ESPGHAN Coeliac Diagnostic Criteria (Biopsy-Sparing Pathway) and Paediatric Crohn's/Ulcerative Colitis

Coeliac Disease and Paediatric Inflammatory Bowel Disease: ESPGHAN Biopsy-Sparing Guidelines and IBD Therapeutics

Chronic gastrointestinal disorders in children frequently present with overlapping symptoms of abdominal pain, altered bowel habits, and faltering linear growth. Among these, Coeliac Disease and Paediatric Inflammatory Bowel Disease (PIBD) represent the two most important immune-mediated enteropathies encountered in paediatric practice. Recent decades have seen major advances in diagnostic algorithms—most notably the validated biopsy-sparing pathway for coeliac disease established by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN)—as well as evidence-based therapeutic protocols such as Exclusive Enteral Nutrition (EEN) for paediatric Crohn's disease. Mastering these European clinical practice guidelines is essential for candidates sitting the European Board of Paediatrics (EBP-EAP) examination.

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Coeliac Disease: Autoimmune Pathophysiology and Immunogenetics

Coeliac disease is a systemic, immune-mediated enteropathy triggered by the ingestion of gluten (the alcohol-soluble storage proteins of wheat [gliadins], rye [secalins], and barley [hordeins]) in genetically susceptible individuals. It affects approximately 1% of the paediatric population in Europe.

                                  [Dietary Gluten (Gliadin)]
                                              |
                               [Lamina Propria Translocation]
                                              |
                        [Deamidation by Tissue Transglutaminase (tTG-2)]
                                              |
                     [Presentation on HLA-DQ2 / HLA-DQ8 to CD4+ T Cells]
                                              |
         +------------------------------------+------------------------------------+
         |                                                                         |
  [Th1/Th17 Pro-inflammatory Cascade]                               [Intraepithelial CD8+ CTL Activation]
  - IFN-gamma, TNF-alpha, IL-21                                      - IL-15 driven reprogramming
  - B-cell differentiation: anti-tTG, anti-EMA                       - Enterocyte apoptosis & villous atrophy

Cellular and Molecular Immunopathology

1. Enzymatic Modification (Deamidation): Gluten peptides are resistant to luminal gastric and pancreatic proteolysis due to their high proline and glutamine content. Resistant 33-mer gliadin peptides traverse the epithelial barrier into the lamina propria, where the calcium-dependent enzyme tissue transglutaminase-2 (tTG-2) deamidates specific neutral glutamine residues into negatively charged glutamic acid.
2. HLA Binding and T-Cell Activation: Negatively charged deamidated gliadin peptides fit with high affinity into the positively charged peptide-binding grooves of human leukocyte antigen class II molecules: HLA-DQ2 (primarily encoded by alleles DQA1*05:01 and DQB1*02:01, present in ~90–95% of patients) or HLA-DQ8 (encoded by DQA1*03:01 and DQB1*03:02, present in the remaining 5–10%). Antigen-presenting dendritic cells display these complexes to CD4+ T-helper cells.
3. Pro-inflammatory and Cytotoxic Destruction: Activated CD4+ T cells secrete high levels of pro-inflammatory cytokines, predominantly interferon-gamma (IFN-$\gamma$) and interleukin-21 (IL-21). Enterocytes simultaneously overexpress interleukin-15 (IL-15), which reprograms intraepithelial CD8+ T lymphocytes into natural killer-like cytotoxic T cells. These killer lymphocytes engage stress ligands (MIC-A/MIC-B) on enterocytes, driving widespread enterocyte apoptosis, villous blunting, crypt hyperplasia, and loss of absorptive surface area.
4. Humoral Autoantibody Production: Activated T cells stimulate B lymphocytes to differentiate into plasma cells producing antibodies directed against tissue transglutaminase (anti-tTG), endomysium (anti-EMA), and deamidated gliadin peptides (anti-DGP).

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Clinical Manifestations and High-Risk Cohorts

The clinical presentation of coeliac disease in paediatrics varies from life-threatening malabsorption to subtle, extra-intestinal or entirely asymptomatic presentations:

