MEDICINE 2

CYSTIC FIBROSIS/ Dr. Jose Edzel V. Tamayo / June 28, 2017

OUTLINE CATEGORIES OF CFTR MUTATIONS

o Brief Epidemiology
o Physical and Pathophysiology  We now have extensive understanding about the production,
o Clinical Manifestation (focus pulmonary) folding, trafficking, of CFTR protein to the apical membrane
o Diagnosis o Absence of synthesis (class1): nucleus
o Prognosis o Defective protein maturation and premature
o Treatment degradation (class2): endoplasmic reticulum
o Applicability in the Philippines o Disordered gating/regulation, such as diminished adenosine
triphosphate (ATP) binding and hydrolysis (class3): apical
INTRODUCTION
membrane
 Cystic fibrosis (CF) is an autosomal recessive
exocrinopathy affecting multiple epithelial tissues o Defective conductance through the ion channel pore
- external gland na may problema sa pag secrete nang (class 4):
o A reduced number of CFTR transcripts due to a
kanyang secretion
promoter or the splicing abnormality (class 5): nucleus
 The gene product responsible for CF is the Cystic fibrosis
o Accelerated turnover from the cell surface (class 6)
transmembrane conductance regulator [CFTR]
 The disease is most common among whites (~1 in 3300 live
births) and much less frequent among African Americans
(~1 in 15,000) or Asian populations (~1 in 33,000).
- Not common here in the Philippines but it still has its
applicability here
- CFTR regulates the amount and secretion of the exocrine
glandnot only the exocrine glands in the airway but other
glands in the body as well
- CFTR allows normal ciliary extension and ciliary transport,
therefore if CFTR is abnormal there will be depletion of
your periciliary fluid  cilia will collapse

PROTEIN FUNCTION AND BIOCHEMISTRY

 CFTR is situated in the apical plasma membranes of acinar
and other epithelial cells where it regulates the amount
and composition of secretion by glands.
 Along respiratory mucosa, CFTR is necessary to provide
sufficient depth of the pericilliary fluid layer [PCU], allowing A. Extrusion of mucus secretion onto the epithelial
surfaces of airways in cystic fibrosis
normal cilliary extension and muccocilliary transport.
o A schematic of glandular structure of the human
 CFTR-deficient airway cells exhibit depleted PCL causing
airway
cilliary collapse and failure to clear overlying mucus.
- Mucus that overlies the epithelial and goblet cell
- In cystic fibrosis, nagpo-produce ng mucus na
matigas hindi mailabas/mai-propel ng airway so
dumidikit na lang siya sa airway epithelium 
static mucus  mabubulok yung mucus tutuboan
ng bacteria  on/off pulmonary
infection/pneumonia  destruction of lung tissue
 permanent damage  BRONCHIECTASIS

Transer: AHBC
Edited by:
 B. The submucosal glands of a patient with cystic
fibrosis are filled with mucus, and mucopurulent
debris overlies the airway surfaces, essentially
burying the epithelium.

RESPIRATORY MANIFESTATIONS
C. A higher magnification view of mucus plug
tightly adhering to the airway surface, with
arrows indicating the interference between  The major morbidity and mortality associated with CF is
infected and inflamed secretions and the attributable to respiratory compromise,
underlying epithelium to which the secretions characterized by copious, hyperviscous, and
adhere. Infected secretions obstruct airways adherent pulmonary secretions that obstruct small
and, over time dramatically disrupt the normal and medium sized airways.
architecture of the lung.  CF airway secretions are exceedingly difficult to clear, and
a complex bacterial flora that includes Staphylococcus
aureus, Haemophilus influenzae, and Pseudomonas
aeruginosa (among other pathogens) is routinely
cultured from CF sputum.
 Robust pulmonary inflammation in the setting of
inspissated mucus (naninigas na mucus) and chronic
bacterial infection leads to collateral tissue injury
(bronchiectasis) and further aggravates respiratory
decline.
 CYSTIC FIBROTIC LUNG


- The CF airway is characterized by an aggressive, 
unrelenting, neutrophilic inflammatory response 
with the release of protease and oxidants leading

to airway remodeling and bronchiectasis.

- Nag-iiba na yung itsura ng airway epithelium 
leading to permanent damage  BRONCHIECTASIS 

- Link for Doc Tamayo’s CFTR pathophysio video: 
https://www.youtube.com/watch?v=_j99-xgOIaw

- CFTR gene mutation is not exclusive for lungs it also 
affects hepatobiliary, sinuses, pancreas, lahat ng Gross picture of lungs with cystic fibrosis (image on the next
meron exocrine glands including skin. page)
- Naninigas ang mucus, adherent to the airways
- Accumulation of chloride in the skin because it - Dilated airways  brocnhiectasis
Histologic picture of lungs with cystic fibrosis (image on the
doesn’t get reabsorbed  principle of Sweat
next page)
Chloride test
- Inspissated mucus on the airway (right image)

