The major complication of GERD is the development of Barrett esophagus, which is considered as a pre-cancerous lesion. It is necessary to stress that these data are strongly influenced by the use of powerful antisecretory drugs PPIs. Further studies are needed to better elucidate this matter and overcome the present limitations represented by the lack of large prospective longitudinal investigations, absence of homogeneous definitions of the various forms of GERD, influence of different treatments, clear exclusion of patients with functional disorders of the esophagus.
Typical symptoms of gastro-esophageal reflux disease GERD , such as heartburn and regurgitation, are widespread in the community. The prevalence of GERD based on symptom perception in individual cross-sectional surveys varies from 2.
It is worth noting that the overall prevalence of GERD has increased since and consequently also the disease burden is enhanced. However, Gaddam et al.
Furthermore, the presence of erosive esophagitis at baseline is independently associated with subsequent development of Barrett's esophagus BE 5 years later and this is the precursor of esophageal adenocarcinoma EAC. In the past two decades, we have witnessed a progressive increase in direct and indirect costs related to the diagnosis, treatment and surveillance of GERD and its complications, such as BE and EAC.
Thus, a better understanding of GERD natural history would help in selecting patients really requiring endoscopic surveillance i. The aim of this review is to provide a summary of current information on the natural history of GERD, taking into account the evolution of its definition and the worldwide gradual change of its epid-emiology. To identify relevant studies, a computerized Medline and manual literature search was performed for the period up to December , with particular focus on the past 15 years.
We critically reviewed all full-text papers and relevant abstracts published in English. The reference lists from identified papers were searched to identify any additional studies that may have been missed during the process. The lack of an universally accepted definition of GERD up to and the unavailability of powerful antisecretory drugs, such as PPIs, until s in the past century have made it difficult to achieve a sound knowledge of the natural history of GERD.
According to Montreal classification, GERD is defined as a condition which develops when the reflux of gastric content causes troublesome symptoms, impairs quality of life, or leads to mucosal damage or complications. In fact, the sub-classification of GERD into esophageal and extraesophageal syndromes supports the clinical feeling that reflux patients suffer from a broad range of symptoms, besides heartburn.
The severity of reflux esophagitis is usually classified according to the Los Angeles criteria from A to D denoting increasing severity and extension of inflammation , 34 which has superseded the old Savary-Miller classification I—IV. The prevalence of GERD is frequently detected by means of appropriate questionnaires on the frequency and impact on quality of life of heartburn or regurgitation in large population-based studies. However, the lack of pathophysiological data has always led to overestimate the prevalence of GERD diagnosis, since also patients with FH were included in past series.
In a study by Dent et al. On the basis of only two studies, the incidence in the Western world was approximately 5 per person years, and the low rate of incidence with regard to the prevalence has been attributed to the recognized GERD chronicity. Overall, data of this study confirmed that GERD is highly prevalent worldwide, although prevalence estimates show considerable geographic variation. Indeed, GERD prevalence ranged from Regarding GERD incidence, the rate was assessed between 0.
Particularly, data are still lacking from important countries such as Japan, Brazil, India, Russia and from an entire continent such as Africa. In this regard, a study by Wall et al. As demonstrated in several studies, only a minority of BE patients develop EAC with an estimated risk of 0.
In keeping with the former hypothesis patients tend to remain in the same class during the whole life, whereas they can pass from one class to another according to the spectrum hypothesis. Such a different vision has a relevant impact on our therapeutic approach and surveillance programs.
In fact, a categorial disease requires focus on symptom control rather than on endoscopic surveillance and vice versa. Unfortunately, the analysis of medical literature on this point does not help us in favoring one or the other hypothesis. In fact, the majority of published studies are retrospective, only small numbers of patients are assessed, the adopted medical therapies are heterogeneous and this makes difficult to interpret their influence on the disease outcome and, finally, endoscopic examinations aimed at verifying the evolution of the different clinical conditions and the fluctuation from one class to another are often done with different intervals and without uniform methods of classification.
