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Molecules to Malady > Module 2 - Cystic Fibrosis > Flashcards

Module 2 - Cystic Fibrosis Flashcards

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0
Q

What was the early characterisation of CF? (post 1938)

A

Fat and protein malabsorption
Failure to thrive
Lung disease
Abnormal electrolyte composition in sweat

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1
Q

When was cystic fibrosis first identified and how?

A
  1. Identified mucous plugs in pancreas in babies dying of malnutrition.
    Condition called “cystic fibrosis of the pancreas.”
    In 1940s it became apparent that CF was of genetic inheritance.
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2
Q

How was the gene responsible for CF identified?

A

1983 - abnormal cAMP-mediated regulation of chloride transport (sweat ducts)
1985 - gene associated with CF mapped to chromosome 7q31.2 by linkage in families
1989 - gene identified by positional cloning

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3
Q

Describe the CFTR gene

A

“Cystic Fibrosis Transmembrane conductance Regulator”
90kb DNA
27 exons coding for 1480 amino acids
Codes for large integral glycosylated membrane-spanning protein

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4
Q

Describe the CFTR protein. What type of protein is it and how is it regulated?

A

Member of ABC (ATP-binding cassette) superfamily
Chloride channel protein. It is different from other ABC transporters because the passage of ions is via passive diffusion.
Regulated by cAMP-dependent phosphorylation
Expressed in epithelial cells (apical membranes)

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5
Q

What are the domains of the CFTR protein?

A

5 domains.
2 membrane spanning domains (MSD) - forma channel for passage of chloride ions
2 nucleotide-binding domains (NBD) - bind and hydrolyse ATP
1 regulatory domain (R) - phosphorylation by cAMP-dependent protein kinase)

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6
Q

How does CFTR interact with other proteins?

A

Carboxy-terminal is anchored to cytoskeleton and kept close to other proteins.
These proteins influence CFTR functions such as:
- conductance
- regulation of other channels (e.g. eNAC: epithelial sodium channel)
- signal transduction
- localisation at apical plasma membrane

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7
Q

Describe CFTR function in the airways and how a can mutation affect its function in a patient with CF.

A

In a normal lung: CFTR assists in Cl- secretion. Cl- ions move out of the cell down a concentration gradient, while Na+ ions and water move into the cell. CFTR inhibits ENac so that there is less absorption of Na+.
In a CF lung: Cl- ions build up within the cell resulting in an even greater movement of Na+ ions and water into the cell. –> dehydrated mucous in airways.

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8
Q

Describe CFTR function in the sweat duct and how a mutation can affect its function in a CF patient.

A

In normal sweat ducts: Cl- ions move into the cell, down a concentration gradient, together with Na+ ions and water. CFTR activates ENac in the sweat duct. Sweat is secreted into the duct by the gland and both Na+ and Cl- are normally reabsorbed by the duct cells before reaching the skin surface.
In CF sweat ducts: Cl- ions cannot enter the cell and Na+ and water remain in the sweat duct. –> elevated Na+ and Cl- levels in the sweat.

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9
Q

How many known mutations of CF are there? What can they cause? In which exons are the majority of mutations found?

A

More than 1900 known mutations.
These mutations are a variety of CF-causing, non CF-causing, varied penetrance and unknown significance.
Most mutations are found in exons 4, 8, 14 and 20.

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10
Q

What is a Class I mutation? Provide an example of one.

A

No protein production.

E.g. Spice mutation intron 4 donor site (G -> T) in MSD1. Absent protein, normal mRNA abundance.

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11
Q

What is a Class II mutation? Provide an example of one.

A

Defective processing (maturation, premature degradation)

E.g. F508del in NBD 1.

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12
Q

What is a Class III mutation? Provide an example of one.

A

Defective regulation (e.g. decreased ATP binding and hydrolysis).

E.g. S1255P in NBD2.

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13
Q

What is a Class IV mutation? Provide an example of one.

A

Defective/reduced ion conductance or channel gating.

E.g. R117H in MSD1. Alteration of Cl- channel.

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14
Q

What is a Class V mutation? Provide an example of one.

A

Reduced protein production (e.g. promoter or splicing abnormality)

E.g. Splice mutation intron 4 donor site (G -> T) in MSD 1. Reduced number of transcripts.

