Celiac Disease

Celiac disease is a chronic, immune-mediated systemic disorder in which dietary gluten — the storage protein complex in wheat, barley, and rye — triggers an inappropriate T-cell-mediated immune response in genetically susceptible individuals. Gluten peptides resist complete digestion, cross the intestinal epithelium, and are deamidated by the enzyme tissue transglutaminase 2 (tTG2), which increases their affinity for the HLA-DQ2 and/or HLA-DQ8 molecules carried by essentially all patients with the disease. The resulting immune response damages the small-intestinal mucosa, producing the histologic hallmark of untreated celiac disease: villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis.^[1][2] The severity and extent of small-bowel involvement determine how much malabsorption results — from none at all to severe multi-nutrient deficiency.

Celiac disease affects roughly 1% of the general population in Western countries, and around 10% of first-degree relatives of an affected patient.^[2] A framing point that matters directly to pharmacists and is easy to underestimate: there is no approved drug therapy for celiac disease itself. A strict, lifelong gluten-free diet (GFD) is the only effective treatment — it is genuinely curative for the intestinal injury in the great majority of patients, and no medication reviewed anywhere in this chapter substitutes for it. What pharmacotherapy exists in this chapter treats a consequence of the disease (a nutrient deficiency, or the dermatitis herpetiformis skin manifestation) or is a specialist-directed, off-label option reserved for confirmed refractory disease — not first-line, ambulatory-initiated treatment for typical celiac disease.^[1]

The presentation spectrum — most patients today are not "classic"

Textbook celiac disease — chronic diarrhea, steatorrhea, weight loss, and overt malabsorption — is now the minority presentation. A genuinely wide spectrum exists, and a substantial share of patients are atypical, oligosymptomatic, or entirely silent (identified only through screening of an at-risk group or an incidental finding), which is exactly why unexplained iron-deficiency anemia, unexplained elevated transaminases, or unexplained infertility deserve a real celiac work-up rather than being pursued down every other pathway first.^[1]

What untreated celiac disease looks like under the microscope

High-magnification H&E-stained duodenal biopsy in untreated celiac disease, showing the histologic hallmark: blunted, atrophic villi, crypt hyperplasia, and a dense intraepithelial and lamina propria lymphocytic infiltrate. With sustained strict gluten-free diet adherence, this architecture typically normalizes over time. (Nephron, Wikimedia Commons, CC BY-SA 3.0)

Conditions associated with a meaningfully increased risk

Screening is reasonable, and often specifically recommended, in patients with type 1 diabetes, autoimmune thyroid disease, other autoimmune liver disease, Down syndrome, Turner syndrome, Williams syndrome, and selective IgA deficiency — prevalence in each of these groups is meaningfully higher than the roughly 1% general-population rate, and presentation in these groups is disproportionately silent or atypical, so symptom-triggered testing alone will miss real cases.^[1][2]

• HLA-DQ2 and/or HLA-DQ8 — carried by 90% or more of patients with celiac disease (the large majority HLA-DQ2), with most of the remainder HLA-DQ8-positive. These alleles are necessary but not sufficient: they are also carried by a substantial share of the general population who never develop the disease, which is exactly why genetic testing is used to help rule the diagnosis out, not to rule it in (see Assessment & Diagnosis).^[2]
• A first-degree relative with celiac disease — roughly 10% of first-degree relatives are affected, several-fold higher than the general-population rate.^[2]
• Type 1 diabetes mellitus — meaningfully increased prevalence; often silent, which is why periodic screening is reasonable in this group.
• Autoimmune thyroid disease and other autoimmune conditions (autoimmune liver disease, Sjögren syndrome, autoimmune-mediated dermatologic disease) — celiac disease clusters with other autoimmunity.
• Down syndrome, Turner syndrome, and Williams syndrome — each carries a substantially increased prevalence and is a recognized indication for periodic serologic screening.
• Selective IgA deficiency — meaningfully enriched in celiac disease compared with the general population, and clinically important for a second reason: it causes false-negative IgA-based serology (see Assessment & Diagnosis).
• Diagnosed more often in women than men in most series, though this partly reflects ascertainment — women are tested more often, commonly triggered by iron-deficiency anemia or infertility investigations.
• No amount of alcohol, obesity, or metabolic risk drives celiac disease — unlike several other chapters in this GI group, its risk factors are genetic and immunologic, not exposure-based.

