Cystic Fibrosis Brick Flashcards
What is Cystic Fibrosis?
multisystem hereditable genetic disorder
causes:
- obstructive lung disease
- gastrointestinal disease (malabsorption)
- infertility
How is Cystic Fibrosis Characterized?
thickened, viscous airway mucus leading to obstructed airflow and increased respiratory infections
What are the manifestations of CF due to?
defects in cellular chloride transport
In which population demographic does cystic fibrosis (CF) most commonly occur?
CF occurs most often in white populations of European descent.
What are the respiratory symptoms of CF?
- persistent, productive coughing, wheezing, and dyspnea (labored breathing)
- frequent lung infections
- Sinus obstruction leads to postnasal drip, recurrent sinus infections, nasal congestion, headaches
- sleep apnea (frequent awakening from sleep).
What are the gastrointestinal symptoms of CF?
- constipation (thick, sticky meconium (initial stool) in a neonate–creating a blockage in the intestine (meconium ileus).
- Malabsorption of fat and fat-soluble vitamins may occur later –> greasy stools, diarrhea, weight loss, and failure to thrive.
- Gastroesophageal reflux disease (GERD) is common causing substernal (chest) burning and pain.
What are the reproductive symptoms of CF?
- male infertility via absence of vas deferens (pair of tubules that form ejaculator and transport sperm cells)
- thickened cervical mucus in females and greater difficulty conceiving but usually fertile
What are the characteristic pulmonary symptoms of patients with cystic fibrosis (CF)?
Characteristic pulmonary symptoms of CF include persistent productive coughing, wheezing, shortness of breath, and frequent lung infections.
How is CF caused?
reduced epithelial cell chloride ion transport
What is CFTR?
a transport protein/ion channel found on the apical membrane of epithelial cells that mediates chloride ion movement
In epithelial cells (lungs, pancreas), what does CFTR transport?
chloride (and bicarbonate) out of the cell and into the extracellular fluid, including respiratory and gastrointestinal (GI) secretions
in sweat glands (skin) what does CFTR transport?
chloride (and bicarbonate) in the cell
What does a defect in CFTR function cause?
- decreased ion transport
- increased viscosity in mucus, sweat, saliva, tears, and digestive fluids –> CF
What maintains the fluidity of mucus, sweat, saliva, tears, and digestive fluids?
CFTR
CF is caused by mutations in the ____ gene.
CFTR
Where is the CFTR gene located?
long arm (q) of chromosome 7
What mode of inheritance is CF?
autosomal recessive
- both alleles of CFTR gene must be mutated (recessive) for phenotypic expression
What is the most common mutation CFTR?
deletion of the phenylalanine 508 –> misfolding after translation
- CFTR stays in rER instead of migrating to cell membrane as it should
What are other mechanisms of CFTR defects?
- reduced/absent synthesis (translation)
- CFTR produced but ion channel does not open or conduct properly –> reduced chloride transport
What is the most common mutation type in cystic fibrosis (CF)?
The most common type of mutation in CF is deletion of phenylalanine 508 in the cystic fibrosis transmembrane conductance regulator gene, which leads to a protein processing mutation.
What role does chloride secretion play?
modulates fluidity of luminal fluids like airway mucus in respiratory tract
Chloride secretion ___________ the ___________ of the extracellular fluid, encouraging sodium ions to migrate out of the cell into the extracellular fluid.
increases the electronegativity
The increased ions in the extracellular space increase its _________, causing water to remain in the airway or lumen rather than entering the cell.
osmolality
How does the increase water flow/osmolality in the lumen/airway prevent CF?
The increased water in the mucus or pancreatic secretion prevents it from becoming too viscous (sticky)
With fewer ions in the extracellular fluid, water is more likely to enter the cell, and the remaining mucus is _______________. This results in the typical CF pathology.
more viscous
What effect does a faulty cystic fibrosis transmembrane conductance regulator (CFTR) protein have on epithelial cell chloride secretion?
When CFTR is defective, epithelial cell chloride secretion decreases.
In an obstructive pulmonary disease like CF, a spirometry will show a reduced …….
reduced FEV1 and FEV1/FVC ratio
Why do recurrent infections like sinusitis and pneumonia happen with CF?
thick mucus impairs cilia function to restore epithelial cells and remove pathogens from the airway
The chronic inflammation of CF leads to what irreversible dilation and scarring of the bronchioles and bronchi?
