ORIGINAL ARTICLE
Distribution of Esophageal Motor Disorders in Diabetic Patients With Dysphagia Nina S. George, MD,* Vikram Rangan, MD,* Zhuo Geng, MD,* Freeha Khan, MD,* Adam Kichler, DO,w Scott Gabbard, MD,w Stephen Ganocy, PhD,* and Ronnie Fass, MD, FACG*
Background: Diabetes mellitus can cause various gastrointestinal symptoms. Assessment of esophageal dysmotility in diabetic patients has been scarcely studied. The aim of this study was to determine the esophageal motor characteristics of diabetic versus nondiabetic patients who present with dysphagia. Methods: High-resolution esophageal manometries (HREMs) of 83 diabetic patients and 83 age and gender-matched nondiabetic patients with dysphagia from 2 medical centers were included in this study. Demographic information, medical comorbidities, and medication usage were recorded for each patient in a single registry. HREM of each patient was evaluated and the different functional parameters were recorded. Key Results: Overall, 46% of diabetic patients were found to have an esophageal motor disorder. Diabetic patients with dysphagia were more likely to have failed swallows on HREM (50.6% vs. 33.7%; P = 0.03) as compared with nondiabetic patients. Among diabetic patients, those being treated with insulin were more likely to have failed (69.0% vs. 40.7%; P = 0.01) and weak (65.5% vs. 33.3%; P = 0.005) swallows as compared with diabetic patients not on insulin. Among diabetic patients, those with abnormal manometry were more likely to demonstrate diabetic retinopathy (27.0% vs. 8.7%; P = 0.04). There was a trend toward increased incidence of esophagogastric junction outflow obstruction in diabetic patients (10.8% vs. 2.4%; P = 0.057) as compared with nondiabetic patients. Conclusions: Nearly half of diabetic patients with dysphagia have some type of an esophageal motility disorder. Diabetic retinopathy and the use of insulin are predictive of esophageal motor abnormalities among diabetic patients. Key Words: esophagus, diabetes mellitus, esophageal dysmotility, dysphagia
(J Clin Gastroenterol 2017;00:000–000)
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iabetes mellitus (DM) is a chronic metabolic disease that in 2008 was estimated to affect >347 million people across the world.1 The disease affects numerous organs throughout the body, and significantly contributes to a decrease in quality of life. Many patients with diabetes Received for publication March 31, 2017; accepted June 1, 2017. From the *The Esophageal and Swallowing Center, Division of Gastroenterology and Hepatology, MetroHealth Medical Center; and wThe Esophageal Center, The Cleveland Clinic Foundation, Cleveland, OH. The authors declare that they have nothing to disclose. Address correspondence to: Ronnie Fass, MD, FACG, Case Western Reserve University; Division of Gastroenterology and Hepatology, Esophageal and Swallowing Center; MetroHealth Medical Center, 2500 Metrohealth Drive, Cleveland, OH 44109 (e-mails: [email protected]; [email protected]). Copyright r 2017 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MCG.0000000000000894
complain of gastrointestinal (GI) symptoms as well, but the extent to which these symptoms correlate with abnormalities in GI motility remains to be elucidated.2 Prior studies have documented abnormal esophageal manometry in 58% to 63% of diabetic patients.3,4 However, one of these studies noted that there was no significant difference in the prevalence of dysphagia between those with normal and those with abnormal esophageal manometry, and that the majority of patients with abnormal esophageal manometry did not report dysphagia as their primary gastrointestinal complaint.3 Bytzer et al5 estimated that up to 15.4% of diabetic patients do have esophageal symptoms including heartburn, dysphagia, or both. Several underlying mechanisms have been proposed to explain the presence of esophageal motility abnormalities in patients with DM. They include impaired esophageal motility due to events of acute hyperglycemia; abnormal functioning of the interstitial cells of Cajal and the enteric nervous system; decreased nitric oxide synthase expression and alteration of nitergric neurotransmission; and fibrosis in the setting of microvascular damage from longstanding diabetes, with a resulting increase in esophageal stiffness and decreased compliance.4–9 In addition, it has been postulated that patients with longstanding diabetes may have impaired esophageal perception, manifested as reduced esophageal sensitivity secondary to increased esophageal wall stiffness, and decreased compliance.3,8 Very few studies have evaluated large cohorts of diabetic patients with dysphagia. Most studies have shown limited correlation between symptoms of dysphagia and odynophagia, and esophageal manometric abnormalities.10,11 Prior studies have demonstrated that abnormal manometry is common in patients with gastroesophageal reflux disease12–15 with reported rates of abnormal manometry ranging from 39% to 48%,12–14 and with ineffective esophageal motility (diagnosed on the basis of conventional manometry parameters) being the most frequently encountered abnormality.12,13 The aims of our study were to compare esophageal motor characteristics, using high-resolution esophageal manometry (HREM), between diabetic and age and gendermatched nondiabetic patients presenting with dysphagia. In addition, to determine which of the DM-associated abnormalities drives esophageal motor findings.
METHODS Subjects HREM studies from October 2013 to August of 2015 were reviewed in consecutive manner from 2 medical centers— MetroHealth Medical Center/Case Western Reserve University and Cleveland Clinic Foundation. Patients were included if they
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were over the age of 18, were diagnosed with DM before the esophageal manometry, were referred to the procedure for dysphagia, and were able to fully complete a HREM. Patients who were not capable of undergoing a complete HREM, and those with diagnosis of achalasia on esophageal manometry were excluded. We identified 83 patients with DM, which was defined as documented fasting plasma glucose of Z126 mg/dL, or documented hemoglobin A1c of Z6.5%. This was further substantiated by a diagnosis of DM that was noted in primary care physician or endocrinologist’s chart documentation. All patients underwent HREM during the aforementioned specified time period for dysphagia, and did not meet any of the above exclusion criteria. From the same period of time, we identified 160 nondiabetic patients who underwent HREM for dysphagia, and created an age and gender-matched list of 83 nondiabetic patients for comparison. Demographics, clinical characteristics, manometric diagnosis (using the Chicago Classification version 3.0), and detailed manometric findings were documented. Patients’ electronic medical records were evaluated for clinical characteristics related or unrelated to DM, such as medication usage, invasive and noninvasive tests, comorbidities, and complications of DM (presence of diabetic retinopathy, peripheral neuropathy, and nephropathy). The information obtained from the 2 medical centers was incorporated into a single registry. This study protocol was approved by the Institutional Review Boards of both MetroHealth Medical Center and Cleveland Clinic Foundation.
were used to model data which was in the form of numerical counts. Multivariate logistic regression analysis was used to model dichotomous outcome data and multinomial logistic regression analysis was used to model outcome data which was polytomous. A type-I error rate of 5% was used to determine statistical significance with no adjustment made for multiple testing/comparisons. SAS version 9.4 and R statistical programs were used to perform statistical analysis. We performed both univariate and multivariate regression analysis to assess for predictors of abnormal manometry, presence of esophagogastric junction (EGJ) outflow obstruction, presence of other major motor disorders, presence of minor motor disorders, and presence of weak and failed swallows. We assessed demographic variables [gender, body mass index (BMI), ethnicity], disease comorbidities (presence of DM, GERD, smoking history), and use of various medications (proton pump inhibitor calcium channel blockers, nitrates, skeletal muscle relaxants, opioids, and prokinetics) as possible predictors. In addition, among diabetic patients, we assessed whether insulin use, and documented presence of various diabetic complications (retinopathy, neuropathy, and nephropathy) served as predictors. For each outcome variable, each individual predictor was first assessed using univariate regression analysis. Those individual variables found to be predictors with a type-I error rate of 25% were then included in a multivariate regression analysis for each outcome variable.
