Chapter 313 - Cystic Fibrosis

Question 1

What is the gene product responsible for cystic fibrosis?

Answer 1

CFTR (cystic fibrosis transmembrane condunctance regulator).

Question 2

In general terms, how do you explain the functions of CFTR?

Answer 2

CFTR “serves as an anion channel in the apical (luminal) plasma membranes of epithelial cells and regulates volume and composition of exocrine secretion.”

Question 3

How would you describe pathophisiologically the respiratory involvement in cystic fibrosis?

Answer 3

“The majohr morbitiy and mortality associated with CF is attributable to respiratory compromise, characteized by copious hyperviscous and adherent pulmonary secretions that obstruct small and medium-sized airways.”

Question 4

Which pathogens might one find in the respiratory flora of cystic fibrosis patients?

Answer 4

Staphylococcus aureus, Haemophilus influenzae, Pseudomonas aeruginosa, among others.

Question 5

In cystic fibrosis, an early colonization often endergs lifelong pulmonary infection by the same genetic strain of Pseudomonas aeruginosa.
True or False?

Answer 5

True.

Question 6

What is the pathophysiology of Pseudomonas aeruginosa? Which type of this bacteria might be indicative of poorer prognosis?

Answer 6

“Over the course of many years, P. aeruginosa exhibit a sterotypic mode of pathoegenisis; a sentinel and early colonization event often endengers lifelong pulmonary infection by the same genetic strain. Over the course of many years, P. aeruginosa evolves in CF lungs to adopt a mucoid phenotype (attributable to release of alginate exoproduct) that ocnfers selective advantage for the pathogen and poor prognosis for the host.”

Question 7

Besides Pseudomonas aeruginosa, which other bacteria is indicative of a less favorable prognosis?

Answer 7

Burkholderia cepacia.

Question 8

How does one characterize a cystic fibrosis of the pancreas?

Answer 8

“cystic fibrosis of the pancreas, refers to profound tissue destruction of the exocrine pancreas, with fibrotic scarring and/or fatty replacement, cyst proliferation, loss of acinar tissue, and ablation of normal pancreatic architecture.”

Question 9

How do you clinically characterize chronic pancreatic insufficiency?

Answer 9

“The sequelae of exocrine pancreatic insufficiency include chronic malabsorption, poor growth, fat-soluble vitamin insufficiency, high levls of serum immunoreactive trypsinogen (a diagnostic test used in newborn screening), and loss of pancreatic islet cell mass.”

Question 10

How frequent is diabetes mellitus in cystic fibrosis (CF)? What is its pathogenesis?

Answer 10

“CF-related diabetes mellitus is a manifestation in over 30% of adults with the disease and is likely multifactorial in nature (attributable to progressive destrunction of the endocrine pancreas, insulin resistance due to stress hormones, and other factors).”

Question 11

Besides the pancreas, which other gastrointestinal organ might be affected?

Answer 11

Liver.

Question 12

What are the characteristics of liver involvement in cystic fibrosis and how frequent is it?

Answer 12

“Obstruction of intrahepatic bile ducts and parenchymal fibrosis are commonly observed in pathologic specimens, with multilobular cirrhosis in 4-15% of patients with CF and significant hepatic insufficiency as a resulting manifestation among adults.”

Question 13

Which condition occurs in 10-20% of newborns with cystic fibrosis? What is its mirror condition in adults?

Answer 13

Meconium ileus and distal intestinal obstructive syndrome, respectively.

Question 14

Men are always infertile if affected by cystic fibrosis.

True or False?

Answer 14

False.
“Men typically exhibit complete involution of the vas deferens and infertility (despite functioning spermatogenesis), and approximately 99% of males with CF are infertile.”

Question 15

Is there any common finding between the pathogens found in cystic fibrosis lungs and sinus?

Answer 15

Yes, the same pathogens are found, which suggests that the sinus may serve as a reservois for bacterial seeding.

Question 16

Which organs/tissues might be affected by cystic fibrosis?

Answer 16

Lungs, pancreas, liver, reproductive system, ileon, sinus, among others.

Question 17

How many amino-acids does the CFTR protein have?

Answer 17

~1480.

Question 18

Explain the abnormalities of pulmonary fluid in cystic fibrosis at the mollecular level.

Answer 18

“CFTR is situated in the apical plasma membranes of acinar and other epithelial cells where it regulates the amount and composition of secretion by exocrine glands. In numerous epithelia, chloride and bicarbonate release is followed passively by the flow of water, allowing for mobilization and clearance of exocrine products. Along respiratory mucosa, CFTR is necessary to provide sufficient depth of the periciliary fluid layer (PCL), allowing normal ciliary extension and mucociliary transport. CFTR-deficient airway cells exhibit depleted PCL, causing ciliary collapse and failure to clear overlying mucus. In airway submucsal glands, CFTR is highly expressed in acini and may participate both in the formation of mucus and extrusion of glandular secretion onto the airway surface.”

Question 19

How does cystic fibrosis lead to bronchiectasis?

Answer 19

“The CF airway is characterized by an aggressive, unrelenting, neutrophilic inflammatory response with release of proteases and oxidants leading to airway remodeling and bronchiectasis. Intense pulmonary inflammation is largely driven by chronic respiratory infection. Macrophages resident in CF lungs augment elaboration of proinflammatory cytokines which contribute to innate and adaptive immune reactivity.”

Question 20

Besides bacterial susceptibility due to abnormalities of fluid clearance in cystic fibrosis lungs and neutrophilic inflammation, is there any other mechanisms that might explain the pulmonary remodeling?

Answer 20

“CFTR-dependent abnormalities of airway surface fluid composition (e.g., pH) have been reported as contributors to impaired bacterial killing in CF lungs. The role of CFTR as a direct mediator of inflammatory responsiveness and/or pulmonary remodeling represents an important and topical area of investigation.”

Question 21

Do you expect to find CFTR in the plasma membrane of patients with F508del mutation?

Answer 21

No.
““CFTR encoding F508del retains partial ion channel function but protein maturation is arrested in the endoplasmic reticulum, and CFTR fails to arive at the plasma membrane.”

Question 22

Which class of defects is the most common in cystic fibrosis?

Answer 22

Class II (which include the mutations that disrupt protein maturation, such as F508del).

Question 23

What is the most frequent mutation for cystic fibrosis in the United States?

Answer 23

“F508del alone accounts for ~70% of defective CFTR alleles in the United States, where approximately 90% of individuals with CF carry at least one F508del mutation.”