Celiac Disease & Non-Celiac Gluten Sensitivity
Celiac disease is the autoimmune condition that hides in broad daylight. It affects roughly 1% of the global population — yet 83% of those who have it remain undiagnosed.
Celiac Disease & Non-Celiac Gluten Sensitivity
The Autoimmune Iceberg
Celiac disease is the autoimmune condition that hides in broad daylight. It affects roughly 1% of the global population — yet 83% of those who have it remain undiagnosed. That is not a screening failure in some distant, resource-poor setting. That is data from the United States, where the average celiac patient sees five doctors over eleven years before receiving a correct diagnosis.
The reason is simple and damning: we look for the wrong symptoms. The textbook presentation — a malnourished child with chronic diarrhea, distended belly, and failure to thrive — represents the tip of the iceberg. Below the waterline: iron deficiency anemia unresponsive to supplementation, osteoporosis in a 35-year-old, recurrent miscarriage, peripheral neuropathy, depression, dermatitis herpetiformis, elevated liver enzymes, dental enamel defects, aphthous ulcers, and fatigue that no amount of sleep resolves. Celiac is a systemic autoimmune disease that happens to be triggered by a dietary protein. The gut is often the last place it shows up.
The Biology of Celiac Disease
Genetic Requirement
Celiac disease requires the presence of HLA-DQ2 (carried by ~95% of celiac patients) or HLA-DQ8 (most of the remaining 5%). Without one of these genetic haplotypes, celiac disease cannot develop. Period. This makes genetic testing a powerful rule-out tool: if HLA-DQ2 and DQ8 are both absent, the lifetime risk of celiac is essentially zero.
But the genetics are necessary, not sufficient. Roughly 30-40% of the general population carries HLA-DQ2 or DQ8, and only a fraction develop celiac. Something must trigger the disease in genetically susceptible individuals — and that trigger involves gluten, intestinal permeability, and environmental factors (infections, microbiome disruption, early introduction of gluten in infancy).
The Gluten-Zonulin-Permeability Connection
Alessio Fasano’s research at Massachusetts General Hospital revealed a critical mechanism: gliadin (the prolamine component of gluten) triggers the release of zonulin — a protein that opens tight junctions between intestinal epithelial cells. Tight junctions are the seals between cells that control what passes from the gut lumen into the body. When zonulin opens these junctions, partially digested gliadin peptides cross the epithelial barrier.
Once inside the lamina propria, gliadin peptides are deamidated by the enzyme tissue transglutaminase (tTG). The deamidated peptides bind with extraordinary affinity to HLA-DQ2 or DQ8 molecules on antigen-presenting cells, which present them to gluten-reactive T cells. This triggers a Th1-mediated immune response that attacks the intestinal epithelium — specifically the villi, the finger-like projections that provide the vast absorptive surface area of the small intestine.
The result: villous atrophy. The absorptive surface shrinks. Nutrients cannot be absorbed. The body starves in the presence of food.
Simultaneously, the immune system produces antibodies against both the gliadin peptide and the tTG enzyme itself — which is why anti-tTG antibodies are the primary serological marker for celiac disease.
Testing: The Right Tests in the Right Order
Serological Screening
- tTG-IgA (tissue transglutaminase IgA): First-line screening test. Sensitivity 93-96%, specificity 96-98%. But — and this is crucial — it requires that the patient has normal total IgA levels. Selective IgA deficiency affects 2-3% of celiac patients (10-15 times the rate in the general population). If total IgA is low, tTG-IgA will be falsely negative.
- Total IgA: Must be checked alongside tTG-IgA. If deficient, switch to IgG-based testing.
- DGP-IgG (deamidated gliadin peptide IgG): The backup test for IgA-deficient patients. Also useful in children under 2, where tTG-IgA may be less reliable.
- EMA (endomysial antibodies): Highly specific (nearly 100%) but less sensitive than tTG. Used as a confirmatory test when tTG is equivocal.
Critical point: The patient must be eating gluten at the time of testing. At least 2-3 slices of bread daily (or equivalent) for 6-8 weeks before serological testing. If the patient has already eliminated gluten, antibodies may be falsely negative — and the diagnosis is missed.
Endoscopic Biopsy
Remains the gold standard for definitive diagnosis. Duodenal biopsies (at least 4 from the duodenum plus 1-2 from the bulb) are graded using the Marsh classification:
- Marsh 0: Normal mucosa
- Marsh 1: Increased intraepithelial lymphocytes (>25 per 100 enterocytes) — may represent early/latent celiac
- Marsh 2: IEL increase plus crypt hyperplasia
- Marsh 3a: Partial villous atrophy
- Marsh 3b: Subtotal villous atrophy
- Marsh 3c: Total villous atrophy
Some gastroenterologists now accept a “no-biopsy” diagnosis in adults with tTG-IgA >10x the upper limit of normal plus positive EMA on a separate blood sample — following the approach validated in the pediatric ESPGHAN guidelines. But biopsy remains standard practice in most settings.
