Etiology and Natural History of Gastroesophageal Reflux Disease and Predictors of Progressive Disease

Progression of Gastroesophageal Reflux Disease Under Therapy

Two scenarios have been proposed regarding the natural history of GERD. The first is that GERD is a categorical disorder, and the patient can be categorized as having either nonerosive reflux disease (NERD) or erosive reflux disease (ERD) and patients remain in their diagnosed category. The second is that GERD is a spectrum disorder with NERD at one end of the spectrum and BE and esophageal adenocarcinoma at the other end, with the ability of the disease to progress through the spectrum over time. Current clinical evidence appears to support the spectrum concept in that there are several studies showing progression of patients from their initial category to a more advanced category.

One of the largest studies of GERD progression was the ProGERD study involving 2721 patients from Germany, Switzerland, and Austria. Patients were categorized endoscopically as having NERD or ERD based on the Los Angeles (LA) classification. Patients with BE were excluded. The study consisted of an initial endoscopy to categorize the patients, followed by 4 to 8 weeks of PPI therapy, followed by maintenance therapy provided by the patients' primary care physician. A follow-up endoscopy was performed at 2 and 5 years. Progression to BE, confirmed by endoscopy and biopsy during the 5 years of therapy, was observed in 5.9% of patients with NERD, 12.1% of patients with ERD (LA grade A/B), and 19.7% of patients with severe ERD (LA grade C/D). Patients with severe ERD on initial endoscopy had the highest incidence of progression to BE. Overall, 10% of patients progressed to BE during the 5-year follow-up period. This study clearly showed that disease progression occurred in a proportion of patients while receiving PPI therapy and established that, although regular and consistent PPI therapy can improve symptoms and heal erosive esophagitis, it does not stop progression to BE.

The second study consisted of a group of 33 patients who were referred to a gastrointestinal clinic in Milan, Italy with the diagnosis of NERD. Patients were endoscopically normal but had an abnormal 24-hour esophageal pH monitoring study at baseline. The patients were observed for 10 years. During the first 5 years of follow-up, 18 patients had a repeat endoscopy and 17 (94.4%) had esophagitis. When active PPI therapy was discontinued after 10 years of follow-up, symptoms relapsed in 96.6% of the available patients (28/29). This study showed that GERD of all severities requires long-term medical therapy. It further showed the progressive capability of NERD and that the absence of endoscopic esophagitis at presentation is not a positive prognostic factor.

A third study of 40 Swedish patients with GERD, confirmed by an abnormal esophageal acid exposure on 24-hour pH monitoring, showed that when progression occurred during PPI treatment, it was associated with the development of manometric abnormalities of the lower esophageal sphincter (LES). Patients in the study underwent endoscopy, esophageal manometry, and 24-hour esophageal pH monitoring at the beginning and end of a 21-year follow-up period. At baseline, 24 patients had NERD and 16 ERD. None had endoscopic or histologic evidence of BE. Of the 24 patients with NERD, a baseline 14 progressed to ERD and 10 (41.7%) to BE. Of the 16 patients with ERD at baseline, 8 developed BE (50%). Overall, 18 of 40 (45%) progressed to BE over the 21-year follow-up period. Progression was associated with a significantly shorter LES mean intraabdominal length ( P = .01) and a significantly greater esophageal acid exposure on pH monitoring ( P = .004) compared with patients who did not progress. Furthermore, the study population showed a trend toward increased use of PPIs over the 21-year follow-up period, and an increase in the number of patients who developed erosive esophagitis. These results indicate that patients with a long duration of GERD are more likely to progress despite PPI treatment, likely due to deterioration of the LES during the course of therapy.

