Diagnosis and management of celiac disease

Key points

• Celiac disease is frequently undiagnosed, in part because of its highly variable clinical presentation.

• Celiac disease can present with classic gastrointestinal symptoms (e.g., diarrhea, abdominal pain, bloating, weight loss), atypical or extraintestinal manifestations (e.g., anemia, osteoporosis, neurologic symptoms, infertility, fatigue) or asymptomatic presentations detected from screening.

• The first-line serologic screening test measures tissue transglutaminase immunoglobulin A and should be conducted while the patient is consuming gluten.

• Complications of celiac disease include nutritional deficiencies, osteoporosis, increased risk of viral infections and pneumonia, and, rarely, risk of malignancy.

• Adherence to a lifelong, strict gluten-free diet with regular monitoring of disease activity and nutritional status is key for symptom management and to prevent complications.

Over the past 2 decades, celiac disease has become the most prevalent autoimmune disorder of the gastrointestinal tract globally, with a reported seroprevalence of 1% to 2%.¹ However, celiac disease is often undiagnosed and many patients experience substantial diagnostic delay, partly because of the broad spectrum of possible presentations, which requires a high level of clinical awareness for early diagnosis.¹ Patients with celiac disease often describe a decreased quality of life. Long-term complications related to malabsorption and immune activity include nutritional deficiencies, poor growth, infertility and adverse pregnancy outcomes, osteoporosis and fractures, increased risk of infections, and, rarely, lymphoma.² We discuss the diagnosis and management of celiac disease based on a review of current evidence (Box 1). Non-celiac gluten sensitivity is a gluten-related disorder with a pathophysiology distinct from celiac disease and is beyond the scope of this review.

Box 1: Evidence used in this review .

We searched PubMed and the Cochrane Library for articles addressing the epidemiology, diagnosis, and management of celiac disease using the search terms “celiac,” “celiac diagnosis,” “celiac management,” and “gluten” and their related search terms. We manually searched the reference lists of relevant original articles, review articles, and practice guidelines.

What is celiac disease?

Celiac disease is an immune-mediated condition, driven by gluten (a protein found in wheat, rye, and barley) that primarily affects the proximal small intestine in genetically predisposed individuals.³

Almost all people with celiac disease carry DQ2, DQ8, or both DQ2 and DQ8 haplotypes of human leukocyte antigen (HLA) genes, which are necessary but not sufficient to develop the disease. Gluten proteins, rich in proline and glutamine, resist full digestion, and the resulting peptides are deamidated by tissue transglutaminase (tTG), increasing their affinity for HLA-DQ2 and HLA-DQ8 molecules on antigen-presenting cells.⁴ Presentation of these immunogenic peptides to CD4-positive T cells in the lamina propria initiates a cascade of immune responses, including cytokine release, B cell activation with autoantibody production (in most cases), and recruitment of cytotoxic intraepithelial lymphocytes that damage enterocytes. Diagnosis is based on the presence of elevated serologic antibodies (tTG, endomysial, and deamidated gliadin peptide immunoglobulin [Ig] A or IgG antibodies) and histologic findings of villous atrophy with crypt hyperplasia and intraepithelial lymphocytosis in duodenal biopsies.^3,4

How common is celiac disease and who gets it?

The reported prevalence of celiac disease varies depending on whether it is measured by positive serology testing or by biopsy-confirmed enteropathy. A 2018 systematic review and meta-analysis suggested that the incidence and prevalence of celiac disease has increased over the last 2 decades, with a current global seroprevalence of 1.4% and histologically confirmed prevalence of 0.7%.⁵ A recent population-level study from Alberta, Canada, showed that the age- and sex-standardized incidence of celiac disease rose from 31.5 (95% confidence interval [CI] 29.8 to 33.2) per 100 000 person-years in 2015 to 40.3 (95% CI 38.4 to 42.2) per 100 000 person-years in 2020, for an annual average percent change of 6.2% (95% CI 3.1% to 9.5%), despite no change in the rate of tTG–IgA testing.⁶ This suggests a real increase in prevalence, likely related to environmental factors including viral infections, early exposure to antibiotics, and, possibly, introduction of large amounts of gluten in childhood.^6,7