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15
Q

What is a Class VI mutation? Provide an example of one.

A

Accelerated turnover from cell surface.

E.g. Q1412X. Instability at cell surface.

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16
Q

What is the most common mutation in CF?

A

F508del. (Class II)
Accounts for 70-75% of mutations in people from Northern European descent. Homozygosity in about 50% of patients with CF.
Misfolded protein retained in ER and targeted for degradation.

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17
Q

What are some class-specific therapies?

A

Class I: Nonsense mutations corrected by compounds that allow ‘read through’ of mRNA. (e.g. aminoglycoside antibiotics)
Class II: ‘correctors’ to improve processing
Class III: ‘potentiators’ to activate protein
Class IV: flavonoid compounds to augment channel function (increase open probability
Class V: often splicing mutations. Increase levels of correctly spliced mRNA.

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18
Q

What diagnostic test can be used for a F508del mutation?

A

PCR + gel electrophoresis.

Homozygotes will show a shorter band due to the deleterious nature of the mutation.

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19
Q

How are mutation panels used in testing?

A

PCR +/- restriction enzymes.
Number of mutations in testing panels differs throughout the world.
Some mutations are specific to particular ethnic groups.
Previously, in VIC a total of 12 mutations were tested, together accounting for 80% of mutations. A further 7 mutations were added.

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20
Q

Testing of mutations by SNP analysis

A

Multiplex PCR - single reaction, multiple primers, fluorescent tags.
Assay involves primer extension of each hybridised primer so that each product incorporates a coloured fluorescent tag (dNTP) and the colour of the peak depends on which dNTP has been added.
Analysis of each mutation performed in 2 batches on capillary gel electrophoresis.

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21
Q

Most recent VIC CFTR mutation panels and testing

A

New diagnostic panel includes 38-40 mutations, accounting for 91% of mutations in VIC population.
SNP genotyping + measuring of mass of allele-specific products following PCR.
MALDI-TOF MS - Matrix assisted laser desorption/ionization-time of flight mass spectrometry.
Can genotype a large number of samples (100s-1000s) and a medium number of SNPs (10s-100s)

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22
Q

What is the pattern of inheritance for CF?

A

Autosomal recessive
Carrier frequency of 1 in 25.
Often no family history.

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23
Q

What ethnicity does it most commonly affect? What is the incidence rate?

A 
Caucasian descent (especially Northern European). 
Incidence of approx. 1/2500-3000 live births.
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24
Q

Why are there different rates of prevalence around the world?

A

Ethnic-specific mutations.

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25
Q

What are the genotype-phenotype correlations in terms of class and lung disease/pancreatic function?

A

Weak genotype-phenotype correlations for lung disease, more for pancreatic disease.

Classes I, II, and III (and probably VI) - severe lung disease; pancreatic insufficiency.
Classes IV and V - milder lung disease; pancreatic sufficiency.

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26
Q

What is one challenge of mutations with uncertain clinical significance?

A

Penetrance of mutation may also depend on another intragenic polymorphism.

E.g. R117H and poly T tract in intron 8 in cis.

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27
Q

Environmental and genetic modifiers both play a role in the resultant phenotype of a CF patient. What phenotypes are not well correlated with CFTR mutations?

A

Lung function, neonatal intestinal obstruction, diabetes and anthropometry (e.g. weight and height).

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28
Q

It is important to identify genetic modifiers because:

A
  • Identifies new targets for therapies
  • Increases understanding of disease variability
  • Expect these genes/variants to be minimally penetrant in healthy people but effects unmasked in CF patients.
  • These gene modifiers may contribute to development or progression of common diseases in general population
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29
Q

What are 3 types of association studies that can be carried out to identify genetic modifiers of CF?

A
  1. Linkage: Track genes/markers associated with specific phenotype in families with CF
  2. Candidate gene expression: Genes with known function; correlate variations in gene with presence of features/phenotype in CF patients.
  3. Genome wide association studies (GWAS): Examine DNA markers at many positions on multiple chromosomes in populations with and without CF phenotype of interest. Look for SNPs that are shared with much greater frequency in those with same phenotype.
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30
Q

What are the limitations of genome wide association studies?

A
  • When genes/SNPs are less penetrant, then need a greater sample size.
  • Need to replicate studies for validation.
  • Need to demonstrate correlation and cause (not just association) by conducting research showing specific mechanisms.
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31
Q

What are 3 genetic modifiers of lung disease in CF?

