By
Sara Mohammed El Taras
Supervised by
DR/ El Behiry El Sayed El Behiry
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
>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
his 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
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 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
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
pathogenesis for cystic fibrosis–associated liver disease
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
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 appearance meconium
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
High intestinal obstruction
,possible pnumatosis and
intraperitoneal free air
worrisome for NEC.
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
Hepatobiliary Manifestations
Hepatic manifestations of CF include steatosis,
hepatomegaly, and focal biliary cirrhosis, which can
lead to frank cirrhosis and portal hypertension.
Focal biliary cirrhosis occurs in up to 40% of CF
patients
The incidence of hepatic involvement is 20-50%.
Development of cirrhosis is uncommon, seen in fewer
than 5% of CF patients .
Hepatobiliary Manifestations
Fatty liver changes are commonly asymptomatic,
occurring 30% of the time .
Steatosis may become severe and cause
hepatomegaly.
Focal fat deposition in centrilobular and periportal
regions can occur, creating difficulty discerning portal
triads .
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
Sweat Test
The sweat test
measures the
level of chloride in
sweat using small
electric current.
Pilocarpine increases
sweating+ Mild electric
current
The sweat is collected
on a gauze for 30
minutes, then weighed in
a weighing jar.
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
Histology
The histologic hallmark of CF-related liver disease
is the deposition of inspissated bile
(appearing as eosinophilic material with variable
degrees of periodic acid–Schiff positive reaction)
in dilated cholangioles.
Histology
There is focal periportal obstructive disease with
bile duct proliferation and cholangitis, a variable
combination of inspissation, inflammation
around the portal tracts, fatty infiltration.
Fibrosis and fatty infiltration are the most
common features, whereas the presence of
inspissated bile in cholangioles is infrequent.
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 vitamins- especially vitamin
E&K
Insulin for hyperglycemia
Intestinal obstruction
Pancreatic enzymes + osmotically active agents
Distal- hypertonic radiocontrast material via enema
Treatment options for CF-associated
liver disease
Bile acid therapy.
Nutritional support.
Treatment of portal hypertension and end-stage
of liver disease.
Liver transplantation.
Future Therapies
Gene Therapy
- Add Normal CF genes to correct defective genes in
hopes to cure the disease
- Phase I Trials
Protein Repair
- Correct functions of defective CFTR gene to help
facilitate movement of salt and chloride across lung
cell membranes
- Phase II trials
Future Therapies
Anti inflammatories
- Phase II
Oral N--acetylcysteine
Sildenafil
Inhaled Glutathione
- Phase I
Pioglatazone
Simvastatin
Hydroxychloroquine
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
