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M2C > Cystic Fibrosis Brick > Flashcards

Cystic Fibrosis Brick Flashcards

1
Q

What is Cystic Fibrosis?

A

multisystem hereditable genetic disorder

causes:
- obstructive lung disease

  • gastrointestinal disease (malabsorption)
  • infertility
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2
Q

How is Cystic Fibrosis Characterized?

A

thickened, viscous airway mucus leading to obstructed airflow and increased respiratory infections

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3
Q

What are the manifestations of CF due to?

A

defects in cellular chloride transport

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4
Q

In which population demographic does cystic fibrosis (CF) most commonly occur?

A

CF occurs most often in white populations of European descent.

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5
Q

What are the respiratory symptoms of CF?

A
  • 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).
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6
Q

What are the gastrointestinal symptoms of CF?

A
  • 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.
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7
Q

What are the reproductive symptoms of CF?

A
  • 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
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8
Q

What are the characteristic pulmonary symptoms of patients with cystic fibrosis (CF)?

A

Characteristic pulmonary symptoms of CF include persistent productive coughing, wheezing, shortness of breath, and frequent lung infections.

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9
Q

How is CF caused?

A

reduced epithelial cell chloride ion transport

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10
Q

What is CFTR?

A

a transport protein/ion channel found on the apical membrane of epithelial cells that mediates chloride ion movement

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11
Q

In epithelial cells (lungs, pancreas), what does CFTR transport?

A

chloride (and bicarbonate) out of the cell and into the extracellular fluid, including respiratory and gastrointestinal (GI) secretions

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12
Q

in sweat glands (skin) what does CFTR transport?

A

chloride (and bicarbonate) in the cell

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13
Q

What does a defect in CFTR function cause?

A
  • decreased ion transport
  • increased viscosity in mucus, sweat, saliva, tears, and digestive fluids –> CF
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14
Q

What maintains the fluidity of mucus, sweat, saliva, tears, and digestive fluids?

A

CFTR

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15
Q

CF is caused by mutations in the ____ gene.

A

CFTR

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16
Q

Where is the CFTR gene located?

A

long arm (q) of chromosome 7

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17
Q

What mode of inheritance is CF?

A

autosomal recessive

  • both alleles of CFTR gene must be mutated (recessive) for phenotypic expression
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18
Q

What is the most common mutation CFTR?

A

deletion of the phenylalanine 508 –> misfolding after translation

  • CFTR stays in rER instead of migrating to cell membrane as it should
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19
Q

What are other mechanisms of CFTR defects?

A
  • reduced/absent synthesis (translation)
  • CFTR produced but ion channel does not open or conduct properly –> reduced chloride transport
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20
Q

What is the most common mutation type in cystic fibrosis (CF)?

A

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.

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21
Q

What role does chloride secretion play?

A

modulates fluidity of luminal fluids like airway mucus in respiratory tract

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22
Q

Chloride secretion ___________ the ___________ of the extracellular fluid, encouraging sodium ions to migrate out of the cell into the extracellular fluid.

A

increases the electronegativity

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23
Q

The increased ions in the extracellular space increase its _________, causing water to remain in the airway or lumen rather than entering the cell.

A

osmolality

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24
Q

How does the increase water flow/osmolality in the lumen/airway prevent CF?

A

The increased water in the mucus or pancreatic secretion prevents it from becoming too viscous (sticky)

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25
Q

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.

A

more viscous

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26
Q

What effect does a faulty cystic fibrosis transmembrane conductance regulator (CFTR) protein have on epithelial cell chloride secretion?

A

When CFTR is defective, epithelial cell chloride secretion decreases.

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27
Q

In an obstructive pulmonary disease like CF, a spirometry will show a reduced …….

A

reduced FEV1 and FEV1/FVC ratio

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28
Q

Why do recurrent infections like sinusitis and pneumonia happen with CF?

A

thick mucus impairs cilia function to restore epithelial cells and remove pathogens from the airway

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29
Q

The chronic inflammation of CF leads to what irreversible dilation and scarring of the bronchioles and bronchi?

A

Bronchiectasis

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30
Q

Nasal polyps, recurrent sinusitis, and sinus obstruction that lead to headaches and facial pain are caused by what ?

