What causes cystic fibrosis?

The cause of cystic fibrosis is the mutation of the gene of the cystic fibrosis transmembrane conduction regulator ( CFTR) located in the middle of the long arm of the chromosome 7. As a result of the mutation of the gene, the secret produced by the exocrine glands becomes excessively viscous, which determines the pathogenesis of the disease. More than 1000 different variants of mutations, leading to the development of the disease with different degrees of symptoms, have been found.

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

The main severity - lesions of the bronchopulmonary system and pancreas. Involvement of the airways is typical for cystic fibrosis, but early pulmonary changes usually occur after 5-7 weeks of a child's life in the form of hypertrophy of bronchial mucous glands and hyperplasia of goblet cells. The mechanism of self-cleaning of the bronchi has been broken, which promotes the multiplication of pathogenic microflora and the appearance of inflammation - bronchiolitis and bronchitis. Subsequently, edema of the mucous membrane, secondary bronchospasm and bronchospasm decrease, increased production of viscous bronchial secretion, progressive deterioration of mucociliary clearance - a vicious circle of bronchial obstruction arises.

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

The earliest and most threatening intestinal symptom is the meconial ileus (obstructive obstruction of the terminal ileum due to the accumulation of viscous meconium), which develops due to pancreatic insufficiency and dysfunctions of the glands of the small intestine. Meconial ileus, according to the literature, occurs in 5-15% of patients (an average of 6.5%), it is considered to be a sign of a severe form of cystic fibrosis.

Changes in the hepatobiliary system, usually long-term asymptomatic, are noted in virtually all patients at different ages.

What happens in cystic fibrosis?

Bronchopulmonary system

Goblet cells and glands of the mucous membrane of the respiratory tract produce a large amount of secretion. In cystic fibrosis, the secret produced is characterized by increased viscosity, which causes its accumulation in the lumen of the bronchi and bronchioles and their complete or partial obturation. In cystic fibrosis already in childhood, often in the first year of life, the lungs form the conditions for the reproduction of pathogenic and opportunistic bacteria. Mechanisms of anti-microbial protection, including active mucociliary clearance, which are normally able to withstand external pathogenic agents, inhibit and prevent the development of infection, are untenable in cystic fibrosis. Particularly sharply weakened local mechanisms of protection against the background of respiratory viral infections, "opening gates" for the penetration of pathogenic microorganisms - Staphylococcus aureus, Haemophilius influenzae, Pseudomonas aeruginosa. Accumulations of viscous mucus are a nutrient medium for microorganisms, and as a result of their proliferation develops purulent inflammation. In conditions of violation of mucociliary clearance, obstruction grows, which leads to weight gain, more tissue damage and the formation of a vicious circle - "obstruction-infection-inflammation."

Most often, the first bacterial agent that affects the lower respiratory tract becomes S. Aureus (most often it is sown from the sputum of children with cystic fibrosis during the first years of life). Later in the pathogenic microflora appears P. Aeruginosa. When P. Aeruginosa and S. Aureus and other pathogenic bacteria are detected in sputum in children less than 6 months of age, it is safe to speak of chronic colonization of the lower respiratory tract of the child with these microorganisms. Progression of a chronic infectious process caused by P. Aeruginosa is usually accompanied by a weighting of the symptoms of the lower respiratory tract with a progressive impairment of lung function. Part of the pathogens can be transformed into mucoid (mucous) forms, resistant to the action of immune protection factors and antimicrobial leukemia. 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 often become infected with H. Influenzae, which leads to severe respiratory disorders. The role of Burkholderia cepacia in the lesion of the lower respiratory tract of patients with cystic fibrosis has increased . Approximately 1/3 of patients with the infection of Burkholderia cepacia have frequent exacerbations of the infectious and inflammatory process in the bronchopulmonary system. There is a so-called seraa-syndrome, characterized by the development of fulminant pneumonia and septicemia (indicates a poor prognosis). In other patients Burkholderia cepacia does not significantly affect the course of the disease. The presence of C. Cepacia in the sputum testifies to the high risk of superinfection of P. Aeruginosa, S. Aureus and H. Influenzae.

Occasionally, sputum microflora - Klebsiella pneumonie, Escherichia coli, Serratia marcescens are found in the sputum of patients with cystic fibrosis . Stenotrophomonas mallophilia u spp. spp., whose role in the pathogenesis of cystic fibrosis has not been fully established.

Fungal infection of the lungs also often develops in cystic fibrosis. Aspergillus fumigatus causes the most severe and clinically vivid form of mycosis of the lungs in cystic fibrosis - allergic bronchopulmonary aspergillosis, the frequency of development of which varies from 0.6 to 11%. With untimely diagnosis 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), in the pulmonary tissue of fetuses with cystic fibrosis, the concentration of proinflammatory cytokines is increased, which indicates the early onset of inflammatory processes preceding the development of infection. Immunological disorders are aggravated by prolonged colonization of the lower respiratory tract P. Aeruginosa. In the course of their reproduction, these microorganisms produce virulence factors:

• damage to the epithelium of the lower respiratory tract;
• stimulating the production of inflammatory mediators;
• increasing the permeability of capillaries;
• stimulating leukocyte infiltration of the lung tissue.

Pancreas

Pancreatic ducts can be clogged with clots of secretion, which often occurs before the birth of a child. As a result, pancreatic enzymes produced by acinar cells do not reach the duodenum, and, eventually accumulating and activating in blocked ducts, cause autolysis of pancreatic tissue. Often in the first month of life the pancreas looks like a cluster of cysts and fibrous tissue (hence the other name for the disease is cystic fibrosis). As a result of destruction of the exocrine part of the pancreas, digestion and absorption processes (primarily fats and proteins) are violated, deficiency of fat-soluble vitamins (A, D, E and K) develops, in the absence of adequate treatment leading to a delay in the child's physical development. With some mutations of the gene of the cystic fibrosis transmembrane conduction regulator, changes in the pancreas form slowly, and its function persists for many years.

Gastrointestinal tract

Meconial ileus - occlusion of the distal parts of the small intestine by dense and viscous meconium. This is a complication of cystic fibrosis that develops in newborns due to a disruption in the transport of sodium, chlorine and water in the small intestine, and often leads to its atresia. Excessively inflated contents of the intestinal wall may burst, causing the development of meconial peritonitis (often this occurs before the birth of the child).

The secretion of intestinal glands with increased viscosity can, together with the calves, cover the lumen of the gut 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 and proximal parts of the colon. Intestinal obstruction in children with cystic fibrosis is often caused by intussusception of the small intestine.

Gastroesophageal reflux in patients with cystic fibrosis is often due to delayed evacuation of stomach contents, increased production of hydrochloric acid and impaired gastric motility. The development of gastroesophageal reflux is also facilitated by the administration of certain drugs. Lowering the tone of the lower esophageal sphincter (theophylline, salbutamol), or certain types of physiotherapy. Recurrent or permanent casting 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 covers

In cystic fibrosis in the secretion of sweat glands, the sodium chloride content exceeds the normal value by about 5 times. Such changes in the function of the sweat glands can be detected already at the birth of the child, they persist throughout the life of the patient. In a hot climate, excessive loss of sodium chloride with sweat leads to disruption of electrolyte metabolism and metabolic alkalosis, predisposing thereby to a thermal shock.

Reproductive system

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

The decrease in fertility in women is due to the increase in the viscosity of the cervical uterine canal that separates, which makes it difficult to migrate spermatozoa from the vagina.