Bronchiectasis
Nasal polyps, recurrent sinusitis, and sinus obstruction that lead to headaches and facial pain are caused by what ?
inflammation from chronic rhinosinusitis in the upper airways
What causes thick meconium (the neonate’s first stool) and creates a bowel obstruction known as meconium ileus and present itself in older patient with the same mechanism causing recurrent constipation?
thick, sticky intestinal secretions
if the pancreas is unable to release enzymes into the gut for digestion and absorption of macromolecules (ie, fats, proteins, carbohydrates), it leads to …..
pancreatic insufficiency
if fatty acids and vitamins are poorly absorbed, malabsorption can lead to what?
malnutrition and failure to thrive
Why might patients develop bone disease?
due to malabsorption of vitamin D
what is steatorrhea and how does it come about?
– loose, fatty stools
mucus & fat nutrients remain in gut lumen
what is the pancreatic exocrine function?
digestion
what is the endocrine function?
insulin production
True or False?: cystic fibrosis–related diabetes mellitus (CFRD), shares features of both type 1 and type 2 diabetes.
True
how does CF lead to liver disease?
reduced flow of thickened bile (cholestasis) –> biliary cirrhosis
- liver scarring
- liver failures
- increased portal vein pressure (hypertension)
- increased gallstones
- cholecystitis (gall bladder inflammation) —> abdominal pain
What percentage of males are infertile due to CF?
98%
What are two reasons why females with CF have trouble getting pregnant?
1.Thicker cervical mucus makes it harder for sperm to penetrate the cervix
- Poor nutrition that accompanies CF CAN CAUSE IRREGULAR ovulation
How can cystic fibrosis (CF) cause bowel obstruction in the neonate?
Bowel obstruction may occur in CF because of meconium ileus, which is caused by excessively thick meconium.
How Do We Diagnose Cystic Fibrosis?
through newborn screening, DNA genetic testing, or sweat testing
How are newborns screened for cystic fibrosis (CF)?
Newborn screening for CF uses DNA mutation panels or immunoreactive trypsinogen testing (IRT).
True or False: If the newborn screening test is positive, the newborn does not have to complete sweat chloride testing that diagnostically confirms it.
False. The sweat chloride test (QPIT) must be done to show the functional effects of the CFTR mutation and analyze a sample of the patient sweat for chloride content.
How does CF affect the skin?
CF prevents absorption of chloride (& indirectly sodium) into epithelial cells lining sweat ducts
- increases chloride and sodium in the sweat
How does sweat testing work?
performed by delivering pilocarpine, an M3 muscarinic agonist, into a small area on the forearm.
This stimulates sweat production and the sweat from the stimulated area is collected and analyzed for chloride content.
How Do We Manage Cystic Fibrosis?
no known cure for cystic fibrosis
- Nonpharmacologic and pharmacologic methods are used to reduce symptoms and complications, especially infections.
What are nonpharmacologic methods for treating CF?
Respiratory & nutritional support
What respiratory support is used to treat the respiratory consequences of CF?
Chest physiotherapy
- percussion vest: mechanically breaks up thick mucus by vibrating the patient’s chest at scheduled sessions held multiple times per day.
Why is prevention of CF infection so important ?
Infections cause high mortality in people with CF
What methods of CF prevention can be life changing?
- vaccination
- physical distancing from other patients with respiratory infections
Why do CF patients require a high calorie and high fat diet with adult formula supplementation?
Because of malabsorption and malnutrition associated with CF
What supplemental fat-soluble vitamins do CF patients take?
Vitamins A,D,E,K
Pharmacologic therapy for CF can be divided into what drugs?
- New drugs that target mutated epithelial cell itself
- Drugs that treat complications like pancreatic insufficiency
What are CFTR modulators & what is their goal?
New drugs that help correct malfunctioning CFTR protein itself
- restore function of ion channel to prevent and reverse disease effects
What is the most widely used combination drug agent used for patients with specific CFTR mutations?
elexacaftor-tezacaftor-ivacaftor (ETI)
What are the benefits of the ETI CFTR drug?
