Gastroesophageal reflux and dental erosion in United Kingdom medical literature

Dental Erosion

In this literature review, we will examine the scholarly medical literature referencing studies from the United Kingdom regarding Gastroesophageal reflux and dental erosion, Barrett's oesophagus (BO). Oesophagitis and oesophageal adenocarinoma after defining each malady, its history, prevalence, diagnosis and the treatment for each of the diseases. It is the aim of the author in this literature review to compare and contrast the authors in the way that they diagnose and manage each disease in the United Kingdom.

Some interesting continuities in terms of diagnostic tools that we will examine in the diagnosis and treatment of the above disorders include questionaires, the use of the UK's CPRD and followup longitudinal studies. In this way, the data points can be connected to systematically diagnose, treat and hopefully cure acid reflux related health issues to increase the quality of life for patients. This is especially critical in cases such as when BO can bring about the onset of cancer.

Analysis Breakdown by Disease Type

Gastroesophageal Reflux and Dental Erosion

Gastroesophageal reflux disease is a condition in which contents of the stomach contents (liquid and/or food) can leak backwards from the stomach into the esophagus. This type of action can irritate the esophagus, causing heartburn and other symptoms in the process. GORD can cause a great amount of dental erosion in a person's mouth, hence the natural linkage of the two maladies. Gastroesophageal reflux is the result of both endogenous (intrinsic) acid and exogenous (extrinsic) sources of the acids that are responsible for the increasing incidence and also high prevalence of tooth erosion and the associated sensitivity in teeth observed in children and adults in many countries, including the U.K. Not only can tooth erosion from endogenous acid be much more severe than that from exogenous acids, but additionally, gastric reflux, regurgitation and microaspiration can also have significant adverse effects upon the mucosa of the oropharynx, esophagus and the respiratory system (Zero and Lussi 2000 124-125).

Although first reported in 1971, it is only since the early 1990s that there has been a considerable amount of attention placed upon the connection of GORD and dental erosion. The most common symptoms include heartburn and acid regurgitation along with dysphagia. The treating physician will need a detailed historical knowledge of the patient's condition for an accurate diagnosis. Useful investigations can include an ambulatory Esophageal pH Monitoring, esophageal manometry, barium swallow X-rays, and Esophagogastroduodenoscopy (EGD) (ibid.).

In a study in the British Medical Journal, the authors seek to determine the relative risks as well as the benefits and risks of laparoscopic fundoplication surgery as an alternative therapy to long-term drug treatment for chronic GORD. The study was designed as a multicentre and pragmatic randomised trial along with parallel preference groups in 21 UK hospitals. The main outcomes measured were the disease specific REFLUX quality of life score as a primary outcome, the SF-36, the EQ-5D and the medication used as measured at time points that were equivalent to three to 12 months after surgery. This included surgical complications. Main results and difference between the BMJ and other studies is that the randomised participants had received drugs for GORD for a median of 32 months before entry into the trial (Grant et al. 2009 1-5).

The baseline REFLUX scores were 63.6 (SD 24.1) and 66.8 (SD 24.5) for the surgical and medical randomised groups, respectively. Of those that were randomised to surgery, 111 or 62% had total or partial fundoplication. Surgical complications were not common and there was a conversion rate of 0.6% with no mortality. By the twelfth month, 38% (59/154) were randomised to surgery (14% (14/104) among the patients who had fundoplication) were taking their reflux medication as opposed to 90% (147/164) that were under randomised medical management. The REFLUX score therefore favoured the randomised surgical group (with a 14.0, 95% confidence interval 9.6 to 18.4; P

In terms of conclusions, the authors found tha Laparoscopic fundoplication increased the patients' health status by at the least twelve months after surgery. The narrowing of the differences in the health status between three and twelve months can reflect a postoperative placebo effect or may also indicate a decreasing effectiveness of surgery over time. For this reason, the authors mandated an annual follow-up that used similar questionnaires that planned to report the long-term effectiveness after five years of follow-up to treatment (ibid. 8).

