Archives of Clinical and Biomedical Research

ISSN

2572-5017

Abstracting and Indexing

Review ArticleOpen Access

Pathophysiology and Clinical Applications of Gastro-Esophageal Reflux Disease

Qindeel Kamran1*, Muhammad Danish Mund2, Hafiz Akbar Ali3, Muhammad Qasim Barkat1

1Institute of Pharmacy, Physiology and Pharmacology, University of Agriculture Faisalabad, Pakistan.
2Institute of Animal and Dairy Sciences, University of Agriculture Faisalabad, Pakistan.
3Faculty of pharmaceutical Sciences, Government College University, Faisalabad, Pakistan.

*Corresponding Author: Qindeel Kamran, Institute of Pharmacy, Physiology and Pharmacology, University of Agriculture Faisalabad, Pakistan, E-mail: qindeelkamran24@gmail.com

Received: 1 September 2017; Accepted: 03 October 2017; Published: 06 October 2017


Abstract:

Gastro-esophageal reflux disease is a persistent affliction of gastrointestinal tract upper part with the growing prevalence throughout the world. By the time there has been an increase in the cognizance of its pathophysiology, clinical presentation and management. The disease could be identified easily by the symptoms. Many of the risk components are involved in the occurrence of disease including medications, obesity, pregnancy and asthma. It can be diagnosed by a number of procedures like manometry, ambulatory pH monitoring , endoscopy and radiology. Although different drugs are being utilized to treat GERD but PPIs (Proton pump inhibitors) have shown remarkable achievement in the curing the disease. When proton pump inhibitors are utilized for the extended period several of the safety ways are being explored to avoid any side effect. There has been a debate over the use of long term medications and surgery for quite a long time. Although both surgery and long term usage of PPI’s have proven effective in managing the disease.


Keywords:

GERD; Pathophysiology; Diagnosis and Treatment

Untitled Document

1. Introduction
GERD is an incessant digestive disease. It occurs when acid or stomach content circulates backward into the esophagus. The typical symptoms include heartburn, regurgitation, disturbances in sleep, pain in chest, hoarseness, cough, asthma, and dental erosions. The incompetence of the anti- reflux barrier at the esophago-gastric junction is the principal reason of GERD. Salivary production and peristalsis promote esophageal clearance. GERD may result in esophagitis, barrette’s esophagus, esophageal cancer and adenocarcinoma. Gastro-esophageal reflux disease effect 3-7% of U.S population each year [1]. About 2-3 times it is more pervasive in men than women [2]. It is considered clinically significant if the manifestations arise twice weekly. 10-30% of the population in North America and Europe suffers from the symptoms at least once weekly [3, 4]. 34-89% of asthmatic patients irrespective of the bronchodilators use have gastro-esophageal disease [5]. Occurrence of disease is related to the changes in sleep pattern, diet and physical activity [6]. It is scarcely found in Africa [7]. Gastro-esophageal disease has been divided into two groups upon endoscopy findings with the mucosal damage of the esophagus (erosive esophagitis, and Barrett’s esophagus) and in the absence of damage in the mucosa (non- erosive reflux disease termed as NERD). Upon 24 hour evaluation of pH, NERD is subdivided into three types as in type 1, an abnormal time for acid exposure in patients is recorded similar to the patients of erosive esophagitis [8]. Type 2 is referred as hypertensive esophagus as there is repeated reflux along with normal time of acid exposure [9, 10]. In type 3, patients have symptoms of reflux with balanced pH studies [11]. The occurrence of symptoms does not vary between Caucasians and African Americans in U.S [12]. Increased prevalence of esophagitis is related to the age and sex [13-15]. As compared to normal BMI, obese individuals are 2.5 times more susceptible to it [16]. The risk of GERD becomes greater due to presence of plethora belly fat creating pressure on the stomach, the build-out of hiatal hernia causing the flow of acid in backward direction or hormonal changes (increase in estrogen exposure). Risk factors for GERD and esophagitis are alcohol use and hiatus hernia [17-19]. The size and presence of hiatus hernia are related with grievous damage of mucosa, increased acid exposure, defective peristalsis and incompetence of inferior esophageal sphincter [20]. In accordance with the studies in Japan, alcohol use and cigarette smoking were the chief causes of gastro-esophageal reflux disease [21]. Whereas in Nigeria, use of cola and coffee by the medical student for the purpose of staying awake during examinations resulted in GERD. By the use of medications (calcium channel blockers, anti-cholinergic, theophylline, benzodiazepines, dopamine, nicotine, nitrates, progesterone, estrogen, glucagon and prostaglandins) and food (coffee, alcohol, chocolate, fatty meals), it is reported as it result in the transient lower esophageal sphincter relaxation. Mostly patients with connective tissue disease (scleroderma) and chronic obstructive airway disease developed it [22]. The hormonal variations during the period of pregnancy cause the lower esophageal muscles to relax more frequently causing acid reflux particularly while lying down. During second and third trimester while the fetus is growing, the uterus expands and stomach is under more pressure, which causes food contents and acid to flush back towards esophagus [23].

