About Coeliac Disease

Introduction
Epidemiology
Pathogenesis
Symptomatology
Risk Factors
Diagnosis
History of Serologic Markers for Coeliac Disease
Small bowel lining during endoscopy and in histology
Therapy
Refractory Coeliac Disease and Intestinal T-Cell Lymphoma

Introduction

Coeliac Disease is a chronic autoimmune disease mainly of the small intestine that is triggered and maintained by the storage proteins (gluten) of wheat, barley and rye in genetically predisposed individuals[1,2].

Coeliac Disease is also known as gluten intolerance, celiac sprue, non-tropical sprue and gluten sensitive enteropathy.

In Coeliac Disease patients the linings of the jejunum and ileum are attacked and the finger-like protrusions, the villi, are progressively being destroyed resulting in a flat mucosa.

Diagnosis is often difficult or missed as the symptomatology is unspecific.

Left untreated, Coeliac Disease has the potential to result in various health problems ranging from malabsorption with nutrient deficiencies, anemia and osteoporosis to autoimmune problems and malignancies[3].

There is currently no other treatment than a life-long avoidance of gluten containing food.

 

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Epidemiology

It is estimated that Coeliac Disease affects 1% of the general population. Time of diagnosis ranges from early infanthood, after introduction of a gluten containing diet, throughout the adult life as well as in the elderly[4,5].

The at-risk genotypes (HLA-DQ2/8) are born by approximately 30% of the general population with Coeliac Disease being twice as frequent in women as in men[6,7].

Often Coeliac Patients are unaware of gluten exposure as it may be contained not only in wheat, barley or rye, but also in vitamin supplements, ale, soy sauce, some lipsticks, and stamps and envelop glue.

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Pathogenesis

Coeliac Disease is characterized by a chronic inflammation of the lining of the small bowel resulting in progressive destruction of the villi, known as villous atrophy and crypt hyperplasia. As a result, the mucosa becomes flat and is unable to effectively absorb nutrients. This often leads to malabsorption related  health problems such as growth retardation in children, anemia and osteoporosis.

In Coeliac Disease patients the barrier function of the small gut epithelium is compromised and allows gliadin peptides (contained in gluten) to enter the lamina propria. Based on an initial inflammatory response the ubiquitous enzyme tissueTransGlutaminase (tTG) is activated and starts to process the gliadin peptides resulting in deamidated gliadin peptides (DGP).

Virtually all patients with Coeliac Disease share the HLA genes DQ2 and DQ8 as a common genetic background. The corresponding molecules are expressed on antigen presenting cells, mainly macrophages, dendritic cells and B cells. Deamidation of gliadin peptides by tissueTransGlutaminase creates potent immunostimulatory epitopes that are presented via HLA-DQ2 or HLA-DQ8 on antigen presenting cells. Subsequently CD4+ T cells are activated secreting mainly Th1 cytokines such as IFN-γ, which activates myofibroblasts, finally resulting in mucosal remodeling and villous atrophy. Additionally Th2 cytokines are produced driving the production of (auto-)antibodies to gluten and tissueTransGlutaminase[7].

Furthermore, early exposure of infants to dietary gluten, early infection with enteropathic viruses, or a change of the bacterial flora were shown to favor the evolution of clinically manifest Coeliac Disease in children[8,9].

The degree of destruction of the small bowel lining can be rated using the extensively validated Marsh classification system with 0 for a normal mucosa and 4 for total villous atrophy[10]

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Symptomatology

Among the classical symptoms of Coeliac Disease are diarrhea, bloating and abdominal pain. Atypical symptoms however are considerably more frequent and render diagnosis difficult.

Patients with symptomatic disease can present with an extremely variable set of symptoms that are also seen in patients with IBS or rheumatoid arthritis:

  • Diarrhea
  • Abdominal pain
  • Anorexia
  • Steatorrhea
  • Vomiting
  • Weight loss
  • Anaemia
  • Arthritis
  • Dermatitis herpetiformis
  • Constipation
  • Fatigue
  • Infertility
  • Osteoporosis
  • Peripheral neuropathy
  • Epilepsy
  • Dental enamel hypoplasia
  • Aphthous stomatitis
  • Intestinal Lymphoma
  • Obesity

Symptomatic Coeliac Disease patients comprise just the tip of the coeliac iceberg. In contrast, asymptomatic patients lie hidden below the surface and are large in numbers. The can be characterized as those with either silent or latent disease, sometimes called potential disease. Both, silent and latent have the genetic predisposition and auto-antibodies, but silent disease presents with an intestinal damage. Silent Coeliac Disease is active and can be diagnosed via a small bowel biopsy[11].

