Clinical Epidemiology and Natural History of Gastroesophageal Reflux Disease

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Amnon Sonnenberg and Hashem B. El-Serag Department of Veterans Affairs Medical Center and The University of New Mexico, Albuquerque, New Mexico

In the MUSE classification ofgastroesophageal reflux disease (GERD), esophagitis is assessed by the presence ofmetaplasia, ulcer, stricture, or erosion, each being graded as absent, mild or severe. Daily reflux symptoms affect about 4 to 7 percent of the population; erosive esophagitis occurs in about 2 percent; the prevalence rate ofBarrett's metaplasia is 0.4 percent; and esophageal adenocarcinoma leads to two deaths per million living population. In persons with GERD symptoms, about 20 percent arefound to have erosive esophagitis, while ulcers or strictures arefound in less than 5 percent of all patients with erosive esophagitis. No clear-cut temporal progression exists between successive grades ofdisease severity, as the most severe grade of GERD is reached at the onset ofthe disease. Mildforms ofGERD tend to be more common in women than men, while severe GERD characterized by erosive esophagitis, esophageal ulcer, stricture or Barrett's metaplasia are far more common in men than women. All forms of GERD affect Caucasians more often than African Americans or Native Americans. The prevalence of GERD is high among developed countries in North America and Europe and relatively low in developing countries in Africa and Asia. During the past three decades, hospital discharges and mortality rates of gastric cancer, gastric ulcer and duodenal ulcer have declined, while those of esophageal adenocarcinoma and GERD have markedly risen. These opposing time trends suggest that corpus gastritis secondary to Helicobacter pylori infection protects against GERD. This hypothesis is consistent with the geographic and ethnic distributions of GERD. Case-control studies also indicate that cases with erosive esophagitis are less likely to harbor active or chronic corpus gastritis than controls without esophagitis.

INTRODUCTION history and focus attention on recent developments in these two areas. New data The general epidemiology of gastroe- are emerging to suggest that, besides pep- sophageal reflux disease (GERD)b was tic ulcer and gastric cancer, gastrointesti- presented in several previous articles [1- nal infection with Helicobacterpylori may 3]. Rather than provide another compre- also explain several characteristic features hensive review of GERD epidemiology, in of GERD epidemiology. We conclude by the present article we will discuss primar- listing the many remaining open questions ily its clinical epidemiology and natural of GERD.

a To whom all correspondence should be addressed: Amnon Sonnenberg, M.D., M.Sc., Department of Veterans Affairs Medical Center 1 1 1-F, 1501 San Pedro Drive SE, Albuquerque, NM 87108. Tel.: 505-265-171 1; Fax: 505-256-5751; E-mail: [email protected]. b Abbreviations: GERD, gastroesophageal reflux disease; NSAIDs, non-steroidal anti- inflammatory drugs. 81 82 Sonnenberg and El-Serag: GERD epidemiology

