bs_bs_banner
doi:10.1111/jgh.12777
O R I G I N A L A RT I C L E S
Gastroesophageal reflux disease in patients with diabetes: Preliminary study Mariko Fujiwara,* Takashi Miwa,* Takashi Kawai† and Masato Odawara* *Department of Diabetes, Endocrinology and Metabolism and †Endoscopy Center, Tokyo Medical University Hospital, Tokyo, Japan
Key words Diabetes, Gastroesophageal reflux disease(GERD), Intraesophageal pressure. Correspondence Masato Odawara, Department of Diabetes, Endocrinology and Metabolism, Tokyo Medical University Hospital, 6-7-1 Nish Shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan. Email: [email protected] Potential conflicts of interest: All authors have read and approved the submission of this manuscript. The authors declare no potential conflicts of interest relevant to this article.
Abstract Background and Aim: Some studies report that complications of gastroesophageal reflux disease (GERD) occur more frequently in patients with diabetes mellitus (DM) than in non-diabetic patients. This study used transnasal endoscopy to elucidate the current status of concurrent GERD in patients with type 2 diabetes mellitus, and to examine the associations between intraesophageal pressure and GERD, as well as other neuropathic conditions. Methods: The study included 57 outpatients with type 2 diabetes mellitus. The mean age was 67 years and the duration of DM was 13 years. The mean hemoglobin A1c was 6.8%. Transnasal endoscopic evaluation items were (i) the presence or absence of esophagitis and its severity; (ii) intraesophageal pressure; and (iii) Helicobacter pylori status, which was evaluated by endoscopic findings, such as the presence or absence of gastritis and peptic ulcer, and by urea breath test. Results: Of 57 patients, 24 (42.1%) were given a diagnosis of GERD based on endoscopy. Patients with concurrent GERD were younger, had shorter duration of DM, and were taller and heavier. Interestingly, no difference in body mass index was observed. There was no significant association between the presence of concurrent GERD and diabetic complications, including peripheral neuropathy, and infection or non-infection with H. pylori. Although there was no significant association between the presence of concurrent GERD and intraesophageal pressure values, we found aging, reduced estimated glomerular filtration rate, and the presence of autonomic nerve symptoms to correlate with reduced intraesophageal pressure. Conclusion: The results of this study could be used to answer the question of whether or not endoscopic GERD is a diabetic complication; however, further study is required.
Introduction Diabetes mellitus (DM) is a chronic disease causing numerous pathological conditions as the disease progresses, and such diabetic complications substantially impair patients’ quality of life (QOL). Notably, diet is the main component of treatment in patients with DM, and therefore the presence or absence of upper gastrointestinal dysfunction as a complication is an extremely important pathological condition that not only impairs QOL but is also directly linked to favorable versus poor glycemic control. Gastric symptoms represented by the so-called heavy feeling and nausea are the widely recognized upper gastrointestinal symptoms commonly observed in patients with DM. Meanwhile, as esophageal dysfunction lacks specific symptoms, it is anticipated that patients with DM may often have impaired QOL without recognizing the presence of this disorder. This study used transnasal endoscopic measurements with the aim of elucidating the current status of concurrent gastroesopha-
geal reflux disease (GERD), in terms of baseline characteristics such as complication rate, severity, and glycemic control, in patients with type 2 diabetes mellitus (T2DM) by focusing on GERD as an upper gastrointestinal dysfunction, and examining the associations between intraesophageal pressure and GERD, as well as other neuropathic conditions.
Methods Subjects. The study included 57 patients with T2DM (29 men, 28 women) who regularly visited the outpatient department of Tokyo Medical University Hospital and gave written informed consent to participate in this study. The mean age of all patients was 67 ± 9 years (mean ± standard deviation) and the duration of DM was 13 ± 7.4 years. The mean body mass index (BMI) was 25.7, showing an overall tendency for the patients to be overweight. The hemoglobin A1c was 6.8 ± 1.2%. Fasting blood glucose was 148 ± 56 mg/dL. Treatments for DM were dietary and
Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 1): 31–35 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
31
Gastroesophageal reflux disease and diabetes
M Fujiwara et al.
exercise therapy alone in 17%, oral agents in 60%, and insulin in 23% of patients. Retinopathy and nephropathy were present in 25% and 26% of patients, respectively. For the screening of diabetic peripheral neuropathy, a questionnaire on symptoms of neuropathy (Italian Society of Diabetology)1 was adopted as the medical interview method. Patients scoring ≥ 4 points were determined to be “patients with diabetic neuropathy,” and those scoring ≥ 2 points for at least one of the questions numbered 6–10 were determined to be “patients with autonomic nerve symptoms” (Fig. 1). In total, 55% of patients had autonomic nerve symptoms. As supplementary objective indices of peripheral neuropathy, motor nerve conduction velocity (MCV) in the median and peroneal nerves and the coefficient of variation of R-R intervals (CV R-R) based on electrocardiography were calculated. Concurrent coronary artery and cerebrovascular diseases were found in 16% and 7% of patients, respectively.
