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23 Cards in this Set

  • Front
  • Back
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
– Homozygous or compound heterozygous for severe
– 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
Pancreas: endocrine and exocrine
insufficiency; chronic pancreatitis
Pancreas: endocrine and exocrine
insufficiency; chronic pancreatitis
Intestine: meconium ileus,
Intestine: meconium ileus,
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
– Right heart failure
– Hypoxemia
– Bacteremia and sepsi
• Infectious organisms
– Specific organisms
• H. influenza and S. aureus
• P. aeruginosa later)
is a marker for chronic hypoxemia
Fat maldigestion
and decrease HCO3
CF causes a sweat gland defect
• Excess NaCl/KCl sweat loss
• Electrolyte and volume depletion
• Basis of commonly used
diagnostic test (“Sweat chlorides”)
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
• Decreased ciliary
• Decreased bacterial
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
• 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
• 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
– Severe constipation and obstipation
– Male sterility
– Chronic sinusitus + bronchectesis
Therapies for CF
– Aggressive hydration/electrolyte
– Prophylactic antibiotics (inhaled)
– DNAase
– Physical therapy
– Lung transplant
• Pancreatic insufficiency
– Oral exogenous pancreatic
– 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
• Therapies for lung disease have doubled life
• Gene therapy has not been successful