Cystic Fibrosis
Overview
Plain-Language Overview
Cystic fibrosis is a genetic disorder that mainly affects the lungs and digestive system. It causes the body to produce thick and sticky mucus that can clog the airways and lead to breathing problems. People with cystic fibrosis often have frequent lung infections and difficulty digesting food because the mucus blocks the pancreas. This condition is present from birth and requires ongoing medical care. Although it is a serious illness, treatments have improved, helping many people live longer and healthier lives.
Clinical Definition
Cystic fibrosis is an autosomal recessive genetic disorder caused by mutations in the CFTR gene, which encodes the cystic fibrosis transmembrane conductance regulator protein. This protein functions as a chloride channel critical for maintaining salt and water balance across epithelial surfaces. Defective CFTR leads to impaired chloride and bicarbonate transport, resulting in thick, viscous secretions in multiple organs. The lungs are primarily affected, with mucus accumulation causing chronic bacterial infections, inflammation, and progressive bronchiectasis. The pancreas also suffers from exocrine insufficiency due to ductal obstruction, leading to malabsorption and nutritional deficiencies. Other manifestations include elevated sweat chloride levels, male infertility due to congenital bilateral absence of the vas deferens, and liver disease from biliary obstruction. Diagnosis is supported by clinical features, elevated sweat chloride testing, and genetic analysis. Management focuses on airway clearance, infection control, pancreatic enzyme replacement, and nutritional support. The disease course is variable but often progressive, with respiratory failure being the leading cause of mortality.
Inciting Event
- There is no specific inciting event; disease manifestations result from genetic mutation and progressive organ damage.
Latency Period
- none
Diagnostic Delay
- Mild or atypical symptoms in early life can lead to delayed recognition of cystic fibrosis.
- Misattribution of respiratory symptoms to recurrent infections without considering CF delays diagnosis.
- Lack of newborn screening in some regions contributes to delayed diagnosis.
Clinical Presentation
Signs & Symptoms
- Chronic productive cough with thick sputum.
- Recurrent respiratory infections.
- Malabsorption leading to steatorrhea and failure to thrive.
- Salty-tasting skin due to elevated sweat sodium and chloride.
- Nasal polyps and sinusitis.
History of Present Illness
- Chronic productive cough with thick sputum and recurrent respiratory infections.
- Poor weight gain and failure to thrive despite adequate nutrition.
- Steatorrhea and bulky, foul-smelling stools due to pancreatic insufficiency.
- Nasal polyps and chronic sinusitis may be present.
- Episodes of dyspnea and wheezing due to airway obstruction.
Past Medical History
- History of recurrent respiratory infections including pneumonia and bronchitis.
- Previous diagnosis of meconium ileus in the neonatal period.
- Chronic pancreatic insufficiency requiring enzyme replacement therapy.
- History of infertility in males due to congenital bilateral absence of the vas deferens.
Family History
- Autosomal recessive inheritance pattern with affected siblings or relatives.
- Family members may be carriers of CFTR mutations without symptoms.
- Positive family history of cystic fibrosis or related symptoms such as chronic lung disease or pancreatic insufficiency.
Physical Exam Findings
- Digital clubbing of the fingers due to chronic hypoxia.
- Crackles and wheezes heard on lung auscultation.
- Nasal polyps visible on nasal examination.
- Barrel-shaped chest from chronic lung disease.
- Signs of malnutrition such as thin extremities and poor muscle mass.
Diagnostic Workup
Diagnostic Criteria
Diagnosis of cystic fibrosis requires either a positive newborn screening or clinical features consistent with the disease, plus evidence of CFTR dysfunction. This evidence includes an elevated sweat chloride concentration greater than 60 mmol/L on two separate occasions, identification of two disease-causing CFTR mutations, or abnormal nasal potential difference testing. Clinical features often include chronic respiratory symptoms, pancreatic insufficiency, or a family history of cystic fibrosis. Confirming the diagnosis early is critical for initiating appropriate management.
Pathophysiology
Key Mechanisms
- Mutation in the CFTR gene leads to defective chloride channel function, causing thick, viscous secretions in multiple organs.
- Impaired chloride and bicarbonate transport results in dehydrated mucus, promoting airway obstruction and chronic infection.
- Viscous secretions cause pancreatic duct obstruction, leading to exocrine pancreatic insufficiency and malabsorption.
- Chronic pulmonary infections and inflammation cause progressive bronchiectasis and respiratory failure.