HREM Protocol and Analysis
Demographic and Clinical Characteristics of Subjects
All patients undergoing HREM were nil per os after midnight before the study. The patient’s nares were numbed with 2% viscous lidocaine, and a lubricated high-resolution manometry catheter was advanced through the patient’s nose into the stomach. Lower esophageal sphincter (LES) location was verified by 1 deep breath and one 5 mL swallow. The catheter was allowed to warm to body temperature for 5 minutes, and then taped in place with the patient lying on the left side. The patient then consumed ten 5 mL water bolus swallows. Resting pressures were then obtained, and the manometry probe removed. HREM data were analyzed using Medical Measurement System (MMS) software. For each swallow, the presence of small (2 to 5 cm) or large (> 5 cm) breaks, distal contractile integral, integrated residual pressure, and distal latency were recorded. Each patient’s series of 10 Clouse plots was reviewed by an expert in esophageal motor disorders, and a diagnosis based on the Chicago 3.0 Classification of esophageal motor disorders was made.
Statistical Analysis For continuous variables the mean and SD, or median and interquartile range, were used to provide descriptive statistics. Number and frequency were reported for categorical data. Two-sample t tests and analysis of variance (ANOVA) techniques were used to compare differences among groups for outcome variables which were continuous and normally distributed. For continuous outcome variables which did not satisfy the normality assumption, nonparametric methods were used. Categorical data were compared for group differences via w2 analysis and the Fisher exact test where applicable. Count regression models
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RESULTS
A total of 83 diabetic patients and 83 nondiabetic patients who underwent HREM for dysphagia were included in this study. The mean age of patients in this study was 60 ± 11.5 years in both groups. Patients in this study were mostly female and white. Diabetic patients had a higher mean BMI (32.8 ± 7.4 vs. 30.3 ± 6.8 kg/m2; P = 0.04), were more likely to be smokers (46.2% vs. 29.6%; P = 0.05), and were less likely to report GERDrelated symptoms (56.1% vs. 81.9%; P < 0.001) as compared with nondiabetic patients. Mean hemoglobin A1c for diabetic patients in this study was 7.3% ± 1.6%. There were more diabetic patients diagnosed with gastroparesis by gastric emptying scintigraphy tests (both 1 and 4 h tests were included) compared with nondiabetic patients (16.9% vs. 3.6%; P = 0.01). Table 1 lists the full demographic and clinical characteristics of the patient cohort comparing diabetic versus nondiabetic patients.
Esophageal Motor Abnormalities We observed a trend toward increased incidence of primary EGJ outflow obstruction in diabetic patients compared with nondiabetics (10.8% vs. 2.4%; P = 0.057) (Table 2). Among diabetic patients with a diagnosis of EGJ outflow obstruction, the mean of median integrated residual pressure value was 21.54 ± 8.39 mm Hg, compared with 5.06 ± 5.53 mm Hg in diabetic patients without a diagnosis of EGJ outflow obstruction (P < 0.001 for the difference between these mean values). Of the patients diagnosed with EGJ outflow obstruction, 1 patient had a nonobstructive Schatzi ring that was dilated on prior endoscopy, and one other patient had a 3 cm hiatal hernia. No other endoscopic
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Esophageal Disorders in Diabetes
TABLE 1. Demographic Features of Patients
n (%) Measures Age [mean (SD)] (y) Gender Females Males Ethnicity White Black Other BMI [mean (SD)] Smoker Hemoglobin A1c [mean (SD)] Opioids Proton pump inhibitor Muscle relaxant Prokinetic Calcium channel blocker Nitrate GERD History of gastroparesis
Diabetics (n = 83)
Nondiabetics (n = 83)
60.0 (11.5)
60.0 (11.5)
67 (80.7) 16 (19.3)
67 (80.7) 16 (19.3)
P 1.00 1.00 0.10
42 30 11 32.8 29 7.3
(50.6) (36.1) (13.3) (7.4) (47.5) (1.6)
52 26 4 30.3 33 5.3
(63.4) (31.7) (4.9) (6.8) (28.2) (1.0)
0.04 0.01 < 0.001
26 (31.3) 69 (83.1)
19 (22.9) 79 (91.6)
0.22 0.10
13 (15.7) 5 (6.1) 21 (25.3)
14 (15.9) 9 (10.8) 17 (20.5)
0.83 0.27 0.46
14 (16.9) 46 (56.1) 14 (16.9)
8 (9.6) 68 (81.9) 3 (3.6)
0.17 < 0.001 0.01
BMI indicates body mass index.
abnormalities of the distal esophagus were noted in patients with EGJ outflow obstruction. More nondiabetic patients were diagnosed with other major esophageal motor disorders (jackhammer esophagus, absent contractility, and distal esophageal spasm) compared with diabetic patients (12.1% vs. 2.4%; P = 0.03) (Table 2). There was no significant difference in the prevalence of minor esophageal motor disorders in diabetic versus nondiabetic patients (31.3% vs. 25.3%; P = 0.39). Within the group of patients diagnosed with a minor motility disorder, the majority of patients carried the diagnosis of ineffective esophageal motility (Table 2). On multivariate regression analysis, there were no demographic variables, disease comorbidities, medications, or diabetes complications that served as independent predictors for abnormal esophageal manometry. Increased
BMI was the only predictor of EGJ outflow obstruction [odds ratio (OR), 1.16 for presence of EGJ outflow obstruction, 95% confidence interval (CI), 1.04-1.30; P = 0.01] on multivariate analysis. The presence of diabetes did serve as a predictor of EGJ outflow obstruction on univariate analysis (OR, 4.93; 95% CI, 1.03-23.54; P = 0.05), but did not remain a significant predictor on multivariate analysis (OR, 2.32; 95% CI, 0.35-15.23; P = 0.38). A larger percentage of diabetic patients had documented failed swallows on esophageal manometry (50.6% vs. 33.7%; P = 0.03), although the mean number of failed swallows was not significantly different between the groups (1.53 ± 2.23 in diabetic patients vs. 1.36 ± 2.78 in nondiabetic patients; P = 0.67). No other manometric parameter reached a statistical significance between diabetics and nondiabetic patients (Table 3). The presence of diabetes was also a predictor for the presence of failed swallows on both univariate and multivariate regression analysis (OR, 2.01 for the presence of failed swallows on multivariate regression analysis; 95% CI, 1.08-3.76; P = 0.03).