As shown in the 2018 systematic review and meta-analysis, the prevalence of celiac disease is slightly higher among females (0.6%) than among males (0.4%), and higher among children (0.9%) than among adults (0.5%).⁵ In Canada, a 2017 cross-sectional screening study of nearly 3000 people in the culturally diverse city of Toronto found a celiac disease seroprevalence of 0.88%, with the highest prevalence among White people (1.48%) and no cases found among people of East Asian and South Asian descent.⁸ The study did not disaggregate fully by race or ethnicity and did not report prevalence among Black and Indigenous people. Originally considered a disorder confined largely to populations of northern European descent, celiac disease is now recognized as being equally prevalent in several Asian and Middle Eastern regions, including India (particularly Punjab), Turkey, Israel, Saudi Arabia, Syria, and Iran.⁵

Although around 99% of people with diagnosed celiac disease carry celiac disease–associated HLA genes, only a minority of genetically predisposed people develop the disease. Genetic susceptibility — most commonly through expression of HLA-DQ2, HLA-DQ7, or HLA-DQ8 — is found in about 30% of the general population, with prevalence varying across countries. The absence of these alleles makes celiac disease highly unlikely.⁴ First-degree relatives of patients with celiac disease carry the highest lifetime risk, with reported prevalence ranging from 11% to 15%, while second-degree relatives (e.g., grandparents, aunts, uncles, cousins) show lower rates of around 2% to 7%.⁹

Other populations at increased risk for celiac disease include those with coexisting autoimmune conditions. The prevalence of celiac disease is higher among people with type 1 diabetes mellitus (5% to 6%), Hashimoto thyroiditis (2% to 6%), autoimmune hepatitis (3%), primary biliary cholangitis (6%), or Sjögren syndrome (7%) than among the general population.¹⁰ Patients with inflammatory bowel disease are also at increased risk, and this association appears to be bidirectional.¹¹ In addition, celiac disease is more common in several genetic and chromosomal disorders, including selective IgA deficiency (≥ 6%), Down syndrome (9.8%), Williams syndrome (6.9%), and Turner syndrome (3.8%), as well as among people with both IgA and IgG deficiency who are seronegative for celiac disease (1% to 5%) (Table 1).¹⁰ The relationship between celiac disease and dermatitis herpetiformis is unclear. Most patients with dermatitis herpetiformis demonstrate gluten-sensitive enteropathy — even if asymptomatic — but around 19% of patients show no evidence of celiac disease by standard diagnostic criteria, and about 25% lack classic villous atrophy despite exhibiting celiac-type inflammation.¹¹

Table 1:

Considerations for screening for celiac disease¹⁰

Condition	Associated prevalence of celiac disease, %
Peripheral neuropathy	27
Hyposplenism	19–60
First-degree relative of a patient with celiac disease, even if asymptomatic	11–15
Dermatitis herpetiformis	10–17
Dentistry-identified enamel defects or recurrent oral aphthous	15
Chronic diarrhea	3–12
Short stature or delayed growth	7–11
Microscopic colitis	10
Down syndrome	6–9
Williams syndrome	6–7
Idiopathic pancreatitis	7
SjÖgren syndrome	7
Cryptogenic hypertransaminasemia	6
Primary biliary cholangitis	6
Iron-deficiency anemia	3–6
Type 1 diabetes	3–6
Irritable bowel syndrome	3–5
Idiopathic ataxia	4
Turner syndrome	3–4
Autoimmune hepatitis	3
Autoimmune atrophic gastritis	2–9
Inflammatory bowel disease11	2–4
Chronic fatigue syndrome	2–3
Autoimmune thyroid disease	2–7
IgA nephropathy	3
Selective IgA deficiency	2

Note: IgA = immunoglobulin A.

How is the condition diagnosed?

