What is cystic fibrosis and what symptoms does it have? Causes, diagnosis

Cystic fibrosis (CF) is an inherited disease. It affects multiple organs of the human body. It is recognisable at birth, but some forms may not be diagnosed until adulthood.

The most serious part of cystic fibrosis is thought to be damage to the lungs and liver. This is ultimately the cause of the shortened life of cystic fibrosis patients.

Treatment is complex and addresses symptoms in all organ systems. Failure of conservative treatment is followed by organ transplantation. Transplantation is often necessary at a young age.

Cystic fibrosis is a disease known since the Middle Ages. Its main symptom is the production of mucus. Because of this, it was given its older name - mucoviscidosis.

The first medical description of the disease was made in 1936 by Dr. Fanconi, a paediatrician working in Switzerland. Over time, he was joined by other doctors and scientists who added important findings to the diagnosis.

One of the most important discoveries in relation to this disease was the localisation of the gene whose mutation causes cystic fibrosis and its symptoms.

This discovery was made by molecular biologists Robert Williamson and L. C. Tsui, who located the gene in 1985 and successfully isolated it and its product in 1989.

The gene for cystic fibrosis is located on chromosome 7. Its product is the cystic fibrosis transmembrane conductance regulator (CFTR).

This is a chloride channel that is found in the membranes of every single cell in the human body. It passes chloride ions outwards or inwards into the cell. Mutations in this gene will cause the chloride channel to become dysfunctional.

One in 2,500 children will be born with a mutation in the CFTR gene. This is the most common inherited disease in the Caucasian race. In the past, the disease was considered fatal because children often did not reach puberty.

With today's modern treatments, cystic fibrosis is considered a "life-shortening" disease.

A person with cystic fibrosis can live to be 45 years old.

However, CFTR mutation carriage is much more common in the population. Approximately one in 25 people carries the chloride channel mutation.

Paradoxically, in the Middle Ages, these people were favored with "immunity" to the deadly cholera (the causative agent of Vibrio cholerae).

Cholera caused massive diarrhea with massive leakage of salts and water from the body. People died mainly from dehydration and internal environmental disruption.

However, the cholera toxin could not bind to the mutated CFTR channel. Thus, people with this mutation did not develop diarrhoea with chloride and water leakage.

The main cause of cystic fibrosis is a mutation in the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene, which is located on the long arm of chromosome 7.

In practice, this means that both parents are carriers of the mutation, called asymptomatic heterozygotes (Aa).

If their child inherits the recessive allele (a) from each parent, the child will develop the disease (aa). If both parents carry the mutated gene, the chance of having a sick child is 25%.

The disease is always inherited horizontally, i.e. from parent to offspring, in two generations. Both sexes can be affected equally. In consanguineous marriages, the risk of the mutation increases.

There are currently approximately 1500 known mutations that can damage the cystic fibrosis gene and disable the chloride channel.

Dysfunction of the gene is defined as a complete failure of the gene to function, an inability to integrate into the cell membrane in the correct place or insufficient production of the gene in the body.

In addition to moving chloride ions in and out of the cell, the chloride channel has many other functions.

It regulates other membrane channels for the movement of other ions, acidifies cell organelles (specifically the Golgi apparatus, which is actively involved in the transport of important products), regulates the transport of proteins into and out of the cell, and is responsible for the antibacterial and bactericidal ability of cells by forming nitrogen oxides.

Chloride channel dysfunction causes high levels of chloride (Cl) and sodium (Na) ions in sweat. The sweat of children with cystic fibrosis is therefore salty (NaCl).

There is increased sodium absorption in other important organ systems such as the respiratory system, gastrointestinal system (especially the pancreas, gallbladder, liver, intestine) and reproductive system.

Because sodium is also absorbed into the cells at an increased rate with water, all secretions produced by the organs are dehydrated.

Dehydration of secretions results in thick and viscous mucus in the respiratory tract, impaired secretion of pancreatic enzymes, thickened bile, thick mucus in the intestines, in the genital tract, and decreased sperm production.

Impaired acidification (decreased pH) of the Golgi apparatus results in decreased production of important chemical sulfur compounds that have the function of "thinning" mucus.

A second important function of the Golgi apparatus is the activity of sialotransferases, the disruption of which results in the production of asialogylcosides, which subsequently form a receptor for bacteria primarily from the Pseudomonas species group.

These are strains of bacteria that are resistant to a wide range of antibiotics. Their treatment is difficult and lengthy. Chronic colonisation by this pathogen is typical of patients with cystic fibrosis.

Cystic fibrosis is a disease with damage to multiple organs. Chloride channel dysfunction affects all organs with their progressive loss.

