Cystic fibrosis

Cystic fibrosis is a genetic autosomal recessive monogenic disease characterized by a disorder of secretion of exocrine glands of vital organs with damage primarily to the respiratory and digestive systems, severe course and unfavorable prognosis.

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Epidemiology

The incidence of cystic fibrosis fluctuates between 1:2,500 and 1:4,600 newborns. Every year, about 45,000 people with cystic fibrosis are born worldwide. The incidence of cystic fibrosis gene carriers is 3-4%, with about 275 million people worldwide being carriers of this gene, of which about 5 million live in Russia and about 12.5 million in the CIS countries.

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Causes cystic fibrosis

Cystic fibrosis is transmitted in an autosomal recessive manner. The cystic fibrosis gene is located in autosome 7, contains 27 exons and consists of 250,000 nucleotide pairs.

A single gene can have many mutations, each of which is specific to a particular population or geographic region. More than 520 mutations have been described, the most common of which is delta-P-508, i.e., a substitution of the amino acid phenylalanine at position 508.

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Pathogenesis

Mutations in the cystic fibrosis gene disrupt the structure and function of a protein called CFTR (cystic fibrosis transmembrane regulator). This protein acts as a chloride channel involved in the water-electrolyte exchange of epithelial cells of the bronchopulmonary system, gastrointestinal tract, pancreas, liver, and reproductive system. As a result of disruption of the function and structure of the CFTR protein, chloride ions Cl ^- accumulate inside the cell. This leads to a change in the electrical potential in the lumen of the excretory ducts, which facilitates the flow of large amounts of sodium ions (Na ⁺ ) from the lumen of the duct into the cell and further enhanced absorption of water from the pericellular space.

As a result of these changes, the secretion of most exocrine glands thickens, its evacuation is disrupted, which leads to pronounced secondary disorders in organs and systems, most pronounced in the bronchopulmonary and digestive systems.

A chronic inflammatory process of varying intensity develops in the bronchi, the function of the ciliated epithelium is sharply disrupted, the sputum becomes very viscous, thick, very difficult to evacuate, its stagnation is observed, bronchiolo- and bronchiectasis are formed, which over time become more common. These changes lead to an increase in hypoxia and the formation of chronic pulmonary heart disease.

Patients with cystic fibrosis are extremely predisposed to the development of chronic inflammation in the bronchopulmonary system. This is due to pronounced disturbances in the local bronchopulmonary defense system (reduced levels of IgA, interferon, phagocytic function of alveolar macrophages and leukocytes).

Alveolar macrophages play a major role in the development of chronic inflammation in the bronchopulmonary system. They produce large amounts of IL-8, which dramatically increases neutrophil chemotaxis in the bronchial tree. Neutrophils accumulate in large quantities in the bronchi and, together with epithelial cells, secrete many proinflammatory cytokines, including IL-1, 8, 6, tumor necrosis factor, and leukotrienes.

An important role in the pathogenesis of bronchopulmonary system damage is also played by the high activity of the enzyme elastase. A distinction is made between exogenous and endogenous elastase. The first is produced by bacterial flora (especially Pseudomonas aeruginosa), the second - by neutrophilic leukocytes. Elastase destroys the epithelium and other structural elements of the bronchi, which contributes to further disruption of mucociliary transport and the rapid formation of bronchiectasis.

Neutrophilic leukocytes also secrete other proteolytic enzymes. Alpha-1-antipyrsin and secretory inhibitor of leukoproteases counteract the influence of proteolytic enzymes and, therefore, protect the bronchopulmonary system from their damaging influence. However, unfortunately, in patients with cystic fibrosis, these protective factors are suppressed by a significant amount of neutrophilic protease.

All of these circumstances contribute to the introduction of infection into the bronchopulmonary system and the development of chronic purulent bronchitis. In addition, it should be taken into account that the defective protein encoded by the cystic fibrosis gene changes the functional state of the bronchial epithelium, which favors the adhesion of bacteria to the bronchial epithelium, primarily Pseudomonas aeruginosa.

Along with the pathology of the bronchopulmonary system, cystic fibrosis also causes severe damage to the pancreas, stomach, large and small intestines, and liver.

