Yes, the patient continues to consume unrestricted gluten

Test for celiac disease with anti-tissue transglutaminase IgA antibody (TTG-IgA) and total serum IgA (a value above 20 mg/dl would make this test reliable). For some children less than age 2 years, deamidated gliadin IgG may perform better than TTG-IgA, thus it is recommended to add deamidated gliadin IgG in this age group.^[1](#fhir-question-footnote-1)^

Positive Celiac Disease Assay

Perform endoscopy with biopsy to confirm celiac disease while patient continues to consume gluten. Collect a minimum of 4 distal duodenal biopsies and 1-2 biopsies of duodenal bulb (preferably from 9 or 12 o’clock position).^[2](#fhir-question-footnote-2)^

Normal (No Marsh Lesion)

Confirm sufficient gluten intake. Review biopsies with an experienced pathologist. Consider repeating serological assays at a different laboratory as variability may exist. Ensure that alternative explanations for the patient’s symptoms and positive serologies have been excluded (e.g., IBD or other autoimmune disease). Consider wireless capsule endoscopy to exclude gross evidence of distal villous atrophy as a small subset of patients may lack duodenal mucosal injury. Consider HLA DQ2 (DQA1\*05:01/05:05 and DQB1\*02:01/02:02)/DQ8 (DQA1\*03:01 and DQB1\*03:02) genotyping.

Positive

If HLA is positive for DQ2 (DQA1\*05:01/05:05 and DQB1\*02:01/02:02) and/or DQ8 (DQA1\*03:01 and DQB1\*03:02), with sufficient gluten intake, reliable serology, and well-oriented non-diagnostic biopsies confirmed by pathologist, **consider wireless capsule endoscopy** to evaluate for more distal mucosal lesions; **consider alternative explanations for elevated TTG-IgA** (e.g., other autoimmune disease, inflammatory bowel disease). **If these interventions are unrevealing:** Patient may have potential celiac disease: this diagnosis is made more convincing, as opposed to false positive, if EMA are also positive. Consider treatment for celiac disease if laboratory evidence remains strong and compelling clinical circumstances warrant prompt treatment (advancing pubertal state and growth deficits, for example). Otherwise, leave to the family, after appropriate information, the decision of continuing to follow on an unrestricted, gluten-containing diet or beginning a gluten-free diet. If left on gluten, consider rebiopsy if elevated TTG-IgA is persistent, or if the patient’s condition (such as growth and symptoms) worsen.

Negative

STOP celiac disease evaluation if HLA typing, inclusive of half DQ2 heterodimer (DQA1\*05:01/05:05 OR DQB1\*02:01/02:02) determination, is negative. Celiac disease has been excluded.

Marsh I or II

This is an equivocal lesion which may still be consistent with celiac disease, though care should be taken in such cases prior to rendering the diagnosis. Confirm sufficient gluten intake. Review biopsies with an experienced pathologist; ensure proper orientation and exclude Helicobacter pylori infection and use of NSAIDs. Consider repeating serological assays at a different laboratory as variability may exist. Ensure that alternative explanations for the patient’s symptoms and positive serologies have been excluded (e.g., IBD or other autoimmune disease). Consider HLA DQ2 (DQA1\*05:01/05:05 and DQB1\*02:01/02:02)/DQ8 (DQA1\*03:01 and DQB1\*03:02), genotyping.

Positive

If HLA typing is positive for DQ2 (DQA1\*05:01/05:05 and DQB1\*02:01/02:02) and/or DQ8 (DQA1\*03:01 and DQB1\*03:02), sufficient gluten intake, reliable serology, well-oriented non-diagnostic biopsies confirmed by pathologist: In this setting, a Marsh I or II lesion along with clinical and serological data supports a celiac disease diagnosis.^[3](#fhir-question-footnote-3)^ Consider treatment with a GFD. Monitor for decline of the patient’s serologies and symptoms. Consider a repeat biopsy following treatment to evaluate for mucosal recovery. If there are questions raised regarding the clinical, histologic, or laboratory evidence and the patient is not in a vulnerable state, consider observation with repeat serologic and histologic assessment.

Negative

STOP celiac disease evaluation if HLA typing, inclusive of half DQ2 heterodimer (DQA1\*05:01/05:05 OR DQB1\*02:01/02:02) determination, is negative. Celiac disease has been excluded.

