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CRRAB II Week 8/9 - WLB > Cystic Fibrosis - Scott > Flashcards

Cystic Fibrosis - Scott Flashcards

1
Q

What is the inheritance pattern of cystic fibrosis?

A

autosomal recessive

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2
Q

What kind of mutation causes cystic fibrosis? Gene?

A

inactivating mutations in cystic fibrosis transmembrane conductance regulator (CFTR) gene

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3
Q

What is the CFTR? (i.e. what does it translate into?

A

chloride ion channel

(found on apical surface of epithelial cells lining airways, pancreatic ducts, intestine and other tissues)

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4
Q

What are 90% of deaths in cystic fibrosis due to?

A

respiratory failure

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5
Q

Besides lung pathology, what additional problems become more prevalent as people live longer?

A
  • Liver- CF liver disease
  • Pancreas- pancreatic insufficiency, CF diabetes
  • Intestine- obstruction, malabsorption, cancer
  • Male fertility
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6
Q

What was the median survival age for cystic fibrosis in 1970? 2013?

A

1970 → 16 yoa

2013 → 37.4 yoa

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7
Q

What kind of treatment strategy is helping people with cystic fibrosis live longer better quality lives?

A
  • Treatment at specialized centers
    • close monitoring
    • rapid intervention especially pulmonary and GI manifestations
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8
Q

How does the normal CFTR ion channel work?

A
  • CFTR is a chloride and bicarbonate ion channel
    • When channel opens → Cl- and HCO3- ions flow through it (down electrochemical gradient)
    • The electrochemical gradient across the airway epithelial apical cell membrane favors the flow of ions out of the cell, into the extracellular space
    • Increased concentration of Cl- and HCO3- ions outside cell → creates osmotic conditions for flow of H2O out of the cell.
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9
Q

What is the structure of the normal CFTR?

A
  • Membrane spanning domains (MSD) form a pore for chloride ion channel.
  • Two nucleotide binding domains (NBD) and a Regulatory domain provide regulatory sites that promote opening of channel
    • NBD binds ATP
    • R has phosphorylation sites for PKA
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10
Q

What is the normal activity of the CFTR ion channel?

A
  • Exist in two states- open and closed
    • Open conformation forms aqueous pore
    • Ions flow in direction of electrochemical gradient
  • Constantly moving between open and closed conformations
    • Activity = Amount of time spent in open conformation is regulated or gated
  • Pore has size and electrochemical properties that allow only specific ions to flow through
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11
Q

What three things does the CFTR channel control?

A
  • CFTR controls luminal ion concentrations and pH
  • CFTR channel controls movement of H2O to apical surface of airway epithelial cell.
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12
Q

Apical export of Cl- by CFTR maintains luminal concentration of what?

A

H2O

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13
Q

Opening of the CFTR channel requires what two signals?

A
  • protein kinase A,(PKA) → phosphorylates R domain
  • 2 ATPs bind NBD domains
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14
Q

What are the five steps in the regulation of the CFTR channel?

A
  1. External stresses → activate cAMP
  2. Cyclic AMP intercellular signaling pathway
  3. Activation of PKA
  4. Phosphorylation of R domain
  5. ATP binding
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15
Q

Why is it important that > 1900 mutations have been identified in cystic fibrosis, only 5 mutations occur in > 1% of cases, and about 160 mutations account for > 95% of cases?

A
  • Mutation based diagnostic tests are feasible
  • Possible to design diagnostic tests to identify mutations
  • Molecular based therapies are feasible → possible to design molecular based therapies
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16
Q

What are the major classifications of CFTR mutations?

A
  • More Severe:
    • Class 1 = no protein produced
      • Nonsense mutation creates stop codon
    • Class 2 = defective protein folding
      • degradation of protein
    • Class 3 = defective gating or regulation of
      • channel opening
  • Less Severe:
    • Class 4 = defective in ion transport
    • Class 5 = normal CFTR produced but decreased amounts
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17
Q

What specific CF allele is associated with Class 1 CFTR mutations and is due to a nonsense mutation that creates stop codon resulting in no protein produced?

A

G542X

(5% of CF alleles)

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18
Q

What specific CF allele is associated with Class 2 CFTR mutations and is due to defective protein folding which results in degradation of protein?

