1. Introduction

The diagnosis of CD relies upon the concordance of clinical, histological, serological and genetic features making it often a medical challenge. In reality, facing the bed and not the bench, not all the above features exist to confirm the diagnosis. In the past, an elevated AB level was regarded as the main indication for a subsequent biopsy. With the advance of serological biomarkers and amelioration of their diagnostic reliability, they became essential to achieve cost-effective case-finding in CD ^{[1, 2]}. Accepted assay sensitivities are above 74 and 81 and specificities above 99 and 97, for anti endomysial (EmA) and anti tissue transglutaminase (tTg), antibodies, respectively ^[3]. Good assay performance and reliability, were the basis for omitting an intestinal biopsy, in certain circumstances in pediatric CD, as per the revised ESPGHAN diagnostic criteria ^[4]. However, the CD committee recommended IgA-tTg and IgA-EmA but failed to mention the other CD associated autoantibodies (anti IgA/IgG deamidated gliadin peptide, anti IgA/IgG neo-epitope tTg) in their diagnostic flow chart ^{[5, 6, 7]}. Very recently, neo-epitope tTg AB test were found to outperform tTg AB tests ^[8]. The newer serological markers of CD, including anti TG2, are more accurate than many other autoantibodies currently used in autoimmune diseases, however, they are gluten consumption dependent.

Due to the pivotal importance of anti tTg AB in screening and diagnosis of CD, the present review will concentrate on false + and false – detection of the serological “gold standard” anti IgA-tTg autoantibody. The aim being to increase the awareness of the professionals for the frequency and the significance of the titers that are above or below the normal ranges of IgA-tTg, in face of celiac versus non-celiac disease, respectively.

2. Normal Limits and Limitations of ELISA Anti TG2 ABs

Many clinically used serological ELISA kits of anti TG2 ABs are available, and they have a wide range of different cut-off levels. This is the main reason why one cannot define their precise normal limits. It is easier to decide on the relative lower normal limit, which is IgA-Tg2<1 ULN and intermediate relative levels between 1ULN and above ^[9]. However, the upper cut-off levels provided by the manufacturers for their IgA-TG2 ELISA determinations are so variable, making back-to-back comparisons, over time and across populations quite difficult. The situation is further complicated by the local, in house laboratory determinations of the upper limit cut-off, frequently different from the manufacturers’ ones. It goes without saying that these different cut-off levels impact the performance of the test, namely sensitivity, specificity and positive and negative predictive values. Literature surveys on the sensitivity and specificity of IgA-TG2 is marked by extensive heterogeneity in the kit’s performance, depending on both the commercial assay variant used and the cut-offs provided by the supplier. The significant range of test accuracies makes selection of their mean performances very arbitrary. In fact, several studies investigated specifically the variation in test results of different manufactures’ kits on the same individual sera and showed a wide range of variability ^{[10, 11, 12]}. Manipulating the cut-offs or using a combination test, combining a more specific test with a more sensitive one, affects dramatically the results. As an example, Barak et al, reported that the sensitivity of the neo-epitope TG2 is higher than that of IgA-TG2 at all levels while the specificity is somewhat lower. As expected, the sensitivities of the combined results of >10,>5, or >2 UNL of either neo-epitope or IgA-TG2 were improved in comparison to each test alone ^[12]. The manipulations of the cut-offs and the combination of the tests, might greatly affect the recent diagnostic flow chart of ESPGHAN ^[4] concerning the necessity for HLA determination and the need to perform a small bowel biopsy ^{[9, 12]}.

It is well known that PPV and NPV depend strongly on the prevalence (pre-test probability). The ESPGHAN X10ULN cut-off suggestion was derived from essentially 3 studies ^{[13, 14, 15]}, based on a very high prevalence of up to 100%. But, it is known that the pre-test probability in symptomatic patients, in clinical practice may be as low as 3-10% ^{[10, 16]}. The performance of the AB assays at higher cut-offs for CD diagnosis are still lacking. Despite numerous efforts by the CD societies, there is no sufficient standardization and adequate reference protocols and no reliable quality assessment of the ELISA AB kits for CD diagnosis and follow-up of dietary adherence ^{[17, 18, 19]}.

