Cystic fibrosis, sometimes referred to as cystic fibrosis (ICD-10: E84), is autosomal recessively inherited lethal exocrine disease, which primarily affects the gastrointestinal and respiratory systems. It is characterized by pancreatic failure, recurrent and chronic lung infections, intestinal obstruction, and male infertility.
Cystic fibrosis is the most common life-threatening genetic disease in the white population. The incidence is 1 in 3200 births. Due to improved therapy, about 50% of patients with cystic fibrosis are adults.
Etiology of cystic fibrosis
Cystic fibrosis gene or cyst fibrosis transmembrane permeability regulator gene (CFTR). Cystic fibrosis transmembrane conductance regulator gene ) is located on the long arm of chromosome 7 and as an autosomal recessive trait is present in about 3% of the white population.
More specifically, this gene encodes an epithelial protein chloride channel, a cAMP-regulated chloride channel that controls chlorine and sodium transport across the epithelial membrane. Epithelial channels for chloride transport in cystic fibrosis cannot be activated by cAMP, and such cells cannot excrete chlorine normally, resulting in its retention within the cells.
Epithelial sodium channels (ENaC), responsible for transporting sodium ions from the luminal secretion to the cells, are inhibited by the normal function of said chloride channels. If their function is not normal, the activity of ENaC will be increased, and a larger amount of NaCl and water will accumulate in the cell. As a result, there is an increased density of mucus that blocks the airways, pancreatic ducts, biliary ducts, and intestinal system, which is why cystic fibrosis was formerly called cystic fibrosis.
Contrary to the developments listed above, in sweat glands, CFTR mutations lead to a decrease in ENaC activity, causing NaCl accumulation in the lumen of the tubules and the formation of extremely salty sweat.
Pathophysiology
Almost all exocrine glands are affected by the disease, with a different distribution of involvement and degree of involvement. Glands may become obstructed by viscous or solid eosinophilic material in the lumen (pancreas, intestinal glands, intrahepatic bile ducts, gallbladder, and submaxillary glands); look histologically abnormal and produce too much secretion (tracheobronchial and Brunner glands); appear histologically normal but secrete excessive amounts of Na and Cl (sweat, parotid gland, and small salivary glands).
Respiratory system
The lungs are generally histologically normal at birth, but most patients begin to develop lung disease early in childhood. Mucosal plugs and chronic bacterial infections accompanied by pronounced inflammatory response damage the airways, possibly leading to bronchiectasis and respiratory failure. The disease’s course is characterized by episodic exacerbations with infections and a progressive decrease in lung function.
Lung damage probably begins with diffuse small airway obstruction with abnormally viscous mucous secretions. Bronchiolitis and mucopurulent airway obstruction occur secondary to obstruction and infections. Respiratory changes are more common than parenchymal changes, and emphysema is not prominent.
About 50% of patients have bronchial hyperreactivity that responds to bronchodilators. In patients with more advanced lung disease, chronic hypoxemia results in pulmonary artery muscle hypertrophy, pulmonary hypertension, and right ventricular hypertrophy. Most pulmonary damage can be caused by inflammation secondary to the release of proteases and proinflammatory cytokines from the airway.
Pathogenic bacteria colonize the lungs of most patients. Staphylococcus aureus is the most common pathogen early in the disease course, but as the disease progresses, it is most often isolated Pseudomonas aeruginosa. Mucoid variant P.aeruginosa is uniquely associated with cystic fibrosis and indicates a worse prognosis than the nonmucoid Pseudomonas.
The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in the respiratory tract is now higher than 25% – patients with MRSA have lower survival rates than those without MRSA. Colonization with Burkholderia cepacia complex occurs in about 3% of patients and may be associated with faster lung deterioration.
Potential pathogens are also non-tuberculous mycobacteria (e.g., Mycobacterium avium complex). The prevalence varies with age and geographical location and probably exceeds 10%.
Gastrointestinal system
The pancreas, intestines, and hepatobiliary systems are often affected by the disease. Exocrine pancreatic function is compromised in about 85 to 95% of patients.
