Reflux, dyspepsia, and disorders of the foregut.

Abstract: Disorders of the foregut are an increasingly common cause of symptoms in Western populations. This review summarizes recent advances in the understanding and treatment of gastroesophageal reflux disease, dyspepsia and celiac disease.

Key Words: reflux disease, dyspepsia, celiac disease

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Symptoms of foregut disease, such as reflux, dyspepsia, bloating and diarrhea are an increasingly common reason for primary care physician visits. More efficient approaches to investigating and managing patients with these symptoms have evolved based on the results of well-designed outcome studies. In this paper, we will review current concepts in the diagnosis and management of common diseases of the foregut including gastroesophageal reflux disease, dyspepsia and celiac disease.

Gastroesophageal Reflux Disease (GERD)

Heartburn and/or acid regurgitation are the typical symptoms of GERD, and are reported to occur at least weekly in 20 to 29% of the US population. (1) Less than half of these individuals will actually present to their primary care physician and fewer than 20% will have an endoscopy. (2) Nonetheless, patients presenting with symptoms of GERD may account for up to 5% of the primary care workload in Europe, a rate which is increasing. (3) As well as the discomfort of heartburn, up to 80% of patients with frequent reflux report difficulty eating, sleeping and working due to the symptoms, and thus experience impaired quality of life. (4) In addition, it is increasingly recognized that reflux contributes to a significant number of extraesophageal manifestations, including noncardiac chest pain, asthma, laryngitis, chronic cough and sleep apnea. (5)

Although the symptoms of GERD are common, the majority of patients with reflux do not have evident esophagitis at endoscopy. The prevalence of erosive esophagitis in patients with reflux symptoms ranges from 26 to 38%, with a higher yield in treatment-naive patients. (6,7) In fact, most patients with reflux symptoms have a macroscopically normal esophagus, and are often labeled as having nonerosive reflux disease (NERD). A recent prospective study of primary care patients with reflux symptoms found that male gender, high body mass index, alcohol use and a history of smoking were all independent predictors of erosive esophagitis. (8) A smaller study among VA employees in the US found that white patients, those with weekly heartburn symptoms and users of over-the-counter antacids were more likely to have erosive esophagitis at endoscopy. (6)

The pathogenesis of erosive esophagitis is primarily due to the excess contact of acidic gastric contents with the esophageal mucosa. This occurs due to a number of pathophysiological changes, including transient lower esophageal relaxations (TLERs), hiatal hernia, poor esophageal clearance of gastric contents and impaired mucosal defenses. Although TLERs are not more frequent in patients with GERD, they account for the majority of acid reflux episodes. (9,10) These can be triggered by fatty foods, smoking, alcohol and certain medications (including nitrates, benzodiazepines and calcium channel blockers). (11) Increased exposure of the esophageal mucosa to acid and pepsin, which initially damages intercellular junctions, leads to increased mucosal permeability. (12) Laboratory studies have demonstrated that not only acid and pepsin, but also alcohol, hot beverages and smoking can disrupt esophageal mucosal integrity, thus exacerbating acid pepsin-mediated injury. (13,14) The final effect is the presence of acid pepsin in the submucosa, which stimulates both sensory neurons (pain) and an inflammatory response (erosive esophagitis). (11) Our current understanding is that patients who have heartburn symptoms but no erosions (NERD) have microscopic defects in mucosal barrier function that allow acid pepsin to reach nociceptors and cause pain, but not sufficient to progress to erosions. (15) In contrast, patients with erosive esophagitis have extensive acid infiltration that causes cell edema and necrosis. This hypothesis explains the lack of endoscopic evidence of esophagitis in patients with NERD, and their response to acid-reducing therapy.

