Murillo - Cystic Fibrosis Flashcards
(35 cards)
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
17
Q
How does age affect bronchodilator responsiveness in CF?
A
Decreases it
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
21
Q
What are the main drivers of bronchiectasis devo in CF patients?
A
- Mucus plugs/secretions and persistent inflammation are the main drivers to develop bronchiectasis
22
Q
What are some of the important signs of CF exacerbations?
A
- Frequency of the cough
- Sputum volume and color
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
What is the most clinically significant infection for pts with CF?
Pseudomonas
Can predict infection by age group (Staph A. also common in younger CF patients)
26
How does CF affect the mucous in the GI tract?
Can damage bile ducts in liver and create plugs in pancreas
27
How is the degree of lung function related to CF survival?
- **Degree of pulm impairment is predictive of survival**
- _FEV1 \< 30% predicted is associated with a 2-year survival less than 50%_ -\> these patients will be getting evaluated for possible lung transplant
1. Degree of lung function loss is approximate 2% per year, so a person who is 40 has a very high probability to be in the transplant list.
- _Females tend to have a greater deterioration of lung function with age_ than males
1. If women get pregnant, they have a better outcome during pregnancy; we don’t know why
28
How is the pancreas affected by CF?
- Dysfunction of exocrine pancreas leads to fat malabsorption and malnutrition, so pts have frequent _greasy, bulky stools_, or difficulty w/bowel movements
- **Malabsorption of fat-soluble vitamins** (A, D, E, and K) can lead to vitamin deficiency and _coagulopathy_ -\> _night blindness_
1. Usually on very high dose of vitamins (more than you can get at Walgreens)
- **Glucose intolerance** occurs in 50 to 70% -\> test performed in almost all patients
1. Diabetes occurs in 15% (insulin tx only; no oral med treatment for diabetes in CF)
- _No pancreatic enzymes_
29
How is the liver affected in CF?
- _Biliary cirrhosis_ due to thick secretions in biliary ducts
- Manifested as **abnormal LFT's**
- Diffuse liver involvement _can lead to portal HTN_
1. Once portal HTN is set, liver transplant is the only therapeutic option
30
How does CF affect the GI tract?
- _Meconium ileus_ present in about 40% of infants w/CF
1. **Pathognomic** for this disorder
- Older adults have similar disorder called distal intestinal obstruction syndrome (DIOS) due to inspissated mucus in GI tract that may require surgery
1. **DIOS**: 4-5 days of constipation, abdominal pain, fever (haven’t taken their enzymes probs cause -\> may need surgery or colonoscopy to relieve the obstruction; colon dilated; full of fluid, gas)
31
Why should pregnancy be planned in CF patients?
- Because you have to think about medications and vitamin levels
- Want patient in most perfect condition they can be in
32
How does CF affect fertility?
- _95% of M sterile_ due to congenital bilateral absence of the vas diferens
1. Still produce sperm, but are not communicated
- _Females not infertile, but may have difficulty conceiving_ due to thick cervical mucus and may not have effective follicular phase and pregnancy if they do not have good nutritional status
1. Pregnancy can be successful
2. Maternal function does not deteriorate after pregnancy
- **Chloride concentration of sweat above 60 is the definition of abnormal sweat chloride test**
33
What are the most common CFTR sequence variations?
34
How common is the delta F508 mutation?
- F508 is the most important one, and the one that we need to remember
- Know these numbers
35
CF Summary
- G551D fixing the CF problem by helping the gate to function -\> drops your sweat chloride almost 50 points ($294,000/yr.)
- Remember chromosome 7 because it is a flipped
- Diagnostic test is sweat, then genetic
- Tx: pulmozyme (breaks down DNA in mucous for expectoration) and tobi (inhibit infection) and postural
- Hard to take so many medications each day -\> compliance is the main issue for why people may have different lung function with the same genotype