Marsh 3

In the setting of elevated TTG IgA ± symptoms, and in exclusion of other autoimmune disease which may explain elevated serologies and a mucosal lesion consistent with celiac disease, this evidence is consistent with a diagnosis of celiac disease.

Negative Celiac Disease Assay

Yes

If symptoms are temporally related to the consumption of wheat products, consider ImmunoCAP specific IgE testing for wheat allergy +/- Skin prick testing.^[4](#fhir-question-footnote-4)^ If negative, consider EGD to exclude seronegative celiac disease (rare in children) and to exclude other causes of the patient’s symptoms. Consider an empiric trial of gluten exclusion if symptoms are clearly temporally related to gluten intake. Consider HLA DQ2 (DQA1\*05:01/05:05 and DQB1\*02:01/02:02)/DQ8 (DQA1\*03:01 and DQB1\*03:02) genotyping, though this is mainly useful if negative as presence of HLA DQ2 (DQA1\*05:01/05:05 and DQB1\*02:01/02:02)/DQ8 (DQA1\*03:01 and DQB1\*03:02) may be nonspecific in this setting. If HLA typing is negative, inclusive of half DQ2 heterodimer (DQA1\*05:01/05:05 OR DQB1\*02:01/02:02) determination, celiac disease has been excluded and one should continue to evaluate for other explanations of the patients symptoms.

No

Verify IgA sufficiency and if the patient is IgA-deficient send IgG based testing (TTG-IgG or DGP-IgG). If gluten intake was insufficient, instruct the patient to consume sufficient gluten (roughly 2 servings of gluten - e.g., 2 slices of wheat-based bread - daily for 6-8 weeks)^[5](#fhir-question-footnote-5),[6](#fhir-question-footnote-6)^ and retest. Review biopsies with an experienced pathologist. Consider repeating serological assays at a different laboratory as variability may exist. Ensure that alternative explanations for the patient’s symptoms have been excluded (e.g., IBD or other autoimmune disease). Consider HLA DQ2 (DQA1\*05:01/05:05 and DQB1\*02:01/02:02)/DQ8 (DQA1\*03:01 and DQB1\*03:02) genotyping, particularly if the patient is not able to tolerate a sufficient gluten challenge.

Positive

If HLA typing is positive for DQ2 (DQA1\*05:01/05:05 and DQB1\*02:01/02:02) and/or DQ8 (DQA1\*03:01 and DQB1\*03:02), the patient must undergo a sufficient gluten challenge (roughly 2 servings of gluten - e.g., 2 slices of wheat-based bread - daily for 6-8 weeks).^[5](#fhir-question-footnote-5),[6](#fhir-question-footnote-6)^ If this has been undertaken and symptoms persist with reliable (negative) serology, and well-oriented non-diagnostic biopsies confirmed by pathologist, consider alternative explanations for the patient’s symptoms. If symptoms worsen without explanation, consider repeating serologic assessment for celiac disease.

Negative

STOP celiac disease evaluation if HLA typing, inclusive of half DQ2 heterodimer (DQA1\*05:01/05:05 OR DQB1\*02:01/02:02) determination, is negative. Celiac disease has been excluded.

No, the patient is NOT consuming gluten

Yes, the patient is willing to participate in a gluten challenge

Instruct the patient to consume sufficient gluten (roughly 2 servings of gluten - e.g., 2 slices of wheat-based bread - daily for 6-8 weeks)^[5](#fhir-question-footnote-5),[6](#fhir-question-footnote-6)^ and test for celiac disease with anti-tissue transglutaminase IgA antibody (TTG-IgA) and total serum IgA (a value above 20 mg/dl would make this test reliable.

Positive Celiac Disease Assay

Perform endoscopy with biopsy to confirm celiac disease while patient continues to consume gluten. Collect a minimum of 4 distal duodenal biopsies and 1-2 biopsies of duodenal bulb (preferably from 9 or 12 o'clock position).^[2](#fhir-question-footnote-2)^ At the time of biopsy, add serum titers of Anti-Endomysium Antibodies (EMA).

