Pathophysiology\Etiology of Cystic Fibrosis

The disorder is caused by mutation in the CF transmembrane conductance regulator (CFTR) gene on chromosome 7. There are at least 2,000 mutations on the CFTR gene. CFTR is an ATP-responsive chloride channel that also affects other cellular activities, such as sodium transport across the respiratory epithelium, composition of cell surface glycoprotein and antibacterial defences.

There are 6 substantial mutations on the CFTR that contribute to Cystic Fibrosis:

• Complete absence of CFTR protein synthesis
• Defective protein maturation and early degradation
• Disordered regulation (diminished ATP binding and hydrolysis)
• Defective chloride conductance or channel gating
• Diminished transcription due to promoter or splicing abnormality
• Accelerated channel turnover from the cell surface

These mutations cause decreased secretion of chloride and increased reabsorption of sodium and water across epithelial cells. This causes fluid retention and decreased hydration of mucus results in mucus that is stickier to bacteria, which promotes infection and inflammation.

Other problems include

Pulmonary problems: chronic infections of the lung, emphysema, progressive respiratory insufficiency

Gastrointestinal problems: pancreatic insufficiency, intestinal obstruction, continuing deficiency of pancreatic enzymes, biliary tract obstruction(blockage of the bile system), constriction of the common bile duct, cirrhosis of the liver

Heart problems: cor pulmonale (right sided heart enlargement), polycythemia         Reproductive problems: 98% infertility in males

Focus on Lungs

Mucus plugging and chronic bacterial infection, damages the lung tissue ultimately leading to bronchiectasis (difficulty in clearing mucus) and respiratory insufficiency. Another substantial effect is chronic hypoxemia which then results in muscular hypertrophy of the pulmonary arteries, pulmonary hypertension, and right ventricular hypertrophy.

Focus on GI

The pancreas, intestines, and hepatobiliary system are frequently affected. Exocrine pancreatic function is decreased in 85 to 95% of patients. Patients with pancreatic insufficiency have malabsorption of fats (and fat-soluble vitamins) and protein. Duodenal fluid is abnormally thick and has decreased HCO 3 - concentration. Endocrine pancreatic dysfunction is not affected as much, but can result in diabetes mellitus is present in about 2% of children, 20% of adolescents, and at least 40% of adults.

Bile duct becomes plugged due to mucus and causes hardening of liver tissue (hepatic  fibrosis) in 30% of patients. 

http://kidshealth.org/parent/medical/lungs/cf.html

http://emedicine.medscape.com/article/1001602-overview#a3

http://patient.info/doctor/cystic-fibrosis-pro

http://classes.kumc.edu/cahe/respcared/cybercas/cysticfibrosis/mazetio.html