Cystic Fibrosis

Paolo Aquino
Internal Medicine-Pediatrics
January 13, 2005

Outline

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 (F508) 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
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 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 F508 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

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

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

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 appearancemeconium
Small colon

Manifestations
Gastrointestinal
Meconium ileus equivalent or distal intestinal
obstruction syndrome

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

Manifestations
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

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 -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