Transcript Cystic fibrosis

Definition
Cystic fibrosis is a autosomal recessive genetic
disorder with features that reflect mutations in the
cystic fibrosis transmembrane conductance regulator
(CFTR) gene which encodes a protein expressed in the
apical membrane of exocrine epithelial cells.
The CFTR gene is found on the long (q) arm of
human chromosome 7. Children need to inherit one
copy of the gene from each parent in order to have the
disease. If children inherit only one copy, they won't
develop cystic fibrosis. However, they will be carriers
and possibly pass the gene to their own children.
 Most common mutation of CF chromosomes (70% ) is
 ( 3 base pair deletion ) leading to absence of
phenylalanine at position 508 (DF508) of the CF
transmembrane conductance regulator (CFTR)
 Dysfunction in CFTR gene leads to different effects on
patterns of electrolyte and water transport ,result in a
thick and sticky mucus in the respiratory, digestive
and reproductive systems, as well as increased salt in
sweat.
Pathophysiology
 CFTR transports chloride (Cl-) ions across the
membranes of cells in the lungs, liver, pancreas,
digestive tract, reproductive tract, and skin.
• Lungs:
– Raised trans-epithelial electric potential difference.
– Raised sodium transport and decreased chloride
transport.
– High rate of sodium absorption and low rate of chloride
secretion reduces salt and water content in mucus and
depletes peri-ciliary liquid.
– Mucus adheres to airway surface, leads to decreased
mucus clearing.
– Predisposition to Staph and Pseudomonas infections.
• Gastrointestinal:
– Pancreas:
 Leads to retention of enzymes in the
pancreas, destruction of pancreatic tissue.
– Intestine
•
Decrease in water secretion leads to thickened
mucus.
•
Obstruction of small and large intestines.
 Biliary tree
Retention of biliary secretion, Bile duct
proliferation, Chronic cholecystitis and
cholelithiasis
 Sweat
 Normal volume of sweat
 Inability to reabsorb NaCl from sweat as it
passes through sweat duct

Symptoms
Screening of newborns for cystic fibrosis is
essential for diagnosis within the first month of
life, before symptoms develop.
Cystic fibrosis signs and symptoms vary,
depending on the severity of the disease. Some
people may not experience symptoms until
adolescence or adulthood.
People with cystic fibrosis have a higher than
normal level of salt in their sweat. Parents often
can taste the salt when they kiss their children.
 Respiratory signs and symptoms
 The thick and sticky mucus associated with cystic
fibrosis narrow or block airways. This can cause
signs and symptoms such as:
 A persistent cough that produces thick sputum.
 Wheezing.
 Breathlessness.
 Exercise intolerance.
 Repeated lung infections.
 Inflamed nasal passages.
 Digestive signs and symptoms
 The thick mucus can also block tubes that carry
digestive enzymes from pancreas to small intestine
that interfere with absorption of the nutrients.
The result is often:
 Foul-smelling, greasy stools.
 Poor weight gain and growth.
 Intestinal blockage, particularly in newborns
(meconium ileus).
 Severe constipation and rectal prolapse.
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.
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
 Lung
 Antibiotics




Early intervention, long course, high dose.
Staphylococcus- Penicillin or cephalosporin.
Pseudomonas treated with two drugs with
different mechanisms to prevent resistance
e.g. cephalosporin + aminoglycoside
 Inhaled B-adrenergic agonists to control
airway constriction but no evidence of
long-term benefit.
 Oral glucocoticoids for allergic
bronchopulmonary aspergillosis
 Studying benefits of high dose NSAID
therapy for chronic inflammatory
changes.
 Gastrointestinal
 Pancreatic enzyme replacement
 Replacement of fat-soluble vitamins- especially
vitamin E & K
 Insulin for hyperglycemia
 End-stage liver disease- transplantation
 Hepatic and gallbladder complications treated
as in patient without CF.
Complications
Respiratory system complications
 Bronchiectasis.
 Chronic infections: Sinus infections, bronchitis or
pneumonia ( Intially with H. influenzae and S. aureus and
subsequently P. aeruginosa )
 Nasal polyps.
 Pneumothorax.
 Respiratory failure.
 Acute exacerbations.
Digestive system complications
 Nutritional deficiencies:
 Diabetes.
 Blocked bile duct.
 Intestinal obstruction.
Reproductive system complications
 Almost all men with cystic fibrosis are infertile
because vas deferens is either blocked with mucus or
missing entirely.
 Although women with cystic fibrosis may be less fertile
than other women, it's possible for them to conceive
and to have successful pregnancies. Still, pregnancy
can worsen the signs and symptoms of cystic fibrosis.
Other complications
 Osteoporosis.
 Electrolyte imbalances,
 Dehydration.
Prognosis:
Although cystic fibrosis requires daily care,
people with the condition are usually able to
attend school and work, and often have a better
quality of life than affected people in previous
decades.
With improvements in screening and treatments,
people with cystic fibrosis now may survive into
their mid- to late 30s, on average, and some are
living into their 40s and 50s.
Thank you
Dr. Emad M. Alhadeethi
Potential difference can be measured by placing
an electrode on the lining of the nose. Then the
lining of the nose is bathed in a series of solutions
that contain different salts. These solutions are
designed to change the flow of ions across the
epithelium in predictable ways, thus changing the
potential difference in predictable ways.
These solutions contain :
(1) Ringer’s saline solution (a special salt solution
used to obtain the baseline NPD).
(2) Amiloride which blocks sodium channels.
(3) Chloride-free solution.
(4) Isoproterenol, which stimulates CFTR.
The solutions are always administered in the same
order during the NPD testing.
Sweat chloride test
A colorless, odorless chemical (pilocarpine) and a
little electrical stimulation is applied to a small
area of an arm or leg to encourage the sweat glands
to produce sweat. A person may feel tingling in the
area, or a feeling of warmth.
The sweat is then collected on a piece of filter
paper or gauze and sent to the laboratory to
measure chloride is in the sweat.