What causes cystic fibrosis?

The cause of cystic fibrosis is a mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, located in the middle of the long arm of chromosome 7. As a result of the gene mutation, the secretion produced by the exocrine glands becomes excessively viscous, which causes the pathogenesis of the disease. More than 1,000 different mutation variants have been discovered, leading to the development of the disease with varying degrees of severity of symptoms.

Mutations of the gene in the homozygous state lead to disruption of the synthesis of the protein that forms the chloride channel in the membranes of epithelial cells, providing passive transport of chloride ions. As a result of this pathology, the exocrine glands secrete a viscous secretion with a high concentration of electrolytes and protein.

The most severe ones are the lesions of the bronchopulmonary system and pancreas. Involvement of the respiratory tract is typical for cystic fibrosis, but early pulmonary changes usually occur after 5-7 weeks of the child's life in the form of hypertrophy of the bronchial mucous glands and hyperplasia of goblet cells. The mechanism of self-cleaning of the bronchi is impaired, which contributes to the proliferation of pathogenic microflora and the occurrence of inflammation - bronchiolitis and bronchitis. Subsequently, edema of the mucous membrane, secondary bronchospasm and a decrease in the lumen of the bronchi, an increase in the production of viscous bronchial secretions, a progressive deterioration in mucociliary clearance develop - a vicious circle of bronchial obstruction occurs.

In the pathogenesis of gastrointestinal disorders, the main role is played by secretory disorders, which are based on a decrease in the water-electrolyte component and thickening of pancreatic juice, difficulty in outflow and stagnation, leading to expansion of the excretory ducts, atrophy of glandular tissue and the development of fibrosis. The development of these changes in the pancreas occurs gradually, reaching the stage of complete scarring by 2-3 years. There is a violation of the excretion of pancreatic enzymes (lipase, trypsin and amylase) into the intestinal cavity.

The earliest and most serious intestinal symptom is meconium ileus (obstructive obstruction of the terminal ileum due to accumulation of viscous meconium), which develops due to pancreatic insufficiency and dysfunction of the glands of the small intestine. According to literature, meconium ileus occurs in 5-15% of patients (on average, 6.5%), and is considered a sign of a severe form of cystic fibrosis.

Changes in the hepatobiliary system, usually asymptomatic for a long time, are observed in almost all patients at different ages.

What happens in cystic fibrosis?

Bronchial system

Goblet cells and glands of the respiratory tract mucosa produce a large amount of secretion. In cystic fibrosis, the secretion produced is characterized by increased viscosity, which causes its accumulation in the lumen of the bronchi and bronchioles and their complete or partial obstruction. In cystic fibrosis, already in childhood, often in the first year of life, conditions for the reproduction of pathogenic and opportunistic bacteria are formed in the lungs. The mechanisms of antimicrobial protection, including active mucociliary clearance, normally capable of resisting external pathogenic agents, suppressing and preventing the development of infection, are ineffective in cystic fibrosis. Local defense mechanisms are especially sharply weakened against the background of respiratory viral infections, "opening the gates" for the penetration of pathogenic microorganisms - Staphylococcus aureus, Haemophilius influenzae, Pseudomonas aeruginosa. The accumulation of viscous mucus is a nutrient medium for microorganisms, and as a result of their reproduction, purulent inflammation develops. In conditions of impaired mucociliary clearance, obstruction increases, which leads to aggravation of the condition, greater tissue damage and the formation of a vicious circle - "obstruction-infection-inflammation".

Most often, the first bacterial agent affecting the lower respiratory tract is S. aureus (most often it is isolated from the sputum of children with cystic fibrosis during the first years of life). Later, P. aeruginosa appears in the pathogenic microflora. If P. aeruginosa and S. aureus and other pathogenic bacteria are detected in the sputum of children under 6 months, we can confidently talk about chronic colonization of the child's lower respiratory tract with these microorganisms. The progression of the chronic infectious process caused by P. aeruginosa is usually accompanied by an increase in the severity of symptoms of lower respiratory tract damage and a progressive deterioration in lung function. Some pathogens are capable of transforming into mucoid (mucous) forms that are resistant to immune defense factors and antimicrobial drugs. With the development of a chronic infectious process of the lower respiratory tract, P. aeruginosa is almost impossible to completely eliminate.

