Cystic Fibrosis Notes

Cystic Fibrosis

An important genetic disorder discussed under respiratory disorders due to its association with recurrent pneumonias, but remember that it is a multisystem disorder affecting the gastrointestinal tract, genitourinary tract, and sweat glands. It is one of the most common life-limiting genetic disorders, primarily observed in the Western population but increasingly reported in India. The incidence varies, but in Caucasian populations, it's approximately 1 in 2,500 to 1 in 3,500 live births.

Genetic Defect

The basic genetic defect lies in the CFTR gene. CFTR stands for Cystic Fibrosis Transmembrane Regulator. This gene codes for a protein with the same name, CFTR protein, which is a chloride channel involved in the pathogenesis of the disease. This protein regulates the movement of chloride and sodium ions across epithelial cell membranes, which is crucial for maintaining the proper consistency of mucus, sweat, and digestive fluids.

The CFTR gene is located on chromosome number 7, specifically on the long arm (q) of chromosome 7 (7q31.2). This location is critical for genetic testing and counseling.

Common Genetic Mutation

More than 2,000 mutations (up from 500) have been described in the CFTR gene, but the most common one to remember for exams is delta f508. This signifies the deletion of phenylalanine at the 508th position. This mutation results in a misfolded protein that is recognized and degraded by the cell's quality control mechanisms, preventing it from reaching the cell membrane where it functions.

Mucobiscidosis

The problems in cystic fibrosis can be summarized as mucobascidosis, indicating thick mucus secretions in the body.

Pathogenesis

Consider the respiratory tract epithelium:

  • Normal Function: CFTR channel transports chloride ions from the intracellular portion into the lumen, making the mucus thin, facilitating mucociliary clearance, enabling the mucus to be easily expelled out. Sodium and water follow chloride passively, hydrating the airway surface.

  • Cystic Fibrosis: The CFTR channel is inactive, preventing chloride ions from entering the lumen. Consequently, sodium and water are excessively absorbed from the lumen, leading to dehydration of the airway surface and very thick mucus. This cannot be easily expelled, predisposing to recurrent respiratory infections and pneumonias.

In healthy patients, the respiratory tract is clear, while in cystic fibrosis patients, the lumen is plugged with thick mucus.

Clinical Features

Cystic fibrosis is a multisystem disorder with common respiratory problems. However, it also affects the gastrointestinal tract, sweat glands, and the genitourinary tract. The severity of symptoms can vary widely among individuals due to the type of CFTR mutation and other genetic and environmental factors.

Gastrointestinal Manifestations

  • Meconium Ileus: This is an early manifestation where meconium (the first stool of a newborn) becomes very thick and gets stuck in the ileum, causing intestinal obstruction. It leads to a delay in the passage of meconium and abdominal distension. This typically occurs within the first 24-48 hours of life.

    • If present, meconium ileus is virtually diagnostic of cystic fibrosis, although it only occurs in 10-15% of the patients. A family history of CF increases the likelihood.

    • On X-ray with barium contrast enema, the colon appears small (microcolon), and there are filling defects. The level of obstruction is at the terminal ileum. Proximal parts of the ileum and jejunum are distended, showing air fluid levels. The contrast enema can sometimes relieve the obstruction.

    • Sometimes, a plain X-ray of the abdomen shows ground glass appearance in the lower abdomen due to meconium mixed with air.

  • Distal Intestinal Obstruction Syndrome (DIOS): In older children and adults, constipation occurs due to impaction of fecal material in the distal ileum. This is often associated with dehydration, decreased pancreatic enzyme use, or changes in diet. Management involves rehydration, bowel irrigation, and osmotic laxatives.

  • Exocrine Pancreatic Insufficiency: Thick pancreatic secretions are not expelled into the duodenum, leading to fat malabsorption and steatorrhea. This results in a deficiency of fat-soluble vitamins A, D, E, and K. Approximately 85-90% of children with cystic fibrosis are affected. Pancreatic enzyme replacement therapy is crucial to improve nutrient absorption.

  • Endocrine Pancreatic Problems: In the second decade, patients may develop decreased insulin secretion and potentially cystic fibrosis-related diabetes (CFRD). CFRD is distinct from type 1 or type 2 diabetes and requires careful monitoring and management, often with insulin.

  • Rectal Prolapse: Once common in older children, it has become less frequent due to early supplementation of pancreatic enzymes. It occurs due to chronic cough, malnutrition, and increased intra-abdominal pressure.

Respiratory Tract Manifestations

Recurrent infections are common. The organisms causing infection vary by age:

  • Early Childhood: Staphylococcus aureus and Haemophilus influenzae are the most common organisms. Early infections can lead to structural lung damage.

  • Late Childhood/Adolescents/Adults: Pseudomonas aeruginosa is the most common. It produces mucoid secretions, forming a biofilm that provides antibiotic resistance, making infections chronic and difficult to eradicate. Chronic Pseudomonas infection is associated with a poorer prognosis.

  • Burkholderia cepacia complex: This organism is associated with an increased risk of death and can lead to a rapid decline in lung function in patients with cystic fibrosis. Screening for Burkholderia cepacia is essential in CF care centers.