The following is the summary of limitations that are important to clinicians, laboratory staff, dieticians, researchers and others that are dealing with gluten sensitive conditions, concerning IgA-TG2 ABs ^[18]:

1. The diversity of available test kits, impeding comparisons between manufacturers and population studies.

2. The discrepancy between selective scientific validation, at the bench or bed environment and less “sterile”, field originating or diverse populations.

3. The ABs reflect the activity of reactive but not innate immunity, or the intestinal inflammatory state of the CD intestinal mucosa.

4. The performance of the ABs is age dependent. In children they are more accurate for CD diagnosis. IgA-TG2 AB are more often negative in CD patients older than 70y ^[20].

5. They are not reliable in monitoring disease activity in GFD CD treated patients ^{[18, 19]}.

6. No data exist on the impact of the serological activities on long-term prognosis, complications, extraintestinal manifestations or autoimmunity genesis or progression.

7. In view of the multi-functions of the endogenous enzyme and its specific AB, the field of loss/enhancement of TG2 functions induced by IgA-TG2 autoantibodies is far from being explored. It is clear that the balance between the two and the AB levels will impact both disease establishment and progression.

8.The debate whether to use only IgA-TG2 or to com bine a complementary diagnostic autoantibody, to improve diagnosis and follow-up performance, is as yet unresolved ^{[2, 5, 12, 21]}.

9. A discrepancy between manufacturer’s cut-off and receiver operating characteristic plot derived cut-off values, modifies decision thresholds of the kits assays. More so, Kappa analysis demonstrates variable degrees of agreement ^[22]. Sometime this variability can reach 75% ^[20].

10. In young children and even in older ones, seropositivity of IgA-TG2, may be a transient phenomenon, and not necessarily predictive of CD development.

11. Several authors have raised questions regarding the diagnostic performance of IgA-TG2 ABs in routine clinical practice ^{[23, 24]}. Several strategies have been suggested to improve performance or interpretation of the test, but these have not gained wide laboratory application ^{[16, 25, 26]}.

In summary, IgA-TG2 AB is a highly reliable, non-invasive celiac diagnostic test. However, its reflection of the intestinal damage and monitoring of disease activity, is disappointing. It has multiple limitations and the debate as to whether it should be combined with an additional serological marker or replaced with a better marker is still ongoing. It seems that the currently available serological biomarkers’ performances, like EMA or DGP, are not sufficient to replace IgA-TG2 AB ^{[27, 28]}, but recent data indicates that the neo-epitope TG2 AB is a prime candidate in this race ^[8]. Still, a combination test may prove better ^{[2, 5, 10, 11, 12]}.

3. False Positive Anti IgA-TG2 ABs

Seropositivity has two main aspects: Positive IgA-TG2 in face of a normal small bowel biopsy in a definitive CD patient, or false positive ABs, in face of a non-CD condition.

Small bowel pathology can be Marsh1 grade, generally none specific, or normal, in face of positive serology ^{[19, 29]}. The interpretation might be the patchy distribution of the disease, missed duodenal bulb pathology, more distal enteropathy, or latent CD. Sometimes, subepithelial IgA-TG2 complexes can be detected, if looked for, further substantiating the diagnosis.

Several situations can be encountered in positive serology in none CD conditions:

1. Autoimmune diseases. False + anti TG2 AB have been widely described in celiac associated and none associated autoimmune disease ^{[30, 31, 32]}. Connective tissue disease, IBD, Primary biliary cirrhosis, Goodpasture’s syndrome, Wegener’s granulomatosis, rheumatoid arthritis, SLE, progressive systemic sclerosis, type 1 diabetes, IgA pemphigus, are some of them.

2. Non-autoimmune diseases. Interestingly, 6.1% of patients having diverse diagnoses but increased serum IgM rheumatoid factor levels were found to be false-positive for anti TG2 ABs attesting to the fact that false positivity exists in none autoimmune serological conditions ^[33]. Additional examples are none autoimmune cirrhosis, linear IgA dermatosis, herpes gestationis, vasculitis, etc. Exploring the reasons for such false positivity, Sardy et al found that minor impurities in the recombinant human TG2 used and raised IgA antibody levels can explain the phenomenon ^[30].

3. When anti TG2 is positive, in the face of a negative EMA, the rate of CD is very low ^[34].

4. Transient positivity of anti TG2 ABs. Several groups reported on the natural longitudinal variation of serum levels of TG2 ABs in diabetic or genetic high risk CD young children or adolescents ^{[35, 36, 37]}.

