Refractory Gastroesophageal Reflux Disease - Literature review Example

Teacher Refractory Gastroesophageal Reflux Disease: A Literature Review Gastroesphageal Reflux Overview Refractory Gastroesophageal Reflux Disease is so common that it can mistaken as not being such a serious disease. The reality is, however, that this particular disease of the esophagus can manifest itself in various degrees, and can become quite serious if not treated. Refractory Gastroesophageal Reflux Disease is considered to be a chronic condition that becomes noticeable when various acids within the contents of the stomach actually leak back into the esophagus, causing extreme irritation (Aguirre 730). This most commonly results in heartburn, which is a painful feeling that an individual experiences that feels like a burning in their chest or throat. Because this is an adverse reaction that is not considered to be normal, the condition must be treated in order to avoid long term damage to the esophagus itself. There are a great number of studies that have been commission to ascertain the symptoms and proper diagnosis of acid reflux, and those findings will be discussed in this literature review. In addition, it is important to note that there are multiple indicators for Refractory Gastroesophageal Reflux Disease, so not all treatment options will work in every case (Fass 4). For this reason, it is critical to understand the different symptoms associated with the disease itself before a proper treatment regime can be properly introduced. Acid Reflux Symptoms Acid Reflux Diagnosis Epidemiology Many Western countries, the united States among them, have seen the prevalence of Refractory Gastroesophageal Reflux Disease impact up to 20 percent of the population. The most common age group affected appears to be those in the range of 50 to 70 years of age (Armstrong 592). Ironically, given the ever increasing life expectancy of individuals in the developed world, leading to an ever ageing population, the prevalence of Refractory Gastroesophageal Reflux Disease is only expected to increase even more in coming years (Fletcher 45). While it might not be chronic, it is estimated that more than sixty percent of the adult population exhibits one or more symptoms of Refractory Gastroesophageal Reflux Disease each year. Of this, roughly twenty to thirty percent will have weekly symptoms of the disease (Fujiwar & Arakawa 762). In the United States alone, more than seven million people are estimated to have one or more symptoms of Refractory Gastroesophageal Reflux Disease (Garcia-Compean 207). It is important to note that obesity has been directly linked with the onset of Refractory Gastroesophageal Reflux Disease and that rates of obesity in the United States, and other western developed countries, has increased by more than 100 percent in the last decade (Hunter 677). This has lead to the conclusion that as the general population continue to become more obese, the number of individuals afflicted by Refractory Gastroesophageal Reflux Disease is likely to continue to increase on that basis alone. In a recent seven year time span, the diagnosis of either primary or secondary Refractory Gastroesophageal Reflux Disease showed an increase of over 200 percent (Kahrilas 986). While older adults continue to be the most sizeable portion of the population affected by the disease, children are increasing exhibiting symptoms as well. In fact, children with symptoms of Refractory Gastroesophageal Reflux Disease have increase by more than 40 percent in infants, and more than 80 percent in children and adolescents between the ages of 2 and 17. In a recent study, slightly more than 9.1 percent of patients hospitalised dues to Refractory Gastroesophageal Reflux Disease presented with other health related concerns as well (Krishan & Pandolfino 45). These included weight loss, severe episodes of vomiting, and anaemia. Such health concerns are particularly troubling because they do signal the onset of Refractory Gastroesophageal Reflux Disease and other oesophageal related disorders (Mattar 852). In epidemiological terms, slightly more than 4 percent of all people hospitalised with Refractory Gastroesophageal Reflux Disease also present with some type of oesophageal disorder. Some of these afflictions have proven quite serious with an estimated 1,150 deaths annually in the United States alone being attributed to Refractory Gastroesophageal Reflux Disease (Modin 392). In addition, of the individuals that now claim they a weekly problem with one or more symptoms of