Presentation

The clinical presentation of celiac disease is highly heterogeneous, with some patients presenting with gastrointestinal symptoms or extraintestinal manifestations, and other patients being asymptomatic, with celiac disease identified through screening. Extraintestinal features — including short stature, fatigue, or headaches in children, and anemia, fatigue, headaches, or psychiatric disorders in adults — are commonly reported.^12,13 Although the mechanisms underlying these manifestations are not fully understood, they are thought to be mediated by T cell– or antibody-driven immune responses to gluten. Gastrointestinal symptoms such as abdominal pain, bloating, diarrhea, or constipation occur in around 30% of adults.^12–14 Poor growth and short stature are more common among children; most adults with celiac disease present with normal weight (57% to 61%), overweight (15% to 28%), or obesity (6.8% to 11%), with under-nutrition affecting fewer than 10% of patients (Table 2).^14,15

Table 2:

Features of celiac disease

System	Common features
Gastrointestinal	Diarrhea Constipation Bloating Abdominal distension Esophageal reflux Dyspepsia IBS-like symptoms
Hematologic	Anemia Thrombocytosis Hyposplenism IgA deficiency Leukopenia or neutropenia
Nutritional	Weight loss Overweight or obesity Micronutrient deficiencies (iron, zinc, copper, selenium, vitamins)
Gynecologic or obstetric	Late menarche Early menopause Infertility Recurrent abortions Hypertransaminasemia
Liver	Associated liver disorders (hepatitis, primary biliary cholangitis)
Mucocutaneous and dental	Dermatitis herpetiformis Psoriasis Alopecia areata Eczema or atopic dermatitis Recurrent oral ulcers Dental enamel defects
Musculoskeletal	Osteopenia or osteoporosis Bone fractures Arthralgia or arthropathy
Neuropsychological	Peripheral neuropathy Gluten ataxia Epilepsy Migraines Anxiety Depression Chronic fatigue

Note: IBS = irritable bowel syndrome, IgA = immunoglobulin A.

Dental concerns can be the only indication of celiac disease, especially in the pediatric population, most commonly dental enamel defects and recurrent aphthous ulcers, which occur bilaterally or symmetrically. Enamel abnormalities may be caused by malabsorption of calcium and immunological factors associated with celiac disease. Celiac disease may also present with laboratory abnormalities, such as unexplained elevation of liver enzymes or micronutrient deficiencies, most notably iron deficiency. Celiac disease may be identified through associated conditions or complications, including osteoporosis with fractures, infertility, and, more rarely, lymphoma or small bowel carcinoma.²

Physical examination

A targeted physical examination can help identify signs and symptoms associated with celiac disease. Careful assessment of the patient’s overall appearance is important for detecting features of malnutrition, such as pallor, lethargy, brittle nails, muscle wasting, fat depletion, and edema.^15,16 Dermatologic manifestations may also be present, most notably dermatitis herpetiformis, an intensely pruritic, blistering rash that often appears symmetrically on the elbows, knees, and buttocks. Abdominal examination may reveal hepatomegaly or splenomegaly; however, this occurs only in a small proportion of patients.¹⁶ Measurement of height and weight should be performed at each clinical visit to monitor growth in children and to evaluate abnormal weight changes in adults.¹⁷

Diagnostic testing

A recent guideline recommends screening for celiac disease for all patients with associated symptoms or patients from high-risk populations.¹⁰ Figure 1 offers a detailed approach to diagnostic testing. A list of associated conditions and high-risk populations is presented in Table 1.

Figure 1:

Diagnostic testing process for celiac disease. Note: GI = gastrointestinal, HLA = human leukocyte antigen, IgA = immunoglobulin A, IgG = immunoglobulin G. See Related Content tab for accessible version.

For adults and children aged 2 years and older, the first-line screening test for celiac disease recommended across international guidelines is tTG–IgA serology, which has a sensitivity and specificity of 90% to 95%.^17,18 A positive tTG–IgA test is strongly suggestive of celiac disease but is not diagnostic, as false-positive and false-negative results occur in about 10% of patients.^2,17 A patient’s diet must include sufficient gluten at the time of testing, as low gluten intake can result in a false-negative tTG–IgA result.¹⁸ In a person eating sufficient gluten, a negative result makes celiac disease unlikely but does not exclude it, particularly when clinical suspicion remains high. Selective IgA deficiency, which is more common among those with celiac disease than in the general population, will result in a negative tTG–IgA test. Thus, the clinician should confirm a patient has sufficient IgA when measuring tTG–IgA. Fortunately, most laboratories in Canada automatically test for sufficient IgA in the sample before measuring tTG–IgA, and, if IgA levels are low, reflexively test for tTG–IgG or anti-endomysial IgG. Alternatively, measurement of total serum IgA can detect selective IgA deficiency.^3–18

Accurate serologic and histologic testing requires patients to consume gluten regularly. For those already on a gluten-free diet, a gluten challenge is advised, with ingestion of at least 6 to 10 g of gluten daily (equivalent to about 2 slices of wheat bread, which often contains 3 to 5 g of gluten per slice) for a minimum of 6 weeks before testing.^19,20 Given interindividual variability in gluten sensitivity, consuming more rather than less gluten can minimize the risk of a false-negative result.