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Symptoms cystic fibrosis

Cystic fibrosis manifests itself with various clinical symptoms. In newborns, the disease can manifest itself with meconium ileus. Due to a lack or even complete absence of trypsin, meconium becomes very dense, viscous, and accumulates in the ileocecal region. Further, intestinal obstruction develops, which is manifested by intense vomiting with an admixture of bile, abdominal distension, lack of meconium excretion, development of peritonitis symptoms, and rapid increase in clinical manifestations of severe intoxication syndrome. The child can die in the first days of life if urgent surgical intervention is not performed.

In less severe cases, a characteristic sign of cystic fibrosis is abundant, frequent stool, unctuous, with a large amount of fat, with a very unpleasant odor. In 1/3 of patients, prolapse of the rectum is observed.

Subsequently, patients continue to experience intestinal dysfunction, malabsorption syndrome, severe physical development disorders, and severe hypovitaminosis.

In the first or second year of life, symptoms of damage to the bronchopulmonary system (mild form of the disease) appear, which is manifested by a cough that can be extremely pronounced and resemble a cough with whooping cough. The cough is accompanied by cyanosis, shortness of breath, and the separation of thick sputum, initially mucous, and then purulent. Gradually, a clinical picture of chronic obstructive bronchitis and bronchiectasis, pulmonary emphysema and respiratory failure is formed. Children are extremely susceptible to acute respiratory viral and bacterial infections, which contributes to exacerbations and progression of bronchopulmonary pathology. The development of infection-dependent bronchial asthma is possible.

In school-age children, cystic fibrosis may manifest itself as "intestinal colic". Patients complain of severe paroxysmal abdominal pain, bloating, and repeated vomiting. When palpating the abdomen, dense formations are determined, located in the projection of the large intestine - fecal masses mixed with thick, dense mucus. Children are very prone to the development of hypochloremic alkalosis due to excessive excretion of salt with sweat in hot weather, while "salt frost" appears on the child's skin.

Bronchopulmonary system disorders in adults

Damage to the bronchopulmonary system in patients with cystic fibrosis (pulmonary form of the disease) is characterized by the development of chronic purulent obstructive bronchitis, bronchiectasis, chronic pneumonia, pulmonary emphysema, respiratory failure, and pulmonary heart disease. Some patients develop pneumothorax and other complications of cystic fibrosis: atelectasis, lung abscesses, hemoptysis, pulmonary hemorrhage, and infection-dependent bronchial asthma.

Patients complain of a painful paroxysmal cough with very viscous, difficult to separate mucopurulent sputum, sometimes with an admixture of blood. In addition, shortness of breath is extremely characteristic, first during physical exertion, and then at rest. Shortness of breath is caused by bronchial obstruction. Many patients complain of chronic rhinitis caused by polyposis and sinusitis. Significant weakness, progressive decrease in performance, frequent acute respiratory viral diseases are also characteristic. Upon examination, attention is drawn to pale skin, puffiness of the face, cyanosis of the visible mucous membranes, and severe shortness of breath. With the development of decompensated pulmonary heart disease, edema appears in the legs. Thickening of the terminal phalanges of the fingers in the form of drumsticks, and nails in the form of watch glasses may be observed. The chest takes on a barrel-shaped form (due to the development of pulmonary emphysema).

Percussion of the lungs reveals signs of emphysema - a box sound, a sharp limitation of the mobility of the pulmonary edge, and a lowering of the lower border of the lungs. Auscultation of the lungs reveals harsh breathing with an extended exhalation, scattered dry wheezing, and moist medium and fine bubbling wheezing. With severe emphysema of the lungs, breathing is sharply weakened.

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Extrapulmonary manifestations of cystic fibrosis

Extrapulmonary manifestations of cystic fibrosis can be quite pronounced and occur frequently.

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Pancreatic damage

Insufficiency of the exocrine function of the pancreas of varying severity is observed in 85% of patients with cystic fibrosis. With minor damage to the pancreas, maldigestion and malabsorption syndromes are absent, there are only laboratory manifestations of exocrine insufficiency (low levels of trypsin and lipase in the blood and duodenal contents; often severe steatorrhea). It is known that to prevent maldigestion syndrome, secretion of only 1 to 2% of total lipase is sufficient. Only significant disturbances of the exocrine function are clinically manifested.

