Assessment of the Clinical Profile of Dyspepsia with Predominantly Abdominal Bloating Symptoms in Type 2 Diabetes Mellitus Patients: A Cross-sectional Observational Study

INTRODUCTION

Dyspepsia is defined by the clinical guidelines of the American College of Gastroenterology and the Canadian Association of Gastroenterology as a predominant epigastric pain that lasts for at least 1 month and is accompanied by any other upper gastrointestinal (GI) symptoms, such as heartburn, epigastric fullness, nausea, or vomiting.¹ Organic dyspepsia involves identifiable pathological processes, while functional dyspepsia lacks such identifiable causes. It emphasizes the importance of endoscopy and Helicobacter pylori testing to exclude organic causes. Diabetic patients can have various GI complications, such as pancreatopathy, small intestinal bacterial overgrowth (SIBO), gastro-esophageal reflux disease (GERD), gastroparesis, neuropathy, and non-alcoholic fatty liver disease, which can present with symptoms like pain, nausea, diarrhea, early satiety, and constipation. These GI symptoms affect 75% of the population in diabetic outpatient clinics.² In type 2 DM, autonomic neuropathy and microvascular damage are key factors in exocrine insufficiency. There are various invasive and non-invasive tests for the assessment of pancreatic exocrine insufficiency (PEI). Pancreatic fecal elastase, secreted by acinar pancreatic cells can be easily detected in stool by enzyme- linked immunosorbent assay (ELISA) and is a non-invasive easy-to-perform test to assess PEI. Another cause implicated in dyspepsia in type 2 diabetic patients is SIBO, defined as the presence of excessive bacteria in the small intestine. It presents as chronic diarrhea and malabsorption. Reduced stomach acid output and small intestinal dysmotility are the two factors that make bacteria more likely to proliferate. Long-standing and poorly controlled diabetes can damage the gut nervous system, leading to disordered GI motility and SIBO.¹ Small intestinal bacterial overgrowth can be assessed by jejunal aspirate culture (gold standard) and glucose hydrogen breath test (HBT). Gastroparesis is another important cause of diabetic dyspepsia. It is defined as an objective delay in gastric emptying without any mechanical obstruction. It occurs with poor glycemic control due to dysfunction of the coordination and function of the autonomic nervous system, pacemaker cells (interstitial cells of Cajal, ICC) of the stomach and intestine, and the smooth muscle cells of the gastrointestinal tract. Gastroparesis is assessed by measuring gastric emptying by gastric scintigraphy.² Thus, our study aims to assess the various causes of dyspepsia in type 2 diabetic patients via upper gastrointestinal endoscopy (UGIE), gastric scintigraphy, urea breath test (UBT), glucose HBT, and pancreatic fecal elastase and to assess the correlation of diabetic control and dyspepsia.

MATERIALS AND METHODS

RESULTS

A total of 41 participants were included in the study. The mean age of participants was 53.39 ± 7.94 years. Among the total sample, 42.5% (17) of the participants were male, rest were female. We also evaluated for associated comorbidities, 57.5% (23) of the participants had no comorbidities, 37.5% (15) of the participants had associated hypertension, while 2.5% (1) of the participants had decompensated chronic liver disease. The most predominant symptom was indigestion, seen in 63.4% (26) participants, while heartburn was present in 24.3% (10) participants, and nausea and regurgitation were present in 7.3% (3) of the participants and 4.8% (2) of the participants, respectively. The mean SF-LDQ score was 7.68 ± 2.30. The mean HbA1c (%) was 8.52 ± 1.52. HbA1c was ≤7% in 22% (9) of the participants and was >7% in the remaining. Non-parametric tests (Spearman Correlation) were used to explore the correlation between HbA1c and SF-LDQ (degree of dyspepsia) as at least one of the variables was not normally distributed. There was no statistically significant correlation between HbA1c (%) and SF-LDQ (rho = 0.18, p = 0.247). Baseline characteristics of the study population are shown in Table 1. The stool routine was normal in all 100% of the participants. H. pylori UBT was conducted to rule out H. pylori gastritis. Urea breath test was positive in 42.5% (17) of the participants, rest was negative. Non-parametric tests (Wilcoxon–Mann–Whitney U-test) were used to make group comparisons (between variable HbA1c and positive and negative UBT). There was no significant difference between the groups in terms of HbA1c (%) (W = 263.000, p = 0.119), as depicted in Table 2. Glucose HBT was done to rule out SIBO. Of all the participants, 100% (41) had negative HBT. Upper gastrointestinal endoscopy was done to rule out organic causes, abnormal UGIE findings were present in 36.5% (15) of the participants. Among the participants with abnormal UGIE, 19.5% (8) had antral erythema, and 7.3% (3) showed mucosal atrophy in their UGIE. Hiatus hernia was present in 4.8% (2) of the participants. Esophagitis was present in 2.4% (1) of the participants. Peptic ulcer disease was present in 2.4% (1) of the participants. Non-parametric tests (Wilcoxon–Mann–Whitney U-test) were used to make group comparisons between variable HbA1c and UGIE findings. There was no significant difference between the groups in terms of HbA1c (%) (W = 134.500, p = 0.102), as depicted in Table 3. Gastric scintigraphy was done to assess gastric motility. Rapid gastric emptying was present in 87.8% (36) of the participants, rest had slow gastric emptying. Non-parametric tests (Wilcoxon–Mann–Whitney U-test) were used to make group comparisons between variable HbA1c and gastric emptying. There was a significant difference between the two groups in terms of HbA1c (%) (W = 28.500, p = 0.014), with the median HbA1c (%) being highest in the Gastric Scintigraphy: Slow gastric emptying group, as depicted in Table 4. Pancreatic fecal elastase was done to rule out PEI. Pancreatic exocrine insufficiency was present in 36.6% (15), rest had normal pancreatic fecal elastase (PFE). 22.0% (9) of the participants had mild-to-moderate PEI. And 14.6% (6) of the participants had severe PEI. Non-parametric tests (Spearman correlation) were used to explore the correlation between HbA1c% and PFE and this correlation was statistically significant (rho = –0.51, p = < 0.001), as depicted in Table 5.