In patients with IgA deficiency and in children younger than 2 years, IgG-based assays, such as tTG–IgG or deamidated gliadin peptide IgG testing, should be employed; for children younger than 2 years, these tests are recommended in addition to tTG-IgA.^3,18

Because serologic testing alone can result in misdiagnosis, potentially leading to unnecessary dietary restriction and ongoing monitoring, a North American guideline recommends upper endoscopy with duodenal biopsies to confirm celiac enteropathy. ¹⁸ Patients should therefore be referred to a gastroenterologist if serologic testing is positive or if there is high clinical suspicion for celiac disease despite negative serology.

The role of duodenal biopsies in establishing a definitive diagnosis of celiac disease has been a subject of debate. Current guidelines from the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) and the American College of Gastroenterology recommend histologic confirmation in most cases.^17,18 However, the ESPGHAN guideline suggests that biopsies are not required for children with tTG–IgA titres exceeding 10 times the upper limit of normal and positive anti-endomysial IgA, measured on a separate blood sample.¹⁷ A similar strategy has been proposed for adults, although no consensus has yet been reached.^20–22 Although avoiding invasive biopsy has clear advantages — including reduced procedural burden, reduced health care cost, and shorter time to diagnosis — this approach carries risks of misdiagnosis and unnecessary dietary restriction, which can be harmful given that following a gluten-free diet is challenging, and usually costly and socially restrictive.¹⁸

How is celiac disease managed?

Modifications to diet

Currently the only treatment for celiac disease is strict, lifelong adherence to a gluten-free diet, which means the complete removal of wheat, rye, barley, and derived gluten-containing ingredients from food and drinks.^3,18 However, maintaining a nutritionally balanced gluten-free diet is difficult, and long-term consequences of a nutritionally imbalanced diet — such as micronutrient deficiences, metabolic syndrome, and liver steatosis — are increasingly common among patients with celiac disease.²³ Therefore, referral to a registered dietitian with expertise in celiac disease is a cornerstone of treatment initiation and ongoing management. ^18,23,24 Dietitians play a key role in helping patients adhere to a gluten-free diet by providing education on avoiding common sources of inadvertent gluten exposure, preventing food cross-contamination, identifying additional food intolerances that may trigger symptoms, and ensuring the diet remains nutritionally adequate (Table 3 and Appendix 1, available at www.cmaj.ca/lookup/doi/10.1503/cmaj.230091/tab-related-content).^27–29

Table 3:

