gastroesophageal reflux disease (GERD)
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Introduction
Retrograde flow of stomach contents into the esophagus & possibly into the pharynx.
Etiology
- incompetent lower esophageal sphincter (LES)
- transient relaxation of the LES (not associated with swallowing) is the most common cause of GERD
- smoking may diminish LES pressure
- foods & beverages lowering the LES pressure:
- chocolate
- alcholic beverages
- citrus fruits (& juices)
- coffee
- onions
- peppermint
- pharmaceuticals lowering LES pressure:
- estrogen & progestin might reduce LES pressure by increasing blood levels of nitric oxide
- increased abdominal pressure puts stress on the lower esophageal sphincter (LES)
- lying supine shortly after eating (postprandial supination)
- pregnancy[19]
- delayed gastric emptying time may contribute
- gastroparesis
- fatty foods & fried foods
- large meals
- opiates[19]
- impaired esophageal clearance may contribute
- diminished salivary production of bicarbonate[8]
- associated with hiatal hernia
- 80% of patients with GERD have hiatal hernia
- 50% of patients with hiatal hernia have GERD
- obesity[19]
- connective tissue disease[38]
- age > 50 years
Epidemiology
- most common cause of non-cardiac chest pain
- 10-20% of adults have weekly symptoms; 15-40% monthly symptoms
- more common in elderly than young
Pathology
- transient, inappropriate LES relaxation
- loss of crural diaphragm contribution to LES pressure
- refluxed pepsin, bile & acidity may play roles in esophageal injury
- diminished esophageal pH may induce bronchospasm
- microaspiration may also induce bronchospasm
- at any given level of acid exposure, reflux symptoms less severe in elderly[14]
Clinical manifestations
- heartburn
- radiation towards mouth
- precipitated by meals or recumbent position
- sour taste
- regurgitation or vomiting
- early satiety
- belching
- bloating
- hoarseness[19]
- up to 1/3 of patients have extra-esophageal manifestations
- non-cardiac chest pain
- chronic cough
- chronic laryngitis
- wheezing, asthma (bronchospasm)
- dyspnea
- globus sensation
- hoarseness
- psychological factors (especially depression) may play an important role in the perception of symptoms[44]
alarm symptoms
Laboratory
Diagnostic procedures
- ECG exercise stress test to rule out cardiac etiology[19]
- other cardiac stress testing if not eligible
- upper GI endoscopy
- indications:
- dysphagia, odynophagia, chest pain, hematemesis, melena, anemia, weight loss, recurrent vomiting
- follow-up after 2 months' therapy with PPI for severe erosive esophagitis to assess healing & rule out Barrett esophagus
- routine screening for Barrett esophagus not indicated[19]
- continued GERD symptoms after 8 weeks of PPI*
- history of esophageal stricture & recurrent dysphagia
- men age > 50 years + > 5 years of GERD with additional risk factors[19]
- nocturnal reflux, elevated BMI, tobacco use, abdominal fat[19]
- only men, not women should be screened for Barrett's esophagus
- older men with frequent or chronic heartburn despite PPI[41]
- evaluation of esophagitis, ulceration, stricture
- identification of Barrett's esophagus
- identification of esophageal adenocarcinoma
- non-erosive GERD is not a risk factor for esophageal cancer & may not require follow-up upper GI endoscopsy[43]
- endoscopic therapies without long-term benefit[19]
- indications:
- 24 hour esophageal impedance - pH monitor (ambulatory)
- definitive diagnostic test (gold standard)
- correlates symptoms with pH above LES < 4
- GERD refractory to empiric proton pump inhibitor
- if upper GI endoscopy is negative[34][40]
- perform while patient is on proton pump inhibitor[19]
- Bernstein test (sensitivity & specificity low)[41] .