Treatment Recommendations for GERD

A key question that arises in patients presenting with GERD symptoms is who needs further investigation. Do the endoscopic findings matter, given that the initial therapy for reflux disease is acid suppression in almost all cases? The American College of Gastroenterology recommends initial empiric therapy for uncomplicated disease, and that endoscopy should be "considered in patients who have symptoms suggestive of complicated disease, those at risk of Barrett's esophagus, or when the patient or physician feel early endoscopy to be appropriate". (16) The difficulty with this advice, acknowledged by the authors, is that symptoms are poor predictors of endoscopic findings in patients with GERD. (17) The serious complications of GERD, Barrett esophagus and adenocarcinoma are rare in patients with reflux symptoms, and most patients with these complications have little in their presentation to differentiate them from benign reflux. A recent population-based survey reported a prevalence of Barrett esophagus in 1.6% (1.1% had short segment Barrett, and 0.5% had long segment Barrett), and 40% of these had no symptoms. (18) Even the traditional approach of performing endoscopy in patients with so-called "alarm symptoms" of weight loss, dysphagia or anemia is a poor predictor of those likely to have or develop esophageal cancer. A review of 18,000 patients who underwent endoscopy at community practices for reflux symptoms found that no patients under the age of 50 with reported "alarm symptoms" had esophageal cancer. (19) The small number of older patients who were found to have esophageal cancer had no higher prevalence of alarm symptoms than other subjects in this study. This suggests that age may be as useful a predictor of underlying cancer as alarm symptoms. Given these uncertainties, some experts have called for endoscopic screening of all patients with reflux for Barrett esophagus and cancer. However, this recommendation is highly controversial since GERD is very common, esophageal adenocarcinoma relatively rare, and no studies have demonstrated benefit from such a screening approach. (20,21)

In younger patients who are not suspected of having complicated reflux disease, an empiric trial of acid suppression remains the standard approach. Many patients will already have tried over-the-counter antacids, which improve symptoms in about 20% of patients in the long term. (22) The proton pump inhibitors (PPIs) produce symptom response and heal esophagitis in up to 80% of patients, compared with 60% of patients on histamine receptor antagonists (H2RAs), and 25% on placebo. (16) Similar results have been reported in treating GERD-associated asthma symptoms with improvement in up to 70% of patients in small trials. (23) Two different approaches to empiric therapy can be used; "step up" from initial antacids to H2RAs then PPIs, or "step down" from initial daily PPIs to on-demand PPIs or H2RAs. The "step down" approach is associated with more rapid symptom relief and improved quality of life when compared with a "step up" approach. (24,25) A recent study has shown that "stepping down," even from chronic PPI use, can be successfully done without adversely affecting quality of life. (26) However, the reasons for considering changing from daily PPIs to intermittent PPIs or H2RAs are usually economic rather than clinical.

There are few differences between the commonly used PPIs in terms of efficacy and side effects in the acute treatment of reflux esophagitis, and in symptom response in non-erosive disease. (27,28) In those patients who require chronic PPI use for symptom relief, none of the clinical concerns about chronic acid suppression have been borne out. Recent studies suggesting a link between PPI use and community-acquired pneumonia and Clostridium difficile infection are of interest but require further validation. (29,30)

Although the majority of patients will respond to acid-suppression therapy, a subgroup will experience persistent symptoms despite maximum PPI therapy. Such "PPI failure" occurs in up to 30% of patients with GERD, and counter intuitively, is more prevalent in patients with nonerosive disease. (27,31) The most common reasons for PPI failure are poor compliance, inadequate dosing, delayed gastric emptying and esophageal visceral hypersensitivity. Despite their excellent side effect profile, a study from primary care demonstrated that only 55% of patients actually took their PPI daily for four weeks as prescribed. (32) When compliant, it is ideal that patients take the drug half an hour before a meal to ensure maximum efficacy. Doubling the PPI dose does appear to have modest benefits in both healing rates and symptom relief in both GERD and NERD, and this is a reasonable approach. (31) Delayed gastric emptying can be demonstrated in up to 40% of patients with GERD; this group may not respond to PPIs and may have significant dyspepsia symptoms, as well. (31) Visceral hypersensitivity refers to an altered visceral pain perception threshold in patients with functional heartburn symptoms, which are triggered not only by acid exposure but by other stimuli such as cold or carbonated beverages or even by swallowing saliva. (33) As a consequence, the majority of patients with this abnormality do not respond completely to PPIs.