acid reflux have had the issue present in their life for more than five years. One recent survey revealed 130,000 people reporting some sign or reflex disease or heartburn. Our of those, fully 95 percent reported one or more symptoms as having been occurring for more than 18 months, and just over 50 percent reported the symptoms occurring for more than five years now. Of those having symptoms for more than five years, a full 75 percent of those responding have symptoms recurring a minimum of two times per week (Ray 39). Interestingly enough, heartburn (one of the main symptoms of Refractory Gastroesophageal Reflux Disease) appears to occur more frequently during the night, as opposed to during the daytime hours. More than half of those surveyed expressed this fact, with 63% of respondents reporting that they actually have difficulty sleeping at times due to their heartburn and that their ability to perform basic daily functions often suffered the next day (Richter 615). It is also estimated that about one percent of individuals diagnosed with Refractory Gastroesophageal Reflux Disease also have developed Barrett’s espophagus (Souza, Huo, & Mittal 1778). Refractory Gastroesophageal Reflux Disease has incurred a high financial toll on society as well. Consider the fact that, in the United States alone, there are more than 18 million ambulance calls resulting in a rush to the hospital that attributed to Refractory Gastroesophageal Reflux Disease (Szarka & DeValu 99). During a recent year more than 3 million people were hospitalised for Refractory Gastroesophageal Reflux Disease related symptoms, complications, or treatment. At the same time, in the United States alone nearly 65 million prescriptions of one sort or another are written for Refractory Gastroesophageal Reflux Disease related medication every year (Wall & Jacoby 148). It is also estimated that nearly 5 percent of all consults conducted by a patients primary care physician are now attributed to symptoms bought on by Refractory Gastroesophageal Reflux Disease (Zamir 392). People with Refractory Gastroesophageal Reflux Disease tend to report a lower quality of life when it comes to health related factors. This includes eighty percent of individuals with Refractory Gastroesophageal Reflux Disease prorating a reduced enjoyment level with for, sixty percent reporting some type of sleep problem or deprivation, and 40 percent reporting difficult concentrating at work when symptoms of Refractory Gastroesophageal Reflux Disease are present (Deeb & Dib 220). Finally, the American College of Gastroenterology estimates that the symptoms of Refractory Gastroesophageal Reflux Disease has now resulted in over $2 billion in lost productivity every week throughout the year (Fass 4). Doing the math, that is a direct costs to society in excess of 100 billion dollars in lost productivity alone, not to mention direct financial setbacks as well. Consider the age group that Refractory Gastroesophageal Reflux Disease affects the most, it is estimated that 27 percent of all older patients currently on Medicare in the United States are prescribed some type of Refractory Gastroesophageal Reflux Disease medication (Furuta 223). This includes antacids and anti-secretory agents. This total estimated financial cost for this age group alone in roughly 5.6 billion US dollars. In one recent seven year period, the elderly were found to account for 30 percent of all hospitalisations due to primary Refractory Gastroesophageal Reflux Disease diagnoses (Gutschow & Holscher 665). In addition, they accounted for roughly half of all diagnoses of Refractory Gastroesophageal Reflux Disease that did not result in hospitalization. Statistics do reveal that Refractory Gastroesophageal Reflux Disease is most commonly diagnosed in people that are over 40 years of age, with nearly 50 percent of all such diagnoses for Refractory Gastroesophageal Reflux Disease coming in individuals between the ages of 45 and 64 (Hunter 675). As far as gender goes, women appear to be more likely than men to be hospitalised as a result of Refractory Gastroesophageal Reflux Disease symptoms. In fact, women now account for more than 60 percent of all hospitalisations attributed to Refractory Gastroesophageal Reflux Disease. Hospital stays for individuals receiving a primary Refractory Gastroesophageal Reflux Disease diagnosis, and who lived in a household with an income level below the median level, increased some 30 percent in the past 7 years. At this same time, such diagnoses actually decreased by about 16 percent in