Clinical Spectrum Natural History And Epidemiology Of Gerd

Heartburn and Acid Reflux Cure Program

GERD Treatment at Home

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F. Pace and G. Bianchi Porro

Chair and Department of Gastroenterology, "L. Sacco"University Hospital, Milan, Italy

Summary

GERD is a spectrum disease, i.e., a disease composed by many patient subgroups, ranging from symptomatic disease without mucosal lesions (or NERD) to the complications of erosive esophagitis, such as esophageal stricture, ulceration or Barrett's esophagus. Almost all the transitions are possible amongst groups, even if the progression from one stage to the other has been described mainly based upon retrospective data.

The natural history of the disease is poorly investigated: available data would suggest that symptoms of GERD tend to persist and to worsen with time, independently from the presence and severity of muco-sal lesions or the severity of esophageal acid exposure at presentation.

As far as the epidemiological features are concerned, the prevalence of at least monthly GERD symptoms ranges between 26% to 44% in western countries, whereas the prevalence of endoscopic esophagitis at open access endoscopy or in symptomatic patients seem to be very high, up to 20%, with an incidence rate in the general population about hundred time lower.

The principal complication, e.g., Barrett's esophagus, has a prevalence of 15-20% of the GERD population, with a rate of adenocarcinoma development of about 0.5% per patient year of follow up. Mortality for uncomplicated GERD is negligible.

Introduction

The backward flow of gastric content into the esophagus, that is, gastroesophageal reflux (GER), is up to a certain extent a physiological phenomenon, in particular during the early postprandial phase [1]. When the threshold of normality is surpassed, GER may induce inflammatory changes of the esophageal mucosa, dif ferent esophageal and extra-esophageal symptoms (even in the absence of detectable lesions), and macroscopic lesions such as erosive or ulcerative esophagitis or so-called atypical manifestations (laringytis, far-ingytis, dental erosions, and many others).

From this brief introduction is already clear that GER disease (GERD) is a broad disease, with a large clinical spectrum of signs and symptoms, interesting not only the esophageal area but many other regions of the body, including the mouth, lungs, ear, nose and throat, and which can be accompanied or not by esoph-ageal lesions. It is therefore evident that the epidemiology of GERD is difficult to assess because this disease encompasses at least three broad groups of patients: (a) those with typical symptoms, such as heartburn and regurgitation but without reflux esophagits, so called non erosive reflux disease (NERD) patients; (b) patients with reflux esophagitis, and with or without complication, such as stricture, specialized intestinal metaplasia; (c) patients with atypical manifestations (Table 1).

In this chapter, we will address the topic of the clinical spectrum of the disease as well as its natural history, and review the epidemiological data available in the literature.

Clinical spectrum

Compared to relatively few years ago, the concept of GERD clinical spectrum has deeply changed during the last decade. During the last years, in fact, it has been increasingly recognized that the GERD patient population is indeed a multifaceted one; the schematic representation of the entire population of patients, previously presented as an iceberg [2] (see

Fig. 1) has been modified to take into account, as an example, the changing epidemiology of Helicobacter pylori infection (Fig. 2), a factor believed to be linked in some way to GERD [3] and it has been revisited up to a point that it has been suggested by Fass [5] that the original iceberg may in fact break into three smaller icebergs (or populations), completely separated and not communicating each other anymore

(Fig. 3). The latter schematization does in fact represent a new conceptual framework, in that it categorize GERD patients into 3 unique groups of patients: non-erosive reflux disease, erosive esophagitis and Barrett's esophagus; we disagree with this model, for various reasons, but basically we think that the principal conceptual mistake lies in the fact that the Fass' view mix together the concept of natural

Table 1. Atypical (or extraesophageal,or supraesohageal ) GERD manifestations

Pulmonary

Ear, nose and throat

Others

- Asthma (non seasonal, non allergic)

- Chronic bronchitis

- Aspiration pneumonia

- Bronchiectasis

- Pulmonary fibrosis

- Chronic obstructive disease

- Pneumonia

- Chronic cough

- Laryngitis

- Hoarseness

- Globus

- Pharyngitis

- Sinusitis

- Vocal cord granuloma

- Laryngeal carcinoma (possible)