CLINICAL EPIDEMIOLOGY the submucosa. In a minority of patients, healing of erosions or ulcers results in Clinical presentation scarring and formation of a peptic stricture. The term gastroesophageal reflux dis- The Savary-Miller classification of ease (GERD) is used to describe the symp- GERD puts much emphasis on various toms and changes of the esophageal types of erosions, but lumps esophageal mucosa that result from reflux of stomach metaplasia, ulcers and strictures into one contents into the esophagus. GERD grade. Moreover, it does not account for patients present with symptoms of epigas- the frequent concurrence of Barrett's tric pain, heartburn, pharyngeal burning, epithelium with stricture or stricture with regurgitation of gastric contents, acidic erosions. The newer, more refined, MUSE taste and dysphagia. Such symptoms may classification grades esophagitis according be experienced daily, weekly or only few to presence of metaplasia, ulcer, stricture times per month. With respect to GERD, or erosion, each being assigned a value individual symptoms carry a sensitivity or ranging from 0 to 2, that is, absent, mild or specificity that, in general, do not exceed severe, respectively [5]. 65 percent or 80 percent, respectively [4]. Barrett's epithelium is considered a The frequency and severity of symptoms premalignant lesion, as the incidence rate from gastroesophageal reflux do not corre- of esophageal adenocarcinoma developing late with the amount of morphologic from Barrett's mucosa is 1 percent per changes of the mucosa seen on endoscop- year [6]. In the International Classification ic examination of the esophagus. of Diseases, esophageal adenocarcinoma Most commonly used grading sys- is listed as "cardiac cancer." The demo- tems of GERD are based on the Savary- graphic characteristics and time trends of Miller classification [5]. Subjects with esophageal adenocarcinoma (or cancer of reflux symptoms but no macroscopically the gastric cardia) are very similar to those visible lesions are said to have reflux dis- of GERD. They are strikingly different ease without esophagitis, sometimes from those of adenocarcinoma in the gas- referred to as "grade 0." Peptic esophagitis tric body and antrum or squamous carci- is graded according to the extent and noma of the esophagus. Despite these severity of macroscopically visible ero- obvious similarities and its origin from sions: single patchy, large confluent or cir- Barrett's metaplasia, however, esophageal cumferential erosions representing grade I, adenocarcinoma is not included in the II, or III, respectively. The terms "compli- classification of esophagitis. cated esophagitis" or "grade IV" relate to esophagitis accompanied by Barrett's Prevalence rates mucosa, ulcers or strictures. The syn- onyms "Barrett's esophagus," "epitheli- Daily reflux symptoms affect about 4 um" or "metaplasia" refer to the replace- to 7 percent of the population, while ment of esophageal squamous epithelium esophageal adenocarcinoma leads to 2.5 by a gastric type of columnar epithelium deaths per million living population [2-3]. with (or without) intestinal metaplasia that The prevalence rates of the other presenta- reaches 2 to 3 cm above the lower tions of reflux disease in the middle range esophageal sphincter. Barrett's epithelium between these two extremes are far less is more susceptible than the regular squa- well characterized. A recent study from mous epithelium of the esophagus to the China estimated a 5 percent prevalence development of deep ulcers that reach into rate of erosive esophagitis [7]. Of those Sonnenberg and El-Serag: GERD epidemiology 83 presenting with symptoms suggestive of salivary secretion interferes with normal GERD, 18.5 percent were found to have esophageal clearance and also results in an erosive esophagitis. A Swedish study increased risk for erosive esophagitis [15]. reported an incidence rate of 120 new Presently, there are no risk factors cases of erosive esophagitis per 100,000 known to disrupt tissue resistance, except per year [8]. Assuming a case history of 20 for non-steroidal anti-inflammatory drugs years yields a crude estimate 2.4 percent (NSAIDs). Several authors have suggested for the prevalence rate. Ulcers or strictures that more severe forms of peptic esophagi- were found in less than 5 