So, it is not surprising that some Authors sustain that progression from endoscopy-negative reflux disease through ERD to BE is rarely observed and esophageal physiology and mucosal biology is not shared across the all forms of the disease spectrum, while others are firmly convinced that NERD represents mild illness, increasing grades of endoscopic esophagitis are the reflection of a progressively worsening disease and BE is the most severe form of GERD and the transition from one severity class to another as a continuum still holds true.
Table 1 reports the most relevant studies on GERD natural history published in the last 15 years. On the other hand, according to a systematic review by Fullard et al. Cohort studies of the natural history of reflux disease published between and In , a large multicenter prospective study named pro-GERD assessed the progression versus regression of the various GERD forms over 2 years in a cohort of almost patients under routine clinical care in Germany, Austria and Switzerland.
At the discretion of their physician, these patients were treated with PPIs, H2 antagonists and antacids on a regular or on-demand basis, and underwent endoscopy with biopsy at the end of the 2-year follow-up. Among patients with ERD at baseline, In detail, the incidence of histologically-confirmed BE was 0. Overall, this study showed a relevant rate of changes between GERD categories, thus supporting the spectrum disease hypothesis.
In the same year, a study by Sontag et al. Thus, they concluded that the overwhelming majority of patients with disturbing GERD symptoms will never develop complications when treatment is symptom-driven, even after a decade of antireflux therapy interruption. However, the length of the study was such that patients enrolled pertained to both pre- and post-PPI era, making the results heterogeneous and difficult to interpret. Kawanishi et al.
In keeping with these findings, Pace et al. In keeping with these findings, the Authors concluded that the majority of patients with GERD do not appear to develop BE in the short period, when this metaplastic condition is not present on index endoscopy. In contrast, in patients with ERD a progression to BE was clearly demonstrated and, of note, patients who progressed to a more severe disease had prior demonstration of mild degree esophagitis Grade A and B.
Falkenback and coworkers in reported on a small cohort of patients referred for reflux symptoms and objectively diagnosed with pathological reflux at pH-testing, between and At mean follow-up of Interestingly, patients with esophagitis were less likely to have a positive Helicobacter pylori test than NERD.
Thus, the Authors concluded that after 20 years a considerable part of the cohort still experienced GERD symptoms and showed endoscopic progression. Furthermore, they suggested that H. In , Malfertheiner et al. Most patients remained stable or showed improvement in their esophagitis, indicating that current therapeutic management is usually adequate. Patients who remained unhealed after initial treatment were predisposed to GERD progression.
Recently, a large longitudinal year follow-up study included patients who had typical GERD symptoms at baseline, that was heartburn or regurgitation at a frequency of more than once a week, and collected as part of an investigation recruiting a population for H. The Authors evaluated the behavior of these symptoms at 10 years and observed that they persisted in one-third of individuals Among the individuals who were asymptomatic at study entry, 7.
While no predictors of persistent GERD symptoms were identified, the new-onset GERD symptoms were associated with poor quality of life or presence of irritable bowel syndrome at baseline and higher body mass index at 10 years. At last, a retrospective study evaluating the natural history of 96 asymptomatic ERD patients showed that most of them did not experience GERD symptoms and exhibited unchanged endoscopic findings Of particular importance is the fact that subjects having taken antisecretory drugs, such as PPIs and H2-receptor antagonists, were excluded from the study.
Up to now, data from different studies did not help to definitively understand the natural history of GERD. The evaluated studies are mainly retrospective and different in their methodology, and are confounded by a range of factors that make comment on progression rates quite difficult: duration and dosage of PPI treatment, the presence of anti-secretory therapy at the moment of endoscopic evaluation and the overlap between functional gastrointestinal symptoms and GERD diagnosis.
The lack of prospective longitudinal studies regards mainly the period before the widespread availability of powerful antisecretory agents PPIs and it is well known that retrospective analyses are not useful to look consistently at the natural history of a disease and, in particular, GERD. We don't have information on the results of pathophysiological tests that might have been performed at least once during the clinical history of patients, although they are the only tool which is able to address an adequate therapy in GERD patients.
