Intraepithelial lymphocytes, scores, mimickers and challenges in diagnosing gluten-sensitive enteropathy (celiac disease)

Table 1 Revised Updated Marsh-Oberhuber classification of gluten-sensitive enteropathy (5 states of submucosal injury 0-4)

Type 0

Pre-infiltrative: normal V:C ratio and crypts with < 20-25 IELs per 100 enterocytes (1:5 or 1:4)

Type 1

Infiltrative type: normal V:C ratio and crypts, but ↑ IELs (≥ 20-25 IELs/100 enterocytes)

Type 2

Infiltrative-hyperplastic type: normal V:C ratio, but crypt hyperplasia with ↑ IELs

Type 3

Destructive (flat mucosa) type of GSE lesion according to the degree of villous atrophy

Type 3a: mild villous atrophy with V: C < 3:1, and ↑ IELs

Type 3b: marked villous atrophy with V: C < 1:1, and ↑ IELs

Type 3c: total villous atrophy with completely flat mucosa and ↑ IELs

Type 4

Atrophic type (hypoplastic); flat mucosa with only a few crypts and near-normal IEL count

V:C: Villous to crypt ratio (normal, V:C > 3:1); GSE: Gluten-sensitive enteropathy; IEL: Intraepithelial lymphocytes. The upper limit of IEL may be considered 20 or 25 according to the country, institution, and physician’s preference, although mostly 25 seems to be the most accepted current threshold.

Table 2 Corazza-Villanacci classification

Grade A

Nonatrophic, with normal V:C ratio and ↑ IELs (> 25 IELs/100 enterocytes)

Grade B1

"Atrophic", V:C < 3:1, but villi still detectable and ↑ IELs (> 25 IELs/100 enterocytes)

Grade B2

Atrophic and flat, villi not detectable and ↑ IELs (> 25 IELs per 100 enterocytes)

V:C: Villous to crypt ratio (normal, V:C > 3:1); GSE: Gluten-sensitive enteropathy; IEL: Intraepithelial lymphocytes.

Table 3 Most common duodenal infections potentially mimicking gluten-sensitive enteropathy

	Agent	Villi	CH	LPI	IELs	PMNs	Sup.-D.	Target	Site	Stain
Giardiasis	G. lamblia	0-3A	Nil	0/+/++	< 20/↑	Rarely	Nil	None	IL	GS
Cryptosporidia	C. parvum	1-3A	+	+/++	< 20	Focal	Focally	Enterocytes	IE	WS
Microsporidia	E. bieneusi	1-3A	+	+/++	< 20	Nil	Focally	Enterocytes/macrophages	IEv/ IEc	WS
	E. intestinalis
Cyclospora	C. coyetanensis	1-3A	+	+/++	< 20/↑	Nil	Focally	Enterocytes	IEv	NA
Isospora	I. belli	1-3A	+	+/++	< 20	Nil	Focally	Enterocytes	IEv	NA
Whipple D	T. whipplei	1-3A	Nil	++1	↑	Nil	Nil	Macrophages	LP	PAS
										ZN
MAI	M. avium intracellulare	1-3A	Nil	++1	< 20	Nil	Nil	Macrophages	LP	PAS
										ZN
										AR
Leishmaniasis	L. donovani	1-3A	Nil	+/++	< 20	Nil	Nil	Macrophages	LP	NA
Cryptococcosis	C. neoformans	1-3A	Nil	0/+	< 20	Nil	Nil	None	LP	DPAS
										MS
CMV	Cytomegalovirus	Ulcers	2	+/++	< 20/↑	+/-	Focally	Epithelium/endothelium	LP	IHC

¹Pale macrophages;

²Crypt damage; IIIA partial atrophy, IIIB subtotal atrophy, IIIC total atrophy. 0-3A: 0, no inflammation, 1, IELs, 2 mild hyperplasia/mild inflammation. IL: Intraluminal; IE: Intraepithelial (surface and crypt epithelium); IEv: Intraepithelial at the villous tips; IEc: Intraepithelial at the crypts; LP: Lamina propria; CH: Crypt hyperplasia; AR: Auramine-rhodamine stain; DPAS: Diastase-periodic acid Schiff stain; GS: Giemsa stain; IHC: Immunohistochemistry with antibodies against the cytomegalovirus antigens; MS: Methenamine-silver stain; WS: Warthin-Starry stain; ZN: Ziehl-Nielsen stain.

Table 4 North American - European divergences across oceans in gluten-sensitive enteropathy

	Target	Screening	PS Tests1	HLA-DQ	EMA	AGA
ESPGHAN	Paediatric	Anti-tTG-IgA and IgA2	Anti-tTG-IgG/anti-DPG-IgG3	Yes, if	Yes, in confirming PS tests	No
				↑EMA/anti-tTG
ACG	Paediatric/adult	Anti-tTG-IgA	Anti-tTG-IgG/anti-DPG-IgG3	Yes, if biopsy/serology disagreement	NS	No
WGO	NS	Anti-tTG-IgA/anti-DPG IgG	NS	Yes, if biopsy/serology disagreement	Yes, in confirming PS tests	No

¹Postscreening tests;

²Total serum IgA;

³Anti-DPG: Anti-deamidated gliadin peptide. ESPGHA: European Society of Pediatric Gastroenterology, Hepatology and Nutrition; ACG: American College of Gastroenterology; WGO: World Gastroenterology Organization; NS: Not specified.