Common concerns for patients hoping to adhere to a gluten-free diet^*

Concern	Recommendation
Alcohol labelling	Distilled alcohol, gluten-free beer, and wine are safe to consume. Malt-based beverages and regular and reduced-gluten beer contain gluten and are not safe. Possible gluten in pre-mixed drinks — check labels.
Oats	Oats are safe for most patients with celiac disease, provided they are labelled as gluten free and processed following a purity protocol. Otherwise, oats are highly contaminated, which may lead to persistent symptoms and celiac disease activity. There is no consensus on whether oats should be restricted in the first 6 months of celiac disease diagnosis.
Corn products	A 2012 surveillance article by the Canadian Food Inspection Agency reported contamination of most corn flour.25 Whenever flour is processed in the same facility as other flours, there is a potential for gluten cross-contamination or contact. Certified gluten-free corn flour and corn meal are recommended.
Medications	Although medications will likely contain no gluten or a very low amount of gluten, when several medications and supplements are taken daily, gluten may become a problem if the total amount of gluten exceeds tolerated limits. Until new regulations come into effect in Canada, people with celiac disease should work with a pharmacist to make sure their medications do not contain gluten.
Lotions and cosmetics	Evidence indicates that it would be rare for enough gluten to be absorbed into the intestine to produce a reaction after exposure to cosmetics, shampoo, other toiletries, and skin care products. Most products have a negligible amount of gluten and the amount (if any) normally ingested is small.
Health and wellness	Some patients are concerned about contamination with gluten from kissing. In theory, this can cause contamination and precautions are advised.
Religious practice	A study showed that religious practice could be a trigger for violating the gluten-free diet.26 Use of very low–gluten hosts made with wheat starch that has been processed to remove as much gluten protein as possible or celebrating with only the consecrated wine are 2 options for incorporating religious practice with a gluten-free diet. Oat matzo made from gluten-free oats or matzo made from potato and tapioca starch are available.
Dining out	Despite the increase in gluten-free menu options, it is important to alert the staff about dietary needs, including review of menu item ingredients and the need to avoid cross-contamination during food preparation and service. Patients should call the restaurant ahead of time to discuss accommodations.
Travel	With research and planning, it is possible to eat gluten free while away from home. Bringing one’s own food, having access to a private kitchen, and finding a grocery store with gluten-free foods locally are some suggestions to prepare for the trip.

^*See https://www.celiac.ca/living-gluten-free-menu/ for more information.

Access to gluten-free products can be limited, and the production and removal of gluten from food adds incremental costs. A Canadian study found that gluten-free products may be 4 to 5 times more expensive than their gluten-containing counterparts, which increases nonadherence to a gluten-free diet³⁰ — with rate estimates ranging from 42% to 91% — particularly among males, adolescents, and asymptomatic people with histologic evidence of active disease.^30,31 In addition, gluten-free products are often of lower nutritional quality than their gluten-containing equivalents. Despite the availability of a wide variety of naturally gluten-free grains and starches — such as amaranth, arrowroot, buckwheat, corn, millet, potato, quinoa, rice, sago, sorghum, tapioca, taro, and teff — most processed gluten-free products rely heavily on rice and corn. These processed products may be high in saturated fats and refined carbohydrates, which may contribute to visceral adiposity, insulin resistance, hepatic steatosis, and cardiometabolic risk.^27,28,32

According to international regulatory agencies, products labelled as gluten free must contain less than 20 ppm (mg/kg) of gluten, a negligible amount for people with celiac disease.²⁹ In Canada, no requirements for labelling gluten as an ingredient in medications currently exist. Based on guidance from the US Centers for Disease Control and Prevention and other experts, if wheat, rye, and barley are absent from both ingredients and excipients, the gluten content is likely minimal and considered safe for people with celiac disease.^33–35

Sensitivity to gluten cross-contamination varies among patients. A 2008 systematic review reported that some people could tolerate small amounts of gluten (34 to 36 mg/d, roughly equivalent to a pinch of wheat flour) without developing mucosal damage, whereas others experienced mucosal abnormalities after consuming as little as 10 mg/d.³⁶ Common issues encountered by patients are summarized in Table 3 and Appendix 1.

Management of persistent symptoms

Around 40% of patients with celiac disease experience nonresponsive celiac disease, defined as persistent symptoms — such as diarrhea, constipation, bloating, abdominal pain, nausea, or vomiting — despite adherence to a gluten-free diet for at least 12 months. The most common cause is inadvertent gluten exposure, which should be excluded through careful dietary review before pursuing other investigations. Alternative or contributing diagnoses may include lactose or fructose intolerance, irritable bowel syndrome, bacterial overgrowth in the small intestine, exocrine pancreatic insufficiency, or microscopic colitis.¹⁸ Patients with celiac disease with persistent diarrhea and ongoing histologic injury despite adherence to a gluten-free diet may benefit from oral budesonide, ^37,38 administered as an open capsule, which has been shown to be more effective than closedcapsule budesonide.³⁹ The optimal duration of treatment varies and should be individualized based on clinical response.

Adjuvant therapies that may provide symptomatic relief include a low-fermentable carbohydrate diet³⁹ under the guidance of a registered dietitian, as well as pharmacologic agents to manage individual symptoms, such as loperamide, ondansetron, dimenhydrinate, or laxatives, as clinically indicated.