percent of all tis, associated with large confluent ero- patients with erosive esophagitis. Lastly, a sions, strictures and Barrett's esophagus, post-mortem study from Olmsted County are more common in patients on chronic in Minnesota found a prevalence rate of consumption of NSAIDs [16-18]. In the 0.4 percent for Barrett's esophagus [9]. population of veterans, many of the dis- Since symptoms are a poor indicators eases commonly treated with NSAIDs, for disease severity, a study trying to such as osteoarthritis, back pain or tension assess the true prevalence of erosive headache, were associated with a small but esophagitis and its complications would nevertheless significant odds ratio of about need to subject a large group of persons to 1.4 for reflux esophagitis [16]. upper gastrointestinal endoscopy. For Frequent occurrence of nighttime obvious reasons, such a study is difficult reflux can irritate the pharyngeal and and expensive to conduct. Because symp- laryngeal structures and result in laryngitis tomatic patients are more likely to under- or even hoarseness and aphonia. go endoscopy, incidence and prevalence Aspiration of gastric contents has been rates based largely on routine endoscopy associated with asthma, pneumonia, and reports may overestimate the prevalence bronchiectasies [19-21]. In our epidemio- rate of erosive esophagitis in the general logical study of GERD among U.S. mili- population. The prevalence of GERD tary veterans, we found both erosive varies markedly between different popula- esophagitis and esophageal stricture to be tions [1, 10]. During the past three decades significantly associated with sinusitis, the prevalence of GERD has increased aphonia, pharyngitis, laryngeal stenosis, more than two-fold, and previously report- laryngitis, chronic bronchitis, asthma, ed data may no longer apply to present day chronic obstructive pulmonary disease, populations [3]. With all these caveats in pulmonary fibrosis, bronchiectasis, pul- mind, one should consider the data cited monary collapse and pneumonia [21]. above as crude estimates only. While the odds ratios for sinus, laryngeal and pharyngeal diseases ranged between Diseases associated with GERD 1.5 and 2.0, the odds ratios for the association between GERD and pulmonary dis- Esophageal clearance is markedly ease did not exceed 1.5. This may reflect, impaired in CRST syndrome and systemic in part, the a high overall prevalence of sclerosis because muscle atrophy results in respiratory disease in the population of dysfunction of the lower sphincter and veterans. aperistalsis of the tubular esophagus [11- Except for the striking example of 15]. Among the population of U.S. mili- Zollinger-Ellison syndrome, the associa- tary veterans, we found systemic sclerosis tion between the amount of acid output to be associated with a six-fold increased and the occurrence or severity of reflux risk for erosive esophagitis [ 16]. In disease has remained elusive [22-24]. Sjogren's syndrome, reduced or absent There appears to exist a weak correlation 84 Sonnenberg and El-Serag: GERD epidemiology between the amount of acid reflux and the NATURAL HISTORY occurrence of Barrett's esophagus, as well as, with its length above the lower Initially, it was thought that in the nat- esophageal sphincter [25-26]. Several ural history of the disease, mild forms of authors have also reported a coincidence GERD progressed to more severe forms. of duodenal ulcers and erosive esophagitis This concept led to the original Savary and in patients without Zollinger-Ellison syn- Miller classification of GERD by grades drome [27]. Both endoscopy and, to a less- of severity [1]. Physicians were advised to er extent, barium swallow are primary prevent the more severe grades of GERD modalities to diagnose reflux esophagitis, involving Barrett's mucosa or strictures by as well as peptic ulcer. This makes it diffi- early and vigorous treatment of mild cult to discern a true association from an forms, such as single erosions or even association brought forth by a detection reflux symptoms only. bias. On one hand, epidemiologic studies show that hiatus hernia is frequently found in patients with GERD and that all forms of GERD tend to cluster in the same patient population [1-3]. In our study of the population of veterans, on average, any