5. Children with cerebral palsy tend to have false positive anti TG2 and anti gliadin ABs. False positivity was associated with lower weight, height and BMI in those children ^[38].

6. In clinical practice, even strongly positive anti IgA-TG results (even >X10 UNL) are not specific in individual patients, do not necessarily correlate with the degree of severity of biopsy change and, as a result, are also unlikely to be useful for monitoring diet compliance ^[39].

7. Even during an infectious febrile illness, anti TG2 Abs are transiently detected in serum. The authors suggest that those ABs may not be produced by the intestinal mucosa ^[40].

4. False Negative Anti IgA-TG2 ABs in CD

IgA-TG2 seronegativity, per definition, will occur when the AB titer is negative in face of a pathological small bowel biopsy in a definitive CD patient. False negativity of serological IgA-TG2 ABs have been described in the following conditions:

1. Complete IgA deficiency. Much more prevalent in CD. Appears in 0.14-0.2% of the general population and in 2.6% of CD patients. However, low but detectable total IgA do not appear to affect the test specificity ^[19]. When the possibility of IgA deficiency exists, IgG based tests can circumvent the problem, but they are not suitable for monitoring dietary compliance.

2. Normal to low positive titers have been described in refractory CD and small-intestinal bacterial overgrowth ^[41].

3. Age dependency: 50% of CD patients >70 years old were negative for IgA-TG2 compared to 15% of the younger CD patients ^[42].

4. Intestinal autoantibody deposits in face of negative systemic antiTG2 ABs. TG2-targeted autoantibodies were deposited in small-bowel mucosa even when EMA and IgA-TG2 ABs were absent in the serum of CD patients ^[43]. These deposits proved to be the best predictor of subsequent CD development ^[44].

5. Gluten free diet. Many gluten sensitive populations start GFD deliberately. Such custom may jeopardize the performance of the gluten- dependent CD-associated ABs. GFD may induce false negative IgA-TG2 test.

6. The prevalence of CD is lower in primary care (0.5-1.0%) than in endoscopy units (1.0-5.2%), affecting the performance of the diagnostic flow chart. The prevalence of CD with negative IgA-TG2 ABs was 0.4%, inan endoscopy set-up ^[45].

7. Seronegative CD is defined by the negativity of anti-TG2 ABs in the presence of pathological CD duodenal biopsies. A recent comparison of several studies reported the prevalence of anti-TG2 ABs in non-atrophic CD to be within the range of 0-88% ^[3]. Several potential explanations for this were suggested: 1. The mucosal deposits of the enzyme and its autoantibodies counteract the passage of the ABs into the bloodstream, 2. Incomplete maturation of the plasma cells or immunoglobulin deficiencies with a consequent failure of AB production ^[3].

8. Transient celiac serology or just temporary fluctuation? The levels can be high or low, depending upon the CD diagnosis/gluten intake, thus presenting as false positive/false negative, respectively ^{[37, 46]}. Collin et al, reported on 4 children and adults with negative CD serology and normal intestinal biopsies, developing classical serological and pathological CD 2-17 years later ^[46].

9.In the face of negative anti Tg2 results, the titers are independently related to age and the indication for the serological testing, be it because of suggestive CD symptoms or high risk history ^[47].

In summary, the present review highlight and increases the awareness of the professional communities that screen, diagnose and follow CD, for the multiple circumstances of false +/- IgA-TG2 serology. It is hoped that it will help in making clinical decisions, since each year of delay in CD detection is associated with a significant increase in medical care costs. Its correct diagnosis can lead to considerable decrease in morbidity, mortality, and saving of both economic and medical resources ^[48].

5. Conclusions

The medical CD professionals are using routinely IgA-TG2 serology and face often the dilemma of its interpretation. Understanding the circumstances and the significance of the false positive/false negative anti-TG2 ABs will improve the clinical judgment of the CD associated health workers in face of a suspected CD patient. The information contained in the present reviews, hopefully, will stimulate the scientific community to explore these issues, and stimulate the diagnostic serology manufacturers to improve their product performance.