Diabetes Complications When comparing normal versus abnormal esophageal manometry in diabetic patients, diabetic retinopathy was more common in patients with abnormal manometry (27.0% vs. 8.7%; P = 0.04) (Table 4). Diabetic retinopathy was a predictor for abnormal esophageal manometry on univariate analysis as well (OR, 3.89; 95% CI, 1.11-13.66; P = 0.03), although this was not noted on multivariate analysis (OR, 2.63; 95% CI, 0.58-11.90; P = 0.21). Diabetic patients treated with insulin (insulin alone or in combination with an oral hypoglycemic) were more likely to have failed (69.0% vs. 40.7%; P = 0.01), and weak swallows (65.5% vs. 33.3%; P = 0.005) compared with diabetic patients not on insulin therapy (Table 5). Insulin use also trended toward being predictive of minor motor disorders on multivariate analysis (OR, 2.42; 95% CI, 0.89-6.55; P = 0.08). There were no significant differences in any manometric parameters in patients with poorly controlled diabetes (defined as hemoglobin A1c > 7) compared with those with hemoglobin A1cr7 (Table 6).
TABLE 3. Comparison of High-resolution Esophageal Manometry Parameters Between Diabetics and Nondiabetics TABLE 2. Comparison of High-resolution Esophageal Manometry Findings Between Diabetics and Nondiabetics With Dysphagia
n (%) Esophageal Manometry Diagnosis
Diabetics (n = 83)
EGJ outflow obstruction Other major disorders Distal esophageal spasm Absent contractility Jackhammer esophagus Minor disorders Ineffective esophageal motor disorder Fragmented peristalsis Normal
9 2 2 0 0 26 23
(10.8) (2.4) (2.4) (0.0) (0.0) (31.3) (27.7)
3 (3.6) 46 (55.4)
Nondiabetics (n = 83) 2 10 1 6 3 21 20
(2.4) (12.1) (1.2) (7.2) (3.6) (25.3) (24.1)
1 (1.2) 50 (60.2)
P 0.06 0.03
0.39
0.53
Measures
Diabetics (n = 83)
Nondiabetics (n = 83)
IRP [median (IQR)] 4.0 (2.0-9.0) 4.0 (2.0-9.0) Mean DCI [median (IQR)] 932 (448-2205) 1008 (389-1718) Patients with 5 (6.0) 6 (7.2) hypercontractile swallows [n (%)] Patients with failed 42 (50.6) 28 (33.7) swallows [n (%)] Patients with weak 37 (44.6) 48 (57.8) swallows [n (%)] Patients with premature 13 (15.7) 8 (9.6) swallows [n (%)] DL [median (IQR)] 7.2 (6.5-8.6) 7.4 (6.5-8.3)
P 0.66 0.51 0.76 0.03 0.09 0.24 0.83
DCI indicates distal contractile integral; DL, distal latency; IQR, interquartile range; IRP, integrated residual pressure.
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TABLE 4. Comparison of Clinical Characteristics Between Diabetic Patients With Abnormal Esophageal Manometry Versus Those With Normal Esophageal Manometry
n (%) Measures
Abnormal Manometry (n = 37)
Diabetes treatment Insulin only Oral hypoglycemic only Combined oral hypoglycemic and insulin Diet GERD Gastroparesis Diabetic neuropathy Diabetic nephropathy Diabetic retinopathy
Normal Manometry (n = 46)
P 0.05
14 10 1 12 21 8 16 7 10
DISCUSSION This study is the first to evaluate both clinical and esophageal manometry features of diabetic patients with dysphagia using HREM. In our study, 46% of diabetic patients with dysphagia had a definable esophageal motor disorder using the Chicago Classification version 3.0. We observed an increased likelihood of failed swallows in diabetic patients. Diabetes has been shown to cause enteric neuropathy in animal models,16 which in turn can affect smooth muscle activity. Although our study did not note an association between documented neuropathy and abnormal esophageal manometry, a prior study utilizing conventional esophageal manometry noticed that documented diabetic motor neuropathy was associated with decreased esophageal peristaltic amplitude.17 Additional possible explanations include the systemic effect of acute hyperglycemia, which was demonstrated in 1 prior study to result in decreased LES pressure and impaired esophageal motility, likely via decreased vagal cholinergic activity during hyperglycemia.6 Prior studies have also demonstrated lower systemic levels of nitric oxide in diabetics, and have postulated an association between insulin resistance and nitric oxide–dependent vasodilation,9 which could
TABLE 5. Comparison of High-resolution Esophageal Manometry Parameters Between Diabetic Patients on Insulin and Those Off Insulin
(37.8) (27.0) (2.7) (32.4) (56.8) (21.6) (43.2) (18.9) (27.0)
12 25 2 7 25 6 18 5 4
(26.1) (54.4) (4.4) (15.2) (55.6) (13.0) (39.1) (10.9) (8.7)
0.91 0.30 0.70 0.30 0.04
serve as another cause of impaired esophageal motor function in diabetic patients. Finally, microvascular changes from longstanding diabetes can lead to fibrosis and decreased esophageal wall compliance,8,9 which are both potential causes for impaired esophageal motor activity. In this study, we also found that diabetic patients treated with insulin were more likely to have both failed and weak swallows compared with diabetic patients not treated with insulin. Increased hemoglobin A1c was not associated with the presence of weak or failed swallows. We believe that the reason for this discrepancy is the fact that insulin use serves as a more accurate marker for severity and duration of the underlying DM in our patient population. In addition, there was a significant variability when HgA1c was measured in relation to the date of the HREM. In contrast, insulin usage was documented at the time of the HREM. Furthermore, many patients with well-controlled diabetes (as reflected by hemoglobin A1c < 7) at the time of the study might have had years of alternating poorly and well-controlled disease, during which damage to the enteric nervous system of the esophagus had already been established. It is unlikely that insulin use itself has a direct inhibitory effect on esophageal motor function. Watkins and colleagues demonstrated that insulin had a reversing effect on delayed gastric emptying due to gastric antral neural nitric oxide synthase deficiency in diabetic mice, and suggested that both insulin and sildenafil (a phosphodiesterase inhibitor that
n (%) Measures Median IRP [median (IQR)] Mean DCI [median (IQR)] Patients with hypercontractile swallows Patients with failed swallows Patients with weak swallows Patients with premature swallows DL [median (IQR)]
On Insulin (n = 29)
Not on Insulin (n = 54)
P
4.0 (3.0-9.0)
4.0 (2.0-11.0)
0.88
n (%)
767 (410-1488) 1217 (525-2275) 0.12 2 (6.9)
3 (5.6)
1.00
20 (69.0)
22 (40.7)
0.01
19 (65.5)
18 (33.3)
0.005
4 (13.8)
9 (16.7)
1.00
8.0 (7.2-8.7)
6.9 (6.2-8.0)
0.04
DCI indicates distal contractile integral; DL, distal latency; IQR, interquartile range; IRP, integrated residual pressure.
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TABLE 6. Comparison of High-resolution Esophageal Manometry Parameters Between Patients With HgA1cr7 and Those With HgA1c > 7
Measures
A1cr7 (n = 38)
A1c > 7 (n = 45)
IRP [median (IQR)] 4.0 (2.0-13.0) 4.0 Mean DCI [median (IQR)] 941 (458-2225) 882 Patients with 3 (7.9) 2 hypercontractile swallows Patients with failed swallows 16 (42.1) 26 Patients with weak swallows 18 (47.4) 19 Patients with premature 5 (13.2) 8 swallows DL [median (IQR)] 7.8 (6.8-8.6) 7.1
P
(1.8-7.1) 0.39 (384-1934) 0.57 (4.4) 0.66 (57.8) (42.2) (17.8)
0.15 0.64 0.56
(6.4-8.7)
0.41
DCI indicates distal contractile integral; DL, distal latency; IQR, interquartile range; IRP, integrated residual pressure.
