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41 Cards in this Set

  • Front
  • Back
What is CLASSIC Cystic Fibrosis?
No CFTR function
Disease Progression Variable
homozygous or compound heterozygous for severe mutations
What is NON-CLASSIC Cystic Fibrosis?
Some (10%) CFTR Function
heterozygous for severe mutation
or compound heterozygous for mild
What is the primary defect associated with Cystic Fibrosis?
Chloride secretion
What is the mutation in CF?
Cystic Fibrosis Transmembrane Regulator
What factors influence phenotype expression (therefore, making them variable)?
modifying genetic background/genes
CFTR function and mutation
What organs can be quite variable with CF?
Pulmonary and Pancreatic disease
What organs are involved in CF?
lungs, reproductive, pancreas, intestines, skin, hepatobilary (6)
What are the clinical manifestations in the lungs?
respiratory failure
What are the clinical manifestations in hepatobilary?
bile duct obstruction
bilary cirrhosis
what are the clinical manifestations in the pancreas?
endocrine and exocrine insufficiency
chronic pancreatitis
What are the clinical manifestations in the intestines?
meconium ileus
What are the clinical manifestiation in the reproductive organs?
congenital absence of the vas deferens
What are the presenting symptoms in newborns?
failure to thrive
bowel obstruction
meconium ileus
What are the presenting symptoms in children?
severe constipation
pancreatic insufficiency
recurrent pancreatitis
What are the presenting symptoms in adults?
-Unexplained respiratory disease
–Pancreatic insufficiency
–Chronic sinusitis
What are the critical pathological features of CF?
-Thickened viscous secretions (mucus
and proteinaceous debris)
- Disordered fluid/electrolyte secretion - Exuberant inflammatory response
with pulmonary disease, what are the infectious organisms?
H. influenza and S. aureus
• P. aeruginosa later)tissue
What are the clinical outcomes with CF in the pulmonary system?
-Recurrent pneumonia
–Progressive loss of lung tissue
–Right heart failure
–Bacteremia and sepsis
What changes does CF cause on the cellular level that promotes bacterial infections?
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
How does CF effect the exocrine and endocrine system?
exocrine = decreased fat maldigestion and HCO3-
endocrine- diabetes
What are the major consequences of exocrine pancreas insufficiency?
fat malabsorption
•Decreased concentration of lipase and colipase
• Decreased Duodenal pH
• Inactivation of pancreatic lipase pH<4.5
• Precipitation of bile salts
What happens as a result of CF and its effects on sweat glands?
sweat gland defects
• Excess NaCl/KCl sweat loss
• Electrolyte and volume depletion
• Basis of commonly used
diagnostic test (“Sweat chlorides”)
What is the pathophysiology of CF?
• Structure of the CFTR protein
• Regulation of chloride secretion
• Mechanism of mutations
• Organ-specific issues
CFTR- Cystic Fibrosis transmembrane conductase regulator
-150 KD transmembrane glycoprotien
- DF508 mutation causes about 70% of CF
- Only individuals homozygous for specific “severe” CFTR mutations develop classic cystic
Chloride Channels and Disease
• 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.
How does CFTR effect the lungs?
• Decreased fluid and
electrolyte secretion
• Increased viscosity of mucus
• Decreased ciliary function
• Decreased bacterial clearance
How does changes in the F808 effect the lungs?
CFTR Reduces Fluid/NaCl secretion,
Increases Mucus Production and Compresses Cilia
CFTR Reduces Mucus Velocity and the
Ability of Cilia to Clear Bacteria
What are the major functional units of the exocrine pancreas?
what are the function of the acinus?
•Secretory products
•Proenzymes and enzymes
•Small amounts of water
and electrolytes•Secretory products
•Proenzymes and enzymes
•Small amounts of water
and electrolytes
what are the function of the pancreatic ducts?
secrete water and electrolytes
What are the pancreatic defects of cystic fibrosis?
• Chronic pancreatitis
• Exocrine
–Decreased digestive enzyme secretion
–Decreased bicarbonate secretion
• Low duodenal pH
• Enzyme inactivation
• Bile salt inactivation
• Mucosal damage
• Endocrine =Diabetes
What are the clinical results of pancreatic dysfunction?
• Exocrine
–Malabsorption of fat
–Malabsorption of fat soluble vitamins
• Endocrine
–Glucose intolerance and diabetes
What are the effects of CFTR in the intestines?
• CFTR is the major determinant of chloride secretion by the small intestine;
decreased secretion increases the viscosity of mucus and causes
• Enhanced CFTR function can be associated with diarrhea
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
what are the 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
What are the clinical signs?
–Failure to thrive in neonate or child
–Recurrent pneumonia
–Diarrhea (steatorrhea or fat loss
–Severe constipation and obstipation
–Male sterility
–Chronic sinusitus + bronchectesis
what are the diagnostic tests?
• Increased sweat chlorides after
• Genetic testing (detects >99%
classic mutations)
• Nasal potential difference
what is the course of treatment in the respiratory system?
–Aggressive hydration/electrolyte
–Prophylactic antibiotics (inhaled)
–Physical therapy
–Lung transplant
what is the course of treatement in the pancreatic system?
–Oral exogenous pancreatic
–Fat soluble vitamins
–High caloric intake
–Insulin for diabetes
What do you do to manage risk for donating CF genes?
• 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
How can you screen newborns?
– Blood trypsinogen ($1.50
– Genetic (d508: $20.00; multiple $50.00)
– Sweat chlorides