A

F508del

(70% of CF alleles)

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19
Q

What specific CF allele is associated with Class 3 CFTR mutations and is due to defective gating or regulation of channel opening?

A

G551D

(4% of CF alleles)

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20
Q

For the more severe CFTR mutations like Class I, II, III; what percent of CFTR activity remains?

A

≤ 1% CFTR activity remaining

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21
Q

For the more severe CFTR mutations like Class I, II, III; how early is typical diagnosis?

A

usually in first year

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22
Q

For the more severe CFTR mutations like Class I, II, III; what is the median survival?

A

37.4 years

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23
Q

For the more severe CFTR mutations like Class I, II, III; what are the associated health problems?

A
  • Pancreatic insufficient
  • At risk for CF-related diabetes, liver disease
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24
Q

For the less severe CFTR mutations like Class IV and V; what is the percentage of remaining CFTR activity?

A

about 5% CFTR activity remaining

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25
Q

For the less severe CFTR mutations like Class IV and V; when is the typical diagnosis?

A

May have late presentation

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26
Q

For the less severe CFTR mutations like Class IV and V; what is the median survival?

A

Survival to 50 yoa not uncommon

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27
Q

What is the result of the CFTR mutation G542X?

A
  • Mutation creates stop codon at amino acid 542
    • Results in:
      • Decreased mRNA and/or non-functional protein
28
Q

What is the result of the CFTR mutation G551D?

A
  • Ion channels constantly move between open and closed conformations
  • Mutation makes it unable to respond to ATP (opening signal)
    • Results in = greatly increased time in closed conformation
29
Q

What is the result of the CFTR mutation F508del?

A
  • Almost complete loss of functional protein
    • Folding defect leads to degradation of most
    • Small fraction of protein at cell surface is defective in gating, stability
30
Q

What is the most common CFTR mutation that is responsible for 70% of alleles, 50% homozygous, and 40% one allele?

A

F508del

31
Q

What is the principle defect in the F508del mutation?

A

folding

32
Q

Why is the synthesis of CFTR protein considered a complex process?

A
  • Takes place at the endoplasmic reticulum (ER) membrane
  • Requires intra-domain folding and inter-domain interactions
  • Requires interaction with series of chaperones
33
Q

What does incorrect folding ultimately result in?

(Hint: F508del)

A
  • altered interaction with chaperones
  • retention in the ER and activation of quality control pathways
  • degradation by the proteasome
34
Q

Can you predict the severity of disease based on which mutation class the cystic fibrosis is classified?

A

NO

  • Mutation class does not predict severity of disease in individuals
  • All mutations in “Severe” category cause defect in pancreatic ducts → pancreatic enzyme insufficiency
  • Those with “Severe” mutations tend to have worse pulmonary disease
  • But factors that affect immune system and development of fibrosis also affect outcome
  • “Severe” mutations are necessary but not sufficient for development of CF-related diabetes and liver disease
35
Q

How does loss of chloride ion channel function cause manifestations of cystic fibrosis?

A
  • CFTR is essential to maintain protection:
    • Expansion of mucin
      • Luminal epithelial surface is protected from pathogens by mucin layer and by movement of cilia
    • Maintains airway surface liquid volume (ASL) which helps in clearance of mucus
  • In absence of CFTR: mucin is descicated, ineffective barrier
36
Q

Why does inactivation of CFTR affect respiratory function?

A

Loss of luminal H20 and ion balance

37
Q

Why does inactivation of CFTR affect respiratory function?

A

CF is characterized by unresolved, excessive and ineffective inflammation.

  1. Decreased ASL (water layer) → ineffective mucin barrier failure to clear bacteria
  2. Constant activation of inflammatory pathways in airway epithelial cell
    • LPS > TLR4 > MyD88 > NFκB
  3. Increased mucin secretion (which is ineffective)
  4. Inflammatory mediators (IL-1β, TNF-α, IL-8) → Neutrophil recruitment
  5. Neutrophils release elastase → Damage CFTR itself and epithelial cell
    • DAMPs stimulate further inflammatory signaling
38
Q

What is the pathology behind cystic fibrosis?