* empirical trial of proton pump inhibitor (PPI) QD for 8 weeks
Radiology
- upper GI series - detection of ulcerations & strictures
- esophagram - to rule out cricopharyngeal spasm
- don't use barium radiographs for diagnosis[22]
Complications
- erosive esophagitis (50%) -> ulceration (bleeding)
- esophageal stricture -> dysphagia (8-10%)[7]
- Barrett's esophagus (12-18%)[7]
- esophageal cancer
- increased risk for cancers of the upper aerodigestive tract in older adults[33]
- laryngopharygeal reflux
- pulmonary aspiration
- dental erosions
- supraventricular arrhythmias ?[11]
- complications more frequent in the elderly[8]
- nocturnal GERD may disturb sleep in the absence of heartburn[17]
- bronchospasm; exacerbation of asthma[18]
* poor correlation between laryngeal lesions & reflux esophagitis on endoscopy[13]
Differential diagnosis
- peptic ulcer disease
- ischemic heart disease
- GERD & coronary ischemia may coexist
- GERD may aggravate coronary ischemia
- medication-induced esophagitis
- scleroderma: refractory GERD, constipation, telangiectasias[19]
- dyspepsia, including functional dyspepsia*
- esophageal web
* a history of GERD does not guarantee symptoms due to GERD or the diagnosis is correct (case presentation)[19]
Management
- phase 1: diet & lifestyle modifications
- weight reduction & smoking cessation routinely recommended
- evidence supporting other recommendations is weak[19]
- dietary modifications
- decrease fat intake
- high-fat/low-carbohydrate diet of benefit in obese women[31]
- avoid high acidity foods
- other foods to avoid
- onions, chocolate, peppermint
- avoid alcohol
- rapid eating promotes postprandial reflux[10]
- decrease fat intake
- elevation of the head of the bed lessens supine-only supraesophageal reflux[29]
- avoid late or large evening meals
- discontinue medications that decrease LES pressure
- sleeping in left lateral decubitus position lessens esophageal exposure to gastric acid[39]
- phase 2: proton pump inhibitor (PPI) vs H2-receptor antagonist
- do not test; treat empirically QD for 8 weeks[19][40]
- proton pump inhibitor (PPI) first line, except if CKD4 when H2-receptor antagonist is more appropriate[19]
- various PPIs show the same level of efficacy[22]
- PPIs superior to H2 receptor antagonists[19]
- 8-week course of PPI for healing of erosive esophagitis[22]
- efficacy of PPI maximum when taken before meals[34]
- if partial response to QD PPI dosing, increase to BID[19]
- if symptoms do not respond to 8 week trial of PPI or recur after an 8 week trial of PPI, upper GI endoscopy is indicated to assess for alternative diagnosis (MKSAP19)[19]
- trial of another PPI suggested prior to upper GI endoscopy[34]
- response to proton pump inhibitors is NOT a good diagnostic test for GERD[9]
- trial of deprescribing proton pump inhibitor after a minimum of 4 weeks of therapy with resolution of symptoms
- a decrease, discontinuation or change to on-demand acceptable[38]
- formerly a trial of discontinuation after 1 year[19]
- deprescribing PPI not indicated in patients with Barrett esophagus, severe esophagitis (grade C or D), or history of bleeding GI ulcers[38]
- upper GI endoscopy takes precedence if indicated (see above)[41]
- other medical therapies
- addition of a QHS dose of H2-receptor antagonist to a proton pump inhibitor for breakthrough acid secretion at night[4]*
- addition of a daily H2-receptor antagonist to maximal PPI therapy does not result in meaningful additional acid blockade[42] (MKSAP19)