A

EDNRA (encodes endothelin receptor type A) - variants alter smooth muscle tone in airways and/or vasculature

MBL2 (encodes mannose binding lecting) - role in innate immunity. MBL2 deficiency predisposes to early infection with P. Aeruginosa.

TGFB1 (encodes transforming growth factor beta) - role in regulating inflammation and tissue remodeling. Increased expression causes worse lung function.

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32
Q

What is a genetic modifier of intestinal obstruction?

A

MSRA (encodes methionine sulphoxide reductase) - role in modifying intestinal enzymes such as alpha 1-antitrypsin. Variants may alter digestion of intestinal contents and contribute to formation of viscous meconium.

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33
Q

What is a genetic modifier of diabetes?

A

TCF7L2 (encodes transcription factor 7-like 2) - role in proliferation and function of beta cells of pancreatic islets. Modify risk for diabetes in CF patients who have not had recent or prolonged exposure to systemic steroids.

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34
Q

What are some environmental modifiers that are associated with poorer health outcomes?

A
  • being female
  • lower socio-economic status
  • exposure to tobacco smoke - active and passive
  • infectious exposures
  • disease self-management
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35
Q

What are 3 purposes of screening for CF?

A
  • Identify babies at risk of developing CF (newborn screening)
  • Identify carriers who are relatives of a diagnosed baby (cascade testing)
  • Identify carriers from the general population (population carrier screening)
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36
Q

Describe newborn screening for CF

A
  • Immunoreactive trypsinogen (IRT) on newborn screening (Guthrie cards)
  • Heel prick at 2-3 days
  • Elevated samples undergo further testing
  • DNA testing for initial 12 mutation panel - if necessary include extended panel. (2 mutations. Homozygotes and compound heterozygotes have CF)
  • Heterozygotes brought in for sweat test and maybe gene sequencing.
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37
Q

What is a challenge with cascade testing?

A

Lack of communication within families may lead to poor uptake. Only 12% of eligible relatives underwent testing even when test was at no charge.

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38
Q

What are some reproductive options for carrier couples?

A

No children, adoption, pregnancy with no testing, pre-implantation genetic diagnosis (PGD) - test and implant unaffected embryos.

39
Q

What are the consecutive branches of a lung?

A 
Upper airways
Trachea
Bronchi
Bronchioles
Terminal Bronchioles
Respiratory Bronchioles
Alveolar Ducts
Alveoli
40
Q

What are the stages of lung development and the corresponding weeks of gestation?

A 
Embryonic - 0-6 weeks gestation
Pseudoglandular - 6-16 weeks gestation
Canalicular - 16-26 weeks gestation
Sacular/Alveolar - 26-36 weeks gestation
Postnatal - birth to ?? (2-adult)
41
Q

What occurs in the embryonic stage of lung development?

A

Lung bud appears day 26-28.
Ventral outpouching of the primitive foregut.
Endodermal origin.
Proximal branching of the airways into surrounding mesoderm.

42
Q

What happens in the pseudoglandular stage of lung development?

A

Weeks 6-16.
Airways develop (branch) to the level of terminal bronchioles (pre-acinar bronchi)
16 generations of airways.

43
Q

What occurs in the canalicular stage of lung development?

A

Weeks 16-26.
Acinar region develops
Thinning of peripheral epithelium
Type I and II pneumonocytes develop.

44
Q

What occurs in the sacular/alveolar stage of lung development?

A

Weeks 26-36.
Sacules form into the alveolar ducts and alveoli
Marked decrease in interstitial tissue
Sacules become thin walled
Sacules and alveoli form further generations of alveoli by septation
Alveoli at birth 100 x 10^6; Adult 300 x 10^6
Surface area at birth 4 sqm; adult 10 sqm

45
Q

What are the functions of the lung?

A 
Gas exchange
defence
acid-base exchange
metabolic
heat exchange
water balance
phonation
46
Q

What are the physical and cellular defence mechanisms of the lung?

A

Physical - upper airway filter; reflexes (sneeze, cough); mucociliary escalator.
Cellular - phagocytes (e.g. alveolar macrophages), immunological

47
Q

What is the mucociliary escalator?