• Classical (Gastrointestinal / Malabsorptive) Presentation: Typically seen in toddlers aged 9 to 24 months following the introduction of gluten. Manifests with chronic watery or pale, foul-smelling diarrhea, anorexia, abdominal distension ('pot-belly'), generalized muscle wasting (particularly visible in gluteal folds), irritability, and faltering linear growth and weight gain.
• Non-Classical (Older Children / Extraintestinal) Presentation: More prevalent in older children and adolescents. Gastrointestinal symptoms may be subtle (recurrent abdominal pain, nausea, bloating, or even intractable constipation). Extraintestinal manifestations frequently predominate:
  • Iron Deficiency Anemia: Unresponsive or poorly responsive to oral iron supplementation due to duodenal enterocyte damage where active iron absorption occurs.
  • Short Stature and Delayed Puberty: Isolated short stature or pubertal arrest may be the sole presenting sign.
  • Dental Enamel Hypoplasia: Symmetrical, chronological enamel defects affecting permanent teeth.
  • Recurrent Aphthous Stomatitis: Painful, recurrent oral ulcerations.
  • Coeliac Hepatitis: Unexplained elevation of serum aminotransferases (ALT/AST) that normalizes within 6 to 12 months on a strict gluten-free diet.
  • Osteopenia / Osteoporosis: Secondary to chronic calcium and vitamin D malabsorption.
  • Dermatitis Herpetiformis: A cutaneous manifestation characterized by intensely pruritic, symmetrical papulovesicular eruptions over extensor surfaces (elbows, knees, buttocks, scalp). Direct immunofluorescence of perilesional skin biopsies reveals pathognomonic granular IgA deposits within the dermal papillae.

High-Risk Cohorts Mandating Routine Screening

Screening via serology should be performed even in the complete absence of gastrointestinal symptoms in:

• First-degree relatives of patients with coeliac disease (prevalence 5–15%)
• Type 1 Diabetes Mellitus (prevalence 5–10%)
• Autoimmune Thyroiditis (Hashimoto's thyroiditis)
• Autoimmune Hepatitis
• Down Syndrome (Trisomy 21) (prevalence 5–12%)
• Turner Syndrome (45,X) (prevalence 4–8%)
• Williams Syndrome
• Selective IgA Deficiency (prevalence 10- to 15-fold higher than general population)

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The Revised ESPGHAN 2020 Diagnostic Guidelines

The ESPGHAN 2020 diagnostic guidelines modernized the diagnosis of coeliac disease by expanding the biopsy-sparing pathway and streamlining testing protocols.

                    [Suspected Coeliac Disease (Symptomatic or High-Risk)]
                                              |
                   [Total Serum IgA  +  IgA anti-tTG (on gluten diet)]
                                              |
         +------------------------------------+------------------------------------+
         |                                                                         |
  [Total IgA Normal]                                                    [Low Total IgA for Age]
  [IgA anti-tTG ≥ 10x ULN]                                              [e.g., <0.2 g/L above age 3 years]
         |                                                                         |
  [Second Independent Blood Draw]                                       [Measure IgG anti-tTG or IgG anti-DGP]
  [Test for anti-EMA (IgA)]                                                        |
         |                                                                         +------------+
         +---------------------+                                                                |
         |                     |                                                                |
  [EMA Positive]        [EMA Negative]                                                          |
         |                     |                                                                |
[COELIAC CONFIRMED]     [Proceed to Endoscopy]                                                  |
[No Biopsy Needed]      [Multiple Duodenal Biopsies]                                            |
[No HLA Test Needed]           ^                                                                |
                               +----------------------------------------------------------------+

1. Initial Screening Step

Testing must always be conducted while the child is consuming a normal, gluten-containing diet. Premature elimination of gluten before serological testing leads to false-negative results. The initial screening investigation consists of:

• Quantitative Total Serum IgA, AND
• IgA anti-tissue Transglutaminase (anti-tTG-IgA).

2. The Biopsy-Sparing Pathway (No-Biopsy Approach)

ESPGHAN 2020 established that upper endoscopy and duodenal biopsy can be safely omitted if all the following criteria are fulfilled:

1. The child has IgA anti-tTG levels $\ge 10$ times the upper limit of normal (ULN) using a validated commercial assay (e.g., if assay ULN is 10 U/mL, the child's titer must be $\ge 100\text{ U/mL}$).
2. Total serum IgA is within the age-appropriate normal range.
3. A second, independent venipuncture is obtained and tests positive for anti-endomysial antibodies (EMA-IgA) in an accredited laboratory using indirect immunofluorescence.

3. Duodenal Biopsy Pathway

Duodenal endoscopy with multiple biopsies remains mandatory if:

• IgA anti-tTG is positive but $< 10$ times the ULN.
• IgA anti-tTG is $\ge 10$ times ULN, but the confirmatory EMA test on the second sample is negative or discordant.
• High clinical index of suspicion for coeliac disease persists despite negative serology.
• Biopsy Protocol: At least 4 biopsies from the distal duodenum (second and third parts) and at least 1 to 2 biopsies from the duodenal bulb must be obtained, as mucosal lesions may be patchy or confined to the bulb.
• Histological Marsh-Oberhuber Classification:
  • Marsh 0: Normal mucosal architecture.
  • Marsh 1 (Infiltrative): Preserved mucosal architecture with increased intraepithelial lymphocytes (>25 IELs per 100 enterocytes).
  • Marsh 2 (Hyperplastic): Increased IELs accompanied by crypt elongation and hyperplasia.
  • Marsh 3 (Destructive): Crypt hyperplasia, increased IELs, and progressive villous atrophy:
    • Marsh 3a: Partial villous blunting.
    • Marsh 3b: Subtotal villous atrophy.
    • Marsh 3c: Total villous flat mucosa.