2. Pathophysiology
Lower sphincter of the esophagus is 3-4 cm long and composed of smooth muscles present at the distal portion of esophagus [24]. Reflux is prevented by this sphincter that generates a high pressure in between stomach and esophagus. Reflux is produced normally by the relaxation of lower sphincter. Transient relaxation occurs more frequently in GERD patients. High calcium influx mediated by the cholinergic neuron helps the sphincter to maintain higher tone than other structures. Resting sphincter has high intracellular calcium levels as compared to non-sphincteric esophageal muscles. Due to hiatus hernia, there is decreased pressure in the lower sphincter as well as decreased peristalsis in distal esophagus resulting in reduced clearance of refluxed acid. Delayed gastric emptying is also a cause as it increases the time of the gastric contents that stay there for a long time, thus increasing transient relaxations of lower sphincter muscles along with the gastric acid secretions. During sleep the reflux episodes increases because of reduced swallowing of saliva, which neutralizes the gastric acid [25].

3. Signs and symptoms
A common symptom is heartburn, which is a sensation of burning in the middle of the abdomen, middle of chest and behind breastbone and. Other common symptoms in adults include bad breath, nausea, pain in stomach, respiratory problems, painful swallowing, wearing away of teeth and vomiting [26]. In case of pediatric patients crying, loss of appetite, bradycardia, vomiting, wheezing, stridor, recurrent pneumonitis, chest pain or abdominal pain, hoarseness, sore throat, chronic cough, water bash, Sandifer syndrome, bloating and hiccups can be observed [27].

4. Diagnosis
In Accordance with The Society of American Gastrointestinal Endoscopic Surgeon, GERD can be confirmed by the existence of mucosal break in endoscopy, peptic strictures and Barrett’s esophagus [28]. Reflux syndrome includes heartburn and regurgitation that are diagnosed easily due to these characteristic symptoms [29, 30]. Diagnosis of erosive esophagitis by radiology has low specificity and sensitivity therefore, the choice of investigation is endoscopy. The most frequent Savary-Miller grading system is used having various grades [31]. Grade 1 is characterized by one or multiple erosions on a single fold with exudative or non- exudative erosions. Grade 2 consists of multiple erosions affecting many folds with confluent erosions. Grade 3 comprises of multiple circumferential erosions. Grade 4 consists of ulcer, stenosis and esophageal shortening and Grade 5 with Barrett’s epithelium (columnar metaplasia in circular or non- circular extensions). A to D classification of Los Angeles grades is more recent where grade A has single or multiple breaks in mucosa none of them longer than 5mm and not a single one extending between the top of mucosal folds. Grade B with one or many mucosal breaks longer than 5mm, not extending between the top of two mucosal folds. In Grade C, mucosal breaks extend in between 2 or more folds of mucosa. Grade D has mucosal breaks which involves more than or equal to 75 percent of the mucosal circumference [32]. In NERD different histological lesions have been discussed that differentiated it from GERD like dilation of intercellular spaces (DIS) [33], basal cell hyperplasia [34], papilla elongation [35], intraepithelial eosinophils [36] and neutrophils [37]. GERD is diagnosed by biopsy. During a biopsy, a tiny apparatus is passed that removes a small piece of esophageal lining which is further analyzed in pathology lab in order to confirm the underlying cause as cancer of esophagus. Barium swallow radiograph is a painless procedure that is useful for evaluating patients with dysphagia where a patient swallows a barium solution and then X-rays of esophagus are taken. It is not a useful test in those patients who had GERD because the patients had little or no damage to the esophageal lining and not used in routine diagnosis. The X-rays show ulcers and strictures. Only 1 out of every 3 patients with GERD have changes in esophagus being visible on X-rays. According to the American Gastroenterological Association short term PPIs treatment is carried out to check out the symptomatic relief in patients. GERD is suggested by the significant improvement of the symptoms. The test may have either false positive or false negative results [38]. Motor esophageal abnormalities are identified by manometry. The function and peristaltic activitiy of the lower sphincter of esophagus and esophagus are analyzed by manometry before the anti-reflux surgery. Dysphagia is diagnosed by manometry when no mechanical obstruction is determined. Abnormal exposure of the esophagus to acid by manometry localizes LES for subsequencial monitoring of pH and indicated for the preoperative assessment of anti-reflux surgery to exclude achalasia [39]. Ambulatory pH monitoring is the best way by which patients of NERD not responding to medications are evaluated. Ambulatory esophageal pH monitoring monitors the duration when the intra-esophageal pH stays less than 4 [40]. All types of reflux (weakly acidic, acidic and weakly basic) can be detected by multichannel intraluminal impedance monitoring with a pH sensor (MII-pH). Resistance in electrical conductivity of esophageal content is measured that detects any change in esophageal pH because of liquid presence or gas reflux [41, 42]. Ambulatory testing could be carried out by radiotelemetry capsule monitoring to measure acid and non- acid reflux by attaching to esophageal mucosa a capsule [43]. Esophageal impedance monitoring is performed mostly in combination with manometry to obtain complete information of esophagus functions using a manometry tubes along with electrodes that are placed at distinct points along the length measuring the rate at which gases and liquids pass through the esophagus. When such outcomes are compared with manometry findings, it is effectively known that how esophageal contractions move substances through the esophagus into stomach [44].

