print Print Back Back

Human Leukocyte Antigen (HLA) Testing for Celiac Disease

Policy Number: MP-545

Latest Review Date: December 2020

Category: Laboratory

Policy Grade: B


Genetic testing for HLA-DQ2 and HLA-DQ8, when used to rule out celiac disease, may be considered medically necessary when one or more of the following criteria are met:

  • Patient has discordant serologic and histologic (biopsy) findings; OR
  • Patient has persistent symptoms despite negative serology and histology.

Genetic testing for HLA-DQ2 and HLA-DQ8 testing for celiac disease is considered not medically necessary and investigational in all other situations.


Celiac disease (CD) is currently diagnosed by serologic results in patients and a consistent history with confirmation by small intestinal biopsy. Human leukocyte antigen (HLA) testing may be useful for ruling out disease in symptomatic patients when findings of other tests are inconclusive.


Celiac disease is characterized by inflammation of the small intestine resulting from an immunologic intolerance to gluten (i.e., the proteins derived from wheat, barley, and rye). The symptoms of the disease are markedly variable and can be broadly subdivided into intestinal and extra intestinal manifestations; the latter is thought to be related to nutrient malabsorption. For example, osteopenia and osteoporosis, which are commonly seen in adults with untreated celiac disease, are related to the impaired absorption of vitamin D and binding of intraluminal calcium and magnesium to unabsorbed dietary fatty acids, forming insoluble soaps. The only treatment for celiac disease is lifelong adherence to a gluten-free diet.

Many of the symptoms of celiac disease, (e.g., diarrhea, abdominal pain and weight loss) are nonspecific and are often overlooked. In addition, the disease may develop at any time in life, from infancy to very old age. In children, the disease typically presents following weaning between 6 and 24 months, and is characterized by abnormal stools, poor appetite, and irritability. In adults, diarrhea is the main presenting symptom, but presenting symptoms may be entirely nonspecific, such as anemia or infertility. Typical or classical celiac disease refers to the presence of malabsorption, while atypical celiac disease consists primarily of extra intestinal manifestations.

Celiac disease is a human leukocyte antigen (HLA) -associated disease. Approximately 90% to 95% of patients with celiac disease carry the HLA-DQ2 allele and the remaining 5% to 10% carry the HLA-DQ8 allele. However, not all people with one of these two alleles will develop celiac disease. It is believed that approximately 25% to 40% of the general population of the U.S. carries either the HLA-DQ2 or HLA-DQ8 allele but only about 3% of individuals carrying the DQ2/DQ8 alleles will develop gluten intolerance.

Given the nonspecific nature of the symptoms, definitive diagnosis has been based on the results of small intestinal biopsies showing a flattened intestinal mucosa in association with an inflammatory infiltrate. Diagnostic criteria were first established in 1969 by the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHN) and consisted of a series of three intestinal biopsies: one at diagnosis, one after the institution of a gluten-free diet, and the third after a repeat gluten challenge. This cumbersome method of diagnosis was revised in 1990 by simplifying the diagnostic criteria to a positive biopsy at presentation in conjunction with the consistent history and serologic results, followed by clinical response to a gluten-free diet.


While a positive biopsy result is considered the gold standard for diagnosis, the serologic evaluation of patients with possible celiac disease, together with a consistent clinical history and a positive response to a gluten-free diet, can sometimes be adequate for diagnosis. Serologic studies are also useful in triaging the large numbers of patients with nonspecific symptoms for biopsy. In approximately 10% of cases in which clinical suspicion suggests celiac disease, serologic testing and intestinal biopsy are non-diagnostic, either because the results of serology and biopsy are discordant, or because both tests are negative despite persistent symptoms suggestive of celiac disease. In these cases, HLA testing may be useful for ruling out a diagnosis of celiac disease.

National guidelines and position statements recommend serologic testing as the first step in diagnosing CD and recommend the immunoglobulin (Ig) A antibody to human recombinant tissue transglutaminase test. Guidelines have indicated that the IgA antibody to anti-endomysium antibody test has similar sensitivity and specificity as the tissue transglutaminase IgA test, but national organizations have indicated that the anti-endomysium antibody test is more prone to interpretation error. For subjects with known selective IgA deficiency, testing with tissue transglutaminase IgG and/or anti-endomysium antibody IgG is recommended.


This policy is updated regularly through a literature search. The most recent literature review was performed through September 22, 2020. 

Summary of Evidence

For individuals who are suspected of having celiac disease and have discordant serologic and biopsy findings or who are symptomatic for celiac disease and have negative serologic and biopsy findings, the evidence includes several retrospective and prospective cohort studies. The relevant outcomes are test validity, other test performance measures, and change in disease status. Several studies have reported that the sensitivity and negative predictive value (NPV) of HLA-DQ2 and HLA-DQ8 genotype testing for celiac disease approached 100%, meaning that this test is highly accurate for ruling out celiac disease. In contrast, a substantial number of patients who do not have celiac disease carry the HLA-DQ2 and/or HLA-DQ8 alleles, resulting in suboptimal specificity, meaning that this test is less accurate for confirming the diagnosis. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Practice Guidelines and Position Statements

American College of Gastroenterology

The clinical practice update on diagnosis and management of celiac disease (CD) from guidelines from the American College of Gastroenterology (2019) stated the following on human leukocyte antigen (HLA) gene testing:

"Determination of HLA-DQ2/DQ8 has a limited role in the diagnosis of CD. Its value is largely related to its negative predictive value to rule out CD in patients who are seronegative in the face of histologic changes, in patients who did not have serologic confirmation at the time of diagnosis, and in those patients with a historic diagnosis of celiac disease; especially as very young children prior to the introduction of celiac-specific serology."

