Coeliac disease presenting atypically: A much wider spectrum

Abstract

Atypical coeliac disease in young children is frequently missed when it presents atypically as non-gastrointestinal presentations to different specialties. There was a greater delay (54 months) in establishing the diagnosis in those with atypical coeliac disease (p < 0.001). No difference was observed in the mode of delivery or duration of breast feeding, but significant difference was observed between gestational age at birth (p < 0.001). Most cases showed stunted growth and underweight. Irritability, anaemia, rickets, dermatitis herpetiformis, alopecia and intussusception were other common predictors of atypical coeliac disease. Because of a myriad spectrum of non-gastrointestinal symptoms, at any age with diverse presentation, a high index of suspicion is therefore required.

Keywords

Atypical presentation spectrum subclinical celiac disease

Introduction

Coeliac disease (CD) is a systemic immune-mediated disorder triggered by gluten in genetically susceptible individuals. A specific serum autoantibody response and evidence of small intestinal mucosal damage is diagnostic. Its prevalence in rich countries and northern India is estimated at 1% but at 0.6% in India as a whole.¹ Recent trends have reported decrease in the percentage of classical form of CD from 73% to 43%.^2,3 CD with atypical features is increasingly being recognised, probably due to increased awareness, availability of sensitive serological markers and recognition of subgroups.⁴

Traditionally, CD has been considered a disease of early childhood with symptoms of diarrhoea being predominant, alluded to as the ‘classical or typical’ presentation. The increasing recognition that CD can present at any age with non-classical (atypical) features such as constipation, intussusception, abdominal distension with or without other systemic manifestations including seizures, alopecia, aphthous stomatitis, liver disease and portal vein obstruction.⁵ An apparent increase in case numbers may be that CD is recognised in patients with autoimmune disorders and in first-degree relatives of an index case.

We report a prospective cohort of children with CD presenting to a single institution over five years and discuss the myriad of its presentations. Since those with subclinical or ‘forme fruste’ variation are likely to have significant morbidity and mortality because of delay in diagnosis hence, it is important that clinicians are aware of these atypical presentations to get a correct diagnosis and reduce the diagnostic odyssey of this subgroup of patients.

Materials and methods

Consecutive patients between the ages of 1 and 18 years presenting with a clinical suspicion of CD were enrolled. Diagnosis of CD was confirmed according to ESPGHAN 2012 criteria.⁶ Clearance was obtained from the Institutional Ethics Committee. Clinical details were collected for gender, mode of delivery, duration of breast-feeding, nature of introduction of complementary feeding, age at first symptom and presentation to the clinic. Anthropometry including height, weight and body mass index were assessed. Short stature and malnutrition were classified according to WHO/IAP charts in children ≤5 and >5 years of age, respectively.^7,8

Venous blood was obtained from each patient to assess anti tTG-IgA (tTG) levels, performed by ELISA using commercial kit, Biomerica (CA, USA), using a recommended cut-off for tTG as >7 U/L. After obtaining parental consent, all patients with these elevated titres underwent gastroduodenoscopy and a four-fold punch duodenal biopsy. The histopathological findings were graded using the modified Marsh classification.⁹ Once CD was confirmed, counselling about the need and adherence to gluten-free diet (GFD) and micronutrient supplementation was imparted.

Statistical analysis was done by using STATA 11.0 version (Stata Corp, USA). Qualitative data was depicted as number (percentage) and the difference among the groups were computed by Fisher exact test and χ² test. Quantitative data was presented as median (range), and the difference of median among the groups was computed by Mann–Whitney U test. A p-value <0.05 was considered to be statistically significant.

Results

Details of the study are depicted in the study flow (Figure 1). CD was diagnosed in 513/4719 (10.8%) of the referrals. The classical presentation (Group A) was seen in 320 (62.37%) and atypical (Group B) in 193 (37.6%) cases. There was no difference in the median age of onset of symptoms in groups A and B (p = 0.760); however, the age of presentation was significantly different being 72 months (13–216) in Group A and 84 months (2–198) in Group B (p = 0.036). A statistically significant difference was observed in the delay in diagnosis between Groups A (8 months) and B (54 months) (p < 0.001). No sex differences were found and no difference in the mode of delivery between groups (p = 0.469). Gestation at birth differed significantly between groups (p < 0.001). No difference between breast-feeding duration and age at introduction of complementary-feeding was observed (p = 0.081 and p = 0.776, respectively). A significant difference was observed in the feeding practices between Groups A and B (p = 0.044). Larger proportion of patients from both groups was introduced with mixed cereals (wheat and rice-based) diet and comparatively low proportion of patients from both groups were introduced with only wheat-based diet.

