Ages of celiac disease: From changing environment to improved diagnostics

Table 1 The ages of celiac disease

Age	Date	Clinics	Diagnosis	Pathogenesis
The origins	-1888	At the borders of the fertile crescent
The age of steatorrhea Fat in stools and diet as a treatment	1888-1952	Intestinal syndrome	Fatty stools	Chronic indigestion
				Diet attempts
The age of gluten. An intolerance to a protein	1952-1965	Gut disease Celiac crisis	Crosby-kugler capsule assisted diagnosis Acid fat measure in feces allows diet follow-up A very rare disease	Wheat, barley and rye gluten is guilty Flat mucosa is responsible for a malabsorption syndrome The “three biopsies” approach suggested that gluten susceptibility in celiacs is a permanent condition
The age of AGA. CD as an immune disorder	1965-	AGA assay allowed characterization of the atypical form or even the diagnosis of asymptomatic subjects founded the celiac society	AGA Three biopsies	CD is an immune disorder, like a chronic infection by gluten Association to specific HLA variants
The Age of AEA. CD is associated with autoimmunity.	1973-	Definition of silent and latent CD The risk of autoimmunity in CD is, at least in part, related to the duration of exposure to gluten	AEA Three biopsies CD screening by means of AGA and AEA testing A disease more frequent than expected	Gluten is just the trigger, endomysium the target AEA and other autoantibodies in CD are gluten-dependen HLA DQ2 restricted anti-gluten T cells in biopsies The “celiac iceberg” model
The Age of transglutaminase: from target to diagnostic tool.	1997-	Widening spectrum of CD associated disorders	tTG antibodies One biopsy Screening on a few blood drops Anti-deaminated gluten peptides (DGP) antibodies ESPGHAN guidelines for diagnosis without biopsy	Tissue transglutaminase (tTG) is the autoantigen in endomysium tTG increase the affinity of gluten peptides for HLA DQ2 Interaction between tTG and gluten peptides could be responsible for autoimmune reactions and “antigen spreading”
The future. Will new tools identify new diseases?	2011-	A new definition for gluten intolerance with normal serum tTG antibodies	Mucosal tTG in potential CD	Mucosal assay for local tTG antibodies Phage display libraries to unravel CD pathology

CD: Celiac disease; AGA: Age of gliadin antibodies; AEA: Age of anti-endomysium anti-bodies; ESPGHAN: European Society for Paediatric Gastroenterology, Hepatology and Nutrition; HLA: Human leukocyte antigen.

Table 2 Old and new celiac disease before and after the identification of age of anti-endomysium anti-bodies

	Old CD, Pre-AEA age	New CD, Post-AEA age
Pathogenesis	Immune, intestinal	Autoimmune, systemic
Diagnosis	AGA + 3 biopsies	AEA + 1 biopsy
Prevalence	Rare 1:500-1:5000	Frequent 1:100 worldwide
Clinical picture	Malabsorption syndrome	Autoimmune disorders Malabsorption syndrome
Intestinal pathology	Severe villous atrophy and criptae hypertrophy	Severe villous atrophy and criptae hypertrophy or increased mucosal lymphocytes (latent celiac disease)

CD: Celiac disease; AGA: Age of gliadin antibodies; AEA: Age of anti-endomysium anti-bodies.