The original guideline from the American College of Gastroenterology (2013) stated the following:

  1. “HLA-DQ2/DQ8 testing should not be used routinely in the initial diagnosis of CD (Strong recommendation, moderate level of evidence).
  2. HLA-DQ2/DQ8 genotyping testing should be used to effectively rule out the disease in selected clinical situations (Strong recommendation, moderate level of evidence).
  3. Examples of such clinical situations include but are not limited to:
  • Equivocal small-bowel histological finding (Marsh I-II) in seronegative patients
  • Evaluation of patients on a gluten-free diet (GFD) in whom no testing for CD was done before GFD
  • Patients with discrepant celiac-specific serology and histology
  • Patients with suspicion of refractory CD where the original diagnosis of celiac remains in question

The National Institute for Health and Clinical Excellence (NICE)

A 2009 guideline by this United Kingdom-based organization on celiac disease includes the following statement on HLA typing:

“Do not use human leukocyte antigen (HLA) DQ2 (DQ2.2 and DQ2.5)/DQ8 testing in the initial diagnosis of coeliac disease in non-specialist settings.

Only consider using HLA DQ2 (DQ2.2 and DQ2.5)/DQ8 testing in the diagnosis of coeliac disease in specialist settings (for example, in children who are not having a biopsy, or in people who already have limited gluten ingestion and choose not to have a gluten challenge).”

American Gastroenterological Association Institute

In 2006, the American Gastroenterological Association Institute issued a position statement on the diagnosis and management of celiac disease. Regarding serologic testing, they concluded that, in the primary care setting, the transglutaminase IgA antibody test is the most efficient single serologic test for diagnosing celiac disease. They state that the antiendomysial antibodies (EMA) IgA test is more time-consuming and operator dependent than the tTG. If IgA deficiency is strongly suspected, testing with IgG EMA and/or tTG IgG antibody test is recommended. If serologic test results are negative and celiac disease is still strongly suspected, providers can test for the presence of the disease-associated HLA alleles and, if present, perform small intestinal mucosal biopsy. Alternatively, if signs and symptoms suggest that small intestinal biopsy is appropriate; patients can proceed to biopsy without testing for HLA alleles.

National Institutes of Health (NIH)

In 2004, the National Institutes of Health issued a consensus statement based on a meeting and an independent literature review. The National Institutes of Health considered serologic testing as the first step in pursuing a diagnosis of CD and stated that the best tests are the tTG IgA and EMA IgA tests, which the Institutes considered to be of equivalent accuracy. In patients with suggestive symptoms and negative tTG IgA or EMA tests, it was recommended that consideration be given to IgA deficiency and, if identified, that a tTG IgG or EMA IgG be performed. When the diagnosis of CD is uncertain because of indeterminate results, testing for certain genetic markers (HLA haplotypes) was recommended to stratify individuals into high- or low-risk for CD. Greater than 97% of individuals with CD have the DQ2 and/or DQ8 marker, compared with about 40% of the general population. Therefore, an individual negative for DQ2 or DQ8 would be extremely unlikely to have CD (high negative predictive value). Biopsy of the proximal small bowel was indicated in those with a positive CD antibody test, except those with biopsy-proven dermatitis herpetiformis. No specific approach was suggested when there was a positive serology and normal biopsy findings. Options included additional biopsies, repeat serology testing and a trial of a gluten-free diet. Testing was indicated in patients with gastrointestinal tract symptoms and other signs and symptoms suggestive of CD.

U.S. Preventive Services Task Force Recommendations

The US Preventative Service Task Force (2017) released guidelines on screening adults and children for CD. These guidelines reviewed the use of tissue transglutaminase tests IgA testing followed by an intestinal biopsy to screen asymptomatic patients. Genotype testing was not discussed. The overall conclusion of this review was that the current balance of evidence is insufficient to assess benefits and harms resulting from screening for CD.


Celiac disease, HLA testing, HLA-DQ2, HLA-DQ8, CD, human leukocyte testing, genome testing


Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Several methods are used for HLA typing, including simple sequence-specific-primer, polymerase chain reaction, reverse dot blot hybridization, and real-time polymerase chain reaction. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.


Coverage is subject to member’s specific benefits.  Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP:  Special benefit consideration may apply.  Refer to member’s benefit plan.  FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.