The previous study was the first to introduce the concept that the progression of GERD while on PPI therapy was likely due to progressive LES damage during therapy. In practice the byword became, the greater the LES damage, the less effective the PPI therapy. This concept was examined prospectively in a study of GERD patients with different degrees of LES and esophageal body functionality prior to therapy. A damaged LES was defined as a pressure less than 8 mm Hg and/or a LES abdominal length less than 1.2 cm. More than 20% ineffective peristaltic contractions were used to indicate a compromised esophageal body. PPI failure, shown by the recurrence of symptoms or esophagitis, occurred in 7.7% (2/26) of patients with a normal LES and normal esophageal body, 38.1% (24/63) of patients with a damaged LES and normal esophageal body, and 79.5% (31/39) of patients with a damaged LES and a compromised esophageal body. These results strongly indicated that PPI therapy was less effective in patients with a damaged LES than in those with a normal LES and that a compromised esophageal body added to their ineffectiveness.

In an effort to understand further the effects of mechanical factors in the progression of GERD under PPI therapy, we studied the existence of mechanical abnormalities in the spectrum of GERD. This included factors such as anatomic distortion of the hiatal anatomy by a hiatal hernia, abnormalities of the LES, and the effects of LES incompetency on esophageal exposure to acid and bile. Fifty symptomatic consecutive patients were identified for each of the four stages of GERD from the preoperative records of those who had a laparoscopic Nissen fundoplication performed by us. The stages were (1) NERD, (2) mild ERD, defined as “healable esophagitis” with PPI therapy, (3) severe ERD, defined as “difficult to heal esophagitis” that persisted despite PPI therapy, and (4) BE. Exclusion criteria were normal preoperative esophageal acid exposure on pH monitoring, esophageal pH monitoring performed elsewhere, previous antireflux surgery, and a named esophageal motility disorder or a low contraction amplitude in distal half of the esophagus. Patients who could not be contacted for study approval were also excluded. All patients' records contained a detailed preoperative clinical questionnaire, and all underwent a preoperative upper gastrointestinal endoscopy, esophageal manometry, and distal esophageal pH monitoring. Patients who had received PPI therapy prior to their initial endoscopy were excluded from the NERD group. BE was diagnosed by the presence of microscopic intestinal metaplasia on biopsy of an endoscopic visible columnar-lined esophagus of any length. The final studied population consisted of 39 patients with NERD, 42 with mild ERD (i.e., healable esophagitis), 35 with severe ERD (i.e., difficult to heal esophagitis), and 44 with BE.

The significant anatomic and physiologic differences between the patient groups are shown in Fig. 16.1 . The differences between the patient groups “healable esophagitis” and the “difficult to heal esophagitis” was the status of their LES. Preoperative mechanical factors (i.e., altered hiatal anatomy, LES resting pressure, and LES lengths) were significantly more impaired in patients with “difficult to heal esophagitis” and BE compared with those with “healable esophagitis” and NERD. Esophageal acid and bile exposure also was worse in the more severe GERD stages with the most severe in patients with BE. The composite pH score, which includes all the acid reflux measures in a weighted calculation of reflux severity, discriminated most clearly between the different GERD stages. These findings support the importance of LES length and resting pressure in the etiology and severity of GERD. The findings also link the extent and severity of endoscopic mucosal injury with the extent and severity of mechanical abnormalities at the gastroesophageal barrier. Furthermore, they suggest that progression of GERD in a patient on PPI therapy commonly requires a concomitant reduction in LES length and pressure and altered hiatal anatomy. These findings are similar to other studies of regression analysis which show that the status of the LES and size of the hiatal hernia are dominant determinants of esophagitis and its severity.

Taken together, the above studies show most importantly the following: (1) the treatment of GERD with PPIs does not prevent progression of disease, (2) the stages of GERD severity correlate well to the altered mechanical features of the gastroesophageal reflux barrier, (3) damage to the LES is associated with altered hiatal anatomy, increased esophageal exposure to refluxed acid and bile, and (4) PPI therapy does not protect against continuing LES damage. These findings encourage the concept that to stop the progression of GERD requires (1) early recognition of the symptoms and signs of progressive disease, (2) manometric assessment of the LES, (3) measurements of esophageal acid exposure, (4) endoscopic examination of the esophagus, and, if indicated, (5) early surgical intervention to correct the LES abnormalities. To do so requires an understanding of the pathophysiology and the histopathology of GERD.