4. Protocol When Total IgA Is Low

Low total IgA can cause false-negative IgA-based coeliac tests. ESPGHAN recommends IgG-based testing when IgA is low for age, or $<0.2\text{ g/L}$ above age 3 years. This practical testing threshold is distinct from a formal diagnosis of selective IgA deficiency.

• The clinician must order IgG-based serology: IgG anti-tissue transglutaminase (anti-tTG-IgG) or IgG anti-deamidated gliadin peptides (anti-DGP-IgG).
• If IgG serology is positive, the child must proceed to upper endoscopy with duodenal biopsies; the biopsy-sparing pathway is not validated for IgG-based testing.

Management: The Gluten-Free Diet (GFD)

Definitive treatment is a strict, lifelong gluten-free diet, completely excluding wheat, rye, and barley. Pure, uncontaminated oats are tolerated by most patients but must be introduced cautiously under supervision. Serological titers (anti-tTG) should be rechecked at 6 and 12 months, with expected normalization within 1 to 2 years.

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Paediatric Inflammatory Bowel Disease: Crohn's Disease vs Ulcerative Colitis

Paediatric Inflammatory Bowel Disease (PIBD) encompasses Crohn's Disease (CD), Ulcerative Colitis (UC), and IBD-Unclassified (IBD-U). Approximately 25% of all IBD diagnoses are established during childhood or adolescence.

Clinical and Pathological Comparison

Diagnostic Biomarkers and Staging Workup

• Fecal Calprotectin: A calcium- and zinc-binding protein derived predominantly from migrating neutrophils. Elevated levels (e.g., $>250\text{ mcg/g}$) suggest intestinal inflammation but are not specific to IBD. Interpret with symptoms, infection testing and specialist assessment; serial measurements help monitor treatment response.
• Complete Endoscopic and Imaging Staging: Diagnostic staging includes endoscopy with biopsies and appropriate small-bowel imaging. Exclude enteric infection; small-bowel imaging can be deferred when endoscopy and histology show typical UC:
  1. Ileocolonoscopy with multiple biopsies from every segment (rectum, sigmoid, descending, transverse, ascending colon, and terminal ileum).
  2. Upper Gastrointestinal Endoscopy (Esophagogastroduodenoscopy - EGD) with routine serial biopsies from the esophagus, stomach, and duodenum (frequently reveals non-caseating granulomas even without gross lesions).
  3. Magnetic Resonance Enterography (MRE): When small-bowel imaging is indicated, MRE assesses luminal wall thickening, hyperenhancement, strictures, pre-stenotic dilatation, and extraluminal fistulae or phlegmons without exposing the paediatric patient to ionizing radiation.

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Evidence-Based Medical Therapeutics in Paediatric IBD

                                  [Paediatric IBD Therapeutics]
                                                 |
         +---------------------------------------+---------------------------------------+
         |                                                                               |
  [Crohn's Disease: Stratify Risk]                                            [Paediatric Ulcerative Colitis]
  - INDUCTION: Exclusive Enteral Nutrition (EEN)                                  - INDUCTION: Oral & Rectal 5-ASA (Mesalazine)
    for 6 to 8 weeks (Low-Risk First-Line)                                                   (Mild-to-Moderate)
  - Corticosteroids if nutritional induction is not feasible                     - Oral Steroids if indicated; IV Steroids for ASUC
  - MAINTENANCE: Thiopurines or Methotrexate                                - MAINTENANCE: Oral 5-ASA (First-Line)
    *Mandatory Pre-Treatment TPMT Testing*                                        - Thiopurines for frequent steroid-relapsing
  - High-Risk CD: Early Anti-TNF; continue for maintenance                                  - Biologics: Infliximab for acute severe colitis

