Cystic Fibrosis- Biomedical Science
Terms
undefined, object
copy deck
- 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)?
-
enviroment
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?
-
Pneumonia
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?
-
obstruction
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
bronchetesis - What are the presenting symptoms in adults?
-
-Unexplained respiratory disease
–Pancreatic insufficiency
–Chronic sinusitis
–Azoospermia - 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
early
⬢ 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
–Hypoxemia
–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 chloridesâ€) - 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
fibrosis - 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?
-
acinus
duct - 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
constipation
⬢ 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
diarrhea)
–Severe constipation and obstipation
–Male sterility
–Chronic sinusitus + bronchectesis - what are the diagnostic tests?
-
⬢ Increased sweat chlorides after
stimulation
⬢ Genetic testing (detects >99%
classic mutations)
⬢ Nasal potential difference - what is the course of treatment in the respiratory system?
-
–Aggressive hydration/electrolyte
replacement
–Prophylactic antibiotics (inhaled)
–DNAase
–Physical therapy
–Lung transplant - what is the course of treatement in the pancreatic system?
-
–Oral exogenous pancreatic
enzymes
–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