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augments nitric oxide signaling) may increase gastrointestinal motility by reversing the effect of decreased nitergic signaling in the stomach and other organs.18 Of note though, it is possible that increased nitergic signaling in the setting of insulin use could lead to decreased LES pressure, which in turn could lead to an increase in acid reflux events. An increase in acid reflux events could potentially lead to an increase in weak swallows, as there is a well-documented association between ineffective esophageal motility (which is defined as at least 5 ineffective swallows, weak or failed, on high-resolution manometry in the absence of any major motor disorder)19 and GERD, though the direction of causality remains to be elucidated.20,21 Prior studies have identified associations between diabetic autonomic neuropathy, peripheral neuropathy, and retinopathy with esophageal dysmotility. In our study, diabetic retinopathy was the only long-term complication associated with abnormal esophageal manometry in diabetic patients. Diabetic retinopathy is a microvascular complication of DM, and is the leading cause of blindness in the United States in persons aged 20 to 64.22 Gustafsson et al4 and Hyett et al23 have previously described the association between diabetic retinopathy and esophageal dysmotility or gastroparesis, respectively. The mechanism for this relationship is thought to originate from fibrosis and vasculitis of small vessels of the smooth muscle layers of the GI tract, similar to the microvascular complications seen in scleroderma.4,24 It is unclear as to why our study as well as the aforementioned studies only demonstrated an association between diabetic retinopathy and abnormal esophageal manometry, but no similar association between diabetic neuropathy or nephropathy, both of which are also microvascular complications of DM type 2, and abnormal esophageal manometry. Interestingly, however, the studies of Gustafsson et al4 and Hyatt et al23 have also demonstrated no association between esophageal dysmotility and gastroparesis, and diabetic complications other than retinopathy (the study of Hyett et al specifically examined diabetic neuropathy and nephropathy, as did our study). Our study findings combined with the above-mentioned studies suggest a potential unique mechanism underlying diabetic retinopathy, making patients with this condition more prone to develop esophageal motor abnormalities. We demonstrated a trend toward increased frequency of EGJ outflow obstruction in diabetic patients, and found that increased BMI was a predictor of EGJ outflow obstruction on multivariate regression analysis. Although the increased prevalence of EGJ outflow obstruction in diabetic patients did not reach the level of statistical significance, we believe that it warrants further discussion. The exact mechanism by which diabetes and increased BMI may lead to increased prevalence of EGJ outflow obstruction is unclear, though prior literature has suggested that both diabetes and insulin resistance (which increased BMI likely serves as a surrogate marker for) are associated with decreased nitric oxide production.7,9 The previously cited study by Watkins et al18 also demonstrated that in models of diabetic mice, there was impaired nitergic signaling in both the pylorus and esophagus, providing a possible mechanism for decreased relaxation of the LES in the setting of diabetes. The study of Roman et al25 also demonstrated increased resting EGJ pressure in patients with hyperglycemia at the time of HREM (in contrast with the findings of De Boer et al6), suggesting an effect of acute hyperglycemia on the function of the distal esophagus, and specifically the LES.
Esophageal Disorders in Diabetes
A major strength of our study is the inclusion of a diverse, multicenter population with all data gathered from detailed individual chart review, and with high HREM available for each patient. This study featured a relatively large group of diabetic patients with dysphagia, and the comparison group of nondiabetic patients was matched on the basis of age and gender, thus controlling for multiple possible confounding factors. All patients’ medications and disease comorbidities were documented at the time of the HREM. The limitations of this study are mainly attributable to its retrospective design. For example, we did not have data on patients’ blood glucose levels at the time of the HREM, and did not have standardized assessment of HbA1c before the performance of the HREM. In addition, given that there was frequently a lag between the clinical onset of diabetes and documentation of this disorder in patients’ charts, we were unable to accurately assess the duration of diabetes in this study population. In conclusion, almost half of the diabetic patients with dysphagia in this study were noted to have some type of an esophageal motor disorder. There was a trend toward increased incidence of primary EGJ outflow obstruction in diabetic patients compared with nondiabetic patients. Diabetic patients were more likely than nondiabetic patients to have failed swallows, and among diabetics, use of insulin further increased the likelihood of weak and failed swallows. Diabetic patients with retinopathy were also significantly more likely than diabetic patients without this complication to have abnormal esophageal manometry. This study provides new information about the degree of esophageal motor dysfunction in patients with DM. As the number of DM patients continues to grow in the general population, so we believe will increase the number of DM patients with dysphagia seen in GI clinic for further evaluation. Consequently, further understanding of the risks of esophageal dysmotility in DM patients with dysphagia is needed.
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8. Fokjaer JB, Brock C, Brun J, et al. Esopahgeal distension parameters as potential biomarkers of impaired gastrointestinal function in diabetes patients. Neurogastroenterol Motil. 2012;24:1016–e544. 9. Botker HE, Moller N. ON NO—the continuing story of nitric oxide, diabetes and cardiovascular disease. Diabetes. 2013;62: 2645–2647. 10. Smout A, Fox M. Weak and absent peristalsis. Neurogastroenterol Motil. 2012;24(suppl):40–47. 11. Lazarescu A, Karamanolis G, Aprile L, et al. Perception of dysphagia: lack of correlation with objective measurements of esophageal function. Neurogastroenterol Motil. 2010;22: 1292–1297. 12. Tsutsui H, Manabe N, Uno M, et al. Esophageal motor dysfunction plays a key role in GERD with globus sensation— analysis of factors promoting resistance to PPI therapy. Scand J Gastroenterol. 2012;47:893–899. 13. Patcharatrakul T, Gonlachanvit S. Gastroesophageal reflux symptoms in typical and atypical GERD: roles of gastroesophageal acid refluxes and esophageal motility. J Gastroenterol Hepatol. 2014;29:284–290. 14. Diener U, Patti MG, Molena D, et al. Esophageal dysmotility and gastroesophageal reflux disease. J Gastrointest Surg. 2001; 5:260–265. 15. Chrysos E, Prokopakis G, Athanasakis E, et al. Factors affecting esophageal motility in gastroesophageal reflux disease. Arch Surg. 2003;138:241–246. 16. Yarandi SS, Srinivasan S. Diabetic gastrointestinal motility disorders and the role of enteric nervous system: current status
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and future directions. Neurogastroenterol Motil. 2014;26: 611–624. Kinekawa F, Kubo F, Matsuda K, et al. Relationship between esophageal dysfunction and neuropathy in diabetic patients. Am J Gastroenterol. 2001;96:2026–2032. Watkins CC, Sawa A, Jaffrey S, et al. Insulin restores neuronal nitric oxide synthase expression and function that is lost in diabetic gastropathy. J Clin Invest. 2000;106:373–384. Kahrilas PJ, Bredenoord AJ, Fox M, et al. International High Resolution Manometry Working Group. The Chicago classification of esophageal motility disorders, v3.0. Neurogastroenterol Motil. 2015;27:160–174. Simic AP, Skrobic OM, Gurski RR, et al. Can different subsets of ineffective esophageal motility influence the outcome of Nissen fundoplication? J Gastrointest Surg. 2014;18:1723–1729. Ho S, Chang C, Wu C, et al. Ineffective esophageal motility is a primary motility disorder in GERD. Dig Dis Sci. 2002;47:652–656. Crawford TN, Alfaro DV, Kerrison JB, et al. Diabetic retinopathy and angiogenesis. Curr Diabetes Rev. 2009;5:8–13. Hyett B, Martinez FJ, Gill BM, et al. Delayed radionucleotide gastric emptying studies predict morbidity in diabetics with symptoms of gastroparesis. Gastroenterology. 2009;137:445–452. Semenkovich CF. We know more than we can tell about diabetes and vascular disease: The 2016 Edwin Bierman award lecture. Diabetes. 2017;66:1735–1741. Roman S, Marjoux S, Thivolet C, et al. Oesophageal function assessed by high-resolution manometry in patients with diabetes and inadequate glycaemic control. Diabet Med. 2014; 31:1452–1459.