As discussed above, pharmacological therapy at adequate dosage is effective in resolving symptoms and healing esophagitis in the vast majority of patients who are compliant, and is a safe long-term option. For those who have persistent reflux symptoms or esophagitis despite medical therapy, or do not wish to take lifelong medication, the treatment options have evolved to include minimally invasive antireflux procedures. Surgery, in the form of Nissen fundoplication, is associated with good short-term results, with up to 90% of patients reporting significant symptom improvement. (34) Over time, however, symptoms do recur; one study found 62% of surgical patients regularly using antireflux medications 10 years later, and no reduction in the development of esophageal cancer in those patients who had Barrett esophagus. (35) A meta-analysis and recent report have confirmed this absence of reduction in cancer risk in patients who undergo antireflux surgery. (36,37) There is also variation in the benefits between study cohorts and routine practice, with one community-based study finding only 61% of patients satisfied, and 32% taking antacid or acid antisecretory medications on a regular basis within just 20 months of the surgery. (38)

Endoscopic antireflux procedures have been promoted as safer, less-invasive methods of mechanically tightening the gastroesophageal sphincter. A number of methods, including plication (suturing), radiofrequency energy and polymer injection have been developed for administration via an endoscope. Most of the techniques have been tested only in short-term, open-labeled trials using patients with mild disease. (39) One of the better designed studies reported no difference between radiofrequency energy combined with a sham procedure in the patients' medication use or esophageal acid exposure at 6 months, but less reflux symptoms and improved quality-of-life in those treated with radiofrequency energy alone. (40) Interestingly, 40% of patients who received the sham procedure in this trial no longer required daily antireflux medication, suggesting a strong placebo effect in patients with reflux symptoms selected for these procedures. The recent withdrawal of one of the polymer injection techniques due to safety concerns (ENTERYX, Boston Scientific) emphasizes the fact that endoscopic antireflux procedures are still in development and have not yet proven themselves to be a valuable part of routine GERD management. (34)

Dyspepsia

The term "dyspepsia" refers to the presence of chronic or recurrent upper abdominal pain or discomfort. (41) Many studies and trials examining dyspepsia include patients with reflux symptoms, and the two often overlap in practice, but we will focus on nonreflux symptoms for this section of the review. The annual prevalence of dyspepsia is 25% in the US, but less than half of these individuals seek medical care, accounting for up to 5% of primary care visits. (42,43) The associated healthcare costs for dyspepsia are rising, despite little change in the overall prevalence. Dyspepsia is generally a chronic relapsing condition, with up to 80% of patients still reporting symptoms 2 years after diagnosis. (44)

As in GERD, the majority of patients (approximately 60%) who seek medical advice for dyspepsia will have no evident abnormality of their foregut, and are labeled with functional, or nonulcerative, dyspepsia. Even patients who are found to have minor erosions, a hiatal hernia or gastritis at endoscopy often have functional disease, as these endoscopic findings are also common in the asymptomatic population. There are many hypotheses as to the pathophysiology of functional dyspepsia, including gastric dysmotility and gastric visceral hypersensitivity. (45) For example, up to 40% of patients with functional dyspepsia have delayed gastric emptying, but symptoms alone are poor at predicting which patients have this dysfunction. (46) Other factors, such as psychological distress and infections have been associated with functional dyspepsia but not confirmed. The role of Helicobacter pylori infection in the pathogenesis of functional dyspepsia is unclear, as the prevalence of infection ranges from 39 to 87% in this group. (41) A meta-analysis of the effect of Helicobacter pylori eradication on symptoms in patients with dyspepsia reported a small (8%) relative risk reduction in dyspepsia symptoms, suggesting the overall influence on dyspepsia symptoms is minor. (47)

Peptic Ulcer Disease and Esophagitis

Peptic ulcer disease and esophagitis are the most common structural findings at endoscopy in patients with dyspepsia, both occurring in 5 to 15% of cases. Despite many attempts, no useful predictors of underlying pathology have been established based on symptoms alone. (48) The percentage of patients with gastric and duodenal ulcers due to Helicobacter pylori remains high, 90% and 70% respectively, although NSAIDs have been implicated in an increasing number of cases. (49) As Helicobacter pylori prevalence continues to decline, and cardioprotective aspirin use increases, it is likely that NSAID use will become the predominant cause of gastric ulcers. Other causes of dyspepsia, such as cancer, biliary pain, celiac disease and pancreatitis are rare. (19)

As with reflux symptoms, the approach to investigation and management of patients with dyspepsia has been the focus of intense study among primary care physicians and gastroenterologists. (41,50) The most recent (2005) recommendations from the American Gastroenterology Association state that all patients with dyspepsia aged >55 years, or any patient with alarm symptoms, should have an endoscopy. Alarm symptoms include unintentional weight loss, vomiting, bleeding and dysphagia. Although alarm symptoms have a poor positive predictive value (<11%) for malignancy, their absence has a high negative predictive value (>97%), and thus should always be determined in patients with new dyspepsia symptoms. (41) In those aged under 55, and in the absence of alarm symptoms, there are three viable approaches to management of dyspepsia; empiric acid suppression, test-and-treat for Helicobacter pylori infection, and early endoscopy.

