Prevalence and predictors of coeliac disease in patients with irritable bowel syndrome: A prospective study from Rajasthan,India

Abstract

Our study aims to assess the prevalence of coeliac disease (CD) among patients with irritable bowel syndrome (IBS), a recognised high-risk group for CD, in Rajasthan. We found 9/287 consecutive adult IBS patients seropositive or with biopsy-confirmed CD. Lower haemoglobin levels were independently associated with CD.

Keywords

Coeliac disease irritable bowel syndrome anaemia IgA-anti-tTG malabsorption

Introduction

Coeliac disease (CD) is a chronic, systemic immune-mediated enteropathy triggered by gluten ingestion in genetically predisposed individuals. With the advent of better diagnostic modalities and increasing awareness about the disease, CD is now recognised as a global health concern, with a rising prevalence worldwide.¹ Its estimated prevalence in India is 1.04%, which is significant considering its large population.² While classical CD presents with gastro-intestinal symptoms such as chronic diarrhoea and malabsorption, extraintestinal manifestations are well documented. Moreover, many patients exhibit non-classical symptoms such as dyspepsia, constipation, and symptoms overlapping with IBS.³ IBS is classified as a disorder of gut–brain interaction and is characterised by recurrent abdominal pain associated with altered bowel habits.⁴ Multiple studies show that IBS is common in the Indian population and its prevalence varies from 0.4 to 4.2%.^5–7 Notably, there is considerable symptom overlap between CD and IBS. Studies suggest that up to 4% patients with IBS may have underlying CD, and up to 35% patients with CD have IBS-like symptoms.⁸ This overlap poses a diagnostic challenge, as IBS is typically diagnosed clinically, and organic conditions such as CD may remain undetected without targeted evaluation. Furthermore, some patients with CD may continue to experience IBS-like symptoms despite adherence to a gluten-free diet, further complicating clinical differentiation. Regional differences in the prevalence of CD have also been well described, largely due to variations in dietary habits and staple foods, with a prevalence higher in wheat-consuming populations,⁹ such as Rajasthan. However, there is a lack of systematic data on the prevalence of CD in this region. While population-based studies are ideal for determining the true disease prevalence and provide the most accurate estimates of disease burden, they are resource-intensive and often not feasible in low- and middle-income settings. Alternatively, studying high-risk groups, such as individuals with chronic diarrhoea, type 1 diabetes, anaemia, short stature, or IBS, can provide valuable insights, as the prevalence of CD in these groups is expected to be significantly higher than in the general population.¹⁰ Establishing a high prevalence in such groups may pave the way for future population-based studies.

Materials and methods

Our prospective observational study was conducted at a tertiary care centre in Rajasthan between November 2021 and December 2022. Consecutive adult patients diagnosed with IBS attending as out-patients were screened for inclusion. The primary objective was to determine the prevalence of CD among patients with IBS, while the secondary objective was to identify potential clinical and biochemical predictors of CD in this population.

Our study was designed, data collected and analysed, and the manuscript written independently by the study authors without involvement from any funding agency or external sponsor. All authors vouch for the accuracy and completeness of the data. The study adhered to good clinical practice standards, and written informed consent was obtained from all participants. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Institutional Ethics Committee (Approval No. AIIMS/IEC/2021/3609).

Patients aged ≥18 years who fulfilled the Rome IV diagnostic criteria for IBS and provided informed consent were included. We excluded pregnant women, patients with type 1 diabetes mellitus, inflammatory bowel disease, Down's syndrome, dermatitis herpetiformis, co-existing malignancy, co-existing severe organ dysfunction (viz. decompensated heart failure, chronic kidney disease on haemodialysis, respiratory failure requiring oxygen therapy etc.), and those with previously diagnosed CD or taking a gluten-free diet.

Baseline data including demographic details and laboratory investigations (e.g. liver function tests, alkaline phosphatase, complete blood count, and coeliac serology) were recorded.

All enrolled patients were screened for CD using IgA anti-tissue transglutaminase (anti-tTG) antibody levels measured via ELISA (Quanta Lite^® R h-tTG IgA ELISA, Innova Diagnostics, USA). Test results were interpreted as negative (<4 U/ml), equivocal (4–8 U/ml), and positive (>8 U/ml). All those with positive results underwent upper gastro-intestinal endoscopy and at least four biopsies were obtained from the second part of the duodenum. These were evaluated for mucosal changes by an expert histopathologist with a particular interest in gastro-intestinal pathology, who was blinded to patients’ clinical or serological results. Histological changes were graded according to the modified Marsh classification system.¹¹