Serologic testing

IgA tissue transglutaminase antibody (tTG-IgA), paired with a total serum IgA level, is the preferred first-line test.^[1][3] The paired total IgA matters because selective IgA deficiency is meaningfully more common in celiac disease than in the general population, and a patient with true IgA deficiency will have a falsely low or negative tTG-IgA despite having celiac disease.^[3] Total IgA low (IgA-deficient) order an IgG-based test instead — IgG-tTG or IgG-deamidated gliadin peptide (DGP-IgG) — rather than trusting a falsely reassuring IgA-based result.^[1][3]

Duodenal biopsy — still an active, not optional, confirmatory step

Endoscopy with multiple duodenal biopsies (current guidance recommends at least 4 biopsies from the second/third portion of the duodenum plus at least 1 from the duodenal bulb, since patchy disease can be missed on a single sample) remains the standard confirmatory step in adults with positive serology, even when serology is strongly positive.^[1] A modified Marsh classification is used to grade the histologic severity.

A minority of adults with a very high tTG-IgA titer (commonly discussed as more than 10 times the upper limit of normal) plus a positive endomysial antibody (EMA) on a separate sample may be diagnosed without biopsy where the patient is unable or unwilling to undergo endoscopy — this is an exception, not the routine pathway, and should be a shared, documented decision.^[1]

HLA-DQ2/DQ8 genetic testing

Genetic testing has a high negative predictive value — a patient who carries neither HLA-DQ2 nor HLA-DQ8 is highly unlikely to have celiac disease, which makes this test most useful for ruling the diagnosis out, particularly in a patient who has already started a gluten-free diet and is unwilling to undergo a gluten challenge, or in an equivocal serology/biopsy picture. It is not a diagnostic test on its own — a substantial share of the general population also carries these alleles without ever developing celiac disease.^[2]

Differential diagnosis

• Irritable bowel syndrome — genuinely overlaps symptomatically and is a common reason celiac serology is ordered in the first place.
• Other causes of villous atrophy: tropical sprue, autoimmune enteropathy, common variable immunodeficiency (CVID)-associated enteropathy, Whipple disease, giardiasis and other infectious causes, small intestinal bacterial overgrowth, NSAID-associated enteropathy, and drug-induced enteropathy (olmesartan-associated enteropathy is a well-described mimic that resolves after stopping the drug, not after starting a GFD).
• Inflammatory bowel disease, particularly Crohn disease with small-bowel involvement.
• Non-celiac gluten (or wheat) sensitivity — genuine GI and extraintestinal symptoms with gluten exposure, but negative serology, negative biopsy, and no HLA-DQ2/DQ8 requirement; distinguishing this from celiac disease matters because the dietary strictness and monitoring intensity differ.

Baseline evaluation at diagnosis

• CBC and ferritin, serum folate, vitamin B12, calcium, and alkaline phosphatase.^[2]
• 25-hydroxyvitamin D.
• TSH and free T4, given the frequent thyroid-autoimmunity overlap.
• Liver enzymes — unexplained elevated transaminases can itself be the presenting feature.
• Bone density (DEXA) is not routine at diagnosis itself but is recommended after roughly 1 year of dietary treatment in a patient with additional osteoporosis risk factors, or in anyone over 55 (see Monitoring & Follow-Up).^[2]

• Achieve full clinical, serologic, and — over time — histologic remission through strict, lifelong dietary gluten elimination.
• Identify and correct existing nutrient deficiencies (iron, folate, vitamin B12, vitamin D, calcium, and others as indicated) at diagnosis, not just going forward.
• Prevent long-term complications of unrecognized or unresolved disease: osteoporosis, infertility/pregnancy complications, and, in refractory disease, malignancy.
• Confirm dietary adherence objectively over time using trending serology, not symptom resolution alone — symptoms and mucosal healing do not always track together.
• Recognize and correctly manage dermatitis herpetiformis as a cutaneous manifestation of the same underlying disease, not a separate skin condition.
• Identify and eliminate hidden sources of gluten exposure, including medication excipients, when response is incomplete.
• Support durable adherence through dietitian-led education, since this is a lifelong, entirely diet-dependent treatment with no pharmacologic substitute.

