10.4 IBD Medical Therapy, Coeliac Disease & Malabsorption

3. Medical Management of Inflammatory Bowel Disease

Crohn's Disease Management

• Induction of Remission (Mild-to-Moderate): Oral budesonide (9 mg once daily for 8 weeks) is preferred for mild-to-moderate ileocaecal disease; high first-pass hepatic clearance (~90%) confers lower systemic glucocorticoid toxicity. For more widespread disease, oral prednisolone (40 mg daily, tapered by 5 mg weekly over 8 weeks). Exclusive enteral nutrition (EEN) is an established first-line alternative, especially in paediatric and adolescent populations.
• Induction of Remission (Moderate-to-Severe / Refractory): Intravenous hydrocortisone (100 mg QDS) or early biologic therapy: Infliximab (chimeric monoclonal anti-TNF-alpha antibody), Adalimumab (fully human anti-TNF), Ustekinumab (anti-IL-12/23 p40 subunit), or Vedolizumab (gut-selective alpha-4-beta-7 integrin antagonist). Pre-biologic safety mandate: Must screen for latent tuberculosis (chest radiograph and interferon-gamma release assay [IGRA]) and chronic viral hepatitis (HBV/HCV serology) before commencing anti-TNF therapy.
• Maintenance of Remission:
  • Thiopurines: Oral Azathioprine (2.0–2.5 mg/kg/day) or Mercaptopurine (1.0–1.5 mg/kg/day). Critical safety requirement: Measure thiopurine methyltransferase (TPMT) enzymatic activity or genotype prior to initiating therapy. Individuals with homozygous mutations or negligible TPMT activity (<10%) metabolize thiopurines via hypoxanthine phosphoribosyltransferase (HPRT) into excessive, toxic levels of 6-thioguanine nucleotides (6-TGN), triggering catastrophic, potentially fatal bone marrow aplasia. Regular FBC and LFT monitoring is mandatory.
  • Methotrexate: Intramuscular or subcutaneous weekly injection (with oral folic acid) is an effective maintenance agent for azathioprine-intolerant CD patients. Strictly teratogenic.
  • Note on 5-ASAs: Mesalazine and sulfasalazine have no proven role in the maintenance of remission in Crohn's disease.

Ulcerative Colitis Management

• Mild-to-Moderate Proctitis: First-line therapy is topical mesalazine (5-ASA) suppositories (1 g once daily). Topical 5-ASA is clinically superior to oral 5-ASA and superior to topical corticosteroids for inducing and maintaining proctitis remission.
• Mild-to-Moderate Left-Sided or Extensive Colitis: Combined high-dose oral 5-ASA (e.g., mesalazine 2.4–4.8 g daily) plus topical 5-ASA enema (1 g/day). If inadequate clinical improvement within 2–4 weeks, add oral prednisolone (40 mg daily tapering over 8 weeks).
• Maintenance of Remission: Lifelong oral 5-ASA (mesalazine 1.6–2.4 g daily). Thiopurines (azathioprine) or biologics are escalated if frequent relapses occur.

Acute Severe Ulcerative Colitis (ASUC) — Emergency Protocol

Acute severe ulcerative colitis is a life-threatening medical emergency requiring immediate hospital admission to a specialist gastroenterology unit.

Truelove and Witts Criteria for Severe Colitis

Diagnosis requires meeting the mandatory stool frequency criterion plus at least one marker of systemic toxicity:

