Celiac disease laboratory tests
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: : Iqra Qamar M.D.[2]
Overview
Laboratory findings consistent with the diagnosis of celiac disease include electrolyte abnormalities such as hypokalemia, hypocalcemia, hypomagnesemia, metabolic acidosis, hypoalbuminemia, hypoproteinemia, hypocholesterolemia and low serum carotene level. Hematologic findings include low folate and vitamin B-12 levels, low serum iron level and prothrombin time (PT) prolongation. Stool examination may show fat droplets on Sudan stain and a 72-hour fecal fat collection may be used for documentation of steatorrhea. Genetic testing is usually positive for HLA-DQ2 and HLA-DQ8. Serologic markers include IgA endomysial antibody (IgA EMA), IgA tissue transglutaminase antibody (IgA tTG), IgG tissue transglutaminase antibody (IgG tTG), IgA deamidated gliadin peptide (IgA DGP), and IgG deamidated gliadin peptide (IgG DGP). Serum IgA EMA and IgA tTG have the highest diagnostic accuracy. The IgA and IgG antigliadin antibodies (AGA) are not recommended for establishing diagnosis because of high rate of false positive results comparing to IgA tTG and IgA DGP assays.
Laboratory Findings
Laboratory findings consistent with the diagnosis of Celiac disease include:[1]
Electrolyte abnormalities:
- Hypokalemia
- Hypocalcemia
- Hypomagnesemia
- Metabolic acidosis
- Hypoalbuminemia
- Hypoproteinemia
- Hypocholesterolemia
- Low serum carotene level
Hematologic findings:
- Low folate and vitamin B-12 levels
- Low serum iron level
- Prothrombin time (PT) prolongation
Stool examination:
- Fat droplets may be seen on Sudan stain.
- A 72-hour fecal fat collection may be used for documentation of steatorrhea.
Oral tolerance tests:
- Breath hydrogen excretion- increased in celiac disease
- Oral D-xylose tolerance test-
- Decreased urinary D-xylose excretion
- Decreased peak blood xylose levels
- Lactose tolerance test
Genetic testing:
Serologic Markers
Serological testing may be divided into 3 groups based upon antibodies against respective antigens:
- IgA endomysial antibody (IgA EMA)
- Anti-TTG antibody tests
- IgA tissue transglutaminase antibody (IgA tTG)
- IgG tissue transglutaminase antibody (IgG tTG)
- Anti-gliadin antibody tests
- IgA deamidated gliadin peptide (IgA DGP)
- IgG deamidated gliadin peptide (IgG DGP)
IgA endomysial assay:
- Endomysial antibodies bind to the endomysium and can be seen via indirect immunofluorescence producing a staining pattern. The target antigen is a tissue transglutaminase.
- IgA EMA have high specificity and even low titers indicate a positive test result.
- It has moderate sensitivity but high specificity for untreated celiac disease and is negative in treated patients.[2][3][4][5][6][7][8][9][10][11][12][13]
Anti-tissue transglutaminase antibodies:
- These antibodies are directed against the tissue transglutaminase-2 (tTG) antigen.[14]
- They can be easily detected by ELISA[15]
- Anti-tTG antibodies have high diagnostic accuracy.[16][17][18][19][20]
Antigliadin antibody assays
- Antigliadin antibody (AGA) tests have low positive predictive value and are not recommended generally.[21]
- The anti-deamidated gliadin peptide [DGP] assays have higher specificity and are thus preferred over antigliadin antibody (AGA) tests.[22][23]
NOTE:
- Serum IgA EMA and IgA tTG have the highest diagnostic accuracy.
- The IgA and IgG antigliadin antibody (AGA) are not recommended for estabilishing diagnosis as they have low accuracy and give more false positive results when compared with IgA tTG and IgA DGP assays.
- The anti-deamidated gliadin peptide (DGP) assays also have high diagnostic accuracy.
Sensitivity and Specificity of Antibody testing:
Literature review has shown that IgA endomysial and IgA tissue transglutaminase antibodies have a sensitivity more than 95% and a specificity almost 100%. However variations in results are seen among different laboratories.[2][24][25][22][23][26][27]
| Test | sensitivity | specificity |
|---|---|---|
| IgA enomysial antibody | 85 to 98% | 97 to 100% |
| IgA tissue transglutaminase antibody | 90 to 98% | 95 to 97% |
| IgA deamidated gliadin peptide | 94% | 99% |
| IgG deamidated gliadin peptide | 92% | 100% |
| Test | sensitivity | specificity |
|---|---|---|
| HLA-DQ2 | 94% | 73% |
| HLA-DQ8 | 12% | 81% |
Algorithm for diagnostic testing of Celiac disease
Abbreviations:DGP: deamidated gliadin peptide; HLA: human leukocyte antigen; Ig: immunoglobulin; TTGA: tissue transglutaminase antibody.