- baclofen diminishes transient lower esophageal sphincter relaxation
- antacids of uncertain benefit[19]
- addition of a QHS dose of H2-receptor antagonist to a proton pump inhibitor for breakthrough acid secretion at night[4]*
- surgery:
- Nissen fundoplication[5]
- indications:
- may be beneficial for a minority of patients with refractory GERD[36]
- refractory symptoms despite optimal medical therapy
- adverse effects of PPI[19]
- large hiatal hernia
- patient not interested in long-term medical therapy
- upper GI endoscopy & ambulatory pH monitoring confirm diagnosis of GERD[19]
- does not reduce risk of esophageal cancer[6]
- uncertain long-term benefit[19]
- surgery associated with improved quality of life at 5 years relative to medical management[23]
- indications:
- LINX Reflux Management System
- esophagectomy
- high-grade dysplasia
- esophageal cancer
- Nissen fundoplication[5]
- patient education:
- GERD is an irreversible lifelong condition
- most patients 85-92% acheive 5 year remission with either proton pump inhibitor or surgery[20]
- diaphragmatic breathing improves excessive GERD-related belching[32]
- follow-up evaluation for complications of GERD
- esophagitis
- stricture
- Barrett's esophagus (women do not need screening)[19]
- prevention[37]
- no smoking
- drink < 3 cups of coffee, tea or soda daily
- Mediterranean diet, Dash diet, or vegetarian diet
- at least minutes of moderate-to-vigorous exercise daily
- normal body weight (BMI < 25 kg/m2)[37]
* proton pump inhibitors work best by inhibiting acid secretion triggered by meals
More general terms
More specific terms
- gastroesophageal reflux disease (GERD) in the elderly
- laryngoesophageal reflux (LPR)
- non-erosive reflux disease (NERD)
Additional terms
References
- ↑ Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 325-26
- ↑ Manual of Medical Therapeutics, 28th ed, Ewald & McKenzie (eds), Little, Brown & Co, Boston, 1995, pg 339-340
- ↑ Kaiser Permanente Clinical Practice Guidelines
- ↑ 4.0 4.1 Prescriber's Letter 14(3): 2007 What You Should Know About Proton Pump Inhibitors Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=230307&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 5.0 5.1 Journal Watch 21(13):103, 2001 Spechler et al JAMA 285:2331, 2001 Kabrilas JAMA 285:2376, 2001
- ↑ 6.0 6.1 Journal Watch 22(1):3, 2002 Ye et al Gastroenterology 121:1286, 2001
- ↑ 7.0 7.1 7.2 Geriatrics Review Syllabus, American Geriatrics Society, 5th edition, 2002-2004
- ↑ 8.0 8.1 8.2 8.3 Chait M, Clinical Geriatrics 12(4): 39, 2004
- ↑ 9.0 9.1 Journal Watch 24(10):79, 2004 Numans ME, Lau J, de Wit NJ, Bonis PA. Short-term treatment with proton-pump inhibitors as a test for gastroesophageal reflux disease: a meta-analysis of diagnostic test characteristics. Ann Intern Med. 2004 Apr 6;140(7):518-27. PMID: https://www.ncbi.nlm.nih.gov/pubmed/15068979
- ↑ 10.0 10.1 Journal Watch 24(21):161, 2004 Wildi SM, Tutuian R, Castell DO. The influence of rapid food intake on postprandial reflux: studies in healthy volunteers. Am J Gastroenterol. 2004 Sep;99(9):1645-51. PMID: https://www.ncbi.nlm.nih.gov/pubmed/15330896
- ↑ 11.0 11.1 Cuomo R, De Giorgi F, Adinolfi L, Sarnelli G, Loffredo F, Efficie E, Verde C, Savarese MF, Usai P, Budillon G. Oesophageal acid exposure and altered neurocardiac function in patients with GERD and idiopathic cardiac dysrhythmias. Aliment Pharmacol Ther. 2006 Jul 15;24(2):361-70. PMID: https://www.ncbi.nlm.nih.gov/pubmed/16842463
