cystic fibrosis - wayne state university school of · ppt file · web...

Cystic FibrosisCystic Fibrosis

Paolo AquinoPaolo AquinoInternal 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?


• 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


• 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


• 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%)


• 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


• 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

Mutation of CFTRMutation of CFTR


• 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

• Normal airway epithelia

• CF altered airway epithelia


• 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


• 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


• 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


• Respiratory tract– Chronic sinusitis

• Nasal obstruction• Rhinorrhea• Nasal polyps in 25%; often requires surgery

– Chronic cough• Persistent• Viscous, purulent, green sputum


• 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


• 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


• Respiratory tract– Complications

• Pneumothorax ~10% of CF patients• Hemoptysis• Digital clubbing• Cor pulmonale• Respiratory failure


• Gastrointestinal– Meconium ileus

• Abdominal distention• Failure to pass stool• Emesis

– Abdominal flat plate• Air-fluid levels• Granular appearancemeconium• Small colon


• Gastrointestinal– Meconium ileus equivalent or distal intestinal

obstruction syndrome• RLQ pain• Loss of appetite• Emesis• Palpable mass• May be confused with appendicitis


• 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


• 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

cystic fibrosis - wayne state university school of · ppt file · web...

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