Gastro-oesophageal reflux disease in type 2 diabetics: symptom load and pathophysiologic aspects - a retro-pro study

Gastro-oesophageal reflux disease (GERD) is one of the most common disorders of the upper gastrointestinal tract in developed countries. Up to 40% of the adult population suffers from reflux symptoms [1]. At the same time, diabetes mellitus (DM), especially DM type 2 (T2D), which accounts for up to 95% of diabetes cases, is dramatically increasing worldwide. In 2010, 284.8 million people were affected. It has been estimated that that number will rise to 438.7 million diabetic adults in the year 2030 [2]. Thus, both disorders are of increasing medical and socioeconomic interest.

T2D has been described as a possible risk factor for the development of GERD [3–6]. More recently, it has been suggested that the metabolic syndrome defined by visceral fat accumulation, dyslipidaemia, hypertension, and hyperglycaemia correlates with the occurrence of GERD [7]. As recently reviewed, several pathophysiologic factors may explain this finding: (i) hyperglycaemia causes increased gastric H⁺ secretion, higher levels of bile acids, and reduced bicarbonate levels; (ii) delayed oesophageal and gastric emptying, increased rates of transient lower oesophageal sphincter (LES) relaxations, and decreased LES pressure has been reported during hyperglycaemia in patients with T2D; and, (iii) hiatal hernia and increased obesity rates may also contribute to the development of GERD in these patients [8].

However, many of the reviewed studies did not discriminate between GERD-specific symptoms and general upper gastrointestinal symptoms, which are frequently found in diabetics [8]. Moreover, most studies were based on GERD questionnaires and did not determine GERD using standard pH-metry and manometry [3–5, 9, 10]. To date, no study exists about GERD and GERD-specific symptoms in patients with T2D that has included upper gastrointestinal endoscopy, barium oesophagogram, manometry, and 24-hour oesophageal pH-monitoring concurrently.

The aim of this study was to investigate GERD-specific symptoms and reflux parameters in patients with T2D using these standard diagnostic tools. Second, the results were compared to non-diabetic GERD-patients in order to explore possible diabetes-related differences. Special emphasis was placed on extra-oesophageal GERD symptoms that have not been described for diabetics thus far.

Diabetes is a major health problem, as it is an important contributor to various other diseases and its incidence still continues to rise. Despite the fact that its role as a risk factor for GERD has been demonstrated and that GERD itself is of high clinical relevance, little light has been shed on the connection between the two diseases [3, 4, 6]. For the first time, the present study characterizes GERD patients concurrently affected by T2D using well-established diagnostic methods for oesophageal testing.

The individual symptom load differs between diabetics and non-diabetics [19]. In our study, dysphagia and globus sensation were found significantly more frequently in GERD patients with T2D. In the course of GERD, dysphagia may be caused by decreased oesophageal motility or by peptic oesophageal stricture due to acid reflux [20, 21]. In our study population, impaired peristalsis, as assessed by manometry, was somewhat more frequent among patients with T2D. Moreover, dysphagia has been shown to be related to the presence of high LES pressure in patients with a hypertensive LES [22, 23], which is also true for our investigation.

Globus sensation has been reported to be a common functional symptom due to inflammation of the throat caused by GERD [24, 25]. In our study, however, there was no significant difference in DeMeester scores between the two groups. Diabetics used antidepressants more frequently than non-diabetics. Psychological impairment has been discussed as another possible factor contributing to globus sensation [26]. The approximately two-fold higher prevalence of laryngeal lesions in patients with T2D may also contribute to the increased prevalence of globus sensation. The exact etiology of globus sensation, however, remains incompletely understood [27, 28].

Epigastric pain and heartburn are known to be the most frequent GERD-associated symptoms, occurring in up to 90% of patients with proven T2D [29]. Similar results have been found in the present investigation. The higher prevalence of heartburn, defined as “hypersensitivity” to acid reflux in the non-diabetes group, may be explained, at least partly, by diabetic neuropathy [4, 8, 30]. Moreover, the higher rates of hiatal hernia in the non-diabetes group in our study may have also contributed to the higher heartburn rate [31]. However, epigastric pain and heartburn are not necessarily associated with GERD. Studies that deal with symptoms only, without oesophageal testing, cannot verify the actual presence of GERD [3–5, 9, 10]. Thus, a direct comparison between the results of these studies and our findings is not valid.

Regurgitation, a major problem for many reflux patients, is predominant in non-diabetics and within the range described for this population [8]. Increased rates of hiatal hernia in the non-diabetes group may have had an impact on this finding [31]. For patients with T2D, however, the regurgitation rate of about 48% was much higher in our study compared to 16% in a previous series of type 2 diabetics [32]. Impaired peristalsis was found more frequently in patients with T2D, which may be another explaination for our findings.

Microaspiration of the gastro-oesophageal refluate and subsequent airway inflammation, are the major mechanisms that cause respiratory symptoms in GERD patients [33–35]. Although the overall prevalence of respiratory symptoms did not differ between T2D patients and non-diabetics, it is noteworthy that laryngeal lesions, including leukoplakia and ulcerations, were observed more frequently in patients with T2D. Recently, epidemiologic evidence has suggested that cancer incidence is associated with DM, as well as certain diabetic risk factors, including obesity [36–38]. Our goal, however, was not the long-term observation of possible precancerous lesions. Nevertheless, to the best of our knowledge, this is the first report describing extra-oesophageal reflux symptoms in diabetic GERD patients.