Empiric acid suppression is easily instituted in primary care, produces rapid results, and is the cheapest option per patient treated. In uninvestigated dyspepsia, proton pump inhibitors are more effective than H2RAs and antacids, and improve symptoms in up to 70% of cases, although the relapse rates after discontinuation of therapy are high. (51,52) When compared with other management strategies, outcomes with empiric acid suppression for uninvestigated dyspepsia in primary care are dependant on the population under study. Trials from primary care in the US and Europe have not shown a significant difference between empiric acid suppression and H pylori test-and-treat approaches when applied to all patients presenting with dyspepsia. (53-55) However, as H pylori eradication is more effective than acid suppression in infected individuals, the benefits of a test-and-treat strategy depend on the prevalence of H pylori infection in that population. Similarly, there is little difference between empiric acid suppression and early endoscopy in curing dyspepsia, and initial endoscopy is certainly not cost-effective in the general population. (56,57) A recent meta-analysis of trials that compared early endoscopy to H pylori test-and-treat for dyspepsia concluded that endoscopy provides a small advantage over the latter approach in curing dyspepsia at one year follow-up. (58)

Experts in this area have concluded that all patients under the age of 55 with no alarm symptoms who present with uninvestigated dyspepsia should be tested for H pylori, using breath testing or stool antigen testing. Those who test positive should receive eradication therapy, and those who test negative should receive a trial of PPI therapy. This assumes a H pylori prevalence of at least 10% in the community, which is the level that currently exists in the U.S.

Two management issues that often arise in primary care are how to treat patients who have dyspepsia but a normal endoscopy (functional dyspepsia), and the approach to NSAID-induced dyspepsia. The many randomized controlled trials that have examined treatment of functional dyspepsia have shown that PPIs and H pylori eradication are superior to placebo in improving functional dyspepsia symptoms. (59,60) About 50 to 70% of patients respond, but the placebo response rate is as high as 40% in these trials. The benefits of other interventions such as prokinetics, sucralfate, antidepressants and psychological therapy remain unclear. (41,59)

Dyspepsia occurs in up to 30% of patients receiving NSAIDs, and to a lesser degree with the COX-2 inhibitors. (61,62) A review of trials in the prevention of ulcers in chronic NSAID use reported that misoprostol, PPIs and double dose H2RAs were all effective in reducing peptic ulcers by at least half, although only high-dose misoprostol actually prevented complications such as bleeding and perforation. (63) PPIs have been shown to prevent dyspepsia symptoms, heal NSAID-induced ulcers, and prevent ulcer recurrence in patients taking NSAIDs. (61,64) An expert panel recently concluded that patients who require chronic NSAID use and have at least one risk factor for gastrointestinal ulcers should receive prophylactic PPI therapy. (65) The risk factors they identified were age >65, concurrent aspirin therapy or a previous gastrointestinal event. An economic analysis suggests that adding a PPI to nonselective NSAIDs is only cost-effective in those at high risk of GI adverse events. (66) Despite this evidence, it is clear that the majority of at-risk patients are not prescribed such preventative measures by their physicians, and even those with prescriptions are poorly compliant in up to 60% of cases. (61)

Celiac Disease

Although long considered a rare foregut disorder, celiac disease has achieved prominence recently, as its true prevalence in the US population is increasingly recognized. (67) All primary care physicians should be aware of celiac disease as it occurs in almost 1% of the US population, yet in the majority of cases remain undiagnosed. (68,69) Celiac disease occurs due to an immune reaction to ingested gluten (proteins from wheat, barley and rye) in predisposed individuals; a reaction characterized by lymphocytic invasion of the mucosa and subsequent villous atrophy. (70) The resultant enteritis can lead to malabsorption, anemia and osteoporosis. (71) It has also been associated with a wide variety of complications, including dermatitis herpetiformis (an itchy, blistering skin disorder), small bowel lymphoma, elevated hepatic transaminases, cerebellar ataxia, peripheral neuropathy, depression, and reduced fertility. (72)

