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ORIGINAL ARTICLE
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Clinical profile and spectrum of Duodenal biopsy and other investigational abnormalities in NUD patients


 Department of Internal Medicine, Army Hospital (Research and Referral), New Delhi, India

Date of Submission13-Mar-2022
Date of Decision31-Mar-2022
Date of Acceptance06-Apr-2022
Date of Web Publication10-Aug-2022

Correspondence Address:
Sreenivasu Mamidi,
Medical Division, Army Hospital (Research and Referral), Subroto Park, Dhaula Kuan, Delhi- 110010, New Delhi
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jmms.jmms_41_22

  Abstract 


Aim of Study: The study was done to find out the prevalence of rapid urease test (RUT) positivity, IgA-tTG, and spectrum of duodenal abnormalities in nonulcer dyspepsia (NUD) patients. Methods: This descriptive observational study was carried out in the gastroenterology center in GOI research institute from August 2020 to March 2021. Initially, 200 dyspepsia patients were selected. Fifty patients were excluded due to various reasons. Finally, 150 patients who met the Rome 4 criteria for NUD/functional dyspepsia were recruited. The inclusion criteria were patients above 18 years of age, dyspepsia for ≥ Six months, and no evidence of underlying malignancy, pan gastritis, previous gastric ulcers, and pancreatitis. The patients underwent RUT, upper gastrointestinal endoscopy, duodenal biopsy, and serum IgA-tTG antibody. Results: The mean age was 46.3 years ± 14.12 years, of which 49.3% were female and 50.70% were male. The prevalence of epigastric pain syndrome (EPS) was found in 37.3%, postprandial distress syndrome (PDS) in 30.7%, and both EPS + PDS in 32%. Thirty-eight percent of the NUD patients were positive on RUT suggesting Helicobacter pylori infection. 88.7% of the NUD patients were IgA-tTG antibody negative and 11.3% serologically positive. The duodenal biopsy was normal in 48% of the patients, 21.3% had mild inflammation/duodenitis, 8% had chronic duodenitis, and 22.7% had various grades of celiac disease (CeD) (as per Marsh grading). These 22.7% showing evidence of CeD on histopathological examination showed Marsh Grade 1 in 12.7%, Grade 2 in 2%, Grade 3A in 6.7%, and Grade 3B in 1.3%. Only 17.6% of biopsy positive had IgA-tTG antibody positivity, but only 4% of the total cases were positive for both biopsy and IgA-tTG antibody (P = 0.05). Eosinophilic infiltration in the duodenum was common in NUD patients. It was observed that 17.33% (26/150) of the NUD patients had duodenal eosinophilia. Duodenal eosinophilia association with various other Gastrointestinal disorders, It was observed that 33.33%(19/57) of the H. pylori patients had duodenal eosinophilia with p<0.001. It was also observed that 7.52% (7/93) of others, such as normal individuals, chronic duodenitis, and mild inflammation/duodenitis, had duodenal eosinophilia. Conclusion: The prevalence of H. pylori and IgA-tTG antibodies in NUD patients was 38% and 11.3%, respectively. The spectrum of duodenum biopsy abnormalities in NUD patients included mild inflammation/duodenitis, chronic duodenitis, and CeD. 22.7% of the NUD patients had various degrees of CeD morphology on D2 biopsy, and only 17.6% of these biopsy-positive patients were positive for IgA-tTG. Only 4% of the total NUD patients were positive for both biopsy and IgA-tTG antibody labeled as CeD. There is a significant association between H. pylori and duodenal eosinophilia.

Keywords: Celiac disease, epigastric pain syndrome, IgA tissue transglutaminase, postprandial distress syndrome, rapid urease test, upper GI endoscopy



How to cite this URL:
Singh S, Bansal N, Mamidi S, Singh PK, Sharma P K, Jain R, Brar K S. Clinical profile and spectrum of Duodenal biopsy and other investigational abnormalities in NUD patients. J Mar Med Soc [Epub ahead of print] [cited 2022 Oct 5]. Available from: https://www.marinemedicalsociety.in/preprintarticle.asp?id=353657




  Introduction Top


Nonulcer dyspepsia (NUD)/functional dyspepsia/idiopathic dyspepsia is defined as chronic or recurrent epigastric pain lasting for 3 months with onset at least 6 months before the presentation. The symptoms include one or more of bothersome postprandial fullness, early satiation, epigastric pain, epigastric burning, and no evidence of underlying structural disease explaining the symptoms.[1] There is a strong evidence of association between  Helicobacter pylori Scientific Name Search ection, celiac disease (CeD), and NUD, but the present data from India are scarce. The present study was planned to decipher the clinical profile, prevalence of H. pylori, IgA-tTG, and spectrum of duodenal biopsy abnormalities in NUD patients.