Under normal conditions, the acini of the pancreas produce a liquid secretion rich in enzymes. As the secretion moves along the excretory duct, it is enriched with water and anions, and it becomes even more liquid. In cystic fibrosis, due to a disorder in the structure and function of the transmembrane regulator (chloride channel), the pancreatic secretion does not receive a sufficient amount of liquid, it becomes viscous, and the speed of its movement along the excretory duct slows down sharply. The proteins of the secretion are deposited on the walls of small excretory ducts, resulting in their obstruction. As the disease progresses, destruction and atrophy of the acini ultimately develop - chronic pancreatitis with exocrine pancreatic insufficiency is formed. This is clinically reflected in the development of maldigestion and malabsorption syndromes. Pancreatic insufficiency is the main cause of fat malabsorption in cystic fibrosis, but this is usually observed with a significant lipase deficiency. Forsher and Durie (1991) indicate that in the complete absence of pancreatic lipase, fat is broken down and absorbed by 50-60%, which is due to the presence of gastric and salivary (sublingual) lipases, the activity of which is close to the lower limit of the norm. Along with the disruption of fat breakdown and absorption, there is a disruption of protein breakdown and reabsorption. About 50% of the protein received with food is lost with feces. Carbohydrate absorption is affected to a lesser extent despite the deficiency of α-amylase, but carbohydrate metabolism can be significantly disrupted.

Damage to the pancreas is expressed in the development of maldigestion and malabsorption syndrome with significant weight loss and abundant fatty stools.

The development of maldigestion and malabsorption syndromes is also facilitated by severe dysfunction of the intestinal glands, impaired secretion of intestinal juice and a decrease in the content of intestinal enzymes in it.

Maldigestion and malabsorption syndromes are also called the intestinal form of cystic fibrosis.

Impaired endocrine function of the pancreas (diabetes mellitus) is observed in patients with cystic fibrosis in the late stages of the disease (in 2% of children and 15% of adults)

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Liver and biliary tract damage

In 13% of patients with mixed and intestinal forms of cystic fibrosis, liver cirrhosis develops. It is most typical for mutations W128X, delta-P508 and X1303K. Biliary cirrhosis of the liver with portal hypertension is detected in 5-10% of patients. According to Welch, Smith (1995), clinical, morphological, laboratory, instrumental signs of liver damage are detected in 86% of patients with cystic fibrosis.

Many patients with cystic fibrosis also develop chronic cholecystitis, often calculous.

Dysfunction of the sex glands

Patients with cystic fibrosis may experience azoospermia, which is the cause of infertility. Reduced fertility is also typical for women.

Stages

There are three degrees of severity of pulmonary cystic fibrosis.

The mild form of cystic fibrosis is characterized by rare exacerbations (no more than once a year); during periods of remission, clinical manifestations are practically absent, and patients are able to work.

Moderate severity - exacerbations are observed 2-3 times a year and last about 2 months or longer. In the exacerbation phase, there is an intense cough with difficult to separate sputum, shortness of breath even with minor physical exertion, subfebrile body temperature, general weakness, sweating. At the same time, there is a violation of the exocrine function of the pancreas. In the remission phase, working capacity is not fully restored, shortness of breath during physical exertion remains.

Severe course is characterized by very frequent exacerbations of the disease. Remissions are practically absent. In the clinical picture, severe respiratory failure, symptoms of chronic pulmonary heart disease, often decompensated, hemoptysis is typical, come to the fore. Significant weight loss is observed, patients are completely disabled. As a rule, severe bronchopulmonary pathology is accompanied by a sharply expressed dysfunction of the pancreas.

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Forms

1. Bronchopulmonary lesions
   • Repeated and recurrent pneumonia with a protracted course.
   • Abscessing pneumonia, especially in infants.
   • Chronic pneumonia, especially bilateral.
   • Bronchial asthma refractory to traditional therapy.
   • Recurrent bronchitis, bronchiolitis, especially with Pseudomonas aeruginosa culture.
2. Changes in the gastrointestinal tract
   • Meconium ileus and its equivalents.
   • Syndrome of impaired intestinal absorption of unknown genesis.
   • Obstructive jaundice in newborns with a protracted course.
   • Liver cirrhosis.
   • Diabetes mellitus.
   • Gastroesophageal reflux.
   • Cholelithiasis.
   • Rectal prolapse.
3. Changes in other organs and systems
   • Growth and developmental disorders.
   • Delayed sexual development.
   • Male infertility.
   • Nasal polyps.
   • Siblings from families with cystic fibrosis.