■ Non-cardiac chest pain

■ Dental erosion

Table 2. Epidemiology of GERD

Epidemiologic factor

Reference

Incidence and prevalence of reflux symptoms

- Symptoms of reflux in USA healthy subjects (at least monthly)

36%

[40]

- Symptoms of reflux in the USA adult population (at least monthly)

44%

[41]

- Symptoms of reflux in the Italian adult population (at least monthly)

26%

[42]

- Symptoms of reflux in the ingaporean population (at least monthly)

< 2%

[43]

Prevalence of esophagitis

- in symptomatic patients (Europe)

« 30%

[37], [38]

- in symptomatic patients (Japan)

15%

[39]

- open access endoscopy

20%

[35]

Incidence of esophagitis

- in general populations

120/100,000

[34]

Complications of GERD

- Hemorrhage (% of patients with massive UGI bleeding)

6%

[48]

- Stricture (% of patients seeking medical care)

10%

[50]

- Stricture (% of patients with Barrett's esophagus)

50%

[35]

- Barrett's esophagus (% of patients with symptomatic GERD)

5-20%

[35]

- Adenocarcinoma in Barrett's (incidence per patient year of follow up)

0.5%

Mortality

- Death rate per year (general population)

history, which is the tendency of the disease to progress and to worsen in the absence of therapy, with the concept of clinical spectrum, which simply signifies that many clinical manifestations of a disease are clinically possible. We therefore strongly defend the concept of GERD as a disease composed by many patient subgroups with almost all the transitions possible from one group to the other (Fig. 4).

Fig. 1. The iceberg of GERD population (modified from [2].The "iceberg" represents the populations of patients with gastroesophageal reflux. The largest group are those with mild disease who self medicate with over-the-counter drugs and rarely if ever visit doctors because of their symptoms. The smallest group are those who visit gastroenterologists because of severe disease requiring continuous high-dose therapy. (A) represents those with complications (e.g., symptoms and complications), (B) those with symptoms who seek medical care (e.g., symptoms and complaints), (C) those with symptoms who self medicate and do not seek medical care (e.g.,symptoms and no complaints)

Barret'» J esophagus

Erosive esophagitis

Symptomatic GERD

Fig. 1. The iceberg of GERD population (modified from [2].The "iceberg" represents the populations of patients with gastroesophageal reflux. The largest group are those with mild disease who self medicate with over-the-counter drugs and rarely if ever visit doctors because of their symptoms. The smallest group are those who visit gastroenterologists because of severe disease requiring continuous high-dose therapy. (A) represents those with complications (e.g., symptoms and complications), (B) those with symptoms who seek medical care (e.g., symptoms and complaints), (C) those with symptoms who self medicate and do not seek medical care (e.g.,symptoms and no complaints)

Barret's esophagus

Erosive esophagitis

Symptomatic GERD

■ Symptomatic esophagus » QERD

Erosive esophagitis

Fig. 3. The GERD iceberg revisited. According to Fass [5] the iceberg of GERD population may in fact be composed by three unique groups of patients: nonerosive reflux disease, erosive esophagitis and Barrett's esophagus, independent from each other and not communicating (modified from [4])

Fig. 3. The GERD iceberg revisited. According to Fass [5] the iceberg of GERD population may in fact be composed by three unique groups of patients: nonerosive reflux disease, erosive esophagitis and Barrett's esophagus, independent from each other and not communicating (modified from [4])

History Acid Reflux

Fig. 2. The "iceberg"of GERD in countries where chronic atro phic gastritis and gastric cancer are common and GERD is rare (from [3]).This illustration depicts the change in the presenta tion of gastroesophageal reflux associated with the change in the average pattern of gastritis from an atrophic pangastritis to a nonatropic gastritis or normal stomach. Gastric cancer becomes rare, whereas duodenal ulcer and GERD become problems among the populations with H. Pylori infection. Thus, the prevalence of GERD is inversely related to that of gastric cancer. This change in patterns occurred during the last part of the 19th and early 20th centuries and is currently ongoing in many countries