  Methods Top


This descriptive observational study was carried out in a gastroenterology center in GOI research institute, after the ethical committee approval, from August 2020 to March 2021. Finally, 150 patients meeting the Rome 4 criteria for NUD/functional dyspepsia were recruited. These criteria included one or more of the following symptoms, such as bothersome postprandial fullness, early satiety, epigastric pain, epigastric burning with no evidence of structural disease that is likely to explain the symptoms lasting for 3 months, and onset of symptoms at least 6 months before the diagnosis. The inclusion criteria were patients above 18 years of age and dyspepsia for ≥6 months. The patients with no underlying malignancy, pan gastritis, previous gastric ulcers, and pancreatitis were excluded from the study. The patients underwent rapid urease test (RUT), upper gastrointestinal endoscopy, duodenal biopsy, and serum IgA-tTG antibody.


  Results Top


This descriptive observational study was conducted at the gastroenterology center of government hospital in North India, with an aim to study the prevalence of RUT positivity, IgA-tTG, and spectrum of duodenal abnormalities in NUD patients. Further, the clinical profile of patients with respect to diagnostic tests – IgA-tTG test and duodenal biopsy – was evaluated to understand the pathophysiology of the disease. Based on the defined inclusion and exclusion criteria, finally, 150 patients in the age group of 20–80 years were enrolled in the study, and the mean age of patients was 46.30 ± 14.12 years.

RUT was performed to indirectly diagnose H. pylori infection in NUD patients. We found a positivity rate of 38% of H. pylori infection [Table 1].
Table 1: Percentage of Helicobacter pylori in nonulcer dyspepsia patients/rapid urease test association in nonulcer dyspepsia patients

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Tissue transglutaminase IgA (tTG-IgA) test was performed in all the NUD patients for the diagnosis of CeD. We found that 11.3% of the NUD patients are positive for IgA-tTG [Figure 1].
Figure 1: IgA-tTG associated with NUD. IgA-tTG: IgA tissue transglutaminase, NUD: Nonulcer dyspepsia

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Further evaluation to check for duodenal abnormalities is done. Duodenal abnormalities on duodenal biopsy were typified including by Marsh grade which provides the degree of mucosal damage. Normal biopsy with no damage was found in 48%, 22.7% showed various degrees of CeD according to Marsh grading, 12.7% had Marsh Grade 1, 2% had Marsh Grade 2, and 6.7% had Marsh Grade 3a and Grade 3b in 1.3% of the patients. 21.3% had mild inflammation/duodenitis, while 8% had chronic duodenitis [Table 2].
Table 2: D2 biopsy associated with nonulcer dyspepsia patients

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Duodenal biopsy data were correlated within the study groups and a statistically significant difference in number of patients with inflammation/duodenitis when compared between the three groups (P = 0.041). The details are shown in [Table 3].
Table 3: D2 biopsy associated with epigastric pain syndrome, postprandial distress syndrome, and epigastric pain syndrome + postprandial distress syndrome

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Patients were distributed according to biopsy-proven CeD and IgA-tTG test, and it was observed that 17% of the NUD patients with biopsy-proven CeD had positive IgA-tTG, while 82% of the NUD patients with biopsy-proven CeD had negative IgA-tTG. The details are shown in [Figure 2].
Figure 2: Association between D2 biopsy suggestive of Marsh grade celiac disease and IgA-tTG. IgA-tTG: IgA tissue transglutaminase

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Only 4% of the NUD patients had positive for biopsy that suggested CeD with positive IgA-tTG. They are labeled as CeD. The details are shown in [Table 4].
Table 4: Association between biopsy-proven celiac disease and immunoglobulin A-tissue transglutaminase

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No significant association was found between duodenal biopsy (Marsh staging) and IgA-tTG positivity and negativity among these patients. Overall, we found that NUD and infection by H. pylori and CeD were most common among the patients from North India.

