What is cystic fibrosis?

Cystic Fibrosis: A Comprehensive Overview

Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by mutations in the CFTR gene, characterized by abnormal mucus production that affects multiple organ systems, primarily the lungs and digestive tract, leading to progressive respiratory failure and nutritional deficiencies. 1

Genetics and Pathophysiology

Cystic fibrosis results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene located on chromosome 7q31.2. This gene encodes a protein that functions as a chloride ion channel in epithelial cell membranes. Over 900 mutations have been identified, with the F508del mutation being the most common, accounting for 30-88% of CF chromosomes worldwide depending on ethnicity. 1

The CFTR protein contains five domains:

• Two membrane-spanning domains
• A regulatory domain
• Two nucleotide-binding domains that interact with ATP 1

When CFTR function is impaired, it causes:

• Defective chloride ion transport across epithelial cell membranes
• Abnormal fluid transport
• Thickened mucus secretions
• Impaired function of multiple organs 1

CFTR mutations are categorized into four classes:

1. Class I: Defective protein production
2. Class II: Defective protein processing
3. Class III: Defect in channel regulation
4. Class IV: Defective conductance through the channel (milder mutations) 1

Epidemiology

• Most common autosomal recessive disease in Caucasian populations
• Prevalence: approximately 1 in 2,500-3,500 live births in Caucasians
• Less common in other ethnic groups: 1/4,000-10,000 births in Hispanics and 1/15,000-20,000 births in non-Hispanic blacks
• Overall prevalence in the United States is approximately 1/3,700 births 1

Clinical Manifestations

Respiratory System

• Viscous mucus in the lungs leading to decreased mucociliary clearance
• Recurrent and persistent pulmonary infections
• Progressive bronchiectasis
• Chronic cough and wheezing
• Respiratory failure (primary cause of death in >90% of CF patients) 1, 2

Gastrointestinal System

• Pancreatic insufficiency (occurs in 85% of affected individuals)
• Malabsorption and steatorrhea
• Poor weight gain and growth failure
• Neonatal meconium ileus (10-20% of newborns with CF)
• Distal intestinal obstruction syndrome
• Gastroesophageal reflux disease 1, 2, 3

Other Manifestations

• Excessive salt loss through sweat glands
• Chronic sinusitis and nasal polyps
• Liver disease and hepatobiliary complications
• Pancreatitis
• CF-related diabetes
• Congenital bilateral absence of the vas deferens (CBAVD) in males 1, 2

Diagnosis

Diagnosis of CF typically involves:

1. Newborn screening: Measurement of immunoreactive trypsin
2. Sweat chloride testing: Diagnostic if >60 mmol/L
3. Genetic testing: Detection of pathogenic variants in the CFTR gene 1

Treatment Approaches

Respiratory Management

• Airway clearance techniques to remove thick secretions
• Mucolytics such as dornase alfa (Pulmozyme) to break down DNA in sputum and reduce viscosity 4, 5
• Inhaled antibiotics (e.g., tobramycin) for chronic bacterial infections, particularly Pseudomonas aeruginosa 1, 6
• Anti-inflammatory medications (e.g., azithromycin) 5
• CFTR modulators: Small molecular therapies that facilitate CFTR production and/or function, such as ivacaftor and elexacaftor-tezacaftor-ivacaftor 5

Nutritional Support

• Pancreatic enzyme replacement therapy
• High-calorie, high-protein diet
• Fat-soluble vitamin supplementation
• Nutritional monitoring and intervention 1

Management of Complications

• Treatment of acute pulmonary exacerbations with antibiotics
• Management of hemoptysis and pneumothorax
• Treatment of CF-related diabetes
• Monitoring and management of liver disease 2, 7

Prognosis

With advances in treatment, the median survival for CF patients has improved significantly. The overall average survival is approximately 30 years, though this continues to improve with newer therapies. 1, 5

Key Considerations in Management

• Early diagnosis through newborn screening allows for early intervention
• Multidisciplinary care teams including pulmonologists, gastroenterologists, dietitians, and respiratory therapists are essential
• Regular monitoring of lung function and nutritional status
• Aggressive treatment of pulmonary infections
• Attention to nutritional status and growth in children
• Genetic counseling for families 1, 5

Recent Advances

CFTR modulators represent a significant advancement in CF treatment, addressing the underlying genetic defect rather than just managing symptoms. For example, in patients with the F508del variant, the combination of elexacaftor-tezacaftor-ivacaftor has shown substantial improvements in lung function and reduced pulmonary exacerbations. 5

Gene therapy and genome editing approaches are under development as potential future treatments for CF. 8