Example of grade C esophagitis
Los Angeles classification of reflux esophagitis 
One or more mucosal breaks no longer than 5 mm, not bridging the tops of mucosal folds
One or more mucosal breaks longer than 5 mm, not bridging the tops of mucosal folds
One or more mucosal breaks bridging the tops of mucosal folds, involving <75% of the circumference
One or more mucosal breaks bridging the tops of mucosal folds, involving >75% of the circumference
Epidemiology: Overall, the prevalence of erosive esophagitis is approximately 5%, but varies widely among countries, continents, and studies. In patients without reflux symptoms, a recent literature review reported a prevalence of 12.1% in Sweden, 8.6% in Italy, 6.1% in China, and from 1.6 to 22.8% in health-check programs in six Asian countries . In many of these studies, most “asymptomatic” patients probably have dyspepsia , a condition where the prevalence of esophagitis is more than 13% in some studies . The prevalence of erosive esophagitis in patients with GER symptoms is considered to be less than 50% , and probably even less since, nowadays, most patients with upper gastrointestinal (GI) symptoms are prescribed proton pump inhibitors (PPIs) as first-line empirical therapy. Indeed, most patients referred for upper GI endoscopy have previously received one or more PPI treatment course, and therefore, the current prevalence of erosive esophagitis in patients with GER symptoms is probably much lower. It has been reported that 6–30% of patients with persisting symptoms on PPIs have erosive esophagitis [7, 8].
Pathophysiology: In erosive esophagitis related to GERD, mucosal damage results from the effects of aggressive factors of the refluxate (mainly acid, pepsin, and bile acids) that overcome the protective factors of the esophageal mucosa (mainly effective esophageal peristalsis to decrease acid-mucosa contact time, efficient epithelial and postepithelial defense ). The results of a recent study have challenged the concept of “caustic” acid injury of the esophageal mucosa, by showing that refluxed gastric juice may initiate a cytokine-mediated inflammatory process and ultimately erosions . In patients with GERD, the factors associated with the development of erosive esophagitis are male gender, increased esophageal acid exposure, presence of a hiatal hernia, esophageal dysmotility, and older age [11, 12]. Data on the association between erosive esophagitis and obesity are inconsistent because of variations in study populations and methods used to determine obesity but recent studies have shown that abdominal visceral adipose tissue volume is associated with an increased risk of erosive esophagitis in both males and female .
Symptoms: Symptoms of erosive esophagitis are not different from symptomatic gastroesophageal reflux, i.e., mainly heartburn, acid regurgitation, and chest pain. Dysphagia may be present in one-third of patients whatever the severity of endoscopic lesions, and even in the absence of esophageal stricture . The diagnosis of erosive esophagitis requires upper gastrointestinal endoscopy. If most patients with reflux symptoms may be treated empirically with PPIs, and will not be investigated by endoscopy, this procedure is indicated in patients with alarm symptoms (dysphagia, bleeding, anemia, weight loss, and recurrent vomiting) or when GERD symptoms persist despite a therapeutic trial of 4–8 weeks of twice-daily PPI therapy [15, 16].
How Is Erosive Esophagitis Treated?
Response to the Patient
Most erosive esophagitis will be successfully treated by antisecretory drugs, such as proton pump inhibitors (“PPIs”) which significantly decrease (but not completely abolish) gastric acid secretion. Antisecretory drugs can’t avoid the reflux of the gastric content into the esophagus but make the refluxate less acidic and therefore less harmful for the esophageal mucosa. Most erosive esophagitis (90%) will be healed by a 4- to 8-week course of PPI treatment. Only very severe esophagitis may be refractory to PPIs and need surgery, which is a rare situation. Most patients with erosive esophagitis have reflux symptoms such as heartburn and regurgitation, which will also resolve with PPIs. However, in some cases, esophagitis can heal and symptoms persist. In patients with refractory esophagitis and/or symptoms, an anti-reflux surgery may be indicated. This surgery, called “fundoplication ,” consists in creating a wrap around the lower esophagus with the upper part of the stomach. By creating an efficient anti-reflux barrier, the procedure is effective to achieve mucosal healing and symptom resolution in patients with gastroesophageal reflux refractory to medical therapy.
