Cystic Fibrosis Cystic Fibrosis

Question 1

Cystic Fibrosis
Multisystem disease affecting

Answer 1

epithelia of the respiratory tract, exocrine
pancreas, intestine, hepatobiliary
system, and exocrine sweat glands

Question 2

The most common life-shortening
disease

Answer 2

Cystic
Fibrosis

Question 3

Cystic Fibrosis are ……………. disease
Mutations in CFTR gene on chromosome …..
that encodes the cystic fibrosis
transmembrane conductance regulator
(CFTR) protein.

Answer 3

Autosomal recessive disease

chromosome 7

Question 4

CFTR protein act as ?

Answer 4

transports chloride and
bicarbonate across the apical surface of
secretory epithelia (sweat gland, airway,
gastrointestinal tract, pancreas, and vas
deferens).

Question 5

Cystic fibrosis-related diabetes
Due to?

Answer 5

~ 35% of adults.
• Loss of islet cells and varying degrees of insulin resistance leading to impaired glucose tolerance
Insulin remains the only guideline recommended treatment.

Question 6

Pathophysiology (Lungs)
CFTR-mediated? Normally function
Defective CFTR?

Answer 6

CFTR-mediated chloride secretion and sodium absorption by the epithelial sodium channel regulate airway surface liquid hydration, which is essential for ciliary function and antimicrobial activity

Defective CFTR dehydrates the airway surface resulting in thick mucopurulent secretions, impaired mucociliary clearance, chronic infection, inflammation, and progressive structurallung damage.
Dysfunctional CFTR also affects mucus viscosity, and regulation of airway surface liquid pHewith effects on antimicrobial peptide functions.

Question 7

Manifestations: Lung Disease

Answer 7

• Chronic upper (rhinosinusitis and nasal polyps) and lower (muco-obstructive, neutrophic inflmmation, and chronic infection respiratory tract disease.
• Abnormal secretions cause chronic airway obstruction and reduce bactericidal killing, leading to progressive pulmonary colonization with pathogenic bacteria
• Chronic infection causes an inflammatory response and tissue destruction, causing bronchiectasis.
• Infection with Pseudomonas aeruginosa is particularly favored in patients with CF due to abnormally decreased oxygen tension within the hyperviscous mucous layer.
• Respiratory failure develop over time

Question 8

Pathophysiology (Pancreatic Duct)
CFTR-mediated? Normally function
Defective CFTR?

Answer 8

CFTR-mediated chloride and bicarbonate secretion
alkalinises ductal fluid, neutralises peptic acid, and
optimises pH for digestive enzyme function.

• Pancreatic disease begins in the uterus ang is
  caused by ductal obstruction and epithelial damage
• Pancreatic proteins build up behind the obstructed
  ducts leading to increased blood concentrations of
  these proteins, including trypsinogen
• Ongoing duct obstruction, inflammation, fibrosis,
  and fatty infiltration cause eventual pancreatic
  destruction.

Question 9

Pathophysiology Gastrointestinal Tract

Answer 9

Defective bicarbonate secretion can
result in intestinal mucus obstruction and meconium ileus

Liver disease is characterised by hyperviscous biliary secretions, cholestasis, and eventual cirrhosis.

Question 10

Manifestations: Gastrointestinal Tract

Answer 10

• The abnormal bile and pancreatic secretions cause maldigestion and malabsorption, progressive liver and pancreatic disease, rectal prolapse, and intestinal obstruction (distal intestinal obstruction
  syndrome or intussusception) .
• ~ 85% of babies born with cystic fibrosis have pancreatic insufficiency
• Meconium ileus

Question 11

Symptomatic presentation in infants and children

Answer 11

• Meconium ileus
• Respiratory symptoms
Failure to thrive
• For infants presenting with meconium ileus, the
median age of diagnosis is two weeks.
• For those presenting with other symptoms, the
median age of diagnosis is 14.5 months.
Echogenie bowel

Question 12

Diagnosis cystic fibrosis

Answer 12

• Two abnormal sweat chloride values (>60 mEq/L in infants age > 6 months).
• Identification of biallelic pathogenic or likely pathogenic variants in CFTR.
• Transepithelial nasal potential difference measurements characteristic of CF.

In an infant: elevated trypsinogen on newborn screening immunoreacuve trypsinogen
(IRT) assay AND
• Identification of biallelic CF-causing pathogenic variants in CFTR
OR
An abnormal sweat chloride value ≥60 mEq/L

Question 13

Management:
CFTR modulators

Answer 13

• Ivacaftor:
• Age ≥2 years
• At least one p.Gly551Asp mutation
Ivacaftor/lumacaftor:
• Age ≥12 years
• Homozygous for p.Phe508del