Pathophysiology of Cystic Fibrosis

Cystic fibrosis (CF) is an inherited multisystem disorder of children and adults, characterized chiefly by obstruction and infection of airways and by maldigestion and its consequences.

CF is inherited as an autosomal recessive trait. The CF gene codes for a protein of 1,480 amino acids called the CF transmembrane regulator (CFTR).

Four long-standing observations are of fundamental pathophysiologic importance:

1. failure to clear mucous secretions,
2. a paucity of water in mucous secretions,
3. an elevated salt content of sweat and other serous secretions, and
4. chronic infection limited to the respiratory tract

In addition, there is a greater negative potential difference across the respiratory epithelia of CF patients than across the respiratory epithelia of control subjects. Aberrant electrical properties were also demonstrated for CF sweat gland duct epithelium. The membranes of CF epithelial cells are unable to secrete chloride ions in response to cyclic adenosine monophosphate (cAMP)–mediated signals and, at least in the respiratory tract, excessive amounts of sodium are absorbed through these membranes.

Cyclic AMP-stimulated chloride conductance is a function of CFTR itself; this function is absent in epithelial cells with many different mutations of the CFTR gene.

The postulated epithelial pathophysiology in airways involves an inability to secrete salt and secondarily to secrete water in the presence of excessive reabsorption of salt and water. The proposed outcome is insufficient water on the airway surface to hydrate secretions. Desiccated secretions become more viscous and elastic (rubbery) and are harder to clear by mucociliary and other mechanisms.These secretions are retained and obstruct airways, starting with those of the smallest caliber, the bronchioles. Airflow obstruction at the level of small airways is the earliest observable physiologic abnormality of the respiratory system.

It is plausible that similar pathophysiologic events take place in the pancreatic and biliary ducts (and in the vas deferens), leading to desiccation of proteinaceous secretions and obstruction.

The earliest pathologic lesion in the lung is that of bronchiolitis (mucous plugging and an inflammatory response in the walls of the small airways). With time, mucus accumulation and inflammation extend to the larger airways (bronchitis).

With long-standing disease, evidence of airway destruction such as bronchiolar obliteration, bronchiolectasis, and bronchiectasis becomes prominent.

The paranasal sinuses are uniformly filled with secretions containing inflammatory products, and the epithelial lining displays hyperplastic and hypertrophied secretory elements. Polypoid lesions within the sinuses, mucopyocele, and erosion of bone have been reported.

The pancreas is usually small, occasionally cystic, and often difficult to find at postmortem examination. The extent of involvement varies at birth. In infants, the acini and ducts are often distended and filled with eosinophilic material. In 85–90% of patients, the lesion progresses to complete or almost complete disruption of acini and replacement with fibrous tissue and fat.

The intestinal tract shows only minimal changes.