The exception is a subgroup of patients who have certain “mild” mutations in cystic fibrosis, in which pancreatic function is consequently intact. Patients with pancreatic insufficiency have malabsorption of fat (and fat-soluble vitamins) and protein.
The duodenal fluid is abnormally viscous and shows signs of enzyme inactivation and decreased concentration of bicarbonate ion – trypsin and chymotrypsin are absent, or their concentration stool is reduced. Endocrine pancreatic dysfunction is less common, but diabetes mellitus is present in about 2% of children, 20% of adolescents, and at least 40% of adults.
The bile ducts’ involvement with the bile duct and obstruction of the bile ducts leads to asymptomatic liver fibrosis in about 30% of patients. About 2 to 3% of patients progress to irreversible multinodular biliary cirrhosis with varicose veins and portal hypertension, usually by 12—years of age. Hepatocellular failure is a rare and late event. There is an increase in cholelithiasis incidence, which is usually asymptomatic.
Abnormally viscous intestinal secretions usually cause meconium ileus in the newborn and sometimes meconium obstruction of the colon. Older children and adults may also have occasional or chronic constipation and intestinal obstruction.
Other gastrointestinal problems include intussusception, volvulus, rectal prolapse, perpendicular abscesses, pancreatitis or an increased risk of hepatobiliary and gastrointestinal tract cancer, gastroesophageal reflux disease, and esophagitis.
Infertility occurs in about 98% of adult men secondary to the development of vas deferens or other forms of obstructive azoospermia. In women, infertility is slightly lower by secondary viscous cervical secretions – many women have brought their pregnancies to term.
The outcome of pregnancy for both mother and child depends on the mother’s health. Other complications include osteopenia and osteoporosis, kidney stones, iron deficiency, anemia, episodic arthralgia, and arthritis.
Symptoms and signs
Globally, in fifty percent of newborns who have not been diagnosed with neonatal screening (genetic screening of CF is not done systematically in Croatia), lung manifestations are presented first, usually in early childhood. Recurrent or chronic infections are common and manifest by coughing, sputum production, and wheezing.
Cough is the most common complaint, accompanied by sputum, vomiting, and sleep disturbance. Intercostal retractions, accessory respiratory muscles, barrel deformity of the thorax, batty fingers, and cyanosis occur with disease progression. Upper respiratory tract involvement involves nasal polyps and chronic or recurrent sinusitis.
Adolescents may have slow growth, delayed puberty onset, and decreased physical exertion tolerance. Pulmonary complications include pneumothorax, non-tuberculous mycobacterial infections, hemoptysis, allergic bronchopulmonary aspergillosis, and right heart failure secondary to pulmonary hypertension.
Meconium ileus due to the ileum’s obstruction by viscous meconium is probably the earliest sign and is present in about 15 to 20% of neonates affected by cystic fibrosis. It is typically manifested by abdominal distension, vomiting, and the inability to pass meconium. Some newborns have intestinal perforation, with signs of peritonitis and shock.
Newborns with meconium blockage have delayed passage of meconium. They may have similar obstruction signs or very mild and transient symptoms that go unnoticed. Elderly patients may have constipation episodes or develop recurrent and sometimes chronic episodes of partial or complete small or large bowel obstruction. Symptoms include cramping, abdominal pain, changes in the pattern of defecation, decreased appetite, and sometimes vomiting.
In neonates without meconium ileus, the disease’s onset may announce a delay in regaining weight at birth or inadequate weight gain at 4. to 6. weeks of birth.
Occasionally, malnourished infants present with generalized edema secondary to protein malabsorption.
Pancreatic insufficiency
Pancreatic insufficiency is usually clinically evident early in life and can be progressive. Manifestations include frequent voluminous passage, foul-smelling, fatty stools, and slowed growth with decreased subcutaneous tissue and muscle mass despite normal appetite. Clinical manifestations may occur secondary to a deficiency in fat-soluble vitamins.
Rectal prolapse occurs in 20% of untreated children. Gastroesophageal reflux is relatively common among older children and adults.
Excessive sweating in warm weather or fever can lead to hyponatremic/hypochloremic dehydration and circulatory failure. In dry climates, newborns may present with chronic metabolic alkalosis. The formation of salt crystals and the salty taste on the skin strongly suggest cystic fibrosis.