households that had an income level about the median. Globally, it is now estimated that between 5 to 7 percent of the population has one or more symptoms of Refractory Gastroesophageal Reflux Disease. The most commonly report symptom is heartburn (Kahrilas 985). As just alluded to, the most well known symptom of this affliction is heartburn. Heartburn itself is also known as either pyrosis, cardialgia, or acid indigestion. Typically it manifests itself as a burning sensation in the upper chest area of the person, just behind the breastbone, or in the upper central part of the abdomen, or the epigastrium. At heartburn progresses, the pain associated with it typically begins to rise throughout the chest area, and may actually radiate back down to the neck, throat, or jaw area. Usually, heartburn results in the regurgitation of gastric acid, also referred to as gastric reflux, which makes it a primary symptom of Refractory Gastroesophageal Reflux Disease (Kahrilias & Lee 325). Classification In the past decade alone, heartburn and other related symptoms associated with Refractory Gastroesophageal Reflux Disease has risen more than 50%. This is according to a study commissioned in Norway that followed more then 30,000 people for approximately 11 years. At the inception of the study, roughly 11.6% of those 30,000 were experiencing some form of acid reflux related symptoms. By the end of the 11 years, however, that percentage increased to just over 17.1% percent, reflecting a nearly 47% increase in the number of individuals affected to some degree by Refractory Gastroesophageal Reflux Disease (Katle & Hatlebakk 221). While studies such as the one just mentioned to not necessarily inform us about the specific reasons why acid reflux is on the rise, there are certain factors that physicians are attributing to the fact. Obesity, for example, is one the rise throughout the world, and this has been attributed as the most likely cause of the increase in the number of individuals that are suffering from Refractory Gastroesophageal Reflux Disease. This is particularly concerning today because the studies reveal that people what have been suffering from acid reflux for quite a long period of time are known to be more susceptible to the development of cancer of the oesophagus. This was once a rare affliction affecting only a minority of people, but the number of cases reported annually is experiencing an alarming spike as of late (Krishnan & Pandolfino 45). The American Cancer Society has recently estimated that in a recent year nearly 17,000 new incidences of oesophageal cancer were diagnosed in the United States alone. As a result, nearly 15,000 Americans died of this particular disease (Krishnan & Pandolfino 45). In addition to heartburn, a common symptom of Refractory Gastroesophageal Reflux Disease is known as acid reflux. This malady happens when the contents of the stomach actually backward directly into the oesophagus. It is true that roughly 20 percent of individuals who have acid reflux end up resolving their symptoms on their own, independent of medical treatment, this still leaves 4 out of 5 individuals suffering form the disease to seeks out costly and often painful medical treatment (Kunsch & Neesse 315). The study in Norway also uncovered that the number of people reporting some degree of acid reflux related symptoms actually rose by some 30 percent during the decade under the scope of the study itself. Even more alarming, perhaps, is that the prevalence of the most severe symptoms rose by a reported 24 percent. It was also discovered that women tended to report new cases of acid reflux symptoms as they got older. Out of all demographic groups, women younger than 40 were the least likely to report any type of symptoms attributed to acid reflux. There was no signifiant difference in the number of older mean and women that reported new cases of acid reflux (Lacy 587). While obesity seems to be a major contributing factor leading to Refractory Gastroesophageal Reflux Disease, it is by no means exclusive. While many patients are certainly overweight and practice regular unhealthy eating habits, there are many others that have a normal and weight and practice extreme care in terms of the diet that they consume. One doctor remarked that, “This is not just a disease of older people and people who are overweight. I have many young patients whose weight is normal and they have terrible reflux” (Slaughter 869). As a result, physicians have developed a list of lifestyle factors that they believe can help minimise the