Coeliac disease or gluten sensitive enteropathy is an immune mediated inflammatory disease of small intestine. The condition arises within genetically predisposed individuals and may be engendered due to sensitivity to prolamins as wheat (gliadin), barley (hordein), rye (secalin) and oats (avenin). Activated innate and adaptive immune response to prolamins characteristically induces inflammatory infiltration of lamina propria and mucosal epithelium by chronic inflammatory cells as lymphocytes in concurrence with villous atrophy, features which engender intestinal malabsorption.
Intraepithelial lymphocytosis within small bowel appearing secondary to gluten ingestion is associated with partial or total atrophy of intestinal villi and hyperplasia of intestinal crypts along with chronic inflammatory exudate confined to lamina propria [1,2]. Additionally designated as coeliac sprue, sprue, non-tropical sprue, gluten sensitive enteropathy or gluten induced enteropathy, coeliac disease is preponderantly encountered within small intestine. Histological confirmation within small intestinal surgical tissue samples along with cogent serology are a pre-requisite for appropriate disease discernment [1,2].
A female predominance is observed with male to female proportion of 1:1.85. Coeliac disease enunciates a bimodal disease distribution at ~12months and third decade to fourth decade. Mean age of disease discernment is 8.4 years [1,2]. Coeliac disease may concur with autoimmune diseases as dermatitis herpetiformis, type 1 diabetes mellitus, Hashimoto’s thyroiditis, Graves’ disease, idiopathic disorders as dilated cardiomyopathy, epilepsy, multiple sclerosis and chromosomal diseases as Down’s syndrome, Turner’s syndrome, or William syndrome [1,2].
HLA class II genes as HLA DQ2 and HLA DQ8 situated upon chromosome 6 may induce genetic susceptibility to coeliac disease. Implication of first-degree relatives is indicative of significant hereditary component. HLA molecules represented upon antigen presenting cells introduce laminins to CD4+ T lymphocytes with consequent activation. Gluten rich diet configures as an environmental trigger. Fragments of gluten peptides resistant to degradation are transported across intestinal epithelium through transcellular pathways [1,2].
Altered intestinal permeability may concur with release of cellular contents or enzyme tissue transglutaminase (tTG). CD71 (transferrin) receptor appears upregulated within active coeliac disease [1,2]. Secretion of interferon gamma (IFNγ) and interleukin 21 induces epithelial damage following activation of T lymphocytes by antigen presenting cells [1,2]. Innate immune response is initiated by intraepithelial lymphocytes (IELs), which expound NK receptor MHC class I related chains A and B along with HLE confined to epithelial cells with propagation of epithelial destruction [1,2]. IL15 upregulates NK receptors situated within cytotoxic intraepithelial lymphocytes and induces T cell receptor independent cellular demise. Refractory sprue is denominated by a process wherein disease persists despite circumvention of dietary laminin and intraepithelial lymphocytes (IELs) acquire a predominantly activated NK phenotype [1,2].
Refractory disease is categorized as
• Refractory coeliac disease type I demonstrating intraepithelial lymphocytes which express CD3, CD8 and TCRβ, akin to preliminary or active coeliac disease. Type I exhibits a superior prognosis upon initiation of immunosuppressive therapy [1,2].
• Refractory coeliac disease type II is devoid of CD8, CD4 and TCRαβ and enunciates an adverse prognosis. Intracellular CD3ε and clonal TCR genetic rearrangement may be delineated [1,2]. Coeliac disease may be engendered due to genetic factors as HLA DQ2 and HLA DQ8, ingestion of gluten rich diet or variable innate and adaptive immune responses [1,2]. Besides, decimated diversity of gastrointestinal tract microbiota and elevated Firmicutes/Bacteroidetes species appear to be implicated. Paediatric coeliac disease characteristically exhibits diarrhoea, anorexia, abdominal distension, or failure to thrive [1,2]. Incriminated older children enunciate diarrhoea, bloating, constipation, abdominal pain, or
weight loss [1,2]. Incriminated adults exemplify malabsorption
syndrome associated with chronic diarrhoea, weight loss and
Extra-intestinal coeliac disease manifests with:
i. Iron deficiency anaemia with microcytic blood picture
ii. Macrocytic anaemia due to deficient vitamin B12
iii. Osteopenia or osteoporosis due to altered absorption of
calcium and vitamin D3
iv. Growth retardation or defective tooth enamel, aphthous
stomatitis and elevated serum transaminases ~dermatitis
v. Nonspecific symptoms as headache, paraesthesia,
neuro-inflammation, anxiety, or depression symptoms concurrent
with reproductive function as delayed menarche, amenorrhea,
recurrent miscarriage, premature birth, early menopause
in females and altered quantification and mobility of male
Refractory coeliac disease (RCD) is delineated by persistent
malabsorption and villous atrophy despite strict adherence
to gluten free diet for minimally 6 months to 12 months in the
absence of associated active coeliac disease or overtly malignant
disorders [1,2]. Type I and type II variant of refractory coeliac
disease enunciates severe complications as ulcerative jejunitis or
enteropathy associated T cell lymphoma [1,2].