• Strict avoidance of wheat, barley, and rye in every form — including less obvious sources: soy sauce, malt (malt vinegar, malt flavouring, malt beverages), some processed meats and sauces used as thickeners or fillers, beer (unless specifically gluten-free), and communion wafers.
• Cross-contamination matters as much as ingredient selection — shared toasters, cutting boards, deep-fryer oil, and cooking surfaces can carry enough gluten to trigger symptoms and mucosal injury in a genuinely sensitive patient; counsel on separate preparation surfaces/utensils at home and on questioning restaurant staff about shared equipment when eating out.
• Reading food labels carefully. Canada's food-labelling rule is stricter than the numeric tolerance used in some other jurisdictions: the Food and Drug Regulations prohibit labelling, packaging, selling, or advertising a food as "gluten-free" if it contains any gluten protein or modified gluten protein fraction derived from a gluten-containing grain — not merely a level under a fixed parts-per-million tolerance.^[4]
• Hidden gluten in medications is a genuinely pharmacist-relevant, easy-to-miss issue — unlike food, non-medicinal (excipient) ingredient labelling on prescription and over-the-counter products does not reliably or consistently disclose the botanical source of a starch or filler. Wheat starch is used as an excipient in some tablet and capsule formulations. Directly contacting the manufacturer is the most reliable way to confirm a specific product's gluten status when a patient is exquisitely sensitive or a formulation change has occurred — do not assume a product is gluten-free simply because the label is silent on the point.^[5] Review every new prescription and OTC recommendation for a celiac patient with this specifically in mind, and document a confirmed gluten-free alternative when a concern is identified.
• Favour whole, naturally gluten-free foods over packaged gluten-free substitutes where practical — many commercial gluten-free breads, pastas, and snack products are lower in fibre and several micronutrients (folate, iron, B vitamins are often fortified into wheat flour but not into gluten-free flour blends) and higher in fat/sugar than their gluten-containing equivalents; dietitian-guided balance, not simple product substitution, produces the most nutritionally adequate diet.
• Connect the patient with a celiac-disease patient-support/advocacy organization — practical, peer-sourced label-reading and dining-out guidance meaningfully improves real-world adherence beyond what a single clinic visit can cover.
• Screen close (especially first-degree) relatives, given the roughly 10% familial risk, rather than treating the diagnosis as relevant to only the index patient.^[2]

Pregnancy

Unrecognized or poorly controlled celiac disease is associated with infertility, recurrent miscarriage, and adverse pregnancy outcomes, which is why unexplained infertility or recurrent pregnancy loss is a reasonable trigger for celiac serology. A strict gluten-free diet meaningfully improves fertility and pregnancy outcomes and should be continued without interruption throughout pregnancy and lactation. Folate status deserves particular attention — baseline folate deficiency is common in untreated celiac disease, and adequate folate is independently important for pregnancy; confirm repletion is complete and standard prenatal folic acid supplementation is in place. If dapsone is being used for dermatitis herpetiformis, use it in pregnancy only under specialist direction, with attention to the risk of neonatal hemolysis and methemoglobinemia, particularly near term.

