Cystic Fibrosis
Paolo Aquino
Internal Medicine-Pediatrics
January 13, 2005
Outline
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What is cystic fibrosis (CF)?
What causes CF?
What are the manifestations?
How do you diagnose CF?
How do you treat CF?
Cystic Fibrosis
• Inherited monogenic disorder presenting
as a multisystem disease.
• Typically presents in childhood
– 7% of CF patients diagnosed as adults
• Most common life limiting recessive trait
among whites
Cystic Fibrosis
• Prognosis improving
– >38% of CF patients are older than 18
– 13% of CF patients are older than 30
• Median survival
– Males: 32 years
– Females: 29 years
Genetics of CF
• Autosomal recessive
• Gene located on chromosome 7
• Prevalence- varies with ethnic origin
– 1 in 3000 live births in Caucasians in North
America and Northern Europe
– 1 in 17,000 live births of African Americans
– 1 in 90,000 live births in Hawaiian Asians
Genetics of CF
• Most common mutation
– Occurs in 70% of CF chromosomes
– 3 base pair deletion leading to absence of
phenylalanine at position 508 (DF508) of the
CF transmembrane conductance regulator
(CFTR)
• Large number (>1000) of relatively
uncommon muations (~2%)
Genetics of CF
• Difficult to use DNA diagnosis to screen for
heterozygotes
• No simple physiologic measurements yet
available for heterozygote detection
Genetics of CF
• The CFTR protein
– Single polypeptide chain, 1480 amino acids
– Cyclic AMP regulated chloride channel
– Regulator of other ion channels
– Found in the plasma membrane of normal
epithelial cells
Genetics of CF
• DF508 mutation leads to improper
processing and intracellular degradation of
the CFTR protein
• Other mutations in the CF gene produce
fully processed CFTR proteins that are
either non-functional or partially functional
Mutation of CFTR
Genetics of CF
• Epithelial dysfunction
– Epithelia containing CFTR protein exhibit
array of normal functions
• Volume absorbing (airway, distal intestine)
• Salt absorbing without volume (sweat ducts)
• Volume secretory (proximal intestine, pancreas)
– Dysfunction in CFTR gene leads to different
effects on patterns of electrolyte and water
transport
Persistence of CF
• Is there a reason why CF mutations are so
prevalent?
• Hypothetical resistance to morbidity and
mortality associated with cholera
• Evidence shows intestinal epithelial cells
homozygous for the DF508 mutation are
unresponsive to the secretory effects of
cholera toxin
Pathophysiology
• Lung
– Raised trans-epithelial electric potential
difference
– Absence of cAMP-dependent kinase and
PKC-regulated chloride transport
– Raised sodium transport and decreased
chloride transport
– Alternative calcium-regulated chloride channel
in airway epithelia which is a potential
therapeutic target
• Normal airway
epithelia
• CF altered airway
epithelia
Pathophysiology
• Lung
– High rate of sodium absorption and low rate of
chloride secretion reduces salt and water
content in mucus, depletes peri-ciliary liquid
– Mucus adheres to airway surface, leads to
decreased mucus clearing
– Predisposition to Staph and Pseudomonas
infections
Pathophysiology
• Gastrointestinal
– Pancreas
• Absence of CFTR limits function of chloridebicarbonate exchanger to secrete bicarbonate
• Leads to retention of enzymes in the pancreas,
destruction of pancreatic tissue.