Symptoms from the respiratory system

The thickened mucus present in the airways clogs especially the small parts of the bronchial tree. The movement of tiny cilia is also prevented. Cilia are thin projections of mucous membrane that clear the airways by their undulating movement.

As a result, the natural defences of the airway mucosa are reduced. In addition, the exhaled air contains low levels of nitrogen, which has an antimicrobial function.

These pathological processes result in the following symptoms:

• immune-mediated chronic airway inflammation
• bronchiectasis (dilatation of bronchioles with inflammation)
• formation of cysts with a rim of fibrous (stiff and inflexible) tissue
• chronic inflammation of the paranasal sinuses - pansinusitis
• nasal polyps
• repeated infections with resistant bacteria of the genera Pseudomonas, Streptococcus Aureus, Haemophilus Influenzae and Burkholderia Cepacia, leading to cepacia syndrome (inflammation of the lungs with abscess formation and development of sepsis and organ failure)
• frequent mycoses - infections of the respiratory tract by fungi
• respiratory insufficiency (lung failure) leading to premature death
• stiff fingers - caused by opening of vascular connections during prolonged hypoxia (insufficient oxygen supply to tissues)

Symptoms from the digestive system

Thickened mucus is present in the intestines. It impedes the movement of intestinal villi and impairs intestinal passage. Intestinal blockage occurs.

This symptom may be present in a baby already in utero. Meconium (similar to fetal stool) accumulates in the intestines and the baby is unable to expel the first stool after birth. An intestinal obstruction called meconium ileus develops.

In adulthood, this is called distal intestinal obstruction syndrome (DIOS). It is caused either by insufficient fluid intake or by eating sticky food such as cooked corn.

The pancreas is a gland that secretes liquid pancreatic juices containing digestive enzymes. When these juices become thick and drain, the ducts of the gland become blocked.

However, the pancreas does not stop producing these juices. The juices accumulate inside the organ and form cysts. The cysts are encased in hard fibrotic tissue.

The pressure of the accumulating secretion and the numerous cysts degrade the pancreatic tissue, which gradually loses its function of producing enzymes.

The juice-filled cysts burst when overfilled. Digestive enzymes spill into the surrounding organs, digesting, destroying and "nibbling" the surrounding abdominal organs.

This condition is accompanied by severe pain in the upper abdomen, around the umbilicus and below the left rib cage. The condition is called pancreatitis.

Pancreatitis recurs episodically. The inflamed tissue heals and forms a fibrotic scar. Cystic fibrosis of the pancreas develops. This typical symptom may be the first and only sign of cystic fibrosis.

Repeated inflammation of the pancreas and the formation of the fibrous scar also damage the islets of Langerhans, which produce insulin. Reduced secretion of insulin into the blood results in the development of diabetes mellitus.

The bile ducts contain thickened bile, which is difficult to excrete. Stasis of bile and formation of gallstones occurs. Chronic inflammation leads to necrosis (death) of cells and formation of fibrotic tissue. This leads to liver cirrhosis.

The reduced defences of the mucous membrane of the digestive tract lead to the proliferation of bacteria, especially clostridia. These bacteria cause diarrhoea, which is accompanied by pancreatic disorders with a high content of fatty stools.

Summary of GIT symptoms:

• intestinal obstruction
• recurrent pancreatitis
• diabetes
• gallstone formation and gallbladder inflammation
• cirrhosis of the liver
• clostridial diarrhoea
• prolapse of the rectum

Malnutrition in patients with CF

Patients with cystic fibrosis, which causes breathing difficulties, chronic cough and recurrent infections, have increased nutritional requirements.

Poor intestinal passage, impaired absorption of nutrients through thick mucus covering the intestinal mucosa, dysfunctional pancreas and reduced digestive enzymes, gallstones and impaired secretion of bile into the intestine cause impaired digestion and absorption of important nutrients, especially fats.

In addition, the swallowing of coughed-up mucus, abdominal pain and the presence of chronic inflammation in the body reduce appetite. CF patients therefore suffer from malnutrition and malnutrition. They may suffer from severe vitamin deficiencies, especially those that are fat-soluble, i.e. A, D, E and K.

Symptoms in the reproductive system

Sexual maturation and the onset of puberty are delayed in children with CF. This is due to chronic inflammation and malnutrition. This is mainly due to a lack of fats, which are essential for sexual maturation and the production of sex hormones.

The majority of men (98%) with cystic fibrosis are infertile. This is due to the narrowing or 'sticking together' of the walls of both fallopian tubes.

The fallopian tubes carry sperm from the testicles to the urethra, where they are expelled during ejaculation. Sperm cannot pass from the testicle to the ejaculate. Sexual function is, however, completely preserved.

