Cystic Fibrosis

Question 1

What is cystic fibrosis (CF)?

Answer 1

Autosomal recessive genetic condition that results in a multisystem syndrome of chronic sinopulmonary infections; malabsorption; and nutritional abnormalities. Most common life-shortening genetic disease in Caucasians in the US (1:3000)

Question 2

Which chromosome mutation causes CF?

Answer 2

Gene that encodes for the CF transmembrane conductance regulator (CFTR) protein. On Chr. 7. Causes a deft in the ATP-binding cassette transporter gene

Question 3

What is the most common mutation?

Answer 3

F508del. But there are more than 1500 others identified

Question 4

How are CF gene mutations categorized?

Answer 4

5 main classes (I-V). Grouped by molecular consequences.

Question 5

What is a class I mutation?

Answer 5

No synthesis of CFTR. Often caused by nonsense G542X

Question 6

What is a class II mutation?

Answer 6

Block in CFTR synthesis. Often caused by AA deletion (F508del)

Question 7

What is a class III mutation?

Answer 7

Block in gating. Often caused by missense G551D

Question 8

What is a class IV mutation?

Answer 8

Altered conductance of CFTR. Often caused by missense R117H

Question 9

What is a class V mutation?

Answer 9

Reduced synthesis of CFTR. Often caused by missense mut or alternative splicing

Question 10

What effects do defects/deficiences of CFTR proteins cause?

Answer 10

Problems in salt and water movement across cell membranes; resulting in abnormally thick secretions in various organ systems

Question 11

Why are CFTR effects in lungs often major cause of morbidity and mortality?

Answer 11

Depleted periciliary layer in the lung leads to impaired mucociliary clearance and altered host defense; critical to the pathogenesis of CF lung disease. Chronic infections with CF-related pathogens and excessive inflammatory response progressively damage the airways and lung parenchyma. Results in widespread bronchiectasis; decline in lung function; early death from respiratory failure

Question 12

What are typical clinical features in sinus?

Answer 12

Chronic sinus infections; nasal polyps

Question 13

What are typical clinical features in lung?

Answer 13

Recurrent respiratory infections (endobronchitis) with opportunistic bacteria (e.g. Staphylococcus aureus; Pseudomonas aeruginosa and Burkholderia cepacia); Bronchiectasis

Question 14

What are typical clinical features in pancreas?

Answer 14

Exocrine pancreatic insufficiency (85%) - greasy; bulky; malodorous stools; failure to thrive and malabsorption nutritional consequences; CF-related diabetes

Question 15

What are typical clinical features in GI?

Answer 15

Meconium ileus; rectal prolapse; constipation; distal ileal obstructive syndrome (DIOS)

Question 16

What are typical clinical features in liver?

Answer 16

Cholestasis; sclerosis; cirrhosis

Question 17

What are other clinical presentations of CF?

Answer 17

Congenital absence of the vas deferens; digital clubbing on examination; sweat chloride > 60 mmol/L

Question 18

How are most newborns with CF identified in the US?

Answer 18

Most are asymptomatic and identified through newborn screening. Some (10-15%) are identified with meconium ileus. Infants with meconium ileus should be treated presumptively as having CF until a sweat test or genotyping can be obtained.

Question 19

In CO; what is our approach for newborn screening?

Answer 19

IRT/IRT/DNA. 1st screen for elevated immunoreactive trypsinogen (pancreatic enzyme). If ^ repeat IRT in 2 months. If still ^ do CF DNA panel

Question 20

What is traditional treatment of CF?

Answer 20

Historically targeted “downstream affects;” tried to manage symptoms. Requires specialized/multidisciplinary team to focus on nutrition; lung disease; antibiotic therapy; anti-inflammatory treatments

Question 21

How is nutrition in CF Pts usually treated?

Answer 21

Management of exocrine pancreatic insufficiency with enzyme supplementation; high calorie; high protein; and high fat diet; and fat soluble vitamin supplements. Also daily salt supplement due to salt loss in sweat

Question 22

How is lung disease in CF Pts usually treated?

Answer 22

Try to target cycle of mucous obstruction; airway infection; inflammatory response. Do airway clearance treatment to loosen and remove thick mucus from airways. Daily percussive therapy (Chest PT; vest therapy). Recombinant human DNAse (Pulmozyme); an inhaled mucolytic agent. Inhaled hypertonic saline. Bronchodilators. Also antibiotic therapy and anti-inflammatory treatments

Question 23

What kind of antibiotic therapy is done in CF?

Answer 23

Targets common CF related bacteria such as P. aeruginosa. Inhaled tobramycin; aztreonam. Oral or IV antibiotics

Question 24

What kind of anti-inflammatory therapy is done in CF?

Answer 24

High dose ibuprofen. Chronic azithromycin

Question 25

What new drugs are on the horizon for CF?

Answer 25

CFTR modulator. Target specific CFTR mutations.

Question 26

What is ivacaftor (kalydeco)?

Answer 26

CFTR potentiator FDA approved for people age 2 years or older with at least one G551D mutation or another gating mutation (Class III); potentially will help in partial function (Class IV and V) mutations as well

Question 27

What is Lumacaftor/ Ivacaftor (Orkambi)?

Answer 27

combination CFTR corrector and potentiator FDA approved for people ages 12 years or older with 2 copies of the F508del mutation (Class II)