Cystic Fibrosis Paolo Aquino Internal Medicine-Pediatrics January 13, 2005.
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Transcript of Cystic Fibrosis Paolo Aquino Internal Medicine-Pediatrics January 13, 2005.
Cystic FibrosisCystic Fibrosis
Paolo AquinoPaolo Aquino
Internal Medicine-PediatricsInternal Medicine-Pediatrics
January 13, 2005January 13, 2005
OutlineOutline
• What is cystic fibrosis (CF)?
• What causes CF?
• What are the manifestations?
• How do you diagnose CF?
• How do you treat CF?
Cystic FibrosisCystic 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 FibrosisCystic 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 CFGenetics 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 CFGenetics of CF
• Most common mutation– Occurs in 70% of CF chromosomes– 3 base pair deletion leading to absence of
phenylalanine at position 508 (F508) of the CF transmembrane conductance regulator (CFTR)
• Large number (>1000) of relatively uncommon muations (~2%)
Genetics of CFGenetics of CF
• Difficult to use DNA diagnosis to screen for heterozygotes
• No simple physiologic measurements yet available for heterozygote detection
Genetics of CF 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 CFGenetics of CF
• F508 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
Genetics of CFGenetics 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 CFPersistence 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 F508 mutation are unresponsive to the secretory effects of cholera toxin
PathophysiologyPathophysiology
• 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
PathophysiologyPathophysiology
• 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
PathophysiologyPathophysiology
• Gastrointestinal– Pancreas
• Absence of CFTR limits function of chloride-bicarbonate 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
PathophysiologyPathophysiology
• Gastrointestinal– Biliary tree
• 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
ManifestationsManifestations
• Common presentations– Chronic cough– Recurrent pulmonary infiltrates– Failure to thrive – Meconium ileus
ManifestationsManifestations
• Respiratory tract– Chronic sinusitis
• Nasal obstruction• Rhinorrhea• Nasal polyps in 25%; often requires surgery
– Chronic cough• Persistent• Viscous, purulent, green sputum
ManifestationsManifestations
• Respiratory tract– Chronic cough
• Exacerbations require aggressive therapy– 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
ManifestationsManifestations
• 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
ManifestationsManifestations
• Respiratory tract– Complications
• Pneumothorax ~10% of CF patients• Hemoptysis• Digital clubbing• Cor pulmonale• Respiratory failure
ManifestationsManifestations
• Gastrointestinal– Meconium ileus
• Abdominal distention• Failure to pass stool• Emesis
– Abdominal flat plate• Air-fluid levels• Granular appearancemeconium• Small colon
ManifestationsManifestations
• Gastrointestinal– Meconium ileus equivalent or distal intestinal
obstruction syndrome• RLQ pain• Loss of appetite• Emesis• Palpable mass• May be confused with appendicitis
ManifestationsManifestations
• Gastrointestinal– Exocrine pancreatic insufficiency
• 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
ManifestationsManifestations
• 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
DiagnosisDiagnosis
• 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
DiagnosisDiagnosis
• 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
TreatmentTreatment
• 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
TreatmentTreatment
• Lung– >95% of CF patients die from complications of
lung infection– Breathing exercises– Flutter valves– Chest percussion– ? Hypertonic saline aerosols
TreatmentTreatment
• 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
TreatmentTreatment
• 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
TreatmentTreatment
• Lung– Inhaled -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
TreatmentTreatment
• 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
TreatmentTreatment
• Gastrointestinal– Pancreatic enzyme replacement– Replacement of fat-soluble vitamins-
especially vitamin E & K– Insulin for hyperglycemia– Intestinal obstruction
• Pancreatic enzymes + osmotically active agents• Distal- hypertonic radiocontrast material via enema
TreatmentTreatment
• Gastrointestinal– End-stage liver disease- transplantation
• 2 year survival rate >50%
– Hepatic and gallbladder complications treated as in patient without CF
SummarySummary
• 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