Overall, the summed scores of GERD symptoms were comparable in diabetics and non-diabetics in our study. Similar results have been published earlier [19, 39]. Likewise, GERD-specific quality of life was comparable in diabetic and non-diabetic patients although there were some minor differences in health related quality of life [40]. All in all, data on the prevalence of reflux symptoms vary widely within T2D patients, ranging from 25.3% to 45.0% [3, 39]. In contrast to other studies, we did not screen for GERD-related symptoms in diabetics since these symptoms were an inclusion criterion in our study.

Notably, the duration of T2D and the presence of neuropathia had no major impact on GERD symptoms in our investigation [41, 42]. In the present series, this was not the case. This is probably due to the fact that (i) patients with T2D were under adequate glycaemic control, has already been pointed out earlier [3, 9, 43]. Moreover, (ii) the duration of GERD symptoms did not differ compared to non-diabetics.

Hiatal hernia rates were relatively high in both groups. Patients referred to our motility laboratories for GERD diagnostics are usually those who still suffer from GERD-related symptoms despite PPI intake. In general, hiatal hernia is the major reason for persisting complaints [44]. This could possibly be some kind of ‘pre-selection’ of our patients. However hiatal hernia rates were more frequent in non-diabetics. This is a surprising result considering that higher BMI levels are known to be a risk factor for the presence of hiatal hernia, and that higher BMI levels were found in patients with T2D in our study [37, 45]. Nevertheless, our results are in accordance with a previous report demonstrating that, in morbidly obese patients, the rate of hiatal hernia was inversely correlated with glycaemic control [46]. In diabetics, delayed gastric emptying and decreased proximal retention of meals have been reported [47]. Furthermore, an inverse correlation between proximal gastric volume and the formation of a sliding hiatal hernia has been described [48]. Thus, altered intragastric meal distribution in patients with T2D may contribute to a lower prevalence of hiatal hernias in diabetic patients.

Higher BMI levels, as found in the T2D patients in our study, are an established risk factor for the development of GERD, and, thus, for esophagitis [49]. Notably, histological rates of esophagitis and Barrett’s oesophagus, as well as low-grade and high-grade dysplasia, were somewhat higher in T2D patients compared to controls. Although these results failed to reach statistical significance, which is probably due to the relatively low number of patients, one has to emphasize the possible clinical importance of such results, because, for example, low-grade dysplasia was more than twice as high in diabetics than in non-diabetics (10.8% vs. 3.8%). It has already been suggested that visceral fat, another contributing factor to T2D, was associated with Barrett’s esophagitis, and with increased esophageal inflammation and high-grade dysplasia in subjects with Barrett’s esophagitis [50]. Moreover, since patients with T2D may have a lower oesophageal sensitivity, as suggested by the decreased heartburn rates, GERD and, in consequence, precancerous lesions, might be diagnosed later than in non-diabetics. However, the primary goal of our study was not to prove the increased risk of T2D patients for developing oesophageal adenocarcinoma, but to describe T2D-related differences in the symptom load and the pathophysiology of GERD. Consequently, surveillance studies will be necessary in order to explore the cancerous potential of T2D in GERD patients.

Our results showed significantly higher rates of helicobacter pylori infection in patients with T2D. This is in accordance with the published literature, as diabetics, especially those with poor glycaemic control, are more prone to infections [8, 43]. Nevertheless, other studies reported even higher percentages of helicobacter pylori infection, with differences between diabetics and non-diabetics of up to 80% versus 30%, respectively [51, 52]. The discrepancy between these results and our findings may be explained by the fact that many of our patients had been pretreated by eradication therapy.

Hyperglycaemia decreases LES pressure in diabetics, with up to 92% of patients having resting LES pressure between 0 and 8mmHG [30]. Consequently, lower LES pressure predisposes to GERD [8]. In our investigation, however, T2D patients had significantly higher LES pressure levels compared to non-diabetics. Various studies have dealt with LES pressure in diabetic subjects [30, 53]. However, these data are only partly comparable to our results, since all of these studies included diabetic patients without a history of GERD.

DeMeester scores were lower in T2D patients, although not statistically significant. The higher prevalence of hiatal hernia in the non-diabetic group and the significantly lower LES pressure may account for this finding. In addition, high helicobacter pylori infection rates could have ameliorated gastric secretion [8].

Notably, our data show no significant correlations between HbA1c levels and LES pressure, relaxation time, or peristalsis. Gastrointestinal symptoms and complications do not always correlate with the duration of DM and glycaemic control [43]. To date, no single risk factor for GERD in T2D has been identified, as the aetiology of GERD is multifactorial [43].

The limitation of our study is the retrosprective design, although all data were derived from a prospective database. The relatively low number of patients might be considered another drawback of the study. To the best of our knowledge, however, this is the largest investigation on proven GERD in T2D.

T2D GERD patients (i) exhibit other types of symptoms than do non-diabetics, especially dysphagia, globus sensation, and, at least to some extent, extra-oesophageal symptoms with higher rates of proven laryngeal lesions; (ii) are infected with helicobacter pylori more frequently; and (iii) show higher LES pressure levels; and (iv) lower rates of hiatal hernia. The results may have some implications for diagnostic and therapeutic strategies in diabetic GERD patients. Since the incidence of the most frequently encountered GERD symptom, namely heartburn, is lower in patients with T2D, other signs and symptoms should lead to the suspected diagnosis of GERD. Particularly with regard to possibly higher rates of dysplasia and Barrett metaplasia in T2D GERD patients, the diagnostic work-up in diabetic patients could be of the utmost importance.