Anyway, the largest number of studies showed that GERD rarely causes serious complications when treatment is symptom-driven; if initial endoscopy excludes BE and EAC, repeated endoscopies are not necessary to document complete healing and to search for cancer, unless alarm symptoms appear. It is likely that those patients who remain unhealed after initial treatment are predisposed to have GERD progression.
They probably need continuous treatment and strict endoscopic surveillance. Strictures and other complications are very rare. However, further studies are necessary with particular regard to data from pathophysiological investigations in order to exclude those patients who are affected by functional disorders and do not pertain anymore to the realm of GERD. Edoardo Savarino, MD, PhD : data collection and ana-lysis, writing of the manuscript, approving final version.
Nicola de Bortoli, MD, PhD : data collection and an-alysis, writing of the manuscript, approving final version. Chiara De Cassan, MD : data collection and an-alysis, approving final version.
Marco Della Coletta, MD : writing of the manus-cript, approving final version. Ottavia Bartolo, MD : data collection and analysis, approving final version. Manuele Furnari, MD : data collection, approving final version.
Andrea Ottonello, MD : data collection, approving final version. Elisa Marabotto, MSD : data collection, approving final version. Giorgia Bodini, MD : data collection, approving final version. Vincenzo Savarino, MD : data analysis, writing of the manuscript, approving final version.
Prevalence, clinical spectrum and atypical symptoms of gastro-oesophageal reflux in Argentina: a nationwide population-based study. Aliment Pharmacol Therapeut ; 22 4 : — Google Scholar. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Asan-si, Korea. Am J Gastroenterol ; 4 : — Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota.
Gastroenterology ; 5 : — Prevalence, clinical spectrum and health care utilization of gastro-oesophageal reflux disease in a Chinese population: a population-based study. Aliment Pharmacol Therapeut ; 18 6 : — Kennedy T , Jones R. The prevalence of gastro-oesophageal reflux symptoms in a UK population and the consultation behaviour of patients with these symptoms. Aliment Pharmacol Therapeut ; 14 12 : — Epidemiology of gastro-oesophageal reflux disease: a systematic review.
Gastro-oesophageal reflux is more prevalent in Western dyspeptics: a prospective comparison of British and South-East Asian patients with dyspepsia. Aliment Pharmacol Therapeut ; 21 12 : — Differences in the risk factors of reflux esophagitis according to age in Korea.
Dis Esophagus ; 27 2 : — Overweight is a risk factor for both erosive and non-erosive reflux disease. Dig Liver Dis ; 43 12 : — 5. Impact of anthropometric measures and serum leptin on severity of gastroesophageal reflux disease. Dis Esophagus ; 28 7 : — 8. Role of endoscopy in the management of GERD. Gastrointest Endosc. The most recent systematic review Ness-Jensen et al.
Systematic review: the effects of conservative and surgical treatment for obesity on gastro-oesophageal reflux disease. Ness-Jensen et al. A large prospective cohort observed that smoking cessation led to a reduction in reflux symptoms among non-obese patients odds ratio [OR]: 5. A reduction in supine acid exposure was also observed in RCTs comparing late evening meals to early meals and head of bed elevation versus flat position 17 Despite the relative dispute in the evidence about the benefit of some of the behavioral and lifestyle interventions to reduce GERD symptoms, they are widely used in clinical practice.
Henry MACA. Guidelines for the diagnosis and management of gastroesophageal reflux disease: an evidence-based consensus. Antacids were initially developed after an empirical observation that calcium carbonate CaCO3 was able to alleviate troublesome manifestations of gastric acid secretion by neutralizing intraluminal acidity 15 Several other antacids were historically used with this purpose - sodium bicarbonate, aluminum hydroxide, and magnesium hydroxide, for instance.
However, alginate-antacids combinations of alginic acid with small doses of conventional antacids are currently considered superior to antacids alone when recommended to short-term relief of mild infrequent symptoms or as rescue medication 6 6. Nevertheless, the current knowledge about their effect has indicated that antacids remain active in the stomach for a very short period of time, providing poor therapeutic effect for most GERD patients.