Emergency Inpatient Management Algorithm

1. Immediate Resuscitation & Medical Measures:
   • Intravenous crystalloid fluid replacement and aggressive correction of electrolyte disturbances, specifically hypokalaemia and hypomagnesaemia (hypokalaemia paralyzes colonic smooth muscle, predisposing to toxic megacolon).
   • Intravenous Hydrocortisone 100 mg four times daily (or IV methylprednisolone 60 mg daily).
   • Thromboprophylaxis: Administer prophylactic low-molecular-weight heparin (LMWH) subcutaneously to all inpatients. Critical Exam Trap: Never withhold heparin because of visible rectal bleeding; ASUC confers a massive risk of fatal pulmonary embolism.
   • Diagnostic Tests: Stool microscopy, culture, and Clostridioides difficile toxin PCR to rule out superinfection. Unprepared, gentle flexible sigmoidoscopy with minimal air insufflation to confirm severe mucosal ulceration and biopsy for cytomegalovirus (CMV) inclusion bodies.
   • Contraindicated Drugs: Strictly discontinue all antidiarrhoeal antimotility agents (loperamide, diphenoxylate, codeine phosphate), NSAIDs, and anticholinergics, as they precipitate acute colonic dilatation.
   • Monitoring: Daily clinical assessment, twice-daily vital signs, serial CRP, and daily plain abdominal radiography to monitor colonic calibre. Toxic megacolon is defined radiologically as non-obstructive transverse colon dilatation >6.0 cm with loss of haustrations, mucosal islands, and systemic toxicity.
2. Day 3–5 Assessment (Oxford Criteria): Patients exhibiting stool frequency >8 per day OR stool frequency 4–8 per day combined with CRP >45 mg/L on Day 3 of IV corticosteroid therapy have an ~85% likelihood of failing medical therapy and requiring colectomy.
3. Second-Line Rescue Therapy: If no objective improvement by Day 3–5, initiate rescue medical therapy:
   • Infliximab: Monoclonal anti-TNF antibody (5 mg/kg IV infusion; accelerated dosing 10 mg/kg in hypoalbuminaemic patients due to rapid faecal drug loss).
   • Ciclosporin: Calcineurin inhibitor administered as a continuous IV infusion (2 mg/kg/day targeting whole blood trough levels of 150–250 ng/mL). Requires normal renal function and screening for hypomagnesaemia (hypomagnesaemia lowers seizure threshold).
4. Emergency Surgical Indications: Failure of rescue medical therapy within 48–72 hours, toxic megacolon unresponsive to decompression within 24 hours, colonic perforation, or torrential lower GI bleeding dictates emergency subtotal colectomy with end-ileostomy and preservation of the rectal stump.

---

4. Malabsorption & Coeliac Disease

Pathophysiology & Genetic Architecture

Coeliac disease is an immune-mediated systemic enteropathy triggered by the dietary ingestion of gluten (specifically the alcohol-soluble gliadin fraction found in wheat, barley, and rye) in genetically susceptible individuals.

• Genetics: Virtually all patients express Human Leukocyte Antigen (HLA) Class II heterodimers: HLA-DQ2 (encoded by DQA1*05:01 and DQB1*02:01, present in ~95% of patients) or HLA-DQ8 (present in ~5%). HLA testing carries an exceptional negative predictive value (>99%); the absence of both HLA-DQ2 and HLA-DQ8 virtually excludes coeliac disease.
• Immunological Cascade: Luminal gliadin peptides resist gastric and pancreatic enzymatic digestion. Gliadin crosses the mucosal barrier into the lamina propria, where it is deamidated by the enzyme tissue transglutaminase (tTG). Deamidation introduces negative charges, allowing gliadin peptides to dock with high affinity into the positively charged binding grooves of HLA-DQ2/DQ8 on antigen-presenting dendritic cells. These stimulate CD4+ T helper cells to produce proinflammatory cytokines (interferon-gamma, IL-21), triggering intraepithelial CD8+ cytotoxic T-cell activation and massive enterocyte apoptosis.

