National Medical Policy

National Medical Policy Subject: Celiac Disease Laboratory Testing Policy Number: NMP255 Effective Date*: February 2006 Updated: April 2016 This ...
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National Medical Policy Subject:

Celiac Disease Laboratory Testing

Policy Number:

NMP255

Effective Date*: February 2006 Updated:

April 2016 This National Medical Policy is subject to the terms in the IMPORTANT NOTICE at the end of this document

For Medicaid Plans: Please refer to the appropriate State’s Medicaid manual(s), publication(s), citation(s), and documented guidance for coverage criteria and benefit guidelines prior to applying Health Net Medical Policies The Centers for Medicare & Medicaid Services (CMS) For Medicare Advantage members please refer to the following for coverage guidelines first: Use

X

Source National Coverage Determination (NCD) National Coverage Manual Citation Local Coverage Determination (LCD)* Article (Local)* Other None

Reference/Website Link

Use Health Net Policy

Instructions  Medicare NCDs and National Coverage Manuals apply to ALL Medicare members in ALL regions.  Medicare LCDs and Articles apply to members in specific regions. To access your specific region, select the link provided under “Reference/Website” and follow the search instructions. Enter the topic and your specific state to find the coverage determinations for your region. *Note: Health Net must follow local coverage determinations (LCDs) of Medicare Administration Contractors (MACs) located outside their service area when those MACs have exclusive coverage of an item or service. (CMS Manual Chapter 4 Section 90.2)  If more than one source is checked, you need to access all sources as, on occasion, an LCD or article contains additional coverage information than contained in the NCD or National Coverage Manual.

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If there is no NCD, National Coverage Manual or region specific LCD/Article, follow the Health Net Hierarchy of Medical Resources for guidance.

Current Policy Statement Health Net, Inc. considers the following serological tests in the diagnosis of Celiac Disease medically necessary: 1.

Immunoglobulin A (IgA) anti-tissue transglutaminase (TTG), (also referred to as TTG-IgA) testing, or IgA anti-endomysial antibodies (IgA-EMA) testing for detection of celiac disease (CD) in individuals over the age of 2 years in any of the following:     

Individuals with symptoms, signs, or laboratory evidence suggestive of malabsorption, (e.g., chronic diarrhea with weight loss, steatorrhea, postprandial abdominal pain, bloating) Individuals with symptoms, signs, or laboratory evidence for which CD is a treatable cause Individuals with a first-degree family member who has a confirmed diagnosis of CD when the individual shows possible signs or symptoms or laboratory evidence of CD. Individuals with elevated serum aminotransferase levels when no other etiology is found Individuals with Type I diabetes mellitus (DM) if there are any digestive symptoms, or signs, or laboratory evidence suggestive of CD.

2.

Measurement of total IgA, when there exists a high probability of CD and the possibility of IgA deficiency. (IgA deficiency is more common in CD than in the general population). An alternative approach is to include both IgA and IgGbased testing, such as IgG-deamidated gliadin peptides (DGPs), in these highprobability individuals.

3.

IgG-based testing (IgG DGPs and IgG TTG) in individuals when a low IgA or selective IgA deficiency is identified.

4.

IgA TTG test in combination with DGP (IgA and IgG) in children younger than 2 years of age when CD is suspected

5.

HLA-DQ2 / DQ8 genotyping testing to rule out the disease in selected clinical situations. (HLA-DQ2 / DQ8 testing should not be used routinely in the initial diagnosis of CD). Examples of such clinical situations include but are not limited to:  Equivocal small-bowel histological finding (Marsh I-II) in seronegative individuals  Evaluation of individuals on a gluten free diet (GFD) in whom no testing for CD was done before GFD  Individuals with discrepant celiac-specific serology and histology  Individuals with suspicion of refractory CD where the original diagnosis of celiac remains in question  Individuals with Down’s syndrome

6.

Serologic testing is also useful in monitoring the response to gluten-free diet. (Serum levels of IgA-EMA and IgA-TTG fall on a gluten-free diet and the test often becomes negative in treated patients)

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Note: All diagnostic serologic testing should be done with patients on a glutencontaining diet. Per the American College of Gastroenterology, antibodies directed against native gliadin are not recommended for the primary detection of CD Health Net Inc. considers screening for asymptomatic celiac disease, using the IgA endomysial or IgG tTG assays, investigational, as studies have noted lower sensitivity and specificity, and their benefit has not yet been demonstrated. Although potential advantages of screening for asymptomatic celiac disease exist, additional peer-reviewed studies are needed to determine if this type of testing should be advocated.