Nasal polyps are also common. Bilateral nasal polyps in a child should prompt evaluation for cystic fibrosis. They occur due to chronic inflammation and can contribute to upper airway obstruction.

Other Affected Areas

  • Biliary Tract: Can lead to biliary cirrhosis, and some newborns may present with neonatal cholestasis due to thickening of biliary secretions. Ursodeoxycholic acid may be used to improve bile flow.

  • Genitourinary Tract: All affected males are infertile due to congenital bilateral absence of the vas deferens (CBAVD) because of the failure of development of wolfian duct structures. Assisted reproductive technologies may be necessary for males desiring fertility. Females have decreased fertility rates due to thickened cervical mucus and irregular ovulation.

  • Sweat Glands: Excessive loss of sodium and chloride in sweat occurs because the CFTR protein does not properly reabsorb these electrolytes in the sweat ducts. This leads to salty-tasting skin, and frosting of the skin may be observed. Parents often notice this when kissing their child.

    • This can lead to hyponatremic hypochloremic metabolic alkalosis, particularly in hot weather or during exercise. Monitoring electrolytes is important.

    • Increased sweat chloride levels can be used for diagnosis. The sweat chloride test is performed via pilocarpine iontophoresis.

Diagnostic Criteria
Suspicion

Consider cystic fibrosis if a child has:

  • Typical clinical features (recurrent pneumonia, steatorrhea, pancreatic insufficiency, azoospermia).

  • A sibling with cystic fibrosis (autosomal recessive disorder). The recurrence risk for siblings is 25%.

  • A positive newborn screening test (Immunoreactive Trypsin Testing - IRT). Elevated IRT levels are followed by CFTR mutation analysis.

Confirmation

Confirmation is done by lab tests:

  • Elevated Sweat Chloride: Two elevated sweat chloride values (more than 60 milliequivalents per liter) via pilocarpine iontophoresis. Values between 30-59 mmol/L are considered intermediate and require further evaluation.

  • CFTR Mutation Identification: Identification of at least two cystic fibrosis-causing mutations (e.g., delta f508) through genetic testing. Carrier testing is available for family members.

  • Trans Epithelial Nasal Potential Difference Measurement: Measures the difference in electrical potential across the nasal epithelium, reflecting CFTR function. A single abnormal value is sufficient for diagnosis but is less commonly used than sweat chloride testing or genetic testing.

Management
Respiratory Care

  • Airway Clearance:

    • Physiotherapy: Chest physiotherapy (CPT), including percussion and postural drainage, helps to mobilize and clear mucus.

    • Mucolytic therapies like inhaled hypertonic saline (3% saline) and human recombinant DNase (Dornase alpha). Hypertonic saline hydrates airway secretions, while DNase breaks down DNA in mucus, reducing its viscosity.

  • Respiratory Infections:

    • Treat aggressively with antibiotics based on sputum cultures and sensitivities.

    • Common antibiotics: Co-amoxiclav (amoxicillin and clavulanic acid) as the first antibiotic, followed by fluoroquinolones or azithromycin. Inhaled antibiotics like tobramycin or aztreonam are used for chronic Pseudomonas infections.

    • Prophylaxis for Pseudomonas infection: Inhaled tobramycin or aztreonam, or oral azithromycin three times per week to decrease colonization. Long-term azithromycin can also have anti-inflammatory effects.

Dietary Management

  • High-fat, high-protein, and high-calorie diet to compensate for malabsorption and increased energy expenditure due to chronic infection and inflammation. Nutritional needs should be assessed regularly by a registered dietitian.

  • Salt supplementation, especially in hot climates or during exercise, to replace sodium and chloride losses in sweat.

  • Pancreatic enzyme supplementation: Enterically coated microspheres; this is the cornerstone of gastrointestinal management. Dosing is adjusted based on stool output and fat absorption.

  • Fat-soluble vitamin supplementation: Especially vitamin A, vitamin D, vitamin E, and vitamin K. Monitoring vitamin levels is important.

CFTR Modulators

Emerging treatments to improve CFTR channel function. These drugs can improve chloride transport and reduce the severity of CF symptoms. Genotype-based therapy is becoming increasingly important.

  • Ivacaftor: Approved for children more than two years of age who have specific CFTR mutations (e.g., G551D). It potentiates the CFTR channel, increasing the amount of time the channel is open.

  • Lumacaftor: Used in combination with ivacaftor for children more than six years of age who are homozygous for the delta f508 mutation. Lumacaftor helps the CFTR protein fold correctly, allowing it to reach the cell surface. However, it is less effective as a monotherapy.

  • Ivacaftor plus Tesacaftor: Indicated for children above the age of 12 years with certain mutations. Tesacaftor has a similar mechanism to lumacaftor, helping with CFTR protein folding.

  • Triple Combination Therapy: Ivacaftor plus tezacaftor plus elexacaftor; covers most cystic fibrosis mutations and is the most promising evolving treatment. Elexacaftor also helps with CFTR protein folding and trafficking to the cell surface. This combination has shown significant improvements in lung function and quality of life for many patients with CF.