References

[1]	Freeman HJ. Small intestinal mucosal biopsies for case-finding in celiac disease. International Journal of Celiac Disease. 2015; 3: 50-52.
	In article
[2]	Lerner A, Neidhöfer S, Matthias T. Serological markers and/or intestinal biopsies in the case-finding of celiac disease. International Journal of Celiac Disease. 2015; 3: 53-55.
	In article
[3]	Ierardi E, Losurdo G, Piscitelli D, Giorgio F, Sorrentino C, Principi M, et al.Seronegative celiac disease: where is the specific setting? Gastroenterol Hepatol Bed Bench. 2015; 8: 110-6.
	In article		PubMed
[4]	Husby S, Koletzko S, Korponay-Szabó IR et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr. 2012; 54: 136-60.
	In article		View Article  PubMed
[5]	Lerner A. Serological Diagnosis of Celiac Disease –Moving Beyond the Tip of the Iceberg. International Journal of Celiac Disease. 2014; 2: 64-66.
	In article
[6]	Remes-Troche JM, Rios-Vaca A., Ramírez-Iglesias MT, Rubio-Tapia A., Andrade-Zarate V., Rodríguez-Vallejo F., López-Maldonado F., Gomez-Perez FJ, Uscanga LF. High prevalence of celiac disease in Mexican Mestizo adults with type 1 diabetes mellitus. J Clin Gastroenterol. 2008; 42: 460-5.
	In article		View Article  PubMed
[7]	Porcelli B, Ferretti F, Vindigni C, Terzuoli L. Assessment of a Test for the Screening and Diagnosis of Celiac Disease. J Clin Lab Anal. 2014: Nov 10.
	In article		View Article
[8]	Matthias T, Jeremias P, Neidhöfer S, Lerner A. Comparison of the reliability of celiac disease serology to reflect intestinal damage. 49th ESPGHAN congress, Amsterdam 6-9th May, 2015.
	In article
[9]	Wolf J, Hasenclever D, Petroff D, Richter T, Uhlig HH, Laaβ MW, et al. Antibodies in the diagnosis of coeliac disease: a biopsy-controlled, international, multicentre study of 376 children with coeliac disease and 695 controls. PLoS One. 2014; 9: e97853.
	In article		View Article  PubMed
[10]	Rozenberg O., Lerner A., Pacht A., Grinberg M., Reginashvili D., Henig C., Barak M.A new algorithm for the diagnosis of celiac disease. Cell Mol Immunol. 2011; 8: 146-9.
	In article		View Article  PubMed
[11]	Rozenberg O, Lerner A, Pacht A, Grinberg M, Reginashvili D, Henig C, Barak M. A novel algorithm for the diagnosis of celiac disease and a comprehensive review of celiac disease diagnostics. Clin Rev Allergy Immunol. 2012; 42: 331-41.
	In article		View Article  PubMed
[12]	Barak M, Rozenberg O, Froom P, Grinberg M, Reginashvili D, Henig C, et al.Challenging our serological algorithm for celiac disease (CD) diagnosis by the ESPGHAN guidelines. Clin Chem Lab Med. 2013; 51: e257-9.
	In article		View Article  PubMed
[13]	Hill PG, Holmes GK. Coeliac disease: a biopsy is not always necessary for diagnosis. Aliment Pharmacol Ther. 2008; 27: 572-7.
	In article		View Article  PubMed
[14]	Dahlbom I, Korponay-Szabó IR, Kovács JB, Szalai Z, Mäki M, Hansson T. Prediction of clinical and mucosal severity of coeliac disease and dermatitis herpetiformis by quantification of IgA/IgG serum antibodies to tissue transglutaminase. J Pediatr Gastroenterol Nutr. 2010; 50: 140-6.
	In article		View Article  PubMed
[15]	Vivas S, Ruiz de Morales JG, Riestra S, Arias L, Fuentes D, Alvarez N, et al.Duodenal biopsy may be avoided when high transglutaminase antibody titers are present. World J Gastroenterol. 2009; 15: 4775-80.
	In article		View Article  PubMed
[16]	Vermeersch P, Geboes K, Mariën G, Hoffman I, Hiele M, Bossuyt X. Defining thresholds of antibody levels improves diagnosis of celiac disease. Clin Gastroenterol Hepatol. 2013; 11: 398-403.
	In article		View Article  PubMed