Diagnostic testing in low probability celiac disease patients
| Low Probability (<5%) | |||||||||||||||||||||||||||||||||||||||
| TTGA IgA ± IgA level | |||||||||||||||||||||||||||||||||||||||
| Positive TTGA | Negative TTGA ↓ IgA | Negative TTGA Normal IgA | |||||||||||||||||||||||||||||||||||||
| TTGA IgG ± DGP IgG | |||||||||||||||||||||||||||||||||||||||
| If any positive | All negative | ||||||||||||||||||||||||||||||||||||||
| Biopsy | Celiac disease unlikely | ||||||||||||||||||||||||||||||||||||||
Diagnostic testing in high probability celiac disease patients
| High probability (>5%) | |||||||||||||||||||||||||||||||
| • Duodenal biopsy • TTGA IgG | |||||||||||||||||||||||||||||||
| Both negative | Both positive | Serology/biopsy disagreement | |||||||||||||||||||||||||||||
| Celiac disease unlikely | Celiac disease | Needs • HLA DQ2 and DQ8 genotyping •IgA level ± TTGA/DGP IgG •work up for other causes of villous atrophy | |||||||||||||||||||||||||||||
References
- ↑ Anderson RP, Henry MJ, Taylor R, Duncan EL, Danoy P, Costa MJ, Addison K, Tye-Din JA, Kotowicz MA, Knight RE, Pollock W, Nicholson GC, Toh BH, Brown MA, Pasco JA (2013). "A novel serogenetic approach determines the community prevalence of celiac disease and informs improved diagnostic pathways". BMC Med. 11: 188. doi:10.1186/1741-7015-11-188. PMID 23981538.
- ↑ 2.0 2.1 Mäki M (1995). "The humoral immune system in coeliac disease". Baillieres Clin. Gastroenterol. 9 (2): 231–49. PMID 7549026.
- ↑ Bürgin-Wolff A, Gaze H, Hadziselimovic F, Huber H, Lentze MJ, Nusslé D, Reymond-Berthet C (1991). "Antigliadin and antiendomysium antibody determination for coeliac disease". Arch. Dis. Child. 66 (8): 941–7. PMC 1793455. PMID 1819255.
- ↑ Chorzelski TP, Beutner EH, Sulej J, Tchorzewska H, Jablonska S, Kumar V, Kapuscinska A (1984). "IgA anti-endomysium antibody. A new immunological marker of dermatitis herpetiformis and coeliac disease". Br. J. Dermatol. 111 (4): 395–402. PMID 6435666.
- ↑ Ferreira M, Davies SL, Butler M, Scott D, Clark M, Kumar P (1992). "Endomysial antibody: is it the best screening test for coeliac disease?". Gut. 33 (12): 1633–7. PMC 1379574. PMID 1487164.
- ↑ Grodzinsky E, Hed J, Skogh T (1994). "IgA antiendomysium antibodies have a high positive predictive value for celiac disease in asymptomatic patients". Allergy. 49 (8): 593–7. PMID 7653735.
- ↑ Kapuscinska A, Zalewski T, Chorzelski TP, Sulej J, Beutner EH, Kumar V, Rossi T (1987). "Disease specificity and dynamics of changes in IgA class anti-endomysial antibodies in celiac disease". J. Pediatr. Gastroenterol. Nutr. 6 (4): 529–34. PMID 3323442.
- ↑ Kumar V, Lerner A, Valeski JE, Beutner EH, Chorzelski TP, Rossi T (1989). "Endomysial antibodies in the diagnosis of celiac disease and the effect of gluten on antibody titers". Immunol. Invest. 18 (1–4): 533–44. PMID 2499536.
- ↑ Unsworth DJ, Brown DL (1994). "Serological screening suggests that adult coeliac disease is underdiagnosed in the UK and increases the incidence by up to 12%". Gut. 35 (1): 61–4. PMC 1374633. PMID 8307451.
- ↑ Ladinser B, Rossipal E, Pittschieler K (1994). "Endomysium antibodies in coeliac disease: an improved method". Gut. 35 (6): 776–8. PMC 1374877. PMID 8020804.
- ↑ Volta U, Molinaro N, de Franceschi L, Fratangelo D, Bianchi FB (1995). "IgA anti-endomysial antibodies on human umbilical cord tissue for celiac disease screening. Save both money and monkeys". Dig. Dis. Sci. 40 (9): 1902–5. PMID 7555440.
- ↑ Kárpáti S, Meurer M, Stolz W, Bürgin-Wolff A, Braun-Falco O, Krieg T (1992). "Ultrastructural binding sites of endomysium antibodies from sera of patients with dermatitis herpetiformis and coeliac disease". Gut. 33 (2): 191–3. PMC 1373928. PMID 1541414.
- ↑ Valeski JE, Kumar V, Beutner EH, Lerner A, Chorzelski TP (1990). "Immunology of celiac disease: tissue and species specificity of endomysial and reticulin antibodies". Int. Arch. Allergy Appl. Immunol. 93 (1): 1–7. PMID 2128295.