A

Airway surface liquid (ASL) has 2 layers - periciliary layer + mucus gel layer
Mucus produced by secretory cells including goblet cells.
Mucus propelled by cilia - 12-15 beats/second; 1mm/minute

48
Q

What can be measured through spirometry?

A

Forced expiratory volume (FEV1) - volume exhaled in first second
Forced vital capacity (FVC) - total volume exhaled

49
Q

What are pulmonary exacerbations associated with CF? What are some other features?

A

Increased cough and sputum production
Increased dyspnoea (shortness of breath/awareness of breathing)
Lethargy/poor appetite
Reduced lung function
Progressive decline in lung function
Respiratory failure
Death/transplantation (30% lung function)

50
Q

On which cell types is CFTR expressed?

A

Apical plasma membrane of ciliated epithelial cells in airways
Serous cells of submucosal glands
Alveolar epithelial type II cells
Cells of immune system (alveolar macrophages, neutrophils)

51
Q

What is the significance of CFTR dysfunction and ASL?

A

ASL volume is decreased due to water entering the cells. This has consequences on ciliary beating as the periciliary layer is decreased. Absence of lubrication also results in adherent mucus plaque.

These can promote chronic infection.

52
Q

How are CFTR dysfunction and pH related to lung function?

A

CFTR mediates transport of bicarbonate and regulates pH of ASL. Deficiency of this inhibits antimicrobial function.

53
Q

What is the consequence of CFTR dysfunction in the maintenance of glutathione and thiocyanate?

A

Glutathione deficiency might contribute to lung inflammation and oxidative stress.

54
Q

How does CF create an anaerobic environment in the lung?

A

Thick mucus plaques adherent to epithelial surface + increased oxygen consumption by CF epithelia.

Pseudomonas converts to anaerobic biofilm mode of growth.

55
Q

What happens when CFTR dysfunction promotes chronic airway infection?

A

Exaggerated, predominantly neutrophilic inflammation.

May also directly affect airway immunity.

56
Q

What role do neutrophils play in CF airways?

A
  • role in ensuing tissue damage and disease progression
  • Possess an array of mediators, oxidants and proteases, critical for response against infection
  • Large amounts of these enzymes escape from neutrophils in cell death and during phagocytosis

Antiprotease defences in the airways overwhelmed by the protease burden in the lung

57
Q

What is the relationship between CF inflammation and oxygen?

A

CF airways exposed to oxygen radicals derived from environmental oxygen and bacterial products and also from host immune response.
Oxidative stress exacerbates pulmonary deterioration and advances bronchiectasis.
Oxidative stress may lead to oxidation of airway proteins.
May further augment cytokine release and airway inflammation.

58
Q

What are some extracellular triggers of inflammation in CF?

A 
Bacteria
Vriuses
Fungi
GER
Protease/anti-protease balance
ROS/anti-oxidants balance
59
Q

Explain the proinflammatory property of CF airway epithelium.

A

Increased cellular response to inflammatory triggers.

May be due to dysregulated activity of transcription factors.

60
Q

What can lead to the deposition of DNA in the airways?

A

Accumulation of abnormally folded CFTR in ER triggers ‘cell stress’ and apoptosis. Ceramide (breakdown product of sphingomyelin found in plasma membrane and in endolysosomal compartments) accumulation may further augment inflammation by inducing apoptosis with subsequent deposition of DNA in airways.

61
Q

What are some intracellular triggers of inflammation in CF airway cells?

A

Inherent abnormal intracellular pathways, primarily in airway epithelial cells, lead to apoptosis on the one hand, and to cell stress and excessive cytokine production on the other, perpetuating the inflammatory response in the airways.

62
Q

What is bronchiectasis?

A

Dilation and damage of airways due to infection, inflammation and obstruction of airways.

63
Q

What are some pathogens that can cause lung disease in CF?

A 
Haemophilus influenzae
Staphylococcus aureus
Pseudomonas aeruginosa 
Burkholderia cepacia 
Stenotrophomonas maltophilia
Non-tuberculosis mycobacteria
64
Q

What body systems can be affected by CF?

A 
Chronic pulmonary disease
Pancreas
Nutrition
Liver
Gut
Electrolyte disturbance
ENT
Muscoloskeletal
Genito-urinary
Renal
65
Q

What is the sweat test?