[17]	Stern M, Working Group on Serologic Screening for Celiac Disease. Comparative evaluation of serologic tests for celiac disease: a European initiative toward standardization. J Pediatr Gastroenterol Nutr. 2000; 31: 513-9.
	In article		View Article  PubMed
[18]	Adriaanse M, Leffler DA. Serum markers in the clinical management of celiac disease. Dig Dis. 2015; 33: 236-43.
	In article		View Article  PubMed
[19]	Leffler DA, Schuppan D. Update on serologic testing in celiac disease. Am J Gastroenterol. 2010; 105: 2520-4.
	In article		View Article  PubMed
[20]	Dahle C, Hagman A, Ignatova S, Ström M. Antibodies against deamidated gliadin peptides identify adult coeliac disease patients negative for antibodies against endomysium and tissue transglutaminase. Aliment Pharmacol Ther. 2010; 32: 254-60.
	In article		View Article  PubMed
[21]	Samaşca G, Iancu M, Farcău D, Butnariu A, Pop T, Pîrvan A, et al. IgA anti-tissue transglutaminase antibodies, first line in the diagnosis of celiac disease. Clin Lab. 2011; 57: 695-701.
	In article		PubMed
[22]	Naiyer AJ, Hernandez L, Ciaccio EJ, Papadakis K, Manavalan JS, Bhagat G, Green PH. Comparison of commercially available serologic kits for the detection of celiac disease. J Clin Gastroenterol. 2009; 43: 225-32.
	In article		View Article  PubMed
[23]	Green PH, Cellier C. Celiac disease. N Engl J Med. 2007; 357: 1731-43.
	In article		View Article  PubMed
[24]	Abrams JA, Brar P, Diamond B, Rotterdam H, Green PH. Utility in clinical practice of immunoglobulin a anti-tissue transglutaminase antibody for the diagnosis of celiac disease. Clin Gastroenterol Hepatol. 2006; 4: 726-30.
	In article		View Article  PubMed
[25]	Vermeersch P, Geboes K, Mariën G, Hoffman I, Hiele M, Bossuyt X.Serological diagnosis of celiac disease: comparative analysis of different strategies. Clin Chim Acta. 2012; 413: 1761-7.
	In article		View Article  PubMed
[26]	Pallav K, Leffler DA, Bennett M, Tariq S, Xu H, Kabbani T, et al. Open conformation tissue transglutaminase testing for celiac dietary assessment. Dig Liver Dis. 2012; 44: 375-8.
	In article		View Article  PubMed
[27]	Lewis NR, Scott BB. Meta-analysis: deamidated gliadin peptide antibody and tissue transglutaminase antibody compared as screening tests for coeliac disease. Aliment Pharmacol Ther. 2010; 31: 73-81.
	In article		View Article  PubMed
[28]	Lewis NR, Scott BB. Systematic review: the use of serology to exclude or diagnose coeliac disease (a comparison of the endomysial and tissue transglutaminase antibody tests). Aliment Pharmacol Ther. 2006; 24: 47-54.
	In article		View Article  PubMed
[29]	Weir DC, Glickman JN, Roiff T, Valim C, Leichtner AM. Variability of histopathological changes in childhood celiac disease. Am J Gastroenterol. 2010; 105: 207-12.
	In article		View Article  PubMed
[30]	Sárdy M, Csikós M, Geisen C, Preisz K, Kornseé Z, Tomsits E, et al. Tissue transglutaminase ELISA positivity in autoimmune disease independent of gluten-sensitive disease. Clin Chim Acta. 2007
	In article		View Article  PubMed
[31]	Villalta D, Crovatto M, Stella S, Tonutti E, Tozzoli R, Bizzaro N. False positive reactions for IgA and IgG anti-tissue transglutaminase antibodies in liver cirrhosis are common and method-dependent. Clin Chim Acta. 2005; 356: 102-9.
	In article		View Article  PubMed
[32]	Bizzaro N, Villalta D, Tonutti E, Doria A, Tampoia M, Bassetti D, Tozzoli R.IgA and IgG tissue transglutaminase antibody prevalence and clinical significance in connective tissue diseases, inflammatory bowel disease, and primary biliary cirrhosis. Dig Dis Sci. 2003; 48: 2360-5.
	In article		View Article  PubMed
[33]	Song KS, Choi JR. Tissue transglutaminase autoantibodies in patients with IgM rheumatoid factors. Yonsei Med J. 2004; 45: 960-2.
