Malabsorption and Small Bowel Disease — Written Clinical Reasoning

Part A — Diagnosis

The diagnosis is coeliac disease, established by the combination of:

1. Compatible clinical features (weight loss, chronic diarrhoea, and iron deficiency anaemia).
2. Positive serology — anti-tTG IgA at 14 times the upper limit of normal and anti-endomysial IgA positive, with a normal total IgA (1.2 grams per litre), excluding selective IgA deficiency.
3. Diagnostic duodenal histology — Marsh 3c total villous atrophy with crypt hyperplasia and increased intraepithelial lymphocytes (45 per 100 enterocytes, above the threshold of 30). [1]

The microcytic iron deficiency anaemia (MCV 71, ferritin 4) is the expected consequence of proximal small bowel disease: iron is absorbed predominantly in the duodenum, the site most affected by coeliac enteropathy. Iron deficiency anaemia is in fact the single most common adult presentation of coeliac disease [1]. The pruritic vesicular rash on extensor surfaces is dermatitis herpetiformis, the cutaneous manifestation of coeliac disease, which would show granular IgA deposition at the dermoepidermal junction on skin biopsy [1].

Part B — Immunopathogenesis

Coeliac disease is an immune-mediated enteropathy triggered by dietary gluten in genetically susceptible individuals carrying the HLA-DQ2 or HLA-DQ8 haplotype (present in over 95 per cent of patients). The pathogenic cascade proceeds as follows [2]:

1. Gliadin peptides (from wheat, barley, rye) resist luminal digestion and cross the intestinal epithelium.
2. Tissue transglutaminase (tTG) in the lamina propria deamidates specific glutamine residues in gliadin, creating negatively charged residues that bind with high affinity to the HLA-DQ2 or DQ8 antigen-binding groove.
3. Deamidated gliadin is presented to CD4-positive T helper cells, driving a Th1 inflammatory response with interferon-gamma release.
4. The cascade drives intraepithelial lymphocyte infiltration, crypt hyperplasia (compensating for surface loss), and villous atrophy — the histological triad on the biopsy.
5. B cells produce autoantibodies against tissue transglutaminase (anti-tTG) and endomysium (anti-EMA), which are the serological markers. [1]

This mechanism explains why tTG is both the autoantigen and the target of the diagnostic serology, and why coeliac disease is strongly associated with other autoimmune conditions (type 1 diabetes, autoimmune thyroid disease, autoimmune hepatitis, Addison disease). [1]

Part C — Management plan

The gluten-free diet

The only treatment is a lifelong strict gluten-free diet — complete exclusion of wheat, barley, and rye. Oats are tolerated by most but should be introduced cautiously and sourced gluten-free. Key elements [1]:

• Dietitian referral for education on label reading, hidden gluten, and cross-contamination.
• Screen for and correct nutritional deficiencies — iron, folate, calcium, vitamin D, and the fat-soluble vitamins.
• DEXA scan at diagnosis for osteoporosis (common from chronic calcium and vitamin D malabsorption).
• Monitor anti-tTG IgA response — it should fall to normal over 6 to 12 months on a strict diet.
• Pneumococcal and influenza vaccination (for hyposplenism-associated infection risk).
• Screen first-degree relatives by serology (10 per cent risk).

Dermatitis herpetiformis

For the rash, dapsone provides rapid control of pruritus and vesicles within days by inhibiting neutrophil recruitment, used as a bridge while the gluten-free diet takes effect over months. Glucose-6-phosphate dehydrogenase (G6PD) status must be checked before starting dapsone because of the risk of haemolysis and methaemoglobinaemia [1].

Part D — Complications and surveillance

The complications to monitor and counsel on include:

• Iron, B12, and folate deficiency anaemia — corrected by the gluten-free diet and supplementation.
• Osteoporosis and osteomalacia — from calcium and vitamin D malabsorption; DEXA at diagnosis and periodically, with calcium and vitamin D supplementation and a bisphosphonate if osteoporotic.
• Hyposplenism — with increased infection risk, particularly from encapsulated organisms; pneumococcal vaccination is recommended.
• Malignancy — enteropathy-associated T-cell lymphoma (EATL), small bowel adenocarcinoma, and oesophageal and pharyngeal cancer. The risk is reduced to near-normal by a strict gluten-free diet. The highest risk is in undiagnosed or non-adherent disease, refractory type 2 coeliac, and men presenting late in life [4].
• Reproductive — infertility and recurrent miscarriage, which typically resolve on the gluten-free diet.

Part E — Refractory disease and lymphoma

Features that would raise concern for refractory coeliac disease (RCD) include persistent or recurrent malabsorptive symptoms with villous atrophy despite a strict gluten-free diet for more than 12 months [3].

The first step is always to exclude inadvertent gluten ingestion (the most common cause of apparent non-response), confirmed by a dietitian review and persistent anti-tTG elevation. Other causes of villous atrophy — tropical sprue, common variable immunodeficiency, olmesartan enteropathy, and SIBO — must also be excluded. [1]

Refractory disease is then classified by intraepithelial lymphocyte (IEL) phenotyping and T-cell receptor clonality [3]:

• Type 1 RCD — normal IEL phenotype (surface CD3 and CD8 positive), polyclonal T-cell receptor. Low lymphoma risk. Responds to enteric-coated budesonide or steroids.
• Type 2 RCD — aberrant IELs (surface CD3 and CD8 negative, cytoplasmic CD3 positive), monoclonal T-cell receptor. These aberrant clonal lymphocytes are premalignant, carrying a 30 to 50 per cent risk of progression to enteropathy-associated T-cell lymphoma over 5 years. Requires specialist centre management and lymphoma surveillance [4].

Any new symptoms in a treated coeliac patient — fever, worsening diarrhoea, abdominal pain, or weight loss — mandates urgent investigation to exclude EATL, which presents aggressively with a poor prognosis (5-year survival 20 to 60 per cent). [1]

Part F — The tropical sprue scenario

If this patient were returning from 5 years in rural India with seronegative partial villous atrophy and a macrocytic anaemia, the diagnostic framework would shift significantly: [1]

1. The diagnosis would be tropical sprue, not coeliac disease. The distinguishing features are:

   • Negative coeliac serology — anti-tTG and anti-EMA are negative, in contrast to this patient's positive serology.
   • Tropical exposure — a residence or travel history in an endemic area (the Caribbean, southern India, south-east Asia) is essential.
   • No HLA-DQ2 or DQ8 association — the genetic predisposition to coeliac disease is absent.
   • Macrocytic anaemia — from folate and B12 deficiency (the terminal ileum is involved), rather than the microcytic iron deficiency of coeliac proximal disease. [1]

2. The investigation pathway would differ: coeliac serology would be checked (and found negative), the biopsy would show partial villous atrophy without the serological confirmation, and the clinical context (tropical exposure) would drive the diagnosis. Other causes of seronegative villous atrophy — common variable immunodeficiency, autoimmune enteropathy, and olmesartan enteropathy — would also be considered. [1]

3. The treatment would differ: tropical sprue responds dramatically to folate supplementation and a course of oral tetracycline for 3 to 6 months. This is both diagnostic (a response confirms the diagnosis) and therapeutic. A gluten-free diet is unnecessary and would not help [2].

This contrast illustrates the principle that the serological status and the clinical context (tropical exposure, anaemia type) are the key discriminators between coeliac disease and tropical sprue, and that the treatment is fundamentally different — a lifelong gluten-free diet for coeliac disease versus folate and tetracycline for tropical sprue. [1]