risk of developing Slaughter. One such strategy is to avoid eating large meals before bedtime. The recommendation is to each meals a minimum of two to three hours before lying down for the evening. The thought is that this will give food more time to digest and empty from the stomach prior to entering into a deep sleep pattern. In addition, individuals should avoid overeating at any one meal. Instead, people should eat four to five small meals, as opposed to two or three big meals. This will help avoid many of the symptoms associated with heartburn and acid reflux. In addition, people need to know their own tolerance levels. There are certain heartburn triggers that manifest themselves in some people, but not in others. Some people, for example, might develop terrible bouts of heartburn after eating chocolate, while others will have no such symptoms. For some, such triggers might be caffeine, fruit juices, or foods high in fat. If an individual suffers from severe acid reflux, it is also recommended that they avoid smoking and not consume any measurable quantities of alcohol (Mattar 852). Pathogenesis It is commonly accepted in medical circles that acid reflux within the oesophagus begins to develop when a certain level of gastric juices in the stomach actually moves up into the oesophagus. The traditional pathogenesis, then, sees that gastric acid inflict a type of chemical burn on the oesophageal muscosa. Naturally, this is not a normal occurrence, so the individual suffering from this affliction will feel a burning sensation, the like of which can be quite painful in many cases. Many studies conducted about the pathogenesis of Refractory Gastroesophageal Reflux Disease have uncovered that reality a certain number of reflux hydrogen ions do direct damage to the oesophageal epithelial cells. Models conducted of animals have also revealed that the acidic environment that results under these circumstances combine with pepsins to attack the tight junctions between the cells that work to maintain the epithelial barrier (Modin 397). When this occurs, the spaces between the cells themselves have actually been known to dilate. As we have uncovered from the pathogenesis of Refractory Gastroesophageal Reflux Disease, the dilation that occurs actually ends up allowing a certain amount of acid and pepsin to gain access to even deeper epithelial layers, thereby increasing the amount of reflux present in the individual. If such reflux becomes ongoing, it developed into an injury as the cells at the surface level of the oesophagus actually die, triggering not only an inflammatory response in the the form of an infiltration of neutrophilis, but also a proliferative response in the form of basal cell and papillary hyperplasia. The studies related to the pathogenesis of Refractory Gastroesophageal Reflux Disease described here have since been confirmed by studies replicated on hum any biopsies (modin 397). One recent and meaningful study in to the pathogenesis of Refractory Gastroesophageal Reflux Disease was conducted on rats. The researchers began by incorporating the use of a rat model of reflux esophagitis, The goal was to actually create reflux by surgically attaching the oesophagus model to the duodenum. This resulted in a free flow of both gastric and duodenal contents from the stomach into the oesophagus. Upon doing so, the hypothesis that the rats would develop severe reflux esophagitis was realised (Ranjitkar 22). What was realized, however, is that it could take weeks to develop the actual esophagitis that was observed using this model. This was an odd finding given the fact the traditional understanding of Refractory Gastroesophageal Reflux Disease has reflux as being a simple chemical burn, which would surely not takes weeks to develop. Such burns within the oesophagus, we know, tend to develop quite quickly, so further studies were required and conducted (Ranjitkar 22). The researchers opted to then incorporate a systematic study of the early history of the development of reflux esophagitis upon the model of the rat, after an actual esophagoduodenostomy was performed. The thought was that, if reflux esophagitis is truly caused by the adverse effects of gastric acid that is refluxed, then the researchers should see the injury actually begin once the surface epithelial cows of the oesophagus died. Such a death of the surface cells, it was believed, would eventually lead to a proliferation of the basal cells as well. This would have once they tried to take over for the dead surface cells, resulting in basal cell