Other considerations

Patients with celiac disease may be concerned about gluten contamination in vaccines, and that common postvaccination symptoms, such as myalgia or fever, could indicate gluten exposure. However, no evidence that any commercially available vaccines contain gluten exists and vaccination is considered safe for people with celiac disease. In addition to routine vaccinations, current guidelines^17,18 recommend pneumococcal vaccination for patients with celiac disease given their increased risk of pneumococcal pneumonia, which may result from impaired B cell function and hyposplenism, observed in around 30% of patients with either treated or untreated celiac disease. Both the conjugate and polysaccharide vaccines provide protective immunity.⁴⁰

Cohort studies have also reported an increased risk of severe influenza⁴¹ and herpes zoster⁴² among people with celiac disease compared with the general population. However, current evidence indicates that patients with celiac disease are not at increased risk of contracting SARS-CoV-2.⁴³ Whether celiac disease is associated with an attenuated response to hepatitis B vaccination is unclear.^44–46 Clinicians should confirm protective immunity with postvaccination antibody testing and give a booster dose if antibody levels remain low, while persistent nonresponse may require a full repeat vaccination series.

Management of a celiac crisis

Celiac crisis is a rare but life-threatening complication of celiac disease, characterized by acute onset or rapid progression of severe gastrointestinal symptoms, typically diarrhea or vomiting, leading to metabolic disturbances, electrolyte imbalances, and dehydration. ⁴⁷ It is most often precipitated by undiagnosed or untreated celiac disease, infection, surgery, or other physiologic stressors. Typical laboratory findings include hypokalemia, hyponatremia, hypocalcemia, hypomagnesemia, hypoalbuminemia, and, in severe cases, acute renal impairment. Initial management focuses on stabilization through aggressive fluid and electrolyte replacement and nutritional support, including the careful initiation of a strict glutenfree diet.⁴⁸ Pharmacologic therapies, such as corticosteroids or oral budesonide, may be considered in patients with severe inflammation or refractory symptoms. Supportive care, close monitoring, and early consultation with a gastroenterologist are essential to improve outcomes.^47,48 Measurement of gluten immunogenic peptides (GIPs) in stool or urine provides a direct marker of gluten exposure. The commercially available GIP test can accurately detect dietary lapses often missed by serology or symptoms. The stool test has a wider window of detection (3 to 4 d) than the urine test (12 to 24 h). Testing for GIPs is recommended as an adjunct tool to steroids and supportive care when gluten exposure is suspected, but they are not yet recommended for routine use.⁴⁹

Long-term management and monitoring

Patients with celiac disease require regular follow-up and dedicated monitoring because some continue to exhibit abnormal serology, persistent symptoms, or incomplete duodenal mucosal healing, placing them at risk for complications (Table 4).⁴⁹ A small proportion of patients (around 1%) may develop refractory celiac disease, characterized by persistent malabsorptive symptoms and villous atrophy despite strict adherence to a gluten-free diet for more than 1 year.^3,18,50 Follow-up is generally recommended at 3 to 6 months and 12 months after diagnosis, and annually thereafter, once the disease is well controlled. During these visits, clinicians should inquire about new or ongoing signs and symptoms, assess biochemical markers of malabsorption and nutritional status, and monitor weight in adults and growth parameters in children.^17,18,46

Table 4:

Markers for monitoring celiac disease^17,18

Celiac disease marker	Action	Timing
Serology	Serology (tTG–IgA, DGP, EMA) Review of symptoms	At diagnosis and every 3–6 mo until normal, then yearly
Adherence to gluten-free diet	Review with registered dietitian	At baseline (for education on gluten-free diet), then follow-up at 3–6 mo and as needed
Nutritional status	Measure weight, height, growth (for children) Check CBC and levels of iron, ferritin, folate, vitamin B12, zinc, selenium, copper, vitamin D	At diagnosis and every 3–6 mo if abnormal
Bone health	Bone mineral density scan in adults with malabsorption	At diagnosis and every 1–2 yr if abnormal
Prevention of infections	Influenza vaccine	Yearly
	Pneumococcal vaccine	Every 5 yr

Note: CBC = complete blood count, DGP = deamidated gliadin peptide, EMA = endomysial antibody, IgA = immunoglobulin A, tTG = tissue transglutaminase.