Our study also aimed at identifying the various combinations of causes of dyspepsia. We found that 14.6% of the participants had H. pylori gastritis coexisting with abnormal UGIE findings. In 9.8% of the participants, we detected multiple causes of dyspepsia, including H. pylori gastritis, abnormal UGIE endoscopy findings, and PEI. In 9.8% of the participants, we found slow gastric emptying and PEI as causes of dyspepsia. In 2.4% of the participants, we found H. pylori gastritis, abnormal UGIE findings, slow gastric emptying, and PEI as causes of dyspepsia. About 2.4% of the participants had H. pylori gastritis along with PEI. In 26.8% of patients, no cause of dyspepsia could be identified, 34.2% had dyspepsia secondary to a single etiology; 26.8% of patients had two underlying etiologies of dyspepsia, while the remaining had multiple causes of dyspepsia.

DISCUSSION

The study explores the impact of diabetes on the gastrointestinal tract, particularly focusing on diabetic enteropathy and dyspepsia. It highlights that dyspepsia in diabetic individuals may result from various factors, including gastroparesis, GERD, SIBO, PEI, and diabetic neuropathy. A systematic approach is crucial for managing dyspepsia in diabetes to address both organic and inorganic causes, aiming for symptom relief, medication adherence, and improved glycemic control. Our study utilized UGIE, UBT, glucose HBT, PFE test, and gastric scintigraphy to assess common causes of dyspepsia. 42.5% of patients had positive H. Pylori UBT suggestive of H. pylori gastritis. Comparative studies showed a significant association between H. pylori infection and diabetes. Mabeku et al.’s cross-sectional study in Cameroon found H. pylori infection prevalence was 73.11% in type 2 diabetic dyspeptic patients and 58.03% in non-diabetic dyspeptic patients (p = 0.0279).⁵ Bener et al. discovered significantly higher H. pylori antibody titers in type 2 diabetics (IgA > 250: 50.7%, IgG > 300: 73.5%) compared with controls (IgA: 38.2%, IgG: 61.8%), (p < 0.001).⁶ Quatrini et al. found H. pylori in 69% of diabetic and 46% of non-diabetic dyspeptic subjects, with 77% of symptomatic diabetics infected.⁷ These findings underscore the need to consider H. pylori infection as a potential cause of dyspepsia in diabetic patients for improved gastrointestinal symptom management. We ruled out the organic pathology of dyspepsia in type 2 diabetic patients by screening UGIE. Our results showed that 37.5% of patients had abnormal UGIE. According to a study conducted by Osipenko MF et al., 42.3% of type 2 diabetic patients experience dyspepsia due to organic gastrointestinal diseases.³ Bharucha Adil E et al. in their study found that erosive esophagitis is more prevalent in type 2 diabetics with peripheral neuropathy. Hence, our study and other comparative studies showed that UGIE should be routinely undertaken in type 2 diabetic patients presenting with dyspepsia to rule out organic pathology. Small intestinal bacterial overgrowth in type 2 diabetes presents with malnutrition, diarrhea, and abdominal distension. Diagnosis involves the glucose HBT. In a meta-analysis conducted by Xing Feng and Li X-Q, the prevalence of SIBO in diabetes was found to be 29%.⁸ Rana SV et al.’s study found SIBO in 14.8% of type 2 diabetic patients, significantly delaying orocecal transit time.⁹ Additionally, lactose intolerance was higher in diabetic patients, suggesting a link between delayed transit time, SIBO, and malabsorption in diabetes. In our study, we used glucose HBT to rule out SIBO, which has sensitivity and specificity of 62% and 83% compared with gold standard jejunal aspirate culture.⁴