5. Treatment
Treatment includes prevention of complications, healing of esophagus, mitigation of the symptoms and prevention from recurrence. Treatment includes lifestyle modification, pharmacological treatment and surgery.

6. Lifestyle modification / dietary modifications
Lifestyle modification includes upraising the head of bed, cessation of smoking, reducing the intake of fats, avoiding lying horizontally for 3 hours postprandial avoiding coffee, alcohol, citrus juices, tomato products, chocolate, peppermint, avoiding drugs that affect esophageal motility (nitrates, tricyclic antidepressants, anti-cholinergics) or damage lining of mucosa (potassium salts, NSAIDs, alendronate) [45]. Lifestyle modifications are referred as first line therapy to pregnant women with GERD. Along with these modifications, educating the patient about various behaviors that could result in reflux is necessary.

7. Pharmacological therapy
Symptoms are relieved in patients with mild form of GERD by utilization of over the counter medications such as anti- refluxants and antacids. This combination of two therapies is more effective. The treatment plan of GERD has been illustrated in Table 1 and Table 2 respectively.

Drugs

Doses

Age (FDA indicated)

 Histamine 2 receptor antagonists

Cimetidine

20-40mg/kg/day

? 16 years

Ranitidine

5-10mg/kg/day

1 month-16 years

Nizatidine

50mg twice daily for up to 8 weeks

?12 years

Famotidine

<3months to 16 years (0.5-1mg/kg/day)

<3months- 16years

 Proton pump inhibitors

Omeprazole

5 to <10kg (5mg O.D)
10 to <20kg (10mg O.D)
? 20kg (20mg O.D)

1-16 years

Lansoprazole

Short term treatment of GERD/EE:
?30kg (15mg O.D for 12 weeks)
>30kg (30mg O.D for 12 weeks)

1-11 years

Short term treatment of non-erosive GERD:
15mg O.D for 8 weeks
EE: 30mg O.D for 8 weeks

12-17 years

Esomeprazole

EE due to acid-mediated GERD:
3-5kg (2.5mg O.D for 6 weeks)
>5-7kg (5mg O.D for 6 weeks
>7.5-12kg (10mg O.D for 6 weeks)

1 month to < 1 year

Short term treatment of symptomatic GERD:
10mg O.D for 8 weeks
Healing of EE:
<20kg (10mg O.D for 8 weeks)
?20kg (10-20mg O.D for 8 weeks)

1-11 years

Healing of EE:
20-40mg O.D for 4-8 weeks
Symptomatic GERD:
20mg O.D for 4 weeks

12-17 years

Rabeprazole

20mg daily for 8 weeks

12-17 years

<15kg (5-10mg O.D for 12 weeks)
?15kg (10mg O.D for 12 weeks)

1-11 years

Pantoprazole

?15 to <40kg (20mg daily)
?40kg (40mg daily)

?5 years

Table 1: Pediatric doses of medication for GERD

Drugs

 Doses

 Mechanism of action

 Surface barrier

Sodium alginate

10-20mL Q.I.D

Floats on the gastric contents

 Mucosal protectant

Sucralfate

1 g Q.I.D

Binds to damaged tissues

 Histamine 2 receptor antagonists

Cimetidine

200-400mg B.I.D

Competitively inhibit histamine receptors on gastric parietal cells

Famotidine

10-20mg B.I.D

 