Esophagltis Esophageal stricture

8% 38% 51% 22h%

7% 28% 34% 13%

35% 18% 6% 49%

53% 0% 5% 34% /) Hiatus hemia Esophageal ulcer Figure 1. Co-morbid associations between four forms of GERD, each arrow representing one association. The percentage describes the fraction of patients with one form of GERD (where the arrow starts) who also suffer from a second form (to which the arrow points). The circular arrows represent patients who have one form of GERD as their sole presentation. Figure taken from [28]. Sonnenberg and El-Serag: GERD epidemiology 85

o25 co co).20- o~15- 0

0~~~~~~~ gradeO grade I grade II grade III grade IV Severity of esophagitis Figure 2. Relationship between disease severity and length of GERD history. Figure adapted from [1]. form of GERD was 10-times more likely On the other hand, the same study to occur in a patient with another form of failed to show a clear-cut temporal relation- GERD than without, the highest ratio (R = ship between various forms of GERD [28]. 22) found among esophageal ulcers and In few relationships, it appeared as if less stricture [28]. About one-third of all severe forms preceded the more severe patients with esophageal erosions, ulcers ones. For example, hiatus hernia tended to or strictures also had hiatus hernia, and 46 precede esophageal erosions or ulcers. percent of patients a hiatus hernia were Similarly, esophagitis was diagnosed diagnosed to have other forms of GERD. slightly more often before esophageal stric- While hiatus hernia or erosive esophagitis tures. However, appreciable numbers of represented the only diagnosis related to severe and mild forms of GERD presented GERD in half of the patients, strictures simultaneously or with the severe form rarely and esophageal ulcers never before the mild one. For example, in the occurred alone. This pattern leads one to comorbid occurrence of esophagitis, believe that in a fraction of GERD esophageal ulcer represented the initial patients' esophageal erosions may result in diagnosis in 39 percent, whereas esophagi- scarring or progress to deeper ulcerations tis represented the initial diagnosis in only (Figure 1). The clustering of different 22 percent. Overall, no consistent progres- forms of damage to the esophageal sion from mild to severe forms of GERD mucosa in identical patients clearly points could appreciated. One possibility to recon- at a close patho-physiologic relationship cile the seeming contradiction between the among them. The more frequent occur- lack of progression and the patterns of clus- rence of mild forms and the less frequent tering (described in the previous paragraph) occurrence of severe forms of GERD also is to assume that most progression between suggests that the present grading system different grades of severity occurs quite truly reflects consecutive stages of rapidly. Thus, it would appear that the most increasing pathophysiologic derangement. severe grade of GERD is reached at the very onset of the disease. After this initial 86 Sonnenberg and El-Serag: GERD epidemiology

rapid progression, little, if any, further This was in striking contrast with a com- development is noticed subsequently. In the parison group of 5,100 esophagitis individual patient, the presentation of patients who presented initially with GERD and its severity of mucosal damage esophageal ulcers or strictures. During fol- seem to remain stationary or fluctuate only low-up, about 80 percent of these patients between close grades of severity. This con- were diagnosed repeatedly with the same tention is corroborated by other studies that types of esophageal complication. failed to establish a relationship between the length of case history and disease severity (Figure 2) [1]. DEMOGRAPHIC, TEMPORAL AND In a subsequent study, we selected GEOGRAPHIC VARIATIONS OF 29,500 patients with erosive esophagitis, GERD but without ulcers or strictures from the population of veterans and followed them Mild forms of GERD tend to be over a four-year time period (range 1 to 12 slightly more common in women than years). Amazingly, not one of these men, while severe GERD characterized by patients was subsequently diagnosed to erosive esophagitis, esophageal ulcer or have developed such complications [29]. stricture are far more common in men than

100% 100% * control * control 80% esophagitis 80% esophagitis

60% / 60%8

40%- 40%-

20% 20%

0% 0%_ none mild severe none mild severe acute gastritis chronic gastritis

Figure 3. Prevalence rates of various grades of acute (left panel) or chronic gastritis (right panel) of the gastric body in 116 case subjects with and in 148 control subjects without erosive esophagitis. The differences in the prevalence rates of acute and chronic gastritis among case and control subjects were both statistically significant (df = 2, c2 = 6.52, p = 0.0013 and df = 2, c2 = 8.92, p = 0.001 1 for the left and right panel, respectively). Sonnenberg and El-Serag: GERD epidemiology 87