Diagnosing cystic fibrosis
Universal neonatal screening for cystic fibrosis is not carried out systematically in Croatia. Despite advances in genetic testing, the sweat chlorine presence test remains the standard for confirming cystic fibrosis diagnosis due to its sensitivity, specificity, simplicity, and availability.
In the sweating test, localized sweating is stimulated with pilocarpine, the amount of sweat and Cl ions concentration is measured.
The results are valid after 48 hours of life, but it can be difficult to collect an adequate amount of sweat (more than 75 mg on filter paper) before 3. weeks of life. False-negative results are rare but may occur in the presence of edema and hypoproteinemia or inadequate sweating.
False-positive results usually occur due to a technical error. Although the concentration of Cl ions in sweat increases slightly with age, the sweat test is valid at any age. A positive result should be confirmed by another sweat test or by identifying a genetic mutation.
A small proportion of patients have a mild or partial cystic fibrosis phenotype, and their Cl values in sweat are consistently in the middle or even normal range. Also, some patients have manifestations of cystic fibrosis on only one organ – pancreatitis, chronic sinusitis, or congenital bilateral absence of the vas deferens, which may result from partial dysfunction of the CFTR protein.
In some of these patients, the diagnosis of CF can be confirmed by identifying two causative cystic fibrosis mutations – one in each of the CFTR genes.
The pancreatic function should be assessed at the time of diagnosis, usually by measuring 72-hour stool fat excretion or stool elastase concentration. The elastase test is valid even in the presence of exogenous pancreatic enzymes. In neonates who initially have a surplus pancreas and have two “severe” mutations, the pancreatic function should be measured serially to detect its insufficiency progression.
Cystic fibrosis – CT finding
Chest X-rays are done at the time of lung disease exacerbations and routinely every one to two years. CT can help more accurately assess lung damage. Both X-rays and CT scans can show hyperinflation and thickening of the bronchial wall as the earliest finding.
Subsequent changes include areas of infiltrating, atelectasis, and hilar adenopathy. As the disease progresses, segmental or lobar atelectasis, cyst formation, bronchiectasis, and hypertrophy of the pulmonary artery and right ventricle occur. Characteristic is the “branching,” finger-shaped opacities representing the mucous plugs of the dilated bronchi.
Pulmonary function tests are the best indication of clinical status and should be performed routinely four times a year, and certainly during the disease’s exacerbations.
They indicate hypoxemia, a reduction in forced vital capacity (FVC), forced expiratory volume in one second (FEV). 1 ) forced expiratory flow between 25% and 75% of the expired volume 25-75 ) and FEV 1 / FVC ratio; the residual volume and the ratio of residual volume to total lung capacity increase.
Fifty percent of patients have reversible airway obstruction as indicated by improved lung function after administration of aerosol bronchodilators.
Monitoring oropharyngeal or sputum culture should be performed 4 times a year, especially in patients who have not yet experienced P.aeruginosa colonization.
Newborn screening is not routine in Croatia. Screening is based on detecting elevated levels of immunoreactive trypsinogen (IRT) in the blood. A second IRT test can be done after detecting an elevated IRT level – if it is also elevated, a sweat test follows.
In the second case, the first positive IRT test may be followed by testing for CFTR mutations – if 1 or 2 mutations are identified, a sweat test is done. Both strategies have a sensitivity of 90 to 95%.
Prognosis
The disease’s course is largely determined by the degree of lung involvement by the disease. Deterioration is inevitable and leads to disability and eventual death, usually by a combination of respiratory failure and cor pulmonale. The prognosis improved, mainly due to aggressive treatment before the onset of irreversible pulmonary changes.
The average survival in Western countries is 41 years. Long-term survival is significantly better in patients without pancreatic insufficiency. The outcome is also affected by CFTR mutation profile, modification genes, airway microbiology, ambient temperature, exposure to air pollutants (including smoking), adherence to therapy, and socioeconomic status.
The best predictor of survival is FEV 1 (age and gender-adjusted).
Treatment of cystic fibrosis
Treatment of lung problems is based on preventing airway obstruction and prophylaxis against lung infections (or control of lung infections).