But what of dental erosion as a diagnostic tool in the evaluation of GORD or in relation to GORD? In an article on dental erosion that touches on GORD, authors Monika Gupta, IK Pandit, Nikhil Srivastava and Neeraj Gugnani explores the diagnostic protocols with regard to GORD and dental erosion along with the preventive and different restorative options that available to treat this multiple symptom type of malady. In the study, the authors documented a definitive link between anti

asthmatic medications, GORD, and asthma (Gupta, Pandit, Srivastava, and Gugnani 2009 57) . The problem of GORD and dental erosion has especially been reported and documented in children.

The severity of the erosion in children has been documented to be less than in adults. However, this can be attributed to conscious efforts by their parents to restrict the intake of acidic beverages of the children. The study documents a high incidence of GORD as reported in children with cerebral palsy. This is a set of factors that puts these children at a greater risk for erosion (ibid., 58). Treatment by a doctor should precede that of dental treatment (ibid., 60).

Since the treatment of GORD begins with the physician, it would be well to turn to studies more in this direction. In an article in the journal CHEST, the study populations were drawn from the GPRD, This database comprises a coverage of about 3 million UK residents that are registered with a general practitioner (GP) (Garcia Rodriguez, Ruigomez, Martin-Merino, Johansson, and Wallander, 2008-1224).

In this sample population, the authors found that symptoms of GORD were more common in patients with COPD than in the control subjects. The principal aim of the study was to investigate the dichotomy between the diagnoses of COPD and also gastroesophageal reflux disease (GORD) in the arena of primary care. As in the GORD study above, the authors used the UK General Practice Research Database to identify a cohort of patients with a first diagnosis of GORD (n

and a separate cohort of patients that have a first diagnosis of COPD (n

Regarding the results, there was a the 5-year follow-up during in which the RR of an incident COPD diagnosis in patients with a diagnosis of GORD was 1.17 (95% confidence interval ?, 0.91 to 1.49). This was while the RR of an incident GORD diagnosis among the patients with the diagnosis of COPD was in the amount of 1.46 (95% CI, 1.19 to 1.78). A COPD diagnosis was usually associated with current or former cigarette usage, a prior diagnosis of asthma, or the prescription of asthma medication. GORD diagnoses were associated with prior diagnoses of ischemic heart disease (ibid. 1226). In conclusion, the patients with a diagnosis of COPD are at a much more significant risk of a GORD as compared with the individuals that had no COPD diagnosis (ibid., 1230.

While it is true that GORD therapy was unlikely to slow the development of COPD, it might reduce the overall symptom burdens of patients with GORD and COPD. In this way, there will be an improving overall health-related quality of life for the patients. The authors found that the primary care physicians should be cognizant that COPD patients may also be battling the symptoms of GORD. What was different from the other studies this author has reviewed was the use of validated question to diagnose the onset of GORD in order to assess the impact the disease has on the patient's quality of life and that the medical patients issues are managed appropriately (ibid. ).

As in a previous article, the general physician (GP) is the lightning rod for the diagnosis of GORD. While they do not have the more focused experiences of specialty physicians. In this way, the questionaire regarding GORD would be a good diagnostic tool in the GP's office in order to diagnose GORD at the outset. It also might be a good tool in the dental office and in other providers as well to catch the malady at multiple points along the way. Logically, if GORD is not caught any one point along the line of treatment, certainly one provider, nurse or caregiver will pick it up somewhere along the way.

As seen previously, children are especially at risk for GORD. Hashem B. El -- Serag in the journal Clinical Gastroenterology and Hepatology writes about what he sees as the general perception that the incidence of gastroesophageal reflux disease (GORD) is on the rise. However, few studies have tackled the issue head on. By methodologically using a systematic approach, the study aimed assessing whether or not incidence of GORD is has changed with the passage of time (El -- Serag 2007 17).

First of all, population-based studies were subjected to a time-trend analysis with a Poisson regression model that diagnosed the incidence of at least weekly heartburn and/or acid regurgitation.

Secondly, the population-based studies reported the prevalence of the GORD symptoms at two time points in the same source population also were reviewed. Thirdly, the longitudinal studies that charted the incidence of GORD symptoms and also oesophagitis in primary and secondary care venues were examined. The Poisson model revealed a significant (P < .0001) trend for the increase in the incidence of reflux symptoms in the general population with time. An increase in the incidence of GORD or oesophagitis was to be found in the majority of longitudinal studies. There was evidence that the incidence of GORD had increased during the previous two decades. If this trend continues unabated, it could contribute to the rapidly increasing incidence of the more serious complications that are associated with GORD, such as esophageal adenocarcinoma, as well as the costs to healthcare systems and their employers (ibid. 17-18).

