Murillo - Cystic Fibrosis Flashcards
1
Q
What is the epi of CF?
A
- Rare, but deadly disease:
1. Approx. 30,000 in US
2. Over 10 million Americans unknown carriers
3. Around 2,500 children with CF are born each year
4. Caucasian disease (see attached table): most common genotype D508, but # of Hispanic pts on the rise, so less pts having a Delta508 genotype
2
Q
What is the inheritance of CF?
A
- Autosomal recessive:
1. If father and mother carry the gene:
a. 25% chances of a health child
b. 50% of a carrier
c. 25% probabilities of an affected child with CF
3
Q
What is CF?
A
- Genetic mutation in both cystic fibrosis transmembrane conductance regulator (CFTR) alleles
1. CFTR mutations = dysfunctional or absent CFTR protein at apical mem of cells in airways and other areas of the body - Characterized by progressive lung disease, pancreatic dysfunction, and elevated sweat electrolytes, but a wide variability in clinical expression occurs
- Usually found in pops of Caucasian descent, esp. in North America, Europe, and Australasia; also in African, Latin American, and Middle Eastern populations
1. Incidence believed to be underestimated in Africa, but very few cases in Asia
4
Q
What is the CFTR gene? What is the most common mutation?
A
- Located on the long arm of chromosome 7 (KNOW THIS)
- 1522 mutations in CFTR listed on database
- Most common mutation is Δ F508 (70% CF alleles in caucasians)
1. CFTR is located at the cell surface and acts as a regulated chloride channel
2. Delta f508 causes loss of the amino acid phenylalanine located at position 508 in the protein
5
Q
Why is the CFTR (CF) protein so important?
A
- It is the channel primarily responsible for moving chloride into the airway (think of it as a gate that opens/closes)
- It also down-regulates the Na+ channel (ENAC) that reabsorbs sodium
- Volume of airway surface liquid (ASL) critical -> forms periciliary liquid layer and dilutes mucus, facilitating entrapment and clearance of bacteria
1. Optimal ASL volume regulated by Na+ absorption and Cl- secretion - When sodium and chloride move into the airway, fluid volume increases (water moves passivel) -> ion channels maintain optimal height, or volume, of airway surface liquid and mucus (to maintain integrity of mucociliary clearance)
6
Q
What happens when CFTR does not work?
A
- Airway surface liquid layer reduced, and mucus dehydrated, resulting in impaired mucociliary clearance
1. Airways become obstructed w/mucus and infection and inflammation soon follow -> lung destruction - This happens bc CFTR not secreting Cl- and Na+ channel is absorbing too much sodium -> w/o salt secretion, water does not move into the airway
- CFTR inhibits sodium channels -> if mutated, you will see more sodium going through the membrane, leading to thick secretions
- Cystic process: lungs, airways enlarged, full of mucous, infections, bacteria, and then fibrosis
7
Q
What are the normal steps from CF gene to CFTR protein?
A
- Under normal circumstances, DNA is read and transcribed to mRNA, and introns are spliced out
- mRNA strand exits cell nucleus and travels to ribosome, where it is translated to immature CFTR protein product
- In endoplasmic reticulum, o/proteins called chaperones help fold the protein, which is then transferred to the Golgi apparatus
- From the Golgi, transport vesicles are created, and the CFTR protein is transported to the cell surface membrane; this process is also known as trafficking of CFTR
8
Q
How does a CFTR mutation ultimately affect the lung (cycle)?
A
- Mutation will result in dysfunctional CFTR protein that affects the ion and fluid transport
- Impaired mucocilliary clearence will follow (hallmark manifestation of CF), leading to mucus plugging and viscous secretions in exocrine glands and lungs
- These changes will start a cycle of destruction w/bac colonization, recurrent infections & persistent peribronchial inflammation, scar tissue, decrease in lung function and eventually end-stage lung disease
9
Q
What seemingly unassociated conditions might CF infants present with?
A
- Ileus and failure to thrive
- Note: tricky CF presentation in adults
10
Q
What are the CFTR mutation possibilities? Which is hardest to treat?
