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1. Cystic fibrosis
Presentedby
DR.MD.SHARIF AHSAN
Phase B Resident
PULMONOLOGY

2. Introduction
• Since ancient times, children around the world have been
afflicted with cystic fibrosis that leads to shortened
lifespans.
• In medieval Europe, these children were believed to be
cursed by witches and doomed to die. The curse that
became folklore pronounced, “Woe to the child who tastes
salty from a kiss on the brow, for he is cursed and soon will
die.”
• Salty skin was a sign of an impending illness without
cause or cure.

3. Introduction..
• In 1949, Lowe et al. postulated that cystic
fibrosis must be caused by a genetic defect
from the autosomal recessive pattern of
inheritance of the disease.
• High levels of salt in the sweat of patients
with cystic fibrosis suggested an abnormality
in electrolyte transport from the sweat
gland.

4. Introduction...
• It is a chronic disease that frequently leads
to chronic sinopulmonary infections and
pancreatic insufficiency.
• The most common cause of death is
end-stage lung disease.

5. 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.

6. Genetics
 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.

7. Genetics..
• There are over 2000 different mutations in
the CFTR gene that can cause disease. These
mutations are divided into five classes:
• Defective protein synthesis
• Defective protein processing
• Disordered regulation
• Defective chloride conductance
• Accelerated channel turnover

8. Epidemiology
• The most common mutation is delta F508, which is found
in 70% of American white patients with CF and two-thirds
of all cases worldwide.
• This mutation is a class 2 mutation of abnormal folding of the
CFTR protein, leading to premature destruction within the Golgi
apparatus.
• The delta F508 mutation commonly leads to exocrine
pancreatic insufficiency and a higher likelihood of
meconium ileus.

9. Pathophysiology
• CFTR transports chloride (Cl-) ions across
the membranes of cells in the lungs, liver,
pancreas, digestive tract, reproductive
tract, and skin.

10. Class 1 dysfunction
The result of nonsense, frameshift, or splice-
site mutation, which leads to premature
termination of the mRNA sequence.
This fails to translate the genetic information
into a protein product with a subsequent total
absence of CFTR protein, and approximately
2% to 5% of cystic fibrosis cases result.

11. Class 2 dysfunction
• Results in abnormal post-translational
processing of the CFTR protein.
• This step in protein processing is essential for
the proper intracellular transit of the protein.
• As a result, CFTR is unable to be moved to the
correct cellular location.

12. Class 3 dysfunction
Characterized by diminished protein activity in
response to intracellular signaling.
The result is a fully formed protein channel in
the cellular membrane that is non-functional.

13. Class 4 dysfunction
When the protein is produced and correctly
localized to the cell surface.
However, the rate of chloride ion flow and the
duration of channel activation after
stimulation is decreased from normal.

14. Class 5 dysfunction
 The net decreased concentration of CFTR
channels in the cellular membrane as a result of
rapid degradation by cellular processes.
 It includes mutations that alter the stability of
mRNA and others that alter the stability of the
mature CFTR protein.

15. Pathophysiology
• The result of all mutations is decreased secretion
of chloride and consequently increased
resorption of sodium into the cellular space.
• The increased sodium reabsorption leads to
increased water resorption and manifests as
thicker mucus secretions on epithelial linings and
more viscous secretions from exocrine tissues.

16. Pathophysiology
• Thickened mucus secretions in nearly
every organ system involved result in
mucous plugging with obstruction
pathologies.
• The most commonly affected organs
include the sinuses, lungs, pancreas,
biliary and hepatic systems, intestines,
and sweat glands

18. Sinus disease
• occurs when secretion viscosity increases
which obstruct the sinus ostia.
• Ciliary dysfunction, increased inflammatory
mediators, and increased bacterial colonization
with pathogens such as Pseudomonas
aeruginosa.
• Subsequently, chronic sinusitis occurs, and
secondary structural damage may occur.

19. Lung disease
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.

20. Lung disease
Predisposition to Staph and Pseudomonas
infections.
Bronchiectasis and further thick purulent
sputum production occur.
Poorly managed pulmonary manifestations
are the primary cause of death in patients
with CF.

21. Pancreatic manifestations
 Obstruction of the pancreatic ductules by
thickened secretions.
 As a result, intestinal chyme is not enzymatically
processed in the intestines resulting in the
pathognomonic greasy stools, colicky abdominal
pain, and malabsorption of nutrients from foods.
 Specifically, fat-soluble vitamins A, D, E, and
K are notably deficient.

22. Pancreatic manifestations
 Autodigestion of the pancreas may occur as
these enzymes target the pancreatic tissues.
This results in pancreatitis.
 In severe, chronic cases, this can lead to
endocrine pancreatic failure when the islets of
Langerhans begin to be digested by trapped
pancreatic enzymes.
 The lasting impacts of this spectrum of disease
mimic type-1 diabetes mellitus.