Normal (No Marsh Lesion)

Confirm sufficient gluten intake. Review biopsies with an experienced pathologist. Consider repeating serological assays at a different laboratory as variability may exist. Ensure that alternative explanations for the patient's symptoms and positive serologies have been excluded (e.g., IBD or other autoimmune disease). Consider wireless capsule endoscopy to exclude gross evidence of distal villous atrophy as a small subset of patients may lack duodenal mucosal injury. Consider HLA DQ2 (DQA1\*05:01/05:05 and DQB1\*02:01/02:02)/DQ8 (DQA1\*03:01 and DQB1\*03:02) genotyping.

Positive DQ2 (DQA1\*05:01/05:05 and DQB1\*02:01/02:02)/DQ8 (DQA1\*03:01 and DQB1\*03:02)

If HLA is positive for DQ2 (DQA1\*05:01/05:05 and DQB1\*02:01/02:02) and/or DQ8 (DQA1\*03:01 and DQB1\*03:02), with sufficient gluten intake, reliable serology, and well-oriented non-diagnostic biopsies confirmed by pathologist, **consider wireless capsule endoscopy** to evaluate for more distal mucosal lesions; **consider alternative explanations for elevated TTG-IgA** (e.g., other autoimmune disease, inflammatory bowel disease). **If these interventions are unrevealing:** Patient may have potential celiac disease: this diagnosis is made more convincing, as opposed to false positive, if EMA are also positive. Consider treatment for celiac disease if laboratory evidence remains strong and compelling clinical circumstances warrant prompt treatment (advancing pubertal state and growth deficits, for example). Otherwise, leave to the family, after appropriate information, the decision of continuing to follow on an unrestricted, gluten-containing diet or beginning a gluten-free diet. If left on gluten, consider rebiopsy if elevated TTG-IgA is persistent, or if the patient's condition (such as growth and symptoms) worsen.

Negative

STOP celiac disease evaluation if HLA typing, inclusive of half DQ2 heterodimer (DQA1\*05:01/05:05 OR DQB1\*02:01/02:02) determination, is negative. Celiac disease has been excluded.

Marsh I or II

This is an equivocal lesion which may still be consistent with celiac disease, though care should be taken in such cases prior to rendering the diagnosis. Confirm sufficient gluten intake. Review biopsies with an experienced pathologist; ensure proper orientation and exclude Helicobacter pylori infection and use of NSAIDs. Consider repeating serological assays at a different laboratory as variability may exist. Ensure that alternative explanations for the patient's symptoms and positive serologies have been excluded (e.g., IBD or other autoimmune disease). Consider HLA DQ2 (DQA1\*05:01/05:05 and DQB1\*02:01/02:02)/DQ8 (DQA1\*03:01 and DQB1\*03:02) genotyping.

Positive

If HLA typing is positive for DQ2 (DQA1\*05:01/05:05 and DQB1\*02:01/02:02) and/or DQ8 (DQA1\*03:01 and DQB1\*03:02), sufficient gluten intake, reliable serology, well-oriented non-diagnostic biopsies confirmed by pathologist: In this setting, a Marsh I or II lesion along with clinical and serological data supports a celiac disease diagnosis.^[3](#fhir-question-footnote-3)^ Consider treatment with a GFD. Monitor for decline of the patient's serologies and symptoms. Consider a repeat biopsy following treatment to evaluate for mucosal recovery. If there are questions raised regarding the clinical, histologic, or laboratory evidence and the patient is not in a vulnerable state, consider observation with repeat serologic and histologic assessment.

Negative

STOP celiac disease evaluation if HLA typing, inclusive of half DQ2 heterodimer (DQA1\*05:01/05:05 OR DQB1\*02:01/02:02) determination, is negative. Celiac disease has been excluded.

Marsh 3

In the setting of elevated TTG IgA ± symptoms, and in exclusion of other autoimmune disease which may explain elevated serologies and a mucosal lesion consistent with celiac disease, this evidence is consistent with a diagnosis of celiac disease.

Negative Celiac Disease Assay

Yes

If symptoms are temporally related to the consumption of wheat products, consider ImmunoCAP specific IgE testing for wheat allergy +/- Skin prick testing.^[4](#fhir-question-footnote-4)^ If negative, consider EGD to exclude seronegative celiac diseae (rare in children) and to exclude other causes of the patient's symptoms. Consider an empiric trial of gluten exclusion if symptoms are clearly temporally related to gluten intake. Consider HLA DQ2 (DQA1\*05:01/05:05 and DQB1\*02:01/02:02)/DQ8 (DQA1\*03:01 and DQB1\*03:02) genotyping, though this is mainly useful if negative as presence of HLA DQ2 (DQA1\*05:01/05:05 and DQB1\*02:01/02:02)/DQ8 (DQA1\*03:01 and DQB1\*03:02) may be nonspecific in this setting. If HLA typing is negative, inclusive of half DQ2 heterodimer (DQA1\*05:01/05:05 OR DQB1\*02:01/02:02) determination, celiac disease has been excluded and one should continue to evaluate for other explanations of the patient's symptoms.