- reduces pulmonary symptoms
- improves FEV1 (measure of obstructive disease)
- improves malnutrition and increases body weight
What drugs increase airflow and decrease mucus viscosity in CF patients?
Mucolytics, inhaled hypertonic saline, bronchodilators
What are Mucolytics?
inhaled and cleave extracellular DNA contained within mucus, reducing mucus viscosity
What does inhaled hypertonic saline do?
Draws water from cells —> airways and thins mucus
What do bronchodilators do?
Widen airway by dilating smooth muscle, increasing airflow
Ex: albuterol
What drugs reduce inflammation ?
- Ibuprofen (NSAID)
- Azithromycin (antibiotic)
Why are aerosolized antibiotics commonly used to deliver antibiotics directly to the infected airway epithelial instead of into the circulation where there may be more adverse effects?
Because with frequent antibiotic courses, resistant pathogens form and later on larger doses of potentially toxic antibiotics will be required
What are patients with recurrent Pseudomonas aeruginosa given
prophylactic inhaled antibiotics
Ex: tobramycin
What drugs treat pancreatic insufficiency ?
Pancreatic enzymes like lipase, amylase, and protease
CFRD (secondary diabetes) requires …………. since insulin secretion is reduced
insulin treatment
Which medications are used to thin airway mucus in cystic fibrosis (CF)?
Cystic fibrosis–related diabetes mellitus modulators, inhaled hypertonic saline, and inhaled mucolytic agents all thin mucus in patients with CF.
Why is IRT test not the best test to confirm a diagnosis of cystic fibrosis even though it is commonly used as a screening test for CF?
Because it can be positive in conditions other than CF
What is the methacholine challenge used to diagnose? And how?
Asthma. Constricts airways
The oral glucose tolerance test is one of the tests used to diagnose…..
diabetes mellitus
What does spirometry confirm?
Obstructive respiratory disease but not diagnostic CF specifically
True or False: Some patients with CF produce functional CFTR but not to an adequate degree
True
True or False: The CFTR gene mutation directly inhibits an epithelial sodium transporter
False.
What is a common pathogen in CF patients?
Pseudomonas
Bordatella pertussis causes….
Whooping cough, unrelated to CF
- treated y routine vaccination
Haemophilus influenzae can cause pneumonia and laryngitis but would be prevented by …..?
Vaccination
Why are ibuprofen and azithromycin prescribed for patients with cystic fibrosis?
- Ibuprofen has an antiflammatory effect
- Azithromycin prevents acute exacerbations (antibiotic)
What might be seen on a chest x-ray obtained from a patient with cystic fibrosis?
Reticulonodular pattern and opacification of sinuses due to chronic bronchitis and bronchiectasis
What are the diseases commonly associated with digital clubbing?
Respiratory diseases
In cystic fibrosis, how does a decrease in chloride secretion cause thick mucus production in the lungs and gastrointestinal tract?
Low Cl- & H20 secretion —> high intracellular Cl- —> Na+ —> increased H20 —> abnormally thick mucus lungs and GI tract
What diagnosis is suggested if a newborn screening test reveals increased immunoreactive trypsinogen?
Cystic fibrosis
What is the mechanism of action of ivacaftor in cystic fibrosis patients?
Acts as potentiator and maintains chloride channels open leading to improved chloride transport
Which pathogens commonly cause recurrent pulmonary infections in children versus adults with cystic fibrosis?
Staphylococcus aureus: infants and children
Pseudomonas aeruginosa: in adults
What is the function of aerosolized Dornase alfa, inhaled hypertonic saline, and chest physiotherapy in the treatment of cystic fibrosis?
Facilitate mucus clearance
What genetic defect causes cystic fibrosis?
F508 amino acid deletion leading to a defect in the CFTR gene on chromosome 7 (long arm)
What are some late-stage complications of cystic fibrosis?
Endocrine dysfunction (CF related diabetes) biliary cirrhosis, & liver disease
What is the sequelae of a Phe508 deletion in patients with cystic fibrosis?
Misfolded protein that is retained in the rough ER and absent from the cell membrane
What are the 2 respiratory conditions not typically associated with digital clubbing?