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Distribution of Esophageal Motor Disorders in Diabetic Patients With Dysphagia Nina S. George, MD,* Vikram Rangan, MD,* Zhuo Geng, MD,* Freeha Khan, MD,* Adam Kichler, DO,w Scott Gabbard, MD,w Stephen Ganocy, PhD,* and Ronnie Fass, MD, FACG*
Background: Diabetes mellitus can cause various gastrointestinal symptoms. Assessment of esophageal dysmotility in diabetic patients has been scarcely studied. The aim of this study was to determine the esophageal motor characteristics of diabetic versus nondiabetic patients who present with dysphagia. Methods: High-resolution esophageal manometries (HREMs) of 83 diabetic patients and 83 age and gender-matched nondiabetic patients with dysphagia from 2 medical centers were included in this study. Demographic information, medical comorbidities, and medication usage were recorded for each patient in a single registry. HREM of each patient was evaluated and the different functional parameters were recorded. Key Results: Overall, 46% of diabetic patients were found to have an esophageal motor disorder. Diabetic patients with dysphagia were more likely to have failed swallows on HREM (50.6% vs. 33.7%; P = 0.03) as compared with nondiabetic patients. Among diabetic patients, those being treated with insulin were more likely to have failed (69.0% vs. 40.7%; P = 0.01) and weak (65.5% vs. 33.3%; P = 0.005) swallows as compared with diabetic patients not on insulin. Among diabetic patients, those with abnormal manometry were more likely to demonstrate diabetic retinopathy (27.0% vs. 8.7%; P = 0.04). There was a trend toward increased incidence of esophagogastric junction outflow obstruction in diabetic patients (10.8% vs. 2.4%; P = 0.057) as compared with nondiabetic patients. Conclusions: Nearly half of diabetic patients with dysphagia have some type of an esophageal motility disorder. Diabetic retinopathy and the use of insulin are predictive of esophageal motor abnormalities among diabetic patients. Key Words: esophagus, diabetes mellitus, esophageal dysmotility, dysphagia
(J Clin Gastroenterol 2017;00:000–000)
D
iabetes mellitus (DM) is a chronic metabolic disease that in 2008 was estimated to affect >347 million people across the world.1 The disease affects numerous organs throughout the body, and significantly contributes to a decrease in quality of life. Many patients with diabetes Received for publication March 31, 2017; accepted June 1, 2017. From the *The Esophageal and Swallowing Center, Division of Gastroenterology and Hepatology, MetroHealth Medical Center; and wThe Esophageal Center, The Cleveland Clinic Foundation, Cleveland, OH. The authors declare that they have nothing to disclose. Address correspondence to: Ronnie Fass, MD, FACG, Case Western Reserve University; Division of Gastroenterology and Hepatology, Esophageal and Swallowing Center; MetroHealth Medical Center, 2500 Metrohealth Drive, Cleveland, OH 44109 (e-mails: [email protected]; [email protected]). Copyright r 2017 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MCG.0000000000000894
complain of gastrointestinal (GI) symptoms as well, but the extent to which these symptoms correlate with abnormalities in GI motility remains to be elucidated.2 Prior studies have documented abnormal esophageal manometry in 58% to 63% of diabetic patients.3,4 However, one of these studies noted that there was no significant difference in the prevalence of dysphagia between those with normal and those with abnormal esophageal manometry, and that the majority of patients with abnormal esophageal manometry did not report dysphagia as their primary gastrointestinal complaint.3 Bytzer et al5 estimated that up to 15.4% of diabetic patients do have esophageal symptoms including heartburn, dysphagia, or both. Several underlying mechanisms have been proposed to explain the presence of esophageal motility abnormalities in patients with DM. They include impaired esophageal motility due to events of acute hyperglycemia; abnormal functioning of the interstitial cells of Cajal and the enteric nervous system; decreased nitric oxide synthase expression and alteration of nitergric neurotransmission; and fibrosis in the setting of microvascular damage from longstanding diabetes, with a resulting increase in esophageal stiffness and decreased compliance.4–9 In addition, it has been postulated that patients with longstanding diabetes may have impaired esophageal perception, manifested as reduced esophageal sensitivity secondary to increased esophageal wall stiffness, and decreased compliance.3,8 Very few studies have evaluated large cohorts of diabetic patients with dysphagia. Most studies have shown limited correlation between symptoms of dysphagia and odynophagia, and esophageal manometric abnormalities.10,11 Prior studies have demonstrated that abnormal manometry is common in patients with gastroesophageal reflux disease12–15 with reported rates of abnormal manometry ranging from 39% to 48%,12–14 and with ineffective esophageal motility (diagnosed on the basis of conventional manometry parameters) being the most frequently encountered abnormality.12,13 The aims of our study were to compare esophageal motor characteristics, using high-resolution esophageal manometry (HREM), between diabetic and age and gendermatched nondiabetic patients presenting with dysphagia. In addition, to determine which of the DM-associated abnormalities drives esophageal motor findings.
METHODS Subjects HREM studies from October 2013 to August of 2015 were reviewed in consecutive manner from 2 medical centers— MetroHealth Medical Center/Case Western Reserve University and Cleveland Clinic Foundation. Patients were included if they
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were over the age of 18, were diagnosed with DM before the esophageal manometry, were referred to the procedure for dysphagia, and were able to fully complete a HREM. Patients who were not capable of undergoing a complete HREM, and those with diagnosis of achalasia on esophageal manometry were excluded. We identified 83 patients with DM, which was defined as documented fasting plasma glucose of Z126 mg/dL, or documented hemoglobin A1c of Z6.5%. This was further substantiated by a diagnosis of DM that was noted in primary care physician or endocrinologist’s chart documentation. All patients underwent HREM during the aforementioned specified time period for dysphagia, and did not meet any of the above exclusion criteria. From the same period of time, we identified 160 nondiabetic patients who underwent HREM for dysphagia, and created an age and gender-matched list of 83 nondiabetic patients for comparison. Demographics, clinical characteristics, manometric diagnosis (using the Chicago Classification version 3.0), and detailed manometric findings were documented. Patients’ electronic medical records were evaluated for clinical characteristics related or unrelated to DM, such as medication usage, invasive and noninvasive tests, comorbidities, and complications of DM (presence of diabetic retinopathy, peripheral neuropathy, and nephropathy). The information obtained from the 2 medical centers was incorporated into a single registry. This study protocol was approved by the Institutional Review Boards of both MetroHealth Medical Center and Cleveland Clinic Foundation.