- ↑ Omari TI et al, Effect of baclofen on esophagogastric motility and gastroesophageal reflux in children with gastroesophageal reflux disease. A randomized controlled trial. J Pediatr 2006, 149:468 PMID: https://www.ncbi.nlm.nih.gov/pubmed/17011315
Di Lorenzo C Gastroesophageal reflux. Not a time to relax. J Pediatr 2006, 149:436 PMID: https://www.ncbi.nlm.nih.gov/pubmed/17011308 - ↑ 13.0 13.1 Vavricka SR, Storck CA, Wildi SM, Tutuian R, Wiegand N, Rousson V, Fruehauf H, Mullhaupt B, Fried M. Limited diagnostic value of laryngopharyngeal lesions in patients with gastroesophageal reflux during routine upper gastrointestinal endoscopy. Am J Gastroenterol. 2007 Apr;102(4):716-22. PMID: https://www.ncbi.nlm.nih.gov/pubmed/17397404
Vaezi MF. Are there specific laryngeal signs for gastroesophageal reflux disease? Am J Gastroenterol. 2007 Apr;102(4):723-4. No abstract available. PMID: https://www.ncbi.nlm.nih.gov/pubmed/17397405 - ↑ 14.0 14.1 Lee J et al, Effects of age on the gastroesophageal junction, esophageal motility, and reflux disease. Clin Gastroenterol Hepatol 2007, 5:1132 PMID: https://www.ncbi.nlm.nih.gov/pubmed/17936081
- ↑ Prescriber's Letter 15(5): 2008 Treatment of Gastroesophageal Reflux in Children Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=240504&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ Prescriber's Letter 15(8): 2008 Treatment of Gastroesophageal Reflux in Infants Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=240808&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 17.0 17.1 Orr WC et al. Occurrence of nighttime gastroesophageal reflux in disturbed and normal sleepers. Clin Gastroenterol Hepatol 2008 Oct; 6:1099. PMID: https://www.ncbi.nlm.nih.gov/pubmed/18928935
- ↑ 18.0 18.1 Mastronarde JG et al, for the American Lung Association Asthma Clinical Research Centers Efficacy of esomeprazole for treatment of poorly controlled asthma. N Engl J Med 2009 Apr 9; 360:1487 PMID: https://www.ncbi.nlm.nih.gov/pubmed/19357404
- ↑ 19.00 19.01 19.02 19.03 19.04 19.05 19.06 19.07 19.08 19.09 19.10 19.11 19.12 19.13 19.14 19.15 19.16 19.17 19.18 19.19 19.20 19.21 19.22 19.23 19.24 19.25 19.26 19.27 19.28 Medical Knowledge Self Assessment Program (MKSAP) 14, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 2006, 2009, 2012, 2015, 2018, 2021.
Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022 - ↑ 20.0 20.1 Galmiche JP et al Laparoscopic Antireflux Surgery vs Esomeprazole Treatment for Chronic GERD JAMA. 2011;305(19):1969-1977 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/21586712 <Internet> http://jama.ama-assn.org/content/305/19/1969.full
- ↑ Shaheen NJ et al Upper Endoscopy for Gastroesophageal Reflux Disease: Best Practice Advice From the Clinical Guidelines Committee of the American College of Physicians Ann Intern Med. 4 December 2012;157(11):808-816 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23208168 <Internet> http://annals.org/article.aspx?articleid=1470281
Allen JI Endoscopy for Gastroesophageal Reflux Disease: Choose Wisely Ann Intern Med. 4 December 2012;;157(11):827-828 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23208171 <Internet> http://annals.org/article.aspx?articleid=1467444 - ↑ 22.0 22.1 22.2 22.3 Katz PO et al Guidelines for the Diagnosis and Management of Gastroeophageal Reflux Disease. Am J Gastroenterol. 2013 108:308-328 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23419381 <Internet> http://gi.org/wp-content/uploads/2013/03/ACG_Guideline_GERD_March_2013.pdf