Figure 1.

Study flow diagram.

Significant differences were observed in the anthropometric parameters between the two groups. Severely stunted and severely underweight categories of cases were commoner with Group A (p < 0.001); however, stunted and underweight cases were more common in Group B (p = 0.05). Data for presenting complaints, clinical features and comorbidities among the classical and atypical groups in children with CD are depicted in Table 1.

Table 1.

Presenting complaints, clinical features and comorbidities among the classical and atypical groups in children with celiac disease.

	Group A^a	Group B^a	p-value
Presenting complaints
Diarrhoea	320 (100%)	0 (0%)	<0.001
Abdominal pain	181 (56.56%)	66 (34.20%)	<0.001
Abdominal distention/bloating	170 (53.13%)	40 (20.73%)	<0.001
Vomiting	94 (29.38%)	33 (17.10%)	0.002
Constipation	57 (17.81%)	31 (16.06%)	0.631
Weight loss	107 (33.44%)	45 (23.32%)	0.017
Failure to thrive	143 (44.69%)	60 (31.09%)	0.003
Recurrent oral ulcers	18 (5.63%)	16 (8.29%)	0.273
Lethargy	12 (3.75%)	12 (6.22%)	0.204
Pica	13 (4.06%)	34 (17.62%)	<0.001
Arthralgia	56 (17.50%)	48 (24.87%)	0.054
Seizures	3 (0.94%)	3 (1.55%)	0.529
Irritability with the onset of disease	266 (83.13%)	129 (66.84%)	<0.001
Irritability after initiation of GFD	37 (11.56%)	42 (21.76%)
No irritability	13 (4.06%)	12 (6.22%)
Clinical features
Anaemia	280 (88.05%)	152 (78.76%)	0.005
Rickets	58 (18.13%)	52 (26.94%)	0.020
Dental enamel defect	7 (2.19%)	19 (9.84%)	<0.001
Vitamin A deficiency	4 (1.25%)	11 (5.70%)	0.004
Other micronutrient deficiency	3 (0.94%)	8 (4.15%)	0.015
Clubbing	9 (2.81%)	7 (3.63%)	0.609
Lymphadenopathy	18 (5.63%)	16 (8.29%)	0.273
Prolapse rectum	3 (0.94%)	7 (3.63%)	0.033
Hepatosplenomegaly	16 (5%)	13 (6.74%)	0.434
Hepatomegaly	13 (4.06%)	6 (3.11%)	0.638
Splenomegaly	6 (1.88%)	2 (1.04%)	0.458
Hepatitis	14 (4.38%)	11 (5.70%)	0.529
Comorbidities
Type 1 diabetes	21 (6.56%)	18 (9.33%)	0.302
Dermatitis herpetiformis	4 (1.25%)	12 (6.22%)	0.002
Delayed motor development	4 (1.25%)	1 (0.52%)	0.414
Alopecia areata	4 (1.25%)	12 (6.22%)	0.002
Hypothyroidism	2 (0.63%)	7 (3.63%)	0.012
Intussusception	10 (3.13%)	16 (8.29%)	0.012
Chronic liver disease	23 (7.19%)	13 (6.74%)	1.0
Portal hypertension	4 (1.25%)	3 (1.55%)	0.773
Extra hepatic portal vein obstruction	2 (0.63%)	0 (0%)	0.271

GFD: gluten-free diet.

^aNumber, percentage.

Discussion

The diagnosis of CD is evidently challenging as half of the children had atypical presentations. Manifestations are variably influenced by the extent of mucosal injury, dietary habits and age of onset.¹⁰ In fact, the diagnostic odyssey reported from an adult CD in North India and Canadian coeliac association survey reports suggest that 60% of respondents, irrespective of age, had to consult three or more physicians before the diagnosis was made, and 15% had to consult five or more clinicians. The situation in the paediatric population is likely to be no different.¹¹

Evident from studies is the fact that, in richer countries, where early paediatric consultations are the norm, the proportion of atypical presentations of coeliac disease is as high as one-third. In LMICs, it is likely that a large proportion of atypical CD is being missed. Many children had received multiple courses of antibiotics, including empirical treatment for tuberculosis, before being referred with a suspicion of CD. In an undiagnosed population, there were higher odds of CD in females (0.589%) than males (0.415%). A systemic review and meta-analysis reported that the pooled prevalence of CD is higher in females (0.589%) than in males (0.415%) and concluded that there were higher odds of CD among females in an undiagnosed adult population (p < 0.00001).¹²