A

inflammation from chronic rhinosinusitis in the upper airways

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31
Q

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?

A

thick, sticky intestinal secretions

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32
Q

if the pancreas is unable to release enzymes into the gut for digestion and absorption of macromolecules (ie, fats, proteins, carbohydrates), it leads to …..

A

pancreatic insufficiency

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33
Q

if fatty acids and vitamins are poorly absorbed, malabsorption can lead to what?

A

malnutrition and failure to thrive

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34
Q

Why might patients develop bone disease?

A

due to malabsorption of vitamin D

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35
Q

what is steatorrhea and how does it come about?

A

– loose, fatty stools
mucus & fat nutrients remain in gut lumen

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36
Q

what is the pancreatic exocrine function?

A

digestion

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37
Q

what is the endocrine function?

A

insulin production

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38
Q

True or False?: cystic fibrosis–related diabetes mellitus (CFRD), shares features of both type 1 and type 2 diabetes.

A

True

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39
Q

how does CF lead to liver disease?

A

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

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40
Q

What percentage of males are infertile due to CF?

A

98%

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41
Q

What are two reasons why females with CF have trouble getting pregnant?

A

1.Thicker cervical mucus makes it harder for sperm to penetrate the cervix

  1. Poor nutrition that accompanies CF CAN CAUSE IRREGULAR ovulation
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42
Q

How can cystic fibrosis (CF) cause bowel obstruction in the neonate?

A

Bowel obstruction may occur in CF because of meconium ileus, which is caused by excessively thick meconium.

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43
Q

How Do We Diagnose Cystic Fibrosis?

A

through newborn screening, DNA genetic testing, or sweat testing

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44
Q

How are newborns screened for cystic fibrosis (CF)?

A

Newborn screening for CF uses DNA mutation panels or immunoreactive trypsinogen testing (IRT).

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45
Q

True or False: If the newborn screening test is positive, the newborn does not have to complete sweat chloride testing that diagnostically confirms it.

A

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.

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46
Q

How does CF affect the skin?

A

CF prevents absorption of chloride (& indirectly sodium) into epithelial cells lining sweat ducts

  • increases chloride and sodium in the sweat
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47
Q

How does sweat testing work?

A

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.

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48
Q

How Do We Manage Cystic Fibrosis?

A

no known cure for cystic fibrosis

  • Nonpharmacologic and pharmacologic methods are used to reduce symptoms and complications, especially infections.
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49
Q

What are nonpharmacologic methods for treating CF?

A

Respiratory & nutritional support

50
Q

What respiratory support is used to treat the respiratory consequences of CF?

A

Chest physiotherapy

  • percussion vest: mechanically breaks up thick mucus by vibrating the patient’s chest at scheduled sessions held multiple times per day.
51
Q

Why is prevention of CF infection so important ?

A

Infections cause high mortality in people with CF

52
Q

What methods of CF prevention can be life changing?

A
  • vaccination
  • physical distancing from other patients with respiratory infections
53
Q

Why do CF patients require a high calorie and high fat diet with adult formula supplementation?

A

Because of malabsorption and malnutrition associated with CF

54
Q

What supplemental fat-soluble vitamins do CF patients take?

A

Vitamins A,D,E,K

55
Q

Pharmacologic therapy for CF can be divided into what drugs?

A
  1. New drugs that target mutated epithelial cell itself
  2. Drugs that treat complications like pancreatic insufficiency
56
Q

What are CFTR modulators & what is their goal?

A

New drugs that help correct malfunctioning CFTR protein itself

  • restore function of ion channel to prevent and reverse disease effects
57
Q

What is the most widely used combination drug agent used for patients with specific CFTR mutations?

A

elexacaftor-tezacaftor-ivacaftor (ETI)

58
Q

What are the benefits of the ETI CFTR drug?

A
  • reduces pulmonary symptoms
  • improves FEV1 (measure of obstructive disease)
  • improves malnutrition and increases body weight
59
Q

What drugs increase airflow and decrease mucus viscosity in CF patients?

A

Mucolytics, inhaled hypertonic saline, bronchodilators

60
Q

What are Mucolytics?

A

inhaled and cleave extracellular DNA contained within mucus, reducing mucus viscosity

61
Q

What does inhaled hypertonic saline do?