Overview of endoscopy and evaluation items. We used a nasal endoscope with an external diameter of 4–5 mm. As the scope is designed to be inserted into the esophagus without touching the posterior portion of the tongue, patients can swallow during the examination. After the scope had been passed into the esophagus transnasally, a 5Fr manometry catheter was inserted from the forceps channel and the intraesophageal pressure was measured. This procedure enabled simultaneous endoscopic observation of esophageal peristaltic activity and measurement of
the maximal peristaltic pressure in lower esophagus after the wet swallow.2 Endoscopic evaluation items were (i) intraesophageal pressure values, (ii) the presence or absence of esophagitis and its severity (Los Angeles classification), and (iii) the presence or absence of gastritis and gastric ulcer, plus (iv) the presence or absence of infection with Helicobacter pylori was examined by urea breath test. Evaluation of gastroenterological symptoms. For the evaluation of subjective gastroenterological symptoms, the Gastrointestinal Symptom Rating Scale (GSRS),3,4 a specific questionnaire for patients with gastrointestinal symptoms, was adopted. Laboratory data. Oral intake (use) of therapeutic drugs, as well as injection of insulin, was prohibited on the day of endoscopy. On that day, patients underwent blood sampling in the fasting state before endoscopy, and hematological data were obtained. The serum adiponectin was measured with a kit from Otsuka Pharmaceutical Co. Ltd (Tokushima, Japan). Statistical analysis. The Mann–Whitney test and chisquared test were used for the assay, and P < 0.05 was considered statistically significant.
Results Of 57 patients, 24 (42.1%) were given a diagnosis of GERD based on endoscopy. The grades by the Los Angeles classification were MC in 62.5% and A in 16.6%, with low-grade GERD accounting for approximately 80% of patients (Fig. 2). Patients were classified into two groups based on the presence or absence of concurrent GERD, and their clinical backgrounds were compared. Patients with concurrent GERD were younger, had shorter duration of DM, and were taller and heavier. Interest-
Grade MC 62.5%
GERD+ GERD–
Grade A
16.6%
Grade B
12.5%
Grade C
4.2%
Grade D
4.2%
42.1%
(Los Angeles classification for the endoscopic assessment of reflux esophagitis) Figure 1 Questionnaire on symptoms of neuropathy (Italian Society of Diabetology).1 Patients scoring ≥ 4 points were classified as having diabetic neuropathy and those scoring ≥ 2 points for at least one of the questions numbered 6–10 were determined to have an autonomic disorder.
32
Figure 2 Results of endoscopic examinations: 42.1% of the patients were diagnosed with gastroesophageal reflux disease (GERD) by endoscopy, among whom 79.1% had grade A or less in the classification for the endoscopic assessment of reflux esophagitis.
Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 1): 31–35 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
M Fujiwara et al.
Gastroesophageal reflux disease and diabetes
Table 1 Comparison of general patient characteristics and laboratory parameters between diabetic patients with and without gastroesophageal reflux disease (GERD)
Age (years) Duration of diabetes (years) Height (cm) Weight (kg) BMI (kg/m2) Systolic BP (mmHg) Diastolic BP (mmHg) HbA1c (%) FPG (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) Total ADP (μg/mL) CV R-R (%) MCV median (m/s) MCV peroneal (m/s) Diabetic neuropathy score (pt) Intraesophageal pressure (mmHg)
GERD(−) (n = 33)
GERD(+) (n = 24)
P-value
70 ± 8.6 15 ± 7.2 157 ± 8.4 63.0 ± 10.2 25.6 ± 4.1 138 ± 16 77 ± 11 6.6 ± 1.0 153 ± 64 99 ± 26 55 ± 15 8.79 ± 6.10 3.16 ± 1.74 54.1 ± 4.6 43.0 ± 4.0 3.5 ± 2.2 59 ± 44
63 ± 9.1 11 ± 7.2 165 ± 8.6 71.0 ± 16.5 25.9 ± 3.7 137 ± 114 81 ± 111 7.1 ± 1.5 134 ± 41 101 ± 33 54 ± 20 5.59 ± 4.03 2.83 ± 1.29 54.6 ± 2.6 46.5 ± 7.4 3.3 ± 3.1 72 ± 48
0.002 0.021 0.001 0.033 0.790 0.840 0.201 0.275 0.191 0.862 0.387 0.048 0.646 0.802 0.240 0.460 0.330
Data are expressed as percentage or mean ± standard deviation. ADP, adiponectin; BMI, body mass index; BP, blood pressure; CV R-R, coefficient of variation of R-R intervals; FPG, fasting plasma glucose; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MCV, motor nerve conduction velocity.
Table 2 Comparison of Gastrointestinal Symptom Rating Scale between diabetic patients with and without gastroesophageal reflux disease (GERD)
Total Reflux Abdominal pain Indigestion Diarrhea Constipation
GERD(−) (n = 33)
GERD(+) (n = 24)
P-value
1.22 ± 0.51 1.45 ± 0.93 1.31 ± 0.58 1.35 ± 0.50 1.27 ± 0.59 1.22 ± 0.35
1.41 ± 0.60 2.03 ± 1.93 1.25 ± 0.47 1.44 ± 0.73 1.27 ± 0.47 1.47 ± 0.69
0.850 0.477 0.846 0.824 0.810 0.429
Data are expressed as percentage or mean ± standard deviation.
Table 3 Relationship of diabetes with the presence of gastroesophageal reflux disease (GERD) P-value Sex Diabetes management (diet/oral agent/insulin) Autonomic disorder Retinopathy Nephropathy Macroangiopathy Helicobacter pylori infection Endoscopic diagnosis of gastritis
Predominantly male None
0.034 0.194
None None None None None None
0.218 0.193 0.312 0.615 0.519 0.151
Chi-squared test was used for statistical analysis.