IBS was diagnosed based on Rome IV criteria, as recurrent abdominal pain for at least 3 months (with symptom onset at least 6 months prior), associated with two or more of the following: defecation, change in stool frequency, and/or change in stool form. Subtypes were classified using the Bristol Stool Form Scale into IBS-with predominant diarrhoea (IBS-D), IBS-with predominant constipation (IBS-C), IBS-Mixed (IBS-M), and IBS-Unspecified (IBS-U).¹²

CD seropositivity was defined as a positive IgA anti-tTG antibody result. Definite CD biopsy-positivity was made on positive serology and the presence of villous abnormalities of modified Marsh grade ≥2, consistent with Indian Council of Medical Research (2016) and ESPGHAN guidelines.¹³

Continuous variables were summarised as mean ± standard deviation or median with interquartile range, depending on data distribution. Categorical variables were expressed as frequencies and percentages. Comparisons between groups were performed using Student's t-test for normally distributed continuous variables and the Mann–Whitney U test or Kruskal–Wallis test for non-normally distributed variables. Categorical variables were compared using the chi-square test or Fisher's exact test, as appropriate. Sample size was calculated assuming a prevalence of 4% for CD in IBS,¹⁴ with a precision of ±2% at a 95% confidence level, yielding a required sample size of 275. To account for potential exclusions, 300 patients were enrolled. A p-value <0.05 was considered statistically significant. Data were entered using Microsoft Excel (version 16.62) and analysed with RStudio (version 2024.09.1 + 394) with base R and additional packages including tidyverse, readxl, and tableone.

Results

A total of 300 patients were screened for inclusion of whom 287 were included in the final analysis, 13 being excluded owing to incomplete data. Based on ROME IV criteria, patients were classified as IBS-D (n = 158), IBS-C (n = 83), IBS-M (n = 38), and IBS-U (n = 8). Baseline demographic, clinical, and laboratory characteristics of the study population are summarised in Table 1. Patients with biopsy-confirmed CD (n = 6) were broadly similar in terms of age, BMI, and liver function parameters compared to those without (n = 281). Haemoglobin levels were lower in patients with CD; however, this difference did not reach statistical significance (p = 0.07).

Table 1.

Baseline characteristics of IBS patients screened for coeliac disease.

Characteristics	Total population(n = 287)	IBS without CD(n = 281)	IBS with CD(n = 6)	p-value
Age, years; mean ± SD	30 ± 2.6	31 ± 3.5	25.5 ± 3.0	0.13
Gender, males (%)	195(67.9%)	190(67.6%)	5(83.3%)	0.41
BMI(kg/m²); median(IQR)	24(21.1–27)	24(21.2–27)	20.5(18.7–24.8)	0.09
Haemoglobin (g/l); mean ± SD	132 ± 12	133 ± 13	11.5 ± 1.5	0.07
Platelet count (×10⁹/L); median(IQR)	278(222–337)	278(222–336)	267(132–419)	0.82
Creatinine (µmol/L); median(IQR)	71.6(61.9–79.6)	70.7(61.9–79.6)	61.9(53–70.7)	0.20
Total bilirubin (µmol/L); median(IQR)	10.3(8.6–13.7)	10.3(8.6–15.4)	12(5.1–13.7)	0.98
AST (IU/L); median(IQR)	26 (21–34)	26 (21–34)	24 (18–26)	0.46
ALT (IU/L); median(IQR)	26 (17–44)	26 (17–44)	22 (20–35)	0.92
Albumin (g/L); median(IQR)	45 (41–47)	45 (41–47)	42 (38–49)	0.37
ALP (IU/L); median(IQR)	80(68–97)	80(68–97)	92(75–125)	0.16
IBS subtype (%)				0.87
Diarrhoea (IBS-D)	158(55.0%)	154(54.8%)	4(66.7%)
Constipation (IBS-C)	83(28.9%)	82(29.1%)	1(16.7%)
Mixed (IBS-M)	38(13.2%)	37(13.1%)	1(16.7%)
Unsubtyped (IBS-U)	8(2.7%)	8(2.8%)	0

Abbreviations: AST: aspartate transaminases; ALT: alanine transaminases; BMI: body mass index; CD: coeliac disease; IBS: irritable bowel syndrome; SD: standard deviation; IQR: interquartile range.

A total of 9/287 with IBS were seropositive for IgA anti-tTG antibodies, corresponding to a seroprevalence of 3.1% (95% CI: 2.7–4.3%). The distribution of anti-tTG Ab titres (expressed as fold elevation above the upper limit of normal) was: >10-fold elevation in five (1.7%), five- to10 folds elevation in two (0.7%), and two- to fivefold elevation in one (0.3%), respectively (Table 2).

Table 2.

Prevalence of coeliac disease in patients with irritable bowel syndrome.