Codes Related to This Policy NOTE: The codes listed in this policy are for reference purposes only. Listing of a code in this policy does not imply that the service described by this code is a covered or noncovered health service. Coverage is determined by the benefit documents and medical necessity criteria. This list of codes may not be all inclusive. On October 1, 2015, the ICD-9 code sets used to report medical diagnoses and inpatient procedures have been replaced by ICD-10 code sets.

ICD-9 Codes (May not be all inclusive) 285.9 579.0 728.2 780.79 783.21 783.41 V18.5 V77.99

Anemia, unspecified Celiac disease Muscular wasting and disuse atrophy, not elsewhere classified Other malaise and fatigue Loss of weight Failure to thrive Family history of digestive disorders Special screening for other and unspecified endocrine, nutritional, metabolic, and immunity disorders

ICD-10 Codes D64.9 K90.0 M62.50-M62.59 R53.81-R53.83 R62.51 R63.4 Z13.21 Z13.228 Z13.29 Z83.79

Anemia, unspecified Celiac disease Muscle wasting and atrophy, not elsewhere classified Other malaise and fatigue Failure to thrive (child) Abnormal weight loss Encounter for screening for nutritional disorder Encounter for screening for other metabolic disorders Encounter for screening for other suspected endocrine disorder Family history of other diseases of the digestive system

CPT Codes 82784

Gammaglobulin; IgA, IgD, IgG, IgM, each

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83516 83520 86255 86256

Immunoassay for analyte other than infectious agent antibody or infectious agent antigen, qualitative or semiquantitative; multiple step method Immunoassay, analyte, quantitative; not otherwise specified Fluorescent noninfectious agent antibody; screen, each antibody Fluorescent noninfectious agent antibody; titer, each antibody

HCPCS Codes N/A

Scientific Rationale – Update April 2016 Mooney et al. (2015) completed a prospective study of 2 groups of patients from March 2013 through February 2014. In group 1, patients at high risk of celiac disease who tested positive for endomysial antibody (n = 55) were evaluated using the Biocard test (BHR Pharmaceuticals, Nuneaton, UK) and the Celiac Quick Test (Biohit Healthcare UK, Ellesmere Port, UK), which measure antibodies to tissue transglutaminase (anti-tTG), and the Simtomax test (Tillotts Pharma, Rheinfelden, Switzerland), which measures deamidated gliadin peptide antibodies (DGP). Patients in group 2 (508 consecutive patients who underwent an endoscopy examination for any indication) received the DGP test, and also were evaluated using a diagnostic algorithm that incorporated results from the DGP test and data on symptoms. In both groups, point-of-care tests were taken at the time of endoscopy and results were compared with results from histologic analyses of duodenal biopsy specimens from all patients. In group 1, the DGP test identified patients with celiac disease with 94.4% sensitivity, the Celiac Quick Test identified patients with 77.8% sensitivity (P = .03 vs the DGP test), and the Biocard test identified patients with 72.2% sensitivity (P = .008 vs the DGP test). In group 2, the DGP test identified patients with celiac disease with 92.7% sensitivity (95% confidence interval, 83.0-97.3), 85.2% specificity (95% confidence interval, 81.5-88.3), a positive predictive value of 49.2% (95% confidence interval, 40.3-58.2), and a negative predictive value of 98.7% (95% confidence interval, 96.8-99.5). Measurement of serum anti-tTG identified patients with celiac disease with 91.2% sensitivity (95% confidence interval, 81.1-96.4), 87.5% specificity (95% confidence interval, 84.0-90.4), a positive predictive value of 53.0% (95% confidence interval, 43.6-62.2), and a negative predictive value of 98.5% (95% confidence interval, 96.5-99.4). The algorithm identified patients with celiac disease with 98.5% sensitivity; its use could reduce duodenal biopsies by 35%. In a prospective study, a test for DGP identified patients with celiac disease with similar levels of sensitivity and specificity as standard serologic analysis of anti-tTG. Use of the DGP test before endoscopy could increase the accuracy of the diagnosis of celiac disease. Further studies, in lowerprevalence populations, are required to assess the impact of the test in clinical practice.