Genetic Testing
- HLA-DQ2/DQ8: Rules out celiac when negative. Does not diagnose celiac when positive (30-40% of the population carries these alleles). Most useful for first-degree relatives of celiac patients and for patients already on a gluten-free diet where serological and histological testing is unreliable.
Non-Celiac Gluten Sensitivity (NCGS)
NCGS exists. It is real. And it is distinct from celiac disease. Patients experience gastrointestinal and extraintestinal symptoms after gluten ingestion — bloating, abdominal pain, diarrhea, brain fog, fatigue, joint pain, headache, depression — that resolve on a gluten-free diet. But serological markers for celiac are negative, villous architecture is normal on biopsy, and there is no HLA requirement (though DQ2/DQ8 are more common than in the general population).
The Diagnostic Challenge
NCGS is a diagnosis of exclusion. The Salerno Expert Criteria (2015) formalized the diagnostic approach:
- Evaluate symptoms on a gluten-containing diet
- Exclude celiac disease (negative tTG-IgA, normal biopsy) and wheat allergy (negative IgE, skin prick test)
- Place on gluten-free diet for 6 weeks and document symptom improvement
- Perform a double-blind, placebo-controlled gluten challenge: reintroduce gluten (8g/day for one week) versus placebo (rice starch) in randomized crossover fashion. A symptom variation >30% between gluten and placebo confirms NCGS.
What Is Actually Causing the Symptoms?
The trigger may not be gluten alone. Current research identifies several candidates:
- Amylase-trypsin inhibitors (ATIs): Proteins in wheat that activate innate immune responses via TLR4 (the same receptor activated by bacterial endotoxin). ATIs trigger immune activation at concentrations much lower than gluten.
- FODMAPs: Wheat contains fructans, which are fermentable oligosaccharides. Some “gluten sensitivity” may actually be fructan sensitivity. Skodje 2018 published a double-blind crossover trial showing that fructan triggered more symptoms than gluten in self-reported NCGS patients.
- Wheat germ agglutinin (WGA): A lectin that can damage the intestinal epithelium and increase permeability at high concentrations.
- Gluten itself: Through zonulin-mediated permeability increases, even in non-celiac individuals (Hollon 2015).
The Gluten-Free Diet: Hidden Dangers
Strict, lifelong gluten avoidance is the only treatment for celiac disease. But “gluten-free” is harder than it sounds. Gluten hides in:
- Soy sauce: Traditionally brewed with wheat (use tamari or coconut aminos)
- Medications and supplements: Gluten is used as a binder/filler. Always verify with the manufacturer.
- Cosmetics and personal care products: Lipstick, toothpaste, and lotions containing wheat-derived ingredients can cause issues in extremely sensitive individuals
- Cross-contamination in shared facilities: “May contain wheat” labels matter. Shared fryers, toasters, cutting boards, colanders, and even shared butter containers with crumbs
- Restaurant preparation: Shared cooking surfaces, oil, and utensils
- Oats: Pure oats are gluten-free, but most commercial oats are contaminated with wheat, barley, or rye during processing. Only certified gluten-free oats are safe. Even then, ~5% of celiac patients react to avenin (the oat prolamine).
- Beer and malt beverages: Barley-based. Gluten-removed beers are not reliably safe.
- Communion wafers, Play-Doh, envelope glue: The list extends further than most realize.
The threshold for damage in celiac disease is remarkably low: as little as 10-50mg of gluten per day (a fraction of a breadcrumb) can sustain villous atrophy.
Nutritional Rehabilitation Post-Diagnosis
At diagnosis, the celiac patient is typically depleted across multiple nutrients due to months or years of malabsorption. A comprehensive repletion protocol includes:
| Nutrient | Common Deficiency Pattern | Dose | Notes |
|---|---|---|---|
| Iron | 30-50% of celiac patients at diagnosis | Ferrous bisglycinate 25-50mg | Gentler than ferrous sulfate; recheck at 3 months |
| Vitamin B12 | Especially if ileal involvement | 1000mcg sublingual or IM injection | Check methylmalonic acid |
| Folate | Duodenal absorption impaired | Methylfolate 800-1000mcg | Avoid folic acid in MTHFR variants |
| Calcium | Duodenal absorption impaired | 1000-1200mg (citrate form) | With vitamin D for bone protection |
| Vitamin D | 60-70% deficient at diagnosis | 5000 IU daily, adjust by labs | Target 50-80 ng/mL |
| Zinc | Impaired absorption, increased losses | 30-50mg daily for 3 months | Check RBC zinc, repletion then maintenance |
| Magnesium | Common deficiency | 400-600mg glycinate or threonate | Supports 300+ enzymatic reactions |
| Copper | Sometimes depleted | 1-2mg if zinc supplemented long-term | Zinc depletes copper over time |
Gut Healing Protocol
Even after gluten elimination, mucosal healing takes time — 6-12 months in adults (longer than in children). Active support accelerates recovery.