To review, diagnostic tools observed in the previous articles were GORD questionnaires, GPRD and five-year follow-up studies. Certainly, tracking over the lifetime of the disease is critical to the treatment of it.

Barrett's Oesophagus

GORD can also lead to Barrett's oesophagus (BO). This malady is a type of intestinal metaplasia, This is in turn a precursor condition for the problem of carcinoma. The risk of a progression from BO to dysplasia is uncertain but can be estimated in approximately 20% of cases. Due to the risk of a chronic heartburn progression to BO and esophagogastroduodenoscopy (EGD) every five years is the recommended treatment for patients with chronic heartburn or who man take drugs for chronic GORD. BO continues to be increasingly recognized by the medical establishment and is also believed to be a major risk factor for the development of cancers. The incidence of adenocarcinoma of the esophagus continues to rise meteorically. The rate of rise is quite alarming and is widespread in the U.K. (Wang Sampliner 2008 788).

The authors of the study claim that there are a few prospective follow-up BO cohorts that assess the risk of extraoesophageal cancer incidence or mortality. Certainly, some additional studies are necessary so that it is possible to understand the overall risks of cancer and death that is experienced by the patients who had contracted BE. In Cook et al., a cohort of 502 patients diagnosed with BO were identified at the Leeds General Infirmary, England. The mortality and cancer incidence information were both provided by the Office for National Statistics. The standardized mortality ratios (SMR) and the standardized incidence ratios (SIR) were calculated by using indirect standardization. Thus, all cause mortality was elevated in patients with BE [SMR, 1.21; 95% confidence interval (95% CI), 1.06, 1.37] and they remained this way after the esophageal cancers were excluded (SMR, 1.16; 95% CI, 1.01-1.32). Also, increased mortality risks were found for malignancies of the esophagus (SMR, 7.26; 95% CI, 3.87-12.42) and also the diseases of the digestive system (SMR, 2.03; 95% CI, 1.11-3.40) (Cook et al. 2007-2091-2092).

The remaining disease categories produced no altered risk estimates and in the case of circulatory disease the mortality rate was statistically significant (SMR, 1.24; 95% CI, 1.00-1.52; P = 0.053) for those with a specialized intestinal metaplasia diagnosis of BO. In the cancer incidence analyses, esophageal malignancies (SIR, 8.66; 95% CI, 4.73-14.53) and also esophageal adenocarcinomas (SIR, 14.29; 95% CI, 7.13-22.56) were found increased in the case of BO. All of the remaining analyses provided risks to include colorectal cancer. The author's study showed evidence of the increased risk of esophageal cancer and mortality in BO. It has also been shown in the study that those who have a histological BO diagnosis that may also have an increased risk of mortality due to circulatory disease (ibid. 2092-2095).

In another cancer related article in the journal Alimentary Pharmacology Therapy, the development of BE into carcinoma is further investigated. The authors in that article point out that patients with BE are at and increased risk of oesophageal adenocarcinoma. Their observational studies suggested an increase in over-all mortality, however, the data was conflicting in their general review of data, so this influenced the methodology of their research study. In other words, the study aimed to measure off the incidence of death as a cause of BE against the rate for the general They studied patients diagnosed with BE were identified in four hospitals in Leicestershire, UK that are using electronic endoscopy and histopathology records. The data on the deaths from of the patients were identified through the U.K.'s Office of National Statistics. They were then compared with the age and gender adjusted mortality rate in the Leicestershire, U.K. region (Moayyedi et al. 2008 317).

Some 1737 patients with BE were identified, but medical notes could only be retrieved in

1272 or 73.2% of the patients. These BE patients were identified in 245 deaths in the group . Overall mortality was found to have increased [male standardized mortality ratio (SMR) = 552 and also 95% CI = 466 -- 638; female SMR 455, 95% CI = 357 -- 552]. The main disease areas was responsible for this were oesophageal adenocarcinoma (n = 25, male SMR = 2171, 95% CI = 991 -- 3351; female SMR = 1300, 95% CI = 26 -- 2574), bronchopneumonia (n = 70, male SMR = 146, 95% CI = 55 -- 236; female

SMR = 436, 95% CI = 272 -- 601) and ischaemic heart disease (n = 51, male SMR = 186, 95% CI = 97 -- 2748; female SMR = 205, 95% CI = 105 -- 306). To sum up, patients with BE die more commonly of bronchopneumonia and ischaemic heart disease when compared with oesophageal adeno-

carcinoma. The overall mortality rate in this cohort may have increased (ibid., 317-318).