Upon gross examination, villous flattening or blunting of small
gastrointestinal tract is observed. Severe disease is associated
with ulceration [1,2]. Appropriate microscopic evaluation may be
achieved with one or two wisps of tissue obtained from duodenal
bulb and minimally four specimens from post-bulbar duodenum
[1,2]. Upon microscopy, elementary mucosal lesions can be
discerned. Coeliac disease exemplifying increased intraepithelial
T lymphocytes (IELs) is denominated as: • borderline lesions
with 25 - 29 IELs/100 enterocytes • pathological lymphocytosis
with > 30 IELs/100 enterocytes [1,2]. Features such as decreased
enterocyte height, flattening of enterocytes, intracytoplasmic
vacuoles and reduction or absence of brush border may indicate
coeliac disease [1,2]. Crypt hyperplasia is comprised of extension
of regenerative epithelial hyperplasia within crypts associated
with mucosal alterations and > one mitosis per crypt [1,2].
Villous atrophy enunciates decimated villous height or normal
villous: crypt ratio at 3:1 followed by complete disappearance
of villi. Assessment of villous hypertrophy requires appropriate
orientation of surgical tissue samples [1,2] (Figures 1 & 2) (Table
IEL/100 enterocytes: intraepithelial lymphocytes per 100
Coeliac disease is categorized as:
• Type 0 exemplifying normal intestinal epithelium with
improbable coeliac disease.
• Type I exhibiting coeliac disease associated with gluten
free diet or minimal ingestion of gluten or gliadin, dermatitis
herpetiformis, diverse infections, nonspecific factors, or family
members of subjects with coeliac disease [2,3].
• Type II is exceptionally discerned and comprised of coeliac
disease occasionally encountered with dermatitis herpetiformis.
• Type III elucidates spectrum of morphological alterations
associated with symptomatic coeliac disease [2,3]. Grading of
duodenal mucosal lesions of coeliac disease as per simplified
system of Corazza, Roberts and Ensari is designated as
• Grade A/type I: increased intraepithelial lymphocytes in the
absence of villous atrophy.
• Grade B1/type II: shortening and blunting of villi with
symptomatic coeliac disease.
Coeliac disease necessitates segregation from conditions such
as tropical sprue, autoimmune enteropathy, common variable
immunodeficiency, food allergy, intestinal malabsorption,
Crohn’s disease, collagenous sprue, eosinophilic gastroenteritis,
inflammatory bowel disease, HIV enteropathy, giardiasis,
ingested drugs as sartans, mycophenolate or non-steroidal antiinflammatory
drugs, intestinal lymphoma, bacterial or viral
gastroenteritis or irritable bowel syndrome [3,4].
Pertinent investigative technique for ascertaining coeliac
disease is cogent tissue sampling of duodenum with histological
confirmation. Serologic assay is accomplished with evaluation of
tTGA, EMA and IgA class antigliadin antibodies (AGA). Evaluation of
serum tTGA is sensitive (98%) and specific (90%) for ascertaining
coeliac disease although antibodies may be discerned within
individuals upon gluten free diet [3,4]. Endoscopic evaluation of
duodenum or small intestine is a pathognomonic investigative
modality which exhibits patchy, duodenal villous atrophy,
identifiable by magnification endoscopy or chromo-endoscopy.
Also, features as scalloping or notching of mucosal folds can be
observed [3,4]. HLA DQ association test is optimal for ascertaining
HLA DQ2 and HLA DQ8 components, which may be discerned
within populations uninvolved with coeliac disease [3,4]. Flow
cytometry is optimally adopted for quantification of intraepithelial
lymphocytes, designated as IEL lymphogram. Aforesaid graph
demonstrates IELs as antigen experienced T lymphocytes which
denominate αβ (> 90%) and γδ (< 10%) receptors [3,4].
Coeliac disease exhibits elevated total IELs along with
permanently elevated γδ IELs and decimated CD3 IELs [3,4].
Refractory coeliac disease type II typically enunciates decimation
of multiple surface T cell markers as CD3, CD7 or CD8 in > 20%
of intraepithelial lymphocytes upon flow cytometry [3,4]. Upon
fluoroscopy, features such as distension of small intestine,
contrast dilution, multiple non-obstructing intussusceptions with
a ‘coiled spring’ appearance, dilated jejunal loops with completely
decimated jejunal folds or ‘moulage sign’ and flocculation
on account of coarse clumps of disintegrated barium may be
observed [3,4]. Upon computerized tomography or magnetic resonance imaging (CT / MRI), features such as jejunoileal fold pattern reversal, thickened ileal fold, perienteric stranding,
regional lymph node enlargement, ascites or submucosal
deposition of adipose tissue may be encountered, especially in
disease of extensive duration [3,4]. Appropriate therapy of coeliac
disease necessitates correction of nutritional deficiencies and
circumvention of bone depletion. Vaccination for circumventing
hepatitis B and pneumococcal infection is beneficial.
Gluten or laminin free diet is recommended [3,4].
Transglutaminase 2 inhibitors can be employed for treating
coeliac disease. Dermatitis herpetiformis requires therapy with
sulfones. Refractory coeliac disease type II appears resistant to
gluten free diet or various treatment strategies [3,4]. Adoption of
gluten free diet is associated with superior prognostic outcomes.
Proportionate emergence of small bowel adenocarcinoma is
elevated [3,4]. Severe complications as ulcerative jejunitis or
enteropathy associated T cell lymphoma represent with an
unfavourable prognosis [3,4]. Enteropathy associated T cell
lymphoma may concur with refractory coeliac disease type
II within five years of disease occurrence [3,4]. Secondary
enteropathy associated T cell lymphoma may emerge in subjects
with well controlled coeliac disease of extensive duration [3,4].
Enteropathy associated T cell lymphoma concurrent to coeliac
disease or refractory coeliac disease manifests immune nonreactive
CD56- along with gain of chromosomes 1q and 5q [3,4].
Classic subtype of enteropathy associated T cell lymphoma is
frequently associated with coeliac disease [3,4].