Characteristics	Numbers (%)
Seropositive for IgA anti-tTg	9/287
Duodenal biopsy findings (Marsh Grading)	Marsh 1 :3/9 (33.3%) Marsh 2: 0 Marsh 3A: 2 (22.2%) Marsh 3B: 3/9 (33.3%) Marsh 3C: 1/9 (11.1%)
Biopsy positive for CD (Marsh 2 or more)	6
Seroprevalence of CD	3.2% (95% CI: 2.7% - 4.3%)
Biopsy prevalence of CD	2.1% (95% CI: 1.2% - 2.5%)

Abbreviations: CD: coeliac disease; IgA anti-tTG: IgA anti-tissue transglutaminase antibody.

Of nine seropositive patients villous abnormalities consistent with modified Marsh grade ≥2 were identified in six, giving a prevalence of biopsy-confirmed CD of 2.1%, (95% CI: 1.8–2.5%) (Table 2).

Among patients with IBS, univariate analysis identified low haemoglobin, low total protein, and elevated alkaline phosphatase levels as significant predictors of CD. However, on multivariate logistic regression, only anaemia remained independently associated (adjusted OR 0.89, 95% CI: 0.56–0.95, p = 0.03). This suggests an important and clinically relevant indicator to prompt evaluation for CD (Table 3).

Table 3.

Odds ratio for variables as investigated by univariable and multivariable analyses as possible predictors for coeliac disease in irritable bowel syndrome.

Variables	Univariate OR (95% CI)	p-value	Multivariate analysis (95% OR)	p-value
Age	0.94 (0.86–1.03)	0.14
Gender	0.41(0.04–3.62)	0.38
BMI	0.81(0.64–1.04)	0.07
IBS subtype	0.79(0.26–2.38)	0.66
Haemoglobin	0.73(0.53–1.01)	0.05	0.89(0.56–0.95)	0.03
Platelets	0.79(0.76–0.89)	0.79
Total bilirubin	0.93(0.74–1.14)	0.93
Total protein	0.61(0.44–0.85)	0.01
Albumin	0.48(0.22–1.04)	0.08
AST	1.01(0.97–1.04)	0.60
ALT	1.0(0.97–1.03)	0.68
ALP	1.05(1.02–1.08)	0.02

Abbreviations: ALP: alkaline phosphatase; ALT: alanine transaminases; AST: aspartate transaminases; BMI: body mass index; IBS: irritable bowel syndrome.

Bold values were to show significant p-value.

Discussion

We found a relatively high prevalence of CD in patients with IBS in Rajasthan, consistent with reports from other regions of India.^9,15–17 Globally, CD is increasingly recognised in this group.¹⁴ Indian studies suggest variable prevalence, with seropositivity up to 6.1% and biopsy-confirmed disease in 0.8%.⁸ High wheat consumption probably contributes to a CD prevalence similar to or higher than that seen in other northern states. Gluten exposure therefore remains high in these populations, and in the absence of systematic screening strategies, a substantial number with underlying CD may remain undiagnosed.

Although CD is classically associated with diarrhoea-predominant symptoms, non-classical presentations (including constipation or extraintestinal manifestations) are increasingly recognised. Therefore, reliance solely on symptom subtype to suspect CD may lead to underdiagnosis, and screening strategies should not be restricted to diarrhoea-predominant IBS alone. Larger studies are warranted to confirm the association between IBS subtypes and CD.

Anaemia may be a useful clinical clue to prompt CD screening in IBS patients. This finding is clinically relevant and biologically plausible, as iron deficiency anaemia is a well-established extra-intestinal manifestation of CD and may precede gastro-intestinal symptoms. Given that IBS is a functional disorder characterised by subjective symptoms, its diagnosis is typically clinical, with investigations typically reserved for patients with alarm features.¹⁸ Incorporating haemoglobin as a trigger for screening may offer a pragmatic approach in resource-limited settings. Importantly, several organic conditions, including CD, small intestinal bacterial overgrowth, lactose intolerance, and parasitic infections, may mimic or co-exist with IBS.^19,20 Failure to identify these conditions can delay appropriate management. Our findings reinforce the need for a more nuanced approach to IBS evaluation, particularly in high-risk populations.

However, our study has a few limitations; the relatively small number of biopsy-confirmed cases limits the power to detect associations with other predictors. Additionally, serological testing was limited to IgA anti-tTG without confirmatory anti-endomysial antibody testing, which may have influenced diagnostic accuracy. The absence of a non-IBS control group precludes direct comparison with the general population. Finally, the observational design limits causal inference. Nonetheless, our prospective design, systematic screening approach, and use of histological confirmation strengthen the validity of our findings.

In conclusion, our study suggests that CD is not uncommon among patients presenting with IBS-like symptoms, and clinical differentiation based on symptoms alone is unreliable. Targeted screening, particularly in patients with anaemia, may facilitate earlier diagnosis and improve clinical outcomes.

