N503
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- Classic Cystic Fibrosis: CF
-
⬢ Recurrent pneumonia and respiratory failure
often lead to death by age 30
⬢ Mutations in the cystic fibrosis
transmembrane regulator (CFTR)
⬢ Primary defect : chloride secretion -
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 - The Clinical Expression of Classic CF can be Variable
-
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 - what are the Clinical Manifestations of CF
-
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 - CF Presenting Symptoms
-
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 - Critical Pathologic Features of CF
-
⬢ Thickened viscous secretions (mucus
and proteinaceous debris)
⬢ Disordered fluid/electrolyte secretion
⬢ Exuberant inflammatory response - Pulmonary Disease
-
• 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) - is a marker for chronic hypoxemia
- Clubbing
-
Exocrine
insufficiency: -
Fat maldigestion
and decrease HCO3
- -
Endocrine
insufficiency: - Diabetes
- CF causes a sweat gland defect
-
• Excess NaCl/KCl sweat loss
• Electrolyte and volume depletion
• Basis of commonly used
diagnostic test (“Sweat chloridesâ€) - CF Pathophysiology
-
⬢ Structure of the CFTR protein
⬢ Regulation of chloride secretion
⬢ Mechanism of mutations
⬢ Organ-specific issues - 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. - CFTR and lung function
-
⬢ Decreased fluid and
electrolyte secretion
⬢ Increased viscosity of
mucus
⬢ Decreased ciliary
function
⬢ Decreased bacterial
clearance - Pancreatic Defects in Cystic Fibrosis
-
• Chronic pancreatitis
• Exocrine
– Decreased digestive enzyme secretion
– Decreased bicarbonate secretion
• Low duodenal pH
• Enzyme inactivation
• Bile salt inactivation
• Mucosal damage
• Endocrine
– Diabetes -
Clinical Results of Pancreatic
Dysfunction -
• Exocrine
– Malabsorption of fat
– Malabsorption of fat soluble vitamins
• Endocrine
– Glucose intolerance and diabetes - Summary of Major Physiologic Defects
-
• 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 -
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 -
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 - Diagnosis: Clinical
-
• 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 - Therapies for CF
-
Respiratory
– Aggressive hydration/electrolyte
replacement
– Prophylactic antibiotics (inhaled)
– DNAase
– Physical therapy
– Lung transplant -
Therapy
⬢ Pancreatic insufficiency -
– Oral exogenous pancreatic
enzymes
– Fat soluble vitamins
– High caloric intake
– Insulin for diabetes - CF: summary
-
⬢ 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