In terms of strengths, the study's diagnosis of BO was well defined. The cause of death was confirmed from official death certificates viewed against with a patient notes. Community controls were derived as well from the same population group as the BO cases. The weaknesses of the study were that the numbers of BE cases and the length of follow-up were relatively modest. Unfortunately the authors could only evaluate the common causes of mortality and overall mortality. Data were not in existence in some 25% of cases and the study was confined to a single region. The results therefore were not found to be generalizable to the other populations. BO patients were then methodically compared with the expected rates from the general population. The authors therefore did not have the information on potential confounding factors . These factors could not be adjusted for in the analysis (ibid. 319).

In order to overcome the weaknesses in the study methodology, it might be prudent in future research to conduct more detailed research if a questionnaire regarding BO and carcinoma could be distributed to coroners by the Office of National Statistics or if the Office could be persuaded to change the structure of the death certificate paperwork to ask BE and carcinoma related questions. Certainly, it should be a significant enough health issue to justify more attention fro the Office of National Statistics to test specifically for data that would provide more definitive conclusions about BO and carcinoma.

Using this same line of logic, one can only speculate and hope that the future research regarding GORD could be tracked at birth. Certainly, if maternity room personnel could be better educated to detect and record GORD, such data could be useful not just for later statistical analysis (such as our journal articles), but also as a tool for detection and management of the disease in a person's life. The potential improvement in patient quality of life is certainly worth it. We can logically see birth and death as historical life events that serve as access points in the battle to understand and fight acid reflux related disorders. In this way, researchers in future studies of various maladies related to acid reflux can combine and enjoy the best of both worlds of the accuracy of longitudinal information culled from patient notes. In this way, the study and mitigation efforts will truly encompass the problems from cradle to grave.

As mentioned above in our definition of BE, the metaplastic change of the lining of the esophagus is critical to the development of the malady. This metaplastic nature of the esophageal tissue appears at least externally to be a complication of chronic GORD. Unfortunately for the researchers (and the patients), asymptomatic individuals might also be affected. It is also a risk factor for the development of esophageal adenocarcinoma, a subject we have visited above. BO is associated with the symptoms of chronic (GORD), such as heartburn and regurgitation . This important association has led to frequent calls for routine upper gastrointestinal endoscopies for all patients with chronic GORD to detect BO and therefore prompt subsequent endoscopies in order to assess any cancerous progressions. Though this is appealing, research issues exist with regard to the quality of screening and surveillance endoscopy works. The associated financial costs have generally onerous and therefore this type of research has largely stalled (Shaheen Richter 2009 850).

A number of other factors may explain the above association between BO and GORD. One issue is that whether BO is a hereditary condition is unknown. Many reports further suggest that a higher percentage of first-degree relatives of patients with BO have the malady than could be expected by chance. However, no gene has been identified and this data is probably subject to detection bias. Also, the relationship of obesity to BO is not understood. One probable explanation is that the patients who have central obesity are predisposed to hiatal hernia. Also, intragastric pressure increases markedly with obesity and promotes reflux. Perhaps there is a probable hormonal explanation for the association. Also, studies have suggested a synergy between acid and bile in the development of BO, although bile with no acid present does not seem to contribute to the contraction of BO. Unfortunately, the present detection procedures are not optimal or cost worthy. The study looks to the future for better endoscopic imaging technology to provide the medical community better able to gauge the probable linkage between BO and carcinoma (ibid. 858).

While we will look more specifically at the subject of oesophageal adenocarinoma. However, as mentioned above, a number of studies are demonstrating a relationship with cancers. In a journal article in the American Journal of Gastroenterology, a U.K. Study by the University of Birmingham Department of Histopathology and the Cancer Research UK and University Hospitals of Leicester with reference to metaplasia (IM) and dysplasia in BO that are recognized as surrogates for an esophageal adenocarcinoma risk (Harrison et al.. 2007-1154).