Table 4 Relationship between intraesophageal pressure and clinical characteristics
ingly, no difference in BMI was observed. Blood pressure and metabolic markers, including blood glucose, serum lipoprotein, and estimated glomerular filtration rate (eGFR), did not differ significantly. On hematological investigation, only the total serum adiponectin levels in patients with concurrent GERD were significantly lower than those in patients without GERD. There were no differences in the CV R-R, in the MCV of the median nerve and peroneal nerves, nor was there any significant difference in the Italian Society of Diabetology (ISD) neuropathy questionnaire results. No significant difference was observed between the two groups in intraesophageal pressure values obtained using a manometry catheter (Table 1). In GSRS scores, no significant difference was observed between the two groups (Table 2). There was a significant relation between GERD and sex; complicated GERD was predominant in males. In all others, there was no significant association between the presence or absence of concurrent GERD, and the presence or absence of diabetic complications, including autonomic disorder, differences in DM management, infection or non-infection with H. pylori, or the presence or absence of gastritis as an endoscopic finding (Table 3). The mean intraesophageal pressure value of all patients was 64.6 mmHg, which was comparable to the mean value of 65.6 mmHg in 20 healthy volunteers reported by Kawai et al.2 We examined the relationships between intraesophageal pressure values and other clinical parameters, and found aging, reduced eGFR, and the presence of autonomic nerve symptoms to correlate with reduced intraesophageal pressure (Table 4).
P-value Sex, BMI, duration, HbA1c, blood pressure, serum lipoprotein, retinopathy, nephropathy, macroangiopathy, endoscopic diagnosis of gastritis, Helicobacter pylori infection, GSRS score Age eGFR (mL/min−1/1.73 m−2) Autonomic disorder
NS
r = −0.284 r = 0.257 Significant
0.049 0.014 0.046
Chi-squared test was used for statistical analysis. BMI, body mass index; eGFR, estimated glomerular filtration rate; GSRS, Gastrointestinal Symptom Rating Scale; HbA1c, hemoglobin A1c; NS, not significant.
Discussion The actual status of concurrent GERD in patients with DM is still controversial,5–10 and one of the main reasons is “multiplicity in diagnosis.” In other words, the disease concept of GERD includes patients with subjective symptoms but without objective findings (non-erosive reflux disease) and patients with esophageal erosion without subjective symptoms (asymptomatic gastroesophageal reflux); therefore, the results will differ among cases depending on the diagnostic method chosen.
Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 1): 31–35 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
33
Gastroesophageal reflux disease and diabetes
M Fujiwara et al.
The results of this study were obtained from endoscopic diagnosis; among the patients with DM participating in the study, 42.1% had been given a diagnosis of GERD. As to reports of endoscopic studies similar to those of our study, Lee et al. found that 32% of patients with T2DM complicated by neuropathy had esophagitis on endoscopy,11 and Tseng et al. reported 34.3% of diabetic patients to have endoscopic esophagitis and that its prevalence was significantly higher than that in non-diabetic patients.8 Despite the baseline characteristics of diabetic patients in these three studies, including ours, being different, it is very interesting that the rates of concurrent endoscopic GERD were reported to be 30–40% in all of the three. This suggests that medical staff engaging in the care of diabetic patients should always be aware that GERD is present in a certain percentage of their patients. However, it is difficult to perform endoscopy in all patients. Therefore, we investigated the clinical background of the patients according to the presence or absence of endoscopic GERD, thereby exploring factors that would be considered useful for prioritizing endoscopy. As a result, we found that endoscopic GERD is more common in men than in women, that the affected patients are younger, and that the duration of DM is shorter; moreover, it was more common in diabetic patients of “large built” (i.e. taller and heavier) than in those with a relatively high BMI. It might be beneficial to recommend endoscopy to confirm the existence of GERD in diabetic patients with such a clinical background. Some past reports7,9,12 recognized concurrent endoscopic GERD in diabetic patients as a pathology resulting from esophageal motor disorder as a manifestation of autonomic disorder. We focused on intraesophageal pressure, reportedly useful in GERD diagnosis,13 as a parameter for evaluating esophageal function. Using a transnasal endoscope enabled simultaneous observation of the inside of the esophagus and measurement of intraesophageal pressure, thereby achieving a more detailed examination of the association with GERD. The intraesophageal pressure in diabetic patients examined in this study was very similar to that of healthy volunteers reported by Kawai and Yamagashi,13 and the results showed no significant association with endoscopic GERD. This might at least suggest that intraesophageal pressure abnormalities may not contribute to the onset of mild endoscopic GERD observed in diabetic patients. It is noteworthy that reduced intraesophageal pressure was not associated with CV R-R, whereas a significant association was observed with increased symptoms of autonomic nerve disorder demonstrated by medical interviews. In other words, our data suggest that reduced intraesophageal pressure in diabetic patients can be regarded as a form of autonomic nerve disorder, and moreover it could be an indicator reflecting relatively mild autonomic nerve disorder with subjective symptoms alone without changes in CV R-R. Gustafsson et al. reported a close association between retinopathy and esophageal dysfunction in diabetic patients,14 which is also considered to support our theory. In this study, no significant associations were observed between the presence of endoscopic GERD and other existing diabetic complications. In addition, there were no associations with glycemic control or arteriosclerosis markers; therefore, GERD is clearly not a pathology involving the so-called angiopathy. In recent years, however, many researchers have come to regard a group of diseases that had formerly been considered to have no association 34
with DM but have since been found to be significantly increased in diabetic patients in large-scale epidemiological studies, such as sleep apnea syndrome,15 Alzheimer’s disease,16 depression,17 and certain types of cancer,18 as “new” diabetic complications. We believe that the results of this study could be used to answer the question of whether or not endoscopic GERD is a diabetic complication; however, further study is required. Like many diseases, no subjective symptoms are observed in the early stage of GERD in diabetic patients, such that standard treatment using proton pump inhibitors (PPI) would be anticipated to start after the onset of certain symptoms. However, Hershcovici et al. reported that the proportion of patients with T2DM not responsive to PPI (the standard therapy for GERD) is high and that it becomes more difficult to treat GERD as the disease condition progresses, which is likely to result in substantial impairment of QOL.19 Therefore, even in diabetic patients free of subjective symptoms, it is expected that recommending endoscopy for screening proactively will be beneficial in preventing QOL impairment in the early stage. Study limitations. The sample size was small in this study; in order to draw a more universal conclusion, it will be necessary to conduct a study in a larger number of diabetic patients with various stages of disease. As the GERD diagnosed in patients included in this study was mostly mild, this may have resulted in subjective symptom disparities. Patients with advanced GERD must be accumulated and analyzed.