Nizatidine

150mg B.I.D

 

Ranitidine

75-150mg B.I.D

 

 Proton pump inhibitors

Esomeprazole

20-40mg O.D

Irreversible deactivation of H+/K+ proton pump on parietal cell

Lansoprazole

15-30mg O.D

 

Omeprazole

20-40mg O.D

 

Omeprazole-IR

20-40mg O.D

 

Pantoprazole

40mg O.D

 

Rabeprazole

20mg O.D

 

 Prokinetics

Metoclopramide

5-10mg every 6-8 hours

Promotes gastric emptying

 tLSER inhibitors

Baclofen

10-20 mg 3 times daily

Increases lower esophageal tone

Table 2: Doses of medication for GERD

8. Antacids/Alginates
They are effective in relieving of symptoms by neutralizing the gastric acid as they contain alkali ions, thus reducing the damage of esophagus and suppressing pain. They should always be taken after meal or at bedtime [46-48]. These include aluminium hydroxide, magnesium hydroxide and simethicone. Antacids help in the healing of erosive esophagitis while offering symptomatic relief [49].

9. Acid Suppressive Therapy
Acid suppressive therapy is the centerpiece for the treatment of GERD currently [50].

10. Histamine 2 receptor antagonists
Famotidine, ranitidine, cimetidine and nizatidine decrease the secretion of gastric acid after a meal but are  not
efficacious in the healing of esophagitis [51]. Now- a -days these have been used for the relief of nocturnal symptoms and for the milder stage of the disease [52]. In US for the short-term (14 days) treatment of heartburn, omeprazole is available over-the-counter. Because of the development of tolerance within 1-2 weeks, this class is not recommended for long term use.

11. Proton pump inhibitors
Acid suppression can be effectively achieved by the use of proton pump inhibitors (pantoprazole, lansoprazole, esomeprazole, omeprazole, rabeprazole). They are the benzimidazoles which are substituted that works by irreversibly binding to the H+K+ATPase, the last step in gastric acid secretion [53]. Resolution of heartburn is achieved in 61% of the NERD patients having erosive esophagitis by the use of PPIs as compared to 40% relief by histamine 2 receptor antagonists in similar patients [54, 55]. PPI treatment failure occurs because of delayed gastric emptying, residual acid reflux, improper dosing time, weakly acidic reflux, deuodeno-gastroesophageal reflux, esophageal hypersensitivity, nocturnal reflux, eosinophilic esophagitis, residual acid reflux, reducing PPI bioavailability and psychological comorbidity. In chronic or complicated type of GERD, long term PPI therapy has been proven beneficial [56, 57]. In the Netherlands, 21% of the PPIs prescriptions are prescribed for the gastro protection of patient taking non-steroidal anti- inflammatory drugs or aspirin. The PPIs should be taken before meals (before breakfast or evening meal).

 12. Prokinetics
GERD is caused by the esophago-gastric motility problems such as incompetence of lower esophageal sphincter and delay in gastric emptying time. Among the promotility agents (baclofen) may be useful in suppressing acid. Prokinetic medicines (cisapride, metoclopramide) stimulate serotoninergic or dopaminergic receptors in order to increase esophageal and gastric peristalsis resulting in the delayed esophageal clearance [58].

13. Treatment of GERD in pregnancy
Heartburn is reported in 45?80% of pregnant patients and although it is self-limited. Typically, GERD arises in a first trimester of pregnancy, worsens during latter period of pregnancy and resolves after the delivery. GERD occurs during pregnancy due to the increase levels of hormones (progesterone) and growth of the uterus. Owing to the side effects on the growing fetus, pregnant patients are often unwilling to use any medications during pregnancy.

Treatment in pregnancy should begin with lifestyle modifications. According to the Canadian Dyspepsia working group, if lifestyle modifications don’t work, then antacids are recommended as the first line of treatment. Products containing Ca are preferred. Antacids, which contain Na CO3 should not be used leading to metabolic alkalosis and fluid accumulation in both mother and fetus.

