Background Information

Definitions

Cystic fibrosis: genetic condition caused by CFTR gene mutations, leading to defective chloride transport, thick secretions, and multisystem involvement, most notably chronic lung disease and pancreatic insufficiency.^[Ref]

Epidemiology

UK Prevalence: ~ 1:2,500 live births ^[Ref]

Typical age of onset: infancy (identified through screening)

Aetiology

Genetics

• Affected gene → CFTR gene on chromosome 7 ^[Ref]
  • Encodes chloride and bicarbonate ion channels on epithelial cells
  • Most common mutation → F508del
• Inheritance pattern → Autosomal recessive

Pathophysiology

Sweat glands ^[Ref]

• Normal: CFTR reabsorbs Cl^– (and Na+ / H₂O indirectly) from sweat
• CF: Defective Cl^– reabsorption → excessive NaCl in sweat → ↑ sweat chloride concentration (diagnostic hallmark)

Other exocrine glands ^[Ref]

• Normal: CFTR secretes Cl^– (and Na+ / H₂O indirectly) into the gland lumen/ducts
• CF: defective secretion of electrolytes + water → thick, viscous secretions
  • Respiratory tract 
    • Mucus plugging → airway obstruction, chronic infection, neutrophilic inflammation
    • Progressive damage → bronchiectasis → respiratory failure (main cause of death)
  • Pancreas
    • Blocked ducts → autodigestion / fatty replacement of pancreatic tissue
    • Exocrine pancreas affected → Exocrine insufficiency
    • Endocrine pancreas affected → CF-related diabetes
  • Liver & biliary tree
    • Thick bile → focal obstruction & fibrosis → Liver disease (mild steatosis → cirrhosis)
  • GI tract 
    • Viscous secretions → meconium ileus in neonates; distal intestinal obstruction in older patients
  • Reproductive system
    • Males → viscous mucous obstructs vas deferens development (congenital absence of vas deferens) → obstructive azoospermia → infertility
    • Females → thick cervical mucous → may cause subfertility

Clinical features / Manifestations

General

Typical onset of disease manifestations

• Infancy → respiratory / gastrointestinal symptoms
• Childhood onwards → distal intestinal obstruction syndrome, cystic fibrosis-related diabetes, advanced hepatobiliary disease

Respiratory system

1. Obstructive lung disease characterised by progressive bronchiectasis (develops in all affected patients)

• Symptoms
  • Chronic cough + sputum production
  • Dyspnoea
  • Recurrent respiratory infections
  • Wheezing
• Signs / Examination findings 
  • Digital clubbing (in advanced disease)
  • On Auscultation → Crackles, wheezing

2. Chronic rhinosinusitis (30-70% affected) ^[Ref]

• Chronic nasal discharge / obstruction, facial pain, anosmia, nasal polyps

Gastrointestinal system

1. Bowel obstruction

• Meconium ileus (neonates)
  • Suspect if failure to pass meconium / bilious vomiting / abdominal distention in newborns
• Distal intestinal obstruction syndrome (DIOS; ~15-20% adults affected)

2. Constipation (may progress to DIOS or rectal prolapse)

3. Failure to thrive / poor growth (due to malabsorption)

Pancreas

1. Exocrine pancreatic insufficiency (~85% affected)

• Features: steatorrhoea (fatty stools), malabsorption & diarrhoea, abdominal distention

2. Endocrine pancreatic insufficiency

• Cystic fibrosis-related diabetes (~20% of adolescents / 40-50% of adults affected)

3. Pancreatitis (rare)

Cystic fibrosis-related liver disease

Cystic fibrosis-related liver disease is a less common manifestation that may manifest as: ^[Ref]

• Liver
  • Hepatic steatosis
  • Advanced liver disease (cirrhosis and portal hypertension)

• Biliary tract
  • Biliary fibrosis / strictures / cholangitis
  • Cholelithiasis

Prognosis

Median life expectancy: ~53 y/o in high-income countries ^[Ref]

Leading cause of morbidity / mortality → respiratory disease

Complications

Guidelines

Screening

CF is routinely screened in newborns with the spot (heel-prick) test at ~5 days old