References 1 Gentile S, Turco S, Corigliano G, Marmo R. Simplified diagnostic criteria for diabetic distal polyneuropathy: preliminary data of a multicentre study in the Campania region. S.I.M.S.D.N. Group. Acta Diabetol. 1995; 32: 7–12. 2 Kawai T, Yamagishi T, Yagi K et al. Impact of transnasal ultrathin esophagogastroduodenoscopy (UT-EGD) in the evaluation of esophageal peristaltic function. J. Gastroenterol. Hepatol. 2008; 23 (Suppl. 2): S181–5. 3 Svedlund J, Sjodin I, Dotevall G. GSRS: a clinical rating scale for gastrointestinal symptoms in patients with irritable bowel syndrome and peptic ulcer disease. Dig. Dis. Sci. 1988; 33: 129–34. 4 Suzuki H, Masaoka T, Sakai G, Ishii H, Hibi T. Improvement of gastrointestinal quality of life scores in cases of Helicobacter pylori-positive functional dyspepsia after successful eradication therapy. J. Gastroenterol. Hepatol. 2005; 20: 1652–60. 5 Janatuinen E, Pikkarainen P, Laakso M, Pyorala K. Gastrointestinal symptoms in middle-aged diabetic patients. Scand. J. Gastroenterol. 1993; 28: 427–32. 6 Hirata A, Kishida K, Nakatsuji H et al. High prevalence of gastroesophageal reflux symptoms in type 2 diabetics with hypoadiponectinemia and metabolic syndrome. Nutr. Metab. (Lond) 2012; 9: 4. 7 Wang X, Pitchumoni CS, Chandrarana K, Shah N. Increased prevalence of symptoms of gastroesophageal reflux diseases in type 2 diabetics with neuropathy. World J. Gastroenterol. 2008; 14: 709–12. 8 Tseng PH, Lee YC, Chiu HM et al. Association of diabetes and HbA1c levels with gastrointestinal manifestations. Diabetes Care 2012; 35: 1053–60. 9 Lluch I, Ascaso JF, Mora F et al. Gastroesophageal reflux in diabetes mellitus. Am. J. Gastroenterol. 1999; 94: 919–24.
Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 1): 31–35 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
M Fujiwara et al.
10 Ko GT, Chan WB, Chan JC, Tsang LW, Cockram CS. Gastrointestinal symptoms in Chinese patients with type 2 diabetes mellitus. Diabet. Med. 1999; 16: 670–4. 11 Lee SD, Keum B, Chun HJ, Bak YT. Gastroesophageal reflux disease in type ii diabetes mellitus with or without peripheral neuropathy. J. Neurogastroenterol. Motil. 2011; 17: 274–8. 12 Promberger R, Lenglinger J, Riedl O et al. Gastro-oesophageal reflux disease in type 2 diabetics: symptom load and pathophysiologic aspects: a retro-pro study. BMC Gastroenterol. 2013; 13: 132–9. 13 Kawai T, Yamagishi T. Comparison of investigation modalities for evaluation of esophageal peristaltic function. J. Clin. Biochem. Nutr. 2008; 42: 185–90. 14 Gustafsson RJ, Littorin B, Berntorp K et al. Esophageal dysmotility is more common than gastroparesis in diabetes mellitus and is associated with retinopathy. Rev. Diabet. Stud. 2011; 8: 268–75. 15 Shaw JE, Punjabi NM, Wilding JP, Alberti KG, Zimmet PZ. Sleep-disordered breathing and type 2 diabetes: a report from the
Gastroesophageal reflux disease and diabetes
16
17
18
19
International Diabetes Federation Taskforce on Epidemiology and Prevention. Diabetes Res. Clin. Pract. 2008; 81: 2–12. Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P. Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol. 2006; 5: 64–74. van Steenbergen Weijenburg KM, van Puffelen AL, Horn EK et al. More co-morbid depression in patients with type 2 diabetes with multiple complications: an observational study at a specialized outpatient clinic. Diabet. Med. 2011; 28: 86–9. Handelsman Y, Leroith D, Bloomgarden ZT et al. Diabetes and cancer: an AACE/ACE consensus statement. Endocr. Pract. 2013; 19: 675–93. Hershcovici T, Jha LK, Gadam R et al. The relationship between type 2 diabetes mellitus and failure to proton pump inhibitor treatment in gastroesophageal reflux disease. J. Clin. Gastroenterol. 2012; 46: 662–8.
Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 1): 31–35 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
35
doi:10.1111/jgh.12777
O R I G I N A L A RT I C L E S
Gastroesophageal reflux disease in patients with diabetes: Preliminary study Mariko Fujiwara,* Takashi Miwa,* Takashi Kawai† and Masato Odawara* *Department of Diabetes, Endocrinology and Metabolism and †Endoscopy Center, Tokyo Medical University Hospital, Tokyo, Japan
Key words Diabetes, Gastroesophageal reflux disease(GERD), Intraesophageal pressure. Correspondence Masato Odawara, Department of Diabetes, Endocrinology and Metabolism, Tokyo Medical University Hospital, 6-7-1 Nish Shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan. Email: [email protected] Potential conflicts of interest: All authors have read and approved the submission of this manuscript. The authors declare no potential conflicts of interest relevant to this article.
Abstract Background and Aim: Some studies report that complications of gastroesophageal reflux disease (GERD) occur more frequently in patients with diabetes mellitus (DM) than in non-diabetic patients. This study used transnasal endoscopy to elucidate the current status of concurrent GERD in patients with type 2 diabetes mellitus, and to examine the associations between intraesophageal pressure and GERD, as well as other neuropathic conditions. Methods: The study included 57 outpatients with type 2 diabetes mellitus. The mean age was 67 years and the duration of DM was 13 years. The mean hemoglobin A1c was 6.8%. Transnasal endoscopic evaluation items were (i) the presence or absence of esophagitis and its severity; (ii) intraesophageal pressure; and (iii) Helicobacter pylori status, which was evaluated by endoscopic findings, such as the presence or absence of gastritis and peptic ulcer, and by urea breath test. Results: Of 57 patients, 24 (42.1%) were given a diagnosis of GERD based on endoscopy. Patients with concurrent GERD were younger, had shorter duration of DM, and were taller and heavier. Interestingly, no difference in body mass index was observed. There was no significant association between the presence of concurrent GERD and diabetic complications, including peripheral neuropathy, and infection or non-infection with H. pylori. Although there was no significant association between the presence of concurrent GERD and intraesophageal pressure values, we found aging, reduced estimated glomerular filtration rate, and the presence of autonomic nerve symptoms to correlate with reduced intraesophageal pressure. Conclusion: The results of this study could be used to answer the question of whether or not endoscopic GERD is a diabetic complication; however, further study is required.
Introduction Diabetes mellitus (DM) is a chronic disease causing numerous pathological conditions as the disease progresses, and such diabetic complications substantially impair patients’ quality of life (QOL). Notably, diet is the main component of treatment in patients with DM, and therefore the presence or absence of upper gastrointestinal dysfunction as a complication is an extremely important pathological condition that not only impairs QOL but is also directly linked to favorable versus poor glycemic control. Gastric symptoms represented by the so-called heavy feeling and nausea are the widely recognized upper gastrointestinal symptoms commonly observed in patients with DM. Meanwhile, as esophageal dysfunction lacks specific symptoms, it is anticipated that patients with DM may often have impaired QOL without recognizing the presence of this disorder. This study used transnasal endoscopic measurements with the aim of elucidating the current status of concurrent gastroesopha-
geal reflux disease (GERD), in terms of baseline characteristics such as complication rate, severity, and glycemic control, in patients with type 2 diabetes mellitus (T2DM) by focusing on GERD as an upper gastrointestinal dysfunction, and examining the associations between intraesophageal pressure and GERD, as well as other neuropathic conditions.
Methods Subjects. The study included 57 patients with T2DM (29 men, 28 women) who regularly visited the outpatient department of Tokyo Medical University Hospital and gave written informed consent to participate in this study. The mean age of all patients was 67 ± 9 years (mean ± standard deviation) and the duration of DM was 13 ± 7.4 years. The mean body mass index (BMI) was 25.7, showing an overall tendency for the patients to be overweight. The hemoglobin A1c was 6.8 ± 1.2%. Fasting blood glucose was 148 ± 56 mg/dL. Treatments for DM were dietary and
Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 1): 31–35 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
31
Gastroesophageal reflux disease and diabetes
M Fujiwara et al.
exercise therapy alone in 17%, oral agents in 60%, and insulin in 23% of patients. Retinopathy and nephropathy were present in 25% and 26% of patients, respectively. For the screening of diabetic peripheral neuropathy, a questionnaire on symptoms of neuropathy (Italian Society of Diabetology)1 was adopted as the medical interview method. Patients scoring ≥ 4 points were determined to be “patients with diabetic neuropathy,” and those scoring ≥ 2 points for at least one of the questions numbered 6–10 were determined to be “patients with autonomic nerve symptoms” (Fig. 1). In total, 55% of patients had autonomic nerve symptoms. As supplementary objective indices of peripheral neuropathy, motor nerve conduction velocity (MCV) in the median and peroneal nerves and the coefficient of variation of R-R intervals (CV R-R) based on electrocardiography were calculated. Concurrent coronary artery and cerebrovascular diseases were found in 16% and 7% of patients, respectively.
