Cystic Fibrosis

Cystic Fibrosis

Cystic Fibrosis (CF) is the most common fatal autosomal recessive genetic disorder that affects the Caucasian population. It reflects mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The CF gene was cloned 6 years ago, and since then, over 700 mutations have been described. CFTR functions as a cyclic AMP regulated chloride channel and is important for secretion of sodium chloride by the apical membrane of epithelial cells within affected organs. Secretion of water follows that of sodium chloride. As a result of defective CFTR function in organs lined by epithelium, there is intraluminal accumulation of thick, viscid secretions lacking in water(Feldman Williamson Beaudet O'Brien 1988 ).

Clinical Features Of Cystic Fibrosis

The most important clinical features are chronic obstructive pulmonary disease and in most cases pancreatic insufficiency. Babies present with recurrent airway obstruction, atelectasis, failure to thrive, steatorhea. Many other organs are effected too:sweat glands, intestinal obstruction at birth (meconium ileus) and later (distal intestinal obstruction syndrome), liver , vas deferens and male infertility, nasal polyps. Two syndromes that can lead to diagnosis in infants are: a) edema with hypoalbuminemia and anemia due to protein malabsorption; b) hypochloremic alkalotic dehydration, especially during hot weather(Marchi Richards Fenwick Pace Beaudet 1994).

The level of chloride and sodium in sweat is usually above 70meq/l (normal less than 40meq/l) and these allows the pilocarpine iontophoresis sweat test accurately performed in experienced hands, to be the standard method of diagnosis. Today, testing for genetic mutations is helpful in populations where most of the mutations are known, eg. US white caucasians, ashkenazy jews.It can be used for borderline cases, and for prenatal diagnosis and even screening of heterozygotes. As chloride remains within the CF epithelial cells, the potential difference across the apical cell membrane is more negative. Measuring nasal potential difference is useful in diagnosing unusual cases, and in the future may be a way of assessing gene therapy!

Gene Mutation

Mutations in the CFTR gene result in abnormalities of cAMP-regulated chloride transport across epithelial cells on mucosal surfaces. Defective CFTR results in decreased secretion of chloride and increased reabsorption of sodium and water across epithelial cells. Resultant reduced height of epithelial lining fluid and decreased hydration of mucus results in mucus that is stickier to bacteria, which results in infection and inflammation. These abnormalities result in viscid secretions in the respiratory tract, pancreas, GI tract, sweat glands, and other exocrine tissues. Increased viscosity of these secretions makes them difficult to clear. (Hytönen Patjas et al. 2001)

Reason for elevated sodium and chloride levels in sweat

The level of chloride and sodium in sweat is usually above 70meq/l (normal less than 40meq/l) and these allows the pilocarpine iontophoresis sweat test accurately performed in experienced hands, to be the standard method of diagnosis. Defective CFTR results in decreased secretion of chloride and increased reabsorption of sodium and water across epithelial cells. Resultant reduced height of epithelial lining fluid and decreased hydration of mucus results in mucus that is stickier to bacteria, which results in ...