A

Draws water from cells —> airways and thins mucus

62
Q

What do bronchodilators do?

A

Widen airway by dilating smooth muscle, increasing airflow

Ex: albuterol

63
Q

What drugs reduce inflammation ?

A
  • Ibuprofen (NSAID)
  • Azithromycin (antibiotic)
64
Q

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?

A

Because with frequent antibiotic courses, resistant pathogens form and later on larger doses of potentially toxic antibiotics will be required

65
Q

What are patients with recurrent Pseudomonas aeruginosa given

A

prophylactic inhaled antibiotics

Ex: tobramycin

66
Q

What drugs treat pancreatic insufficiency ?

A

Pancreatic enzymes like lipase, amylase, and protease

67
Q

CFRD (secondary diabetes) requires …………. since insulin secretion is reduced

A

insulin treatment

68
Q

Which medications are used to thin airway mucus in cystic fibrosis (CF)?

A

Cystic fibrosis–related diabetes mellitus modulators, inhaled hypertonic saline, and inhaled mucolytic agents all thin mucus in patients with CF.

69
Q

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?

A

Because it can be positive in conditions other than CF

70
Q

What is the methacholine challenge used to diagnose? And how?

A

Asthma. Constricts airways

71
Q

The oral glucose tolerance test is one of the tests used to diagnose…..

A

diabetes mellitus

72
Q

What does spirometry confirm?

A

Obstructive respiratory disease but not diagnostic CF specifically

73
Q

True or False: Some patients with CF produce functional CFTR but not to an adequate degree

A

True

74
Q

True or False: The CFTR gene mutation directly inhibits an epithelial sodium transporter

A

False.

75
Q

What is a common pathogen in CF patients?

A

Pseudomonas

76
Q

Bordatella pertussis causes….

A

Whooping cough, unrelated to CF

  • treated y routine vaccination
77
Q

Haemophilus influenzae can cause pneumonia and laryngitis but would be prevented by …..?

A

Vaccination

78
Q

Why are ibuprofen and azithromycin prescribed for patients with cystic fibrosis?

A
  • Ibuprofen has an antiflammatory effect
  • Azithromycin prevents acute exacerbations (antibiotic)
79
Q

What might be seen on a chest x-ray obtained from a patient with cystic fibrosis?

A

Reticulonodular pattern and opacification of sinuses due to chronic bronchitis and bronchiectasis

80
Q

What are the diseases commonly associated with digital clubbing?

A

Respiratory diseases

81
Q

In cystic fibrosis, how does a decrease in chloride secretion cause thick mucus production in the lungs and gastrointestinal tract?

A

Low Cl- & H20 secretion —> high intracellular Cl- —> Na+ —> increased H20 —> abnormally thick mucus lungs and GI tract

82
Q

What diagnosis is suggested if a newborn screening test reveals increased immunoreactive trypsinogen?

A

Cystic fibrosis

83
Q

What is the mechanism of action of ivacaftor in cystic fibrosis patients?

A

Acts as potentiator and maintains chloride channels open leading to improved chloride transport

84
Q

Which pathogens commonly cause recurrent pulmonary infections in children versus adults with cystic fibrosis?

A

Staphylococcus aureus: infants and children

Pseudomonas aeruginosa: in adults

85
Q

What is the function of aerosolized Dornase alfa, inhaled hypertonic saline, and chest physiotherapy in the treatment of cystic fibrosis?

A

Facilitate mucus clearance

86
Q

What genetic defect causes cystic fibrosis?

A

F508 amino acid deletion leading to a defect in the CFTR gene on chromosome 7 (long arm)

87
Q

What are some late-stage complications of cystic fibrosis?

A

Endocrine dysfunction (CF related diabetes) biliary cirrhosis, & liver disease

88
Q

What is the sequelae of a Phe508 deletion in patients with cystic fibrosis?

A

Misfolded protein that is retained in the rough ER and absent from the cell membrane

89
Q

What are the 2 respiratory conditions not typically associated with digital clubbing?

A

Asthma, chronic obstructive pulmonary disease (COPD)

90
Q

What is the mechanism of action of lumacaftor or tezacaftor in patients with cystic fibrosis?

A

Corrects misfolding of proteins caused by a Phe508 deletion, improving transport of proteins to cell membrane

91
Q

What does the CFTR gene code for?