Footnotes

ORCID iDs

Dholavan Mayur

Ankit Agarwal

Chhagan Lal Birda

Vivek Chowdary Gogineni

Terence Susngi

Ashish Agarwal

Ethics approval

The study protocol was approved by the Institute Ethics committee (Approval No. AIIMS/IEC/2021/3609).

Patient consent

Written and informed consent were taken from all patients before enrolment in the study.

Permission to reproduce material from other sources

Not required.

Author contributions

Conception and design of study was done by AA and BK. Generation, collection, assembly, analysis, and/or interpretation of data were done by DM, AA, VCG, and TS. Drafting or revision of the manuscript was done by DM, AA, VCG, TS, BKG, and AA. Critical revision of the article for important intellectual content was done by AA, CLB, MKG, BK, and AA. Approval of the final version of the manuscript was obtained by all authors.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Writing assistance

None.

Guarantor of article

Ashish Agarwal.

References

Singh

Arora

Strand

, et al. Global prevalence of celiac disease: systematic review and meta-analysis. Clin Gastroenterol Hepatol 2018; 16: 823–836.e2.

Makharia

Verma

Amarchand

, et al. Prevalence of celiac disease in the northern part of India: a community based study. J Gastroenterol Hepatol 2011; 26: 894–900.

Therrien

Kelly

Silvester

. Celiac disease: extraintestinal manifestations and associated conditions. J Clin Gastroenterol 2020; 54: 8–21.

Ghoshal

Sachdeva

Pratap

, et al. Indian Consensus statements on irritable bowel syndrome in adults: a guideline by the Indian neurogastroenterology and motility association and jointly supported by the Indian society of gastroenterology. Indian J Gastroenterol Off J Indian Soc Gastroenterol 2023; 42: 249–273.

Sperber

Bangdiwala

Drossman

, et al. Worldwide prevalence and burden of functional gastrointestinal disorders, results of Rome foundation global study. Gastroenterology 2021; 160: 99–114.e3.

Makharia

Verma

Amarchand

, et al. Prevalence of irritable bowel syndrome: a community based study from northern India. J Neurogastroenterol Motil 2011; 17: 82–87.

Ghoshal

Singh

. Frequency and risk factors of functional gastro-intestinal disorders in a rural Indian population. J Gastroenterol Hepatol 2017; 32: 378–387.

Sharma

Verma

Das

, et al. Prevalence of celiac disease in Indian patients with irritable bowel syndrome and uninvestigated dyspepsia. J Dig Dis 2015; 16: 443–448.

Ramakrishna

Makharia

Chetri

, et al. Prevalence of adult celiac disease in India: regional variations and associations. Am J Gastroenterol 2016; 111: 115–123.

10.

Panezai

Ullah

Ballur

, et al. Frequency of celiac disease in patients with chronic diarrhea. Cureus 2021; 13: e20495.

11.

Oberhuber

Granditsch

Vogelsang

. The histopathology of coeliac disease: time for a standardized report scheme for pathologists. Eur J Gastroenterol Hepatol 1999; 11: 1185.

12.

Lacy

Mearin

Chang

, et al. Bowel disorders. Gastroenterology 2016; 150: 1393–1407.e5.

13.

Mearin

Agardh

Antunes

, et al. ESPGHAN position paper on management and follow-up of children and adolescents with celiac disease. J Pediatr Gastroenterol Nutr 2022; 75: 369–386.

14.

Irvine

Chey

Ford

. Screening for celiac disease in irritable bowel syndrome: an updated systematic review and meta-analysis. Am J Gastroenterol 2017; 112: 65–76.

15.

Sood

Midha

Sood

, et al. Adult celiac disease in northern India. Indian J Gastroenterol Off J Indian Soc Gastroenterol 2003; 22: 124–126.

16.

Sachdev

Srinivasan

Maheswary

, et al. Adult onset celiac disease in north India. Trop Gastroenterol Off J Dig Dis Found 2002; 23: 117–119.

17.

Yachha

Poddar

. Celiac disease in India. Indian J Gastroenterol Off J Indian Soc Gastroenterol 2007; 26: 230–237.

18.

Yang

Wei

Liu

, et al. Predictive value of alarm symptoms in Rome IV irritable bowel syndrome: a multicenter cross-sectional study. World J Clin Cases 2022; 10: 563–575.

19.

Kamboj

Oxentenko

. Clinical and histologic mimickers of celiac disease. Clin Transl Gastroenterol 2017; 8: e114.

20.

Scarmozzino

Pizzi

Pelizzaro

, et al. Refractory celiac disease and its mimickers: a review on pathogenesis, clinical-pathological features and therapeutic challenges. Front Oncol 2023; 13: 1273305.