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 The diagnosis of CF is based in part on clinical symptoms,
 CFTR mutation analysis together with sweat electrolyte
PROGNOSIS
 Median survival age in cystic fibrosis, 1985 – 2001. Data
from the U.S. Cystic Fibrosis Foundation Patient registry.
 Median survival in 2001 was 33.4 years.
DIAGNOSIS
family history, or positive newborn screening
measurements represent cardinal diagnostic tests.
o For difficult cases, complete 1699 CFTR exonic
sequencing together with analysis of splice junctions
and key regulatory elements can be obtained
o Sweat electrolytes following pilocarpine
iontopheresis comprise of invaluable diagnostic
measurement, with levels of chloride markedly
elevated in CF compared to non-CF individuals
o The sweat test result is highly specific and served as
the mainstay diagnosis for many decades prior to
availability of CFTR genotyping.
THERAPEUTICS DIRECTED TOWARD CF SEQUELAE
Standard pulmonary care for outpatients with CF is
intensive, with regimens that include nutritional
supplementation, anti-inflammatory medication,
bronchodilators, and chronic or periodic administration
of oral or aerosolized antibiotics (E.g., as maintenance
therapy for patients with P. aeruginosa)
 Recombinant DNAse aerosols (degraded DNA strands
that contribute to mucus viscosity) and nebulized
hypertonic saline (activate mucociliary clearance, and
mobilize insipissated airway secretions) are
administered routinely.
 Chest physiotherapy several times each day is a standard
means to promote clearance of airway mucus
 The time, complexity, and expense of hoe care are
considerable and take a significant tail on patients and
their families.
 Severe respiratory exacerbation is commonly managed
by hospital admission for frequent chest
physiotherapy and parenteral antibiotics directed
against serious (and often multiply resistant) bacterial
pathogens.
 Poor prognostic indicators such as sputum culture
containing B. cepacia, mucoid P. aeruginosa, or
atypical mycobacteria are rigorously monitored in the
CF patient population.
 Typical inpatient antibiotic coverage includes
combination drug therapy with an aminoglycoside and
B- lactam for up to 14-21 days
 Other CF respiratory sequelae that may require
hospitalization include infection, severe respiratory
exacerbation, hemoptysis and pneumothorax
 Lung transplantation remains a viable therapeutic
option in the setting of end-stage CF pulmonary
failure, with 5- year postoperative survival rates on the
order of 50-60%. (not considered now due to advent of
new medications)
 Based on clinical outcome and limited access to healthy
donor lungs, many CF patients and their families do
not pursue this option. 
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 ORIGINAL NEW DRUG APPLICATION APPROVALS BY US FDA
(15-31 March) 1 April 2015
 Kalydeco
o Active Ingredient: Ivacaftor (potentiates CFTR
channel opening & stimulates ion transport  end
effect Is at the cellular level.)
- Individuals show improvement in lung function,
weight gain, sweat chloride results improve & 
hospitalizations. However, it’s a long term study
and still ongoing
o Strength: 50 mg, 75 mg
o Dosage form: Granule for oral
o Company: Vertex Pharms
o Approval date: March 17, 2015
INTERNATIONAL INVENTORIES
 All of the components in the product are on the following
inventory lists:
o United States Toxic Substances Control Act Section
8(b)
o Canadian Domestic Substances List/ Non- Domestic
Substances List
o European Inventory of Existing Chemical
o Japan Existing and New Chemical Substances
o China Inventory of Existing Chemical Substances
o Korean Existing and Evaluated Chemical Substances
o Philippines Inventory of Chemicals and Chemical
Substances
 CFTR Modulation
o Potentiation of Mutant CFTR gating
o The approved compound Ivacaftor, for example
robustly potentiates CFTR channel opening and
stimulates ion transport.
o Individuals exhibit dramatic improvement in lung
function, weight gain, and other clinical parameters
after only a few weeks of oral therapy.
o Remarkably, sweat chloride values are significantly
improved with this treatment in patients.
o No clinical intervention of any sort has previously
been shown to normalize the CF sweat chloride
abnormality.
o Long- term studies of the drug in patients with G551D
CFTR are ongoing.
o Ivacaftor has been viewed as the harbinger of the
new era for CF therapeutics directed at treating the
most fundamental causes of disease.
impact on overall prognosis.
 Standardization of clinical intervention throughout the
United States has led to remarkable benefit among CF
population.
 Well-defined measures for outpatient care are
nowestablished, including thresholds for hospital
admission, antibiotic regimens, nutritional guidelines,
periodicity of diagnostic tests, and other clinical
parameters.
 These therapeutic recommendations have become
standardized throughout approximately 110 specialized
CF care centers and 55 affiliated programs.
 The initiative has improved endpoints such as weight
gain, body mass index, and pulmonary function.
ENHANCING CASE DETECTION OF SELECTED INHERITED DISORDERS
THROUGH EXPANDED NEWBORN SCREENING IN THE PHILIPPINES
 From 2005 to 2011, a total of 3, 460, 839 newborns were
screened in the CNSP (California Newborn Screening Program),
which included 111, 127 Filipinos. Among the Filipinos, there
were 199 confirmed having screened disorders.
 There are no reported cases in the Philippines but there
were 5 newborns diagnosed with cystic fibrosis in the
CNSP (due to mixed marriages)
 Upon review of the parental ethnicity of the 5 newborns,
it was discovered that these patients were products of
Filipino- Caucasian marriages.
 Given the increasing trend of mixed marriages, the
addition of cystic fibrosis in the newborn screening panel
may prove to be important for our population.

CF QUALITY IMPROVEMENT, INCLUDING ASPECTS OF GLOBAL

HEALTH
 As a direct result of advances in basic research, new
therapies have transformed CF from a disease typically
leading to death in early childhood to a condition with
frequent survival well into the fourth decade of life and
beyond.
 It has also become increasingly clear that specified
approaches to patient management can have an
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