This observation and the still growing therapeutic arsenal for GERD and other gastric-acid related disorders have reserved a secondary role for antacids in the management of the disease. Clinical evidence accumulated since the introduction of this therapeutic strategy has shown that H2RAs cimetidine, ranitidine, famotidine and nizatidine have a more prolonged action than antacids, even being recommended for short-term use or episodic symptoms associated with GERD 4 4. Therefore, there is a significant degree of uncertainty about the efficacy of H2RAs at night in association with regular therapy with PPI 20 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 Syst Rev. In patients with GERD, the relative risk for remission of heartburn symptoms was 0. Besides efficacy results, safety concerns have decreased substantially the use of prokinetics. Cisapride have been withdrawn from the market worldwide due to relevant cardiac adverse events. Furthermore, the still available prokinetics, metoclopramide and domperidone, even used in a large scale in some countries, have poor proven efficacy.
Metoclopramide is not recommended due to neurological risks, while domperidone is not recommended due to cardiovascular risks, in higher doses or prolonged use 6 6. According to international guidelines, a patient diagnosed with GERD by presenting troublesome symptoms twice weekly or more is suitable for empirical therapy with an acid inhibitor without the need for confirmation through endoscopy, preferentially a PPI other drugs should be considered only in contexts where they are not available 6 6.
Am J Gastroenterol. Ann Intern Med. Besides GERD and NERD , PPIs are also recommended for esophagitis, peptic ulcer disease, prevention of nonsteroidal anti-inflammatory drugs associated ulcers, Zollinger-Ellison syndrome, functional dyspepsia and Helicobacter pylori in combination with antibiotics. Thereafter, since its introduction, PPIs have become one of the most prescribed medication classes in the primary care setting 11 The PPIs currently available in Brazil are omeprazole, lansoprazole, pantoprazole, esomeprazole, rabeprazole, and the most recently launched dexlansoprazole 25 Portaria no 45, de 6 de abril de pantoprazol.
Portaria no de 15 de abril de rabeprazol. Registro de medicamento novo: dexlansoprazol. Efficacy and safety of all 6 PPIs were assessed in a network meta-analysis conducted by Chen et al.
The authors evaluated the available evidence about symptom relief and rate of adverse events AEs of different PPIs in different dosing schemes in treating patients with NERD. Overall, in terms of symptomatic relief rate, compared with placebo, all interventions except rabeprazole 5 mg demonstrated clinical benefit. Within direct comparison with active drugs, omeprazole 20 mg was associated with a higher rate of symptom relief versus omeprazole 10 mg OR: 1. Dexlansoprazole 30 mg significantly improved the outcome compared with rabeprazole 5 mg group OR: 2.
For the rate of adverse events, a significant difference among all interventions was not observed, indicating a similar safety profile. As usually performed in network meta-analysis, Chen et al. For symptom relief, dexlansoprazole 30 mg ranked the first among all comparators other PPIs and placebo , while for the rate of AEs, omeprazole 20 mg presented the lowest incidence and lansoprazole 30 mg the highest 31 The efficacy and safety of proton-pump inhibitors in treating patients with non-erosive reflux disease: a network meta-analysis.
Sci Rep. The systematic review conducted by Li et al. Medicine Baltimore. Authors included 25 RCTs enrolling adults with EE receiving PPIs continuously for at least four weeks, using endoscopic healing rates at four and eight weeks as efficacy outcome and discontinuation rates for safety.
All PPIs included dexlansoprazole 60 mg, esomeprazole 20 mg, esomeprazole 40 mg, lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg, rabeprazole 20 mg were statistically superior to placebo in the efficacy evaluation. Comparative analysis versus omeprazole 20 mg indicated that esomeprazole 40 mg improved healing rates at 4 and 8 weeks OR of 1. Versus lansoprazole 30 mg, esomeprazole 40mg was also more effective at four and eight weeks OR of 1.
Only 1 RCT for dexlansoprazole 60 mg was included in the Li et al. In the dexlansoprazole clinical development program, RCTs reported non-inferiority of dexlansoprazole 60 mg and 90 mg to lanzoprazole 30 mg after eight weeks in healing of erosive esophagitis, providing higher healing rates in total sample until six percentage points and of dexlansoprazole 90 mg to lansoprazole 30 mg in healing of moderate to severe EE eight percentage points.
