Medicine – Cystic Fibrosis

Cystic fibrosis (CF) is a chronic, inherited multisystem disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The abnormal CFTR protein disrupts chloride and bicarbonate transport across epithelial surfaces, producing dehydrated, abnormally thick secretions. The respiratory and gastrointestinal systems are particularly affected, although CF can also cause diabetes, infertility, osteoporosis, and other complications.

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1. Autosomal Recessive Inheritance

Cystic fibrosis is inherited as an autosomal recessive disorder. An affected individual therefore inherits a disease-causing CFTR variant from each parent.

People with only one pathogenic variant are generally healthy carriers.

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2. Carrier Frequency

In populations of Northern European ancestry, approximately 1 in 25 people has traditionally been quoted as carrying a CFTR disease-causing variant.

Carrier frequency varies substantially between different ethnic and geographic populations.

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3. Incidence

Older teaching commonly gives an incidence of approximately 1 in 2,000–2,500 live births in White populations.

The incidence varies by population and has also changed with widespread carrier screening, prenatal testing, and demographic changes.

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4. CFTR Gene

The CFTR gene is located on the long arm of chromosome 7 and encodes the cystic fibrosis transmembrane conductance regulator protein.

CFTR functions primarily as an epithelial chloride and bicarbonate ion channel and also influences the activity of other ion channels.

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5. CFTR Mutations

More than 2,000 CFTR variants have now been identified, although not all cause cystic fibrosis.

The most common disease-causing variant is F508del (ΔF508), which results from deletion of three DNA bases and consequently loss of a phenylalanine residue at position 508 of the CFTR protein.

F508del causes abnormal protein folding and processing, so relatively little functional CFTR reaches the epithelial cell surface.

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6. Abnormal Chloride and Water Transport

Defective CFTR function disrupts the movement of chloride, bicarbonate, sodium, and water across epithelial surfaces.

In the respiratory tract, abnormal ion transport causes dehydration of airway secretions. The resulting mucus becomes thick and difficult to clear, impairing normal mucociliary clearance.

This promotes mucus plugging, chronic bacterial infection, inflammation, and progressive structural damage to the airways.

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Diagnosis

7. Sweat Chloride Test

The sweat chloride test remains an important diagnostic investigation because CFTR dysfunction causes abnormally high concentrations of chloride in sweat.

A sweat chloride concentration of ≥60 mmol/L is consistent with cystic fibrosis in an appropriate clinical setting, usually requiring confirmation according to diagnostic protocols.

Values below this threshold require interpretation according to age, symptoms, newborn screening results, and CFTR genetic testing.

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Why Is Sweat Salty?

In normal sweat ducts, CFTR helps reabsorb chloride, with sodium following.

In cystic fibrosis, defective CFTR reduces chloride reabsorption, leaving increased amounts of chloride and sodium in sweat. This explains the characteristically salty sweat of affected patients.

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8. Life Expectancy

The prognosis of cystic fibrosis has improved dramatically.

Older sources described life expectancy as just over 40 years, but this is now outdated in many countries. Improvements in multidisciplinary care, nutritional support, antimicrobial treatment, and particularly CFTR modulator therapy have substantially increased expected survival.

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Respiratory Manifestations

9. Small-Airway Obstruction and Bronchiectasis

Abnormally thick mucus obstructs the small airways and interferes with mucociliary clearance.

Persistent mucus retention promotes recurrent infection and chronic neutrophilic inflammation. Repeated cycles of obstruction → infection → inflammation → airway damage eventually produce bronchiectasis.

Patients commonly develop chronic cough, sputum production, recurrent respiratory infections, breathlessness, and progressive deterioration in pulmonary function.

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10. Respiratory Infection and Colonisation

Patients with CF are susceptible to chronic and recurrent infection with characteristic respiratory organisms.

Important organisms include Staphylococcus aureus, Haemophilus influenzae, Pseudomonas aeruginosa, and Burkholderia cepacia complex.

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Pseudomonas aeruginosa

Pseudomonas aeruginosa becomes particularly important as patients grow older.

Chronic colonisation can produce progressive airway inflammation and declining lung function. The organism may develop a mucoid phenotype, allowing it to persist within the abnormal airway environment and making eradication increasingly difficult.

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Burkholderia cepacia Complex

Burkholderia cepacia complex is especially important because some strains can cause severe respiratory deterioration and are difficult to treat because of antimicrobial resistance.

Cross-infection between patients with CF is also an important infection-control concern.