 

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Risk Factors

Coeliac Disease is strongly associated with the two genetic markers HLA-DQ2 and HLA-DQ8. Other risk factors include:

      Risk       prevalence among those with risk factor

  • Dermatitis herpetiformis 100%
  • First-degree relative with celiac disease 5 to 22%
  • Autoimmune thyroid disease 1.5 to 14%
  • Down syndrome 5 to 12%
  • Turner's syndrome 2 to 10%
  • Children 3 to 8%
  • Type 1 diabetes mellitus

Diagnosis

Diagnosis of Coeliac Disease based on symptoms is difficult due to the heterogeneity of the clinical manifestations and leads to over 90% of patients with a missed diagnosis[3] . Common serological markers changes include the appearance of anti-tissue transGlutaminase, anti-deamidated gliadin peptides and other antibodies (e.g. endomysial antibodies). Endoscopic damage seen in the proximal intestine is also characteristic and a definitive diagnosis depends on a positive small bowel biopsy and response to gluten-free diet.

Histopathology remains the gold standard test for diagnosis of Coeliac Disease, however serologic tests are frequently used and avoid unnecessary and invasive biopsies in suspected cases[12,13].

Endomysial antibodies, transTissueGlutaminase antibodies and gliadin antibodies are commonly used serologic tests for Coeliac Disease. Tests based on these antibodies detect immunoglobulin G and A (IgG, IgA). Although endomysial antibodies are known to be a marker with high sensitivity and specificity they are considered problematic due to cost. Anti-gliadin antibodies are of limited use in clinical practice due to the poor sensitivity and specificity. For Reasons of cost and diagnostic accuracy  tissueTransGlutaminase-IgA has been recommended for Coeliac Disease screening[14,15,16].

Anti-Deamidated-Gliadin peptide antibodies are biomarkers of the most recent family recommended for Coeliac Disease screening[17]. Deamidation involves a modification of gliadin by the enzyme transTissueGlutaminase, resulting in Deamidated Gliadin Peptides (DGPs), which have proven to be highly specific for Coeliac Disease. Serologic tests based on anti-DGP antibodies have been shown to be at least equivalent to the established tests and in case of anti-gliadin antibodies they have been shown to be more accurate[13,18 ].

History of Serologic Markers for Coeliac Disease

The current NICE (National Institute for Clinical Excellence, UK) postulates serological testing for Coeliac Disease when following signs are present:

  • Chronic or intermittent diarrhea
  • Failure to thrive or faltering growth (children)
  • Persistent, unexplained gastrointestinal symptoms
  • Prolonged fatigue
  • Recurrent abdominal pain, cramping and distension
  • Sudden, unexpected weight loss
  • Unexplained iron-deficiency anemia

After a positive serologic diagnosis, a small bowel biopsy has to be performed for confirmation. The Marsh classification system is used to rate the severity of the mucosal damage:

(Wikipedia)

Small bowel lining during endoscopy and in histology

(http://www.aafp.org/afp/2007/1215/p1795.html)

Therapy

Currently there is no treatment other than life-long avoidance of gluten containing food. Evidence suggests that the mucosa will be restored when adhering to a strict gluten-free diet[19]., in children villous restoration will happen faster than in adults.

Refractory Coeliac Disease and Intestinal T-Cell Lymphoma

Refractory Coeliac Disease can develop in 5-10% of adults with long-standing, often undetected, Coeliac Disease. Patients with refractory disease do not respond to or experience a relapse while on a strictly gluten-free diet.

Recent data indicate a relative risk of approximately 3 for patients with untreated Coeliac Disease to develop enteropathy-associated T-cell lymphoma. When patients are on a gluten-free diet for 5 years or more, the risk of developing lymphoma appears to approach that of the general population. [7]

References

1       Hopper AD et al. BMJ 2007;335:558-62

2       Briani C et al. Autoimmun Rev 2008;7:644-50

3       Ravikumara M et al. J Ped Gastr Nutr 2007;45:497-99

4       Freeman HJ et al. WJG 2011;17:2259-2272

5       Ventura A et al. Gastroenterology 1999;117:297-303

6       Mengiorni F et al. Am J Gastroenterology 2008;103:997-1003

7       Schuppan D et al Gastroenterology 2009;137:1912-33

8       Norris JM et al. JAMA 2005;293:2343-2351

9       Collado MC, Curr Issues Intest Microbiol 2007;8:9-14

10     Marsh MN. Gastroenterology 1992;104:3058-67

11     Ferguson A. J Gastroenterol Hepatol Nutr 1999;2:52-56

12     Black JL et al. J Hum Nutr Diet 2011;24:582-7

13     Freeman JH. Can J Gastroenterol 2008;22:273-280

14     Rashtak S et al. Clin Gastroenterol Hepatol. 2008;6:426-32

15     Rostom A et al. Gastroenterology 2005. 2005;128:S38-46

16     Hill ID et al. J Pediatr Gastroenterol Nutr 2005;40:1-19

17     Husby S et al. JPGN 2011 [accepted for publication, in progress]

18     Niveloni S et al. Clinical Chemistry 2077;53:2186-2192

19     Haines ML et al. Aliment Pharmacol Ther 2008;28:1042-66

        Debiopharm Valais Award
        Frost & Sullivan Award