Celiac disease: Prevalence, diagnosis, pathogenesis and treatment

Table 1 Frequency of human leukocyte antigen-DQ2, encoded by human leukocyte antigen-DQB1*02 and human leukocyte antigen-DQ8, encoded by human leukocyte antigen-DQA1*0301-DQB1*0302

< 5%	5%-20%	20%
HLA-DQ2
Albania	Belarus Algeria	Algeria
Canada BC (Athabaskans)	Cameroon	Australia
Cook Islands	Congo	Belgium
Indonesia	Costa Rica	Central African Republic
Japan	China	Croatia
Jordan	Cuba	England
Papua New Guinea	Ecuador Africans	Equatorial Guinea Bioko Island
Philippines	France	Ethiopia
Samoa	India	Germany
	Malaysia	Greece
	Mexico	Iran
	Poland	Ireland South
	Russia	Israel
	Singapore	Italy
	South Korea	Mongolia
	Spain	New Zealand
	Sri Lanka	Pakistan
	Sweden	Saudi Arabia
	Taiwan, China	Slovenia
	Thailand	Tunesia
	Turkey	United States
	Uganda
	Ukraine
	Vietnam
HLA-DQ8
Australia	Algeria	Argentina
China	Belgium	Ecuador
Georgia	Brazil	Ethiopia
Greece	Canada BC (Athabaskans)	Mexico
North India	Croatia	Venezuela
Spain	England Caucasoid
Uganda	France
	South India
	Israel
	Italy
	Japan
	Russia
	South Korea
	Tunisia
	Turkey
	Ukraine
	United States
	European American

Estimates are based on studies included in a comprehensive Internet website[24]. In several countries, the frequency is not known. HLA: Human leukocyte antigen.

Table 2 Prevalence of celiac disease in Europeans based on unselected population serological screenings[36-38] (adapted)

Countries	Prevalence
Czechoslovakia	0.193
Estonia	0.103
Finland	0.110
Hungary	0.101
Ireland	0.126
Italy	0.115
Norway	0.224
Portugal	0.135
Spain	0.124
Sweden	0.174
Switzerland	0.133
Netherlands	0.179
United Kingdom	0.111

Table 3 High risk populations for celiac disease[73] (adapted)

Relatives, especially first-degree

Anemia, especially iron deficiency

Osteopenic bone disease

Insulin-dependent diabetes (type 1), especially children

Liver disorders, especially Autoimmune hepatitis and primary biliary cirrhosis

Genetic disorders, including down and Turner’s syndrome

Autoimmune endocrinopathy, especially thyroid disease

Skin disorders, particularly dermatitis herpetiformis

Neurological disorders, including ataxia, seizures, myasthenia gravis

Others, including immunoglobulin A nephropathy

Table 4 Possible clinical manifestations of celiac disease[8] (printed with permission)

Typical symptoms	Atypical symptoms	Associated conditions
Chronic diarrhea	Secondary to malabsorption	Possible gluten dependent
Failure to thrive	Sideropenic anemia	IDDM
Abdominal distention	Short stature	Autoimmue thyroiditis
	Osteopenia	Autoimmune hepatitis
	Recurrent abortions	Sjogren syndrome
	Hepatic steatosis	Addison disease
	Recurrent abdominal pain	Autoimmune atrophic gastritis
	Gaseousness	Autoimmune emocytopenic diseases
	Independent of malabsorption	Gluten independent
	Dermatitis herpetiformis	Down syndrome
	Dental enamel hypoplasia	Turner syndrome
	Ataxia	Williams syndrome
	Alopecia	Congenital heart defects
	Primary biliary cirrhosis	IgA deficiency
	Isolated hypertransaminasemia
	Recurrent aphthous stomatitis
	Myasthenia gravis
	Recurrent pericarditis
	Psoriasis
	Polyneuropathy
	Epilepsy
	Vasculitis
	Dilatative cardiomyopathy
	Hypo/hyperthyroidism

IgA: Immunoglobulin A; IDDM: Insulin dependent diabetes mellitus.

Table 5 The most important factors contributing to the development of celiac disease[86] (printed with permission)

Factors contributing to the onset of celiac disease	Mechanism
Gluten	Elicit T cell responses
	Induces cytokine production and intestinal lesion
Age of introduction of gluten	Weak gut immune during early childhood
HLA-DQ2 or HLA-DQ8	Gluten presentation
MYO9Bo	Increased permeability of the intestine
Pro-autoimmune genetic background	Shift in Th1/Th2 balance towards Th1
Viral infections	Defect in generation of active tolerance (e.g., regulatory T cells)
	IFN production
Tissue damage	Tissue damage
	Increased level of tTG
	Danger signals
Early termination of breastfeeding	Decreased protection against infections
Gender	Hormone-related pro-autoimmune status

Th1: T helper 1; Th2: T helper 2; tTG: Tissue transglutaminase; HLA: Human leukocyte antigen; IFN: Interferon.