Duodenal eosinophilia was a pathological maker for NUD. Biopsy suggested that duodenal eosinophilia association was checked for various diseases. It was observed that 17.33% (26/150) of the NUD patients had duodenal eosinophilia. We found that 33.33% (19/57) of the H. pylori patients had duodenal eosinophilia with P < 0. 001. 7.52% of others, such as normal individuals, chronic duodenitis, mild inflammation, and CeD patients, had duodenal eosinophilia. The details are shown in [Table 5].
Table 5: Association between the duodenal eosinophilia and Helicobacter pylori and others

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  Discussion Top


NUD is a chronic, recurrent abdominal pain without ulcers and symptoms similar to biliary tract disease, gastroesophageal reflux, chronic pancreatitis, and irritable bowel syndrome.[2] The pathogenesis of NUD still remains unclear. Certain factors such as gastric acid secretion, duodenogastric reflux, environmental exposures, or psychological factors may affect but do not play a major role in pathogenesis. H. pylori infection and associated gastritis are common in NUD, but their etiologic role is controversial.[3],[4] For the diagnosis of NUD, duodenal biopsy is mandatory as it displays characteristic changes of the mucosal structure, crypt elongation, and villous atrophy.[5] Further, CeD, which is gluten-induced inflammation of the small intestine, is also prevalent in dyspepsia patients. Immunoglobulin A (IgA) anti-tissue transglutaminase antibodies (IgA-tTG) play an important role in the diagnosis of CD.[6] Due to multiple symptoms and etiological factors, specific tests for the diagnosis of NUD are still not available. The objective of the study was to find out the prevalence of RUT positivity, IgA-tTG, and the spectrum of duodenal abnormalities in NUD patients. By recognizing the heterogeneity of NUD patients, more rational management might be possible.

This is a descriptive observational study conducted at a gastroenterology center of GOI research institute. Initially 200 patients with symptoms of dyspepsia of at least for 6 months, and were not responding to PPIs for 2 weeks' treatment were seen in OPD. One hundred and fifty patients who met the Rome IV criteria were taken for the study. The mean age was 46.3 years ± 14.12 years, out of which 49.3% (74/150) were female and 50.70% (76/150) were male.

Detailed clinical history of patients was obtained, and based on the presenting symptoms, patients were divided into three groups: (a) patients with epigastric pain syndrome (EPS), (b) postprandial distress syndrome (PDS), and (c) EPS + PDS. The prevalence of the EPS was found in 37.3%, PDS was 30.7%, and 32% of the patients had both EPS + PDS. Among patients with EPS, there were more males than females (60.7% vs. 39.3%) having the symptoms related to epigastric pain, while both in the PDS group and the EPS + PDS group, there were more females than males (52.2% vs. 47.8% and 60.4% vs. 39.6%, respectively).

H. pylori is responsible for progressive gastroduodenal damage, which can be diagnosed with the help of RUT. This test indirectly identifies H. pylori presence based on the presence of nonmammalian enzyme, urease, in or on the gastric mucosa. In the present study, we found that 38% of the NUD patients were positive for H. pylori infection through RUT test.[7] Similar results were reported by Chaudhari et al., wherein they found gastric H. pylori positivity in 48% of the NUD patients.[8] In a study by Agarwal et al., H. pylori infection was diagnosed in 85% of the patients. However, no significant difference in sex- and age-related distribution for H. pylori infection was reported.[9] Further, they found a positive association of H. pylori in 83.3% of the patients with endoscopic abnormalities (45/54).

Noninvasive serological investigations are the first choice for screening of CeD. IgA-tTG was the first test to screen clinically suspicious patients. In our study, 88.7% of the NUD patients were IgA-tTG antibody negative, while 11.3% of the NUD patients were positive.

The duodenal biopsy was done to evaluate for duodenal abnormalities in all NUD patients. Duodenal abnormalities on D2 biopsy were typified by modified Marsh classification or Marsh-Oberhuber Classification which provides the degree of mucosal damage.[10] Among the total patients, 48% (72/150) had normal biopsy, 21.3% (32/150) had mild/inflammation/duodenitis, 8% (12/150) had chronic duodenitis, and 22.7% (34/150) showed various grades of CeD. Out of 22.7% (34/150), 12.7% (19/150) had Marsh Grade 1 indicating increased intraepithelial lymphocytes (>30 IELs/100 enterocytes with absent crypt elongation and villous atrophy) and only 2% (3/150) had Marsh Grade 2 (IELSs >30/100 enterocytes with crypts of Lieberkühn elongation). Marsh Grade 3A (IELs >30/100 with crypt elongation/hyperplasia and mild villous atrophy) was present in 6.7% (10/150). Marsh Grade 3B (IELs >30/100 enterocytes with crypt elongation/hyperplasia and moderate villous atrophy) was found in 1.3% (2/150) of the patients. None of the patients was found to have Marsh Grade 3C where Grade 3B features and severe villous atrophy are present. The maximum number of patients were found to have Marsh Grade 1 (12.7%) CeD. On the contrary, Keshavarz et al. suggested that more than 50% of the patients were in Marsh Grade 1 indicating early-stage disease requiring diet modification and proper management to avoid severe complications.[11],[12]