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11. Treatment of Respiratory Disease

Pulmonary exacerbations are treated with appropriate antibiotics, guided where possible by respiratory cultures and previous microbiological results.

Some patients receive long-term or inhaled antimicrobial therapy to suppress chronic infection.

Management also includes airway-clearance physiotherapy, exercise, mucolytic therapies, and other treatments designed to improve mucus clearance.

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CFTR Modulator Therapy

A major development in modern treatment is the use of CFTR modulators, which target the underlying abnormal CFTR protein rather than simply treating its consequences.

Different combinations are used according to the patient’s specific CFTR genotype, and highly effective modulator therapy has substantially improved lung function and other outcomes in many eligible patients.

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Gastrointestinal Manifestations

12. Pancreatic Insufficiency

Exocrine pancreatic insufficiency occurs in the majority of patients with classic CF.

Thick secretions obstruct the pancreatic ducts, resulting in progressive pancreatic damage and inadequate delivery of digestive enzymes into the intestine.

This causes fat and protein malabsorption, steatorrhoea, poor weight gain, and deficiencies of fat-soluble vitamins A, D, E, and K.

Treatment includes pancreatic enzyme replacement therapy and nutritional supplementation.

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13. Meconium Ileus

Meconium ileus is an important neonatal presentation of cystic fibrosis.

Abnormally thick intestinal contents obstruct the terminal ileum, producing abdominal distension, failure to pass meconium, and intestinal obstruction shortly after birth.

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Distal Intestinal Obstruction Syndrome

Older children and adults with CF can develop distal intestinal obstruction syndrome (DIOS).

Thick intestinal material accumulates, particularly around the terminal ileum and caecum, producing abdominal pain, distension, and partial or complete intestinal obstruction.

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14. Liver Disease

Abnormal CFTR function can produce thickened bile and obstruction of small intrahepatic bile ducts.

Some patients consequently develop CF-associated hepatobiliary disease, which can include focal biliary fibrosis, multilobular cirrhosis, and portal hypertension.

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15. Gallstones

Gallstones occur more frequently in people with CF.

Altered bile composition and gallbladder dysfunction contribute to their development.

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16. Pancreatitis

Recurrent acute or chronic pancreatitis can occur in some individuals with CF, particularly those who retain a degree of pancreatic exocrine function.

Interestingly, patients with severe pancreatic insufficiency may be less likely to develop pancreatitis because extensive pancreatic destruction has already occurred.

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Other Manifestations

17. Cystic Fibrosis-Related Diabetes

Cystic fibrosis-related diabetes (CFRD) becomes increasingly common with age.

Progressive pancreatic damage reduces insulin secretion, while illness-related insulin resistance may contribute. CFRD has features of both type 1 and type 2 diabetes but represents a distinct form of diabetes associated with CF.

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18. Pneumothorax

Advanced bronchiectasis and structural lung disease can predispose patients to spontaneous pneumothorax.

This may present with sudden worsening of breathlessness and pleuritic chest pain and can be particularly serious in patients who already have significantly reduced pulmonary reserve.

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19. Male Infertility

Almost all men with classic cystic fibrosis are infertile, usually because of congenital bilateral absence or severe abnormality of the vas deferens.

Importantly, spermatogenesis may remain intact, so biological fatherhood may sometimes be possible using assisted reproductive techniques.

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20. Female Reproductive Effects

Women with CF are generally capable of becoming pregnant, although fertility may be reduced.

Abnormally thick cervical mucus, nutritional status, and severity of chronic illness can contribute to reduced fertility.

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21. Osteoporosis

Patients with CF have an increased risk of reduced bone mineral density and osteoporosis.

Contributing factors include chronic inflammation, malabsorption of vitamin D, poor nutritional status, reduced physical activity, delayed puberty, and exposure to systemic corticosteroids in some patients.

This increases the risk of vertebral and other fractures.

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Key Clinical Pattern

Think of cystic fibrosis as an autosomal recessive CFTR disorder causing abnormal epithelial ion and water transport and therefore thick, dehydrated secretions.

The classic pattern is chronic/recurrent respiratory infection + bronchiectasis + pancreatic insufficiency and malabsorption + high sweat chloride.

Important organisms include S. aureus, H. influenzae, P. aeruginosa, and B. cepacia complex, while important extrapulmonary complications include meconium ileus/DIOS, CF-related diabetes, hepatobiliary disease, male infertility, and osteoporosis.

Modern CFTR modulator therapy has transformed the outlook for many patients, making the older life-expectancy figures in traditional notes increasingly outdated.