Alginates such as Gaviscon TM, is considered safe during this period. Absorption of aluminum could affect developing organs in the fetus such as the brain and kidneys. Magnesium in larger quantity and ingested over prolonged periods of time could result in nephrolithiasis and respiratory distress. A systematic review by the Motherisk Program (Hospital for Sick Children, Toronto, ON) showed no risk for fetal malformations , teratogenicity, increased risk of low birth weight or miscarriage when H2RAs especially ranitidine was used during the period of pregnancy. In case of failure of therapy, including H2RAs and persistence of symptoms patient should refer physician possibly for the use of a proton pump inhibitor. Omeprazole has been assigned to “category C” by U.S. FDA and lansoprazole to “category B” [59] .
14. Surgical interventions of GERD
Two options of treatment are available to cure the chronic and relapsing nature of GERD such as long term medication and anti-reflux surgery or repair of LES (lower esophageal sphincter). Surgery is indicated when medical treatment plan is failed (severe regurgitation, inadequate or side effects of medication), complications (peptic stricture, Barrett’s esophagus) [60, 61], extra esophageal manifestations (hoarseness, asthma, chest pain, cough, and aspiration) [62-65]. Patients are not subjected to surgical therapy if he is unresponsive to PPIs.

15. Nissen fundoplication
Surgical procedure have been advanced from an open to a laparoscopic method and then in to transoral incisionless fundoplication during 50 years. Nissen fundoplication is the vastly used procedure. Stomach fundus is wrapped around the esophagus to create a new cardiac valve-equivalent at the gastro-esophageal junction in Laparoscopic fundoplication and is suggested in patients with Barrett’s esophagus, postmenopausal women with osteoporosis, erosive GERD, poor compliance of medicine and serious respiratory manifestations. The advantages of laparoscopic fundoplication involve shorter duration of hospital stay, fewer incisional hernias and reduced pain [66]. Complications of this technique are impotence to belch, persistent dysphagia, vomiting, epi-gastric fullness, postprandial pain, temporary swallowing, bloating, and intense flatus [67].

16. Laparoscopy
Laparoscopy is performed by passing a small viewing device and surgical instruments through several small puncture sites in the abdomen avoiding the need for major abdominal incisions.

17. Endoscopic procedures
Endoscopic methods of treating GERD have been currently developed in which sutures near the gastro-esophageal junction are placed using a device connected to the endoscope. This technique improves GERD symptoms, pH probe results and decrease PPIs use in the short term, but it does not reduce total costs because many patients subsequently return to the long term use of PPIs.

18. Radiofrequency ablation (Stretta procedure)
Endoscopically-controlled radiofrequency ablation (Stretta procedure) of the LES has shown to improve typical GERD symptoms thus, decreasing acid exposure to esophagus and medication use in an unrestrained trial with short-term follow-up. High-energy waves are targeted on wall lower esophagus wall which in return produce a less number of scar tissues reducing heartburn and other symptoms in most people. More than one radiofrequency treatment may be required to achieve good results.

19. Long term complication of GERD
If left uncontrolled, persistent heartburn and other serious problems are observed [68]. Esophagitis may cause chest pain, heartburn, swallowing difficulty or bleeding [69]. Barrett's esophagus leads to the cancer of esophagus. Acid reflux causes abnormal changes esophagus lining. Normal cells are replaced with the abnormal ones in lining of esophagus. These abnormal cells are indistinguishable with those found normally in lining of the small intestine. Roughly 1 in 300 people with Barrett's esophagus develops esophageal cancer each year [70]. The damaged lining of the esophagus becomes blemished, narrowing the esophagus resulting in strictures and preventing food and liquid passing in to the stomach. Squamous cell carcinoma is the development of squamous cells lining esophagus usually affecting the upper and middle esophageal area whereas, adenocarcinoma in lower part of the esophagus due to Barrett’s esophagus. Hemorrhage occurs by the widespread gastric mucosal irritation or ulceration with acute bleeding resulting in tarry or bloody stools, syncope, diaphoresis, hypovolemic shock.

20. Conclusion
GERD is one of the aspects of gastroenterology which has encountered stupendous renovations in the last 30?40 years. Multiple factors are involved in the pathophysiology of the GERD. As GERD is a chronic as well as a relapsing disease so, patients should be managed with either long-term medical treatment or surgery after a thorough analysis of the pros and cons of each modality. Where medical therapy affects production of gastric acid only, fundoplication refurbishes the activity of LES and improves peristalsis of esophagus. Fundoplication cannot regress Barrett’s esophagus and prevent adenocarcinoma development. PPIs are being extensively used currently for the treatment. According to my opinion, there is an intense need to develop a combinational therapy to mask the aftereffects of PPIs or a new safer therapeutic agent should be discovered to resolve the underlying issues of treatment that have been remained unresolved after the surgery or by the use of different therapies.