- L-glutamine: 5-10g daily in divided doses. Primary fuel for enterocytes, supports villous regrowth and tight junction repair.
- Zinc carnosine: 75mg twice daily. Stabilizes the mucosal barrier, promotes epithelial cell migration and repair.
- Bone broth: Rich in collagen, glycine, proline, and glutamine. 1-2 cups daily. Provides structural amino acids for mucosal repair.
- Probiotics: Bifidobacterium infantis 35624 (Alflorex/Align) — specifically studied in celiac and IBS, shown to reduce systemic inflammation markers. 1 x 10^9 CFU daily.
- Digestive enzymes with DPP-IV: Dipeptidyl peptidase IV is the enzyme that breaks down proline-rich peptides, including gluten fragments. Mitea 2008 demonstrated that DPP-IV enzymes can degrade small amounts of gluten in vitro. These are not a substitute for a gluten-free diet — but they provide a safety net against accidental exposure. Take with meals when eating outside the home.
- Colostrum: Contains growth factors (IGF-1, TGF-beta) and immunoglobulins that support mucosal healing. 2-5g daily.
Monitoring: The Long View
Celiac disease management does not end at diagnosis. Annual monitoring includes:
- tTG-IgA: Should normalize within 6-12 months on a strict gluten-free diet. Persistently elevated levels suggest ongoing gluten exposure (intentional or hidden).
- Bone density (DEXA scan): At diagnosis and every 2-3 years. Celiac patients have significantly increased osteoporosis and fracture risk.
- Thyroid function: Roughly 30% of celiac patients develop Hashimoto’s thyroiditis. Screen with TSH, free T4, free T3, and thyroid antibodies (TPO, thyroglobulin).
- Liver enzymes: Elevated ALT/AST occurs in 40% of celiac patients at diagnosis and typically normalizes with gluten-free diet. Persistent elevation warrants hepatology evaluation.
- Nutrient levels: Iron studies, B12, folate, vitamin D, zinc, magnesium — annually until stable, then every 2-3 years.
- CBC: Monitor for anemia resolution.
Refractory Celiac Disease
When strict gluten-free diet adherence (confirmed by a dietitian skilled in celiac and by normalized or improving tTG) fails to produce clinical or histological improvement after 12 months, refractory celiac disease (RCD) is considered.
- Type 1 RCD: Normal intraepithelial lymphocyte population. Responds to budesonide 9mg/day or azathioprine. Better prognosis.
- Type 2 RCD: Aberrant clonal intraepithelial lymphocyte population. Risk of progression to enteropathy-associated T-cell lymphoma (EATL). Requires immunosuppression, sometimes chemotherapy. Poor prognosis. Thankfully rare.
The Gluten Cross-Reactivity Debate
Cyrex Array 4 tests for antibodies to proteins that may “cross-react” with gluten — meaning the immune system mistakes them for gluten. The panel includes dairy casein, oats, corn, rice, millet, yeast, coffee, chocolate, and others.
The evidence is mixed. Vojdani and Tarash (2013) demonstrated in vitro cross-reactivity between gluten antibodies and several food proteins. Critics argue that in vitro findings do not necessarily translate to clinical cross-reactivity, and that the clinical utility of Array 4 is unproven.
The practical approach: if a celiac patient on a strict gluten-free diet has persistently elevated tTG, ongoing symptoms, or incomplete mucosal healing — and hidden gluten exposure has been meticulously ruled out — consider eliminating the top cross-reactive foods (dairy, oats, corn, coffee) for 30 days as a therapeutic trial. If symptoms improve and markers drop, the empirical answer is more useful than the academic debate.
The Deeper Question
Celiac disease teaches a lesson that extends far beyond gluten. It demonstrates that the immune system can be permanently altered by a single dietary protein in the genetically susceptible, and that the consequences ripple through every organ system. It challenges the assumption that food is neutral. And it raises a question that functional medicine applies broadly.
If one protein can cause this much systemic damage in the genetically vulnerable, what other dietary-immune interactions are we failing to recognize in other conditions?