Pediatrics

Growth failure or faltering, delayed puberty, short stature, and dental enamel defects are pediatric-specific presentations that are easy to miss without a real index of suspicion. Diagnostic pathways for children can differ meaningfully from the adult biopsy-based approach described in this chapter — some pediatric-specific guidance permits a selected non-biopsy diagnosis in a child with a very high tTG-IgA titer plus a positive EMA on a separate sample — and this decision should be made with a pediatric gastroenterologist rather than by applying the adult pathway rigidly.^[1]

Type 1 diabetes and other autoimmune disease

Periodic serologic screening is reasonable given the meaningfully elevated comorbid prevalence and the frequently silent presentation in this group — glycemic instability or unexplained hypoglycemia can itself be a clue to unrecognized malabsorption.

Selective IgA deficiency

Use IgG-based serologic testing (IgG-tTG or DGP-IgG) rather than standard IgA-based tests, which will be falsely negative (see Assessment & Diagnosis).^[3]

Older adults

Presentation is disproportionately atypical or silent in this group — unexplained iron-deficiency anemia, osteoporosis, or unexplained GI symptoms deserve real consideration of celiac disease rather than being attributed reflexively to age. Bone-health assessment (DEXA) is specifically recommended in anyone diagnosed at or after age 55, in addition to anyone with other osteoporosis risk factors (see Monitoring & Follow-Up).^[2]

Down syndrome and Turner syndrome

Both carry substantially increased celiac disease prevalence and are recognized indications for periodic serologic screening even in the absence of typical symptoms.

• Repeat tTG-IgA at approximately 6 months, then annually once stable — a falling, then normalizing, titer is the objective marker of dietary adherence and mucosal recovery; do not rely on symptom resolution alone, since symptoms and serologic/histologic response do not always track together.^[2]
• Annual nutrient and comorbidity panel: CBC and ferritin, serum folate, vitamin B12, calcium, alkaline phosphatase, 25-hydroxyvitamin D, TSH/free T4, and liver enzymes.^[2]
• Bone density (DEXA) after about 1 year of dietary treatment in a patient with additional osteoporosis risk factors, or in anyone diagnosed at or after age 55; counsel on a total daily elemental calcium intake target of at least 1000 mg (diet plus supplement combined) throughout.^[2]
• Follow-up biopsy is not mandatory in a patient who is asymptomatic on a confirmed gluten-free diet with no features suggesting increased complication risk; reserve repeat biopsy for persistent symptoms, an incomplete serologic response, or any red flag in Red Flags & Refer.^[2]
• Patients on dapsone for dermatitis herpetiformis need ongoing hematologic monitoring (CBC, and a methemoglobin level if symptomatic) for as long as they remain on therapy, with periodic reassessment for tapering as the GFD takes full effect.^[2]
• Medication reconciliation at every visit should specifically include a check for gluten-containing excipients in any new prescription or OTC product, not only at initial diagnosis — formulations change, and this is one of the more overlooked causes of an apparent "non-response" in an otherwise adherent patient.^[5]
• Reinforce dietitian follow-up periodically, not only at diagnosis — real-world adherence and diet quality both benefit from booster visits, especially around major diet-disrupting life events (travel, a new household, a new relationship).

1. Persistent or recurrent symptoms despite a stated gluten-free diet — first confirm the original diagnosis was correct by reviewing the original serology and biopsy results; a misdiagnosis is an underappreciated cause of apparent "treatment failure."^[1]
2. Confirm strict dietary adherence in detail, ideally with a specialist dietitian review — probe specifically for cross-contamination, less obvious ingredient sources, and hidden gluten in medications, checking every current prescription and OTC product against manufacturer information rather than assuming excipients are gluten-free by default.^[5]
3. If genuine unintentional exposure is identified, reinforce dietary and medication counselling and reassess in a further 3-6 months — most apparent non-response resolves once the exposure source is eliminated, without needing further work-up.
4. If adherence is confirmed strict and symptoms persist, evaluate for an overlapping condition rather than assuming refractory disease immediately: microscopic colitis, small intestinal bacterial overgrowth, pancreatic exocrine insufficiency, lactose intolerance, and irritable bowel syndrome are all real, treatable possibilities that coexist with celiac disease often enough to actively screen for.^[1]
5. Still unexplained after confirmed strict adherence and overlapping conditions reasonably excluded — refer to a specialist GI/celiac centre for a refractory celiac disease work-up: repeat duodenal biopsy with intraepithelial-lymphocyte immunophenotyping and clonality studies to distinguish type 1 (normal-phenotype, polyclonal intraepithelial lymphocytes, generally more responsive to specialist-directed immunosuppression) from type 2 (an aberrant, clonal intraepithelial lymphocyte population), given the meaningfully increased risk of enteropathy-associated T-cell lymphoma associated with type 2 disease and its historically poor prognosis.^[2]
6. Type 2 refractory disease, or any suspicion of enteropathy-associated T-cell lymphoma — this needs urgent specialist GI/hematology-oncology co-management, not an outpatient dietary-reinforcement visit (see Red Flags & Refer).^[2]