Diagnostic Evaluation & Serology

• Prerequisite Dietary Requirement: Patients must consume a gluten-containing diet (at least one gluten-containing meal daily for a minimum of 6 weeks) before diagnostic testing. Initiating a gluten-free diet prior to testing causes rapid serological clearance and mucosal healing, yielding false-negative serology and histology.
• Serological Testing Algorithm:
  • First-Line Test: Total Serum IgA + Anti-Tissue Transglutaminase IgA (anti-tTG IgA). Anti-tTG IgA possesses sensitivity and specificity >95%.
  • Selective IgA Deficiency Rule: The incidence of selective IgA deficiency is 10- to 15-fold higher in patients with coeliac disease (~2–3%) compared to the general population (1 in 600). If total serum IgA is low or undetectable (<0.2 g/L), anti-tTG IgA will be falsely negative. In this scenario, IgG-based serology must be performed: IgG anti-tissue transglutaminase (anti-tTG IgG) or IgG deamidated gliadin peptide (anti-DGP IgG).
  • Anti-Endomysial Antibody (EMA IgA): Indirect immunofluorescence assay targeting intermyofibrial connective tissue; highly specific (>99%) and utilized as a secondary confirmatory marker.
• Upper GI Endoscopy & Small Bowel Biopsy: Remains the diagnostic gold standard in adults. Endoscopic inspection of the duodenum reveals scalloped mucosal folds, mosaic "cracked-mud" mucosal pattern, and micronodularity. At least four biopsies from the second/third part of the duodenum (D2/D3) plus at least two biopsies from the duodenal bulb must be taken, as mucosal lesions are frequently patchy.

The Marsh Histopathological Classification

Systemic Manifestations, Associated Conditions & Complications

• Clinical Presentation: Steatorrhoea, chronic osmotic diarrhoea, bloating, flatulence, recurrent abdominal pain, weight loss, and failure to thrive in children. Atypical presentations dominate in adults: unexplained isolated iron deficiency anaemia (microcytic anaemia refractory to oral iron, as iron is absorbed in the damaged proximal duodenum), folate deficiency, fatigue, recurrent aphthous stomatitis, and elevated transaminases ("coeliac hepatitis").
• Associated Autoimmune Disorders: Type 1 Diabetes Mellitus, autoimmune thyroid disease (Hashimoto's/Graves'), primary biliary cholangitis, Sjögren's syndrome, Down syndrome, and Turner syndrome.
• Metabolic Bone Disease (Osteoporosis): Impaired absorption of fat-soluble vitamin D and calcium secondary to proximal villous blunting. All newly diagnosed adults mandate baseline DEXA bone densitometry and supplemental calcium and vitamin D.
• Hyposplenism (Splenic Atrophy): Occurs in up to one-third of adult coeliac patients. Peripheral blood film characteristically shows Howell-Jolly bodies (nuclear remnants in erythrocytes), target cells, and Pappenheimer bodies. Patients have heightened susceptibility to encapsulated pathogens and mandate immunization against Streptococcus pneumoniae, Neisseria meningitidis (groups A, C, W, Y), and Haemophilus influenzae type b (Hib), alongside annual influenza vaccination.
• Malignancy Risk: Long-term untreated coeliac disease confers a significantly increased risk of gastrointestinal malignancies, most notably Enteropathy-Associated T-Cell Lymphoma (EATL)—a rare, highly aggressive, high-grade non-Hodgkin lymphoma arising from intraepithelial T lymphocytes in the jejunum. Presents with fever, anorexia, weight loss, recurrent abdominal pain, and small bowel perforation in patients with refractory coeliac disease. Also elevates risk of small intestinal adenocarcinoma and squamous cell carcinoma of the oesophagus.
• Dermatitis Herpetiformis: Cutaneous manifestation of coeliac disease characterized by intensely pruritic, grouped, polymorphic erythematous papules and vesicles distributed symmetrically over extensor surfaces (elbows, knees, buttocks, scalp). Direct immunofluorescence of perilesional skin demonstrates pathognomonic granular IgA deposition in the dermal papillae. Management comprises oral dapsone for rapid symptomatic relief of pruritus (mandates baseline G6PD screening and monitoring for haemolytic anaemia and methaemoglobinaemia) combined with a lifelong strict gluten-free diet, which heals the underlying mucosal enteropathy and allows dapsone discontinuation.