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23 Cards in this Set
- Front
- Back
Classic Cystic Fibrosis: CF
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• Recurrent pneumonia and respiratory failure
often lead to death by age 30 • Mutations in the cystic fibrosis transmembrane regulator (CFTR) • Primary defect : chloride secretion |
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CF: two general phenotypes depend on
mutation and gene dosing |
Classic
– Homozygous or compound heterozygous for severe mutations – No CFTR function – Disease progression variable • Non-classic – Heterozygous for severe mutation or compound heterozygous for mild mutations – Some (~ 10%) CFTR function |
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The Clinical Expression of Classic CF can be Variable
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Factors that affect phenotype
– CFTR mutations – Modifying genes/genetic background – Environment • Example – Pulmonary and Pancreatic Disease expression can be quite variable– Some (~ 10%) CFTR function |
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what are the Clinical Manifestations of CF
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Lungs: pneumonia, respiratory
failure Pancreas: endocrine and exocrine insufficiency; chronic pancreatitis Pancreas: endocrine and exocrine insufficiency; chronic pancreatitis Intestine: meconium ileus, obstruction Intestine: meconium ileus, obstruction Hepatobiliary: bile duct obstruction, biliary cirrhosis Hepatobiliary: bile duct obstruction, biliary cirrhosis Reproductive: congenital absence of the vas deferens |
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CF Presenting Symptoms
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Presenting Symptoms
• Newborn/infant – Meconium ileus/ bowel obstruction – Failure to thrive • Child – Recurrent pneumonia/bronchectesis – Pancreatic insufficiency – Severe constipation • Adult – Unexplained respiratory disease – Pancreatic insufficiency – Chronic sinusitis – Azoospermia |
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Critical Pathologic Features of CF
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• Thickened viscous secretions (mucus
and proteinaceous debris) • Disordered fluid/electrolyte secretion • Exuberant inflammatory response |
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Pulmonary Disease
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• Clinical outcomes
– Recurrent pneumonia – Progressive loss of lung tissue – Right heart failure – Hypoxemia – Bacteremia and sepsi • Infectious organisms – Specific organisms • H. influenza and S. aureus early • P. aeruginosa later) |
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is a marker for chronic hypoxemia
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Clubbing
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Exocrine
insufficiency: |
Fat maldigestion
and decrease HCO3 - |
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Endocrine
insufficiency: |
Diabetes
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CF causes a sweat gland defect
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• Excess NaCl/KCl sweat loss
• Electrolyte and volume depletion • Basis of commonly used diagnostic test (“Sweat chlorides”) |
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CF Pathophysiology
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• Structure of the CFTR protein
• Regulation of chloride secretion • Mechanism of mutations • Organ-specific issues |
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Chloride channels and disease
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• CFTR is activated by cAMP. The presence of
chloride channels that are activated by calcium has two important implications. – Calcium-activated chloride channels may limit injury to some tissues in patients with CF – Activation of the calcium-activated channels has been used therapeutically. |
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CFTR and lung function
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• Decreased fluid and
electrolyte secretion • Increased viscosity of mucus • Decreased ciliary function • Decreased bacterial clearance |
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Pancreatic Defects in Cystic Fibrosis
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• Chronic pancreatitis
• Exocrine – Decreased digestive enzyme secretion – Decreased bicarbonate secretion • Low duodenal pH • Enzyme inactivation • Bile salt inactivation • Mucosal damage • Endocrine – Diabetes |
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Clinical Results of Pancreatic
Dysfunction |
• Exocrine
– Malabsorption of fat – Malabsorption of fat soluble vitamins • Endocrine – Glucose intolerance and diabetes |
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Summary of Major Physiologic Defects
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• Lungs
– Decreased fluid secretion and viscous mucus; inflammation – Outcome: respiratory failure • Pancreas – Decreased bicarbonate and digestive enzyme secretion; inflammation – Outcome: pancreatic insufficiency: exocrine>endocrine • Intestine – Decrease secretion; viscous mucus – Outcome: severe constipation • Sweat glands – Increased chloride secretion – Outcome: susceptible to dehydration • Hepatobiliary |
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Resistance to two bacterial infections may have
favored survival in those with CFTR mutations |
Key pathologic responses related to CFTR
– Cholera and other bacteria cause diarrhea by stimulating cAMP*- dependent chloride secretion. – CFTR-mediated chloride secretion is stimulated by cAMP *. – Some infectious agents use cell surface proteins as receptors to enter cells |
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Classes of mutations that lead to CFTR
dysfunction |
• I-Defective protein production (stop codon)
• II-Defective processing • III - Defective regulation • IV - Defective function (e.g. ion conduction) • V - Defective cycling |
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Diagnosis: Clinical
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• History
– Failure to thrive in neonate or child – Recurrent pneumonia – Diarrhea (steatorrhea or fat loss diarrhea) – Severe constipation and obstipation – Male sterility – Chronic sinusitus + bronchectesis |
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Therapies for CF
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Respiratory
– Aggressive hydration/electrolyte replacement – Prophylactic antibiotics (inhaled) – DNAase – Physical therapy – Lung transplant |
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Therapy
• Pancreatic insufficiency |
– Oral exogenous pancreatic
enzymes – Fat soluble vitamins – High caloric intake – Insulin for diabetes |
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CF: summary
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• CF is caused by mutations in CFTR
• The major physiologic defect is reduced cAMPdependent Cl- transport • The major organs affected are the lung, pancreas, and intestine. Most deaths come from respiratory failure • Therapies for lung disease have doubled life expectancy • Gene therapy has not been successful |