were used to model data which was in the form of numerical counts. Multivariate logistic regression analysis was used to model dichotomous outcome data and multinomial logistic regression analysis was used to model outcome data which was polytomous. A type-I error rate of 5% was used to determine statistical significance with no adjustment made for multiple testing/comparisons. SAS version 9.4 and R statistical programs were used to perform statistical analysis. We performed both univariate and multivariate regression analysis to assess for predictors of abnormal manometry, presence of esophagogastric junction (EGJ) outflow obstruction, presence of other major motor disorders, presence of minor motor disorders, and presence of weak and failed swallows. We assessed demographic variables [gender, body mass index (BMI), ethnicity], disease comorbidities (presence of DM, GERD, smoking history), and use of various medications (proton pump inhibitor calcium channel blockers, nitrates, skeletal muscle relaxants, opioids, and prokinetics) as possible predictors. In addition, among diabetic patients, we assessed whether insulin use, and documented presence of various diabetic complications (retinopathy, neuropathy, and nephropathy) served as predictors. For each outcome variable, each individual predictor was first assessed using univariate regression analysis. Those individual variables found to be predictors with a type-I error rate of 25% were then included in a multivariate regression analysis for each outcome variable.
HREM Protocol and Analysis
Demographic and Clinical Characteristics of Subjects
All patients undergoing HREM were nil per os after midnight before the study. The patient’s nares were numbed with 2% viscous lidocaine, and a lubricated high-resolution manometry catheter was advanced through the patient’s nose into the stomach. Lower esophageal sphincter (LES) location was verified by 1 deep breath and one 5 mL swallow. The catheter was allowed to warm to body temperature for 5 minutes, and then taped in place with the patient lying on the left side. The patient then consumed ten 5 mL water bolus swallows. Resting pressures were then obtained, and the manometry probe removed. HREM data were analyzed using Medical Measurement System (MMS) software. For each swallow, the presence of small (2 to 5 cm) or large (> 5 cm) breaks, distal contractile integral, integrated residual pressure, and distal latency were recorded. Each patient’s series of 10 Clouse plots was reviewed by an expert in esophageal motor disorders, and a diagnosis based on the Chicago 3.0 Classification of esophageal motor disorders was made.
Statistical Analysis For continuous variables the mean and SD, or median and interquartile range, were used to provide descriptive statistics. Number and frequency were reported for categorical data. Two-sample t tests and analysis of variance (ANOVA) techniques were used to compare differences among groups for outcome variables which were continuous and normally distributed. For continuous outcome variables which did not satisfy the normality assumption, nonparametric methods were used. Categorical data were compared for group differences via w2 analysis and the Fisher exact test where applicable. Count regression models
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RESULTS
A total of 83 diabetic patients and 83 nondiabetic patients who underwent HREM for dysphagia were included in this study. The mean age of patients in this study was 60 ± 11.5 years in both groups. Patients in this study were mostly female and white. Diabetic patients had a higher mean BMI (32.8 ± 7.4 vs. 30.3 ± 6.8 kg/m2; P = 0.04), were more likely to be smokers (46.2% vs. 29.6%; P = 0.05), and were less likely to report GERDrelated symptoms (56.1% vs. 81.9%; P < 0.001) as compared with nondiabetic patients. Mean hemoglobin A1c for diabetic patients in this study was 7.3% ± 1.6%. There were more diabetic patients diagnosed with gastroparesis by gastric emptying scintigraphy tests (both 1 and 4 h tests were included) compared with nondiabetic patients (16.9% vs. 3.6%; P = 0.01). Table 1 lists the full demographic and clinical characteristics of the patient cohort comparing diabetic versus nondiabetic patients.
Esophageal Motor Abnormalities We observed a trend toward increased incidence of primary EGJ outflow obstruction in diabetic patients compared with nondiabetics (10.8% vs. 2.4%; P = 0.057) (Table 2). Among diabetic patients with a diagnosis of EGJ outflow obstruction, the mean of median integrated residual pressure value was 21.54 ± 8.39 mm Hg, compared with 5.06 ± 5.53 mm Hg in diabetic patients without a diagnosis of EGJ outflow obstruction (P < 0.001 for the difference between these mean values). Of the patients diagnosed with EGJ outflow obstruction, 1 patient had a nonobstructive Schatzi ring that was dilated on prior endoscopy, and one other patient had a 3 cm hiatal hernia. No other endoscopic
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Esophageal Disorders in Diabetes
TABLE 1. Demographic Features of Patients
n (%) Measures Age [mean (SD)] (y) Gender Females Males Ethnicity White Black Other BMI [mean (SD)] Smoker Hemoglobin A1c [mean (SD)] Opioids Proton pump inhibitor Muscle relaxant Prokinetic Calcium channel blocker Nitrate GERD History of gastroparesis
Diabetics (n = 83)
Nondiabetics (n = 83)
60.0 (11.5)
60.0 (11.5)
67 (80.7) 16 (19.3)
67 (80.7) 16 (19.3)
P 1.00 1.00 0.10
42 30 11 32.8 29 7.3
(50.6) (36.1) (13.3) (7.4) (47.5) (1.6)
52 26 4 30.3 33 5.3
(63.4) (31.7) (4.9) (6.8) (28.2) (1.0)
0.04 0.01 < 0.001
26 (31.3) 69 (83.1)
19 (22.9) 79 (91.6)
0.22 0.10
13 (15.7) 5 (6.1) 21 (25.3)
14 (15.9) 9 (10.8) 17 (20.5)
0.83 0.27 0.46
14 (16.9) 46 (56.1) 14 (16.9)
8 (9.6) 68 (81.9) 3 (3.6)
0.17 < 0.001 0.01
BMI indicates body mass index.
abnormalities of the distal esophagus were noted in patients with EGJ outflow obstruction. More nondiabetic patients were diagnosed with other major esophageal motor disorders (jackhammer esophagus, absent contractility, and distal esophageal spasm) compared with diabetic patients (12.1% vs. 2.4%; P = 0.03) (Table 2). There was no significant difference in the prevalence of minor esophageal motor disorders in diabetic versus nondiabetic patients (31.3% vs. 25.3%; P = 0.39). Within the group of patients diagnosed with a minor motility disorder, the majority of patients carried the diagnosis of ineffective esophageal motility (Table 2). On multivariate regression analysis, there were no demographic variables, disease comorbidities, medications, or diabetes complications that served as independent predictors for abnormal esophageal manometry. Increased
BMI was the only predictor of EGJ outflow obstruction [odds ratio (OR), 1.16 for presence of EGJ outflow obstruction, 95% confidence interval (CI), 1.04-1.30; P = 0.01] on multivariate analysis. The presence of diabetes did serve as a predictor of EGJ outflow obstruction on univariate analysis (OR, 4.93; 95% CI, 1.03-23.54; P = 0.05), but did not remain a significant predictor on multivariate analysis (OR, 2.32; 95% CI, 0.35-15.23; P = 0.38). A larger percentage of diabetic patients had documented failed swallows on esophageal manometry (50.6% vs. 33.7%; P = 0.03), although the mean number of failed swallows was not significantly different between the groups (1.53 ± 2.23 in diabetic patients vs. 1.36 ± 2.78 in nondiabetic patients; P = 0.67). No other manometric parameter reached a statistical significance between diabetics and nondiabetic patients (Table 3). The presence of diabetes was also a predictor for the presence of failed swallows on both univariate and multivariate regression analysis (OR, 2.01 for the presence of failed swallows on multivariate regression analysis; 95% CI, 1.08-3.76; P = 0.03).