• Letting a patient start a gluten-free diet before serologic and/or biopsy testing is complete — this risks a false-negative result and an unresolved lifelong diagnostic question; the correct response to an already-started GFD is a supervised gluten challenge before testing, not testing anyway.^[1]
• Diagnosing celiac disease from a positive tTG-IgA alone in an adult without biopsy confirmation, outside the specific very-high-titer-plus-EMA exception.^[1]
• Missing selective IgA deficiency and accepting a falsely reassuring negative IgA-based serologic test — always pair tTG-IgA with a total IgA level.^[3]
• Treating dermatitis herpetiformis with dapsone alone and not also starting the gluten-free diet — dapsone controls the rash, not the underlying enteropathy.
• Assuming persistent symptoms in a "compliant" patient always means covert non-adherence, without specifically checking for hidden gluten in medications or genuine cross-contamination.^[5]
• Dispensing or recommending an OTC product for an exquisitely gluten-sensitive patient without checking excipient gluten status, or assuming a silent non-medicinal ingredient list means the product is gluten-free.^[5]
• Not screening for nutrient deficiencies at diagnosis, or assuming the gluten-free diet alone will correct an existing deficiency promptly without directed repletion.
• Recommending packaged gluten-free products as a simple like-for-like nutritional swap without dietitian input — many are lower in fibre and fortified micronutrients than their gluten-containing equivalents.
• Skipping bone-density assessment in a patient with additional osteoporosis risk factors or diagnosed at or after age 55.^[2]
• Missing refractory celiac disease or delaying EATL work-up in a patient who re-presents with red-flag features after previously "stable" disease.^[2]

How to use this table: Doses are adult doses and require patient-specific confirmation (renal/hepatic function, weight, allergy history). Pediatric dosing is weight-based per the current product monograph unless stated. Drug pricing is intentionally omitted. Select any drug name to open its complete Pharmasist Drug Database page.

Reminder: there is no approved drug therapy for celiac disease itself. Every agent below either replaces a specific deficient nutrient, treats a distinct downstream manifestation (dermatitis herpetiformis), or is a specialist-directed option for confirmed refractory disease. A strict, lifelong gluten-free diet is the only treatment for the underlying disease.

Iron-Deficiency Repletion

Start alongside gluten-free diet initiation, not after it — an existing deficiency at diagnosis does not correct itself quickly on diet alone.

Folate and Vitamin B12 Repletion

Check (or confirm already checked) B12 status before or alongside folate repletion — correcting folate alone can mask the hematologic picture of a coexisting B12 deficiency without addressing its neurologic risk.

Vitamin D and Calcium — Bone Health

Target at least 1000 mg/day total elemental calcium intake from diet plus supplement combined; DEXA after ~1 year of diet if additional osteoporosis risk factors or age 55+.

Dermatitis Herpetiformis — Symptomatic Therapy

Treats the rash only, not the underlying enteropathy — the gluten-free diet must start at the same time, not be deferred until the rash is controlled.

Refractory Celiac Disease — Specialist-Directed, Off-Label Options

Not treatment for typical celiac disease. Reserved for confirmed refractory disease after diagnosis is reconfirmed, strict adherence is confirmed, and overlapping conditions are excluded (see Treatment Failure / Next Step).