Cystic fibrosis
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Cystic fibrosis
- 1. MUBASHAR IQBALMUBASHAR IQBAL Roll no.Roll no. 386-1403008386-1403008
- 2. Inherited monogenic disorder presenting as a multisystem disease. Typically presents in childhood 7% of CF patients diagnosed as adults Most common life limiting recessive trait among whites Cystic Fibrosis
- 3. Prognosis improving >38% of CF patients are older than 18 13% of CF patients are older than 30 Median survival Males: 32 years Females: 29 years Cystic Fibrosis
- 4. Autosomal recessive Gene located on chromosome 7 Prevalence- varies with ethnic origin 1 in 3000 live births in Caucasians in North America and Northern Europe 1 in 17,000 live births of African Americans 1 in 90,000 live births in Hawaiian Asians Genetics of CF
- 5. Most common mutation Occurs in 70% of CF chromosomes 3 base pair deletion leading to absence of phenylalanine at position 508 of the CF transmembrane conductance regulator (CFTR) Genetics of CF
- 6. Difficult to use DNA diagnosis to screen for heterozygotes No simple physiologic measurements yet available for heterozygote detection Genetics of CF
- 7. The CFTR protein Single polypeptide chain, 1480 amino acids Cyclic AMP regulated chloride channel Regulator of other ion channels Found in the plasma membrane of normal epithelial cells Genetics of CF
- 8. Protein Function and Biochemistry CFTR controls chloride ion movement in and out of the cell.
- 9. ∆F508 mutation leads to improper processing and intracellular degradation of the CFTR protein Other mutations in the CF gene produce fully processed CFTR proteins that are either non- functional or partially functional Genetics of CF
- 11. Epithelial disfunction Epithelia containing CFTR protein exhibit array of normal functions Volume absorbing (airway, distal intestine) Salt absorbing without volume (sweat ducts) Volume secretory (proximal intestine, pancreas) Disfunction in CFTR gene leads to different effects on patterns of electrolyte and water transport Genetics of CF
- 12. Lung Raised trans-epithelial electric potential difference Absence of cAMP-dependent kinase and PKC- regulated chloride transport Raised sodium transport and decreased chloride transport Alternative calcium-regulated chloride channel in airway epithelia which is a potential therapeutic target Physiology
- 13. Normal airway epithelia CF altered airway epithelia
- 14. Lung High rate of sodium absorption and low rate of chloride secretion reduces salt and water content in mucus, depletes peri-ciliary liquid Mucus adheres to airway surface, leads to decreased mucus clearing Physiology
- 15. Gastrointestinal Pancreas Absence of CFTR limits function of chloride-bicarbonate exchanger to secrete bicarbonate Leads to retention of enzymes in the pancreas, destruction of pancreatic tissue. Intestine Decrease in water secretion leads to thickened mucus and dessicated intraluminal contents Obstruction of small and large intestines Physiology
- 16. Gastrointestinal Biliary tree Retention of biliary secretion Bile duct proliferation Sweat Normal volume of sweat Inability to reabsorb NaCl from sweat as it passes through sweat duct Physiology
- 17. Common presentations Chronic cough Recurrent pulmonary infiltrates Failure to thrive Manifestations
- 18. Respiratory tract Chronic cough Persistent Viscous, purulent, green sputum Lung function Small airway disease is first functional lung abnormality Progresses to reversible as well as irreversible changes in FEV1 Chest x-ray may show hyperinflation, mucus impaction, bronchial cuffing, bronchiectasis Manifestations
- 19. Gastrointestinal Meconium ileus equivalent or distal intestinal obstruction syndrome Loss of appetite Emesis (alkalosis) Palpable mass May be confused with appendicitis Manifestations
- 20. Gastrointestinal Exocrine pancreatic insufficiency Found in >90% of CF patients Protein and fat malabsorption Frequent bulky, foul-smelling stools Vitamin A, D, E, K malabsorption Sparing of pancreatic beta cells Beta cell function decreases with age Manifestations
- 21. Genitourinary Late onset puberty Due to chronic lung disease and inadequate nutrition >95% of male patients with CF have azospermia due to obliteration of the vas deferens 20% of female patients with CF are infertile >90% of completed pregnancies produce viable infants Manifestations
- 22. DNA analysis not useful due to large variety of CF mutations Sweat chloride test >70 mEq/L 1-2% of patients with clinical manifestations of CF have a normal sweat chloride test Nasal transepithelial potential difference Diagnosis
- 23. Criteria One of the following Presence of typical clinical features History of CF in a sibling Positive newborn screening test Plus laboratory evidence for CFTR disfunction Two elevated sweat chloride concentrations on two separate days Identification of two CF mutations Abnormal nasal potential difference measurement Diagnosis
- 24. Major objectives Promote clearance of secretions Control lung infection Provide adequate nutrition Prevent intestinal obstruction Investigation into therapies to restore the processing of misfolded CFTR protein Treatment
- 25. Lung >95% of CF patients die from complications of lung infection Breathing exercises Flutter valves Chest percussion Hypertonic saline aerosols Treatment
- 26. Lung Antibiotics Early intervention, long course, high dose Staphylococcus- Penicillin or cephalosporin Oral cipro for pseudomonas Rapid emergence of resistance Intermittent treatment (2-3 weeks), not chronic IV antibiotics for severe infections or infections resistant to orals Treatment
- 27. Lung Antibiotics Pseudomonas treated with two drugs with different mechanisms to prevent resistance e.g. cephalosporin + aminoglycoside Use of aerosolized antibiotics(convert into a fine spray or colloidal suspension in air.) Increasing mucus clearance N-acetylcysteine not clinically helpful Treatment
- 28. Lung Inhaled β-adrenergic agonists to control airway constriction No evidence of long-term benefit Oral glucocoticoids for allergic bronchopulmonary aspergillosis Treatment
- 29. Lung Respiratory failure therapy Vigorous medical management Oxygen supplementation Only effective treatment for respiratory failure is lung transplantation 2 year survival >60% with lung transplatation Treatment
- 30. Gastrointestinal Pancreatic enzyme replacement Replacement of fat-soluble vitamins- especially vitamin E & K Insulin for hyperglycemia Intestinal obstruction Pancreatic enzymes + osmotically active agents Distal- hypertonic radiocontrast material via enema Treatment
- 31. Gastrointestinal End-stage liver disease- transplantation 2 year survival rate >50% Hepatic and gallbladder complications treated as in patient without CF Treatment
- 32. CF is an inherited monogenic disorder presenting as a multisystem disease Physiology is related to abnormal ion transportation across epithelia Respiratory, GI and GU manifestations Treatment is currently preventative and supportive Summary
- 33.