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MP 2.04.95 Human Leukocyte Antigen Testing for Celiac Disease

Medical Policy    
Subsection Last Review Status/Date
Reviewed with literature search/5:2014
Original Policy Date
Return to Medical Policy Index


Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically. 


Celiac disease is currently diagnosed by serology, medical history, and response to a gluten-free diet, 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, also referred to as celiac sprue or gluten-sensitive enteropathy, is a relatively common disorder with variable clinical expression. Population-based screening surveys suggest a prevalence of 1 in 250 to 500 in most countries, including the U.S. However, this prevalence may vary widely depending on how the disease is defined, ie, whether only clinically apparent cases are considered, as opposed to including all people with any serologic or histologic evidence of disease.

Celiac disease is characterized by inflammation of the small intestine resulting from an immunologic intolerance to gluten, ie, proteins derived from wheat, barley, and rye. The symptoms of the disease are markedly variable and can be broadly subdivided into intestinal and extraintestinal 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, eg, 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 extraintestinal manifestations.

Celiac disease is a 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 1 of these 2 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 people carrying the DQ2/DQ8 alleles will develop gluten intolerance.(1,2)

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 3 intestinal biopsies: at diagnosis, after 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 consistent history and serologic results, followed by a clinical response to a gluten-free diet.(3)

While a positive biopsy result is considered the criterion standard for diagnosis, 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 nondiagnostic, 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.

Regulatory Status

HLA typing for celiac disease is offered by several laboratories such as Quest, LabCorp, and Prometheus. There are several methods that are used for HLA typing including Simple Sequencespecific-Primer, Polymerase Chain Reaction (PCR), reverse dot blot hybridization, and real-time PCR.


HLA-DQ2 and HLA-DQ8 testing may be considered medically necessary to rule out celiac disease in: 

  • patients with discordant serologic and histologic (biopsy) findings; or
  • patients with persistent symptoms despite negative serology and histology.

HLA-DQ2 and HLA-DQ8 testing for celiac disease is considered investigational in all other situations.

Policy Guidelines

There is specific coding for HLA testing in CPT (81370-81383).

One laboratory that performs this testing lists the following coding online:

81377 x 2 HLA Class II typing, low resolution (e.g., antigen equivalents); one antigen equivalent, each
81383 HLA Class I typing, high resolution (i.e., alleles or allele groups); one allele or allele group (e.g., HLA-DBQ1*06:02P), each
Other laboratory websites suggest online that the testing be reported with code 81383 x 2 alone or with 81377 x 2.

Benefit Application
BlueCard/National Account Issues

Serologic diagnosis of celiac disease may be offered by reference laboratories specializing in the evaluation of gastrointestinal diseases.


This policy was created with a literature search of the MEDLINE database through April 12, 2013. It was based in part on archived Policy No. 2.04.30 Serologic Diagnosis of Celiac Disease. A literature review was performed through March 24, 2014. A summary of the key literature is as follows:

Serologic diagnosis in subjects with signs or symptoms suggestive of celiac disease

National guidelines and position statements agree that serologic testing is the first step in diagnosing celiac disease and that the IgA antibody to human recombinant tissue transglutaminase (tTG) test is recommended.(4-6) They state that the IgA antibody to antiendomysium antibody (EMA) test has similar sensitivity and specificity to the tTG IgA test, but 2 of the national organizations mention that the EMA test is more prone to interpretation error. For subjects with known selective IgA deficiency, testing with tTG IgG and/or EMA IgG is recommended. The national organizations also agree that when test results are indeterminate, testing for the genetic markers HLA-DQ2 or HLA-DQ8 is recommended.

Several studies have established that HLA typing has a high sensitivity and a high negative predictive value for the diagnosis of celiac disease. For example, a 2007 prospective study by Hadithi et al included a total of 463 patients who were referred for evaluation of celiac disease.(7) Sixteen (3.5%) of the 463 patients met ESPGHN diagnostic criteria for celiac disease, ie, characteristic histologic findings (Marsh III) on small-bowel biopsy and unequivocal symptom resolution after initiating a gluten-free diet. All 16 patients were positive for HLA-DQ2 and/or HLA-DQ8. In contrast, 192 of 227 (43%) of patients who did not meet diagnostic criteria for celiac disease were positive for 1 or both of these alleles. Testing positive for HLA-DQ2 or HLA-DQ8 had a positive predictive value of 7.7% (95% confidence interval [CI], 4.5% to 12%) and a negative predictive value of 100% (95% CI, 98.6% to 100%).

A study published in 2006 by Kapitany et al included 70 patients who had been diagnosed with celiac disease 2 to 25 years prior using only results of small-bowel biopsy.(8) Based on clinical follow-up, serologic testing and HLA-typing, as well as new biopsies in uncertain cases, evidence of celiac disease was found in 0 of the 15 patients who tested negative for both HLA-DQ2 and HLA-DQ8. Fourteen patients were found to be normal and 1 patient had insufficient data. A diagnosis of celiac disease was supported in 47 of 55 (85%) of patients who were positive for HLA-DQ2 and/or HLA-DQ8. Thirty-nine of the 47 patients (83%) were positive on antitissue transglutaminase (anti-TG) and/or EMA autoantibody serologic tests.