Scientific Rationale – Update April 2015 Pallav et al (2014) reported that negative predictive value (NPV) of celiac disease (CD)-related human leukocyte antigens (HLA) DQ2 and DQ8 approaches 100 % in individual patients. However, studies evaluating its exclusionary utility in patient groups are lacking. The authors aimed to assess the performance of HLA testing when applied to patient groups with varying characteristics and propose evidencebased recommendations for its clinical use. Demographic and clinical information was recorded in patients undergoing HLA testing. Using predetermined criteria, patients were classified as CD, non-CD, or indeterminate. Diagnostic yield of HLA

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testing was defined as the percentage of patients in whom CD could be excluded based on negative HLA test. Two hundred and fifty-six patients underwent testing for CD-related HLA DQ2 and DQ8. 102 (100 non-CD, 2 CD) patients tested HLA negative for a 98 % NPV and 39 % diagnostic yield. Diagnostic yield was highest (60 %) in patients with intraepithelial lymphocytosis plus normal IgA tissue transglutaminase antibody (IgA-tTG) and lowest in patients with positive IgA-tTG plus villous atrophy (0 %). CD was diagnosed in two HLA-negative patients, who carried half of DQ2.5 trans genotype. The authors concluded diagnostic yield of CDrelated HLA testing varies widely depending on clinical indication. HLA testing is a practical and valuable test for most patients in whom initial evaluation for CD is inconclusive. A negative HLA result usually obviates the need for further celiac testing including endoscopy and gluten challenge. Rarely, in patients reported as HLA negative, half of HLA DQ2.5 (cis or trans) is sufficient for development of CD. Delgado et al (2014) sought to determine the relevance of HLA-DR7-DQ2 typing in a prospective cohort of pediatric celiac disease patients from Southern Europe. This cross-sectional study tested 249 pediatric patients with celiac disease. HLA-DR3-DQ2 was typed in combination with HLA-DR7-DQ2 to screen for the HLA-DQ2 haplotype. The histological, analytical and clinical characteristics of the subjects were recorded. A total of 91 celiac patients were diagnosed: 96.7% carried HLA-DQ2 and 4.4% carried HLA-DQ8. In percentage terms, 80.2% of patients carried HLA-DR3-DQ2 and 34.1% carried HLA-DR7-DQ2. The authors did not find significant differences between HLA-DR7-DQ2 and HLA-DR3-DQ2 pediatric patients with respect to histological damage and clinical characteristics, except for irritability and weight loss. These characteristics were more frequent in HLA-DQ2trans than in HLA-DQ2cis (22.2% vs. 0.0% [p = 0.035] and 55.6% vs. 21.4% [p = 0.017], respectively). Celiac-specific autoantibody levels were higher in HLA-DQ2cis than one half of HLADQ2trans patients (105.5 vs. 19.2 U/mL, p = 0.014). The authors concluded small clinical differences were found between pediatric celiac patients carrying HLA-DR7DQ2 and HLA-DR3-DQ2. For a correct screening of HLA-DQ2, at least in our geographical population, the HLA-DR7-DQ2 haplotype should be typed due to its frequency and clinical presentation. Srinivas et al (2014) aimed to develop a simple diagnostic approach that all clinicians could follow to increase the percentage of patients accurately diagnosed with celiac disease at initial presentation. The authors performed a retrospective analysis of data from 752 patients (88 with celiac disease, none were IgA deficient) who attended a UK district general hospital from January 2007 through December 2008 and underwent biopsy analysis and serologic tests to measure endomyseal antibodies and IgA antibodies against tissue transglutaminase (tTG). Patients avoiding gluten in their diet were excluded. Patients were assigned to 1 of 4 groups: high-risk (based on presence of anemia, chronic diarrhea, unintentional weight loss, or dermatitis herpetiformis), low-risk (based on such factors as dyspepsia, abnormal liver function, ataxia, or chronic cough), nutrient deficiency (based on levels of iron, vitamins B12 and D, or folate), or screening (because they had type 1 diabetes or a family history of celiac disease). Patients with celiac disease were identified using the modified Marsh criteria (grades 1-3) for interpreting duodenal histology. The authors compared clinical category, serology profiles, and biopsy results between patients with and without celiac disease. Celiac disease was diagnosed in 64 of 565 patients in the high-risk group (11%), 14 of 156 patients in the low-risk group (9%; P = .47 compared with high-risk group), 7 of 28 patients in the nutrient-deficiency group, and 3 of 3 patients in the screening group. Among 71 patients who tested positive for both antibodies (tTG and endomyseal antibodies), the positive predictive value

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for celiac disease was 97%; a negative test result for tTG had a negative predictive value of 98%. Among 708 patients with normal-looking biopsy samples, only 62 had celiac disease (9%). Among 44 patients with abnormal biopsy samples, 26 had celiac disease (59%). The authors concluded based on a retrospective analysis, patients with and without celiac disease cannot be distinguished based on clinical features. Patients who present with symptoms of celiac disease should be tested for tTG, to identify candidates for duodenal biopsy analysis.

