Celiac Disease: Causes

Pathogenesis (development of disease)

Celiac disease is a chronic autoimmune disease of the mucosa of the small intestine. Celiac disease is based on a genetic predisposition with the presence of the HLA traits DQ2 and DQ8. Almost all celiac disease patients (99%) carry the HLA traits HLA-DQ2, DQ8 or DQ7. Only these HLA molecules can present gliadin antigen fragments. The definitive trigger of celiac disease is gluten, which consists of 90% proteins (gliadins and glutenins), 8% lipids and 2% carbohydrates. Furthermore, highly sensitive and specific autoantibodies against the endogenous enzyme tissue transglutaminase (TG2) play a significant role in the pathogenesis of celiac disease. In gluten-sensitive individuals, cereal protein can only be inadequately digested. As a result, cleavage products are formed during digestion, of which polypeptides consisting in particular of proline and glutamine are held responsible for damage to the mucosa of the small intestine. We are talking about gliadin from wheat and rye protein, secalin from rye protein, hordein from barley protein and avenin from oat protein. The cereal proteins gliadin, secalin, hordein and avenin are individual fractions of gluten and mainly cause the inflammatory processes in the small intestine so that normal digestion is no longer possible. The mucosa of the small intestine and especially the intestinal villi are severely damaged (villous atrophy and crypt hyperplasia) as a result of villous atrophy (tissue atrophy) and their function is considerably restricted. Three different possibilities of small intestinal damage by the cereal proteins gliadin, secalin, hordein, and avenin are known:

  • The cereal proteins have an effect similar to lectins, which proteins form bonds with mono- or oligosaccharides of glycoproteins or glycolipids. Such compounds are said to have membrane-damaging properties.
  • Deficiency of a specific protein or peptide cleaving enzyme in the mucosa of the small intestine, which has the task of breaking down the toxic polypeptides produced during digestion of the aforementioned cereal proteins. Due to the lack of enzyme, the harmful cleavage products accumulate in the mucosal cells of the small intestine, damage the small intestinal mucosa as well as villi and thus trigger the disease.
  • Gluten-sensitive enteropathy is an immunological disease, whereby the immune system regards the polypeptides (allergens) produced during the digestion of gluten as foreign bodies. As a result, T lymphocytes react with the allergens. The T-cell mediated hypersensitivity reaction is the trigger of the damage to the intestinal wall.

By quite a few immunological and clinical findings, predominantly the T-cell mediated hypersensitivity reaction has been supported for the development of celiac disease. It is currently considered to be of greatest importance in the pathomechanism of gluten-sensitive enteropathy. A number of viral infections (adenovirus, enterovirus, hepatitis C virus (HCV), and rotavirus) are discussed as triggers. Enteroviruses possibly trigger celiac disease in children with the DQ2/8 high-risk combination: stool samples showed enteroviruses nearly 50% more frequently in affected individuals before the onset of disease than in children who remained healthy.

Etiology (Causes)

Biographic Causes

  • Genetic burden from parents, grandparents, esp. 1st-degree family members (individuals with HLA-DQ2 or -DQ8 genotype (approximately 30-35% of the total population are positive) develop celiac disease in approximately 2% of cases during their lifetime)
    • 1st degree family members of a celiac patient have a 10-15% risk of developing celiac disease.
    • Genetic risk dependent on gene polymorphisms:
      • Genes/SNPs (single nucleotide polymorphism; English : single nucleotide polymorphism):
        • Genes: HLA-DQA1
        • SNP: rs2187668 in the gene HLA-DQA1
          • Allele constellation: AA (> 6.23-fold).
          • Allele constellation: AG (6.23-fold)
          • Allele constellation: GG (0.3-fold)

Behavioral causes

  • Nutrition
    • Consumption of gluten-containing foods (early and massive gluten exposure).

Disease-related causes

  • Intestinal infections – repeated gastroenteritis (gastrointestinal infections) in the first year of life.
  • Dermatitis herpetiformis – chronic skin disease with grouped standing vesicles.
  • Diabetes mellitus type 1

Celiac disease risk groups*

  • Autoimmune diseases of the liver and biliary tract
  • Dermatitis herpetiformis (Duhring’s disease) – skin disease from the group of blistering autoimmune dermatoses with subepidermal blistering.
  • Diabetes mellitus type 1
  • Hashimoto’s thyroiditis – autoimmune disease that leads to chronic inflammation of the thyroid gland.
  • IgA nephropathy (mesangial IgA glomerulonephritis) – diffuse mesangioproliferative glomerulonephritis) is associated with the deposition of immunoglobulin A (Ig A) in the mesangium (intermediate tissue) of the glomeruli.
  • Juvenile chronic arthritis – chronic inflammatory disease of the joints (arthritis) of the rheumatic type in childhood (juvenile).
  • Selective IgA deficiency
  • Trisomy 21 (Down syndrome)
  • Ullrich-Turner syndrome – in which due to a chromosomal aberration (abnormalities of the sex chromosomes) instead of the two sex chromosomes XX only one functional X chromosome is present in all or only part of all body cells.
  • Williams-Beuren syndrome (WBS; synonyms: Williams syndrome, Fanconi-Schlesinger syndrome, idiopathic hypercalcemia or Elfin-face syndrome) – genetic disease with autosomal dominant inheritance; with symptoms such as cognitive impairment different degrees of severity, growth retardation (already intrauterine), hypercalcemia (calcium excess) in the first years of life, microencephaly (abnormally small head), anomalies of facial shape, etc..

* These patients should be screened regularly for celiac disease. Furthermore, patients with positive typing of HLA alleles DQ2 and/or DQ8.