Cystic Fibrosis

1. CYSTIC FIBROSIS
A Presentation by: Jayatheeswaran. Vijayakumar

2. CYSTIC FIBROSIS
“Woe to the child which when
kissed on the forehead tastes salty.
He is bewitched and soon will die” –
Old Proverb

3. CYSTIC FIBROSIS
 Cystic fibrosis is a disease of exocrine gland function that
involves multiple organ systems but chiefly results in
chronic respiratory infections, pancreatic enzyme
insufficiency, and associated complications in untreated
patients
 Is a lethal autosomal recessive disease
 Has an incidence: 1 in 2000-3000; predominantly in
Caucasian populations (carrier frequency 1 in 22-28)
 Median age at diagnosis of cystic fibrosis is 6-8 months;
two thirds of patients are diagnosed by 1 year of age.

4. CYSTIC FIBROSIS
 The disease gene CFTR (cystic fibrosis transmembrane
conductance regulator) is a regulated epithelial Cl-
channel; influences other ion channels
 The age at diagnosis, the clinical presentation, the
severity of the symptoms, and the rate of disease
progression in the organs involved varies widely.
 Clinical manifestations vary with the patient's age at
presentation. e.g. : patients diagnosed later in childhood
or in adulthood are more likely to have pancreatic
sufficiency and often present with chronic cough and
sputum production

5. GENOTYPE & PHENOTYPE RELATIONSHIP
 Cystic fibrosis (CF) is caused by mutations in the CF
transmembrane conductance regulator (CFTR) gene
which encodes a protein expressed in the apical
membrane of exocrine epithelial cells.
 This genotypic variation provides a rationale for
phenotypic effects of the specific mutations. The
extent to which various CFTR alleles contribute to
clinical variation in CF is evaluated by genotype-
phenotype studies.
 The poor correlation between CFTR genotype and
severity of lung disease strongly suggests an
influence of environmental and secondary genetic
factors (CF modifiers).

6. GENOTYPE & PHENOTYPE RELATIONSHIP
 Several candidate genes related to innate and
adaptive immune response have been
implicated as pulmonary CF modifiers. In
addition, the presence of a genetic CF modifier
for meconium ileus has been demonstrated on
human chromosome 19q13.2.
 The phenotypic spectrum associated with
mutations in the CFTR gene extends beyond
the classically defined CF. Besides patients with
atypical CF, there are large numbers of so-
called monosymptomatic diseases such as
various forms of obstructive azoospermia,
idiopathic pancreatitis or disseminated
bronchiectasis associated with CFTR mutations
uncharacteristic for CF.

7. PATHOPHYSIOLOGY
 Chloride channel.
 Five domains:
 2 membrane spanning
domains (MSD)
 2 nucleotide binding
domains (NBD, for ATP
hydrolysis)
 1 regulatory domain (R).
 Functions in lungs, liver,
pancreas, digestive
tract,
reproductive tract & skin.

8. PATHOPHYSIOLOGY
 In normal airway cells, there
are two Cl- channels. One
channel is regulated by cyclic
AMP and ATP (CFTR), and the
other is activated by Ca2+.
 ATP binding and hydrolysis open
CFTR, so that Cl- can move down
its electrochemical gradient, into
the mucus of the lungs.
 Presence of Cl- in the mucus
ensures its sufficient water
content, required for mucus
removal by the cilia of the airway
cells

9. PATHOPHYSIOLOGY
 In individuals with CF, the defect in
CFTR protein causes decreased
secretion of Cl- ions which cause a
compensatory influx of Na+ ions to
maintain the electro-neutrality of the
cell.
 Increase in the osmolarity inside the
cell causes a water influx from
outside the cell. This leads to the
dehydration of the mucus membrane.
 The now sticky mucus traps
bacteria, is not remove by cilia of the
lung epithelium. As the lungs have
the perfect environment for bacterial
propagation patients with CF typically
get lung infections.

10. CLASSIFICATION
 Class I: normal level of
mRNA ; defective protein
production (premature stop
codon).
No or little CFTR protein is
produced.
 Class II: Defective trafficking:
the protein does not reach
the membrane
 Class III: defective regulation
(opening/closing) of the
CFTR channel
 Class IV: defective conduction
(Cl- doesn’t pass through the
channel)
 Class V: reduced synthesis
of functional CFTR

11. CLASSIFICATION
 The most common CFTR mutant ΔF508, is a
class II defect.
 The defective protein retains substantial
chloride-channel function in cell-free lipid
membranes.
 When synthesized by the normal cellular
machinery, however, the protein is rapidly
recognized as misfolded and is degraded shortly
after synthesis , via proteasome degradation
pathway at endoplasmic reticulum (ER).