Review of the Literature
Medical treatment: The treatment of erosive esophagitis is based on anti-reflux therapy, with the aims of symptom relief, mucosal healing, and prevention of relapse. If lifestyle modifications, weight loss, and topics (antacids, alginates) may help to reduce gastroesophageal reflux symptoms, there is to date no data supporting their efficacy to heal erosive esophagitis. Antisecretory agents are the medications of choice for pharmacologic therapy of GERD, especially when erosive esophagitis is considered. H2-receptor antagonists (H2RAs) and PPIs both decrease gastric acid secretion but PPIs provide a superior control of intragastric pH over a 24-h period. Indeed, by inhibiting the H+/K+-ATPase at the level of the parietal cells, PPIs suppress to a significantly greater degree daytime-, nighttime-, and meal-stimulated acid secretion . As a consequence, it has been clearly established that both esophagitis healing and symptom relief were more complete and occurred faster with PPIs compared to H2RAs . All PPIs provide excellent healing rates at 8 weeks, ranging from 85 to 95% . Healing rates of high-grade esophagitis are slightly lower and longer to be achieved . There is no perfect correlation between mucosal healing and symptom relief: indeed, if most patients with symptom relief will have a complete esophageal mucosal healing, approximately 30% of patients whose esophagitis has healed on PPIs will still experience reflux symptoms . In patients with persisting symptoms, only 30% will have persisting mucosal breaks at endoscopy . In clinical practice, it is not recommended to check for esophageal mucosal healing if the patient is asymptomatic. By contrast, a follow-up endoscopy is mandatory for severe esophagitis not only for mucosal healing but also to verify whether underlying Barret’s esophagus is present once the mucosa has healed (see below). A small proportion of patients may have refractory esophagitis, mainly those presenting initially with the most severe lesions (i.e., grade C and D esophagitis). These refractory esophagitis are related to insufficient acid secretion inhibition. In this situation, physicians should check for compliance which is frequently suboptimal in GERD patients [21, 22]. In addition to compliance, dosing time should also be checked since taking PPIs 15 min before a meal results in a better gastric pH control  although it has not been clearly demonstrated that it was associated with an improved clinical efficacy. Zollinger-Ellison syndrome should also be ruled out by appropriate investigations. Once adherence and dosing time are optimal, anti-reflux surgery may be indicated for refractory esophagitis.
Surgery: Laparoscopic fundoplication has become the gold standard procedure for anti-reflux surgery . Whatever the type of wrap, i.e., complete (Nissen procedure ) or partial (Toupet procedure), fundoplication provides excellent results in terms of symptom relief and esophagitis healing rates at 1 and 5 years . A meta-analysis of randomized controlled trials has shown that, compared to the Nissen procedure, laparoscopic Toupet fundoplication is associated with less dysphagia, gas-related symptoms, and reoperation rates, with a similar reflux control . Recurrence of symptoms may occur in approximately 10% of patients at 5–10 years postoperatively . Mortality is approximately 0.05% in patients younger than 70 years . Fundoplication may have significant side effects such as dysphagia (less than 5%), bloating, early satiety, and flatulence, which may significantly alter the quality of life. However, despite these side effects, patient satisfaction is generally over 90% in most studies coming from academic centers . Functional outcome after fundoplication is probably related to the quality of surgery, which should ideally be restricted to units with experience and high-volume activity . Selection of good candidates for surgery is a crucial issue, especially when symptoms persist despite PPI therapy. Most of these patients don’t have overt persisting and uncontrolled acid GERD, and the challenge for physicians is to establish a relationship between symptoms and gastroesophageal reflux, which is the key for a successful operation [20, 30]. By contrast, when refractory esophagitis is present despite adequate medical treatment, there is little doubt that esophagitis is related to insufficient acid control and the indication for surgery is much easier.
What Will Happen in the Long Run?
Response to the Patient
Gastroesophageal reflux disease is a chronic condition which requires long-term treatment. After an initial 4–8 weeks of treatment, most esophagitis and reflux symptoms relapse over a 6-month period. According to the frequency and severity of relapse, intermittent or continuous treatment is indicated. Some patients may need a daily maintenance treatment while others will manage their treatment on an “on-demand” basis. Patients with severe esophagitis often require permanent treatment and/or anti-reflux surgery. The use of PPIs on the long term as maintenance therapy is safe: side effects are rare (less than 10%, mainly headache and diarrhea), and if potential risks related to PPI use have been suggested (infectious diarrhea, pneumonia, bone fracture), none has been yet clearly confirmed by appropriate studies. The alternative of long-term PPI treatment is surgery (fundoplication) which has been shown to provide excellent results in terms of symptom control, but may have significant side effects such as dysphagia (swallowing problems), pain, bloating, or flatulence. Whatever the treatment, if the reflux is adequately controlled, the overall prognosis is very good. By contrast, if the treatment is not taken or inefficient, patients may develop complications of erosive esophagitis, especially when severe lesions are present initially. The most frequent complications are peptic stricture and Barrett’s esophagus. Peptic stricture is caused by inflammation and fibrosis of the esophageal wall and is defined by a narrowing of the esophagus lumen. This will result in swallowing difficulties (“dysphagia”) especially for solid food and may need endoscopic esophageal dilation in addition to antisecretory treatment. Barrett’s esophagus does not cause symptoms per se. It is defined as a change in esophageal mucosa’s structure (“metaplasia”) that may lead, in the long term, to esophageal cancer. If Barrett’s esophagus is clearly a preneoplastic condition, the occurrence of cancer is a long-term process with intermediate stages (low-grade and high-grade dysplasia). In the absence of dysplasia the risk of cancer is low, approximately 0.2% per year. Even if the overall risk of cancer is low, the presence of Barrett’s esophagus should be detected in patients with severe esophagitis and if present the patient should be included in a screening program with regular endoscopic surveillance of esophageal mucosa.
