly higher number of patients randomly assigned to combination therapy (46 [76%]) had complete reversal of hepatic encephalopathy compared with those randomly assigned to lactulose plus placebo (29 [50.8%]) (P ⫽ 0.004). The combination therapy group also had a significantly lower overall mortality rate (23.8%) than the control group (49.1%) (P ⫽ 0.03). More deaths due to sepsis were seen in patients receiving lactulose alone versus
Update
combination therapy (17 vs. 7 [P ⫽ 0.01]). Patients receiving combination therapy had a shorter hospital stay (5.8 vs. 8.2 days [P ⫽ 0.001]). No difference in gastrointestinal bleeding or hepatorenal syndrome was seen between the groups. Cautions: Longer-term trials are needed to determine whether combination therapy decreases mortality rates and prevents hepatic encephalopathy in patients with cirrhosis. Future studies should include patients with transjugular intrahepatic portosystemic shunt. Implications: A combination of lactulose and rifaximin is more effective in the treatment of overt hepatic encephalopathy than lactulose plus placebo and seems to reduce short-term mortality and duration of hospitalization. From Veterans Affairs Medical Center, Kansas City, Missouri, and Brigham and Women’s Hospital, Boston, Massachusetts. Disclosures: None disclosed. Forms can be viewed at www
.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum ⫽M14-0323. Requests for Single Reprints: Prateek Sharma, MD, Veterans Affairs Medical Center, 4801 East Linwood Boulevard, Kansas City, MO 64128; e-mail, [email protected].
Current author addresses and author contributions are available at www.annals.org.
READERS’ COMMENTS Readers may comment on published articles at www.annals.org. While this service is free to Annals subscribers, readers without subscriptions who wish to comment on articles may purchase temporary access.
www.annals.org
Downloaded From: http://annals.org/ by a Fudan University User on 12/09/2016
5 August 2014 Annals of Internal Medicine Volume 161 • Number 3 209
Annals of Internal Medicine Current Author Addresses: Dr. Sharma: Veterans Affairs Medical Cen-
ter, 4801 East Linwood Boulevard, Kansas City, MO 64128. Dr. Greenberger: Gastroenterology Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115.
Author Contributions: Conception and design: P. Sharma, N.J. Greenberger. Analysis and interpretation of the data: P. Sharma, N.J. Greenberger. Drafting of the article: P. Sharma, N.J. Greenberger. Critical revision of the article for important intellectual content: P. Sharma, N.J. Greenberger. Final approval of the article: P. Sharma, N.J. Greenberger. Administrative, technical, or logistic support: P. Sharma, N.J. Greenberger. Collection and assembly of data: P. Sharma, N.J. Greenberger.
© 2014 American College of Physicians W-3231
Downloaded From: http://annals.org/ by a Fudan University User on 12/09/2016