	In article		View Article
[34]	Weiss B, Bujanover Y, Avidan B, Fradkin A, Weintraub I, Shainberg B.Positive tissue transglutaminase antibodies with negative endomysial antibodies: low rate of celiac disease. Isr Med Assoc J. 2004; 6: 9-12.
	In article		PubMed
[35]	Hojsak I, Zevit N, Waisbourd-Zinman O, Rosenbach Y, Mozer-Glassberg Y, Shalitin S, et al. Concomitant autoantibodies in newly diagnosed diabetic children with transient celiac serology or proven celiac disease. J Pediatr Endocrinol Metab. 2013; 26: 1099-104.
	In article		View Article  PubMed
[36]	Simell S, Hoppu S, Hekkala A, Simell T, Ståhlberg MR, Viander M, et al.Fate of five celiac disease-associated antibodies during normal diet in genetically at-risk children observed from birth in a natural history study. Am J Gastroenterol. 2007; 102: 2026-35.
	In article		View Article  PubMed
[37]	Mahadev S, Bhagat G, Green PH. Transient celiac autoimmunity in an adult. J Clin Gastroenterol. 2011; 45: 912-3.
	In article		View Article  PubMed
[38]	Stenberg R, Dahle C, Lindberg E, Schollin J. Increased prevalence of anti-gliadin antibodies and anti-tissue transglutaminase antibodies in children with cerebral palsy. J Pediatr Gastroenterol Nutr. 2009; 49: 424-9.
	In article		View Article  PubMed
[39]	Freeman HJ. Strongly positive tissue transglutaminase antibody assays without celiac disease. Can J Gastroenterol. 2004; 18: 25-8.
	In article		PubMed
[40]	De Leo L, Quaglia S, Ziberna F, Vatta S, Martelossi S, Maschio M, Not T. Serum anti-tissue transglutaminase antibodies detected during febrile illness may not be produced by the intestinal mucosa. J Pediatr. 2015; 166: 761-3.
	In article		View Article  PubMed
[41]	Leffler DA, Dennis M, Hyett B, Kelly E, Schuppan D, Kelly CP. Etiologies and predictors of diagnosis in nonresponsive celiac disease. Clin Gastroenterol Hepatol. 2007; 5: 445-50.
	In article		View Article  PubMed
[42]	Dahle C, Hagman A, Ignatova S, Ström M. Antibodies against deamidated gliadin peptides identify adult coeliac disease patients negative for antibodies against endomysium and tissue transglutaminase. Aliment Pharmacol Ther. 2010; 32: 254-60.
	In article		View Article  PubMed
[43]	Salmi TT, Collin P, Korponay-Szabó IR, Laurila K, Partanen J, Huhtala H, et al. Endomysial antibody-negative coeliac disease: clinical characteristics and intestinal autoantibody deposits. Gut. 2006; 55: 1746-53.
	In article		View Article  PubMed
[44]	Salmi TT, Collin P, Järvinen O, Haimila K, Partanen J, Laurila K,et al.Immunoglobulin A autoantibodies against transglutaminase 2 in the small intestinal mucosa predict forthcoming coeliac disease. Aliment Pharmacol Ther. 2006; 24: 541-52.
	In article		View Article  PubMed
[45]	Hopper AD, Cross SS, Hurlstone DP, McAlindon ME, Lobo AJ, Hadjivassiliou M, et al. Pre-endoscopy serological testing for coeliac disease: evaluation of a clinical decision tool.BMJ. 2007; 334: 729.
	In article		View Article  PubMed
[46]	Collin P, Kurppa K, Lindfors K, Mäki M, Kaukinen K. Transient celiac autoimmunity or just temporary fluctuation? J Clin Gastroenterol. 2012; 46: 432-3.
	In article		View Article  PubMed
[47]	Vécsei A, Arenz T, Heilig G, Arenz S, Bufler P, Koletzko S. Influence of ageand genetic risk on anti-tissue transglutaminase IgA titers. J PediatrGastroenterol Nutr. 2009; 48: 544-9.
	In article		View Article  PubMed
[48]	Picarelli A, Di Tola M, Borghini R, Isonne C, Donato G, De Vitis I, Frieri G. The High Medical Cost of Celiac Disease Missed Diagnosis: Is it Cheaperto Suspect it in Time? Inter. Med 2014; 4: 3.
	In article