Scientific Rationale – Update April 2014 Mubarek et al. (2013, World Journal of Gastroenterology) completed a study to investigate whether celiac disease (CD) patients with tissue-transglutaminase antibody (tTGA) ≥ 100 U/mL are different from patients with lower tTGA levels. Biopsy-proven (Marsh III) pediatric CD patients (n = 116) were prospectively included between March 2009 and October 2012. The biopsies were evaluated by a single, blinded pathologist. The patients were distributed into 2 groups according to their tTGA level, which was measured using enzyme-linked immunoassay: tTGA ≥ 100 U/mL and tTGA < 100 U/mL. The patients' characteristics, symptoms, human leukocyte antigen (HLA) genotype and degree of histological involvement were compared between the 2 groups. A total of 34 (29.3%) children had tTGA values < 100 U/mL and 82 (70.7%) tTGA levels of ≥ 100 U/mL. Patients with high tTGA levels had lower average body weight-for-height standard deviation scores (SDS) than did patients with tTGA < 100 U/mL (-0.20 ± 1.19 SDS vs 0.23 ± 1.03 SDS, P = 0.025). In the low tTGA group, gastrointestinal symptoms were more common (97.1% vs 75.6%, P = 0.006). More specifically, abdominal pain (76.5% vs 51.2%; P = 0.012) and nausea (17.6% vs 3.7%, P = 0.018) were more frequent among patients with low tTGA. In contrast, patients with solely extraintestinal manifestations were only present in the high tTGA group (18.3%, P = 0.005). These patients more commonly presented with aphthous stomatitis (15.9% vs 0.0%, P = 0.010) and anemia (32.9% vs 11.8%, P = 0.019). In addition, when evaluating the number of CD-associated HLA-DQ heterodimers (HLA-DQ2.5, HLA-DQ2.2 and HLA-DQ8), patients with low tTGA levels more commonly had only 1 disease-associated heterodimer (61.8% vs 31.7%, P = 0.005), while patients with high tTGA more commonly had multiple heterodimers. Finally, patients with tTGA ≥ 100 U/mL more often had a Marsh IIIc lesion (73.2% vs 20.6%, P < 0.001) while in patients with low tTGA patchy lesions were more common (42.4% vs 6.8%, P < 0.001). Patients with tTGA ≥ 100 U/mL show several signs of more advanced disease. They also carry a larger number of CD associated HLA-DQ heterodimers.

Scientific Rationale – Update September 2013 A variety of serologic studies have been described to aid in the diagnosis of celiac disease, including:     

IgA endomysial antibody (IgA EMA) IgA tissue transglutaminase antibody (IgA tTG) IgG tissue transglutaminase antibody (IgG tTG) IgA deamidated gliadin peptide (IgA DGP) IgG deamidated gliadin peptide (IgG DGP)

Serum IgA endomysial and tissue transglutaminase antibody testing have the highest diagnostic accuracy. The IgA and IgG antigliadin antibody tests have lower diagnostic accuracy with frequent false positive results as compared with IgA tTG and IgA DGP assays and are therefore no longer recommended for initial diagnostic

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evaluation or screening. The newer anti-deamidated gliadin peptide (DGP) assays show high diagnostic accuracy. IgA EMA, IgA tTG, IgA DGP and IgG DGP levels fall with treatment; as a result, these assays can be used as a noninvasive means of monitoring the response to a gluten-free diet. Per the American College of Gastroenterology (ACG) guidelines on the Diagnoisis and Management of Celiac Disease (2013) , “In the past, several antibody tests have been developed to detect CD. Antibodies may be directed against native or altered cereal derived peptides. Anti-gliadin antibodies (AGA) have been used for decades and are reasonably accurate when there is a high pretest prevalence of CD. However, it was with the advent of auto-antibodies, first directed against reticulin, then endomysium antibodies (EMA), and finally TTG antibodies, that the truly celiac-specific testing was developed. The identification of TTG IgA antibody as the target antigen for IgA EMA antibodies was a major advance.” The ACG guidelines note further, “While antibodies directed against native gliadin (AGA) have been in use for several decades, there is a wide variability in their diagnostic accuracy. Both IgA and IgG AGA have sensitivities and specificities inferior to those of the TTG-IgA and DGPIgA assays and should no longer be included in the routine testing strategy for CD.” The recent guidelines from the American College of Gastroenterology on the diagnosis and management of Celiac Disease (2013) make the following recommendations regarding serologic testing: 1.

2. 3. 4. 5. 6. 7. 8.