A

An ATP gated CI channel that secretes Cl into lungs & gastrointestinal tract while reabsorbing Cl in sweat glands

92
Q

What is the treatment for severe malnutrition & steatorrhea due to cystic fibrosis?

A

Pancreatic enzyme replacement (pancrelipase)

93
Q

What fungal disease leads to chest infections in cystic fibrosis?

A

Allergic bronchopulmonary aspergillosis

94
Q

What fungal disease leads to chest infections in cystic fibrosis?

A

Allergic bronchopulmonary aspergillosis

95
Q

What is the typical manifestation of CF in a newborn?

A

Meconium ileus

96
Q

Which metabolic derangements may be present in a patient with cystic fibrosis?

A

Hypokalemia & contraction alkalosis

from H20/Na+ loss and renal K+/H+ wasting
(Loop diuretic)

97
Q

What’s the diagnosis for recurrent pulmonary infections, pancreatic insufficiency, & fat-soluble vitamin deficiency?

A

Cystic Fibrosis

98
Q

If someone has CF, should the sweat test show increased or decreased chloride concentration ?

A

Increased chloride concentration

99
Q

What complications occur in gastrointestinal tract as a result of pancreatic insufficiency and biliary cirrhosis in CF patients?

A

Deficiencies of fat-soluble vitamins (ADEK) & malabsorption with steatorrhea

100
Q

What is the cause of male infertility in CF?

A

Absence of vas deferens spermatogenesis may be unaffected

101
Q

What is the reason for sub fertility in females with CF?

A

Amenorrhea and abnormally thick mucus

102
Q

Why does poor growth happen in CF?

A

malnutrition due to blockage of exocrine pancreas
together with the effects of chronic infections.

presence of
undigested food particles.

103
Q

What does elemental formula with table food do?

A

Alleviates the problem of digestive
enzymes that are not activated due to pancreatic blockage.

104
Q

Why does Chronic cough and frequent respiratory infection happen in CF?

A

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.

105
Q

Is 75 mmol/L a high sweat chloride level?

A

Yes. Normal is 40-60 mmol/L.

106
Q

Why does mild clubbing of digits happen in CF?

A

Hypoxia due to poorly functioning airways. Mechanism unknown.

107
Q

What type of protein is the CFTR?

A

ATP-binding cassette transporter (ABC)

108
Q

Which of the following pairs of molecules use the CFTR ?

A

Cl- and HCO3 (bicarbonate)

109
Q

What are ABC Transporters?

A

Superfamily of integral membrane proteins responsible
for ATP-driven translocation of substrates across membranes.

110
Q

What is architecture of the ABC domains?

A

2 ABC domains (nucleotide binding domain)

2 membrane spanning domains (MSD)

Regulatory domain

111
Q

Is CFTR an importer or and exporter?

A

CFTR is an exporter

112
Q

What is substrate translocation by
“alternating-access” resulted by?

A

Substrate & nucleotide dependent conformational changes

113
Q

What is the only ABC transporter that is an ion channel and that consumes its ATP?

A

CFTR

114
Q

How is CFTR regulated?

A
  1. In resting state: channel closed, no interaction with RD
  2. Adenylyl cyclase increases intracellular cAMP
  3. cAMP activates PKA —> PKC
  4. PKC phosphorylates RD
  5. RD increases ATP binding affinity if NBDs
  6. NBDs dimerize
  7. Change in CFTR conformation?
  8. Channel open, probability increases
115
Q

What is MCC?

A

Mucociliary clearance

116
Q

What is ASL?

A

airway surface liquid mucus

117
Q

What is ENaC?

A

Epithelial Na+ channel

118
Q

What is HS?

A

Hypertonic saline

119
Q

Why does hypertonic saline help the CF patient?

A

contains 7.77X more NaCl
than normal physiological NaCl

Draws water out of cells and the intersitium to
hydrate mucus

120
Q

CF affects motile cilia in what organs?

A

Lungs, sinuses, & reproductive tract

121
Q

CF affects what organs that produce mucus?

A

Sinuses (throat & mouth)

Lungs

Liver (obstructive biliary tract disease)

Pancreas (insulin dependent diabetes mellitus)

Intestine (meconium ileus)

M2C (11 decks)

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