Increased IELs with normal villous architecture are also seen in tropical sprue, autoimmune Enteritis, H. pylori infection, Crohn's disease, combined variable immune deficiency, small intestinal bacterial overgrowth, drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs), lymphocytic and collagenous colitis, viral enteritis, and giardiasis.[13],[14] The increased IELs with crypt hyperplasia and villous atrophy can also occur due to certain drugs (such as olmesartan and NSAIDs), lymphoma, and common variable immune disease and are rarely seen in H. pylori and viral enteritis.[14] The definitive diagnosis of the CeD is dependent on the combination of clinical manifestations, serological testing, and D2 biopsy.[16]

It was observed that only 17.6% (6/34 biopsy-proven CeD) of the patients were positive for IgA-tTG antibody. Overall, only 4% (6/150) of the NUD cases were positive for both biopsy and IgA-tTG antibody (P = 0.05). These 4% of the patients were labeled as CeD and advised the gluten-free diet. However, contrary results were reported by Rahmati A et al., wherein they found a significant correlation (P = 0.003) between IgA-tTG titers and degrees of duodenal damage in patients with CeD.[15]

It was observed that in 48% (72/150) of the normal patients on biopsy, IgA-tTG was negative in 90.3% (65/72) of the patients while it was positive in 9.7% (7/72) of the normal patients. Among 21.3% (32/150) of the patients with mild inflammation/duodenitis, only 3.1% (1/32) were positive for IgA-tTG, and in 8% (12/150) with chronic duodenitis, 25% of the patients (3/12) were positive.

Eosinophilic infiltration in the duodenum was common in NUD patients.[17] It was previously not studied because standard quantification methods have not been applied and also D2 biopsy is not routine in gastroenterology practice. Mostly, it is associated with allergy-related hypersensitivity mechanisms in individuals with functional dyspepsia with PDS features including early satiety.[18] Helicobacter infection has been shown to cause inflammatory infiltrates in the stomach, leading to recruitment and degranulation of eosinophils, thereby releasing toxic molecules which generate gastrointestinal symptoms. This recruitment and degranulation cascade might also occur in the duodenum. Leite et al. suggested that there is a significant association between H. pylori and duodenal eosinophilia, but not NUD.[19] We speculated that duodenal eosinophilia would be a positive pathologic marker for the diagnosis of NUD.

In our study, it was observed that 17.33% (26/150) of the NUD patients had duodenal eosinophilia. It was observed that 33.33% (19/57) of the H. pylori patients (RUT POSITIVE) had duodenal eosinophilia; there is a significant association between H. pylori and duodenal eosinophilia (P < 0.001). 7.52% (7/93) of the patients' duodenal eosinophilia positives belong to others such as normal individuals, chronic duodenitis, and mild D2 inflammation.


  Conclusion Top


The prevalence of H. pylori in NUD patients was 38%. The spectrum of duodenum biopsy abnormalities in NUD patients included mild inflammation/duodenitis, chronic duodenitis, and CeD. In 22.7% of the NUD patients, D2 biopsy suggested various grades of CeD (Marsh grading). The prevalence of IgA-tTG antibody in NUD patients was 11.3%. 17.6% (6/34) are biopsy suggested celiac patients had positive for IgA-tTG. However, the definitive diagnosis based on the combination of clinical manifestation, positive serology, and D2 biopsy before labeling a person as CeD. Only 4% (6/150) of the NUD patients were positive for both biopsy and IgA-tTG antibody and labeled as CeD. Early detection and dietary management (gluten-free diet) are essential for the prevention of serious complications. Who were negative for IgA-tTG and they are unlikely for CeD and considered as chronic duodenitis. In Selective IgA deficiency patients with strong clinical suspicion and biopsy suggested for Celiac disease may require IgG DGP (Deamidated Gliadin Peptide) anti bodies,HLA -DQ2 and DQ8 to confirm the diagnosis and find out the exact number having celiac disease in the NUD patients. 17.33% of the NUD patients had duodenal eosinophilia and 33.33% of the H. pylori patients had duodenal eosinophilia. There is a significant association between H. pylori and duodenal eosinophilia in this study.

Limitation

Since the hospital is situated in North India, so more patients were from this region, which might create bias in our result stating that maximum patients with NUD and H. pylori were from North INDIA.

To evaluate the eosinophilic GI disorders, we have obtained only duodenal biopsy, but in True sense which may require multiple biopsy samples from different locations of stomach and duodenum.

For find out the exact no celiac diseases, with strong clinical suspicion who are negative for IgA-tTG, may require serological tests such as IgG-DGP, HLA DQ2, or DQ8. The above tests are not done in this study.