Overview of endoscopy and evaluation items. We used a nasal endoscope with an external diameter of 4–5 mm. As the scope is designed to be inserted into the esophagus without touching the posterior portion of the tongue, patients can swallow during the examination. After the scope had been passed into the esophagus transnasally, a 5Fr manometry catheter was inserted from the forceps channel and the intraesophageal pressure was measured. This procedure enabled simultaneous endoscopic observation of esophageal peristaltic activity and measurement of
the maximal peristaltic pressure in lower esophagus after the wet swallow.2 Endoscopic evaluation items were (i) intraesophageal pressure values, (ii) the presence or absence of esophagitis and its severity (Los Angeles classification), and (iii) the presence or absence of gastritis and gastric ulcer, plus (iv) the presence or absence of infection with Helicobacter pylori was examined by urea breath test. Evaluation of gastroenterological symptoms. For the evaluation of subjective gastroenterological symptoms, the Gastrointestinal Symptom Rating Scale (GSRS),3,4 a specific questionnaire for patients with gastrointestinal symptoms, was adopted. Laboratory data. Oral intake (use) of therapeutic drugs, as well as injection of insulin, was prohibited on the day of endoscopy. On that day, patients underwent blood sampling in the fasting state before endoscopy, and hematological data were obtained. The serum adiponectin was measured with a kit from Otsuka Pharmaceutical Co. Ltd (Tokushima, Japan). Statistical analysis. The Mann–Whitney test and chisquared test were used for the assay, and P < 0.05 was considered statistically significant.
Results Of 57 patients, 24 (42.1%) were given a diagnosis of GERD based on endoscopy. The grades by the Los Angeles classification were MC in 62.5% and A in 16.6%, with low-grade GERD accounting for approximately 80% of patients (Fig. 2). Patients were classified into two groups based on the presence or absence of concurrent GERD, and their clinical backgrounds were compared. Patients with concurrent GERD were younger, had shorter duration of DM, and were taller and heavier. Interest-
Grade MC 62.5%
GERD+ GERD–
Grade A
16.6%
Grade B
12.5%
Grade C
4.2%
Grade D
4.2%
42.1%
(Los Angeles classification for the endoscopic assessment of reflux esophagitis) Figure 1 Questionnaire on symptoms of neuropathy (Italian Society of Diabetology).1 Patients scoring ≥ 4 points were classified as having diabetic neuropathy and those scoring ≥ 2 points for at least one of the questions numbered 6–10 were determined to have an autonomic disorder.
32
Figure 2 Results of endoscopic examinations: 42.1% of the patients were diagnosed with gastroesophageal reflux disease (GERD) by endoscopy, among whom 79.1% had grade A or less in the classification for the endoscopic assessment of reflux esophagitis.
Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 1): 31–35 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
M Fujiwara et al.
Gastroesophageal reflux disease and diabetes
Table 1 Comparison of general patient characteristics and laboratory parameters between diabetic patients with and without gastroesophageal reflux disease (GERD)
Age (years) Duration of diabetes (years) Height (cm) Weight (kg) BMI (kg/m2) Systolic BP (mmHg) Diastolic BP (mmHg) HbA1c (%) FPG (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) Total ADP (μg/mL) CV R-R (%) MCV median (m/s) MCV peroneal (m/s) Diabetic neuropathy score (pt) Intraesophageal pressure (mmHg)
GERD(−) (n = 33)
GERD(+) (n = 24)
P-value
70 ± 8.6 15 ± 7.2 157 ± 8.4 63.0 ± 10.2 25.6 ± 4.1 138 ± 16 77 ± 11 6.6 ± 1.0 153 ± 64 99 ± 26 55 ± 15 8.79 ± 6.10 3.16 ± 1.74 54.1 ± 4.6 43.0 ± 4.0 3.5 ± 2.2 59 ± 44
63 ± 9.1 11 ± 7.2 165 ± 8.6 71.0 ± 16.5 25.9 ± 3.7 137 ± 114 81 ± 111 7.1 ± 1.5 134 ± 41 101 ± 33 54 ± 20 5.59 ± 4.03 2.83 ± 1.29 54.6 ± 2.6 46.5 ± 7.4 3.3 ± 3.1 72 ± 48
0.002 0.021 0.001 0.033 0.790 0.840 0.201 0.275 0.191 0.862 0.387 0.048 0.646 0.802 0.240 0.460 0.330
Data are expressed as percentage or mean ± standard deviation. ADP, adiponectin; BMI, body mass index; BP, blood pressure; CV R-R, coefficient of variation of R-R intervals; FPG, fasting plasma glucose; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MCV, motor nerve conduction velocity.
Table 2 Comparison of Gastrointestinal Symptom Rating Scale between diabetic patients with and without gastroesophageal reflux disease (GERD)
Total Reflux Abdominal pain Indigestion Diarrhea Constipation
GERD(−) (n = 33)
GERD(+) (n = 24)
P-value
1.22 ± 0.51 1.45 ± 0.93 1.31 ± 0.58 1.35 ± 0.50 1.27 ± 0.59 1.22 ± 0.35
1.41 ± 0.60 2.03 ± 1.93 1.25 ± 0.47 1.44 ± 0.73 1.27 ± 0.47 1.47 ± 0.69
0.850 0.477 0.846 0.824 0.810 0.429
Data are expressed as percentage or mean ± standard deviation.
Table 3 Relationship of diabetes with the presence of gastroesophageal reflux disease (GERD) P-value Sex Diabetes management (diet/oral agent/insulin) Autonomic disorder Retinopathy Nephropathy Macroangiopathy Helicobacter pylori infection Endoscopic diagnosis of gastritis
Predominantly male None
0.034 0.194
None None None None None None
0.218 0.193 0.312 0.615 0.519 0.151
Chi-squared test was used for statistical analysis.
