Celiac disease (gluten enteropathy) - Cause

The cause of the development of gluten enteropathy (celiac disease) is a congenital deficiency or decreased production by the small intestine of an enzyme that breaks down gluten. Gluten is found in cereals - wheat, rye, barley, oats.

Gluten intolerance is inherited and occurs in 0.03% of the population. 80% of patients have histocompatibility antigens HLA-B8 and HLA-DW3, which are transmitted in a recessive manner.

Hereditary gluten intolerance occurs in 0.03% of cases in the general population. Its frequency varies in different countries. It is most common (1:300) in Western Ireland. According to research, gluten intolerance is quite rare among the adult population of the central part of our country.

Pathogenesis of celiac disease

There are three hypotheses regarding the mechanism of the damaging effect of gluten:

1. celiac disease occurs as a result of an immunological reaction to dietary gluten;
2. genetic factors facilitate the adverse effects of gluten;
3. Celiac disease is a metabolic disorder in which incomplete digestion of gluten results in the accumulation of toxic substances that damage the mucous membrane.

The role of immune mechanisms in the pathogenesis of celiac disease is evidenced by the increased content of immunoglobulins and lymphocytes in the proper layer of the small intestinal mucosa in patients with untreated celiac enteropathy. The jejunal mucosa of these patients synthesizes significantly more IgA and IgM compared to the control group, whose biopsies were treated with gluten in vitro. Sometimes only the level of serum IgA increases, although cases of celiac enteropathy with selective IgA deficiency have been described. In celiac enteropathy, the percentage of immunoglobulins synthesized by the small intestinal mucosa has antigluten specificity. This suggests that the intestine responds to the effect of gluten by producing antigluten antibodies. Circulating antibodies to gluten fractions are detected in the blood serum of many patients. Some authors consider their appearance as a non-specific reaction to the passage of incompletely split gluten products through the intestinal epithelium with increased permeability and as a kind of cellular hypersensitivity to gluten. It is believed that gluten is activated by an "endogenous effector mechanism" that contributes to its local toxic effect in gluten enteropathy.

Changes in cellular immunity may play a certain role in the pathogenesis of celiac disease. This is evidenced by a marked increase in the number of T-lymphocytes in the proper layer of the small intestinal mucosa and among interepithelial lymphocytes, the number of which is significantly increased in untreated celiac disease, including in the rectal mucosa. It is believed that sensitized T-lymphocytes produce lymphokines in response to the effects of gluten, which contribute to damage to the mucosa.

The possibility of corticosteroid hormones' involvement in the pathogenesis of the disease is discussed. Addition of hydrocortisone to the tissue culture of the jejunal mucosa of patients with untreated celiac enteropathy can suppress the harmful effects of gluten on tissues. Clinical and morphological improvement under the influence of corticosteroids is associated with nonspecific suppression of inflammation and the effect on secondary adrenal insufficiency. A number of authors consider celiac disease as a specific form of allergic or infectious (adenovirus) intestinal damage.

The role of genetic factors in the development of celiac disease is also undoubted. This is evidenced by the significantly higher number of cases of the disease in relatives of patients compared to control populations. In one family, 4 cases of gluten enteropathy confirmed by biopsy were described, as well as 11 sick relatives among 96 examined from 17 families.

Signs of celiac disease in affected relatives were either absent or so minor that they were not considered abnormal. Latent course of gluten enteropathy, which is more common than diagnosed, was prevalent in approximately 10% of first-generation relatives. Histocompatibility antigen HLA-B8 and HLA-DW3, often associated with the HLA-B8 antigen, were found in 80% of patients. However, not all carriers of HLA-B8 and/or DW3 develop gluten enteropathy, just as not all patients with this disease have one or both of these HLA antigens. Antigenic disorders are inherited in a recessive manner.

The development of celiac disease is also caused by metabolic disorders resulting from the accumulation of toxic products in the mucous membrane of the small intestine due to incomplete breakdown of gluten. At the same time, the content of some specific peptidases (aminopeptidases) involved in the digestion of gluten is reduced. After successful therapy, the level of these peptidases in the histologically normal mucous membrane returns to normal.

The products of insufficient breakdown of gluten, in particular its water-soluble fraction, when in contact with the mucous membrane of the small intestine, damage it, which is decisive in the pathogenesis of the disease. Low-molecular acidic polypeptides also have a toxic effect. First of all, the absorptive cells of the mucous membrane of the small intestine are affected, the remaining layers are usually not involved in the pathological process. This damage can vary in severity and extent, which explains the diversity of clinical manifestations of the disease - from asymptomatic course to the development of severe malabsorption syndrome.

The morphological substrate of celiac disease is damage and a decrease in the number of absorptive cells, flattening or disappearance of villi, a significant increase in the number of proliferating undifferentiated crypt cells, noticeable elongation of crypts, and acceleration of cell renewal and migration compared to the norm.

Thus, the development of celiac disease is caused by the following pathogenetic mechanisms:

• Accumulation of toxic substances that damage the mucous membrane of the small intestine

Due to the deficiency of specific enzymes, in particular aminopeptidases, the intestines do not completely break down gluten, which contains L-gliadin, a toxic substance. The products of insufficient gluten breakdown, low-molecular acid polypeptidases and, above all, L-gliadin have a toxic damaging effect on the small intestine. The mechanism of this action has not been fully studied.

• Development of immunological reactions to dietary gluten

In response to gluten entering the intestinal lumen, antigluten antibodies are produced, and the small intestine itself is involved in their production. Gluten binds to specific receptors of enterocytes and interacts with interepithelial lymphocytes and lymphocytes of the lamina propria of the small intestinal mucosa. The resulting antibodies interact with gluten, and an immunological reaction develops with damage to the intestinal mucosa. In addition, sensitized T-lymphocytes produce lymphokines in response to gluten, which aggravate damage to the small intestinal mucosa.

As a result of the influence of the above pathogenetic factors, enterocytes are damaged, atrophy of the small intestinal mucosa develops with the disappearance of villi and crypt hyperplasia. There is also pronounced infiltration of the superficial and pit epithelium by lymphocytes, and the lamina propria by lymphocytes and plasma cells. Atrophy of the mucosa leads to the development of severe malabsorption syndrome.

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