Diabetes Complications When comparing normal versus abnormal esophageal manometry in diabetic patients, diabetic retinopathy was more common in patients with abnormal manometry (27.0% vs. 8.7%; P = 0.04) (Table 4). Diabetic retinopathy was a predictor for abnormal esophageal manometry on univariate analysis as well (OR, 3.89; 95% CI, 1.11-13.66; P = 0.03), although this was not noted on multivariate analysis (OR, 2.63; 95% CI, 0.58-11.90; P = 0.21). Diabetic patients treated with insulin (insulin alone or in combination with an oral hypoglycemic) were more likely to have failed (69.0% vs. 40.7%; P = 0.01), and weak swallows (65.5% vs. 33.3%; P = 0.005) compared with diabetic patients not on insulin therapy (Table 5). Insulin use also trended toward being predictive of minor motor disorders on multivariate analysis (OR, 2.42; 95% CI, 0.89-6.55; P = 0.08). There were no significant differences in any manometric parameters in patients with poorly controlled diabetes (defined as hemoglobin A1c > 7) compared with those with hemoglobin A1cr7 (Table 6).
TABLE 3. Comparison of High-resolution Esophageal Manometry Parameters Between Diabetics and Nondiabetics TABLE 2. Comparison of High-resolution Esophageal Manometry Findings Between Diabetics and Nondiabetics With Dysphagia
n (%) Esophageal Manometry Diagnosis
Diabetics (n = 83)
EGJ outflow obstruction Other major disorders Distal esophageal spasm Absent contractility Jackhammer esophagus Minor disorders Ineffective esophageal motor disorder Fragmented peristalsis Normal
9 2 2 0 0 26 23
(10.8) (2.4) (2.4) (0.0) (0.0) (31.3) (27.7)
3 (3.6) 46 (55.4)
Nondiabetics (n = 83) 2 10 1 6 3 21 20
(2.4) (12.1) (1.2) (7.2) (3.6) (25.3) (24.1)
1 (1.2) 50 (60.2)
P 0.06 0.03
0.39
0.53
Measures
Diabetics (n = 83)
Nondiabetics (n = 83)
IRP [median (IQR)] 4.0 (2.0-9.0) 4.0 (2.0-9.0) Mean DCI [median (IQR)] 932 (448-2205) 1008 (389-1718) Patients with 5 (6.0) 6 (7.2) hypercontractile swallows [n (%)] Patients with failed 42 (50.6) 28 (33.7) swallows [n (%)] Patients with weak 37 (44.6) 48 (57.8) swallows [n (%)] Patients with premature 13 (15.7) 8 (9.6) swallows [n (%)] DL [median (IQR)] 7.2 (6.5-8.6) 7.4 (6.5-8.3)
P 0.66 0.51 0.76 0.03 0.09 0.24 0.83
DCI indicates distal contractile integral; DL, distal latency; IQR, interquartile range; IRP, integrated residual pressure.
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TABLE 4. Comparison of Clinical Characteristics Between Diabetic Patients With Abnormal Esophageal Manometry Versus Those With Normal Esophageal Manometry
n (%) Measures
Abnormal Manometry (n = 37)
Diabetes treatment Insulin only Oral hypoglycemic only Combined oral hypoglycemic and insulin Diet GERD Gastroparesis Diabetic neuropathy Diabetic nephropathy Diabetic retinopathy
Normal Manometry (n = 46)
P 0.05
14 10 1 12 21 8 16 7 10
DISCUSSION This study is the first to evaluate both clinical and esophageal manometry features of diabetic patients with dysphagia using HREM. In our study, 46% of diabetic patients with dysphagia had a definable esophageal motor disorder using the Chicago Classification version 3.0. We observed an increased likelihood of failed swallows in diabetic patients. Diabetes has been shown to cause enteric neuropathy in animal models,16 which in turn can affect smooth muscle activity. Although our study did not note an association between documented neuropathy and abnormal esophageal manometry, a prior study utilizing conventional esophageal manometry noticed that documented diabetic motor neuropathy was associated with decreased esophageal peristaltic amplitude.17 Additional possible explanations include the systemic effect of acute hyperglycemia, which was demonstrated in 1 prior study to result in decreased LES pressure and impaired esophageal motility, likely via decreased vagal cholinergic activity during hyperglycemia.6 Prior studies have also demonstrated lower systemic levels of nitric oxide in diabetics, and have postulated an association between insulin resistance and nitric oxide–dependent vasodilation,9 which could
TABLE 5. Comparison of High-resolution Esophageal Manometry Parameters Between Diabetic Patients on Insulin and Those Off Insulin
(37.8) (27.0) (2.7) (32.4) (56.8) (21.6) (43.2) (18.9) (27.0)
12 25 2 7 25 6 18 5 4
(26.1) (54.4) (4.4) (15.2) (55.6) (13.0) (39.1) (10.9) (8.7)
0.91 0.30 0.70 0.30 0.04
serve as another cause of impaired esophageal motor function in diabetic patients. Finally, microvascular changes from longstanding diabetes can lead to fibrosis and decreased esophageal wall compliance,8,9 which are both potential causes for impaired esophageal motor activity. In this study, we also found that diabetic patients treated with insulin were more likely to have both failed and weak swallows compared with diabetic patients not treated with insulin. Increased hemoglobin A1c was not associated with the presence of weak or failed swallows. We believe that the reason for this discrepancy is the fact that insulin use serves as a more accurate marker for severity and duration of the underlying DM in our patient population. In addition, there was a significant variability when HgA1c was measured in relation to the date of the HREM. In contrast, insulin usage was documented at the time of the HREM. Furthermore, many patients with well-controlled diabetes (as reflected by hemoglobin A1c < 7) at the time of the study might have had years of alternating poorly and well-controlled disease, during which damage to the enteric nervous system of the esophagus had already been established. It is unlikely that insulin use itself has a direct inhibitory effect on esophageal motor function. Watkins and colleagues demonstrated that insulin had a reversing effect on delayed gastric emptying due to gastric antral neural nitric oxide synthase deficiency in diabetic mice, and suggested that both insulin and sildenafil (a phosphodiesterase inhibitor that
n (%) Measures Median IRP [median (IQR)] Mean DCI [median (IQR)] Patients with hypercontractile swallows Patients with failed swallows Patients with weak swallows Patients with premature swallows DL [median (IQR)]
On Insulin (n = 29)
Not on Insulin (n = 54)
P
4.0 (3.0-9.0)
4.0 (2.0-11.0)
0.88
n (%)
767 (410-1488) 1217 (525-2275) 0.12 2 (6.9)
3 (5.6)
1.00
20 (69.0)
22 (40.7)
0.01
19 (65.5)
18 (33.3)
0.005
4 (13.8)
9 (16.7)
1.00
8.0 (7.2-8.7)
6.9 (6.2-8.0)
0.04
DCI indicates distal contractile integral; DL, distal latency; IQR, interquartile range; IRP, integrated residual pressure.