Table 6 Operating characteristics of serological markers to detect the celiac disease in adults[178] (adapted)

Serological tests	Sensitivity	Specificity	Predictive value		Likelihood ratio
	95% CI (%)	95% CI (%)	Positive	Negative	Positive	Negative
IgG AGA	57-78	71-87	0.2-0.9	0.4-0.9	1.96-6	0.25-0.61
IgA AGA	55-100	71-100	0.3-1.0	0.7-1.0	1.89-∞	0-0.63
IgA EMA	86-100	98-100	0.98-1.0	0.8-0.95	43-∞	0-0.14
IgA TGA	77-100	91-100	> 0.9	> 0.95	8.55-∞	0-0.25
IgA TGA and EMA	98-100	98-100	> 0.9	> 0.95	49-∞	0-0.02

IgG: Immunoglobulin G; IgA: Immunoglobulin A; AGA: Anti-gliadin antibodies; EMA: Endomysial; TGA: Transglutaminase.

Table 7 Factors that support the diagnosis of celiac disease in patients with an increased density of intraepithelial lymphocytes but no villous shortening[194] (printed with permission)

Family history of celiac disease	15% of first-degree relatives are affected
Concomitant autoimmune conditions	Risk of coeliac disease approximately 5-fold
Increased density of γδ+ IELs	Sensitivity 0.84, specificity 0.91
Increased density of villous tip IELs	Sensitivity 0.84, specificity 0.95
HLA DQ2 or DQ8	High sensitivity, low specificity
	Negative predictive value high
Gluten dependence	Should be ascertained by gluten challenge or gluten-free diet

IELs: Intraepithelial lymphocytes; HLA: Human leukocyte antigen.

Table 8 Future therapeutic approach for celiac disease treatment

Mechanism		Therapeutic agent	Stage of study
Hydrolysis of toxic gliadin	ALV003	Glutenenases and endoprotease	Phase II
	AN-PEP	Prolyl endopeptidase	Phase II
		Lactobacilli	Discovery
	VSL#3	Lyophilised bacteria, including Bifidobacteria, Lactobacilli and Streptococcus salivarius	Discovery
Prevention of gliadin absorption	Larazotide	Hexapeptide derived from zonula occludens toxin of Vibrio cholera	Phase II
		Synthetic polymer poly (hydroxyethylmethacrylate-co-styrene sulfonate)	Discovery
		Anti-gliadin IgY	Discovery
tTG2 inhibitor		Dihydroisoxazoles	Discovery
		Cinnamoyltriazole	Discovery
		Aryl β-aminoethyl ketones	Discovery
Peptide vaccination	Nexvax2	Three deamidated peptides derived from wheat α-gliadin, ω-gliadin and β-hordein	PhaseI
		Human hookworm (Necator americanus) inoculation	Phase II
Modulate immune response		HLA-DQ2 blocker	Discovery
		Interleukin blocker	Discovery
		NKG2D antagonist	Discovery
Restore intestinal architecture		R-spondin-1	Discovery

tTG2: Tissue transglutaminase 2; PEP: Prolyl endopeptidases; NKG2D: Homodimeric natural killer-activating receptor; HLA: Human leukocyte antigen; IgY: Immunoglobulin Y.

Table 9 Key points from recent findings

Cause

Environmental (gluten) and genetic factors (HLA and non-HLA genes)

Prevalence

0.5%-1% worldwide in normal at-risk population

Higher risk in the population with diabetes, autoimmune disorder or relatives of CD individuals

Pathogenesis

Gliadin gains access via trans- and para-cellular routes to the basal surface of the epithelium, and interact directly with the immune system

Types of CD symptoms: “typical” or “atypical”

Diagnosis

Positive serological (TGA or EMA) screening results suggestive of CD, should lead to small bowel biopsy followed by a favourable clinical and serological response to the GFD to confirm the diagnosis

Current treatment

Strict life-long GFD

Alternative future CD treatments strategies

Hydrolysis of toxic gliadin peptide

Prevention of toxic gliadin peptide absorption

Blockage of deamidation of specific glutamine residues by tissue

Restoration of immune tolerance towards gluten

Modulation of immune response to dietary gliadin

Restoration of intestinal architecture

HLA: Human leukocyte antigen; CD: Celiac disease; EMA: Endomysial; TGA: Transglutaminase; GFD: Gluten-free diet.