Early observational studies suggested a protective role of prolonged breast-feeding and continuous breast-feeding at the time of gluten introduction.¹³ Two large randomised controlled trials found no such protective effect^14,15 as in our study. However, introduction of a vegetarian diet has been found to have a protective role compared to animal-based diet which may trigger a systemic response. The role of human microbiota had been postulated to cause dysbiosis due to microbial modulations in CD. Dysbiosis has been reported with increase in Gram-negative bacteria and bacteroides species and a decrease in Bifidobacterium and Lactobacillus which modulates the cytokine microenvironment and is postulated to amplify the immune response.¹⁶ Our study, as two large cohorts in Denmark and Norway, showed no association with the mode of delivery of developing CD.¹⁷

Oral presentation with aphthous ulcers and dental enamel defects are common atypical manifestations in CD, the latter found in 24.8% with mixed or permanent dentition and 5.8% in deciduous.¹⁸

Rectal prolapse and intussusception are other important presentations of CD. Prolapse may be consequent to increase abdominal pressure from long-standing constipation or may be due to loss of muscle mass consequent to malabsorption. Intussusception is reported in up to 25% cases of newly diagnosed CD and up to 95% in asymptomatic cases.¹⁹ Probable reasons for intussusception are inflammation, evidence by enlarged lymph nodes seen on histopathology and decreased small bowel motility. Growth failure and intussusception should be viewed as pointers of CD.

Functional constipation is a common problem in childhood and affects 5% of an outpatient population. CD was diagnosed among 1 in 28 chronically constipated children, suggesting that screening should be on offer for CD in children who do not respond to simple measures.²⁰ It is postulated that bowel motility is reduced possibly due to its association with gliadin peptide.

Portal hypertension and chronic liver disease have been increasingly reported with CD, found in 14% of patients with non-cirrhotic and 10% patients with unexplained portal hypertension had CD.²¹ Children with cryptogenic liver disease had a 15 times higher prevalence of CD than the normal population.²²

Cavitating mesenteric lymph nodes have been reported as a rare but poorly understood complication of CD.²³ Lymphadenopathy is a general manifestation of both inflammation and autoimmunity, both of which are underlying pathophysiological mechanisms in CD. Not surprisingly. since type 1 diabetes mellitus, primary biliary cirrhosis, rheumatoid arthritis and dermatitis herpetiformis share similar HLA haplotypes, the association between these and CD is explicit. A misdiagnosis of TB is clearly likely in endemic areas.

Conclusion

CD is under-diagnosed, particularly in LMICs; we trust that this article will alert physicians to entertain it as a possible diagnosis in cases as those described.

Footnotes

Authors’ contributions

Concept – Seema Kapoor; Design – Seema Kapoor; Supervision – Seema Kapoor, Meenakshi Bothra, Bhavna Dhingra, Praveen Kumar; Resources – Seema Kapoor; Materials – Avinash Lomash; Data Collection and/or Processing – Avinash Lomash, Abhinaya Venkatkrishnan; Analysis and/or Interpretation – Avinash Lomash, Seema Kapoor; Literature Search – Avinash Lomash, Abhinaya Venkatkrishnan; Writing Manuscript – Avinash Lomash; Critical Review – Seema Kapoor, Meenakshi Bothra, Bhavna Dhingra.

Acknowledgements

We acknowledge the staff of Genetic lab, Department of Pediatrics for their constant support during the study, specially Mrs Vinita Bansal for the technical help in the study.

Ethical clearance

Clearance was obtained from institutional ethical committee of Maulana Azad Medical College and Associated Lok Nayak Hospital.

F.1/IEC/MAMC/(31)/3/2012/NO:236

Date of receiving: 06/11/2012

Informed consent

Written informed consents of the parent/s of all study subjects were obtained after explaining them aim, the extent of their child’s involvement, the risks involved (if any) and the freedom of choice for participation in the study. Proforma were maintained for each patient which included the detailed clinical history and relevant clinical findings.

Guarantor

Seema Kapoor and Avinash Lomash will be the guarantors of the paper.

Declaration of conflicting interests

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

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Avinash Lomash https://orcid.org/0000-0002-2530-599X Praveen Kumar

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