A
- Class I is the hardest to treat
1. I and II have little to no functional CFTR
2. III, IV, and V have CFTR, but it has reduced functionality - Class III is the G551D mutation, which is treatable with Ivacaftor (improves the transport of Cl- through CFTR)
11
Q
How are sweat chloride levels affected in CFTR?
A
- Sweat Cl- level inversely related to CFTR protein func
-
Higher the level of Cl-, lower the % of func CFTR, and more severe the clinical manifestations of disease
1. CF pts w/partial CFTR func and pancreatic sufficiency tend to have lower sweat Cl- levels and better lung func than pts with pancreatic insufficiency (PI)
2. Congenital bilateral absence of the vas deferens have a mild mutation w/o lung disease - Most of the studies evaluating an experimental drug will use sweat test as marker of activity
12
Q
How are classic and non-classic CF different?
A
- Clinical signs and symptoms based on the degree of CFTR function
- Meconium ileus: in meconium ileus, low or distal intestinal obstruction results from the impaction of thick, tenacious meconium in the distal small bowel -> probably most common presentation in kids
- Obstructive azoospermia: no sperm in a man’s semen as a result of a delivery problem
- Adult presentation (33-35 years old) -> non-classic presentation (these adults present later due to the milder symptoms described on the right)
13
Q
How does CFTR present in adults?
A
- Mild mutation, so typical features of CF may not be present
- Chronic sinusitis/nasal polyps: common presentation in pts who reach 18 y/o
- Hemoptysis: equivalent to CF exacerbation, and warrants tx
- Bronchiectasis: upper lobes, or diffuse
- Non-tuberculous mycobacteria: structural disease a good
- Pancreatitis (acute or chronic)
- Portal hypertension: not very common, and assoc w/cirrhosis
- Infertility in males: 90% of cases, but can still be fertile
- Look for red flag signs: idiopathic bronchiectasis plus one of the following -> male infertility, nasal polyposis, ideopathic pancreatitis, send them for a sweat chloride test (the level may be borderline)
14
Q
What do you see in chronic sino-pulmonary disease?
A
- Chronic infection with CF pathogens
-
Endobronchial disease:
1. Cough/sputum production: may be dry, clear, but always chronic
2. Air obstruction—wheezing; evidence of obstruction on PFTs
3. Chest x-ray anomalies
4. Digital clubbing: takes time (may have in 20 years if you are diagnosed as a child) -> not as specific for CF because you can get this with may pulmonary diseases -
Sinus disease:
1. Nasal Polyps
2. CT or x-ray findings of sinus disease
15
Q
What is this?
A
- Clubbing: bulbous swelling at end of fingers
- Normal angle between nail and nail bed lost, aka, Schamroth sign
- Can be associated with pulmonary disease, cardiac disease, ulcerative colitis, and malignancies (lung cancer)
16
Q
What do you see?
A
- Pansinusitis: universal finding in CF
- Nasal polyps occur in 30%
- Frequent complications after lung transplant
- Sinus disease is a major problem and frequently patients requiere several surgeries -> causes fever and chronic cough
18
Q
Will a CXR reveal lung damage in CF patients?
A
Not always… See attached photos from a 7 y/o
19
Q
What test may detect lung damage before lung function decline in CF patients?
A
-
Ct scan: attached image shows bronchiectasis, and evidence of mucus plugging in the upper lobes (red flag)
1. Non-TB mycobacteria and ABPA would also INC your suspicion of CF - FVC, FEV-1, and FEV-1/FVC values in this patient were normal at this time
20
Q
What do you see here?
A
- Lung of a patient who died from CF
23
Q
What do you see here?
A
- Typical CXR of patient at home
1. You can see alveolar opacities, bronchiectasis and fibrotic changes - Pulmonary fibrosis (end-stage lung disease)
24
Q
What do you see?
A
Airway dilations
25
Q
What is the most clinically significant infection for pts with CF?
A
Pseudomonas
Can predict infection by age group (Staph A. also common in younger CF patients)
33
Q
What are the most common CFTR sequence variations?
A
34
Q
How common is the delta F508 mutation?
A
- F508 is the most important one, and the one that we need to remember
- Know these numbers