- ↑ 23.0 23.1 Grant AM et al Minimal access surgery compared with medical management for gastro-oesophageal reflux disease: five year follow-up of a randomised controlled trial (REFLUX). BMJ 2013;346:f1908 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23599318 <Internet> http://www.bmj.com/content/346/bmj.f1908
McCulloch P Surgery or drugs for gastro-oesophageal reflux? BMJ 2013;346:f2263 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23599319 <Internet> http://www.bmj.com/content/346/bmj.f2263 - ↑ Lightdale JR et al Gastroesophageal Reflux: Management Guidance for the Pediatrician. Pediatrics. April 29, 2013 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23629618 <Internet> http://pediatrics.aappublications.org/content/early/2013/04/24/peds.2013-0421.full.pdf
- ↑ 25.0 25.1 Langevin SM et al Gastric Reflux Is an Independent Risk Factor for Laryngopharyngeal Carcinoma. Cancer, Epidemiology, Biomarkers & Prevention. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23703970 <Internet> http://cebp.aacrjournals.org/content/early/2013/05/21/1055-9965.EPI-13-0183
- ↑ Kahrilas PJ, Shaheen NJ, Vaezi MF et al American Gastroenterological Association Medical Position Statement on the management of gastroesophageal reflux disease. Gastroenterology. 2008 Oct;135(4):1383-1391, 1391.e1-5 PMID: https://www.ncbi.nlm.nih.gov/pubmed/18789939
- ↑ El-Serag HB. Time trends of gastroesophageal reflux disease: a systematic review. Clin Gastroenterol Hepatol. 2007 Jan;5(1):17-26. PMID: https://www.ncbi.nlm.nih.gov/pubmed/17142109
- ↑ Tran T, Lowry AM, El-Serag HB. Meta-analysis: the efficacy of over-the-counter gastro- oesophageal reflux disease therapies. Aliment Pharmacol Ther. 2007 Jan 15;25(2):143-53. PMID: https://www.ncbi.nlm.nih.gov/pubmed/17229239
- ↑ 29.0 29.1 Scott DR and Simon RA. Supraesophageal reflux: Correlation of position and occurrence of acid reflux-effect of head-of-bed elevation on supine reflux. J Allergy Clin Immunol Pract 2015 May-Jun; 3:356 PMID: https://www.ncbi.nlm.nih.gov/pubmed/25609349
- ↑ Hom C, Vaezi MF. Extraesophageal manifestations of gastroesophageal reflux disease. Gastroenterol Clin North Am. 2013 Mar;42(1):71-91 PMID: https://www.ncbi.nlm.nih.gov/pubmed/23452632
- ↑ 31.0 31.1 Pointer SD et al. Dietary carbohydrate intake, insulin resistance and gastro- oesophageal reflux disease: A pilot study in European- and African-American obese women. Aliment Pharmacol Ther 2016 Nov; 44:976. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/27582035 <Internet> http://onlinelibrary.wiley.com/doi/10.1111/apt.13784/abstract
- ↑ 32.0 32.1 Ong AM, Chua LT, Khor CJ et al. Diaphragmatic breathing reduces belching and proton pump inhibitor refractory gastroesophageal reflux symptoms. Clin Gastroenterol Hepatol 2017 Nov 2; pii: S1542-3565(17)31307-1 PMID: https://www.ncbi.nlm.nih.gov/pubmed/29104130
- ↑ 33.0 33.1 33.2 33.3 Riley CA, Wu EL, Hsieh MC et al Association of Gastroesophageal Reflux With Malignancy of the Upper Aerodigestive Tract in Elderly Patients. JAMA Otolaryngol Head Neck Surg. December 21, 2017. PMID: https://www.ncbi.nlm.nih.gov/pubmed/29270624 https://jamanetwork.com/journals/jamaotolaryngology/article-abstract/2666578
- ↑ 34.0 34.1 34.2 34.3 NEJM Knowledge+. Question of the Week. July 24, 2018 https://knowledgeplus.nejm.org/question-of-week/1678/