Female infertility is less common. 80% of women can conceive and even bear a healthy newborn. Conception is more difficult, however, because of the thick mucus present on the cervix, which makes it difficult for the sperm to pass to the egg.

Pregnancy itself also carries risks, worsening the course of the disease and increasing the oxygen and nutrient requirements. Therefore, it is necessary to plan the pregnancy in advance, consider the patient's health and monitor the entire pregnancy carefully.

In case of problems with pregnancy, in vitro fertilisation in assisted reproduction centres can be used.

Sweat glands and cystic fibrosis

People with cystic fibrosis sweat just like healthy people and secrete the same amount of sweat.

However, the impaired absorption of salts means that NaCl is not reabsorbed in the sweat duct. Therefore, these salts are subsequently excreted to the skin surface at an increased rate.

This feature of 'salty skin' has been considered a symptom of CF in the past. In fact, 1-2% of patients have normal sweat duct function.

In addition to the typical symptoms of the disease, there are a number of tests that can confirm the diagnosis of cystic fibrosis.

A major advance in diagnosis has been the introduction of whole-baby newborn screening to confirm cystic fibrosis.

It involves analysis of immunoreactive trypsin from a dry drop of blood taken from the heel of the newborn. In CF, this parameter is elevated in the blood. If positive, the child is further genetically tested to confirm the genetic mutation of the CF gene.

Another laboratory test is the so-called pilocarpine iontophoresis, which determines the chloride content of the sweat. The normal Cl level is up to 40 mmol/l. A concentration higher than 60 mmol/l confirms a chloride channel disorder.

The test is considered conclusive if at least three samples are positive. The test is carried out in specialised centres.

Haematological blood tests and haemocoagulation factor tests indicate a bleeding disorder in severe liver damage.

Analysis of fat loss, which is excreted in the faeces, will show the degree of impairment of pancreatic function.

In particular, the function of the lungs is examined in detail. Important examinations include a chest X-ray, which will show changes in the lung parenchyma.

Another functional examination of the lungs is spirometry. The patient exhales into a tube. Based on the airflow measurements, the doctor assesses the functional capacity of the lungs and thus the extent of damage to the lung tissue.

Microbiological examination of coughed sputum, nasal swabs or tonsils can show the presence of pathogens such as Pseudomonas, S. Aureus, H. Influenzae or Burkholderia cepacia, which are typical bacteria affecting the respiratory system of CF patients.

Examination for these pathogens requires lengthy culturing (growing bacteria from a swab) and also long treatment.

In addition to X-ray imaging of the lungs and abdomen, ultrasonography (USG) of the liver, gallbladder or pancreas or HRCT scanning is also used. HRCT monitors the extent of bronchiectasis and emphysema of the lungs.

If there is a family history of cystic fibrosis, genetic counselling may be carried out before a planned pregnancy. Nowadays, prenatal diagnosis, i.e. genetic testing of the child before birth, is also possible.

The first manifestations of CF most often appear in childhood.

However, in recent decades, 30% of CF patients have been diagnosed in adulthood.

These are milder forms of CF that have symptoms from only one organ system, e.g. infertility. When infertility is investigated in adulthood, reduced chloride channel function may be found due to a genetic mutation in cystic fibrosis.

The presence of CF in infancy is indicated by typical symptoms such as intestinal obstruction (meconium ileus) in the newborn immediately after birth. A second suspicious symptom in the newborn is prolonged duration of neonatal jaundice.

Preschool children often suffer from early nasal polyps (growths of the nasal mucosa) and recurrent sinus infections.

In older children, more severe symptoms are already present, such as impaired liver function, stiffening and fibrosis of the liver, coughing up bloody mucus or impaired sexual maturation (delayed puberty).

Throughout life, patients suffer from recurrent inflammation of the airways, both upper respiratory tract and lungs.

Coughing is another symptom of CF. It is choking with coughing up purulent mucus containing bacteria typical of CF, namely Pseudomonas aeruginosa, Burkholderia cepacia and Haemophilus influenzae.

With prolonged inadequate oxygen concentration in the blood, the blood vessels in the fingertips begin to open and enlarge compensatorily. This symptom is called clubbed fingers.

Over time, all the functions of the affected organs deteriorate. Repeated inflammation of the pancreas, diabetes, gallbladder colic with gallstones, liver disorder, fatty bulky stools, vitamin deficiency with malnutrition appear.

Patients of reproductive age suffer from infertility, especially men. Women are able to conceive, but pregnancy is complicated for both mother and fetus.

The survival of CF patients has increased significantly due to the availability of modern treatments. In the past, they lived a maximum of 10-15 years. Today, patients live to 45 years or more.

The cause of death is most often respiratory failure, respiratory tract infection with sepsis or bleeding from esophageal varices in cirrhosis of the liver.