23. Biliary and hepatic systems
 The biliary ductules may be plugged with
secretions.
 Obstructive cirrhosis and post-hepatic
hyperbilirubinemia can occur.
 Gallbladder disease is more likely to occur as a
spectrum of this manifestation of CF, with up to
15% of those with cystic fibrosis having
gallstones

24. Intestinal involvement
 Typically seen in children with meconium ileus at
birth and intestinal obstruction later in life.
 The cause of meconium ileus is multifactorial.
Likely, it is due to increased fluid absorption as a
result of the faulty CFTR channel with
dehydration of the intestinal contents leading to
constipation coupled with a change in luminal
contents from normal secondary to pancreatic
insufficiency.
.

25. Intestinal involvement
 Mechanical obstruction chronically leads to
inflammation and eventual scarring and
stricture formation.
 This may lead to further intestinal
obstruction by fecal impaction or
intussusception later in life.

26. Sweat glands
 Normally, sweat glands move chloride from the
extracellular space into the intracellular space.
Thus, sodium and water are reabsorbed from the
sweat gland tissues into the body.
 However, failure of the chloride channel to
reabsorb chloride leads to a loss of sodium onto
the skin surface and a subsequent fluid loss.
 This causes the pathognomonic salty skin seen
with cystic fibrosis.

27. History and Physical
• Newborns with CF may present with meconium
ileus, prolonged neonatal jaundice, or early lung
infection.
• Infants and children with CF may present with
failure to thrive and poor weight gain, anemia,
undescended testicles in boys, recurrent
sinopulmonary infections, and a distal intestinal
obstructive syndrome with or without pancreatic
insufficiency.
• The median age of diagnosis is 6 to 8 months;
although, individuals may not exhibit clinical signs
and symptoms until later.

28. History and Physical
Lung manifestations of CF include chronic
bronchitis, abnormal pulmonary function tests,
bronchiectasis, atypical asthma, allergic
bronchopulmonary aspergillosis, and colonization
with Pseudomonas aeruginosa.
Sinus manifestations of CF include chronic
rhinosinusitis, chronic post-nasal drip, nasal
polyposis, and panopacification of the paranasal
sinuses.

29. History and Physical
• Pancreatic manifestations include pancreatic
insufficiency, recurrent pancreatitis, and early-onset
diabetes.
• Hepatobiliary manifestations include focal biliary
cirrhosis, cholelithiasis, periportal fibrosis, liver
cirrhosis, portal hypertension, and variceal bleeding.
• Musculoskeletal manifestations include
kyphoscoliosis, osteopenia/osteoporosis, and
arthropathy.
• Hematologic manifestations include iron-
deficiency anemia or anemia of chronic disease
leading to splenomegaly.

30. History and Physical
• Nephrogenic manifestations include
nephrolithiasis, nephrocalcinosis, hyperoxaluria,
and hypocitraturia.
• Dermatologic manifestations include “salty
sweat,” digital clubbing, and cyanosis.
• Additional dermatologic conditions due to
malabsorption include acrodermatitis
enteropathica due to zinc deficiency and scaly
dermatitis associated with fatty acid deficiency.

31. History and Physical
• Males may be infertile due to absent vas
deferens.
• Females have reduced fertility due to
thickened cervical mucus.

32. Evaluation
• In the United States, newborns are screened
for CF as part of a standard newborn
screening panel.
• Some cases of CF are discovered on prenatal
ultrasound, which may demonstrate
meconium peritonitis, bowel dilation, or
absent gallbladder.
• Such findings often lead to prenatal CF carrier
screening

33. To diagnose CF, the following criteria
must be met:
Suspicion for Cystic
Fibrosis
• Sibling with cystic fibrosis
• Positive newborn screen
• Clinical symptoms
consistent with CF in 1 or
more organ systems
• Chronic sinopulmonary
disease
• Gastrointestinal or
nutritional abnormalities
• Salt loss syndromes
• Obstructive azoospermia
Evidence of CFTR
Dysfunction
 Elevated sweat chloride
more than 60 mEq/L on
two occasions
 Two disease-causing
CFTR mutations
 Abnormal nasal potential
difference

34. Investigation
• The diagnostic pathway starts with a sweat
chloride test. If normal but still symptomatic,
a repeat sweat chloride test is indicated.
• If the test is abnormal, DNA testing is
indicated. If one or less CFTR mutations are
found, expanded DNA analysis is indicated.
• However, the finding of 2 CF-related
mutations confirms the diagnosis of cystic
fibrosis.

35. Investigation
• The test for immunoreactive trypsinogen
(IRT), a pancreatic enzyme, increases
sensitivity and specificity in screening
newborns with meconium ileus for CF.
• IRT monitoring can be correlated with the
severity of CF, and when it drops below
detectable levels can indicate the need to
start pancreatic enzyme replacement.