There has been a shift in the pattern of presenting symptoms as serologic testing has uncovered patients with celiac disease who have no or minimal gastrointestinal symptoms. (73) Furthermore, celiac disease is now diagnosed in patients of all ages; the average age at diagnosis in the US is 46 years. Iron deficiency anemia, often in the absence of GI symptoms, is the most common clinical presentation. Mild GI symptoms of bloating, discomfort and altered bowel habits are also common. Up to 5% of patients with diagnostic criteria for irritable bowel syndrome (IBS) have celiac disease, and testing should be considered in all cases of suspected IBS. (74) Patients with unexplained diarrhea, weight loss, abdominal pain, osteoporosis, peripheral neuropathy and unexplained raised transaminases are also candidates for serologic testing for celiac disease. Celiac disease is also associated with other immune-mediated diseases including type 1 diabetes, Sjogren syndrome, and primary biliary cirrhosis. (75)

The initial test of choice is serology for IgA tissue transglutaminase antibodies (TTG) or IgA endomysial antibodies (EMA), which have a sensitivity and specificity in excess of 95%. (76,77) False negatives may occur with IgA deficiency, so those with features of celiac and negative serology should have IgA levels checked. The National Institutes of Health recommend that all those with positive serology should be referred for endoscopy and biopsy to confirm the diagnosis. (67)

Once diagnosed, the treatment requires exclusion of gluten from the diet for life, and correction of any nutritional deficiencies that may have developed (most commonly iron, vitamin D, folic acid, or vitamin [B.sub.12]). As this is a lifetime commitment, and may require significant lifestyle adjustment, advice and support from an expert celiac nutritionist and celiac support group are important. (78) Gluten may be present in many unexpected products such as lipstick, toothpaste, medications and envelope adhesives, making thorough education vital. The majority of patients (approximately 70%) will experience symptom improvement within 2 weeks after exclusion of gluten, but the histologic recovery may take more than 3 months. (71) Strict adherence to the recommended diet reduces the risk of most complications, including malignancy. (79,80)

Summary

Most younger patients with dyspepsia have functional or nonulcerative dyspepsia. The majority of patients with GERD and dyspepsia can thus be safely treated without endoscopy. However, patients with alarm symptoms or those aged >55 years should have endoscopy first to exclude malignant disease. Functional heartburn and dyspepsia are chronic disorders with high relapse rates. Empiric acid suppression is an appropriate first step in those with reflux symptoms and those with dyspepsia where there is a low (<10%) background prevalence of H pylori infection. However, testing and treating for H pylori infection is the recommended initial strategy for most patients with dyspepsia and is associated with higher long-term dyspepsia cure rates. Celiac disease is underdiagnosed in primary care, and serology testing by IgA TTG should be considered in patients with gastrointestinal symptoms, iron deficiency anemia, nutrient deficiencies and early-onset osteoporosis.

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Alan C. Moss, MB, and Ciaran P. Kelly, MD

From the Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.

Reprint requests to Dr. Ciaran P. Kelly, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brook-line Avenue, Boston, MA 02215. Email: [e-mail]

The authors have no disclosures to declare.

Accepted June 27, 2006.

RELATED ARTICLE: Key Points

* The majority of patients with reflux and dyspepsia can be safely treated without endoscopy, as most have functional disease.

* Functional heartburn and dyspepsia are chronic disorders with high relapse rates.

* Testing and treating for H pylori infection is the recommended initial strategy for most patients with dyspepsia.

* Celiac disease is underdiagnosed in primary care, and serology testing by IgA TTG should be considered in patients with gastrointestinal symptoms, iron deficiency anemia, nutrient deficiencies and early-onset osteoporosis.

RELATED ARTICLE: Independent predictors of erosive esophagitis:

* Male gender

* High body mass index

* Alcohol use

* History of smoking

RELATED ARTICLE: PPI "failure" occurs in 30% of patients with GERD and is most often caused by:

* Poor compliance

* Inadequate dosing

* Delayed gastric emptying

* Esophageal visceral hypersensitivity

RELATED ARTICLE

Celiac disease-induced enteritis can lead to:

* malabsorption

* anemia

* osteoporosis

Celiac disease is also associated with a wide variety of complications, including:

* dermatitis herpetiformis

* small bowel lymphoma

* elevated hepatic transaminases

* cerebellar ataxia

* peripheral neuropathy

* depression

* reduced fertility