Table 4 Relationship between intraesophageal pressure and clinical characteristics
ingly, no difference in BMI was observed. Blood pressure and metabolic markers, including blood glucose, serum lipoprotein, and estimated glomerular filtration rate (eGFR), did not differ significantly. On hematological investigation, only the total serum adiponectin levels in patients with concurrent GERD were significantly lower than those in patients without GERD. There were no differences in the CV R-R, in the MCV of the median nerve and peroneal nerves, nor was there any significant difference in the Italian Society of Diabetology (ISD) neuropathy questionnaire results. No significant difference was observed between the two groups in intraesophageal pressure values obtained using a manometry catheter (Table 1). In GSRS scores, no significant difference was observed between the two groups (Table 2). There was a significant relation between GERD and sex; complicated GERD was predominant in males. In all others, there was no significant association between the presence or absence of concurrent GERD, and the presence or absence of diabetic complications, including autonomic disorder, differences in DM management, infection or non-infection with H. pylori, or the presence or absence of gastritis as an endoscopic finding (Table 3). The mean intraesophageal pressure value of all patients was 64.6 mmHg, which was comparable to the mean value of 65.6 mmHg in 20 healthy volunteers reported by Kawai et al.2 We examined the relationships between intraesophageal pressure values and other clinical parameters, and found aging, reduced eGFR, and the presence of autonomic nerve symptoms to correlate with reduced intraesophageal pressure (Table 4).
P-value Sex, BMI, duration, HbA1c, blood pressure, serum lipoprotein, retinopathy, nephropathy, macroangiopathy, endoscopic diagnosis of gastritis, Helicobacter pylori infection, GSRS score Age eGFR (mL/min−1/1.73 m−2) Autonomic disorder
NS
r = −0.284 r = 0.257 Significant
0.049 0.014 0.046
Chi-squared test was used for statistical analysis. BMI, body mass index; eGFR, estimated glomerular filtration rate; GSRS, Gastrointestinal Symptom Rating Scale; HbA1c, hemoglobin A1c; NS, not significant.
Discussion The actual status of concurrent GERD in patients with DM is still controversial,5–10 and one of the main reasons is “multiplicity in diagnosis.” In other words, the disease concept of GERD includes patients with subjective symptoms but without objective findings (non-erosive reflux disease) and patients with esophageal erosion without subjective symptoms (asymptomatic gastroesophageal reflux); therefore, the results will differ among cases depending on the diagnostic method chosen.
Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 1): 31–35 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
33
Gastroesophageal reflux disease and diabetes
M Fujiwara et al.
The results of this study were obtained from endoscopic diagnosis; among the patients with DM participating in the study, 42.1% had been given a diagnosis of GERD. As to reports of endoscopic studies similar to those of our study, Lee et al. found that 32% of patients with T2DM complicated by neuropathy had esophagitis on endoscopy,11 and Tseng et al. reported 34.3% of diabetic patients to have endoscopic esophagitis and that its prevalence was significantly higher than that in non-diabetic patients.8 Despite the baseline characteristics of diabetic patients in these three studies, including ours, being different, it is very interesting that the rates of concurrent endoscopic GERD were reported to be 30–40% in all of the three. This suggests that medical staff engaging in the care of diabetic patients should always be aware that GERD is present in a certain percentage of their patients. However, it is difficult to perform endoscopy in all patients. Therefore, we investigated the clinical background of the patients according to the presence or absence of endoscopic GERD, thereby exploring factors that would be considered useful for prioritizing endoscopy. As a result, we found that endoscopic GERD is more common in men than in women, that the affected patients are younger, and that the duration of DM is shorter; moreover, it was more common in diabetic patients of “large built” (i.e. taller and heavier) than in those with a relatively high BMI. It might be beneficial to recommend endoscopy to confirm the existence of GERD in diabetic patients with such a clinical background. Some past reports7,9,12 recognized concurrent endoscopic GERD in diabetic patients as a pathology resulting from esophageal motor disorder as a manifestation of autonomic disorder. We focused on intraesophageal pressure, reportedly useful in GERD diagnosis,13 as a parameter for evaluating esophageal function. Using a transnasal endoscope enabled simultaneous observation of the inside of the esophagus and measurement of intraesophageal pressure, thereby achieving a more detailed examination of the association with GERD. The intraesophageal pressure in diabetic patients examined in this study was very similar to that of healthy volunteers reported by Kawai and Yamagashi,13 and the results showed no significant association with endoscopic GERD. This might at least suggest that intraesophageal pressure abnormalities may not contribute to the onset of mild endoscopic GERD observed in diabetic patients. It is noteworthy that reduced intraesophageal pressure was not associated with CV R-R, whereas a significant association was observed with increased symptoms of autonomic nerve disorder demonstrated by medical interviews. In other words, our data suggest that reduced intraesophageal pressure in diabetic patients can be regarded as a form of autonomic nerve disorder, and moreover it could be an indicator reflecting relatively mild autonomic nerve disorder with subjective symptoms alone without changes in CV R-R. Gustafsson et al. reported a close association between retinopathy and esophageal dysfunction in diabetic patients,14 which is also considered to support our theory. In this study, no significant associations were observed between the presence of endoscopic GERD and other existing diabetic complications. In addition, there were no associations with glycemic control or arteriosclerosis markers; therefore, GERD is clearly not a pathology involving the so-called angiopathy. In recent years, however, many researchers have come to regard a group of diseases that had formerly been considered to have no association 34
with DM but have since been found to be significantly increased in diabetic patients in large-scale epidemiological studies, such as sleep apnea syndrome,15 Alzheimer’s disease,16 depression,17 and certain types of cancer,18 as “new” diabetic complications. We believe that the results of this study could be used to answer the question of whether or not endoscopic GERD is a diabetic complication; however, further study is required. Like many diseases, no subjective symptoms are observed in the early stage of GERD in diabetic patients, such that standard treatment using proton pump inhibitors (PPI) would be anticipated to start after the onset of certain symptoms. However, Hershcovici et al. reported that the proportion of patients with T2DM not responsive to PPI (the standard therapy for GERD) is high and that it becomes more difficult to treat GERD as the disease condition progresses, which is likely to result in substantial impairment of QOL.19 Therefore, even in diabetic patients free of subjective symptoms, it is expected that recommending endoscopy for screening proactively will be beneficial in preventing QOL impairment in the early stage. Study limitations. The sample size was small in this study; in order to draw a more universal conclusion, it will be necessary to conduct a study in a larger number of diabetic patients with various stages of disease. As the GERD diagnosed in patients included in this study was mostly mild, this may have resulted in subjective symptom disparities. Patients with advanced GERD must be accumulated and analyzed.