A registered dietitian should provide regular follow-up care and use a standardized nutritional assessment to support adherence to a gluten-free diet and provide guidance on lifestyle adjustments. ^27,28 Patients may also benefit from peer support resources, such as those offered by Celiac Canada (www.celiac.ca). Referral to a social worker should be considered in cases of mental health disorders, hypervigilance with the gluten-free diet, or suspected maladaptive eating behaviours.²⁸

Although tTG–IgA serology has limitations as an indicator of disease activity, pediatric and adult guidelines recommend monitoring tTG–IgA levels until they become undetectable.^18,22,49 Typically, tTGIgA levels normalize within 12 months of strict adherence to a gluten-free diet; however, in some patients with markedly elevated tTG-IgA at diagnosis, it may take 2 to 3 years for tTG-IgA levels to normalize while adhering to a strict gluten-free diet.⁵¹ Thus, trends in tTG–IgA levels must be monitored.^17,18,46 Persistent or rising tTG–IgA levels suggest ongoing gluten exposure, whereas undetectable levels do not confirm strict adherence and may not correlate with histologic recovery. Routine repeat duodenal biopsy is generally not indicated until sufficient time has elapsed for mucosal healing, usually around 2 years on a gluten-free diet.⁴⁹ In adults, repeat biopsy may be considered if tTG–IgA levels remain elevated despite adherence, or if symptoms are ongoing despite normalized serology.^18,49

Bone mineral density assessment using dual-energy x-ray absorptiometry (DXA) is indicated in adults with celiac disease who present with malabsorption to evaluate for osteopenia or osteoporosis.⁵² Recommendations for follow-up BMD testing in celiac disease are inconsistent across guidelines. One suggested approach is to repeat DXA after 2 to 3 years for patients with osteopenia and after 1 year for those with osteoporosis.^49,53 Patients with osteopenia should ensure adequate intake of protein (around 1 g/kg/d), vitamin D₃ (1000 to 2000 IU/d), and at least 1 g of calcium daily, obtained from dietary sources or supplements if dietary intake is insufficient.⁵³

Patients with celiac disease have an increased risk of developing small bowel malignancies, including adenocarcinoma and lymphoma, than the general population; however, these cancers remain rare, with an incidence of 0.01% to 0.04%.⁵⁴ The risk of malignancy is increased among people older than 50 years and among those who do not achieve complete mucosal healing. The risk is particularly elevated among patients with refractory celiac disease, underscoring the importance of ongoing specialist monitoring for these patients.^3,18

Conclusion

The incidence of celiac disease appears to be increasing globally, including in Canada, which will place growing demands on primary, emergency, specialist, and allied health care resources. Early recognition and diagnosis are critical, and generalist physicians should maintain a high index of suspicion for celiac disease among patients with suggestive symptoms or those at increased risk of complications. After diagnosis, engagement with a registered dietitian experienced in celiac disease is essential to support initiation and adherence to a gluten-free diet, ensure adequate nutritional intake, and provide guidance on lifestyle adjustments. Regular follow-up — including monitoring of symptoms, serology, nutritional status, and, when indicated, bone health and mucosal healing — is crucial to optimize disease management and detect potential complications such as refractory celiac disease, osteoporosis, or malignancy. Despite advances in understanding and managing celiac disease, several questions remain unanswered, highlighting the need for ongoing research into disease pathophysiology, monitoring strategies, and long-term outcomes (Box 2).

Box 2: Unanswered questions .

• Which factors are driving the apparent global increase in the incidence of celiac disease?

• Why does celiac disease exhibit such diverse clinical presentations and variable symptom severity?

• What are the barriers to gluten-free diet adherence across different socioeconomic and ethnic populations, and how can clinicians better support adherence?

• Can the accuracy of serologic markers be improved to reduce or eliminate the need for duodenal biopsy in definitive diagnosis?

• For infants at high genetic risk of celiac disease, what is the optimal timing and quantity of gluten introduction to prevent disease development?

• Which modifiable factors can be targeted for primary prevention of celiac disease?

• What is the potential future role of adjuvant therapies, such as desensitization against gliadin peptides, in management of celiac disease?