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Cystic Fibrosis - Coggle Diagram
Cystic Fibrosis
DIAGNOSIS
Purpose
- Find symptomatic individuals
- Identify carriers related to diagnosed patients (Cascade Testing)
- Identify carriers for reproductive purposes (Population Carrier Screening)
Newborn Testing
Heel Prick Test (IRT)
- Screen for IRT on a blood spot card
- In highest 1% of levels --> next stage of testing
DNA Testing
- Test for 12 variants
- If two variants, CF diagnosis
- Heterozygotes --> next stage
Sweat Test
- If >60 mmol/L, CF diagnosis
- Normal value is <30-40 mmol/L
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BACKGROUND
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Lung Function
Lung Development
2. Pseudoglandular 6-16 weeks
- Airways branch to terminal bronchioles
- 16 generations of airways
3. Canalicular 16-26 weeks
- Acinar region
- Type I and II pneumocytes
- Peripheral epithelium thins
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4. Sacular/Alveolar 26-36 weeks
- Interstitial tissue decreases
- A lot of alveoli is made
1. Embryonic 0-6 weeks gestation
- Lung bud
- Ventral outpouching
- Endodermal origin
- Proximal branching :arrow_right: mesoderm
Gas Exchange
Measuring Lung Function
- Volume (L)
- Flow (L/sec)
- Pressure
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Forced Expiration (Spirometry)
Defence
Physical (Airway)
- Upper airway filter
- Sneezing, coughing
- Mucociliary Escalator
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SYMPTOMS
Pulmonary
Components
Ion Transport
- ENaC not inhibited
- Cl- not secreted
- HCO3- also not secreted
ASL
- Caused by ion transport messing up
- pH decreases because of less HCO3-
- Impaired antibacterial activity
- Mucus becomes dehydrated, ASL is unbalanced
- Ciliary beating is more difficult
- More prone to infection
Mucus
- CFTR is normally abundant in submucosal glands
- Mucus is altered by defective HCO3-
- Defective CFTR also inhibits mucus secretion
*Mucociliary transport affected
- Contents from degraded neutrophils increase viscosity --> affect transportability
Anaerobic Environment
- Caused by thick mucus plaques and increased O2 consumption
- Optimal for some bacteria, eg. Pseudomonas
Influence
- Equally from genetics and environment
- Exact mechanisms unknown?
- Complex mechanisms btwn host defence + airway microbiology
- Viral infections could initiate events
Pulmonary Disease in CF
- High morbidity and mortality
- Exacerbations
- Progressive decline
- Respiratory failure
Airways
- Infection/inflammation/obstruction >> dilation/damage
Systemic
Pancreas
- Strongly influenced by genetics
- One of the earliest organs affected in CF
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Exocrine: issues (insufficiency) with
*Caused by HCO3- not neutralising acid
Presentation
- Steatorrhoea
- Malnutrition
- Pancreatic secretions (viscous)
- Premature enzyme activation --> organ destruction
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Pancreatitis
- Class IV or V mutations, generally
- Impaired HCO3- secretion :arrow_right: lower pH :arrow_right: tissue damage :arrow_right: zymogen activation :arrow_right: pancreatitis
- Non CF patients with pancreatitis tend to have CFTR mutations anyway
- CFTR genotype severity associated strongly w/ PIP score
- Still some modifiers to severity of disease (environmental, genetic)
- Presents in both CF and non-CF similarly?
- Acute, Acute Recurrent, Chronic
- Acute Treatment: Episode relief
- Chronic Treatment: Reducing environmental factors, medication, surgery
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GIT
- Meconium Ileus
- Rectal prolapse
- Intussuseption
- Gastro reflux
- (CFTR in luminal membrane of epithelial intestinal cells)
Reproductive
- Male infertility (absent vas def)
- Reduced female fertility
Salty Sweat
- Hypo Na and Cl and K
- Headache, cramps, nausea, etc
Liver (CFLD)
- CFTR lines hepatic bile ducts. Bile viscosity increases :arrow_right: ducts are plugged :arrow_right: cirrhosis (initially patchy, then accumulates)
- In 25% of patients
- Mostly evident by 20 years. If not present by then, chances are v low
- Most common presentation: Fatty Liver, Hepatomegaly
- Rare but important presentation: Portal Hypertension
- Diagnose with physical examination, serum enzyme assessment, ultrasound, biopsy
- Increases morbidity by impairing nutrition, growth, pulmonary functiont
- Treat with Ursodeoxycholic Acid, maybe a liver transplant if too severe
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Renal
- CFTR in renal tubules
- No known effect?
- Fat and protein malabsorption
- Failure to thrive
- Lung disease
- Abnormal sweat electrolyte composition
Pathology
CFTR In Disease
- expressed on several cell types
- ASL dehydrates (theory, widely accepted)
- ENaC isn't inhibited enough :arrow_right: Sodium + water absorption into lung
- Cl- not secreted :arrow_right: Sodium + water absorption, into lung
- Eventually, ASL decreases
- :arrow_right: Cilia can't beat, mucus builds up :arrow_right: More susceptibility to infection
- Inhibited bicarbonate transport function :arrow_right: pH of ASL decreases
Immune
Inflammation
- Chronic airway inflamm
- Neutrophilic inflamm mainly
- Directly affect airway immunity
- Can be augmented by ceramide
- NFkB
- Abnormal lipid metabolism
- ROS
- ER Stress
- Interferons defective
- Innate TLR mechanisms in airways are impaired
- Neutrophils can release harmful proteases
- Macrophages
- Dendritic Cells
- T cells can be skewed towards Th2/Th17
- Tregs can be inhibited
- NK cells upregulated
EPIDEMIOLOGY
Worldwide
70,000
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1/15,000-20,000 African Americans
1/350,000 Japnese/Africans/Asians
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ΔF508
Accounts for 70-75% of Northen EU variant #
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Environmental Modifiers
- Female
- SES (lower)
- Tobacco smoke (inc passive)
- Exposure to infection
- Self-management