References 1 Gentile S, Turco S, Corigliano G, Marmo R. Simplified diagnostic criteria for diabetic distal polyneuropathy: preliminary data of a multicentre study in the Campania region. S.I.M.S.D.N. Group. Acta Diabetol. 1995; 32: 7–12. 2 Kawai T, Yamagishi T, Yagi K et al. Impact of transnasal ultrathin esophagogastroduodenoscopy (UT-EGD) in the evaluation of esophageal peristaltic function. J. Gastroenterol. Hepatol. 2008; 23 (Suppl. 2): S181–5. 3 Svedlund J, Sjodin I, Dotevall G. GSRS: a clinical rating scale for gastrointestinal symptoms in patients with irritable bowel syndrome and peptic ulcer disease. Dig. Dis. Sci. 1988; 33: 129–34. 4 Suzuki H, Masaoka T, Sakai G, Ishii H, Hibi T. Improvement of gastrointestinal quality of life scores in cases of Helicobacter pylori-positive functional dyspepsia after successful eradication therapy. J. Gastroenterol. Hepatol. 2005; 20: 1652–60. 5 Janatuinen E, Pikkarainen P, Laakso M, Pyorala K. Gastrointestinal symptoms in middle-aged diabetic patients. Scand. J. Gastroenterol. 1993; 28: 427–32. 6 Hirata A, Kishida K, Nakatsuji H et al. High prevalence of gastroesophageal reflux symptoms in type 2 diabetics with hypoadiponectinemia and metabolic syndrome. Nutr. Metab. (Lond) 2012; 9: 4. 7 Wang X, Pitchumoni CS, Chandrarana K, Shah N. Increased prevalence of symptoms of gastroesophageal reflux diseases in type 2 diabetics with neuropathy. World J. Gastroenterol. 2008; 14: 709–12. 8 Tseng PH, Lee YC, Chiu HM et al. Association of diabetes and HbA1c levels with gastrointestinal manifestations. Diabetes Care 2012; 35: 1053–60. 9 Lluch I, Ascaso JF, Mora F et al. Gastroesophageal reflux in diabetes mellitus. Am. J. Gastroenterol. 1999; 94: 919–24.
Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 1): 31–35 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
M Fujiwara et al.
10 Ko GT, Chan WB, Chan JC, Tsang LW, Cockram CS. Gastrointestinal symptoms in Chinese patients with type 2 diabetes mellitus. Diabet. Med. 1999; 16: 670–4. 11 Lee SD, Keum B, Chun HJ, Bak YT. Gastroesophageal reflux disease in type ii diabetes mellitus with or without peripheral neuropathy. J. Neurogastroenterol. Motil. 2011; 17: 274–8. 12 Promberger R, Lenglinger J, Riedl O et al. Gastro-oesophageal reflux disease in type 2 diabetics: symptom load and pathophysiologic aspects: a retro-pro study. BMC Gastroenterol. 2013; 13: 132–9. 13 Kawai T, Yamagishi T. Comparison of investigation modalities for evaluation of esophageal peristaltic function. J. Clin. Biochem. Nutr. 2008; 42: 185–90. 14 Gustafsson RJ, Littorin B, Berntorp K et al. Esophageal dysmotility is more common than gastroparesis in diabetes mellitus and is associated with retinopathy. Rev. Diabet. Stud. 2011; 8: 268–75. 15 Shaw JE, Punjabi NM, Wilding JP, Alberti KG, Zimmet PZ. Sleep-disordered breathing and type 2 diabetes: a report from the
Gastroesophageal reflux disease and diabetes
16
17
18
19
International Diabetes Federation Taskforce on Epidemiology and Prevention. Diabetes Res. Clin. Pract. 2008; 81: 2–12. Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P. Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol. 2006; 5: 64–74. van Steenbergen Weijenburg KM, van Puffelen AL, Horn EK et al. More co-morbid depression in patients with type 2 diabetes with multiple complications: an observational study at a specialized outpatient clinic. Diabet. Med. 2011; 28: 86–9. Handelsman Y, Leroith D, Bloomgarden ZT et al. Diabetes and cancer: an AACE/ACE consensus statement. Endocr. Pract. 2013; 19: 675–93. Hershcovici T, Jha LK, Gadam R et al. The relationship between type 2 diabetes mellitus and failure to proton pump inhibitor treatment in gastroesophageal reflux disease. J. Clin. Gastroenterol. 2012; 46: 662–8.
Journal of Gastroenterology and Hepatology 2015; 30 (Suppl. 1): 31–35 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
35