hyperplasia being manifested. This type of hyperplasia is consistent with the traditional finding the reflux esophagitis is actually a proliferative response that is triggered by the death of the surface cells themselves. In the end, after exhaustive research, it was discovered that these original theories were not actually accurate. It was found that, “If caustic injury is not the primary mechanism underlying reflux esophagitis, then one alternative hypothesis is that gastroesophageal reflex actually triggers a cytokine-mediated immune response, and it is that immune response that causes the oesophageal injury” (Kunsch & Neesse 315). Regarding the question of whether the pathogenesis for Refractory Gastroesophageal Reflux Disease can entail both the traditional understanding of the malady along with the new findings uncovered in recent research. the results are not conclusive. Models conducted on animals have suggested that, at the earliest signs of any inflammation in the oesophagus, there will be an infiltration of the submucosa by lymphoctyes. Only later does this appear to appear to progress to a situation that involves both neutrophilis and the epithelial surface. It was also discovered during this study that the first trigger of this event is actually a reflux-induced stimulation of the oesophageal squamous cells present in the animal. This typically results in the secretion of inflammatory cytokines. During this process of observation, the researchers did notice a certain loss of surface cells at the 4 week point after the beginning signs of reflux. This finding tends to suggest that the overall effects of the ongoing injury to the oesophagus, in addition to a cytokine-mediated inflammatory injury, may in fact be manifested themselves. This particular pathogenesis and findings, however, are still subject to further study. Nonetheless, they are hopeful breakthroughs in our quest to determine exactly how acid reflux begins and what, if anything, can be done to stem the chemical reaction that sets out to form Refractory Gastroesophageal Reflux Disease (Kunsch & Neesse 315). Reflux Treatment Lifestyle Changes While obesity seems to be a major contributing factor leading to Refractory Gastroesophageal Reflux Disease, it is by no means exclusive. While many patients are certainly overweight and practice regular unhealthy eating habits, there are many others that have a normal and weight and practice extreme care in terms of the diet that they consume. One doctor remarked that, “This is not just a disease of older people and people who are overweight. I have many young patients whose weight is normal and they have terrible reflux” (Slaughter 869). As a result, physicians have developed a list of lifestyle factors that they believe can help minimise the risk of developing Slaughter. One such strategy is to avoid eating large meals before bedtime. The recommendation is to each meals a minimum of two to three hours before lying down for the evening. The thought is that this will give food more time to digest and empty from the stomach prior to entering into a deep sleep pattern. In addition, individuals should avoid overeating at any one meal. Instead, people should eat four to five small meals, as opposed to two or three big meals. This will help avoid many of the symptoms associated with heartburn and acid reflux. In addition, people need to know their own tolerance levels. There are certain heartburn triggers that manifest themselves in some people, but not in others. Some people, for example, might develop terrible bouts of heartburn after eating chocolate, while others will have no such symptoms. For some, such triggers might be caffeine, fruit juices, or foods high in fat. If an individual suffers from severe acid reflux, it is also recommended that they avoid smoking and not consume any measurable quantities of alcohol. As this demonstrates, it is important to treat the causes of acid reflux, but such factors may not be the same for every individual. The key, however, is to manage one’s lifestyle in order to provide the maximum possibility that Refractory Gastroesophageal Reflux Disease will not manifest itself because of areas of life that could be easily managed. While obesity may be a contributing cause to acid reflux disease, the person that is of normal weight yet smokes and drinks alcohol on a regular basis may be just as susceptible to the effects of acid reflux. As a result, as someone begins to battle with acid reflux, a preliminary course of treatment will likely involve changes to the