Prophylaxis against lung infections is based on maintaining immunity to pertussis, Haemophilus influenza, varicella, Streptococcus pneumoniae, measles, and annual influenza vaccination. A neuraminidase inhibitor may be used prophylactically in patients exposed to influenza.
Airway cleansing consisting of postural drainage, percussion, vibration, and assisted coughing is recommended at the diagnosis time and should be done regularly. Regular aerobic exercise is also recommended, which can help clear the airways. Patients with reversible airway obstruction may be given aerosol bronchodilators (corticosteroids are not effective).
Oral corticosteroids can be given to children with prolonged bronchiolitis and patients with refractory bronchospasm, allergic bronchopulmonary aspergillosis, and inflammatory complications (e.g., arthritis, vasculitis).
Prolonged use of corticosteroids (every other day) may slow the decline in lung function but is not recommended due to complications related to corticosteroids. Patients receiving corticosteroids should be monitored for potential diabetes or growth retardation.
Ibuprofen has been shown to slow the rate of decline in pulmonary function (especially in children 5 to 13 years of age) when given for seven years at a dose sufficient to achieve a plasma concentration of 50 to 100 μg / mL.
There is also ivacaftor, a drug that potentiates CFTR ion channels. Other drugs that can correct defective CFTRs or potentiate their function are studied.
Mild pulmonary exacerbations of the disease
A short antibiotic treatment based on culture results and susceptibility should be given for mild pulmonary exacerbations of the disease. For mild to severe pulmonary exacerbations, especially in patients colonized with P.aeruginosa, intravenous antibiotic therapy is recommended. Such patients often need hospital treatment. In patients with chronic colonization of P.aeruginosa, aerosol-administered antibiotics improve clinical parameters and possibly reduce the airways’ bacterial burden.
Chronic eradication Pseudomonas colonization is usually not possible. Nevertheless, it has been shown that early antibiotic therapy, at a time when the airways are initially affected by non-mucoid strains of P.aeruginosa, may be effective in eradicating the organism for some time.
Neonatal intestinal obstruction can sometimes be relieved with an enema containing hyperosmolar or iso-osmolar contrast material. Otherwise, surgical enterostomy may be required to expel viscous meconium from the intestinal lumen.
After the neonatal period, episodes of partial intestinal obstruction can also be treated with hyperosmolar iso-osmolar contrast material via enema or oral administration of intestinal lavage solution. Stool softeners such as sodium sulfosuccinate or lactulose can help prevent such episodes.
Patients with pancreatic insufficiency should be given a replacement pancreatic enzyme therapy with every meal.
Diet
Sufficient calories and protein must be included in patients with cystic fibrosis to allow for normal growth and development. The caloric amount usually has to be 30 to 50% higher than the general population’s recommendations.
Diet should also include normal to high fat intake, water-soluble multivitamin supplements double the recommended daily dose, salt supplementation during childhood, and periods of thermal stress and increased sweating. Children receiving broad-spectrum antibiotics and liver disease patients should take extra vitamin K.
Diabetes associated with cystic fibrosis is caused by insulin insufficiency and shares the characteristics of both type 1 and type 2 diabetes. Insulin is the only recommended treatment.
Patients with symptomatic right heart failure should be treated with diuretics, salt restriction, and oxygen.
Recombinant human growth hormone can improve lung function, increase bone height and mineral content, and reduce the frequency of hospitalizations. It is not usually used due to its high cost and inconvenient application.
Surgical procedures are indicated for localized bronchiectasis or atelectasis that cannot be effectively treated with drugs, nasal polyps, chronic sinusitis, bleeding from esophageal varices secondary to portal hypertension, gallbladder disease, and intestinal obstruction due to volvulus or introsusception.
Liver transplantation has been successfully performed in patients with end-stage liver disease. Bilateral lung transplantation has been performed successfully in patients with advanced lung disease, lobar liver transplantation, and combined lung and liver transplantation in patients with end-stage liver and lung disease.
Bilateral transplantation Lung for severe lung disease is becoming a slightly routine procedure, with greater success and improved techniques. About 60% of people survive 5 years after transplanting both lungs, improving.