Considering patients with baseline grades C or D erosive esophagitis, healing rates are still higher, until 14 percentage points.
Regarding assessment of heartburn relief, dexlansoprazole and lansoprazole demonstrated a similar pattern of efficacy 33 Clinical trials: Healing of erosive oesophagitis with dexlansoprazole MR, a proton pump inhibitor with a novel dual delayed-release formulation - Results from two randomized controlled studies.
Dexlansoprazole has two distinct drug release moments to prolong plasma concentration time and duration of acid suppression, which is a major challenge for GERD management and a therapeutic gap for the PPI class 34 Besides the evidence previously mentioned for the medication, Wu et al.
Indirect comparison of randomised controlled trials: comparative efficacy of dexlansoprazole vs. Safety concerns accompanied the evolution of PPI therapy since its introduction in the s with several reviews being published to address risk of hazards allegedly associated with long term or inappropriate PPI use 36 Recent safety concerns with proton pump inhibitors.
Yadlapati R, Kahrilas PJ. When is proton pump inhibitor use appropriate? BMC Med. Proton pump inhibitor-associated gastric polyps: A retrospective analysis of their frequency, and endoscopic, histologic, and ultrastructural characteristics.
Am J Clin Pathol. It is used in small children where we can study the reflexate to the lung, and the test is easy in small babies in comparison to other invasive tests. Gastroesophageal scintigraphy is used for patient who presents with atypical reflux symptoms like recurrent upper respiratory symptoms. Manometry: It is a very important investigation to exclude motility disorders like achalasia and is indicated in patient who presents with atypical symptoms of gastroesophageal reflux disease.
High-resolution manometry is more sensitive and superior than ordinary manometry in diagnosing esophageal motility disorders. The use of upper gastrointestinal endoscopy showing hiatus hernia in patient with GERD. The use of upper gastrointestinal endoscopy showing peptic stricture. Barium metal showing hiatus hernia. Barium metal showing child hiatus hernia. Hiatus hernia with esophageal spasm. Complications of GERD may cause esophagitis which will result to bleeding.
Predisposition to Barrett esophagus that may turn to malignancy is 40—60 times seen in patient with reflux esophagitis-induced Barrett [ 11 , 12 , 13 ]. Avoid having late meals, heavy meals, spicy or fatty meals, drinking alcohol, and smoking.
Medical treatment where drugs are used to neutralize the effect of the reflux on esophageal mucosa: Antacids: Drugs that will neutralize the acid effect include the following—calcium, aluminum, and magnesium compounds. These are best taken after meals. Their effect is brief; and once they get emptied from the stomach, the symptoms may come back. These need to be given on an hour base to neutralize the acid effect. Histamine antagonists: There are receptors on the acid-producing cells which are stimulated by histamine to produce acid.
These receptors are blocked by histamine-blocking drugs which act on H2 receptors. These drugs are best taken before meals. These include cimetidine which can be given — mg daily, ranitidine given mg twice daily, and famotidine given 20—40 mg twice daily. Proton-pump inhibitors: These include omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole.
Their dosages range from 20 to 40 mg daily. Indication of surgery: Failure of medical treatment. It can be done by lengthening the lower esophageal sphincter to create valve-like action to prevent refluxing of gastric contents in the esophagus.
Fundoplication was previously performed by open surgery. Nowadays, most operations are done laparoscopically Figures 6 and 7 , with excellent outcome on short-term and long-term follow-ups. Laparoscopic view of big hiatus hernia in patient presented with GERD. Laparoscopic view of hiatus hernia in patient came with GERD symptoms. Patient will stop taking the drugs. All patients should be seen by gastroenterologist, ENT specialist, and surgeons before surgery, especially for those patients who come with atypical symptoms of GERD.
For many years, open surgery has been used for hiatus hernia but was rarely applied for GERD without hernia. Many operations can be done, either abdominal approach or thoracic approach. It is also called incisionless surgery.
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