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41 Cards in this Set
- Front
- Back
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What is CLASSIC Cystic Fibrosis?
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No CFTR function
Disease Progression Variable homozygous or compound heterozygous for severe mutations |
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What is NON-CLASSIC Cystic Fibrosis?
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Some (10%) CFTR Function
heterozygous for severe mutation or compound heterozygous for mild |
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What is the primary defect associated with Cystic Fibrosis?
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Chloride secretion
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What is the mutation in CF?
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Cystic Fibrosis Transmembrane Regulator
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What factors influence phenotype expression (therefore, making them variable)?
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enviroment
modifying genetic background/genes CFTR function and mutation |
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What organs can be quite variable with CF?
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Pulmonary and Pancreatic disease
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What organs are involved in CF?
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lungs, reproductive, pancreas, intestines, skin, hepatobilary (6)
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What are the clinical manifestations in the lungs?
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Pneumonia
respiratory failure |
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What are the clinical manifestations in hepatobilary?
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bile duct obstruction
bilary cirrhosis |
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what are the clinical manifestations in the pancreas?
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endocrine and exocrine insufficiency
chronic pancreatitis |
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What are the clinical manifestations in the intestines?
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obstruction
meconium ileus |
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What are the clinical manifestiation in the reproductive organs?
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congenital absence of the vas deferens
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What are the presenting symptoms in newborns?
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failure to thrive
bowel obstruction meconium ileus |
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What are the presenting symptoms in children?
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severe constipation
pancreatic insufficiency recurrent pancreatitis bronchetesis |
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What are the presenting symptoms in adults?
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-Unexplained respiratory disease
–Pancreatic insufficiency –Chronic sinusitis –Azoospermia |
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What are the critical pathological 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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with pulmonary disease, what are the infectious organisms?
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H. influenza and S. aureus
early • P. aeruginosa later)tissue |
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What are the clinical outcomes with CF in the pulmonary system?
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-Recurrent pneumonia
–Progressive loss of lung tissue –Right heart failure –Hypoxemia –Bacteremia and sepsis |
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What changes does CF cause on the cellular level that promotes bacterial infections?
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Altered electrolyte secretion favors the growth of
specific bacteria • Changes in glycosylation of surface proteins and lipids enhance adherence and proliferation of specific bacteria • Reduced phagocytic vesicle acidification required for bacterial killing by macrophages • Formation of biofilms |
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How does CF effect the exocrine and endocrine system?
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exocrine = decreased fat maldigestion and HCO3-
endocrine- diabetes |
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What are the major consequences of exocrine pancreas insufficiency?
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fat malabsorption
•Decreased concentration of lipase and colipase • Decreased Duodenal pH • Inactivation of pancreatic lipase pH<4.5 • Precipitation of bile salts |
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What happens as a result of CF and its effects on sweat glands?
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sweat gland defects
• Excess NaCl/KCl sweat loss • Electrolyte and volume depletion • Basis of commonly used diagnostic test (“Sweat chlorides”) |
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What is the pathophysiology of CF?
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• Structure of the CFTR protein
• Regulation of chloride secretion • Mechanism of mutations • Organ-specific issues |
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CFTR- Cystic Fibrosis transmembrane conductase regulator
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-150 KD transmembrane glycoprotien
- DF508 mutation causes about 70% of CF - Only individuals homozygous for specific “severe” CFTR mutations develop classic cystic fibrosis |
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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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How does CFTR effect the lungs?
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• Decreased fluid and
electrolyte secretion • Increased viscosity of mucus • Decreased ciliary function • Decreased bacterial clearance |
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How does changes in the F808 effect the lungs?
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CFTR Reduces Fluid/NaCl secretion,
Increases Mucus Production and Compresses Cilia CFTR Reduces Mucus Velocity and the Ability of Cilia to Clear Bacteria |
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What are the major functional units of the exocrine pancreas?
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acinus
duct |
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what are the function of the acinus?
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•Secretory products
•Proenzymes and enzymes •Small amounts of water and electrolytes•Secretory products •Proenzymes and enzymes •Small amounts of water and electrolytes |
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what are the function of the pancreatic ducts?
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secrete water and electrolytes
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What are the pancreatic defects of 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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What are the clinical results of pancreatic dysfunction?
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• Exocrine
–Malabsorption of fat –Malabsorption of fat soluble vitamins • Endocrine –Glucose intolerance and diabetes |
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What are the effects of CFTR in the intestines?
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• CFTR is the major determinant of chloride secretion by the small intestine;
decreased secretion increases the viscosity of mucus and causes constipation • Enhanced CFTR function can be associated with diarrhea |
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Resistance to two bacterial infections may have favored survival in those with CFTR mutations
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• 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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what are the classes of mutations that lead to CFTR dysfunction?
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• 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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What are the clinical signs?
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–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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what are the diagnostic tests?
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• Increased sweat chlorides after
stimulation • Genetic testing (detects >99% classic mutations) • Nasal potential difference |
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what is the course of treatment in the respiratory system?
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–Aggressive hydration/electrolyte
replacement –Prophylactic antibiotics (inhaled) –DNAase –Physical therapy –Lung transplant |
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what is the course of treatement in the pancreatic system?
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–Oral exogenous pancreatic
enzymes –Fat soluble vitamins –High caloric intake –Insulin for diabetes |
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What do you do to manage risk for donating CF genes?
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• Known autosomal recessive
–Discovered based on family history or child with CF –Risk of CF to each child with both parents being heterozygous for D508: 1/4 • Prenatal –Aminocentesis or chorionic villi sampling –Fetal echogenic bowel –Pre-implantation genetic diagnosis with IVF • Donor insemination |
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How can you screen newborns?
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– Blood trypsinogen ($1.50
– Genetic (d508: $20.00; multiple $50.00) – Sweat chlorides |
