What is cystic fibrosis?

What is Cystic Fibrosis

Cystic fibrosis is a life-threatening autosomal recessive genetic disorder caused by mutations in the CFTR gene on chromosome 7, resulting in defective chloride and sodium transport across epithelial cells, which produces abnormally thick mucus that obstructs the lungs, pancreas, and other organs, leading to progressive respiratory failure and premature death. 1

Genetic Basis and Epidemiology

• CF is the most common lethal hereditary disorder in Caucasians, with an incidence of approximately 1 in 2,500 to 3,500 live births among non-Hispanic whites 1
• The disease occurs in virtually all ethnic groups but with varying frequencies: 1 in 4,000-10,000 births among Hispanics and 1 in 15,000-20,000 births among non-Hispanic blacks 1
• Approximately 1 in 25 Caucasians are heterozygous carriers 1
• The CFTR gene on chromosome 7q31.2 contains 27 coding exons spanning approximately 230 kb of genomic sequence 1
• Over 1,000 mutations have been identified in the CFTR gene, with the ΔF508 deletion accounting for 30-88% of CF chromosomes worldwide, particularly in persons of northern European ancestry 1

Molecular Pathophysiology

• The CFTR protein is a 1,480 amino acid transmembrane conductance regulator that functions as a cAMP-regulated chloride channel critical for normal ion and fluid transport across epithelial cells 1
• CFTR mutations result in defective chloride and sodium transport in epithelial cells of the sweat glands, airways, pancreas, intestine, liver, and reproductive tract 1
• The abnormal ion transport leads to inadequate hydration of mucus and other exocrine secretions, causing them to become abnormally thick and viscous 1, 2
• In the airways, diminished chloride and water secretion produces viscous secretions with impaired mucociliary clearance 1

Clinical Manifestations

Pulmonary Disease

• Pulmonary disease is the critical factor determining prognosis and survival, accounting for premature death in 90% of CF patients 1
• Thick mucus adheres to airway surfaces, leading to decreased mucociliary clearance and increased risk for inflammation and chronic infection 1
• Recurrent and persistent pulmonary infections are common, with Pseudomonas aeruginosa being the most frequent pathogen isolated from CF sputum across all age groups 1, 3
• Progressive bronchiectasis and respiratory failure develop over time 4

Gastrointestinal and Pancreatic Disease

• Pancreatic insufficiency occurs in 85-90% of affected individuals, resulting from obstruction of intra-pancreatic ducts by thickened secretions 1
• Fat and protein malabsorption leads to steatorrhea (loose, foul-smelling fatty stools), abdominal pain, and fat-soluble vitamin deficiencies 1
• Neonatal meconium ileus occurs in 10-20% of newborns with CF 1
• Other manifestations include chronic sinusitis, nasal polyps, liver disease, and pancreatitis 1

Other Organ Systems

• Defective salt reabsorption in sweat glands produces overly salty sweat (sweat chloride >60 mmol/L), which is the basis for diagnostic testing 1
• Congenital bilateral absence of the vas deferens (CBAVD) affects the reproductive tract 1
• Electrolyte imbalance and dehydration can occur in certain cases 1

Diagnosis

• Newborn screening programs measure immunoreactive trypsin as the initial screening test 1
• Definitive diagnosis requires sweat chloride testing with values ≥60 mmol/L considered diagnostic 1
• Genetic testing for CFTR mutations confirms the diagnosis and identifies specific pathogenic variants 1

Prognosis and Survival

• The overall average survival of patients with CF is approximately 30 years (based on 2002 data), though this has improved with modern therapies 1
• Declining lung function is associated with decreasing nutritional status, leading to increased mortality 1
• Good nutritional status is clearly linked to better lung function, which improves clinical outcomes and survival 1
• Patients with pancreatic sufficiency experience fewer pulmonary problems and have lower mortality compared to those with pancreatic insufficiency 1

Management Principles

• Treatment remains primarily palliative and includes three main strategies: control of infections, clearance of mucus from the lungs, and nutritional support with pancreatic enzyme replacement 1
• Careful nutritional management with a high-fat/high-energy diet, pancreatic enzyme replacement therapy, and supplementation of fat-soluble vitamins and essential fatty acids has dramatic effects on growth and survival rates 4
• Antibiotic therapy against Pseudomonas aeruginosa is critical, with combination therapy preferred over monotherapy to delay antibiotic resistance 3
• Highly effective CFTR modulator therapies that target the underlying molecular defect have fundamentally changed the therapeutic landscape for up to 90% of genetically eligible patients 5