1. Induction of Remission in Crohn's Disease

• Exclusive Enteral Nutrition (EEN): First-line induction for low-risk luminal paediatric Crohn's disease; high-risk patients should receive early anti-TNF therapy.
  • Protocol: The patient consumes 100% of their daily caloric requirements exclusively via a specialized liquid nutritional formula (polymeric or elemental) for 6 to 8 weeks, with the complete exclusion of all solid foods and other beverages (water is permitted).
  • Efficacy: Induces clinical remission in up to 80% of children, which is equivalent to systemic corticosteroids. Crucially, EEN achieves significantly higher rates of endoscopic mucosal healing (70% vs 30%), restores nutritional deficits, promotes linear growth velocity, and completely avoids the devastating side effects of corticosteroids (growth suppression, osteopenia, hypertension, Cushingoid facies).
• Systemic Corticosteroids: Oral prednisolone (1 mg/kg/day, max 40 mg) or IV methylprednisolone is reserved for children unable or unwilling to complete EEN, patients with severe extraintestinal complications, or acute fulminant flares. Steroids should never be used as maintenance therapy.

2. Induction of Remission in Ulcerative Colitis

• Mild-to-Moderate Active UC: First-line therapy is high-dose oral 5-aminosalicylic acid (5-ASA / Mesalazine, 60–80 mg/kg/day) combined with rectal mesalazine (suppositories or enemas) for distal disease.
• Moderate Active UC: Oral corticosteroids may be used when indicated. ASUC (PUCAI $\ge 65$) requires admission and prompt IV corticosteroids. Assess response daily; steroid-refractory disease needs timely specialist rescue (usually infliximab; ciclosporin is an alternative) and surgical review.

3. Maintenance of Remission

• Thiopurines (Azathioprine 2.0–2.5 mg/kg/day or 6-Mercaptopurine 1.0–1.5 mg/kg/day): Options for low-risk Crohn's maintenance include thiopurines or weekly methotrexate; continue effective anti-TNF treatment when used for induction. Thiopurines also maintain remission in steroid-dependent/frequently relapsing UC.

• Biologic Therapy (Anti-TNF-$\alpha$ Monoclonal Antibodies):
  • Infliximab (chimeric IgG1 anti-TNF) administered as IV infusions (weeks 0, 2, 6, then every 8 weeks) and Adalimumab (fully human anti-TNF) administered subcutaneously.
  • Indications: Early treatment of high-risk Crohn's disease, including severe growth impairment or stricturing/penetrating/perianal disease; failure of nutritional/steroid induction, steroid dependence, and steroid-refractory acute severe UC.
  • Safety Requirements: Mandatory pre-treatment screening for latent tuberculosis (tuberculin skin test / Mantoux and Interferon-Gamma Release Assay [IGRA]) and Hepatitis B status. Routine therapeutic drug monitoring (measuring trough infliximab levels and anti-drug antibodies) optimizes efficacy and prevents loss of response.

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Functional Constipation and Dysphagia

Functional Constipation

• Diagnosis is clinical (Rome IV): at least two features for at least one month, such as two or fewer defecations per week, stool retention or retentive posturing, painful or hard stools, large-diameter stools, a large rectal faecal mass, or weekly faecal incontinence after toilet training.
• Red flags that suggest an organic cause include onset in the first month of life, delayed passage of meconium beyond 48 hours (Hirschsprung disease), faltering growth, bilious vomiting or marked abdominal distension, abnormal lower-limb neurology, and a sacral dimple, hair tuft or deviated gluteal cleft (spinal dysraphism).
• Routine abdominal radiographs and blood tests are not needed in typical functional constipation.
• Treatment: disimpact with oral polyethylene glycol (PEG) 1–1.5 g/kg/day for 3–6 days (enemas if PEG is unavailable), then give maintenance PEG as first-line therapy, using lactulose if PEG is unavailable and adding a stimulant if needed. Continue for at least 2 months and at least 1 month after symptoms resolve, then wean gradually. Combine this with regular toilet sitting after meals, positive reinforcement, and normal fibre and fluid intake. Never punish soiling.

Dysphagia

• Oropharyngeal dysphagia (difficulty starting a swallow, coughing or choking, nasal regurgitation) is usually neurological or neuromuscular, for example in cerebral palsy, or structural, such as a cleft palate.
• Oesophageal dysphagia (food sticking after swallowing) has these important causes: eosinophilic oesophagitis, with food impaction in older children and adolescents, often with atopy, diagnosed by biopsy showing at least 15 eosinophils per high-power field and treated with a proton-pump inhibitor, swallowed topical corticosteroid or elimination diet; a retained foreign body; caustic or peptic stricture; achalasia; and extrinsic compression by a vascular ring or mediastinal mass.
• A child who cannot swallow saliva after food impaction or ingestion needs urgent endoscopy.

Sources: ESPGHAN/NASPGHAN functional constipation guideline; ESPGHAN 2024 eosinophilic oesophagitis update.