CPT Codes:


HLA Class II typing, low resolution (e.g., antigen equivalents); 1 antigen equivalent, each


HLA Class II typing, high resolution (i.e., alleles or allele groups); 1 allele or allele group (e.g., HLA-DQB1*06:02P), each


  1. AGA Institute. Medical Position Statement on the Diagnosis and Management of Celiac Disease. Gastroenterology 2006; 131(6):1977-1980.
  2. Bibbins-Domingo K, Grossman DC, Curry SJ, et al. Screening for Celiac Disease: US Preventive Services Task Force Recommendation Statement. JAMA. Mar 28 2017; 317(12): 1252-1257.
  3. Hadithi M, Pena AS. Current methods to diagnose the unresponsive and complicated forms of coeliac disease. Eur J Intern Med 2010; 21(4):247-253.
  4. Hadithi M, Pena AS. Current methods to diagnose the unresponsive and complicated forms of coeliac disease. Eur J Intern Med. Aug 2010; 21(4):247-25
  5. Hadithi M, von Blomberg BM, Crusius JB et al. Accuracy of serologic tests and HLA-DQ typing for diagnosing celiac disease. Ann Intern Med 2007; 147(5):294-302.
  6. Hill ID, Dirks MH, Liptak GS et al. Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2005; 40(1):1-19.
  7. Husby S, Koletzko S, Korponay-Szabo IR et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr 2012; 54(1):136-160.
  8. Husby S, Murray JA, Katzka DA. AGA Clinical Practice Update on Diagnosis and Monitoring of Celiac Disease-Changing Utility of Serology and Histologic Measures: Expert Review. Gastroenterology. Mar 2019; 156(4): 885-889.
  9. Kapitany A, Toth L, Tumpek J et al. Diagnostic significance of HLA-DQ typing in patients with previous coeliac disease diagnosis based on histology alone. Aliment Pharmacol Ther 2006; 24(9):1395-1402.
  10. Maglione MA, Okunogbe A, Ewing B, et al. Diagnosis of Celiac Disease (Comparative Effectiveness Review No. 162). Rockville (MD): Agency for Healthcare Research and Quality; 2016.
  11. Megiorni F, Pizzuti A. HLA-DQA1 and HLA-DQB1 in Celiac disease predisposition: practical implications of the HLA molecular typing. J Biomed Sci 2012; 19:88.
  12. National Institute for Health and Care Excellence (NICE). Coeliac Disease: Recognition, assessment, and management [NG20]. 2015; Accessed September 22, 2020.
  13. National Institute for Health and Care Excellence (NICE). NICE clinical guideline 86: Recognition and assessment of coeliac disease. Available online at:
  14. NIH consensus development conference on celiac disease. Consensus development conference statement. 2004. Available online at:
  15. Pallav K, Kabbani T, Tariq S, et al. Clinical utility of celiac disease-associated HLA testing. Dig Dis Sci. Sep 2014; 59(9):2199-2206.
  16. Piccini B, Vascotto M, Serracca L et al. HLA-DQ typing in the diagnostic algorithm of celiac disease. Rev Esp Enferm Dig 2012; 104(5):248-254.
  17. Rubio-Tapia A, Hill ID, Kelly CP et al. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol 2013; 108(5):656-676; quiz 677.
  18. Walker-Smith JA GS, Schmitz J, et al. Revised criteria for diagnosis of coeliac disease. Report of Working Group of European Society of Paediatric Gastroenterology and Nutrition. Arch Dis Child 1990; 65(8):909-911.
  19. Werkstetter KJ, Korponay-Szabo IR, Popp A, et al. Accuracy in diagnosis of celiac disease without biopsies in clinical practice. Gastroenterology. Oct 2017; 153(4):924-935.


Medical Policy Group, February 2009 (1)

Medical Policy Administration Committee, March 2009

Available for comment March 4-April 17, 2009

Medical Policy Group, September 2010 (1)

Medical Policy Panel, September 2011

Medical Policy Group, January 2012 (1): Update to Key Points and References; no change in policy statement

Medical Policy Panel, May 2013

Medical Policy Group, May 2013 (1): Update to Key Points and References; no change to policy statement

Medical Policy Group, January 2014 (1): Creation of individual policy with all references related to HLA testing for celiac disease removed from medical policies #136 and #161; no change to policy statement

Medical Policy Panel, May 2014

Medical Policy Group June 2014 (1) Update to Key Points and References; no change to policy statement

Medical Policy Panel, May 2015

Medical Policy Group, June 2015 (3):  2015 Update to Key Points & References; removed 81382 from coding section; no change to policy statement.

Medical Policy Panel, November 2017

Medical Policy Group, November 2017 (3):  2017 Updates to Key Points, Key Words, Approved by Governing Bodies & References; no change in Policy Statement.

Medical Policy Panel, November 2018

Medical Policy Group, November 2018 (9): 2018 Updates to Description, Key Points, Approved Governing Bodies, Added key words: CD, human leukocyte testing, genome testing; no change in policy statement.

Medical Policy Panel, November 2019

Medical Policy Group, December 2019 (9): 2019 Updates to Key Points, Description, References. No change to policy statement.

Medical Policy Panel, November 2020

Medical Policy Group, November 2020 (9): 2020 Updates to Key Points, Description, References. No change to policy statement.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.