| Involvement | Details |
|---|---|
| Organs | Lungs are primarily affected with chronic infection, inflammation, and bronchiectasis. |
| Pancreas shows exocrine insufficiency due to ductal obstruction and fibrosis. | |
| Sinuses often develop chronic sinusitis and nasal polyps. | |
| Liver may develop focal biliary cirrhosis from bile duct obstruction. | |
| Intestines can have meconium ileus in neonates and distal intestinal obstruction syndrome. | |
| Tissues | Respiratory epithelium is thickened and inflamed due to chronic infection and mucus stasis. |
| Pancreatic tissue undergoes fibrosis and fatty replacement due to duct obstruction. | |
| Intestinal mucosa may be affected by malabsorption and inflammation. | |
| Lymphoid tissue in the lungs is hyperplastic due to chronic immune activation. | |
| Fibrotic tissue replaces normal lung parenchyma in advanced disease. | |
| Cells | Epithelial cells in the respiratory tract are defective in CF, leading to impaired chloride transport and thick mucus. |
| Neutrophils accumulate in the lungs causing chronic inflammation and tissue damage. | |
| Pancreatic acinar cells fail to secrete adequate digestive enzymes due to duct obstruction. | |
| Goblet cells produce excessive thick mucus contributing to airway obstruction. | |
| Macrophages participate in the inflammatory response but have impaired bacterial clearance. | |
| Chemical Mediators | Interleukin-8 (IL-8) attracts neutrophils to the lungs, promoting inflammation. |
| Tumor necrosis factor-alpha (TNF-α) amplifies the inflammatory response in lung tissue. | |
| Transforming growth factor-beta (TGF-β) contributes to fibrosis and airway remodeling. | |
| Reactive oxygen species (ROS) released by neutrophils cause tissue damage. | |
| Mucins are glycoproteins that increase mucus viscosity and impair clearance. |
Treatment
Pharmacological Treatments
CFTR modulators
- Mechanism: Improve function of defective CFTR protein by potentiating or correcting its folding and trafficking
- Side effects: headache, nausea, elevated liver enzymes
Inhaled antibiotics
- Mechanism: Target chronic lung infections by reducing bacterial load in airways
- Side effects: bronchospasm, cough, voice alteration
Pancreatic enzyme replacement therapy
- Mechanism: Provides digestive enzymes to aid nutrient absorption due to pancreatic insufficiency
- Side effects: abdominal pain, constipation, fibrosing colonopathy
Mucolytics (e.g., dornase alfa)
- Mechanism: Break down DNA in mucus to reduce viscosity and improve clearance
- Side effects: voice alteration, pharyngitis, rash
Bronchodilators
- Mechanism: Relax airway smooth muscle to improve airflow
- Side effects: tremor, tachycardia, nervousness
Non-pharmacological Treatments
- Chest physiotherapy is used to mobilize and clear thick mucus from the lungs.
- Nutritional support including high-calorie, high-fat diet helps manage malabsorption and maintain growth.
- Regular aerobic exercise improves pulmonary function and overall health.
- Lung transplantation may be considered in end-stage pulmonary disease.
- Avoidance of respiratory irritants and infections reduces exacerbations.
Prevention
Pharmacological Prevention
- Use of CFTR modulators (e.g., ivacaftor) to improve protein function in eligible mutations.
- Prophylactic antibiotics to prevent bacterial infections during exacerbations.
- Supplementation with pancreatic enzymes to prevent malabsorption complications.
- Vitamin A, D, E, and K supplementation to prevent deficiencies.
Non-pharmacological Prevention
- Chest physiotherapy to enhance mucus clearance.
- Nutritional support with a high-calorie, high-fat diet to maintain growth.
- Regular vaccinations including influenza and pneumococcal vaccines.
- Avoidance of smoking and environmental lung irritants.
- Early genetic counseling and newborn screening for early diagnosis.
Outcome & Complications
Complications
- Bronchiectasis leading to chronic lung damage.
- Pneumothorax from ruptured blebs.
- Respiratory failure due to progressive lung disease.
- Cor pulmonale from chronic hypoxic pulmonary vasoconstriction.
- Meconium ileus in newborns causing intestinal obstruction.
| Short-term Sequelae | Long-term Sequelae |
|---|---|
|
|
Differential Diagnoses
Cystic Fibrosis versus Asthma
| Cystic Fibrosis | Asthma |
|---|---|
| Persistent productive cough with thick, sticky sputum due to mucus plugging. | Intermittent wheezing and dyspnea triggered by allergens or exercise. |
| Elevated sweat chloride and genetic testing confirming CFTR mutation. | Normal sweat chloride and absence of pancreatic insufficiency. |
| Associated pancreatic insufficiency leading to malnutrition and steatorrhea. | Improvement with bronchodilators and corticosteroids. |
Cystic Fibrosis versus Bronchiectasis (non-CF related)
| Cystic Fibrosis | Bronchiectasis (non-CF related) |
|---|---|
| Diffuse bronchiectasis with elevated sweat chloride and CFTR mutations. | Localized or diffuse bronchial dilation on imaging without elevated sweat chloride. |
| Presence of pancreatic exocrine insufficiency causing malabsorption. | History of recurrent pulmonary infections due to other causes (e.g., immunodeficiency). |
| Meconium ileus or other neonatal intestinal obstruction. | Absence of pancreatic insufficiency and normal growth parameters. |
Cystic Fibrosis versus Primary Ciliary Dyskinesia
| Cystic Fibrosis | Primary Ciliary Dyskinesia |
|---|---|
| Elevated sweat chloride concentration (>60 mmol/L) confirming CFTR dysfunction. | Presence of chronic sinusitis and bronchiectasis with normal sweat chloride test. |
| Presence of meconium ileus in the neonatal period. | History of neonatal respiratory distress without meconium ileus. |
| Pancreatic exocrine insufficiency causing malabsorption and steatorrhea. | Associated with situs inversus in about 50% of cases (Kartagener syndrome). |