Definition

  • Immune response to dietary gluten
  • Damage to proximal small intestine epithelium
  • Malabsorption features
  • Responds to gluten-free diet





Other Names

  • Coeliac sprue
  • Gluten-sensitive enteropathy
    •

Prevalence

  • 0.5 to 1% among those of White European ancestry
  • Most commonly 30-60y with peaks in infancy and in 50s


Morbidity

Patient perceptions

Complaint % reporting
Reduced enjoyment of food 68%
Food costs >£10 per week extra 46%
Food costs a problem 21%
Doing enjoyable things less often 54%
Regret not being diagnosed earlier 66%

Mortality

  • Mainly in undiagnosed and untreated
  • Most mortality from malignancies
  • Long-term survival when properly treated

Pathogenesis

  • Immune-mediated reaction to gluten in intestine
  • Most people have no problem with gluten
  • Thus disease attributable mainly to host factors

Digestion, Ingestion

    • Gluten is ingested in cereal grains (wheat, rye, barley).
    • Gluten is digested by intestinal enzymes to amino acids and peptides.
    • A peptide, gliadin, remains, which cannot be degraded by regular enzymes
    • Gliadin is instead deamidated (has an amide group removed) by tissue transglutaminase (tTG).

APC Presentation, T cell response

    • Deamidated gliadin interacts with HLA DQ2 or HLA DQ8 on antigen presenting cells (APCs).
    • Deamidated gliadin is presented to CD4 T cells.
    • CD4 T cells produce cytokines (such as IFNγ) which cause tissue damage.

B cell response

  • T cells also elicit a B cell response.
  • B cells produce the antibodies:
    • Anti-tissue transglutaminase (anti-tTG)
    • Anti-deamidated gliadin
    • Anti-endomysial antibody (anti-EMA)

IL-15, intraepithelial lymphocytes

  • Gliadin also induces IL-15 production from enterocytes.
  • IL-15 activates and upregulates intraepithelial CD8 lymphocytes.

MIC-A, NKG2D

    • Various stressors causes MIC-A to be expressed on enterocytes.
    • Intraepithelial lymphocytes receive MIC-A via NKG2D in a cytotoxic interaction, killing enterocytes.

Progression

    • Tissue damage progresses with villous atrophy and loss of surface area.
    • Damage allows increased movement of gliadin across the epithelium, amplifying disease.
    • An increased rate of mitosis is seen with reduced enterocyte differentiation and function.
    • Tissue damage, loss of surface area, and reduced function result in malabsorption.

Clinical features

  • Many atypical presentations, often an incidental finding
  • Presentations most commonly 30-60y, but any age
  • Peaks in infancy and 50s
  • No gender difference, but 2-3x more women detected
    • menstrual blood loss potentiates anaemia

Disease associations

  • Immune diseases and atopy:
    • Diabetes mellitus type 1
    • Thyroiditis
    • Sjögren syndrome

  • Other diseases:
    • Epilepsy
    • IgA nephropathy
    • Down syndrome
    • Turner syndrome

Symptoms

Malabsorption-related symptoms

Manifestation                   Malabsorbed nutrient
Steatorrhoea Fats
Diarrhoea Fats, carbohydrates

Manifestation Deficiency
Weight loss, wasting Fats, proteins, carbs
Anaemia Iron, vit B12, folic acid
Paraesthesia, tetany Calcium, vit D
Osteoporosis, arthritis Calcium, vit D
Bleeding, bruising Vit K
Oedema Protein

Dermatitis herpetiformis

  • 10% of patients
  • Similar appearance to herpes
  • Itchy papulovesicular rash

BallenaBlanca [CC-BY-SA-3.0], via Wikimedia Commons

Paediatric

  • Classical:
    • 6-24 months
    • Irritability
    • Abdominal distension, diarrhoea
    • Anorexia, weight loss, failure to thrive
    • Muscle wasting

  • Non-classical:
    • Older ages
    • Abdominal pain, nausea, vomiting
    • Bloating, constipation

Signs

  • Few and non-specific

  • Anaemia
    • tachycardia
    • pallor
  • Bruising (vit K deficiency)
  • Hyperactive bowel sounds
  • Neurological signs
  • Oedema (severe cases)

HLA DQ2, HLA DQ8

  • 95% of patients have at least one
  • accounts for 50% of genetic component

Other risk factors

  • Other immune system polymorphisms:
    • e.g. IL-2, IL-21

  • Other ill-defined genetic components:
    • 10-15% of 1st degree relatives (may be clinically silent)
    • 70% monozygotic twin concordance

  • Breast feeding and gluten introduction ages significant
  • Infant rotavirus infection

Serology

  • Conduct non-invasive serology before biopsy
  • Also for dietary compliance monitoring
  • 2.5% of coeliac patients have IgA deficiency
    • Verify normal levels
    • Investigate IgG if IgA deficient
IgA anti-tTG + sensitive
IgA or IgG anti-demanidated gliadin + sensitive
Anti-EMA ++ specific, - sensitive
HLA DQ2/DQ8 cannot confirm diagnosis
helps exclude diagnosis if negative

Biopsy

  • Small bowel endoscopic biopsy
  • 'Gold standard', but not always necessary in clear-cut cases with serology
  • Not specific, other causes, need serology also

  • Histology:
    • Sub-total villous atrophy
    • Increase in lamina propria, lymphocytes, plasma cells, mast cells and eosinophils

Acute complications

  • Mostly rare
  • Anecdotal intestinal obstructions and perforations

  • Coeliac crisis
    • acute, fulminant worsening of symptoms
    • often with a gluten challenge
    • hypoproteinaemia, oedema
    • severe diarrhoea
    • dehydration, electrolyte imbalance
    • metabolic acidosis
    • hospitalisation, fluid replacement, corticosteroids

Chronic complications

  • Refractory coeliac disease (RCD)
    • improvement with diet, then loss of response
    • increased complications (malignancy), poor prognosis
  • Malignancy risk
    • Enteropathy-assoc. T cell lymphoma
    • Small intestinal adenocarcinoma

Chronic complications

  • Ulcerative jejunitis
  • Anaemia
  • Female infertility
  • Osteoporosis (even when on strict diet)
  • Malnutrition, cachexia
  • Paraesthesia, ataxia, muscle weakness
  • Splenic atrophy
    • need pneumococcal vaccinations

Treated

  • Initial supplementation of mineral and vitamin body stores

  • Gluten-free diet
    • Improvement in symptoms within days/weeks
    • Improvement in morphology after months
    • Long-term survival, unrelated mortality
    • Challenging and costly to maintain

  • Long-term risk of small intestinal and oesophageal malignancy

Untreated

  • Poor compliance relatively common

  • Elaboration of malabsorption features
  • Severe diarrhoea
    • dehydration, electrolyte imbalances
  • Osteoporosis
  • Malignancy
  • Neurological, psychiatric complications

  • Children
    • growth retardation
    • short stature
  • Pregnancy
    • miscarriage
    • congenital malformations

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