Hershcovici T, Fass R. An algorithm for diagnosis and treatment of refractory GERD. Best Pract Res Clin Gastroenterol 2010 Dec; 24:923 PMID: https://www.ncbi.nlm.nih.gov/pubmed/21126704 - ↑ Kahrilas PJ, Altman KW, Chang AB et al Chronic Cough Due to Gastroesophageal Reflux in Adults: CHEST Guideline and Expert Panel Report. Chest. 2016 Dec;150(6):1341-1360. PMID: https://www.ncbi.nlm.nih.gov/pubmed/27614002 Free PMC Article
- ↑ 36.0 36.1 Spechler SJ, Hunter JG, Jones KM et al Randomized Trial of Medical versus Surgical Treatment for Refractory Heartburn. N Engl J Med 2019; 381:1513-1523. Oct 17 PMID: https://www.ncbi.nlm.nih.gov/pubmed/31618539 https://www.nejm.org/doi/full/10.1056/NEJMoa1811424
- ↑ 37.0 37.1 37.2 Mehta RS, Nguyen LH, Ma W, Staller K, Song M, Chan AT. Association of diet and lifestyle with the risk of gastroesophageal reflux disease symptoms in US women. JAMA Intern Med 2021 Jan 4 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33393976 PMCID: PMC7783590 (available on 2022-01-04) https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2774728
- ↑ 38.0 38.1 38.2 38.3 38.4 38.5 38.6 Anand BS Fast Five Quiz: Gastroesophageal Reflux Disease (GERD) Medscape. July 29. 2021 https://reference.medscape.com/viewarticle/955523
Patti MG, Anand BS Gastroesophageal Reflux Disease Medscape. Oct 16, 2020 https://emedicine.medscape.com/article/176595-overview#showall - ↑ 39.0 39.1 Schuitenmaker JM et al. Associations between sleep position and nocturnal gastroesophageal reflux: A study using concurrent monitoring of sleep position and esophageal pH and impedance. Am J Gastroenterol 2022 Feb; 117:346 PMID: https://www.ncbi.nlm.nih.gov/pubmed/34928874 https://journals.lww.com/ajg/Fulltext/2022/02000/Associations_Between_Sleep_Position_and_Nocturnal.28.aspx
- ↑ 40.0 40.1 40.2 Katz PO et al. ACG clinical guideline for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol 2022 Jan; 117:27. PMID: https://www.ncbi.nlm.nih.gov/pubmed/34807007 Review. https://journals.lww.com/ajg/Fulltext/2022/01000/ACG_Clinical_Guideline_for_the_Diagnosis_and.14.aspx
- ↑ 41.0 41.1 41.2 41.3 NEJM Knowledge+ Gastroenterology
- ↑ 42.0 42.1 Maret-Ouda J, Markar SR, Lagergren J. Gastroesophageal reflux disease. JAMA. 2020;324:2565. PMID: https://www.ncbi.nlm.nih.gov/pubmed/33351044
- ↑ 43.0 43.1 Holmberg D et al. Non-erosive gastro-oesophageal reflux disease and incidence of oesophageal adenocarcinoma in three Nordic countries: Population based cohort study. BMJ 2023 Sep 13; 382:e076017. PMID: https://www.ncbi.nlm.nih.gov/pubmed/37704252 PMCID: PMC10496574 Free PMC article https://www.bmj.com/content/382/bmj-2023-076017
- ↑ 44.0 44.1 Guadagnoli L et al. Psychological processes, not physiological parameters, are most important contributors to symptom severity in patients with refractory heartburn/ regurgitation symptoms. Gastroenterology 2023 Oct; 165:848. PMID: https://www.ncbi.nlm.nih.gov/pubmed/37394015 https://www.gastrojournal.org/article/S0016-5085(23)00932-0/fulltext
Geeraerts A et al. Psychological symptoms do not discriminate between reflux phenotypes along the organic-functional refractory GERD spectrum. Gut 2023 Oct; 72:1819. PMID: https://www.ncbi.nlm.nih.gov/pubmed/37336632 https://gut.bmj.com/content/72/10/1819 - ↑ Dunbar KB Gastroesophageal Reflux Disease. Ann Intern Med. 2024. August 13. PMID: https://www.ncbi.nlm.nih.gov/pubmed/39133924 Review. https://www.acpjournals.org/doi/10.7326/AITC202408200
- ↑ National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Acid Reflux (GER & GERD) in Adults https://www.niddk.nih.gov/health-information/digestive-diseases/acid-reflux-ger-gerd-adults