women [2]. All forms of GERD affect ization from esophageal adenocarcinoma Caucasians more often than African increased during the same time period. Americans or Native Americans. Similar The time trends of mortality from gastric patterns characterize the epidemiology of ulcer, duodenal ulcer, gastric cancer and GERD and esophageal adenocarcinoma esophageal adenocarcinoma provide an [30]. In the United States, such variations almost exact replica of the corresponding by gender and ethnicity are revealed simi- patterns in the hospitalization data. larly by different types of epidemiologic parameters, that is, prevalence data, physi- cian visits, hospitalizations and death ROLE OF H. PYLORI IN GERD rates. The prevalence of GERD is high among residents of developed countries in Because H. pylori plays an essential North America and Europe, but relatively role in the pathogenesis of gastric ulcer, low among those of developing countries duodenal ulcer and gastric cancer, the gen- in Africa and Asia [1, 10]. eral decline of its infection rate in Western Between 1970 and 1987, the rates of societies provides the most likely explana- hospitalizations in the National Hospital tion for the time trends of these three dis- Discharge Survey, secondary to erosive eases. The acquisition of H. pylori results esophagitis, rose two-fold in men and in the development of acute gastritis that, women alike [2]. A less striking increase if left untreated, gives way to chronic gas- also occurred with respect to esophageal troduodenitis [32]. Both types of peptic stricture. The rise in hospitalization for ulcer and gastric cancer are strongly corre- esophagitis was not matched by an equal lated with a gastroduodenal infection by rise in surgical procedures, as the rate of H. pylori [33-34]. Antral gastritis found surgical repair of hiatal hernia declined mostly in patients with duodenal ulcer, during the identical time period. The time leaves the ability to secrete acid unaffected trends from the National Hospital or even increases gastric acid output by Discharge Survey are corroborated by compromising somatostatin secretion of similar trends of hospitalizations among the D-cells and its inhibitory effect on gas- U.S. military veterans and U.S. mortality trin output. In contradistinction with antral rates taken from the Vital Statistics of the gastritis, gastritis that involves large areas United States [31]. of the gastric body (corpus) results in par- In the population of veterans, as in tial atrophy of the acid secreting mucosa many other populations, gastric and duo- and hypochlorhydria [35-36]. In general, denal ulcer showed a significant decline of patients with an endoscopically diagnosed their hospitalization rates between 1970 reflux esophagitis are less likely to harbor and 1995, the decline being more pro- active or chronic corpus gastritis than nounced in duodenal than gastric ulcer. patients without esophagitis [37-39]. The hospitalization rates for gastric and Figure 3 shows data from our own series duodenal ulcer were similar among whites of consecutive patients undergoing esoph- and nonwhites. In striking contrast with agogastroduodenoscopy for various upper the behavior of peptic ulcer, the hospital gastrointestinal symptoms [39]. The discharges involving GERD rose four- and patient population comprised of 116 case seven-fold among nonwhites and whites, subjects with and 148 control subjects respectively, during the same time period. without erosive esophagitis. The severity While hospitalization resulting from can- of acute or chronic gastritis in the gastric cer of the gastric corpus and antrum body, characterized by polymorphonuclear declined between 1968 and 1992, hospital- cells and lymphocytes, respectively, were 88 Sonnenberg and El-Serag: GERD Epidemiology