36. Other Invsestigation
Additional diagnostics may be indicated
depending on the presenting symptoms.
• A chest radiograph may help identify hyperinflation,
bronchiectasis, abscesses, or atelectasis.
• Sinus radiography may demonstrate panopacification
of the paranasal sinuses.
• Abdominal radiology may be helpful in neonates who
present with meconium ileus.
• Bronchoalveolar lavage typically shows many
neutrophils

37. Other Invsestigation
• Pulmonary function testing is a major tool for
evaluating and monitoring disease state and
progression in CF.
• Spirometry is the commonly used pulmonary
function test.
• A low FEV1 with a high FVC indicates obstructive
lung disease with airway trapping.
• Cystic fibrosis can be expected to show air
trapping patterns with low FEV1 values
proportional to the severity of the disease.

38. Differential Diagnosis
• Asthma
• Bronchiolitis
• Bronchiectasis
• Celiac disease
• Nutritional considerations in failure to thrive
• Pediatric Aspergillosis
• Primary ciliary dyskinesia
• Sinusitis

39. Treatment / Management
• Cystic fibrosis is a systemic illness that has
broad implications for both quality and
quantity of life when poorly controlled.
• Therefore, treatment should focus on
optimizing function to avoid acute illness
events.

40. Treatment / Management
• This should target maintaining lung function
by aggressively controlling respiratory infection
and clearing airways of mucus, optimizing
nutritional status with pancreatic enzyme
supplements and multivitamins, and finally, by
managing any other health complications that
may arise.
• This is best performed when using a team
approach of specialists who are experienced in
managing cystic fibrosis

41. Treatment / Management
• Pulmonary illness should be managed with
two primary goals: treat the infection and
improve oxygenation. P. aeruginosa typically
induces infectious etiologies, and antibiotic
therapy should have spectrum coverage against
this pathogen.
• However, sputum culture should be obtained
and a sensitivity profile obtained for the
pathogens present.
.

42. Treatment / Management
• CF guidelines recommend at least one
antibiotic to cover each pathogenic bacteria
cultured from respiratory secretions and two
antibiotics for P. aeruginosa infections.
• Ventilation and oxygenation should be
supported through the use of inhaled
bronchodilators, including albuterol and
ipratropium bromide.

43. Treatment / Management
• Agents such as inhaled dornase alfa or
inhaled hypertonic saline are prescribed to
promote airway secretion clearance in
conjunction with chest physiotherapy.
• Anti-inflammatory medicines such as
glucocorticoids are also used to assist in
opening airways to relieve the obstruction.

44. Treatment / Management
• The work of breathing should be optimized,
utilizing nasal cannula oxygen when
appropriate.
• Bilevel positive airway pressure (BiPAP)
ventilation may be necessary to overcome airway
trapping.
• Intubation with mechanical ventilation is an
option but should be avoided whenever possible
and used only when respiratory failure is
imminent.

45. Treatment / Management
• Chronic, supportive therapy for patients with
CF includes regular pancreatic enzymes, fat-
soluble vitamins (A, D, E, K), mucolytics,
bronchodilators, antibiotics, and anti-
inflammatory agents.

46. CFTR modulator therapies
 Designed to correct the dysfunction by improving
production, intracellular processing, or function of the
CFTR protein caused by the mutated gene.
 Each medication is targeted at a specific dysfunction
caused by a specific gene mutation.
 Ivacaftor ,
 Lumacaftor
 combined as lumacaftor/ivacaftor
 combination currently in clinical trials is
tezacaftor/ivacaftor.

48. Treatment / Management
Lung transplant is the treatment of choice for end-
stage lung disease.
• 5-year predicted survival of less than 50%,
• FEV1 fallen to 30% of predicted values,
• Rapidly falling FEV1 despite optimal therapy,
• 6-minute walk distance of less than 400 meters,
• Pulmonary hypertension in the absence of a
hypoxemic exacerbation,
• Acute respiratory failure requiring noninvasive
ventilation,
• Pneumothorax,
• Life-threatening hemoptysis despite bronchial artery
embolization.

49. Diet and Exercise
Encouraged to consume a high-fat diet with
supplemental fat-soluble vitamins to
compensate for malabsorption.
Encouraged to consume a high-calorie diet to
maintain a healthy weight and combat chronic
inflammation and frequent infections that are
commonly encountered.
Regular exercise is encouraged in patients with
CF to maintain and support lung function.

51. Prognosis
• Patients with CF are estimated to live until
about the fourth decade of life before requiring
lung transplantation.
• Lung transplantation confers a median survival
of 8.5 years.

52. Enhancing Healthcare Team Outcomes
• Cystic fibrosis is a systemic illness that has broad
implications for both quality and quantity of life when poorly
controlled.
• This is best performed when using a team approach of
specialists who are experienced in managing cystic fibrosis.
• Specialties that may be part of the team include
pulmonologists, infectious disease, and
gastroenterology.
• Nurses monitor patients and facilitate team communication.
• Pharmacists review all medications,

53. Thank you

54. Potential difference
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.

55. 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.

56. 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.