diet. Individuals can actually reduce their risk of developing heartburn or acid reflux disease by eating foods that are lower in fat and higher in protein. Individuals should also stop eating as soon as they get the sensation that are full in order to avoid gastric acids from refluxing into the oesophagus. Some of the beverages that one suffering from Refractory Gastroesophageal Reflux Disease should consider avoiding are coffee, tea, any other caffeinated beverages, carbonated beverages, and alcohol. Certain fruits, such as oranges and lemons should also be avoided to their high acidic content. Other foods that are known to exacerbate Refractory Gastroesophageal Reflux Disease include tomatoes (included any tomato based products), chocolate, mint, peppermint, spicy foods such as chill or curry, onions, and garlic. Anyone that smokes should also consider breaking the habit, as smoking is known to increase the risk of developing heartburn and acid reflux disease in a variety of different ways. Smoking can actually increase the amount of acid that is secreted by the stomach. As a result, it ends up potentially interfering with the function of the muscles that work to keep the acid down. If these muscles begin to falter, acid will tend to reflux into the oesophagus with relative ease. Doctors also recommend that individuals suffering from Refractory Gastroesophageal Reflux Disease work to use their sleeping patterns to help reduce the actual levels of reflux. Once recommendation is to put blocks under the head of the bed in order to raise it by at least 4 to 6 inches. The prevailing theory here is that the extra height works to help keep the contents of the stomach down, making it much more difficult to experience any type of reflux. It is important to note that the practice of using many extra pillows does not actually work in the same way. This is because doing so actually works to increase pressure on the abdomen. Another recommendation is to stop eating at least two or three hours before lying down in order to avoid the stomach having to do extra hard work while one is trying to get to sleep. Finally, it is recommended that an individual suffering from Refractory Gastroesophageal Reflux Disease try to take their daytime naps in a chair, as opposed to in their bed. The key, as discussed in this section, is to work to reduce the extra pressure that exists around the abdomen. Increased pressure leads to an increase in reflux, which can be quite painful, especially during the nighttime hours. As a result, it is further recommended that tight clothes or belts be avoided, and that excess weight be shed. Antacids and Over-the-Counter Medicine There is some relief to be found in the over-the counter medicine that is readily available in most pharmacies or drug stores. Antacids, for example, to tend to provide quick and short time relief for many people. Naturally, however, such medicine simply masks the symptoms. If lifestyle and dietary changes are not made, the frequency of such episodic attacks of heartburn and acid reflux will only continue to increase, regardless of the effectiveness of antacids. It is recommended that if an individual relies heavily on antacids, consuming them frequently, then they should try to get a prescription for stinger medicine that works to actually decrease the level of stomach acid in the body. Some medicine that has provide helpful in blocking the production acid in the stomach include H2 blockers. These typically coming under the labels of Axis AR, Pepcid AC, Tagament HB, and Zantac 75. It is recommended that individuals suffering from heartburn for more than 14 days in a two consider the use of proton pump inhibitors. These include the brands and labels of Prevacid 24HR, Prilosec OTC, and Zegerid OTC. Anything beyond two weeks of consecutive use, however, should necessitate a visit to a physician in order to develop a more comprehensive treatment plan that will likely include some form of lifestyle change counselling, coupled with medication targeted to the individual and his or her unique needs. Some medication a person takes, for example, could actually trigger heartburn and other symptoms of medications, so a physician should be consulted to determine if that is the case. Such medications that might do so include aspirin, ibuprofen, naproxen, and other anti-inflammatory pain relievers. Also, some muscle relaxants and certain blood pressure drugs have been shown to increase levels of stomach acid, leading to the triggering of heartburn and acid reflux in some people (Kunsch & Neesse 