Cystic Fibrosis (CF) according to Cohen 2004, is the most common fatal hereditary disease amongst children and adults. It is an autosomal recessive disorder, and most carriers of the gene are asymptomatic. The flawed gene that causes CF affects the glandular secretions by altering chloride transport across cell membranes. Thickening of bronchial secretions leads to infection and other respiratory disorders. Other mucus secreting glands, sweat glands, and glands of the pancreas are also involved, causing electrolyte imbalance and digestive disturbance. Pathophysiology:
Cystic fibrosis is caused by defects in the cystic fibrosis gene, which codes for a protein trans-membrane conductance regulator (CFTR) that functions as a chloride channel and is regulated by cyclic adenosine monophosphate (cAMP). Mutations in the CFTR gene result in abnormalities of cAMP-regulated chloride transport across epithelial cells on mucosal surfaces. Six classes of defects resulting from CFTR mutations have been described and are as follows: 1. Complete absence of CFTR protein synthesis
2. Defective protein maturation and early degradation (caused by the most common mutation, 3. Disordered regulation (diminished ATP binding and hydrolysis) 4. Defective chloride conductance or channel gating
5. Diminished transcription due to promoter or splicing abnormality 6. Accelerated channel turnover from the cell surface
CFTR mutations have poor penetrance. This means that the genotype does not predict the pattern or severity of disease. Defective CFTR results in decreased secretion of chloride and increased reabsorption of sodium and water across epithelial cells. The resultant reduced height of epithelial lining fluid and decreased hydration of mucus results in mucus that is stickier to bacteria, which promotes infection and inflammation. Secretions in the respiratory tract, pancreas, GI tract, sweat glands, and other exocrine tissues have increased viscosity, which makes them difficult to clear. Most patients with cystic fibrosis have severe chronic lung disease and exocrine pancreatic insufficiency. Additional manifestations include nasal polyposis, Pansinusitis, Rectal prolapsed, Chronic diarrhea, Pancreatitis, Cholelithiasis, Cirrhosis or other forms of hepatic dysfunction. Additionally, the exact mechanism by which malfunctioning CFTR causes sinus disease is not completely understood. Chloride ions cannot be excreted, sodium is excessively absorbed, and water passively follows. This desiccates the mucosal surface and alters the viscosity of the normal mucus blanket, which alone can lead to obstruction of sinus ostia. Additional abnormalities exist in these patients, including ciliary dysfunction, increased inflammatory mediators, and increased colonization with Pseudomonas aeruginosa, all of which further impair normal sinus clearance and aeration. Chronic sinus infection and inflammation are the net result. Most deaths associated with cystic fibrosis result from progressive and end-stage lung disease. In individuals with cystic fibrosis, the lungs are normal in utero, at birth, and after birth, before the onset of infection and inflammation (except possibly for the presence of dilated submucosal gland ducts in the airways). Shortly after birth, many persons with cystic fibrosis acquire a lung infection, which incites an inflammatory response. Infection becomes established with a distinctive bacterial flora. A repeating cycle of infection and neutrophilic inflammation develops. Together, defects in CFTR lead to reduced chloride secretion with water following into the gut. This may result in meconium ileus at birth and in distal intestinal obstruction syndrome (DIOS) later in life. In addition, other pathologic disorders complicate the simple relationship between the apical chloride and water secretion and the disease. The pancreatic insufficiency decreases the...