A
  1. Decreased ASL(water) layer → build up of viscous mucous, failure to clear bacteria
    • Characteristic CF bacterial infections- Stapholococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia
  2. Persistent colonization and desiccated mucus → inflammation
    • Damaging agents- free radicals, ROS, proteases, Increased mucus production
  3. Infection, inflammation and mucus plugging → long term structural damage
    • bronchiolectasis, bronchiectesis
  4. Ultimate outcome is respiratory failure
39
Q

What is the key clinical issue in cystic fibrosis?

A
  • Airway infection:
    • Infection appears early → 40-60% pediatric patients have Pseudomonas aeruginosa
    • Tend to be pathogens not found in non-CF population
      • Haemophilus influenzae
      • Staphylococccus aureus MRSA
      • Pseudomonas aeruginosa
      • Burkholderia cepacia
    • Difficult to eradicate
40
Q

What is the goal in treatment of CF? How is it accomplished?

A
  • Goal = prevent pulmonary damage
    • Chest physiotherapy to improve drainage
    • Aggressive treatment of infection (antibiotics)
    • Hypertonic saline and Dnase aerosols to make mucus less viscous
    • Anti-inflammatories
41
Q

What is the pathology behind pancreatic duct blockage in CF patients?

A
  • Epithelial cells lining pancreatic duct express CFTR
    • Secrete HCO3-
    • Luminal HCO3- recruits H2O and neutralizes secretions
    • Prevents formation of protein plugs in pancreatic duct
  • Loss of CFTR function → blockage of duct by secreted protein plugs
    • Leakage of proteolytic enzymes, inflammation → destruction of tissue
42
Q

What percent of people with CF have pancreatic duct damage?

A

Pancreatic duct is damaged in ~100% of all CF individuals!

~85% require replacement therapy to prevent malabsorbtion of lipids, fat-based vitamins

(Pancreatic phenotype is directly dependent on severity of genetic mutation)

43
Q

How is CF related to diabetes?

A
  • Pancreatic duct related inflammation leads to destruction of pancreatic islet cells that make insulin
    • (not autoimmune process, INFLAMMATORY process!)
  • CF related diabetes is primarily due to loss of ability to make insulin
    • Insulin resistance may also contribute as a result of chronic systemic inflammation
44
Q

How common is CF-related diabetes?

A

CF related diabetes affects ~20% of CF individuals below 20 yoa

45
Q

What are the intestinal manifestations of CF?

A
  • CFTR is expressed in crypts of intestinal epithelium
    • Loss of function → failure to secrete H2O
      • leads to dehydration of lumen, viscous mucus as in airway epithelium
46
Q

What are the classical intestinal conditions that CF patients may present with?

A
  • Obstruction: meconium ileus
    • occurs in 15% of newborn infants with CF
    • only occurs if two “Severe” alleles
    • Distal intestinal obstruction syndrome (DIOS) in older individuals
  • Inability to absorb protein & fats
    • most require nutritional supplementation
  • Long term → individuals with CF have increased susceptibility to GI cancers
47
Q

What is the pathology behind CF-associated liver disease?

A
  • CFTR expressed in cholangiocytes that line the bile duct not hepatocytes or other liver cells
    • CFTR is required to maintain luminal environment
  • Absence leads to retention of toxic bile acids (taurocholic acid)
  • Toxic bile acids build up → promote synthesis & secretion of MCP1 from both hepatocytes and cholangiocytes
  • Recruitment and activation of hepatic stellate cells leads to fibrogenic myofibroblasts
  • Excess collagen → fibrogenesis
48
Q

How often does CF associated liver disease occur?

A

CF associated liver disease occurs 5-10% of CF individuals

(median age of diagnosis is 10 yoa)

49
Q

Why does male infertility occur as a result of CF?

A
  • Vas deferens is absent in virtually all male CF individuals
    • becomes obstructed in the fetus or during infancy and is then reabsorbed
50
Q

What is the basis of the “Sweat Test” for diagnosing CF?

A
  • In sweat glands the CFTR promotes uptake of Cl- ions from the extracellular space with Na+ following
    • decreased ability to absorb Cl- and Na+ results in increased NaCl in sweat
51
Q

How is molecular genetic knowledge used for better testing and treatment?