Asthma, chronic obstructive pulmonary disease (COPD)
What is the mechanism of action of lumacaftor or tezacaftor in patients with cystic fibrosis?
Corrects misfolding of proteins caused by a Phe508 deletion, improving transport of proteins to cell membrane
What does the CFTR gene code for?
An ATP gated CI channel that secretes Cl into lungs & gastrointestinal tract while reabsorbing Cl in sweat glands
What is the treatment for severe malnutrition & steatorrhea due to cystic fibrosis?
Pancreatic enzyme replacement (pancrelipase)
What fungal disease leads to chest infections in cystic fibrosis?
Allergic bronchopulmonary aspergillosis
What fungal disease leads to chest infections in cystic fibrosis?
Allergic bronchopulmonary aspergillosis
What is the typical manifestation of CF in a newborn?
Meconium ileus
Which metabolic derangements may be present in a patient with cystic fibrosis?
Hypokalemia & contraction alkalosis
from H20/Na+ loss and renal K+/H+ wasting
(Loop diuretic)
What’s the diagnosis for recurrent pulmonary infections, pancreatic insufficiency, & fat-soluble vitamin deficiency?
Cystic Fibrosis
If someone has CF, should the sweat test show increased or decreased chloride concentration ?
Increased chloride concentration
What complications occur in gastrointestinal tract as a result of pancreatic insufficiency and biliary cirrhosis in CF patients?
Deficiencies of fat-soluble vitamins (ADEK) & malabsorption with steatorrhea
What is the cause of male infertility in CF?
Absence of vas deferens spermatogenesis may be unaffected
What is the reason for sub fertility in females with CF?
Amenorrhea and abnormally thick mucus
Why does poor growth happen in CF?
malnutrition due to blockage of exocrine pancreas
together with the effects of chronic infections.
presence of
undigested food particles.
What does elemental formula with table food do?
Alleviates the problem of digestive
enzymes that are not activated due to pancreatic blockage.
Why does Chronic cough and frequent respiratory infection happen in CF?
thick mucus, decreased Cl - transport to
the apical surface of the cells also results in decreased water content and consequently
thick mucus; impaired ciliary movement in airways. Frequent respiratory infections due to
failure to clear pathogens and long residency of otherwise easily-cleared pathogens in
the thicker mucus. P. aeruginosa is most common in CF patient.
Is 75 mmol/L a high sweat chloride level?
Yes. Normal is 40-60 mmol/L.
Why does mild clubbing of digits happen in CF?
Hypoxia due to poorly functioning airways. Mechanism unknown.
What type of protein is the CFTR?
ATP-binding cassette transporter (ABC)
Which of the following pairs of molecules use the CFTR ?
Cl- and HCO3 (bicarbonate)
What are ABC Transporters?
Superfamily of integral membrane proteins responsible
for ATP-driven translocation of substrates across membranes.
What is architecture of the ABC domains?
2 ABC domains (nucleotide binding domain)
2 membrane spanning domains (MSD)
Regulatory domain
Is CFTR an importer or and exporter?
CFTR is an exporter
What is substrate translocation by
“alternating-access” resulted by?
Substrate & nucleotide dependent conformational changes
What is the only ABC transporter that is an ion channel and that consumes its ATP?
CFTR
How is CFTR regulated?
- In resting state: channel closed, no interaction with RD
- Adenylyl cyclase increases intracellular cAMP
- cAMP activates PKA —> PKC
- PKC phosphorylates RD
- RD increases ATP binding affinity if NBDs
- NBDs dimerize
- Change in CFTR conformation?
- Channel open, probability increases
What is MCC?
Mucociliary clearance
What is ASL?
airway surface liquid mucus
What is ENaC?
Epithelial Na+ channel
What is HS?
Hypertonic saline
Why does hypertonic saline help the CF patient?
contains 7.77X more NaCl
than normal physiological NaCl
Draws water out of cells and the intersitium to
hydrate mucus
CF affects motile cilia in what organs?
Lungs, sinuses, & reproductive tract
CF affects what organs that produce mucus?
Sinuses (throat & mouth)
Lungs
Liver (obstructive biliary tract disease)
Pancreas (insulin dependent diabetes mellitus)
Intestine (meconium ileus)