Fig. 4. Natural history of GERD, based on the Markow-state diagram. Each circle indicates a GERD subgroup. In each subgroup is possible to stay (curved arrow) or move into another subgroup (linear arrow). In some cases, data support possibility of reverse movement, whereas in a single instance (transition from NERD to AdenoCa data are insufficient). From [6]

Natural history of GERD

Evaluating the natural history of GERD is useful for a number of reasons, for this knowledge may help to: (a) discern the percentage of the population that will progress from nonerosive to erosive disease and its complications, such as stricture, Barrett's oesophagus, and esophageal adenocarcinoma, or from exclusively esophageal to extraesophageal manifestations; (b) define, assess and validate predictivity of risk factors for such complicated forms of the disease; (c) determine if medical, surgical or endoscopic therapies are able to positively modify the natural course of the disease; and (d) determine the need for maintenance therapy to prevent complications and persistent symptoms.

Others [7], [8] have pointed out that many factors make it difficult to study the natural history of GERD, notably the evolving definition of the disease and the lack of diagnostic standard with an unclear demarcation between physiological reflux and GERD. As a consequence, few studies in the literature have addressed the issue of defining the natural history of erosive GERD, and even less that of nonerosive gastroesophageal reflux disease (NERD), extraesophageal GERD and complications.

Natural history of NERD

Until recently, patients with endoscopic-negative reflux disease (NERD) were considered to suffer from a milder disease [9], i.e., requiring less intensive/prolonged treatment and possibly characterized by a better long-term prognosis. This concept was subsequently proven to be incorrect, since the impairment in disease-related quality of life (HRQoL), for example, appears to be similar in GERD patients with or without endoscopic esophagitis and is related in both instances to symptom severity [10]. Also, the symptomatic acute response to PPI drugs in patients with or without endoscopic mu-cosal damage seems not to be different, and in fact might be worse in NERD [11], [12]. Finally, after discontinuation of acute treatment, symptomatic relapse within 6 months appears to affect a similarly high proportion of both GERD groups [13].

A study of ours published ten years ago was probably the first reporting the natural history of GERD patients without endoscopic esophagitis but with a pa thological esophageal pH-metry [14]. In that study, we showed that 5 of 33 such patients treated with antacids or prokinetc agents developed an endoscopic esophagi-tis ex novo within 6 months, and that the extent of esophageal acid exposure at entry was not predictive of this complication. In a subsequent study [15] we extended the observation of the original patient group up to a median duration of 10 years. The first interesting observation regarding this patient sample is that almost all patients we were able to trace [28], [29] are affected by GERD symptoms when antisecretory drugs are discontinued, and therefore the majority (75%) was on such a therapy due to GERD symptoms. Secondly, a very high proportion (89%) of our patients in whom repeat endoscopy was performed (N = 18) showed an erosive esophagitis. Thus, a considerable proportion of the original patient cohort indeed showed a progression from nonerosive to erosive disease.

Schindlbeck et al [16], in a study investigating the fate of GERD patients with and without esophagitis, reported on 16 patients with pH-documented GERD and no esophagitis 3 years after the diagnosis. During this period, four patients (25%) developed reflux esophagitis, while the majority of patient population, which included also patients with esophagitis at entry, was still taking medications on a daily basis because of their GERD symptoms. Symptoms were rated to be equal or worse than at entry by 70% of patients, in the absence of treatment. In the study by Mc Dougall et al [17], 71% of the 17 patients with a pH-metry documented NERD complained of frequent heartburn 3 to 4.5 years after initial diagnosis, 59% were on daily acid suppressive therapy, and 24% of those patients who had repeat endoscopy developed esophagitis. Again, a progression from nonerosive to erosive GERD was observed, at least in a proportion of patients.

These studies, together with our own, seem to indicate that patients with NERD may indeed move from one part of the spectrum to the adjacent one: the model proposed by Fass and colleague appears to be incorrect, since not only is the progression from nonerosive to erosive GERD substantiated by the literature, but also the transition from erosive to Barrett's esophagus does in fact occurr, as shown, for example, in the study by Mc Dougall, in which 11% of patients with erosive esophagitis at entry showed BE at follow up repeat endoscopy [17].

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