Review of the Literature
Long-term PPI therapy: GERD is a chronic condition which requires a long-term treatment since healing of mucosal injury is not sufficient to change the natural history of the disease. Indeed, randomized controlled trials have shown that 70–90% of patients with erosive esophagitis experience symptomatic and endoscopic relapse over a 6-month period after initial treatment has been stopped [31–33]. Asymptomatic relapse of esophagitis is uncommon. The pretreatment severity of erosive esophagitis is consistently associated with higher relapse rates. As a consequence, long-term antisecretory therapy is mandatory in most patients with esophagitis, the optimal approach being based mainly on symptom relief and pretreatment esophagitis severity. Patients with low-grade esophagitis and intermittent symptoms may be treated “on demand,” while patients with severe esophagitis and frequent symptoms should continue with a daily treatment as a maintenance therapy . Both H2RAs and PPIs could theoretically be used as maintenance therapy but PPIs are much more popular among patients and physicians, considering the more potent acid inhibition with PPIs which are more effective, especially in patients with severe esophagitis [17, 19]. At 5 years, remission rates on maintenance PPI therapy are approximately 90% , although some dose escalation may be mandatory in 1 out of 4 patients as shown in the Lotus study .
Tolerability and safety of PPIs: As a class, PPIs are very well tolerated and can be considered as very safe on the long term, especially when compared with alternative treatments such as surgery (see above). Side effects such as diarrhea and headache occur in less than 10% of patients and can be managed by switching to another PPI molecule. During the past years, several concerns have arisen regarding the long-term use of PPIs. Case-control studies and retrospective reviews have reported an increased risk for Clostridium difficile -associated diarrhea, community-acquired pneumonia, and bone fracture, but conflicting data have been reported and appropriate prospective data are reassuring [17, 19]. Decreased absorption of vitamin B12 has also been reported with limited impact on vitamin B12 plasma levels and in clinical practice vitamin B12 testing is not necessary [19, 34]. There are some controversies regarding the potential interaction between esomeprazole and clopidogrel but appropriate studies did not show any significant clinical impact of this association . More recently, an association between PPI use and chronic kidney disease has been reported that requires further evaluation for confirmation . The potential risk of gastric neoplasm in patients taking long-term PPIs has been a matter of debate for many years, since PPI may increase the incidence of gastric atrophy and intestinal metaplasia—a preneoplastic condition—in patients with Helicobacter pylori infection. Hence, it is now recommended by international guidelines to eradicate Helicobacter pylori in patients treated with PPIs on the long term . Since PPI therapy increases gastric pH, patients on maintenance therapy may have elevated gastrin plasma levels which may increase the density of enterochromaffin-like cells (ECL) in gastric mucosa . However, long-term follow-up (at 5 and 12 years) of two cohorts of patients included in prospective randomized trials did not raise any safety concern associated with long-term PPI use regarding laboratory results and incidence of neoplasms . Data on the effects of very-long-term PPI use (more than 10–20 years) are mandatory but overall most available data available to date are reassuring. This information should be given to the patients when anti-reflux surgery is considered to avoid long-term PPI therapy.
Anti-reflux surgery: Regarding symptomatic outcome, the Lotus study, a large multicentric randomized study, showed that both laparoscopic fundoplication and esomeprazole had remission rate above 90% at 5 years, provided that the dose of PPI could be increased if needed . There was a statistically significant superiority of medical therapy for the primary outcome which was an overall assessment of symptom control by the patient. If each individual reflux symptom was better controlled by the fundoplication (especially regurgitation), the overall assessment was probably hampered by the greater occurrence of side effects in the surgical arm. Therefore, both medical and surgical treatments are valid options for the long-term treatment of GERD, and the decision should be adapted to each individual situation. It is of note that these comparative studies have been conducted in patients whose symptoms were adequately controlled by PPIs. Patients with refractory symptoms represent a different situation which requires an extensive workup to ensure that the persisting symptoms are indeed reflux related, which is usually the case in patients with refractory esophagitis, but much more difficult and challenging in patient with nonerosive reflux disease .
Long-term prognosis: Whatever the treatment, if the reflux is adequately controlled, the overall prognosis is very good, and the incidence of complication is low. On the other hand, if the treatment is not able to adequately control the gastroesophageal reflux (because of poor adherence or insufficient acid secretion inhibition), the patient is exposed to esophagitis relapse and complications.