Cystic Fibrosis

Cystic fibrosis (CF) is a genetic disorder inherited in an autosomal recessive pattern and characterized by multisystem involvement. The fundamental cause of the disease is mutations in the gene encoding the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. Dysfunction of this gene disrupts chloride and water transport across epithelial cells, leading to the production of thick, sticky secretions in multiple organ systems, particularly the lungs and pancreas. CF is one of the most common inherited disorders among white populations, with an estimated prevalence of approximately 1 in 3,000 in Türkiye. Early diagnosis and multidisciplinary treatment significantly improve patients’ quality of life and life expectancy.

Epidemiology and Genetics

Cystic fibrosis occurs in approximately 1 in 2,500 to 3,500 births among white populations and about 1 in 3,000 births in Türkiye. The incidence is higher in communities with a high rate of consanguineous marriages. The CFTR gene is located on the long arm of chromosome 7 and contains 27 exons. It encodes a CFTR protein of 1,408 amino acids. More than 2,000 mutations in this gene have been identified to date. The most common mutation is delta F508. While this mutation is found in 70–80% of cases in Northern Europe, it is present in only 20–25% of CF patients in Türkiye.

Pathophysiology

The CFTR protein is an ATP-dependent chloride channel located on the apical membrane of epithelial cells. Its dysfunction leads to reduced chloride transport across the epithelial surface, which in turn disrupts sodium and water movement. As a result, secretions in the respiratory tract, pancreatic ducts, bile ducts, and gastrointestinal system become thick, viscous, and sticky. These secretions cause bronchial obstruction and recurrent infections in the lungs and impair the delivery of digestive enzymes in the pancreas. Progressive pancreatic damage can lead to diabetes, and in males, congenital absence of the vas deferens can result in infertility.

Clinical Features

Cystic fibrosis exhibits a clinically heterogeneous course. Symptoms vary depending on the patient’s age, mutation type, and affected organs.

Newborn Period

• Meconium ileus
• Prolonged jaundice
• Intrauterine intestinal calcifications
• Abdominal distension
• Scrotal edema

Infancy and Childhood

• Recurrent respiratory tract infections
• Chronic cough and wheezing episodes
• Steatorrhea and failure to thrive due to pancreatic insufficiency
• Rectal prolapse
• Cholestasis and gallstones
• Hypoproteinemia and edema
• Vitamin deficiencies (particularly A, D, E, K)
• Pseudo-Bartter syndrome
• Finger clubbing

Adolescence and Adulthood

• Bronchiectasis
• Hemoptysis
• Delayed puberty
• Congenital bilateral absence of the vas deferens (azoospermia)
• Osteoporosis/osteopenia
• Diabetes mellitus
• Cirrhosis and portal hypertension

Diagnosis

The diagnosis of CF is established by evaluating clinical findings, family history, and diagnostic tests together. The primary diagnostic methods include:

• Sweat Test: This is the gold standard for diagnosis. It should be performed at least twice under appropriate conditions; a chloride concentration of ≥60 mmol/L in sweat confirms the diagnosis. Values between 30 and 60 mmol/L are considered borderline and require further testing for confirmation.
• Genetic Testing: Identification of mutations in both alleles of the CFTR gene confirms the diagnosis. In Türkiye, a mutation panel targeting common local variants may be used. In some cases, full gene sequencing may be necessary.
• Newborn Screening: Since 2015, Türkiye has implemented a newborn screening program in which immunoreactive trypsinogen (IRT) levels are measured in heel-prick blood samples. Infants with elevated IRT levels are referred for further evaluation.

Treatment

CF treatment must be managed through a multidisciplinary approach. The goals are to control symptoms, prevent infections, improve nutritional status, and enhance quality of life.

Respiratory Tract Therapies

• Chest physiotherapy: Should be performed regularly to facilitate mucus clearance.
• Inhaled therapies: Dornase alfa, hypertonic saline, and, when indicated, mannitol are used.
• Antibiotic therapy: Oral or intravenous antibiotics are administered based on culture results during acute exacerbations. Eradication of P. aeruginosa is critically important.
• Inhaled antibiotics: Long-term treatment with agents such as tobramycin and colistin may be employed.

Nutrition and Gastrointestinal Support

• Pancreatic enzyme replacement: Preparations such as Creon are administered before meals.
• High-calorie diet: Special attention should be given to supporting fat-soluble vitamins (A, D, E, K).
• Bile acid therapy: Ursodeoxycholic acid is used in the management of hepatobiliary complications.

Management of Complications

• Diabetes: Cystic fibrosis-related diabetes (CFRD) may require insulin therapy.
• Osteoporosis: Calcium and vitamin D supplementation are necessary.
• Infertility: Azoospermia is common in males due to congenital absence of the vas deferens.

New Therapies

CFTR modulators (such as ivacaftor, lumacaftor, tezacaftor, and elexacaftor) are targeted therapies designed for specific mutations and have been incorporated into treatment protocols in recent years. These medications provide clinical benefits, particularly in individuals carrying the delta F508 mutation.

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