In the study, there were two-hundred ninety-six endoscopies in the study that were performed over a 4-year period in the BO segments which were of a mean length 4 cm (range of 1 -- 11 cm). The resulting biopsies were analyzed. The biopsies were all processed with the routine hematoxylin and eosin (H&E) staining. Using the H&E staining method, the study found that the optimum number of biopsies to diagnose intestinal metaplasia was 8 per endoscopy. This translated into a mean of 67.9% endoscopies that had intestinal metaplasia. The data suggests that at least 8 random biopsies is the minimum to be taken and analyzed with a conventional H&E staining in order to diagnose benign intestinal metaplasia. The taking of more biopsies did not leadstatistically increase the diagnosis of intestinal metaplasia except when greater than sixteen were taken when 100% yield was obtained (ibid. 1155-1161).

Oesophageal Adenocarinoma

Oesophageal Adenocarinoma cancer forms in tissues lining the of the oesophagus. There are two types of esophageal cancer, squamous cell carcinoma constituting 90% of all oesophageal cancers (a cancer that begins in the flat cells lining the esophagus) and adenocarcinoma (a cancer that begins in the cells that make and release mucus and other fluids (Giuli 2003 521).

In a study published in the Journal of Clinical Patholology, ghrelin is investigated. Anorexia and weight loss can occur early in the course of an oesophagogastric malignancy. In gastric cancer, dyspepsia is the only apparent symptom and this occurs more often than anorexia and weight loss. Oesophageal adenocarcinoma sometimes extends distally to involve the upper stomach symptoms such as anorexia and weight loss which are only exceeded in frequency by dysphagia. This can involve the presence of ghrelin, which is an orexigenic gut peptide produced mainly by the stomach. In the study, it is shown that the gastric mucosal ghrelin production may be compromised by the infiltration of an oesophageal adenocarcinoma. In order to more fully assess the expression of ghrelin mRNA and peptides in oesophagogastric adenocarcinomas and also adjacent non-neoplastic mucosa, the presence of ghrelin-positive cells was assessed in the study with regard to cancer and the corresponding non-neoplastic mucosa by immunohistochemistry (Mottersheadm et al. 2007 405 -- 409 ).

A quantitative reverse transcriptase polymerase chain reaction (PCR) for ghrelin mRNA was also done on 24 gastric, 8 sophageal adenocarcinoma specimens, as well as non-neoplastic mucosa. The immunohistochemistry and reverse transcriptase PCR confirm the negligible expression of ghrelin in adenocarcinoma specimens. As opposed to this, the non-neoplastic gastric mucosa was rich in ghrelin-positive cells and also in ghrelin mRNA. The number of ghrelin-positive cells per each 2 mm section of non-neoplastic mucosa was 73 (45 -- 215) in the corpus. This was significantly higher than in the cardia mucosa (9 (0 -- 64), p,0.001) and antral mucosa (5 (0 -- 14), p,0.001). The gastric system and the oesophageal adenocarcinomas have no ghrelin-producing cells. The highest level of ghrelin presence was noted in the non-neoplastic mucosa of the gastric corpus. The disruption of the gastric ghrelin-producing mechanism may also occur during oesophagogastric malignancy (ibid., 406 -- 408).

The study confirms that the gastric corpus has the highest concentration of ghrelin-producing cells in the human body. Cancers that arising in the gastric mucosa are therefore much more likely to cause early disruption of the ghrelin-producing mechanism and could also lead to patients with anorexia nervosa and weight loss before the symptoms owing to luminal obstruction. Similarly, surgical procedures that are affecting this part of the stomach are likely to impair ghrelin production and function. By contrast to this, the absence of a significant ghrelin production in the oesophagus points to the fact that cancers restricted to this region are less likely to affect the overall ghrelin production. In practice, the cancers that arise in the distal oesophagus initially are present with dysphagia owing to the dysmotility and luminal obstruction with anorexia nervosa being a late event. Future studies need to be directed more at the determination of the role of circulating ghrelin and the function of local mechanisms in the anorexia nervosa of foregut cancer. This would promote the understanding of whether compensatory ghrelin production from thenon-gastric sources has any role. The possibility use of synthetic ghrelin agonists for management of cancer cachexia is an intriguing treatment concept that has potential and which should be examined when they become available (ibid. 408-409).

