Name of Policy: Human Leukocyte Antigen (HLA) Testing for Celiac Disease

Name of Policy: Human Leukocyte Antigen (HLA) Testing for Celiac Disease Policy #: 545 Latest Review Date: June 2015 Category: Laboratory Policy Grade: B Background/Definitions: As a general rule, benefits are payable under Blue Cross and Blue Shield of Alabama 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. Page 1 of 8

Description of Procedure or Service: Celiac disease 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, also referred to as celiac sprue or gluten-sensitive enteropathy, is a relatively common disorder that has variable clinical expression. Population-based screening surveys suggest a prevalence of 1 in 250 500 in most countries, including the U.S. However, this prevalence may vary widely depending on how the disease is defined, i.e., whether only clinically apparent cases are considered, as opposed to including all individuals 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, 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 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, 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 extraintestinal 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 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. Page 2 of 8

While a positive biopsy result is considered the gold 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 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. Policy: Genetic testing for HLA-DQ2 and HLA-DQ8, when used to rule out celiac disease, meets Blue Cross and Blue Shield of Alabama s medical criteria for coverage 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 does not meet Blue Cross and Blue Shield of Alabama s medical criteria and is considered investigational in all other situations. Blue Cross and Blue Shield of Alabama 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. Blue Cross and Blue Shield of Alabama 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. Key Points: This policy is updated regularly through a literature search of the MEDLINE database. The most recent literature review was performed through March 18, 2015. A summary of the key literature follows. Serologic Diagnosis in Individuals 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 (CD) and that the IgA antibody to human recombinant tissue transglutaminase (ttg) test is recommended. They state that the IgA antibody to antiendomysium antibody (EMA) test has similar sensitivity and specificity to the ttg IgA test, but two of the national organizations mention that the EMA test is more prone to interpretation error. For individuals 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. Page 3 of 8

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 and colleagues included a total of 463 patients who were referred for evaluation of celiac disease. Sixteen (3.5%) of the 463 patients met ESPGHN diagnostic criteria for celiac disease, i.e., 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]: 4.5-12%) and a negative predictive value of 100% (95% CI: 98.6-100%). In 2014, Pallav et al. published a retrospective report of HLA testing in 256 patients with known or suspected celiac disease. Taking into account all available clinical and laboratory data, a total of 44 patients were diagnosed with celiac disease and, in 173 patients celiac disease was ruled out. A final diagnosis could not be obtained in 39 of 256 (15%) patients. HLA-DQ2 or DQ8 were absent in 40% of patients non-cd and two CD patients. The negative predictive value was 98%. A total of 154 patients were found to carry HLA-DQ2 or DQ8 alleles. Forty-two of the 44 patients diagnosed with celiac disease tested positive for one or both of the above HLA alleles, with a test sensitivity of 95.5%. The diagnostic accuracy data are somewhat limited by the 15% of patients without a definitive diagnosis. Summary of Evidence Several studies have reported that the sensitivity and negative predictive value of HLA 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. 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: HLA-DQ2/DQ8 testing should not be used routinely in the initial diagnosis of CD (Strong recommendation, moderate level of evidence). HLA-DQ2/DQ8 genotyping testing should be used to effectively rule out the disease in selected clinical situations (Strong recommendation, moderate level of evidence). Examples of such clinical situations include but are not limited to: o Equivocal small-bowel histological finding (Marsh I-II) in seronegative patients o Evaluation of patients on a gluten-free diet (GFD) in whom no testing for CD was done before GFD o Patients with discrepant celiac-specific serology and histology Page 4 of 8

o Patients with suspicion of refractory CD where the original diagnosis of celiac remains in question o Patients with Down's syndrome European Society of Paediatric Gastroenterology, Hepatology and Nutrition (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. 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/DQ8 testing in the initial diagnosis of coeliac disease. (However, its high negative predictive value may be of use to gastrointestinal specialists in specific clinical situations. 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 (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) The 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. The 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 individuals 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 due to 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 individuals with gastrointestinal symptoms and other signs and symptoms suggestive of celiac disease. Page 5 of 8

U.S. Preventive Services Task Force Recommendations As of April 2015, there are no recommendations from the U.S. Preventive Services Task Force related to screening for celiac disease in children or adults. Key Words: Celiac disease, HLA testing Approved by Governing Bodies: 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 Sequence-specific-Primer, Polymerase Chain Reaction (PCR), reverse dot blot hybridization, and real-time PCR. Benefit Application: 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. Current Coding: CPT Codes: 81377 HLA Class II typing, low resolution (e.g., antigen equivalents); 1 antigen equivalent, each 81383 HLA Class II typing, high resolution (i.e., alleles or allele groups); 1 allele or allele group (e.g., HLA-DQB1*06:02P), each References: 1. AGA Institute. Medical Position Statement on the Diagnosis and Management of Celiac Disease. Gastroenterology 2006; 131(6):1977-80. 2. 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. 3. 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. 4. 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. 5. 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. Page 6 of 8

6. 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. 7. 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. 8. National Institute for Health and Care Excellence (NICE). NICE clinical guideline 86: Recognition and assessment of coeliac disease. Available online at: nice.org.uk/cg86. 9. NIH consensus development conference on celiac disease. Consensus development conference statement. 2004. Available online at: consensus.nih.gov/2004/2004celiacdisease118html.htm. 10. 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. 11. 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. 12. 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. 13. 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. Policy History: 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. This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a caseby-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. Page 7 of 8

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. Page 8 of 8