Recommendation

In CeD, D2 biopsy was not recommended in all patients with NUD unless the strong clinical suspicion and positive serological tests such as IgA-tTG.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Suzuki H. The application of the Rome IV criteria to functional esophagogastroduodenal disorders in Asia. J Neurogastroenterol Motil 2017;23:325-33.  Back to cited text no. 1
    
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Talley NJ, Phillips SF. Non-ulcer dyspepsia: Potential causes and pathophysiology. Ann Intern Med 1988;108:865-79.  Back to cited text no. 2
    
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Kusters JG, van Vliet AH, Kuipers EJ. Pathogenesis of Helicobacter pylori infection. New Delhi, India: American Society for Microbiology; 2006;19:449-90. doi: 10.1128/CMR.00054-05.  Back to cited text no. 3
    
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van Zanten SJ. Treating non-ulcer dyspepsia and H pylori. BMJ 2000;321:648-9.  Back to cited text no. 4
    
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Kamboj AK, Oxentenko AS. Clinical and histologic mimickers of celiac disease. Clin Transl Gastroenterol 2017;8:e114.  Back to cited text no. 5
    
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Troncone R, Maurano F, Rossi M, Micillo M, Greco L, Auricchio R, et al. IgA antibodies to tissue transglutaminase: An effective diagnostic test for celiac disease. J Pediatr 1999;134:166-71.  Back to cited text no. 6
    
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Uotani T, Graham DY. Diagnosis of Helicobacter pylori using the rapid urease test. Ann Transl Med 2015;3:9.  Back to cited text no. 7
    
8.
Chaudhari AA, Rane SR, Jadhav MV. Histomorphological spectrum of duodenal pathology in functional dyspepsia patients. J Clin Diagn Res 2017;11:EC01-4.  Back to cited text no. 8
    
9.
Agarwal PK, Badkur M, Agarwal R, Patel S. Prevalence of Helicobacter pylori infection in upper gastrointestinal tract disorders (dyspepsia) patients visiting outpatient department of a hospital of North India. J Family Med Prim Care 2018;7:577-80.  Back to cited text no. 9
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Abaylı C, Doran F, Abaylı B, Üsküdar O. Modified marsh classification of the duodenal biopsies of a large database covering 10 years. Cukurova Medical Journal 2014;39:61-9.  Back to cited text no. 10
    
11.
Keshavarz AA, Bashiri H, Ahmadi A, Bazargan-Hejazi S. The prevalence of occult celiac disease among patients with functional dyspepsia: A study from the Western Region of Iran. Gastroenterol Res Pract 2010;2010:170702.  Back to cited text no. 11
    
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Peña AS. What is the best histopathological classification for celiac disease? Does it matter? Gastroenterol Hepatol Bed Bench 2015;8:239-43.  Back to cited text no. 12
    
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Mahadeva S, Wyatt JI, Howdle PD. Is a raised intraepithelial lymphocyte count with normal duodenal villous architecture clinically relevant? J Clin Pathol 2002;55:424-8.  Back to cited text no. 13
    
14.
Serra S, Jani PA. An approach to duodenal biopsies. J Clin Pathol 2006;59:1133-50.  Back to cited text no. 14
    
15.
Rahmati A, Shakeri R, Sohrabi M, Alipour A, Boghratian A, Setareh M, et al. Correlation of tissue transglutaminase antibody with duodenal histologic marsh grading. Middle East J Dig Dis 2014;6:131-6.  Back to cited text no. 15
    
16.
Kumar V, Jarzabek-Chorzelska M, Sulej J, Karnewska K, Farrell T, Jablonska S. Celiac disease and immunoglobulin a deficiency: How effective are the serological methods of diagnosis? Clin Diagn Lab Immunol 2002;9:1295-300.  Back to cited text no. 16
    
17.
Kim HJ. The gastric and duodenal eosinophilia in functional dyspepsia. J Neurogastroenterol Motil 2016;22:353-4.  Back to cited text no. 17
    
18.
Walker MM, Salehian SS, Murray CE, Rajendran A, Hoare JM, Negus R, et al. Implications of eosinophilia in the normal duodenal biopsy – An association with allergy and functional dyspepsia. Aliment Pharmacol Ther 2010;31:1229-36.  Back to cited text no. 18
    
19.
Leite C, Mazzoleni LE, Uchoa DM, Castanho JA, Mazzoleni F, Sander GB. Association of duodenal eosinophilic infiltrate with Helicobacter pylori infection, but not with functional dyspepsia. Arq Gastroenterol 2020;57:74-8.  Back to cited text no. 19
    


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