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Complications and consequences

Complications from the gastrointestinal tract include:

• Diabetes mellitus develops in 8-12% of patients over 25 years of age.
• Fibrosing colonopathy.
• Meconium ileus in the neonatal period (in 12% of newborns with cystic fibrosis), distal intestinal obstruction syndrome, rectal prolapse, peptic ulcer disease and gastroesophageal reflux disease.

Liver complications:

• Fatty liver disease (in 30-60% of patients),
• Focal biliary cirrhosis, multinodular biliary cirrhosis, and associated portal hypertension.

Portal hypertension sometimes leads to death due to esophageal varices.

The prevalence of cholecystitis and gallstones is higher in patients with cystic fibrosis than in other individuals.

Delayed puberty and decreased fertility and other complications. Most men have azoospermia and underdevelopment of the vas deferens.

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Diagnostics cystic fibrosis

General blood analysis - anemia of varying severity is typical, usually normo- or hypochromic. Anemia has a polyfactorial genesis (reduced absorption of iron and vitamin B12 in the intestine due to the development of malabsorption syndrome). Leukopenia is possible, with the development of purulent bronchitis and pneumonia - leukocytosis, increased ESR.

General urine analysis - no significant changes, in rare cases slight proteinuria is observed.

Coprological examination - steatorrhea, creatorrhea are observed. Becker (1987) recommends measuring chymotrypsin and fatty acids in feces. Before determining chymotrypsin in feces, it is necessary to stop taking digestive enzymes at least 3 days before the examination. In cystic fibrosis, the amount of chymotrypsin in feces is reduced, and the amount of fatty acids is increased (normal excretion of fatty acids is less than 20 mmol/day). It is necessary to take into account that increased excretion of fatty acids with feces is also observed in:

• deficiency of conjugated fatty acids in the small intestine due to liver failure, obstruction of the bile ducts, significant bacterial colonization of the small intestine (in this case, intensive hydrolysis of bile acids occurs);
• ileitis;
• celiac disease (with the development of malabsorption syndrome);
• enteritis;
• intestinal lymphomas;
• Whipple's disease;
• food allergies;
• accelerated transit of food masses in diarrhea of various origins, carcinoid syndrome, thyrotoxicosis.

Biochemical blood test - decreased total protein and albumin levels, increased levels of alpha2 and gamma globulins, bilirubin and aminotransferases (in case of liver damage), decreased activity of amylase, lipase, trypsin and iron and calcium levels (in case of development of maldigestion syndrome, malabsorption).

Sputum analysis - presence of a large number of neutrophilic leukocytes and microorganisms (during sputum bacterioscopy).

A study of the absorption function of the small intestine and the exocrine function of the pancreas reveals significant disturbances.

X-ray examination of the lungs - reveals changes, the severity of which depends on the severity and phase of the disease. The most characteristic changes are:

• increased pulmonary patterning due to peribronchial interstitial changes;
• expansion of the roots of the lungs;
• picture of lobular, subsegmental or even segmental atelectasis of the lungs;
• increased transparency of the lung fields, mainly in the upper sections, low position and insufficient mobility of the diaphragm, expansion of the retrosternal space (manifestation of pulmonary emphysema);
• segmental or polysegmental infiltration of lung tissue (in the development of pneumonia).

Bronchography reveals changes caused by obstruction of the bronchi by viscous sputum (fragmentation of the filling of the bronchi with contrast, uneven contours, the phenomenon of bronchial rupture, a significant decrease in the number of lateral branches), as well as bronchoecgases (cylindrical, mixed), localized mainly in the lower parts of the lungs.

Bronchoscopy reveals diffuse purulent bronchitis with abundant thick, viscous sputum and fibrinous films.

Spirometry - already at the early stages of the disease reveals respiratory failure of the obstructive type (decreased FVC, FEV1, Tiffno index), restrictive (decreased FVC) or, most often, obstructive-restrictive (decreased FVC, FVC, FEV1, Tiffno index).

The Gibson and Cook sweat test (sweat electrolyte test) involves stimulating sweating using pilocarpine electrophoresis with subsequent determination of chlorides in the sweat. Doerehuk (1987) describes the test as follows. Pilocarpine electrophoresis is performed on the forearm, the electric current is 3 mA. After cleansing the skin with distilled water, the sweat is collected using filter paper placed on the stimulated area, covered with gauze to prevent evaporation from it. After 30-60 minutes, the filter paper is removed and eluted in distilled water. The amount of sweat collected is measured. To obtain reliable results, it is necessary to collect at least 50 mg (preferably 100 mg) of sweat.

