Cystic Fibrosis: A Multisystem Disease of One Chloride Channel

Introduction

Cystic fibrosis is the commonest life-limiting autosomal recessive condition in white European populations, affecting around 1 in 2,500 live births in the UK with a carrier frequency of approximately 1 in 25.² Roughly 11,000 people in the UK live with it.

The disease is caused by mutations in the CFTR gene on the long arm of chromosome 7, which encodes the cystic fibrosis transmembrane conductance regulator - a cyclic AMP-dependent chloride channel sitting in the apical membrane of epithelial cells. More than 2,000 mutations are described, but delta-F508, a deletion of phenylalanine at position 508, accounts for around 70% of UK alleles and about half of patients are homozygous for it.

From one channel to a multisystem disease

The clinical picture follows logically from what the channel does. Defective chloride secretion, together with excessive sodium absorption through the epithelial sodium channel, draws water out of the airway surface liquid and ductal secretions. The result is thick, dehydrated, sticky mucus that cannot be cleared.

• In the airway - the periciliary fluid layer collapses, cilia can no longer beat effectively, mucus is retained, and chronic infection and bronchiectasis follow
• In the pancreas - inspissated secretions obstruct the ducts, causing autodigestion, fibrosis and exocrine failure, and later destruction of the islets
• In the biliary tree - focal biliary cirrhosis
• In the vas deferens - obliteration during fetal development, producing congenital bilateral absence of the vas deferens
• In the sweat gland - the defect works the other way round. CFTR here reabsorbs chloride from the duct, so the loss of function produces salty sweat with a high chloride concentration. This is the basis of the diagnostic sweat test.

Presentation

Newborn screening

Most UK cases are now identified through the newborn bloodspot (heel prick) test taken at around day 5, which is why classical late presentations are becoming rare. The screening pathway measures immunoreactive trypsinogen (IRT), which is raised because pancreatic secretions cannot reach the gut. A raised IRT triggers DNA analysis for common CFTR mutations, and positive results are confirmed with a sweat test.

Neonatal presentation

• Meconium ileus - occurring in 10 to 20% of babies with CF and virtually diagnostic of it. Presents in the first day or two with failure to pass meconium, abdominal distension and bilious vomiting, and may be complicated by perforation and meconium peritonitis.
• Prolonged neonatal jaundice
• Intestinal atresia

Presentation in infancy and childhood

• Failure to thrive despite a good appetite - a key discriminator
• Steatorrhoea - pale, bulky, greasy, offensive stools that are difficult to flush
• Recurrent chest infections and a persistent wet cough
• Rectal prolapse
• Nasal polyps - always abnormal in a child and should prompt CF testing
• Salty-tasting skin - frequently noticed by parents on kissing the child, and a genuinely useful historical clue
• Hyponatraemic, hypochloraemic dehydration with metabolic alkalosis (pseudo-Bartter syndrome) in hot weather

Late and atypical presentation

Patients carrying mutations with some residual CFTR function may present in adolescence or adulthood, and are increasingly recognised. Consider CF in an adult with:

• Bronchiectasis, particularly upper lobe, or with Staphylococcus aureus or Pseudomonas in the sputum
• Male infertility with azoospermia
• Recurrent pancreatitis
• Chronic rhinosinusitis with nasal polyps
• Unexplained chronic productive cough with a family history

Diagnosis

The sweat test

The sweat test remains the diagnostic gold standard. Sweating is stimulated by pilocarpine iontophoresis, the sweat is collected, and its chloride concentration is measured.

False positives occur in adrenal insufficiency, hypothyroidism, malnutrition, glycogen storage disease, nephrogenic diabetes insipidus and eczema. False negatives occur with oedema, poor technique or an inadequate sweat volume, so an inadequate collection must be repeated rather than reported as negative.

Genetic testing

• CFTR genotyping confirms the diagnosis, guides eligibility for modulator therapy, and enables genetic counselling and cascade testing of relatives
• Antenatal testing by chorionic villus sampling or amniocentesis is available where both parents are known carriers, as is preimplantation genetic diagnosis
• Nasal potential difference measurement is a specialist test used where the diagnosis remains equivocal

Respiratory disease

Respiratory disease determines the prognosis in over 90% of patients. Retained secretions permit chronic bacterial infection, which drives neutrophilic inflammation and progressive bronchiectasis - the same vicious cycle described in bronchiectasis, but beginning in early childhood.

The organisms, in the order they appear

Examination findings

• Finger clubbing - a classical sign, though not universal
• Coarse crackles and wheeze, with hyperinflation
• Reduced BMI and evidence of malnutrition
• Nasal polyps and chronic sinusitis
• Portacath or gastrostomy in longstanding disease
• Signs of cor pulmonale in advanced disease

Non-respiratory manifestations

Gastrointestinal and nutritional

• Exocrine pancreatic insufficiency - in around 85% of patients, causing steatorrhoea, poor weight gain and deficiency of the fat-soluble vitamins A, D, E and K
• Cystic fibrosis-related diabetes - affecting around half of patients by the age of 30, from progressive islet destruction. It behaves differently from both type 1 and type 2 and is treated with insulin; screening with an annual oral glucose tolerance test begins in adolescence.
• Distal intestinal obstruction syndrome (DIOS) - viscid faecal material obstructing the terminal ileum and caecum, presenting with right iliac fossa pain, a palpable mass and vomiting. Treated with oral gastrografin or a bowel cleansing solution, not surgery.
• Liver disease - focal biliary cirrhosis in around a third, progressing to cirrhosis and portal hypertension in 5 to 10%. Ursodeoxycholic acid is used, though the evidence is limited.
• Gallstones and recurrent pancreatitis - the latter particularly in pancreas-sufficient patients
• Gastro-oesophageal reflux, and rectal prolapse in young children

Reproductive

• Congenital bilateral absence of the vas deferens in around 98% of men, causing obstructive azoospermia. Spermatogenesis is normal, so surgical sperm retrieval with intracytoplasmic sperm injection allows biological fatherhood - an important and frequently misunderstood point when counselling.
• Reduced fertility in women - from thickened cervical mucus and the effects of chronic illness on ovulation, but many women with CF conceive and carry successfully. Pregnancy requires specialist multidisciplinary input, since it places substantial demands on lung function and nutrition.