A
  1. Widespread screening
  2. New treatments to correct specific mutation defects
52
Q

How does molecular genetics make widespread screening of CF feasible?

A
  • The gene that is mutated is known
  • The DNA sequences of most mutations that cause the disease are known
  • A panel of 23 mutations that account for 90% of mutations in northern European Caucasians and 70% of mutations in African Americans has been developed into a clinical test
53
Q

Who should be screened for CF?

A
  1. Carrier screening
    • ACOG recommendation is to offer genetic carrier screening to ALL individuals planning a pregnancy or seeking prenatal care
    • Carrier screening- testing of family and more distant relatives of those with CF
  2. Prenatal testing
    • Offered when 25% estimated chance of CF (two carriers)
  3. Screening of ALL newborns
  4. Diagnostic testing
54
Q

What is the CF risk in ANY pregnancy?

A

1/2500 (in any pregnancy)

55
Q

What is the detection rate of CF in genetic testing?

A

With genetic testing → 90% detection rate

56
Q

What are the forms of prenatal testing used if both parents are carriers or parents have a previous child with CF (25% chance of CF)?

A
  • Chorionic villus sampling 10-12 weeks for DNA mmutation testing
  • Amniotic fluid 16-17 weeks for DNA mutation testing
  • Also ultrasound for echogenic bowel
57
Q

Why does early detection of CF in newborns make a difference?

A
  • Nutrition:
    • pancreatic enzyme replacement
  • Pulmonary function:
    • aggressive treatment to prevent obstruction & infection
58
Q

What is the typical screening protocol in Newborn Screeing of CF?

A
  1. IRT immunoreactive trypsin = test of pancreatic function
    • Part of panel done on heel stick blood sample. (screening step 1)
  2. DNA mutation analysis = based on panel representing vast majority of disease causing mutations (screening step 2)
  3. Sweat test = test of CFTR function (diagnostic)
59
Q

What is the definitive diagnostic test for CF?

A

Sweat Test

  • Sweating is induced by chemical treatment on skin
  • Sweat released over 30 min is absorbed onto detective pad
  • Cl- content is measured

(Testing of all family members is also done)

60
Q

What are the current treatment strategies for CF?

A
  • Aggressive, meticulous treatment of all possible manifestations
  • Major objectives:
    • Lungs- clear secretions, control infections
    • Maintain nutrition
    • Prevent intestinal obstruction
  • Carried out by multidisciplinary care team in CF Centers accredited and funded by the Cystic Fibrosis Foundation
61
Q

How successful have multidisciplinary care teams in CF Centers accredited and funded by the Cystic Fibrosis Foundation been at treating CF?

A
  • 1955 → Most children with CF did not enter elementary school
  • 2013 → Median predicted age of survival ~40
62
Q

What are two new treatment strategies in CF?

A
  • Lung transplantation- 60% survival after five years
    • Described as way to extend life, not as cure
  • Drugs to target specific deficiencies of CFTR mutations
63
Q

What drugs were recently developed to correct specific CFTR mutations?

A
  • Ivacaftor (Kalydeco)
    • corrector for G551D
  • Ataluren
    • corrector for G542X
  • Ivacaftor + Lumacaftor
    • Lumacaftor is a corrector for F508Δ
64
Q

How does Ivacaftor (Kalydeco) treat CF?

A
  • Corrector for G551D
  • Keeps channel in open conformation for higher percent of time, even without ATP gating
  • FEV1 increase ~10%
  • FDA approved Jan. 2012
  • $300,000/y
65
Q

How does Ataluren treat CF?

A
  • Corrector for premature stop codon mutations (G542X)
  • Causes ribosome to be less sensitive to stop codons
  • Phase 3 clinical trials show some improvement, but not statistically significant
66
Q

How does Ivacaftor + Lumacaftor treat CF?

A
  • Lumacaftor is a corrector for F508Δ, promotes traffic of protein to the cell surface instead of degradation @ proteasome
  • Combination → 4-7% improvement in FEV1
  • Decrease in severe exacerbations
  • FDA approval July, 2015
  • ~$275,000/y

CRRAB II Week 8/9 - WLB (5 decks)

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