References

  1. Kahrilas PJ. Review article: gastro-oesophageal reflux disease as a functional gastrointestinal disorder. Aliment Pharmacol Ther 20 (2004):50-55.
  2. Ford AC, Moayyedi P. Treatment of chronic gastro-oesophageal reflux disease. BMJ (2009): 339
  3. Dent J, El-Serag H B, Wallander M A, and Johansson S. Epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut 54 (2005): 710?717.
  4. Stanghellini V. Relationship between upper gastrointestinal symptoms and lifestyle, psychosocial factors and comorbidity in the general population: results from the Domestic/International Gastroenterology Surveillance Study (DIGEST),” Scandinavian Journal of Gastroenterology 231 (1999): 29-37. 
  5. Sontag SJ, O’Connell S, Khandelwal S, et al. Most asthmatics have gastroesophageal reflux with or without bronchodilator therapy. Gastroenterology 99 (1990): 613-620.
  6. Segal, “The gastro-oesophageal reflux disease complex in sub-Saharan Africa,” European Journal of Cancer Prevention 10 (2001): 209-212. 
  7. Nwokediuko SC, Ijoma U, Obienu O, Agunyenwa C. Gastroesophgeal reflux disease: a clinical and endoscopic study of Nigerian patients. The Internet Journal of Gastroenterology (2009): 8.
  8. Dent J, Brun J, Fendrick AM, et al. An evidence-based appraisal of reflux disease management? the Genval Workshop Report. Gut 44 (1999): S1?S16.
  9. Fass R, Fennerty MB, Vakil N. Non erosive reflux disease-current concepts and dilemmas. American Journal of Gastroenterology 96 (2001):303-314.
  10. Watson RGP, Tham TCK, Johnston BT, McDougall NI. Double blind cross-over placebo controlled study of omeprazole in the treatment of patients with reflux symptoms and physiological levels of acid reflux?the ‘sensitive oesophagus’. Gut 40 (1997):587-590. 
  11. Drossman Rome D. The Functional Gastrointestinal Disorders. 3rd edition. McLean, Va, USA: Degnon Associates (2006).
  12. Sharma P, Wani S, Romero Y, Johnson D, Hamilton F. Racial and geographic issues in gastroesophageal reflux disease. American Journal of Gastroenterology 103 (2008): 2669-2680. 
  13. Rosaida MS, Goh KL. Gastro-oesophageal reflux disease, reflux oesophagitis and non-erosive reflux disease in a multiracial Asian population: a prospective, endoscopy based study. European Journal of Gastroenterology and Hepatology 16 (2004):495-501.
  14. Hirakawa K, Adachi K, Amano K, et al. Prevalence of non-ulcer dyspepsia in the Japanese population. Journal of Gastroenterology and Hepatology 14 (1999):1083-1087.
  15. Rajendra S, Kutty K, Karim N. Ethnic differences in the prevalence of endoscopic esophagitis and Barrett’s esophagus: the long and short of it all. Digestive Diseases and Sciences  49 (2004):237-242.
  16. El-Serag HB, Graham DY, Satia JA, Rabeneck L. Obesity is an independent risk factor for GERD symptoms and erosive esophagitis. American Journal of Gastroenterology 100 (2005):1243-1250.
  17. Ayazi S, Crookes P, Peyre C. Objective documentation of the link between GERD and obesity. The American Journal of Gastroenterology 102 (2007):138-139.
  18. Ayazi S, Hagen JA, Chan LS, et al. Obesity and gastroesophageal reflux: quantifying the association between body mass index, esophageal acid exposure, and lower esophageal sphincter status in a large series of patients with reflux symptoms. Journal of Gastrointestinal Surgery 13 (2009):1440-1447.
  19. Buttar NS, Falk GW. Pathogenesis of gastroesophageal reflux and Barrett esophagus. Mayo Clinic Proceedings 76 (2001):226-234.
  20. Patti MG, Goldberg HI, Arcerito M, Bortolasi L, Tong J, Way LW. Hiatal hernia size affects lower esophageal sphincter function, esophageal acid exposure, and the degree of mucosal injury. American Journal of Surgery 171 (1996):182-186.
  21. Watanabe Y, Fujiwara Y, Shiba M, et al. Cigarette smoking and alcohol consumption associated with gastro-oesophageal reflux disease in Japanese men. Scandinavian Journal of Gastroenterology  38 (2003): 807-811.
  22. Ruigómez A, Wallander MA, Johansson S, Rodríguez LAG. Irritable bowel syndrome and gastroesophageal reflux disease in primary care: is there a link? Digestive Diseases and Sciences 54 (2009): 1079-1086.