12. THE MOST COMMON CFTR MUTATION
Around 75% of mutations
observed in CF patients
result from a deletion of
three base pairs in CFTR's
nucleotide sequence. This
deletion causes loss of the
amino acid phenylalanine
located at position 508 in
the protein; therefore, this
mutation is referred to as
delta F508 or ΔF508.

13. CLINICAL PRESENTATION
Manifestations
Respiratory
Tract
Urogenital Tract
Gastrointestinal
Tract
Atypical

14. CLINICAL PRESENTATION
 Nose examination may reveal
the following:
 Rhinitis
 Nasal polyps
 Findings related to the pulmonary
system may include the following:
 Tachypnea
 Respiratory distress with
retractions
 Wheeze or crackles
 Cough (dry or productive of mucoid
or purulent sputum)
 Increased anterior-posterior
diameter of chest
 Clubbing
 Cyanosis
 Hyperresonant sound heard upon
chest percussion (crackles are
heard acutely in associated
pneumonitis or bronchitis and
chronically with bronchiectasis)

15. CLINICAL PRESENTATION
 Findings related to the
GI tract include the
following:
 Abdominal distention
 Hepatosplenomegaly
(fatty liver and portal
hypertension)
 Rectal prolapse
 Dry skin
(vitamin A deficiency)
 Cheilosis (vitamin B
complex deficiency)
 Findings related to the
Urogenital tract include
the following:
 Hydrocele
 Undescended testicles
 Amenorrhea
 Sterility
 In males: due to the
absence of the vas
deferens
 In females: fertility is
maintained although it is
severely decreased

16. CLINICAL PRESENTATION
 Examination of other systems may reveal the
following:
 Scoliosis
 Kyphosis
 Swelling of submandibular gland or parotid gland
 Aquagenic wrinkling of the palms (AWP)
 One study reported an association between AWP and
cystic fibrosis.Among patients with cystic fibrosis, a greater
degree of AWP is observed in patients who are
homozygous for the ΔF508 mutation.

17. CLINICAL PRESENTATION
Atypical Manifestations
 Clinical variants have been described, such as adult males with bilateral
absence of the vas deferens who have little other clinical involvement.
Absence of the vas deferens is considered an atypical presentation of
cystic fibrosis, and 80% of men with this presentation have at least
one CFTR gene mutation. Zielenski et al reported that the most common
of these mutations is the IVS8/5T mutation.
 Another atypical manifestation of cystic fibrosis is polyuria and
polyphagia in an infant. Despite not having any initial intestinal
symptoms, such as diarrhea, an infant in Belgium with failure to thrive
was initially treated for diabetes insipidus before being diagnosed with
cystic fibrosis. Although a sweat test result may be abnormal in diabetes
insipidus, cystic fibrosis must be excluded upon any positive sweat test
result.

18. CLINICAL PRESENTATION
Complications
 The following are potential
complications of cystic fibrosis:
 Nasal polyps
 Chronic and persistent sinusitis with
complications such as mucopyocele
formation
 Bronchiectasis
 Atelectasis
 Pneumothorax
 Hemoptysis
 Hypertrophic pulmonary
osteoarthropathy
 Allergic bronchopulmonary
aspergillosis (ABPA)
 Gastroesophageal reflux
 Pulmonary hypertension
 End-stage lung disease
 Cor pulmonale
 Pancreatitis
 Cystic fibrosis–related diabetes mellitus
 Meconium ileus
 Distal intestinal obstruction syndrome
 Rectal prolapse
 Vitamin deficiency (especially fat-
soluble vitamins)
 Fatty liver
 Focal biliary cirrhosis
 Portal hypertension
 Liver failure
 Cholecystitis and Cholelithiasis
 Rickets
 Osteoporosis

19. THE RELATIONSHIP BETWEEN CLINICAL
PRESENTATIONS & RESIDUAL CFTR FUNCTION
% of Normal CFTR Function Clinical Presentations
< 1 Pancreatic insufficiency and below
< 4.5 Pulmonary infection and below
< 5 Positive sweat test and symptoms below
< 10 Congenital absence of vas deferens
10-49 None
50-100 None
 34% of patients reach adulthood
10% live past age of 30
Average Life Expectancy
•Male : 31
•Female: 28

20. TREATMENT
• The major goal in treating CF is to clear the
abnormal and excess secretions, control
infections in the lungs and to prevent
obstruction in the intestines.
• For patients with advanced stages of the
disease, a lung transplant operation may be
necessary.
• Although treating the symptoms does not cure
the disease, it can greatly improve the quality of
life for most patients.

21. TREATMENT
 Modified Diet
Due to pancreatic disorders, children with CF require
a modified diet, including vitamin supplements
(vitamins A, D, E, and K) and pancreatic enzymes.
Maintaining adequate nutrition is essential. The diet
calls for a high-caloric content (twice what is
considered normal for the child's age), which is
typically low in fat and high in protein. Patients or
their caregivers should consult with their health care
providers to determine the most appropriate diet.