DUT antrum - acid 1 / GERD 1 H. pylori GU ? corpus - acid < GERDV Figure 4. Scheme of the interaction between H. pylori infection, acid secretion and disease outcome. both inversely related to the prevalence than whites [31]. In general, nonwhites in rate of erosive esophagitis. Overall, the United States tend to harbor higher patients with erosive esophagitis showed a rates of infection with H. pylori acquired significantly lower prevalence rate of gas- at a younger age than whites [41]. Again, tritis in the body of their stomach. In some this pattern translates into prolonged time patients, the hypochlorhydria secondary to periods of chronic gastritis and a greater corpus gastritis becomes reversible once chance of developing mucosal atrophy of the infection with H. pylori has been treat- the gastric body associated with reduced ed with antibiotics [35-36]. Labenz et al. acid output. Gastric atrophy and reduced followed patients with duodenal ulcer after acid output mean a greater risk for gastric antibiotic cure of H. pylori infection for cancer and a smaller risk for GERD and three years [40]. The incidence of reflux esophageal adenocarcinoma, respectively. esophagitis was 25.8 percent after eradica- The geographic distribution of GERD tion of H. pylori compared to 12.9 percent could also relate to the geographic distrib- in patients with persistent infection. ution of H. pylori. In developed countries Besides being responsible for the decline the decline in H. pylori infection is likely of peptic ulcer and gastric cancer, there- to have resulted in an increases suscepti- fore, the time trends H. pylori infection bility to develop GERD. also offer a possible explanation for the rise of GERD and esophageal adenocarcinoma. The opposing time trends of peptic OPEN QUESTIONS ulcer and gastric cancer on one side versus GERD and esophageal adenocarcinoma Figure 4 illustrates a working model on the other side suggest that H. pylori for the relationship between the infection infection may protect against GERD. with H. pylori, its influence on acid secre- An additional piece of evidence to tion and the occurrence of various diseases support the role of H. pylori in GERD is of the upper gastrointestinal tract. Despite provided by the remarkable differences the strong and multifaceted evidence in among ethnic groups. While U.S. non- favor of H. pylori playing an important whites incurred substantially reduced hos- role in the epidemiology of GERD, many pitalizations and mortality related to issues still remain unresolved. It is present- GERD or esophageal adenocarcinoma, ly unclear why some types of infection are they suffered more from gastric cancer confined predominantly to the antrum Sonnenberg and El-Serag: GERD Epidemiology 89 while others involve the whole stomach. It represents a necessary, but taken alone, not was hypothesized that childhood infection sufficient, prerequisite for the develop- versus infection during adolescence or ment of GERD. Other mechanisms would adulthood may, in part, determine the out- determine how much of the available acid come of gastritis [42]. As indicated by this is capable to exert its corrosive action on scheme, H. pylori infection may exert two the squamous epithelium of the esopha- diametrically opposite influences on the gus. The factors that influence the severity upper gastrointestinal tract, one associated of reflux disease have remained mysteri- with an increased and the other with a ous. What determines whether GERD in decreased risk for GERD. Simple case- an individual patient will be characterized control studies trying to associate H. pylori by erosions or symptoms only? Why do infection with GERD will not be able to some patients develop esophageal ulcers, resolve this mystery. Vicari et al., for strictures and Barrett's mucosa, while oth- instance, found that the occurrence of H. ers with similar amounts of gastroe- pylori infection was lower in 153 GERD sophageal reflux do not develop even the patients than in 57 controls, that is 34 per- slightest break of their esophageal cent versus 46 percent, but this difference mucosa? failed to reach statistical significance [43]. The normal-appearing gastroe- The severity, spread and type of gastritis, sophageal junction can harbor intestinal the immune response by the host and the metaplasia in 18 percent to 36 percent of genetic make-up of the organism may ulti- patients with symptoms of gastroe- mately determine amount of acid output sophageal reflux [45-46]. It appears that and its influence on reflux disease [43-44]. both reflux of gastric contents and H. The second open question concerns pylori infection of the cardia can result in the role of gastric acid secretion in GERD. intestinal metaplasia at the gastroe- On one hand, vigorous inhibition of gas- sophageal junction. Only intestinal meta- tric acid secretion constitutes the most plasia associated with reflux, however, efficacious means to treat GERD. seems capable of promoting cardiac can- Moreover, the exposure time of the cer, as evidenced by the opposing time esophageal mucosa to pH-values less than trends of cardiac versus body or antral 4 correlates with the severity of GERD cancer of the stomach. What are character- [26]. The extreme in the relationship istics that render one type of intestinal between acid output and GERD is exem- metaplasia particularly prone to malignant plified by patients with Zollinger-Ellison transformation? syndrome who tend to suffer from erosive It seems that the discovery of H. esophagitis [22]. Lastly, the protective pylori has not only furthered our concepts influence of corpus gastritis against GERD regarding peptic ulcer and gastric cancer, also points at the essential role of acid in but also that in the near future it will also GERD. On the other hand, Hirschowitz help resolve some of the enigmas sur- has shown in multiple, well-designed stud- rounding GERD. The potential role of H. ies that the amount of gastric acid output pylori infection in the pathogenesis GERD does not correlate with the severity of gives the opportunity to develop interest- GERD [23-24]. How can one reconcile the ing hypotheses and design new epidemio- seemingly contradictory findings? One logic studies. These studies will deepen possible explanation is that gastric acidity our understanding of GERD. 90 Sonnenberg and El-Serag: GERD Epidemiology

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