In 2012, Piccini et al published findings of a case-control analysis that included 89 patients diagnosed with celiac disease and 70 healthy controls.(9) All of the patients with celiac disease and 64% of controls were positive for at least 1 of the HLA alleles known to be associated with the disease. The authors also tested 105 first-degree relatives of patients with celiac disease. Seventy-five percent of the family members were positive for 1 or more predisposing HLA alleles. Confirmatory biopsies were performed in relatives with celiac-associated HLA alleles and 8.6% of them (67% of all family members) were found to be affected by celiac disease.


Several studies have reported that the sensitivity and negative predictive value of HLA testing for celiac disease is 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. National recommendations and study data support the conclusion that HLA typing is useful for ruling out celiac disease when patients have discordant serologic and histologic (biopsy) findings or when patients have persistent symptoms, despite negative serology and histology. Thus, HLA typing may be considered medically necessary in these situations and is otherwise considered investigational.

Practice Guidelines and Position Statements

American College of Gastroenterology: A 2013 guideline on the diagnosis and management of celiac disease stated the following on HLA testing:

“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
- Patients with Down's syndrome.”(10)

ESPGHN: A 2012 guideline on the diagnosis of celiac disease stated that HLA-DQ2/ HLA-DQ8 testing should be offered to patients with an uncertain diagnosis of celiac disease eg, those with negative celiac disease-specific antibodies and mild infiltrate changes in small-bowel specimens. A negative finding renders celiac disease highly unlikely in these people.(11)

The National Institute for Health and Clinical Excellence: A 2009 guideline by this UK-based organization on celiac disease includes the following statement on HLA typing:

“Do not use human leukocyte antigen (HLA) DQ2/DQ8 testing in the initial diagnosis of celiac disease. However, its high negative predictive value may be of use to gastrointestinal specialists in specific clinical situations.”(12)

American Gastroenterological Association: In 2006, the American Gastroenterological Association 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 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.(5)

National Institutes of Health (NIH): NIH issued a Consensus Development Conference Statement in June 2004 based on a 2-day meeting and literature reviews by the University of Ottawa Evidence-based Practice Center. NIH considered serologic testing as the first step in pursuing a diagnosis of celiac disease and stated that the best tests are the tTG IgA and EMA IgA tests, which they considered to be of equivalent accuracy. In patients with suggestive symptoms and negative tTG IgA or EMA tests, consider an IgA deficiency and, if identified, it is recommended that a tTG IgG or EMA IgG be performed. When diagnosis is uncertain because of indeterminate test results, an option according to the NIH statement is to test for the genetic markers HLA-DQ2 or HLA-DQ8. Biopsy of the proximal small bowel is indicated in those with a positive celiac disease antibody test, except those with biopsy-proven dermatitis herpetiformis. No specific approach was suggested when there is positive serology and normal biopsy findings. Options include additional biopsies, repeat serology testing, and a trial of a gluten-free diet. Testing is indicated in patients with gastrointestinal tract symptoms and other signs and symptoms suggestive of celiac disease.(4)

Of note, as of April 2014, there are no recommendations from the U.S. Preventive Services Task Force related to screening for celiac disease in children or adults.

Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.


  1. Hadithi M, Pena AS. Current methods to diagnose the unresponsive and complicated forms of coeliac disease. Eur J Intern Med 2010; 21(4):247-53.
  2. 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.
  3. 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):909-11.
  4. NIH consensus development conference on celiac disease. Consensus development conference statement. 2004. Available online at: Last accessed March, 2014.
  5. AGA Institute Medical Position Statement on the Diagnosis and Management of Celiac Disease. Gastroenterology 2006; 131(6):1977-80.
  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. 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.
  8. 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):1395-402.
  9. 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):248-54.
  10. Rubio-Tapia A, Hill ID, Kelly CP et al. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol 2013; 108(5):656-76; quiz 77.
  11. 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):136-60.
  12. National Institute for Health and Care Excellence (NICE). NICE clinical guideline 86: Recognition and assessment of coeliac disease. Available online at: Last accessed March, 2014.




CPT    See Policy Guidelines
ICD-9 Diagnosis  579.0  Celiac disease
  787.3 Flatulence, eructation, and gas pain (includes bloating)
  787.91 Diarrhea NOS
  789.0 Abdominal pain
ICD-10-CM (effective 10/1/15) K90.0 celiac disease
  R10.0-R10.13; R10.3-
R10.829; R10.84-
Abdominal pain code range
  R14.0 Abdominal distention (gaseous) (includes bloating)
ICD-10-PCS (effective 10/1/15)    Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.

Policy History
Date Action Reason
5/09/13 Add to Medicine: Pathology/Laboratory Policy was created with literature search through April 12,
2013; HLA testing may be considered medically
necessary to rule out celiac disease in patients with
discordant serologic and histologic findings or if persistent
symptoms warrant testing despite negative serology and
histology. HLA testing for celiac disease is considered
investigational in all other situations.
5/22/14 Replace policy Policy updated with literature review through March 24,
2014. References 10-11 added. Policy statements