1.3: Cystic Fibrosis

Cystic fibrosis (CF) is an inherited disorder that affects the exocrine glands of not only the lungs, but also the pancreas, intestines, and bile ducts. We will focus only on the pulmonary aspects here and see how CF produces an obstructive lung disease.

Cystic fibrosis affects the composition of the fluid lining the airways. Changes in this fluid lead to serious sequelae that dramatically shorten life expectancy. Even with modern therapy, many CF patients only live until their thirties or early forties, and some still die in infancy.

There are two hypotheses about the pathophysiological mechanism of CF: the low volume and the high salt. We will focus only on the low volume hypothesis as there is increasing evidence to support this and emerging evidence against the high salt hypothesis.

Pathophysiology of Cystic Fibrosis

Control of the airway fluid relies on the action of ion channels in the apical membranes of epithelial cells, and there are two channels to focus on: CFTR and ENaC. The CFTR channels let chloride out of the cell, while the ENaC lets sodium in (top panel, figure 1.19).

This exchange helps maintain a healthy fluid layer in the airway, but fails in CF because of a nonfunctioning CFTR channel (right panel, figure 1.19).

Figure 1.19: The impact of ion currents in normal and CF cells on fluid layer and cilia.

There are numerous mutations that are known to produce a dysfunctional CFTR channel, but 70 percent of CF cases are due to the delta-F-508 mutation (so named as the mutation leads to a deletion of phenylalanine at position 508 of the CFTR protein). This is a Mendelian recessive trait, and CF occurrence is 1 in 2,500 live births.

So what are the consequences of CFTR dysfunction? Chloride ends up being trapped inside the cell (bottom panel, figure 1.19), and this leads to a greater influx of sodium through the ENaC down its electrochemical gradient, leaving a higher concentration of salt inside the cells that pulls water in from the airway lumen. The low fluid volume in the airway results in:

• viscous mucus, and
• collapse of cilia.

This combination severely impacts mucus clearance (thicker, heavier mucus with compromised cillary escalator). The defective CFTR channel therefore results in mucus retention and airway obstruction. This in turn leads to reduced alveolar ventilation and repeated infections. The two most common culprits for infection in CF are Staphylococcus aureus and Pseudomonsa aeruginosa. Normal functional CFTR appears to suppress P. aeruginosa, perhaps explaining its prevalence in cystic fibrosis where it can be found in the sputum of almost all CF patients.

The consequences of repeated infection are a mixture of serious conditions and pathologies including atelectasis, pneumonia, bronchiectasis, and other structural abnormalities of the airways (figure 1.20).

The findings of CF obviously include the results of other effected organs, such as the pancreas. But nowadays these are more easily addressed, and it is pulmonary involvement that still proves critical. The onset of pulmonary involvement is variable and may be weeks or years after birth.

Clinical Presentation of Cystic Fibrosis

Figure 1.20: Pulmonary consequences of CF.

Findings progress with progressive airway damage (figure 1.21), but start with cough that may be dry at first but transitions to productive to expel the copious, viscous mucus. With poor mucus clearance, the patient experiences repeated infections that exacerbate symptoms at each stage of the disease.

CF patients usually have an abnormal sinus x-ray and evidence of chronic sinusitis as well as a high occurrence of nasal polyps.

With increasing and irreversible airway damage, the patients begins to experience dyspnea, and the damage may lead to hemoptysis, spontaneous pneumothorax, and a barrel chested appearance. Signs of prolonged pulmonary dysfunction appear as the disease progresses, such as finger clubbing, cyanosis, and cor pulmonale (right-sided heart failure caused by lung disease). As the patient approaches respiratory failure the accessory muscles are deployed. Patients succumb to the respiratory failure or an overwhelming infection.

Figure 1.21: Clinical signs of the pulmonary progression of CF.

Because CF also affects sweat gland function, the sweat test remains a standard diagnostic with a chloride level greater than 60 mEq/L being indicative of CF. This test is more reliable in children than adults, who may have developed other conditions that affect the composition of sweat.

Chest x-rays show (figure 1.22) signs of hyperinflation associated with gas trapping and the hallmarks of any other complications that the CF has induced. These are viewed more clearly with the common use of high-resolution computed tomography (HRCT)(figure 1.23) to determine the type and extent of damage that may include bronchiectasis and mucus impactions.

Spirometry detects the airway obstruction and hyperinflation that produce a low vital capacity and high residual volume.

Figure 1.22: Typical chest x-ray findings of CF.

Figure 1.23: HRCT of CF lungs showing multiple, severe bronchiectasis.