Patients with symptoms, signs, or laboratory evidence suggestive of malabsorption, such as chronic diarrhea with weight loss, steatorrhea, postprandial abdominal pain, and bloating, should be tested for CD. (Strong recommendation, high level of evidence) Patients with symptoms, signs, or laboratory evidence for which CD is a treatable cause should be considered for testing for CD. (Strong recommendation, moderate level of evidence) Patients with a first-degree family member who has a confirmed diagnosis of CD should be tested if they show possible signs or symptoms or laboratory evidence of CD. (Strong recommendation, high level of evidence) Consider testing of asymptomatic relatives with a first degree family member who has a confirmed diagnosis of CD. (Conditional recommendation, high level of evidence) CD should be sought among the explanations for elevated serum aminotransferase levels when no other etiology is found. (Strong recommendation, high level of evidence) Patients with Type I diabetes mellitus (DM) should be tested for CD if there are any digestive symptoms, or signs, or laboratory evidence suggestive of CD. (Strong recommendation, high level of evidence) Immunoglobulin A (IgA) anti-tissue transglutaminase (TTG) antibody is the preferred single test for detection of CD in individuals over the age of 2 years. (Strong recommendation, high level of evidence) When there exists a high probability of CD wherein the possibility of IgA deficiency is considered, total IgA should be measured. An alternative approach is to include both IgA and IgG-based testing, such as IgG-deamidated gliadin peptides (DGPs), in these high-probability patients. (Strong recommendation, moderate level of evidence)

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9. 10. 11. 12. 13.

14. 15.

16. 17. 18. 19. 20. 21.

In patients in whom low IgA or selective IgA deficiency is identified, IgG-based testing (IgG DGPs and IgG TTG) should be performed. (Strong recommendation, moderate level of evidence) If the suspicion of CD is high, intestinal biopsy should be pursued even if serologies are negative. (Strong recommendation, moderate level of evidence) All diagnostic serologic testing should be done with patients on a glutencontaining diet. (Strong recommendation, high level of evidence) Antibodies directed against native gliadin are not recommended for the primary detection of CD. (Strong recommendation, high level of evidence) Combining several tests for CD in lieu of TTG IgA alone may marginally increase the sensitivity for CD but reduces specificity and therefore are not recommended in low-risk populations. (Conditional recommendation, moderate level of evidence) When screening children younger than 2 years of age for CD, the IgA TTG test should be combined with DGP (IgA and IgG). (Strong recommendation, moderate level of evidence) The confirmation of a diagnosis of CD should be based on a combination of findings from the medical history, physical examination, serology, and upper endoscopy with histological analysis of multiple biopsies of the duodenum. (Strong recommendation, high level of evidence) HLA-DQ2 / DQ8 testing should not be used routinely in the initial diagnosis of CD. (Strong recommendation, moderate level of evidence) While standard diagnostic tests (specific serology and intestinal biopsy) have a high PPV for CD, they should not be relied upon to exclude CD in patients already adhering to a GFD. (Strong recommendation, high level of evidence) HLA-DQ2 / DQ8 genotyping should be used to try to exclude CD prior to embarking on a formal gluten challenge. (Strong recommendation, high level of evidence) Monitoring of adherence to GFD should be based on a combination of history and serology (IgA TTG or IgA (or IgG) DGP antibodies). (Strong recommendation, moderate level of evidence) Monitoring of people with CD should include verification of normalization of laboratory abnormalities detected during initial laboratory investigation. (Strong recommendation, moderate level of evidence) Early steps in the evaluation should include measurement of celiac serologies and a thorough review of the patient’s diet by a dietitian who is experienced in CD management. (Strong recommendation, high level of evidence)

Shahnaz et al (2013) reported measuring serum tissue transglutaminase immunoglobulin A (tTG IgA) levels is the most widely used screening test for CD. However, given an increased prevalence of IgA deficiency among celiac patients there is a risk of false negative results. Hence, in addition to specific serum tTG IgA, screening tests frequently include total IgA levels. The authors sought to determine whether tTG IgA antibody levels might be used to predict IgA deficiency and hence avoid unnecessary testing of total IgA levels in all individuals. In a retrospective analysis of 9429 serum tTG IgA and corresponding total IgA levels obtained from children and young adults in the East of England between 2007 and 2011. The overall prevalence of IgA deficiency was found to be very low with only 0.9% of individuals affected. Using receiver operating characteristic curve analysis the authors identified a cut-off value for tTG IgA of ≥0.10 μ/mL to be predictive for the absence of total IgA deficiency (IgA