In cancer, it is the Transforming Growth Factor b (TGFb) that increases in the proliferation and promotes invasion via a selective loss of signaling pathways. The malady of oesophageal adenocarcinoma arises from Barrett's oesophagus, and usually progresses rapidly and fatally. The contribution of the TGFb signalling in the promotion of metastasis in this disease has not been fully elucidated. Therefore this UK study investigated the role of TGFb in Barrett's associated oesophageal adenocarcinoma using a row of cell lines (OE33, TE7, SEG, BIC, FLO). 4/5 adenocarcinoma cell lines failed tin the attempt to halt cell cycle arrest, to down-regulate c-Myc or to induce p21 in response to TGFb, as well as to modulate a Smad3/4 specific promoter. These hyperproliferative adenocarcinoma cell lines also displayed a TGFb induced increase in an expression of the extracellular matrix degrading proteinases, the urokinase-type plasminogen activator (uPA) and the plasminogen activator inhibitor 1 (PAI-1). This was correlated with an invasive cell phenotype that was measured by in vitro migration, cell scattering assays and invasion. The inhibition of ERK and JNK pathways have significantly reduced PAI and uPA induction and also inhibited the invasive cell phenotypes. These results further suggest that TGFb Smad-dependent signalling is also perturbed in Barrett's carcinogenesis. This results in a failure of growth-arrest. Rather, TGFb can also promote PAI and uPA expression and invasion through the MAPK pathways. This data would support a theoretical dual role for TGFb in the malady of oesophageal adenocarcinoma (Onwuegbusi, Rees, Lao-Sirieix, Fitzgerald 2007 1-10).

In a study published by Ian L.P. Beales of the Department of Gastroenterology

at Norfolk University Hospital and Olorunseun O. Ogunwobi of the Biomedical Research Centre at the University of East Anglia, in Norwich, oesophageal adenocarcinoma (OAC) is an increasing problem . Although the incidence of squamous cancer of the oesophagus is relatively static, the age-standardised incidence of OAC has increased significantly over the last 30 years in the UK. The reasons for this significant increase as well as the molecular pathology of OAC are not fully understood. However, because of the generally poor prognosis for this cancer, an improved understanding of the causes of oesophageal adenocarcinoma arises in most, if not all cases, from metaplastic columnar oesophageal epithelium (Barrett's oesophagus (BO) Also, the other factors which drive this transformation remain to be elaborated upon. The increased proliferation and the reduced apoptosis of the Barrett's epithelium are believed to be important in the progression of to OAC (Beales and Ogunwobi 2007 4).

The increase in cell division and the reduced cell death probably allow the accumulation and the perpetuation of genetic abnormalities that lead to malignant transformation. The increased proliferation in BO is also associated with an increased risk of the progression to OAC. Because of this factor, it is critical to determine the factors that drive proliferation and inhibit the apoptosis in OAC and BO that are essential to target preventative and treatment strategies. The two main remaining epidemiological risk factors for OAC are obesity and symptomatic gastro-oesophageal reflux. These factors appear to remain independent of each other (ibid. 5).

Experimental studies have shown that the transient exposure of Barrett's oesophageal cells and the oesophageal adenocarcinoma cells to acid in turn stimulates proliferation. It also inhibits apoptosis. The mechanisms behind this are as unclear. However, the growth in the promotion and inhibition of apoptosis by acid have been described using transformed and non-transformed cell lines and biopsy explants. Activation of cellular signalling events including the mitogen activated protein (MAP) kinase cascades, activation of protein kinase C, the Na+/H+ exchanger and upregulation of cyclo-oxygenase-2 (COX-2) and prostaglandin (PG) production have all been implicated in the biological responses to acid, although as yet there is no consensus about how these pathways integrate together to regulate the responses to acid. The mechanisms linking obesity to OAC progression are likely to be multi-factorial but we have hypothesized that increased serum leptin levels may provide a direct link. Leptin is a peptide hormone secreted by adipocytes and serum levels are proportional to body fat mass. Effects of leptin as a regulator of appetite and body weight are well described but we have recently reported that leptin, at the concentrations seen in obese patients, is a potent growth factor for Barrett's oesophageal adenocarcinoma cells .