- ↑ Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken EO, Schuppan D (1997). "Identification of tissue transglutaminase as the autoantigen of celiac disease". Nat. Med. 3 (7): 797–801. PMID 9212111.
- ↑ Tonutti E, Visentini D, Bizzaro N, Caradonna M, Cerni L, Villalta D, Tozzoli R (2003). "The role of antitissue transglutaminase assay for the diagnosis and monitoring of coeliac disease: a French-Italian multicentre study". J. Clin. Pathol. 56 (5): 389–93. PMC 1769943. PMID 12719462.
- ↑ Dieterich W, Laag E, Schöpper H, Volta U, Ferguson A, Gillett H, Riecken EO, Schuppan D (1998). "Autoantibodies to tissue transglutaminase as predictors of celiac disease". Gastroenterology. 115 (6): 1317–21. PMID 9834256.
- ↑ Sulkanen S, Halttunen T, Laurila K, Kolho KL, Korponay-Szabó IR, Sarnesto A, Savilahti E, Collin P, Mäki M (1998). "Tissue transglutaminase autoantibody enzyme-linked immunosorbent assay in detecting celiac disease". Gastroenterology. 115 (6): 1322–8. PMID 9834257.
- ↑ Troncone R, Maurano F, Rossi M, Micillo M, Greco L, Auricchio R, Salerno G, Salvatore F, Sacchetti L (1999). "IgA antibodies to tissue transglutaminase: An effective diagnostic test for celiac disease". J. Pediatr. 134 (2): 166–71. PMID 9931524.
- ↑ Hopper AD, Cross SS, Hurlstone DP, McAlindon ME, Lobo AJ, Hadjivassiliou M, Sloan ME, Dixon S, Sanders DS (2007). "Pre-endoscopy serological testing for coeliac disease: evaluation of a clinical decision tool". BMJ. 334 (7596): 729. doi:10.1136/bmj.39133.668681.BE. PMC 1847864. PMID 17383983.
- ↑ Hopper AD, Hadjivassiliou M, Hurlstone DP, Lobo AJ, McAlindon ME, Egner W, Wild G, Sanders DS (2008). "What is the role of serologic testing in celiac disease? A prospective, biopsy-confirmed study with economic analysis". Clin. Gastroenterol. Hepatol. 6 (3): 314–20. doi:10.1016/j.cgh.2007.12.008. PMID 18328437.
- ↑ Corrao G, Corazza GR, Andreani ML, Torchio P, Valentini RA, Galatola G, Quaglino D, Gasbarrini G, di Orio F (1994). "Serological screening of coeliac disease: choosing the optimal procedure according to various prevalence values". Gut. 35 (6): 771–5. PMC 1374876. PMID 8020803.
- ↑ 22.0 22.1 Sugai E, Vázquez H, Nachman F, Moreno ML, Mazure R, Smecuol E, Niveloni S, Cabanne A, Kogan Z, Gómez JC, Mauriño E, Bai JC (2006). "Accuracy of testing for antibodies to synthetic gliadin-related peptides in celiac disease". Clin. Gastroenterol. Hepatol. 4 (9): 1112–7. doi:10.1016/j.cgh.2006.05.004. PMID 16860613.
- ↑ 23.0 23.1 Prince HE (2006). "Evaluation of the INOVA diagnostics enzyme-linked immunosorbent assay kits for measuring serum immunoglobulin G (IgG) and IgA to deamidated gliadin peptides". Clin. Vaccine Immunol. 13 (1): 150–1. doi:10.1128/CVI.13.1.150-151.2006. PMC 1356631. PMID 16426013.
- ↑ Abrams JA, Brar P, Diamond B, Rotterdam H, Green PH (2006). "Utility in clinical practice of immunoglobulin a anti-tissue transglutaminase antibody for the diagnosis of celiac disease". Clin. Gastroenterol. Hepatol. 4 (6): 726–30. doi:10.1016/j.cgh.2006.02.010. PMID 16630760.
- ↑ Swallow K, Wild G, Sargur R, Sanders DS, Aziz I, Hopper AD, Egner W (2013). "Quality not quantity for transglutaminase antibody 2: the performance of an endomysial and tissue transglutaminase test in screening coeliac disease remains stable over time". Clin. Exp. Immunol. 171 (1): 100–6. doi:10.1111/cei.12000. PMC 3530101. PMID 23199329.
- ↑ Kelly CP, Feighery CF, Gallagher RB, Gibney MJ, Weir DG (1991). "Mucosal and systemic IgA anti-gliadin antibody in celiac disease. Contrasting patterns of response in serum, saliva, and intestinal secretions". Dig. Dis. Sci. 36 (6): 743–51. PMID 2032515.
- ↑ Rostami K, Kerckhaert J, Tiemessen R, von Blomberg BM, Meijer JW, Mulder CJ (1999). "Sensitivity of antiendomysium and antigliadin antibodies in untreated celiac disease: disappointing in clinical practice". Am. J. Gastroenterol. 94 (4): 888–94. doi:10.1111/j.1572-0241.1999.983_f.x. PMID 10201452.