315). Histamines As noted, antacids are often seen to be the first and preferred method of treatment for the initial onset of Refractory Gastroesophageal Reflux Disease. Such products work by combining the properties of aluminium, magnesium, or calcium with either hydroxide or bicarbonate ions in an effort to neutralise stomach acid. Some common brands in this category include Alka-Seltzer, Maalox, Rolaids, and Tums. There are also some products, such as Gaviscon, which actually works by giving the lining of the stomach a layer of foam protection to guard against too much acid buildup. Histamine 2 blockers, however, show even great success as a treatment option for many people. They work to directly treat Refractory Gastroesophageal Reflux Disease. Histamine itself is a compound that has many wide ranging effects on the human body. For Refractory Gastroesophageal Reflux Disease, we are concerned with the positive effects that histamines can have on the stomach. This compound is actually deeply involved in the production of acid, so H2 blockers work to prevent histamine from landing on certain H2 receptors. When this happen, the stomach is actually prevented from making more acid because it never receives a signal to do so. Because of this, not as much acid is produced in the stomach as would be were the H2 blocker not present. As we know, the less acid that is produced actually works to reduce heartburn. Today, H2 blockers are commonly used to treat both Refractory Gastroesophageal Reflux Disease and the onset of peptic ulcers. They are available as both an over-the-counter medication in low doses, and as prescription drugs if a higher dose is required (Kunsch & Neesse 315). Conclusion Living with Refractory Gastroesophageal Reflux Disease can be quite painful and uncomfortable. As this study has illustrated, much is still to be learned about this disease. For many, lifestyle and dietary changes can great lower the likelihood that any major episodes of heartburn and acid reflux will occur. In other individuals, however, it is not as easy. For some, the stomach simply produces too much acid, at the wrong time, and has nowhere to go but up. For these individuals, various treatment options make the disease much more manageable and most people can go on to live happy, healthy, and productive lifestyles. In the end, as with many health related issues in our modern world, cases of Refractory Gastroesophageal Reflux Disease are on the rise largely because of our increase sedentary lifestyle and the diet that we consume. Reversing these factors, if we could, would like see a reduction in the reported cased heartburn and acid reflux, which is ultimately that goal. While medications can make the condition tolerable, little can be done to eliminate the disease altogether, save for minimising the mitigating factors discussed in this study related to Refractory Gastroesophageal Reflux Disease. Works Cited Aguirre, Ciriaco. “Refractory Gastroesophageal Reflux Disease”. The New England Journal of Medicine, 360.7 (2009): 729-730. Ali, Raja. “Refractory Gastroesophageal Reflux Disease in Pregnancy”. Best Practice and Research Clinical Gastroenterology, 21.5 (2007): 793-806. Armstrong, David. “Refractory Gastroesophageal Reflux Disease” Current Opinion in Pharmacology, 5.6 (2005): 589-595. Deeb, Alaa and Dib, Ghazal S. “Gastroesophageal Reflux in Children with Refractory Asthma” Oman Medical Journal, 25.3 (2010: 218-221. Evans, Jerry and Waring, Patrick. “The Effect of Bedtime Ranitidine on the Symptoms of Nocturnal Acid Breakthrough in Patients with Refractory Gastroesophageal Reflux Disease”. American Journal of Gastroenterology, 95.9 (2000): 2418. Fass, Ronnie. “Therapeutic Options for Refractory Gastroesophageal Reflux Disease” Journal of Gastroenterology and Hepatology, 27 (2012): 3-7. Fayed, Scheir. “Prevalence of Celiac Disease.” Journal of Tropical Pediatrics, 54.1 (2008): 43-53. Fletcher, J. “Refractory Gastroesophageal Reflux Disease”. Annals of Internal Medicine,138.1 (2013): 45. Foroutan, Mojgan. “Eosinophilic Esophagitis in Patients with Refractory Gastroesophageal Reflux Disease”. Digestive Disease and Sciences, 55.1 (2010): 28-31. Fujiwar, Yasuhiro and Arakawa, Tetsuo. “Refractory Gastroesophageal Reflux Disease and Sleep Disturbances”. Journal of Gastrenterology, 47.7 (2012): 760-769. Furuta, Takahisa. “Individualized Therapy for Refractory Gastroesophageal Reflux Disease”. Molecular Diagnosis and Therapy, 16.4 (2012): 223. Garcia-Compean, Diego. “Prevalence of Eosinophilic Esophagitis in Patients with