Other systems

• Osteoporosis - from malabsorption of vitamin D and calcium, corticosteroids, chronic inflammation and low BMI
• CF arthropathy and hypertrophic pulmonary osteoarthropathy
• Chronic rhinosinusitis and nasal polyps
• Salt-losing states in hot weather, requiring salt supplementation
• Stress incontinence - very common in women, driven by years of vigorous coughing, and consistently under-reported unless specifically asked about
• Depression and anxiety - screened for routinely at annual review, given the treatment burden

Management

Care is delivered by a specialist multidisciplinary CF centre and includes respiratory physicians, specialist nurses, physiotherapists, dietitians, pharmacists, psychologists and social workers, with annual review of every system.¹

Airway management

• Airway clearance physiotherapy at least twice daily, lifelong - the foundation of care, using the active cycle of breathing technique, autogenic drainage or positive expiratory pressure devices
• Nebulised dornase alfa (DNase) - cleaves the neutrophil DNA that makes CF sputum so viscous. Genuinely beneficial in CF, unlike in non-CF bronchiectasis where it causes harm.
• Nebulised hypertonic saline - to rehydrate airway surface liquid, given after a bronchodilator
• Prophylactic flucloxacillin in young children against Staphylococcus aureus
• Pseudomonas eradication at first isolation - oral ciprofloxacin with nebulised colistin, or nebulised tobramycin
• Long-term inhaled antibiotics (colistin, tobramycin or aztreonam) for chronic Pseudomonas colonisation
• Long-term azithromycin - for its anti-inflammatory effect, after excluding non-tuberculous mycobacteria
• Exacerbations treated with two intravenous antibiotics for 14 days, typically an antipseudomonal beta-lactam with an aminoglycoside, often at home via a long-term line
• Bronchodilators, and oxygen or non-invasive ventilation in advanced disease
• Annual influenza, pneumococcal and COVID-19 vaccination

Nutrition

• A high-calorie, high-fat diet - typically 120 to 150% of the normal energy requirement for age. This directly contradicts general dietary advice and is a common source of confusion for patients and non-specialists.
• Pancreatic enzyme replacement therapy (Creon) taken with every meal and snack containing fat, with the dose titrated against stool frequency, consistency and weight gain
• Fat-soluble vitamin supplementation (A, D, E and K), with annual level monitoring
• Salt supplementation in infants and in hot weather
• Gastrostomy feeding where oral intake cannot maintain weight
• Regular monitoring of growth, BMI and bone density

CFTR modulator therapy

Modulators target the defective protein itself rather than its consequences, and represent the most significant advance in the history of CF care.

• Potentiators (ivacaftor) - hold the channel gate open. Effective in class III gating mutations such as G551D.
• Correctors (lumacaftor, tezacaftor, elexacaftor) - help the misfolded protein traffic to the cell membrane, which is what delta-F508 requires
• Elexacaftor-tezacaftor-ivacaftor (Kaftrio) - a triple combination effective in patients with at least one delta-F508 allele, and therefore in the large majority of patients. It produces substantial gains in FEV1, sweat chloride, weight and quality of life, and marked reductions in exacerbations.
• Modulators do not benefit patients with class I mutations producing no protein at all, for whom gene and mRNA therapies remain under investigation

Advanced disease

• Lung transplantation - considered for progressive respiratory failure. Burkholderia cepacia complex infection is a contraindication in many centres.
• Liver transplantation for end-stage CF liver disease
• Palliative and supportive care alongside active treatment

Complications

• Progressive bronchiectasis and respiratory failure - the cause of death in over 90%
• Haemoptysis - including massive haemoptysis requiring bronchial artery embolisation
• Pneumothorax - occurring in around 3 to 4% of adults and often recurrent
• Allergic bronchopulmonary aspergillosis
• Cor pulmonale and pulmonary hypertension
• Cystic fibrosis-related diabetes
• Distal intestinal obstruction syndrome
• Liver cirrhosis and portal hypertension
• Osteoporosis and fragility fractures
• Male infertility
• Gastrointestinal malignancy - a modestly increased risk, particularly colorectal cancer, for which earlier screening is now recommended
• Psychological morbidity and the burden of a treatment regimen that can occupy hours every day

Red flags

Prognosis

The outlook has been transformed within living memory. In the 1960s most children with CF did not reach school age. Today, median predicted survival for a child born with CF in the UK is over 50 years, and the adult population now exceeds the paediatric one.²

The gains came first from newborn screening, specialist centre care, aggressive nutritional management, physiotherapy and Pseudomonas eradication, and more recently from CFTR modulators, whose effect on lung function and exacerbation frequency has been large enough to change transplant referral patterns.

Adverse prognostic factors remain chronic Pseudomonas or Burkholderia colonisation, low BMI, a rapidly declining FEV1, CF-related diabetes, frequent exacerbations and poor adherence to a demanding treatment regimen. As survival lengthens, the clinical emphasis has shifted towards conditions of adult life - diabetes, osteoporosis, malignancy, fertility, employment and mental health - and towards supporting an adult population living with a very substantial daily treatment burden.