Against the background of a respiratory viral infection, patients with cystic fibrosis are often infected with H. influenzae, which leads to severe respiratory disorders. The role of Burkholderia cepacia in the defeat of the lower respiratory tract of patients with cystic fibrosis has increased. In approximately 1/3 of patients, against the background of infection with Burkholderia cepacia, frequent exacerbations of the infectious and inflammatory process in the bronchopulmonary system occur. The so-called seraaa syndrome appears, characterized by the development of fulminant pneumonia and septicemia (indicating a poor prognosis). In other patients, Burkholderia cepacia does not significantly affect the course of the disease. The presence of B. cepacia in sputum indicates a high risk of developing superinfection with P. aeruginosa, S. aureus and H. influenzae.

Occasionally, other representatives of pathogenic microflora are found in the sputum of patients with cystic fibrosis - Klebsiella pneumoniae, Escherichia coli, Serratia marcescens. Stenotrophomonas mallophilia u spp. spp., the role of which in the pathogenesis of cystic fibrosis has not been definitively established.

Fungal infection of the lungs also develops quite often in cystic fibrosis. Aspergillus fumigatus causes the most severe and clinically obvious form of mycosis of the lungs in cystic fibrosis - allergic bronchopulmonary aspergillosis, the incidence of which varies from 0.6 to 11%. If not diagnosed in time and without adequate treatment, fungal infection is complicated by the formation of proximal bronchiectasis, which causes a rapid increase in the severity of ventilation disorders.

According to S. Verhaeghe et al. (2007), the concentration of proinflammatory cytokines is increased in the lung tissue of fetuses with cystic fibrosis, which indicates an early onset of inflammatory processes preceding the development of infection. Immunological disorders are aggravated by long-term colonization of the lower respiratory tract by P. aeruginosa. In the process of their reproduction, these microorganisms produce virulence factors:

• damaging the epithelium of the lower respiratory tract;
• stimulating the production of inflammatory mediators;
• increasing capillary permeability;
• stimulating leukocyte infiltration of lung tissue.

Pancreas

The pancreatic ducts can become clogged with secretion clots, which often occurs before the baby is born. As a result, pancreatic enzymes produced by acinar cells do not reach the duodenum and, over time, accumulate and become activated in the clogged ducts, causing autolysis of the pancreatic tissue. Often, already in the first month of life, the pancreas looks like a cluster of cysts and fibrous tissue (hence another name for the disease - cystic fibrosis). As a result of the destruction of the exocrine part of the pancreas, the processes of digestion and absorption (primarily fats and proteins) are disrupted, a deficiency of fat-soluble vitamins (A, D, E and K) develops, which, in the absence of adequate treatment, leads to a delay in the physical development of the child. With some mutations of the cystic fibrosis transmembrane conductivity regulator gene, changes in the pancreas are formed slowly, and its function is maintained for many years.

Gastrointestinal tract

Meconium ileus is a blockage of the distal small intestine with thick and viscous meconium. It is a complication of cystic fibrosis that develops in newborns due to impaired transport of sodium, chlorine and water in the small intestine, and often leads to its atresia. The intestinal wall, excessively distended with contents, can rupture, causing the development of meconium peritonitis (often this occurs even before the child is born).

The highly viscous secretion of intestinal glands can, together with feces, obstruct the intestinal lumen in both children and adults. Most often, acute, subacute or chronic obstruction leading to the development of intestinal obstruction occurs in the distal parts of the small intestine and proximal parts of the large intestine. Intussusceptions of the small intestine often lead to the development of intestinal obstruction in children with cystic fibrosis.

Gastroesophageal reflux in patients with cystic fibrosis is often caused by delayed evacuation of gastric contents, increased production of hydrochloric acid and impaired gastric peristalsis. The development of gastroesophageal reflux is also facilitated by taking certain drugs that reduce the tone of the lower esophageal sphincter (theophylline, salbutamol) or certain types of physiotherapy. Recurrent or constant reflux of stomach contents into the esophagus causes the development of esophagitis of varying severity, sometimes - Barrett's esophagus. In the case of high gastroesophageal reflux, aspiration of gastric contents and the development of aspiration pneumonia are possible.

Skin

In cystic fibrosis, the sodium chloride content in sweat gland secretions exceeds the normal level by approximately 5 times. Such changes in sweat gland function can be detected already at birth and persist throughout the patient's life. In hot climates, excessive loss of sodium chloride with sweat leads to electrolyte imbalance and metabolic alkalosis, thereby predisposing to heat stroke.

Reproductive system

In men with cystic fibrosis, primary azoospermia develops due to the congenital absence, atrophy or obstruction of the spermatic cord. Similar anomalies in the structure and functioning of the sex glands are also found in some men who are heterozygous carriers of the mutation of the cystic fibrosis transmembrane conductance regulator gene.

Decreased fertility in women is caused by increased viscosity of the cervical mucus, which makes it difficult for sperm to migrate from the vagina.