In our study, all the patients tested negative, however, SIBO cannot be ruled out completely due to the low sensitivity of the test. We need larger studies and tests like jejunal aspirate culture to assess the prevalence of SIBO in diabetes. Autonomic neuropathy and microvascular damage in diabetes contribute to PEI. We assessed PEI by pancreatic fecal elastase, which showed 37.5% of type 2 diabetic patients with dyspepsia had PEI, defined as PFE <200 µg/g of stool. Studies by Shashank R Joshi et al., Hardt et al., and Shivprasad et al. reported a PEI prevalence of 22.9–31.4% in both type 1 and type 2 DM.^10,11 Significant correlations exist between fecal elastase concentrations and blood glucose levels. These findings underscore the high prevalence of PEI in diabetic patients, particularly those with dyspepsia. Larger multicentric studies are needed to ascertain PEI prevalence in type 2 diabetic dyspeptic patients in India. We also need studies which explore the role of pancreatic enzyme replacement therapy in alleviating dyspepsia in these patients. Another important and troublesome cause of dyspepsia in diabetes is diabetic gastroparesis. Gastroparesis results from gastric motor dysfunction secondary to autonomic neuropathy and damage to the interstitial cells of Cajal. We assessed the gut motility by gastric scintigraphy, which showed that 12.5% of our type 2 diabetic dyspeptic patients had delayed gastric emptying suggestive of diabetic gastroparesis. Almogbel Rakan A et al. found a 10.8% prevalence of gastroparesis symptoms in type 2 diabetics, correlating with HbA1c and duration of diabetes.¹² Horowitz M et al.’s study showed slower gastric emptying in diabetic patients compared with controls. Choung RS et al.’s cohort study found a 5.2% risk of gastroparesis in type 1 diabetics and 1.0% in type 2 diabetics over 10 years.¹³ The results of our study were close to the results of the study by Almogbel Rakan A et al., however, we need larger multicentric Indian studies to validate our results and assess the exact prevalence of gastroparesis in type 2 diabetic patients with dyspepsia. We also tried to identify the correlation between the severity of dyspepsia and glycemic control. The severity of dyspepsia was assessed by SF-LDQ, and glycemic control was assessed via HbA1c. Non-parametric tests (Spearman correlation) were used to explore the correlation between them, however, no statistically significant correlation between HbA1c (%) and SF-LDQ Score (rho = 0.18, p = 0.247) was found. Thus, the severity of dyspepsia could not be related to glycemic control in our study, but we need larger Indian studies to explore the relationship between glycemic control and the severity of dyspepsia. Diabetes affects the entire gastrointestinal tract; hence, various causes of dyspepsia, including gastric causes like H. pylori infection, delayed gastric emptying, and small intestinal causes like SIBO can coexist, our study aimed at identifying the various combinations of causes of dyspepsia. In our study, we found that 26.8% of patients had no identifiable cause of dyspepsia, while 34.2% had dyspepsia from a single cause, and 26.8% had two underlying causes. We investigated similar studies. Huang Ju in their study found a significantly higher H. pylori infection rate in diabetic gastroparesis patients compared with other groups.¹⁴ Reddymasu Savio C and McCallum discovered a 60% prevalence of SIBO in gastroparesis patients.¹⁵ El Kurdi B et al.’s meta-analysis revealed a 38.6% SIBO prevalence in chronic pancreatitis patients, with diabetes mellitus and PEI increasing SIBO risk.¹⁶ These findings suggest dyspepsia in diabetes arises from diverse causes, potentially exacerbating each other, necessitating comprehensive management approaches.

CONCLUSION

Our study assessed the various causes of dyspepsia in type 2 diabetic patients by employing investigations like a UBT, glucose HBT, upper GI endoscopy, PFE, and gastric scintigraphy. It showed that a large proportion of patients had multiple causes of dyspepsia coexisting; hence, systematic evaluation of various causes should be done and etiology-directed management should be undertaken. The strengths of our study lie in the comprehensive approach we took by assessing multiple causes of dyspepsia simultaneously in type 2 diabetic patients. However, it is crucial to recognize the limitations of our study. Firstly, our study was conducted in a single center, which may introduce bias and limit the generalizability of our findings. The inclusion of a larger sample size and multicenter studies would strengthen the external validity of our results. Additionally, some of the tests we used because of their simplicity like the glucose HBT are not gold standard and hence are not 100% sensitive and specific.

ORCID

Ravi Kant https://orcid.org/0000-0003-1144-4478

Itish Patnaik https://orcid.org/0000-0003-2726-3516

Vandana K Dhingra https://orcid.org/0000-0002-3006-8597

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