The screening marker is immunoreactive trypsinogen (IRT)

• Abnormal screening test → elevated IRT
  • This is NOT diagnostic → requires confirmatory sweat chloride testing as outlined below

Investigation and Diagnosis

Test of choice: sweat test

• ↑ Sweat chloride concentration is seen in CF (since CFTR channels are defective, chloride cannot be reabsorbed from the sweat)
• ≥60 mmol/L is a common diagnostic threshold

Genetic testing for CFTR mutations is recommended as an adjunct, especially in adults (as they are more likely to have atypical presentations), and if the sweat test is equivocal. ^[Ref1][Ref2]

Management

CF is a multi-system condition, therefore the management can be split accordingly.

Respiratory

Long Term Management

Offer to all patients:

• Individualised exercise programme
• Airway clearance techniques
  • Recommended to be performed at least daily regardless of age or disease severity
  • If unable to use standard airway clearance techniques → consider non-invasive ventilation

• Mucoactive agent
  • 1st line: rhDNase (dornase alfa) (recombinant human deoxyribonuclease)
  • 2nd line: hypertonic sodium chloride +/- rhDNase
  • 3rd line: inhaled mannitol dry powder

CFTR modulators are not routinely offered to all patients, but only those with F508 deletion mutation in the CFTR gene. Examples:

• Lumacaftor-ivacaftor
• Tezacaftor–ivacaftor
• Ivacaftor–tezacaftor–elexacaftor

Note this is a simplification of the exact NICE technology appraisal guidance.

Infection Management

Antibiotic prophylaxis:

• Flucloxacillin in children up to 3 y/o, consider up to 6 y/o
• Long-term azithromycin if there is deteriorating lung function or repeated pulmonary exacerbation
  • As azithromycin has additional immunomodulatory and anti-inflammatory properties that reduce airway inflammation beyond its antibiotic effects

Choice of antibiotics for common infective organisms in CF:

Monitoring and Assessment

Perform the following at each review:

• Oxygen saturation
• Chest X-ray
• Blood tests, including white cell count, aspergillus serology and serum IgE
• Respiratory samples (ideally sputum, or else cough swab or nasal pharyngeal aspirate) for microbiology investigations
• Spirometry including FEV1, FVC, FEF

Consider low-dose chest CT for children who have not had one before (can help detect early bronchiectasis).

Metabolic

Nutritional Interventions and Exocrine Pancreatic Insufficiency

• Increase calorie intake by eating high-energy food and increasing portion size (if there is weight loss and inadequate weight gain)
• Oral nutritional supplements (esp. fat-soluble vitamins)

Use stool elastase estimation to test for exocrine pancreatic insufficiency

• Offer oral pancreatic enzyme replacement therapy to those with exocrine pancreatic insufficiency
• Consider acid suppression agent (PPI or H2 receptor antagonist) if there is persistent malabsorption despite optimal pancreatic enzyme replacement therapy

CF-related Diabetes

Test for CF-related diabetes yearly from 10 y/o onwards with

• Continuous glucose monitoring, or
• Serial glucose testing over a few days, or
• OGTT

GI

Liver Disease

Perform yearly LFTs, if abnormal:

• Liver ultrasound scan, and
• Consider ursodeoxycholic acid

Distal Intestinal Obstruction Syndrome

Typical presentation:

• Vomiting and abdominal distension
• Palpable mass in right lower quadrant (from faecal loading)

Investigate with abdominal ultrasound or abdominal CT

Management:

• Ensure adequate hydration with oral or IV fluids
• 1st line: Gastrografin (diatrizoate meglumine and diatrizoate sodium solution) orally or via enteral tube
• 2nd line: macrogols ( iso-osmotic polyethene glycol and electrolyte solution) orally or via enteral tube
• Last resort: surgery

To reduce risk of recurrence:

• Encourage drinking plenty of fluids
• Optimise pancreatic enzyme replacement therapy
• Consider regular stool-softening agent (e.g. lactulose)

References