Refractory Gastroesophageal Reflux Disease Symptoms: A Prospective Study”. Digestive and Liver Disease, 43.3 (2011): 204-208. Gutschow, Christian and Holscher, Arnulf. “Surgical Treatments of Refractory Gastroesophageal Reflux Disease.” Langenbeck’s Archives of Surgery, 398.5 (2013): 661-667. Hershcovici, Tiberiu and Wendel, Christopher. “Symptom Indexes in Refractory Gastroesophageal Reflux Disease: Overrated or Misunderstood?” Clinical Gastroenterology and Hepatology, 9.10 (2011): 816-817. Hunter, J. “A Physiologic Approach to Laparoscopic Fundoplication for Refractory Gastroesophageal Reflux Disease.” Annals of Surgery, 223.6 (2006): 673-687. Kahrilas, Peter. “Refractory Gastroesophageal Reflux Disease”. The Journal of the American Medical Association, 276.12 (2006): 983-988. Kahrilias, P. and Lee, T. “Pathophysiology of Gastroesophageal Reflux Disease. Torac Surgey Clinic, 15 (2005); 323-333. Katle, Elin-Johanne and Hatlebakk, Jan. “Gastroesophageal Reflux and Rhinosinusitis” Current Allergy and Asthma Reports, 13.2 (2013): 218-223. Krishnan, Kumar and Pandolfino, John. “Endoscopic Therapies for Refractory Gastroesophageal Reflux Disease” Techniques in Gastrointestinal Endoscopy, 16.1 (2014): 45. Kunsch, S. and Neesse, A. “Prospective Evaluation of Duodenogastroesophageal reflux in Refractory Gastroesophageal Reflux Disease Patients Refractory to Proton Pump Inhibitor Therapy”. Digestion, 86.4 (2012): 315. Lacy, Brian. “The Diagnosis of Refractory Gastroesophageal Reflux Disease”. The American Journal of Medicine, 123.7 (2010): 583-592. Mattar, S. “Treatment of Refractory Gastroesophageal Reflux Disease with Radiofrequency Energy in Patients after Roux-en-Y Gastric Bypass”. Surgical Endoscopy, 20.6 (2006): 850-854. Migliori, Stephen. “The Surgical Management of Refractory Gastroesophageal Reflux Disease” Medicine and Heath, Rhode Island, 87.2 (2004): 33. Miholic, Johannes and Sporn, Emanuel. “Esophageal Sphincter Device for Refractory Gastroesophageal Reflux Disease”. The New England Journal of Medicine, 368.21 (2013): 2038. Modin, Irvin. “Refractory Gastroesophageal Reflux Disease: Then and Now” Journal of Clinical Gastrenterology, 38.5 (2004): 390-402. Moraes-Filho, Joaquim. “Refractory Gastroesophageal Reflux Disease”. Arquivos de Gastroenterologia, 49.4 (2012): 296. Ranjitkar, Sarbin. “Oral Manifestations of Gastroesophageal Reflux Disease” Journal of Gastroenterology and Heptaology, 27.1 (2012): 21-27. Ray, Sherry. “Managing Refractory Gastroesophageal Reflux Disease”. The Nurse Practitioner, 27.5 (2002): 36-53. Richter, J. “The Patient with Refractory Gastroesophageal Reflux Disease”. Diseases of the Esophagus: Official Journal of the International Society for Diseases of the Esophagus, 19.6(2006); 443-447. Richter, J. “Gastrooesophageal Reflux Disease”. Best Practices, 21 (2007): 609-631. Slaughter, James. “Caution About Overinterpretation of Symptom Indexes in Reflux Monitoring for Refractory Gastroesophageal Reflux Disease” Clinical Gastroenterology and Hepatology, 9.10 (2011): 868-874. Souza, R., Huo, X., and Mittal, V. “Gastroesophageal Reflux Might Cause Esophogitis Through a Cytokine-Mediated Mechanism Rather Than Caustic Acid Injury”. Gastroenterology, 137.1 (2009): 1776-1784. Sugimoto, Mitsushige and Nishino, Masafumi. “Characteristics of Non-Erosive Gastroesophageal Reflux Disease Refractory to Proton Pump Inhibitor Therapy”. World Journal of Gastroenterology, 17.14 (2011): 1858-1865. Szarka, L. and DeValu, K. “Diagnosing Refractory Gastroesophageal Reflux Disease”. Mayo Clinic Proceedings, 76.1 (2011): 97-101. Tintiller, Michel. “Esophageal Abscess Complicating Endoscopic Treatment of Refractory Gastroesophageal Reflux Disease by Enteryx Injuection: A First Case Report”. The American Journal of Gastroenterology, 99.9 (2004): 1856-1858. Tobey, N. A., and Hosseini, S. “The Role of Pepsin in Acid Injury to Esophageal Epithelium.” American Journal of Gastroenterol, 96 (2001): 3062-3070. Wall, Geoffrey and Jacoby, Henry. “Refractory Gastroesophageal Reflux Disease” American Journal of Pharmaceutical Education, 66.2 (2012): 148. Weijenborg, Pim and Bredenoord, Albert. “How Reflux Causes Symtpoms: Reflux Perception in Refractory Gastroesophageal Reflux Disease”. Best Practice and Research, 27.3 (2013): 353. Yamaguchi, T. and Yoshida, N. “Cytokine-Induced Neutrophil Accumulation in the Pathogenesis of Acute Reflux Esophagitis in Rats” International Journal of Medicine, 16 (2005): 71-77. Zamir, Doron. “Gastroesophageal Reflux”. European Journal of Internal Medicine, 16.6 (2005): 391-401. Read More