The genetic defect underlying cystic fibrosis, responsible for a defective CFTR protein, results in the production of thick secretions that particularly damage the respiratory and digestive systems. The most common symptoms include recurrent cough, repeated airway infections, persistent diarrhea, and thinness (or growth difficulties in childhood). These symptoms are not specific to cystic fibrosis, which is why it is often mistaken for other illnesses. There are significant variations from case to case in terms of various organs involvement and disease progression. What follows is a description of the “classic” form of the disease, prior to the appearance of CFTR protein modulators. The expectation is that these new drugs, along with others aimed at the underlying defect, will reduce symptoms and, most importantly, organ damage, especially if administered early.
The bronchi and lungs are affected by recurrent bronchitis and bronchopneumonia, triggered by specific bacteria, typically Pseudomonas aeruginosa and Staphylococcus aureus among others. The persistent presence of these bacteria results in chronic lung infection and inflammation, leading to progressive lung deterioration and a gradual decline in respiratory function, which may eventually culminate in respiratory failure (severe limitation of oxygen intake and carbon dioxide elimination). Distinctive respiratory system abnormalities include: bronchiectasis, flaccid dilation of the bronchi; atelectasis, areas of lung tissue thickened by collapse of the alveoli due to complete bronchial obstruction; and obstructive emphysema or hyperinflation due to air entrapment in some areas of the lung caused by partial bronchial obstructions. Possible complications of advanced lung disease include: pneumothorax, where air leaks from the lungs into the pleural cavity; hemoptysis or blood expectoration caused by bleeding from vessels in heavily inflamed lung areas; and allergic bronchopulmonary aspergillosis, a specific inflammatory response triggered by immune reactions to Aspergillus fumigatus, a fungus commonly colonizing the CF lung.
Symptoms can appear even in the upper respiratory tract, including nose and paranasal sinuses, and they can include chronic rhinosinusitis, nasal polyposis and occasionally mucoceles, an obstruction and dilation of certain paranasal sinuses.
The pancreas is affected in about 85% of cystic fibrosis patients, with its ducts becoming obstructed and preventing the release of digestive enzymes into the intestines, a condition called pancreatic insufficiency. This results in diarrhea with fat malabsorption and malnutrition, which typically entails growth delays in terms of weight and height gain in childhood, and delayed puberty and thinness in adolescence. In older patients, progressive pancreatic damage can lead to reduced insulin production, so some people may develop diabetes requiring insulin therapy to control blood sugar levels. However, this happens very rarely in children. In patients with pancreatic sufficiency (10-15% of cases, where the pancreas functions fully or partially), repeated episodes of acute pancreatitis may occur, eventually progressing to chronic pancreatitis as pancreatic enzymes are activated within the pancreas, causing damage and inflammation.
In about 10-15% of children with cystic fibrosis, intestinal obstruction occurs from birth and is known as meconium ileus. In these cases, the meconium (which is the material present in all newborns’ intestines) is abnormally thick, blocking and obstructing the intestine rather than being expelled. Urgent intervention, often surgical, is required to clear the blockage and restore normal intestinal function. Intestinal obstruction caused by thickened, obstructing intestinal secretions, can also develop later in life (late intestinal obstruction) and may even be the first indication leading to a diagnosis.
Some people with cystic fibrosis may also be affected by liver diseases ranging in severity. Thick bile builds up and blocks the bile ducts and, in a small number of cases (about 5%), this complication leads to liver cirrhosis with portal hypertension. In rare cases, this problem can be serious and require a liver transplant. Stagnant bile in the gallbladder can also lead to gallstones.
During warm seasons and episodes of fever, excessive sweating can lead to salt-loss syndrome, as individuals with cystic fibrosis contain excessive levels of salt in their sweat. Acute salt loss due to sweating can be a serious condition that requires prompt diagnosis and intervention, especially in young children. However, a routine salt supplement can effectively prevent these events.
People with cystic fibrosis, over time, tend to develop bone disorders, characterized by a weak scaffold and low calcium levels, leading to osteopenia and osteoporosis. These issues may arise due to poor nutritional conditions or frequent courses of cortisone therapy used to manage pulmonary symptoms.
Even though cystic fibrosis does not impact sexual function, it can lead to fertility problems and consequent difficulty or impossibility in having children naturally. In most men with cystic fibrosis, the ducts transporting sperm are blocked, a condition known as congenital bilateral absence of the vas deferens (CBAVD). A specific evaluation is recommended when a boy reaches sexual maturity to determine whether his sperm contains viable spermatozoa for potential fertilization. Even if sperm transport is blocked, the sperm can be retrieved from the testicles in order to resort to medically assisted reproductive techniques. Women with cystic fibrosis may have irregular menstrual cycles and face greater challenges with conception (hypofertility). Since this affects only a small percentage of women, it is important to use contraception for all sexually active women who wish to prevent unplanned pregnancy.
“Classic” cystic fibrosis is characterized by a combination of respiratory and intestinal symptoms, which typically appear in the first months or years of life. However, there are also milder forms that may not present symptoms for years or may only affect some organs.
The introduction of new CFTR protein modulators, especially when administered early, has the potential to alter the symptoms of the disease and its progression, possibly resulting in milder forms with slower progression of organ damage. Currently, the new modulators only partially correct the underlying defect in the CFTR protein. Nevertheless, improvements in symptoms have been observed in more advanced forms of the disease. While these new drugs may not completely reverse existing organ damage, they can slow down disease progression and significantly improve the quality of life.
Based on what we know today, the lifespan of most people with cystic fibrosis primarily depends on the progression of lung disease, which is determined by a combination of genetic and environmental factors. Genetic factors include the specific mutations in the CFTR gene and variants in other genes called modifiers. These are part of the strictly individual genetic makeup and can positively or negatively affect the CFTR gene function. Environmental factors include the treatments received and the level of adherence to them, the living environment of the person with cystic fibrosis, and the lifestyle he or she adopts. Due to the great variety of combinations of these factors, each patient experiences the disease uniquely, and accurate individual prediction of disease progression does not have sufficient scientific basis today.
The new modulators of the CFTR protein, while only effective for certain individuals with cystic fibrosis and to varying degrees, have had a major immediate impact on the disease. Future research will need to focus on identifying more potent modulators for enhanced correction of the defect, discovering equally effective drugs for currently uncorrectable mutations, and verifying whether the benefits gained from the use of modulators persist in the medium to long term.
CAUSES AND TRANSMISSION
HEALTHY CARRIES
THE CFTR GENE
DIAGNOSIS
TREATMENT