– Intestine
• Decrease in water secretion leads to thickened
mucus and dessicated intraluminal contents
• Obstruction of small and large intestines
Pathophysiology
• Gastrointestinal
– Biliary tree
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Retention of biliary secretion
Focal biliary cirrhosis
Bile duct proliferation
Chronic cholecystitis, cholelithiasis
• Sweat
– Normal volume of sweat
– Inability to reabsorb NaCl from sweat as it
passes through sweat duct
Manifestations
• Common presentations
– Chronic cough
– Recurrent pulmonary infiltrates
– Failure to thrive
– Meconium ileus
Manifestations
• Respiratory tract
– Chronic sinusitis
• Nasal obstruction
• Rhinorrhea
• Nasal polyps in 25%; often requires surgery
– Chronic cough
• Persistent
• Viscous, purulent, green sputum
Manifestations
• Respiratory tract
– Chronic cough
• Exacerbations require aggressive therapy
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Postural drainage
Antibiotics
Become more frequent with age
Progressive loss of lung function
– Infection
• Intially with H. influenzae and S. aureus
• Subsequently P. aeruginosa
• Occassionally, Xanthomonas xylosoxidans, Burkholderia
gladioli, Proteus, E. coli, Klebsiella
Manifestations
• Respiratory tract
– Lung function
• Small airway disease is first functional lung
abnormality
• Progresses to reversible as well as irreversible
changes in FEV1
• Chest x-ray may show hyperinflation, mucus
impaction, bronchial cuffing, bronchiectasis
Manifestations
• Respiratory tract
– Complications
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Pneumothorax ~10% of CF patients
Hemoptysis
Digital clubbing
Cor pulmonale
Respiratory failure
Manifestations
• Gastrointestinal
– Meconium ileus
• Abdominal distention
• Failure to pass stool
• Emesis
– Abdominal flat plate
• Air-fluid levels
• Granular appearancemeconium
• Small colon
Manifestations
• Gastrointestinal
– Meconium ileus equivalent or distal intestinal
obstruction syndrome
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RLQ pain
Loss of appetite
Emesis
Palpable mass
May be confused with appendicitis
Manifestations
• Gastrointestinal
– Exocrine pancreatic insufficiency
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Found in >90% of CF patients
Protein and fat malabsorption
Frequent bulky, foul-smelling stools
Vitamin A, D, E, K malabsorption
Sparing of pancreatic beta cells
– Beta cell function decreases with age
– Increased incidence of GI malignancy
Manifestations
• Genitourinary
– Late onset puberty
• Due to chronic lung disease and inadequate
nutrition
– >95% of male patients with CF have
azospermia due to obliteration of the vas
deferens
– 20% of female patients with CF are infertile
– >90% of completed pregnancies produce
viable infants
Diagnosis
• DNA analysis not useful due to large
variety of CF mutations
• Sweat chloride test >70 mEq/L
• 1-2% of patients with clinical
manifestations of CF have a normal sweat
chloride test
– Nasal transepithelial potential difference
Diagnosis
• Criteria
– One of the following
• Presence of typical clinical features
• History of CF in a sibling
• Positive newborn screening test
– Plus laboratory evidence for CFTR dysfunction
• Two elevated sweat chloride concentrations on two separate
days
• Identification of two CF mutations
• Abnormal nasal potential difference measurement
Treatment
• Major objectives
– Promote clearance of secretions
– Control lung infection
– Provide adequate nutrition
– Prevent intestinal obstruction
• Investigation into therapies to restore the
processing of misfolded CFTR protein
Treatment
• Lung
– >95% of CF patients die from complications of
lung infection
– Breathing exercises
– Flutter valves
– Chest percussion
– ? Hypertonic saline aerosols
Treatment
• Lung
– Antibiotics
• Early intervention, long course, high dose
• Staphylococcus- Penicillin or cephalosporin
• Oral cipro for pseudomonas
– Rapid emergence of resistance
– Intermittent treatment (2-3 weeks), not chronic
• IV antibiotics for severe infections or infections
resistant to orals
Treatment
• Lung
– Antibiotics
• Pseudomonas treated with two drugs with different
mechanisms to prevent resistance
– e.g. cephalosporin + aminoglycoside
• Use of aerosolized antibiotics
– Increasing mucus clearance
• N-acetylcysteine not clinically helpful
• Long-term DNAse treatment increases time
between pulmonary exacerbations
Treatment
• Lung
– Inhaled b-adrenergic agonists to control
airway constriction
• No evidence of long-term benefit
– Oral glucocoticoids for allergic
bronchopulmonary aspergillosis
– Studying benefits of high dose NSAID therapy
for chronic inflammatory changes
Treatment
• Lung
– Atelectasis
• Chest PT + antibiotics
– Respiratory failure and cor pulmonale
• Vigorous medical management
• Oxygen supplementation
• Only effective treatment for respiratory failure is
lung transplantation
– 2 year survival >60% with lung transplatation
Treatment
• Gastrointestinal
– Pancreatic enzyme replacement
– Replacement of fat-soluble vitaminsespecially vitamin E & K
– Insulin for hyperglycemia
– Intestinal obstruction
• Pancreatic enzymes + osmotically active agents
• Distal- hypertonic radiocontrast material via enema
Treatment
• Gastrointestinal
– End-stage liver disease- transplantation
• 2 year survival rate >50%
– Hepatic and gallbladder complications treated
as in patient without CF
Summary
• CF is an inherited monogenic disorder
presenting as a multisystem disease
• Pathophysiology is related to abnormal ion
transportation across epithelia
• Respiratory, GI and GU manifestations
• Treatment is currently preventative and
supportive