Cystic Fibrosis

Cystic Fibrosis

Jonathan Ma, MD, and Michael S. Schechter, MD, MPH

Introduction/Etiology/Epidemiology

•Cystic fibrosis (CF) is the most common life-shortening genetic disease in white people.

•It is an autosomal recessive disorder involving mutations in the gene that produces CF transmembrane conductance regulator (CFTR) protein.

•CFTR is a chloride channel that regulates the epithelial sodium channel.

•CFTR mutations result in abnormal ion and water transport across epithelial membranes, especially in the lungs, pancreas, intestines, biliary tract, sweat glands, and vas deferens.

•CF affects 30,000–40,000 people in the United States and 80,000– 100,000 people worldwide.

•Incidence is approximately 1 in 3,000 white Americans, 1 in 4,000– 10,000 Hispanic Americans, and 1 in 15,000–20,000 African Americans. It is rare in Asian Americans and Native Americans.

Pathophysiology

The pathogenesis of CF is depicted in Figure 67-1.

•More than 1,800 CFTR mutations have been identified.

—The most common mutation is F508del (present in a homozygous or heterozygous form in 80% of people with CF).

—CFTR mutations have been grouped into 6 classes on the basis of the functional abnormality. Class I–III mutations lead to virtually absent CFTR function; some residual CFTR function exists with the class IV–VI mutations, and these patients typically have pancreatic sufficiency.

▪Class I: No functional protein due to a premature stop codon in mRNA that leads to a truncated nonfunctioning protein

▪Class II: Unstable and/or misfolded protein that is improperly processed and degraded in proteasomes before reaching the cell membrane

▪Class III: Defective regulation of gating but properly positioned

▪Class IV: Reduced chloride conductance but properly positioned

▪Class V: Reduced synthesis of functional protein due to aberrant splicing

▪Class VI: Less stable functional protein with accelerated turnover

Figure 67-1. Cystic fibrosis pathogenesis. CFTR = CF transmembrane conductance regulator.

• CFTR dysfunction leads to excessive sodium absorption and deficient chloride secretion at the apical cell membrane, decreasing the osmotic driving force for water transport.

—The resultant “low volume” of airway surface impairs mucociliary clearance of airway secretions.

—The stasis of airway secretions inhibits the ability to clear inhaled bacteria, leading to an unrelenting airway infection that waxes and wanes in intensity but is never cleared.

•CFTR also causes an exaggerated inflammatory response to respiratory pathogens.

—Persistent airway inflammation leads to bronchiectasis, declining lung function, and, ultimately, respiratory failure and death.

•In other organ systems, aberrant ion transport leads to ductal obstruction that results in pancreatic insufficiency and congenital absence of the vas deferens.

Clinical Features

Sweat Glands

•The hallmark of disease is high salt content in the sweat glands (sweat chloride >60 mEq/L [>60 mmol/L] in patients with CF vs <30 mEq/L [<30 mmol/L] in otherwise healthy patients).

•Hyponatremia is a risk in warm environments, particularly in infants.

Respiratory System

•Upper airway disease

—Pansinusitis is universal, and nasal polyps are common.

—Recurrence is common after surgery.

•Lower-airway disease

—Chronic ineradicable airway infection begins in the first year after birth.

▪Haemophilus influenzae and Staphylococcus aureus are the most common infectious organisms early in life.

▪Pseudomonas aeruginosa becomes more common as children get older, and its acquisition is associated with an accelerated decline in lung function.

▪Other key pathogens include

~Stenotrophomonas maltophilia

~Achromobacter xylosoxidans

~Burkholderia cepacia complex

~Nontuberculous mycobacteria (Mycobacterium abscessus, Mycobacterium avium complex)

~Aspergillus fumigatus (primarily associated with allergic bronchopulmonary aspergillosis)

—Pulmonary function tests show obstructive disease, marked by decreased forced expiratory volume in 1 second (FEV₁) and increased residual volume.

—Pulmonary complications include atelectasis, pneumothorax, hemoptysis, and bronchiectasis (Figures 67-2 and 67-3).

—Respiratory failure is the most common cause of death.

Gastrointestinal Tract

•Small intestinal obstruction

•Meconium ileus

—Inspissated material leads to obstruction in the distal ileum.

—It is seen in 20% of patients with CF at birth.

—It warrants prompt surgical consultation because of marked risk for perforation (Figure 67-4).

Figure 67-2. Cystic fibrosis in a 14-year-old girl. Frontal chest radiograph shows bilateral hyperinflation, extensive peribronchial thickening, scattered nodular foci consistent with mucous plugging, and scattered lucencies due to bronchiectasis.