A

Gold standard for diagnosing CF
Transdermal administration of pilocarpine by iontophoresis
Collection and quantitation of sweat onto gauze or filter paper or into a macroduct coil.
Normal value Cl < 40mmol/L

66
Q

What are the clinical features of high salt sweat?

A 
Hyponatremic/hypochloremic dehydration
Hypokalemic metabolic alkalosis secondary to chronic salt loss -Pseudo-Bartter's Syndrome
Headache or irritability
Muscle cramps
Nausea and vomiting
Fatigue
Poor Concentration
67
Q

What are the two functions of the pancreas?

A

Exocrine (Pancreatic acini) - lipase, amylase, protease secretion.
Endocrine (Islet of langerhans) - insulin, glucagon secretion.

68
Q

What are the features of pancreatic dysfunction in CF?

A

Pancreatic enzyme insufficiency in 85% of patients.
Class I, II, III or VI mutations
Steatorrhoea
Fat malaborption
Malnutrition
Low levels of fat soluble vitamins - A, D, E, K
Use of pancreatic enzyme replacement therapy (PERT) - enteric coated

69
Q

Explain how a mutation in CFTR can result in pancreatic disease.

A

Dysregulation of chloride secretion = reduced luminal liquid. This results in viscous pancreatic secretions and thus, pancreatic duct obstruction and progressive fibrosis and fatty infiltration can occur.

Dysregulation of bicarbonate secretion = acidic pH of luminal liquid. This results in premature activation of proteolytic enzymes and therefore, inflammation and destruction of pancreas.

70
Q

What is cystic fibrosis related diabetes mellitus (CFRDM)?

A 
Increasingly common with increasing age (rare under 10 years, 50% over 30 years)
Impaired and delayed insulin secretion
Insulin resistance
Higher mortality rates (6 fold)
Lung function decline
Microvascular complications
71
Q

How can the liver be affected by CF?

A

25% of patients have liver disease.
CFTR in epithelial cells lining intra-hepatic bile ducts. Dysfunction increases viscosity of bile and plugging of intra-hepatic bile ducts. Cirrhosis (replacement of liver tissue by scar tissue and regenerative nodules) in minority
Most cirrhosis evident by 20 yo.

72
Q

What are the clinical features of liver disease?

A

Prolonged neonatal jaundice
Cirrhosis and portal hypertension
Hepatocellular failure is uncommon, 2-3%

73
Q

What are the ways CF can affect the GIT?

A 
Dehydration of luminal contents
Meconium ileus
Constipation
Distal intestinal obstruction syndrome
Gastro-oesophageal reflux
Rectal prolapse (pancreatic insufficient, frequent stools, diminished muscle tone, coughing)
Malignancy
Coeliac disease
Fibrosing colonopathy
74
Q

What is meconium ilieus?

A

Inspissated intraluminal meconium causing bowel obstruction
associated with pancreatic insufficiency
Incidence: 10-15% of CF neonates.
Late complications (increased DIOS risk, adhesive small bowel obstruction)

75
Q

What is distal intestinal obstruction syndrome?

A

Abdominal pain, crampy in right iliac fossa (RIF)
Palpable mass in RIF
Partial or complete bowel obstruction
intussusception
AXR: dilated small bowel with bubbly ileocaecal mass
Constipation also common

76
Q

What is gastro-oesophageal reflux?

A

Very common in CF
Aetiology is multifactorial
Exacerbated lung disease due to aspiration and reflex bronchospasm
Delayed gastric emptying and small bowel transit also common.

77
Q

How does CF affect bone?

A

Osteoporosis in CF patients. Low bone mineral density very common.
Risk factors include: poor lung function, delayed puberty, nutritional failure, steroid use, CFRDM, hypovitaminosis D and K, physical inactivity
2-fold increase in fracture rates in young adults.

78
Q

How does CF affect the genito-urinary system?

A

Pubertal delay and growth delay
Male infertility (99%, absent vas deferens results in azoospermia)
Reduced female fertility
Urinary incontinence
No clinical effect of CFTR in renal tubes. Increased renal clearance of antibiotics (e.g. nephrotoxic aminoglygosides)

79
Q

What are the goals of treatment of CF?