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TABLE 6. Comparison of High-resolution Esophageal Manometry Parameters Between Patients With HgA1cr7 and Those With HgA1c > 7
Measures
A1cr7 (n = 38)
A1c > 7 (n = 45)
IRP [median (IQR)] 4.0 (2.0-13.0) 4.0 Mean DCI [median (IQR)] 941 (458-2225) 882 Patients with 3 (7.9) 2 hypercontractile swallows Patients with failed swallows 16 (42.1) 26 Patients with weak swallows 18 (47.4) 19 Patients with premature 5 (13.2) 8 swallows DL [median (IQR)] 7.8 (6.8-8.6) 7.1
P
(1.8-7.1) 0.39 (384-1934) 0.57 (4.4) 0.66 (57.8) (42.2) (17.8)
0.15 0.64 0.56
(6.4-8.7)
0.41
DCI indicates distal contractile integral; DL, distal latency; IQR, interquartile range; IRP, integrated residual pressure.
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augments nitric oxide signaling) may increase gastrointestinal motility by reversing the effect of decreased nitergic signaling in the stomach and other organs.18 Of note though, it is possible that increased nitergic signaling in the setting of insulin use could lead to decreased LES pressure, which in turn could lead to an increase in acid reflux events. An increase in acid reflux events could potentially lead to an increase in weak swallows, as there is a well-documented association between ineffective esophageal motility (which is defined as at least 5 ineffective swallows, weak or failed, on high-resolution manometry in the absence of any major motor disorder)19 and GERD, though the direction of causality remains to be elucidated.20,21 Prior studies have identified associations between diabetic autonomic neuropathy, peripheral neuropathy, and retinopathy with esophageal dysmotility. In our study, diabetic retinopathy was the only long-term complication associated with abnormal esophageal manometry in diabetic patients. Diabetic retinopathy is a microvascular complication of DM, and is the leading cause of blindness in the United States in persons aged 20 to 64.22 Gustafsson et al4 and Hyett et al23 have previously described the association between diabetic retinopathy and esophageal dysmotility or gastroparesis, respectively. The mechanism for this relationship is thought to originate from fibrosis and vasculitis of small vessels of the smooth muscle layers of the GI tract, similar to the microvascular complications seen in scleroderma.4,24 It is unclear as to why our study as well as the aforementioned studies only demonstrated an association between diabetic retinopathy and abnormal esophageal manometry, but no similar association between diabetic neuropathy or nephropathy, both of which are also microvascular complications of DM type 2, and abnormal esophageal manometry. Interestingly, however, the studies of Gustafsson et al4 and Hyatt et al23 have also demonstrated no association between esophageal dysmotility and gastroparesis, and diabetic complications other than retinopathy (the study of Hyett et al specifically examined diabetic neuropathy and nephropathy, as did our study). Our study findings combined with the above-mentioned studies suggest a potential unique mechanism underlying diabetic retinopathy, making patients with this condition more prone to develop esophageal motor abnormalities. We demonstrated a trend toward increased frequency of EGJ outflow obstruction in diabetic patients, and found that increased BMI was a predictor of EGJ outflow obstruction on multivariate regression analysis. Although the increased prevalence of EGJ outflow obstruction in diabetic patients did not reach the level of statistical significance, we believe that it warrants further discussion. The exact mechanism by which diabetes and increased BMI may lead to increased prevalence of EGJ outflow obstruction is unclear, though prior literature has suggested that both diabetes and insulin resistance (which increased BMI likely serves as a surrogate marker for) are associated with decreased nitric oxide production.7,9 The previously cited study by Watkins et al18 also demonstrated that in models of diabetic mice, there was impaired nitergic signaling in both the pylorus and esophagus, providing a possible mechanism for decreased relaxation of the LES in the setting of diabetes. The study of Roman et al25 also demonstrated increased resting EGJ pressure in patients with hyperglycemia at the time of HREM (in contrast with the findings of De Boer et al6), suggesting an effect of acute hyperglycemia on the function of the distal esophagus, and specifically the LES.
Esophageal Disorders in Diabetes
A major strength of our study is the inclusion of a diverse, multicenter population with all data gathered from detailed individual chart review, and with high HREM available for each patient. This study featured a relatively large group of diabetic patients with dysphagia, and the comparison group of nondiabetic patients was matched on the basis of age and gender, thus controlling for multiple possible confounding factors. All patients’ medications and disease comorbidities were documented at the time of the HREM. The limitations of this study are mainly attributable to its retrospective design. For example, we did not have data on patients’ blood glucose levels at the time of the HREM, and did not have standardized assessment of HbA1c before the performance of the HREM. In addition, given that there was frequently a lag between the clinical onset of diabetes and documentation of this disorder in patients’ charts, we were unable to accurately assess the duration of diabetes in this study population. In conclusion, almost half of the diabetic patients with dysphagia in this study were noted to have some type of an esophageal motor disorder. There was a trend toward increased incidence of primary EGJ outflow obstruction in diabetic patients compared with nondiabetic patients. Diabetic patients were more likely than nondiabetic patients to have failed swallows, and among diabetics, use of insulin further increased the likelihood of weak and failed swallows. Diabetic patients with retinopathy were also significantly more likely than diabetic patients without this complication to have abnormal esophageal manometry. This study provides new information about the degree of esophageal motor dysfunction in patients with DM. As the number of DM patients continues to grow in the general population, so we believe will increase the number of DM patients with dysphagia seen in GI clinic for further evaluation. Consequently, further understanding of the risks of esophageal dysmotility in DM patients with dysphagia is needed.
REFERENCES 1. Danaei G, Finucane MM, Singh GM, et al. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2 7 million participants. Lancet. 2011;378: 31–40. 2. Talley NJ, Young L, Bytzer P, et al. Impact of chronic gastrointestinal symptoms in diabetes mellitus on healthrelated quality of life. Am J Gastroenterol. 2001;96:71–76. 3. Faraj J, Melander O, Sundkvist G, et al. Oesopahgeal dysmotility, delayed gastric emptying and gastrointestinal symptoms in patients with diabetes mellitus. Diabet Med. 2007; 24:1235–1239. 4. 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;8:268–275. 5. Bytzer P, Talley NJ, Leemon M, et al. Prevalence of gastrointestinal symptoms associated with diabetes mellitus: a population-based survey of 15,000 adults. Arch Intern Med. 2001;161:1989–1996. 6. De Boer SY, Masclee AD, Lam WF, et al. Effect of acute hyperglycemia on esophageal motility and lower esopahgeal sphincter pressure in humans. Gastroenterology. 1992;103:775–780. 7. Park KS. Impact of myenteric plexus alterations in diabetes related gastrointestinal dysmotility. J Neurogastroenterol Motil. 2013;19:121–123.
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