If the chloride concentration is more than 60 mmol/l, the diagnosis of cystic fibrosis is considered probable; if the chloride concentration is more than 100 mmol/l, it is reliable; in this case, the difference in the concentration of chlorine and sodium should not exceed 8-10 mmol/l. Hadson (1983) recommends that if the sodium and chloride content in sweat is borderline, a prednisolone test should be performed (5 mg orally for 2 days, followed by determination of electrolytes in sweat). In individuals who do not suffer from cystic fibrosis, the sodium level in sweat decreases to the lower limit of normal; in cystic fibrosis, it does not change. A sweat test is recommended for every child with a chronic cough.

Analysis of blood spots or DNA samples for major mutations of the cystic fibrosis gene is the most sensitive and specific diagnostic test. However, this method is only suitable for countries where the delta-P508 mutation rate is higher than 80%. In addition, the technique is very expensive and technically complex.

Prenatal diagnosis of cystic fibrosis is performed by determining the isoenzymes of alkaline phosphatase in amniotic fluid. This method becomes possible from 18-20 weeks of pregnancy.

The main criteria for diagnosing cystic fibrosis are the following:

• indications in the anamnesis of delayed physical development in childhood, recurrent chronic respiratory diseases, dyspeptic disorders and diarrhea, the presence of cystic fibrosis in close relatives;
• chronic obstructive bronchitis, often recurrent, with the development of bronchiectasis and pulmonary emphysema, often recurrent pneumonia;
• chronic recurrent pancreatitis with a marked decrease in exocrine function, malabsorption syndrome;
• increased chlorine content in the patient's sweat;
• infertility with preserved sexual function.

Successful diagnosis and differential diagnosis of cystic fibrosis is facilitated by identifying risk groups.

Cystic Fibrosis Screening Program

1. General analysis of blood, urine, sputum.
2. Bacteriological analysis of sputum.
3. Coprological analysis.
4. Biochemical blood test: determination of total protein and protein fractions, glucose, bilirubin, aminotransferases, alkaline phosphatase, gamma-glutamyl transpeptidases, potassium, calcium, iron, lipase, amylase, trypsin.
5. Study of the exocrine function of the pancreas and the absorptive function of the intestine.
6. Fluoroscopy and radiography of the lungs, CT scan of the lungs.

7. ECG.
8. Echocardiography.
9. Bronchoscopy and bronchography.
10. Spirometry.
11. Sweat test.
12. Consultation with a geneticist.
13. Analysis of blood spots or DNA samples for major mutations of the cystic fibrosis gene.

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Treatment cystic fibrosis

The type and severity of cystic fibrosis symptoms can vary greatly, so there is no typical treatment plan; it is individualized to each individual.

The therapy consists of the following therapeutic measures:

• Breathing exercises and postural drainage help to get rid of thick mucus that accumulates in the lungs. Some airway clearing techniques require help from family members, friends, or a pulmonologist. Many people use an inflatable chest vest that vibrates at a high frequency.

• Inhalation drugs that have bronchodilatory, draining (mucolytics) and antibacterial effects (for example, fluoroquinolones).
• Preparations containing pancreatic enzymes to improve digestion. These preparations are taken during meals.
• Multivitamins (including fat-soluble vitamins).

In 2015, the FDA approved a second drug to treat cystic fibrosis that targets a defective protein known as CFTR. The first drug, a so-called CFTR modulator, was approved in 2012. CFTR modulators are expected to extend the lives of some people with cystic fibrosis by decades.

Surgery may be required to treat the following respiratory complications:

• Pneumothorax, massive recurrent or persistent hemoptysis, nasal polyps, persistent and chronic sinusitis.
• Meconium ileus, intussusception, rectal prolapse.

Lung transplantation is performed in the terminal stage of the disease.

Forecast

The average survival age of patients with cystic fibrosis ranges from 35 to 40 years. The average survival age is higher in men than in women.

With modern treatment strategies, 80% of patients reach adulthood. However, cystic fibrosis significantly limits the patient's functional capabilities. There is still no cure for this disease.

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