What causes celiac disease to manifest in an adult patient with a history of medication-resistant migraines and positive labs for gluten?

What Causes Celiac Disease to Manifest

Celiac disease manifests when three essential components converge: genetic predisposition (HLA-DQ2 or HLA-DQ8), gluten exposure, and a breakdown of immune tolerance to gluten—all three must be present for disease development. 1

The Genetic Foundation

The genetic component is non-negotiable for celiac disease development:

• Nearly 100% of celiac patients carry HLA-DQ2 and/or HLA-DQ8 genes, with approximately 90% expressing HLA-DQ2.5 specifically. 2, 1
• HLA genes account for 40% of the total genetic risk, while 39 additional non-HLA loci contribute only 14% of genetic variance. 2, 1
• The strong heritability is evident in first-degree relatives (10% prevalence) and monozygotic twins (75% concordance rate). 2, 1

The critical clinical implication: Without HLA-DQ2 or HLA-DQ8, celiac disease will not develop, making negative HLA typing highly effective at ruling out the condition. 2, 1

The Environmental Trigger: Gluten

Gluten exposure is the mandatory environmental trigger:

• Gluten proteins from wheat, rye, and barley are incompletely digested due to their high proline and glutamine content, leaving large peptides in the small intestine. 2, 1
• Tissue transglutaminase (tTG) deamidates these peptides, creating modified forms that uniquely bind to HLA-DQ2 or HLA-DQ8 molecules on antigen-presenting cells. 1, 3
• This binding triggers activation of pathogenic CD4+ T cells in the intestinal mucosa, initiating the autoimmune cascade. 1, 3

The Breakdown of Immune Tolerance

The third essential component—and often the most mysterious—is what causes tolerance to break down in genetically susceptible individuals consuming gluten:

Identified Trigger Factors

• Gastrointestinal infections may compromise epithelial barrier function and initiate intestinal inflammation that breaks tolerance. 2, 1
• Drugs, interferon-α, and surgery have been implicated as potential triggers. 2
• Large amounts of gluten exposure or gluten introduction without ongoing breastfeeding may increase risk. 2, 1
• Early cereal introduction before 3 months of age may increase childhood celiac disease risk, though delaying beyond 3-6 months shows no protective benefit. 1

The Unknown Element

The specific factors leading to the breakdown of tolerance to gluten remain unknown, but local pro-inflammatory changes are of paramount importance. 2 This explains why celiac disease can manifest at any age—even in adults who have consumed gluten without issue for decades.

The Immunological Cascade Once Triggered

Once tolerance breaks down, the disease process unfolds systematically:

• The humoral response targets both gluten antigens and the autoantigen tTG, producing anti-tissue transglutaminase antibodies (TG2Ab) and anti-endomysial antibodies. 1, 3
• Pro-inflammatory cytokine production, lymphocyte infiltration, and subsequent tissue injury lead to the characteristic histological triad: increased intraepithelial lymphocytes, crypt hyperplasia, and villous atrophy. 2, 1

Application to Your Patient with Migraines

For your adult patient with medication-resistant migraines and positive gluten labs:

• Migraine occurs 4 times more frequently in celiac disease patients compared to controls (48.5% prevalence), with attacks that are more frequent but shorter in duration. 4
• The association between migraine and celiac disease is well-established, with gluten diet eliminating attacks in 25% of patients and reducing intensity/frequency in an additional 38%. 4
• Neurological manifestations, including migraine, can occur without any gastrointestinal symptoms, representing part of the "celiac iceberg" where only 24% of those with celiac disease are diagnosed. 5

Critical Clinical Pitfall

Many patients present exclusively with extraintestinal symptoms like migraine without gastrointestinal complaints, leading to significant diagnostic delay. 5 In your patient, the medication-resistant nature of the migraines combined with positive gluten labs suggests celiac disease may have manifested due to a recent breakdown in immune tolerance—possibly triggered by infection, medication, or other environmental stressor—in a genetically predisposed individual with chronic gluten exposure.

The disease will not develop without all three components present: genetic predisposition, gluten exposure, and breakdown of immune tolerance. 1 Your patient likely had the genetic predisposition and gluten exposure for years, but something recently triggered the loss of tolerance, allowing the disease to manifest with neurological symptoms as the primary presentation.