Positive

If HLA typing is positive for DQ2 (DQA1\*05:01/05:05 and DQB1\*02:01/02:02) and/or DQ8 (DQA1\*03:01 and DQB1\*03:02), the patient must undergo a sufficient gluten challenge (roughly 2 servings of gluten - e.g., 2 slices of wheat-based bread - daily for 6-8 weeks).^[5](#fhir-question-footnote-5),[6](#fhir-question-footnote-6)^ If this has been undertaken and symptoms persist with reliable (negative) serology, and well-oriented non-diagnostic biopsies confirmed by pathologist consider alternative explanations for the patient's symptoms. If symptoms worsen without explanation, consider repeating serologic assessment for celiac diseae.

Negative

STOP celiac diseae evaluation if HLA typing, inclusive of half DQ2 heterodimer (DQA1\*05:01/05:05 OR DQB1\*02:01/02:02) determination, is negative. Celiac disease has been excluded.

No

Verify IgA sufficiency and if the patient is IgA-deficient send IgG based testing (TTG-IgG or DGP-IgG). If gluten intake was insufficient, instruct the patient to consume sufficient gluten (roughly 2 servings of gluten - e.g., 2 slices of wheat-based bread - daily for 6-8 weeks)^[5](#fhir-question-footnote-5),[6](#fhir-question-footnote-6)^ and retest. Review biopsies with an experienced pathologist. Consider repeating serological assays at a different laboratory as variability may exist. Ensure that alternative explanations for the patient's symptoms have been excluded (e.g., IBD or other autoimmune disease). Consider HLA DQ2 (DQA1\*05:01/05:05 and DQB1\*02:01/02:02)/DQ8 (DQA1\*03:01 and DQB1\*03:02) genotyping, particularly if the patient is not able to tolerate a sufficient gluten challenge.

Positive

If HLA typing is positive for DQ2 (DQA1\*05:01/05:05 and DQB1\*02:01/02:02) and/or DQ8 (DQA1\*03:01 and DQB1\*03:02), the patient must undergo a sufficient gluten challenge (roughly 2 servings of gluten - e.g., 2 slices of wheat-based bread - daily for 6-8 weeks).^[5](#fhir-question-footnote-5),[6](#fhir-question-footnote-6)^ If this has been undertaken and symptoms persist with reliable (negative) serology, and well-oriented non-diagnostic biopsies confirmed by pathologist consider alternative explanations for the patient's symptoms. If symptoms worsen without explanation, consider repeating serologic assessment for celiac diseae.

Negative

STOP celiac diseae evaluation if HLA typing, inclusive of half DQ2 heterodimer (DQA1\*05:01/05:05 OR DQB1\*02:01/02:02) determination, is negative. Celiac disease has been excluded.

No, the patient cannot/will not agree to a gluten challenge:

Perform HLA DQ2 (DQA1\*05:01/05:05 and DQB1\*02:01/02:02)/DQ8 (DQA1\*03:01 and DQB1\*03:02) genotyping inclusive of half-DQ2 heterodimers (DQA1 05:01/ 05:05 or DQB1 02:01/02:02).

Positive

If gluten challenge is refused or cannot be tolerated, manage in a similar fashion to those with known celiac disease, having however made very clear to the family that the diagnosis of celiac disease remains only presumptive and cannot be confirmed.

Negative

STOP celiac disease evaluation if HLA typing, inclusive of half DQ2 heterodimer (DQA1\*05:01/05:05 OR DQB1\*02:01/02:02) determination, is negative. Celiac disease has been excluded. If symptoms are temporally related to the consumption of wheat products, consider ImmunoCAP specific IgE testing for wheat allergy +/- Skin prick testing. Consider EGD to further investigate symptoms if indicated (exclusion of EoE and allergic gastroenteritis).

Footnotes