  23. Patti MG, Gasper WJ, Fisichella PM, Nipomnick I, Palazzo F. Gastroesophageal reflux disease and connective tissue disorders: pathophysiology and implications for treatment. Journal of Gastrointestinal Surgery 12 (2008):1900-1906.
  24. Kahrilas PJ. Anatomy and physiology of the gastroesophageal junction. Gastroenterol Clin North Am 26 (1997):467-486.
  25. Dodds WJ, Hogan WJ, Helm JF, Dent J. Pathogenesis of reflux esophagitis. Gastroenterology  81 (1981):376-394.
  26. Ferri FF. Ferri's Clinical Advisor 2014: 5 Books in 1. Philadelphia, Pa.: Mosby Elsevier; 2014. https://www.clinicalkey.com. Accessed Jan. 2, 2014
  27. Orr WC, Robinson MG, Johnson LF. Acid clearance during sleep in the pathogenesis of reflux esophagitis. Dig Dis Sci 26 (1981):423-427.
  28. Stefanidis D, Hope WW, Kohn GP, Reardon PR, Richardson WS, Fanelli RD. Guidelines for surgical treatment of gastroesophageal reflux disease. Surgical Endoscopy 24 (2010):2647-2669. 
  29. Wong WM, Lai KC, Lam KF, et al. Prevalence, clinical spectrum and health care utilization of gastro-oesophageal reflux disease in a Chinese population: a population-based study. Alimentary Pharmacology and Therapeutics 18 (2003):595-604.
  30. Vakil N, van Zanten SV, Kahrilas P, et al. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. American Journal of Gastroenterology 101 (2006):1900-1943.
  31. Genta RM, Spechler SJ, Kielhorn AF. The Los Angeles and Savary-Miller systems for grading esophagitis: utilization and correlation with histology. Dis Esophagus 24 (2011):10-17.
  32. Hatlebakk JG. Endoscopy in gastro-oesophageal reflux disease. Best Pract Res Clin Gastroenterol 24 (2010):775-786.
  33. Ismail-Beigi F, Horton PF, Pope CE. Histological consequences of gastroesophageal reflux in man. Gastroenterology 58 (1970):163-174.
  34. Brown LF, Goldman H, Antonioli DA. Intraepithelial eosinophils in endoscopic biopsies of adults with reflux esophagitis. American Journal of Surgical Pathology 8 (1984):899-905. 
  35. Ballem CM, Fletcher HW, Mc Kenna RD. The diagnosis of esophagitis. The American Journal of Digestive Diseases 5 (1960):88-93. 
  36. Knuff TE, Benjamin SB, Worsham GF, Hancock JE, Castell DO. Histologic evaluation of chronic gastroesophageal reflux. An evaluation of biopsy methods and diagnostic criteria. Digestive Diseases and Sciences 29 (1984):194-201. 
  37. Nandurkar S, Talley NJ, Martin CJ, Adams S. Esophageal histology does not provide additional useful information over clinical assessment in identifying reflux patients presenting for esophagogastroduodenoscopy. Digestive Diseases and Sciences 45 (2000):217-224. 
  38. De Vault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. American Journal of Gastroenterology 100 (2005):190-200. 
  39. Waring JP, Hunter JG, Oddsdottir M, Wo J, Katz E. The preoperative evaluation of patients considered for laparoscopic antireflux surgery. American Journal of Gastroenterology 90 (1995):35-38. 
  40. Kahrilas PJ, Shaheen NJ, Vaezi MF. American gastroenterological association medical position statement on the management of gastroesophageal reflux disease. Gastroenterology 135 (2008):1383.e5-1391.e5.
  41. Pohl D, Tutuian R. Reflux monitoring: pH-metry, bilitec and oesophageal impedance measurements. Best Practice and Research 23 (2009):299-311.
  42. Agrawal A, Castell DO. Clinical importance of impedance measurements. Journal of Clinical Gastroenterology 42 (2008):579-583.
  43. National Institutes of Health. Gastroesophageal reflux disease. Am Fam Physician 71 (2005): 2376-2382.
  44. Harvey RF, Hadley N, Gill TR, et al. Effects of sleeping with the bed-head raised and of ranitidine in patients with severe peptic oesophagitis. The Lancet 2 (1987):1200-1203.
  45. Graham DY, Patterson DJ. Double-blind comparison of liquid antacid and placebo in the treatment of symptomatic reflux esophagitis. Digestive Diseases and Sciences 28 (1983):559-563.