A

Maintaining lung function - treat infections; airway clearance
Adequate growth - diet; supplementation
Managing complications - e.g. CFRDM, Liver disease

80
Q

What type of professionals can help with CF?

A

Physicians, nurses, physiotherapists, dieticians, geneticists, pyschologists

81
Q

What types of physiotherapy techniques can be used?

A

Gravity assisted drainage and manual techniques.

  • modified 5 position technique in infants
  • active cycle of breathing techniques (ACBT) (introduced as blowing games)
  • Autogenic drainage (AD)
  • Assisted AD
  • Positive expiratory pressure (PEP) (mask, mouthpiece - MoPEP, Combination, bubble)
  • Activity and exercise
82
Q

In what 2 ways can antimicrobials be useful?

A

prophylaxis and exacerbations

83
Q

What things have to be considered when developing antibiotics?

A

Route of administration - oral,intravenous (home/hospital), nebulised
Susceptibility testing
Resistance
Pharmacokinetics

84
Q

What patterns are there with antimicrobials and CF?

A

Acquisition of pathogens occurs age-wise

Majority eventually acquire pseudomonas

85
Q

How measures are taken to control infection?

A

Cohorting.
Patient to patient spread of infection of pseudomonas aeruginosa, burkholderia cepacia, MRSA
Segregation of patients - in-patient, out-patient, social activities (can have implications on support community)

86
Q

What are some other respiratory therapies?

A

Mucolytics - recombinant human deoxyribonuclease-1 (Pulmozyme), hypertonic saline, mannitol
Anti-inflammatory agents - azithromycin, prednisolone, inhaled steroids, ibuprofen

87
Q

What measures can be taken with regards to nutrition?

A
  • Close monitoring
  • Specialist dietician
  • Energy requirements 120-150% normal - wide variation, increased expenditure, increased losses, reduced intake
  • high fat (35-40%), high protein diet
  • supplemental feeds - oral, nasogastric, gastrostomy (PEG)
  • Improved growth improves lung function
88
Q

Vitamins and electrolytes

A

Fat-soluble vitamins - A, D, E, K

Salt replacement

89
Q

Pancreatic enzymes

A
  • Enteric coated pancreatic enzyme microspheres (e.g. Creon)
  • Derived from porcine extract
  • Taken with all fat, protein and complex carb containing foods
  • contain lipase, amylase, protease
  • 500-2000 units lipase/kg/meal
  • Maximum 10,000 units lipase/kg/day
90
Q

Future therapies

A
  • Novel inhaled antibacterials
  • Anti-inflammatory agents
  • correction of the underlying gene effect
  • protein rescue therapy
91
Q

What are the phases of clinical trials?

A 
Phase 1:
- Safety and pharmacology
- Start with low doses and increase
- Healthy volunteers
Phase 2:
- Examine effectiveness (dose, delivery method, dosing interval)
- Confirm safety
- 100-300 patients
Phase 3: 
- Confirm previous findings
- Demonstrate safety and efficacy
- Determine best dosage
- 1000+ patients
92
Q

What are some examples of novel antibacterials?

A

Dry powder inhalation: colistin, tobramycin, vancomycin

Nebulised: Aztreonam, amikacin, levofloxacin

93
Q

What are some anti-inflammatories?

A

Glutathione (antioxidant)
Sildenafil (phosphodiesterase inhibitor)
KB001A (humanised monoclonal Fab fragment; targets pseudomonas virulence factor and decreases local inflammation)
alpha1-antitrypsin (protease inhibitor; phase 2 study of inhaled version)

94
Q

Gene therapy

A

Introduce a normal copy of the CFTR gene into the cells of the conducting airways. Likely to need repeated application. Lung efficient barrier to foreign material (avoid being cleared from lungs by mucociliary elevator, penetrate mucus and then cell membrane, cross cytoplasm and DNA must enter nucleus, avoid host immune system)

95
Q

Gene therapy vectors

A
  • Viral vectors (adenovirus, retrovirus, adeno-associated virus); Multiple clinical trials in 1990s, repeated administration not efficacious
  • Non viral vectors: cationic liposomes complexed with plasmid DNA, short duration of efficacy (viral promotor exchanged for humanized promoter capable of sustaining prolonged gene expression; mild flu-like symptoms (presence of unmethylated CpG groups on bacterially derived DNA)

Molecules to Malady (1 decks)

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