Using the OE33 cell line we showed that leptin stimulated increased COX-2 mRNA expression and bioactivity via activation the extracellular signal related kinase (ERK), p38 MAP kinase and Akt pathways. Subsequently COX-2 derived PGE2 stimulated cell growth via EP-4 receptor- mediated transactivation of the epidermal growth factor receptor (EGFR) with downstream activation of c-jun-NH2-terminal kinase (JNK) Because both acid exposure and leptin individually adversely affect Barrett's epithelial cells in a manner than would be expected to further promote oesophageal carcinogenesis, we have hypothesized that leptin and acid exposure may interact directly at the cellular level in OAC to promote growth and/or inhibit apoptosis. The study examined the mechanism of these interactions using the OE33 Barrett's oesophageal adenocarcinoma cell line. This has been used previously as an effective model for studying signalling events in Barrett's OAC and in most cases seems a reasonable model for extrapolating to non-transformed BO. In particular we have examined the interaction at the level of early signalling events stimulated by leptin and acid which have been shown to be upregulated in BO and activated by acid, COX-2 and prostaglandin production, which have been reported to be important factors in the progression of OAC and the epidermal growth factor receptor, which has also been implicated in BO and OAC (ibid .6).

In a journal article in Clinical Gastroenterology and Hepatology, the rate of progression in BE to EAC or HGD and EAC combined was found to be low (0.6% and 1.0% annually, respectively) and the rate of mortality due to EAC is even lower (0.3% annually).The study's findings question the assumed effectiveness of the generalized BE surveillance programs. They also mphasize the need for more large studies from other unselected populations that develop a valid risk stratification. Although the risk of EAC is clearly elevated in the BE patients as compared to the general population, the vast majority will not develop EAC. It has also been suggested that very few will die from it. An overall pooled estimate of the fatal EAC in the review was 3.0 per 1,000 persons. This corresponded to an annual risk of 0.3%. Since there was no evidence for heterogeneity, this is a reliable estimate of mortality rate due to EAC for the patients with BE which is under surveillance. When examining the cause-specific mortality in BE patients, it was found that only 7% of the total patients died from EAC and that 93% died due to other causes. Cardiovascular disease only accounted for 34% of the total of patients who died. This was followed by 20% that was due to pulmonary disease and also 16% due to other malignancies. The results emphasize that the EAC mortality in patients with BE under surveillance is relatively low (Sikkema, de Jonge, Steyerberg, and Kuipers 2010 238-239).

In a study that was released in the British Medical Journal, the incidence of oesophageal cancer was found to have increased in people that had one or more previous prescriptions for oral bisphosphonates as compared with those that had no such prescriptions. The risk of oesophageal cancer was significantly higher for 10 or more prescriptions than for one to nine prescriptions and for use for over 3 years. The risk of oesophageal cancer did not differ greatly by bisphosphonate type. The risk in those with 10 or more bisphosphonate prescriptions did not vary significantly by age, smoking status, sex, alcohol intake, or by body mass index. This was also the case in the diagnosis of osteoporosis, a fracture, or for upper gastrointestinal disease. Cancers of the colorectum and the stomach were not associated with a prescription of bisphosphonate:. The relative risks for one or more vis a vis no prescriptions were 0.87 (0.64 to 1.19) and 0.87 (0.77 to 1.00). The specificity of the causal association for oesophageal cancer really argues against a set of methodological problems in the selection of cases and controls or in the analysis . The risk of oesophageal cancer increased with 10 or more prescriptions for oral bisphosphonates and with the prescriptions being issued over a five-year period (Green et al. 2010 1-8).

Conclusion

To sum up, in this literature we have examined the scholarly medical literature that references studies from the United Kingdom regarding Gastroesophageal reflux and dental erosion, Barrett's oesophagus. Oesophagitis and oesophageal adenocarinoma. After briefly defining the malady and examining its history, we examined the prevalence, diagnosis and treatment for each of the diseases. It was the aim of the author in this literature review to compare and contrast the authors in the ways in which they diagnosed and managed each disease in the U.K.

Some interesting continuities in terms of diagnostic tools that saw in the diagnosis and the treatment of the above disorders to include questionaires, the use of the UK's CPRD and followup longitudinal studies. In this way, the data points can be connected to systematically diagnose, treat and hopefully cure acid reflux related health issues to increase the quality of life for patients. This is especially critical in cases such as when BE can bring about the onset of cancer.