  46. Lieberman DA. Medical therapy for chronic reflux esophagitis. Long-term follow-up. Archives of Internal Medicine 147 (1987):1717-1720. 
  47. Poynbard T. Relapse rate of patients after healing of oesophagitis?a prospective study of alginate as self-care treatment for 6 months. Alimentary Pharmacology and Therapeutics 7 (1993):385-392.
  48. Pettit M. Treatment of gastroesophageal reflux disease. Pharm World Sci 27 (2005):432-435.
  49. Bruley des Varannes S, Coron E, Galmiche JP. Short and long-term PPI treatment for GERD. Do we need more-potent anti-secretory drugs? Best Practice and Research 24 (2010):905-921.
  50. Khan M, Santana J, Donnellan C, et al. Medical treatments in the short term management of reflux oesophagitis. Cochrane Database Syst Rev (2007):CD003244.
  51. Tutuian R, Castell DO. Management of gastroesophageal reflux disease. American Journal of the Medical Sciences 326 (2003):309-318.
  52. Richardson P, Hawkey CJ, Stack WA. Proton pump inhibitors. Pharmacology and rationale for use in gastrointestinal disorders. Drugs 56 (1998):307-335. 
  53. Venables TL, Newland RD, Patel AC, Hole J, Wilcock C, Turbitt ML. Omeprazole 10 milligrams once daily, omeprazole 20 milligrams once daily, or ranitidine 150 milligrams twice daily, evaluated as initial therapy for the relief of symptoms of gastro-oesophageal reflux disease in general practice. Scandinavian Journal of Gastroenterology 32 (1997):965-973.
  54. Van Pinxteren B, Numans ME, Bonis PA, Lau J. Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease. Cochrane Database of Systematic Reviews (2006):3CD002095.
  55. Fass R, Sifrim D. Management of heartburn not responding to proton pump inhibitors. Gut 58 (2009) :295-309.
  56. Richter JE. The patient with refractory gastroesophageal reflux disease. Diseases of the Esophagus 19 (2006):443-447.
  57. Tack J. Recent developments in the pathophysiology and therapy of gastroesophageal reflux disease and nonerosive reflux disease. Curr Opin Gastroenterol 21 (2005):454-460.
  58. Gill SK, O’Brien L, Einarson TR et al. The safety of proton pump inhibitors (PPIs) in pregnancy: a meta-analysis. Am J Gastroenterol 104 (2009):1541-1545.
  59. Spechler SJ, Goyal RK. The columnar-lined esophagus, intestinal metaplasia, and Norman Barrett.Gastroenterology 110 (1996):614?621.
  60. Lagergren J, Bergstom R, Lindgen A, Nyren O. Symptomatic gastroesophgeal reflux as a risk factor for esophgeal adenocarcinoma. The New England Journal of Medicine 340 (1999):825?831.
  61. Rakita S, Villadolid D, Thomas A, et al. Laparoscopic nissen fundoplication offers high patient satisfaction with relief of extraesophageal symptoms of gastroesophageal reflux disease. American Surgeon 72 (2006) :207-212.
  62. Meyer TK, Olsen E, Merati A. Contemporary diagnostic and management techniques for extraesophageal reflux disease. Current Opinion in Otolaryngology and Head and Neck Surgery 12 (2004):519-524.
  63. Lindstrom DR, Wallace J, Loehrl TA, Merati AL, Toohill RJ. Nissen fundoplication surgery for extraesophageal manifestations of gastroesophageal reflux (EER) Laryngoscope 112 (2002):1762-1765.
  64. Oelschlager BK, Eubanks TR, Oleynikov D, Pope C, Pellegrini CA. Symptomatic and physiologic outcomes after operative treatment for extraesophageal reflux. Surgical Endoscopy and Other Interventional Techniques 16 (2002):1032-1036.
  65. Catarci M, Gentileschi P, Papi C, et al. Evidence-based appraisal of antireflux fundoplication. Annals of Surgery 239 (2004):325-337.
  66. Rydberg L, Ruth M, Lundell L. Mechanism of action of antireflux procedures. British Journal of Surgery 86 (1999):405?410.
  67. Kahrilas PJ. Clinical manifestations and diagnosis of gastroesophageal reflux in adults (2014). http://www.uptodate.com/home.
  68. American Academy of Otolaryngology-Head and Neck Surgery. Fact Sheet: Gastroesophageal Reflux (GERD). Accessed 7/12/2013
  69. Fennerty MB. The continuum of GERD complications. Cleveland Clinic Journal of Medicine (2003):S33-S33.
  70. Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol 108 (2013):308-328.