Cystic fibrosis is usually seen in Caucasians in early childhood, typified by an autosomal recessive delta 508 mutations in the CFTR gene resulting in thickened mucous affecting multiple organs and chronic respiratory failure.
Description
Cystic fibrosis (CF) is a multi-organ autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, leading to abnormal salt and water transport across epithelial surfaces. This results in the production of thick, viscous secretions in various organs, predominantly affecting the lungs and the digestive system.
Pathogenesis
CF is caused by a mutation in the CFTR gene located on the long arm of chromosome 7, which encodes a protein that regulates the movement of chloride and sodium ions across epithelial cell membranes. Mutations lead to dysfunctional or absent CFTR protein, resulting in abnormal transport of these ions, leading to the characteristic thick, sticky mucous seen in CF.
Epidemiology, Risk Factors & Associations
- Cystic fibrosis is the most common lethal autosomal recessive disorder in Caucasians, with a prevalence of about 1 in 2,500-3,500 live births. It is less common in other ethnic groups, such as the African and Asian populations.
- Both sexes are equally affected.
- The risk of CF is increased in individuals with a family history of the disease, particularly those with a sibling or parent with CF.
- Most patients diagnosed by 3 years of age
Clinical Features
- The most common clinical features of CF are recurrent respiratory infections (commonly with Pseudomonas aeruginosa), chronic sinusitis, and nasal polyps.
- Gastrointestinal symptoms are also common and include pancreatic insufficiency (leading to malabsorption and poor growth), meconium ileus in newborn
- Newborns can also present with meconium ileus, a condition where the meconium, the first stool of an infant, is overly thick and sticky, leading to intestinal obstruction.
- Other manifestations can include male infertility (due to congenital bilateral absence of the vas deferens), liver disease, and diabetes.
Complications
- Chronic respiratory failure: due to progressive lung damage from recurrent infections and bronchiectasis, the leading cause of mortality in CF.
- CF-related diabetes: due to progressive destruction of the insulin-producing islet cells in the pancreas.
- Liver disease: Up to a third of CF patients can develop liver disease from prolonged biliary obstruction, which can progress to cirrhosis
- Meconium ileus: in infants
- DIOS (Distal Intestinal Obstruction Syndrome): Partial or complete obstruction of the distal bowel by sticky stool
- Nutritional deficiencies: Fat-soluble vitamin deficiencies (A, D, E, K) due to pancreatic insufficiency and malabsorption
- Osteoporosis: Due to vitamin D deficiency and general malnutrition
- Infertility: 95% of men with CF are infertile due to congenital absence of the vas deferens. Females have reduced fertility due to thick cervical mucous.
Subtypes
There is no subtype classification for CF. However, the clinical manifestations can vary widely among individuals with CF, depending largely on the specific CFTR mutation and other modulating factors.
Pathological Features
Microbiology
- Staphylococcus aureus: Predominantly seen in younger patients, often the first pathogen to colonise the lungs in CF.
- Pseudomonas aeruginosa: The prevalence of this pathogen increases with age, becoming the most common and significant pathogen in adolescents and adults with CF. It is associated with more severe disease progression and a decline in lung function.
- Haemophilus influenzae: Frequently seen in infants and young children with CF, but its prevalence decreases with age.
- Burkholderia cepacia complex: Though less common, it’s particularly worrisome due to its associated with cepacia syndrome, a rapid decline in lung function and severe systemic illness.
- Non-tuberculous mycobacteria (NTM): Seen in a minority of CF patients, but associated with significant morbidity.
- Fungal pathogens such as Aspergillus fumigatus and Candida albicans can also be seen in CF patients, often as co-infections with bacterial pathogens.
Morphology
- Characteristically, there is plugging of various ducts (respiratory, gastrointestinal, reproductive) with thick, tenacious mucus. The lungs show evidence of chronic infection and inflammation, bronchiectasis, and abscess formation. The pancreas may show fibrosis and destruction of the exocrine glands.
Histopathology
- Characteristic goblet cell hyperplasia, chronic inflammation, and mucus plugging in the respiratory tract. The pancreas often shows loss of acinar tissue, fibrosis, and cystic dilation of ducts.
Biochemistry
- Positive chloride sweat test – from abnormal chloride transport across the epithelial cells on the body’s mucosal surfaces, leading to decreased secretion of water and sodium chloride, resulting in thick mucus.
Genetics
- CF is an autosomal recessive disorder caused by mutations in the CFTR gene. There are over 2,000 known mutations, with delta F508 being the most common.
Radiological Features
General Features
The imaging findings in CF are typically most pronounced in the lungs, where chronic infection and mucus plugging lead to:
- Bronchial wall thickening (earliest finding)
- Bronchiectasis (worse in the upper lobes, right more than left) – progresses from cylindrical type in early stages, to varicoid, saccular and cystic types in advanced disease.
- Mucous plugging, branching opacities, tree-in-bud nodularity, associated atelectasis
- Airspace consolidation from recurrent infections
- Pancreatic insufficiency or intestinal obstruction.
- May be evidence of pulmonary hypertension with enlargement of the central pulmonary arteries and right ventricular enlargement.
By Stage:
- Early Disease: Early radiographic findings may include peribronchial cuffing and tram-line opacities due to bronchial wall thickening. There may also be evidence of hyperinflation due to air trapping.
- Moderate Disease: As disease progresses, more severe bronchiectasis may be seen, characterised by bronchial dilatation, wall thickening and “tree-in-bud” opacities. Mucous plugging and areas of atelectasis or consolidation secondary to infection are also frequently seen.
- Advanced Disease: In advanced disease, extensive bronchiectasis with cystic changes and fibrosis are often present.
Radiological Features
XR
- Early disease: Hyperinflation, bronchial wall thickening, mucous plugging (finger in glove opacities)
- Moderate disease: Ring shadows and tramline shadows (due to bronchiectasis), cystic or saccular bronchiectasis
- Severe disease: Bullae and pneumothorax may be seen due to lung damage
- Normal to increase lung volumes are typical, indicating air-trapping and small airways disease
CT
- Common findings include bronchial wall thickening, mucus plugging, bronchiectasis, a tree-in-bud pattern representing small airways disease, and emphysematous changes.
- Mosaic pattern of attenuation secondary to air trapping due to obstructed bronchi and bronchioles
- In the pancreas, fatty replacement, calcifications, cysts, and fibrosis can be seen due to chronic pancreatic inflammation and damage. There may be sparing of the head.
- In the head, pansinusitis: Hypodeveloped, opacified paranasal sinuses, nasal polyps
US
- Ultrasound may be used to evaluate for complications such as liver disease. Liver findings can include fatty infiltration and cirrhosis.
Grading and Staging
There is no specific grading or staging system for CF. However, the severity of the disease can be estimated using pulmonary function tests, imaging studies, and the nutritional status of the patient.
Differential Diagnosis
Differential diagnoses include other causes of bronchiectasis (such as primary ciliary dyskinesia and immunodeficiency states), other causes of malabsorption (such as coeliac disease), and other causes of neonatal intestinal obstruction (such as Hirschsprung disease).
Management
Management of CF is multidisciplinary and involves respiratory physicians, gastroenterologists, dietitians, physiotherapists, and social workers. Treatment focuses on maintaining lung function,