Cystic Fibrosis Flashcards
What kind of genetic condition is cystic fibrosis?
Autosomal recessive. Therefore, both parents have to be carriers in order to pass it to their child. There is a 1 in 4 chance of a child having cystic fibrosis if both parents are carriers.
What causes cystic fibrosis?
A gene mutation leading to the dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein
What does CFTR stand for?
Cystic Fibrosis Transmembrane Regulator
What is the difference between phenotype presentation and genotype presentation?
Phenotype presentation = the physical manifestation and presentation of the disease. The genotype presentation = the genetic mutations involved that result in cystic fibrosis
What is the most common genetic mutation causing cystic fibrosis?
Delta F508. Causes classic pancreatic deficiency and lung complications. Clinical heterogeneity, presents very different depending on the genetic presentation.
What is the prevalence of cystic fibrosis in the UK?
~1100 people living with CF. 2 people die from CF each week and 5 babies are born with CF each week.
If both parents are carriers for the cystic fibrosis gene, what is the likelihood of the child having cystic fibrosis?
1 in 4
What is the pathogenesis for cystic fibrosis?
Mutations in the gene that encodes for the cystic fibrosis transmembrane regulator (CFTR) protein. The gene is located on the long arm of chromosome 7.
What is the Cystic Fibrosis Transmembrane Conductance Regulator?
A protein ion channel located on the apical (luminal) surface of epithelial cell membranes.
Where are CFTRs located in the body?
The apical surface of epithelial cell membranes. These are present in: the respiratory tract; pancreatic ducts; billiard tract; reproductive tract; sweat duct and kidney.
Name the 6 common systems/organs affected by cystic fibrosis?
- respiratory tract (lungs)
- pancreatic ducts (Pancreas)
- Billiard tract (gall bladder)
- Reproductive tract (ves deferens, leading to infertility in men and the cervix)
- Sweat ducts (skin)
- Kidney
Describe the normal function of the CFTR
The CFTR is an ion channel which normally maintains the balance of salt and water in epithelial cells.
When CFTR does not fully function, chloride (a component of salt) becomes trapped in cells.
CFTR ion channel moves chloride ions out of the cell via electrical charge from inside the cell to the outside (i.e. an electron pump).
Outside the cell they attract a layer of water which allows cilia to sweep back and forth to move music up and out of the epithelial cells.
What happens when in CFTR dysfunction?
When CFTR does not function fully, chloride becomes trapped inside the epithelial cells.
Therefore, water is no longer attracted to the space outside the cell. When there is less water outside the cells, the mucus in the airways/lumen of affected organ becomes dehydrated and thickens causing it to flatten the cilia.
This prevents the cilia from functioning effectively or at all, so they can’t sweep mucus away as sticky mucus weighs them down. The lack of water attracted to the outside of the epithelial cells makes the mucus very thick and sticky. (affects viscosity)
What affects the severity of cystic fibrosis impact?
The genotype determines the severity of CFTR dysfunction. It can either:
1. It doesn’t work well
2. It isn’t produced in sufficient quantities
3. It isn’t produced at all
What is the relationship between the amount of functional CFTR produced and phenotypic expression?
The percentage of normal CFTR function affects the severity of symptoms and disease progression. <1% of CFTR function; <4.5% CFTR function; <5% CFTR function; <10% CFTR function; 10 - 49% CFTR function and 50-100% CFTR function.
When CFTR function is 50-100% what manifestations/symptoms would you expect?
No known abnormalities. Would be asymptomatic heterozygotes (carriers)
When CFTR function is 10 - 49 % what manifestations/symptoms would you expect?
No known abnormality
When CFTR function is <10 % what manifestations/symptoms would you expect?
congenital bilateral absence of the vas deferent (male infertility - can’t produce sperm)
When CFTR function is <5 % what manifestations/symptoms would you expect?
Clinically demonstrable sweat abnormality
When CFTR function is <4.5 % what manifestations/symptoms would you expect?
Progressive pulmonary disease
When CFTR function is <1% what manifestations/symptoms would you expect?
Classic disease with pancreatic insufficiency and recurrent respiratory infection
What are the 5 possible known genetic mutations responsible for CF?
DeltaF508
R117H
G551D
G524X
621+1G->T
What is the most common genetic mutation responsible for CF?
Delta F508
What is the median life expectancy for someone with CF?
~38 but it is increasing due to improved treatments and screening, therefore life expectancy is getting better.
What is the main demographic affected by CF?
Caucasian. More men than women with CF (unknown reason). Young due to early mortality and short life expectancy.
When CF is diagnosed in newborns, what are the primary presentations?
- Neonatal obstruction - meconium ileus.
- Prolonged conjugated jaundice.
- Newborn screening.
- Screening due to familial history.
When CF is diagnosed in infancy and older children, what are the primary presentations?
- Faltering growth.
- Abnormal stools
- Recurrent respiratory infections/symptoms
- Rectal prolapse
- Nasal polyps
When CF is diagnosed in adults, what are the primary presentations?
- Infertility
- Bronchiectasis (from recurrent lung disease)
Most cases present in the first years of life, what are the main symptoms?
Chest infections and faltering growth.
How are newborns screened for potential CF?
Guthrie test. Looks for errors in metabolism and for other conditions. Not specific for CF.
If a newborn screens positive for CF via Guthrie test, what is the next step?
Sweat testing.
What clinical presentation is screened for in a Guthrie test?
Serum levels of immunoreactive trypsinogen.
Newborn infants with CF have raised levels of immunoreactive trypsinogen (IRT) in serum. Raised IRT in the first week of life is sensitive and indicative of potential CF, but not diagnostic.
What does a sweat test screen for in CF?
High levels of chloride.
How is a sweat test performed?
An electrode is attached to the skin, and medicine is driven into the skin via electronic stimulation. Sweat is collected on filter paper or gauze and analysed for chloride ion concentration. High chloride ion concentration is highly likely due to CFTR mutation, but it not completely diagnostic.
What are the mmol/L thresholds for chloride ion level in sweat and what do they mean?
> 60 mmol/L = Cystic fibrosis diagnosis
30 - 59 mmol/L = Unclear diagnosis; further testing required (i.e. genetic)
<30 mmol/L = Cystic fibrosis unlikely.
What does genetic testing test for?
Mutated CFTR genes
When is genetic testing facilitated?
In newborn after Guthrie screening and sweat test indicating CF.
In child or adult after sweat test indicating CF.
Prenatally via amniotic fluid or from the placenta.
How is prenatal CF screening done? And what are the advantages of in-utero screening?
By taking a sample of amniotic fluid or from the placenta. Cells from these samples are checked for gene mutations. Infants with a positive prenatal testing for CF will be further tested after birth to confirm diagnosis.
Advantages = no surprises. Care and testing can be initiated straight away after birth to confirm diagnosis.
Pancreatic insufficiency is common in CF, how would you test for it?
Feacal elastase test: Measures the elastase-3B enzyme in feral matter known as pancreatic elastase 1 (E1).
What are the reference ranges for fecal elastase testing and their implications on pancreatic insufficiency?
<100 µg E1/g feces = severe exocrine pancreatic insufficiency
100 - 200 µg E1/g feces = moderate to mild exocrine pancreatic insufficiency
> 200 µg E1/g feces = Normal exocrine function
How is late diagnosis of CF tested? And what are the implications of late diagnosis CF?
Late presentation = milder genotype.
Often pancreatic sufficient.
Non-classic CF.
May be only single organ involvement.
Sweat test = normal, equivocal or abnormal.
1 disease causing mutation on each CFTR gene or direct quantification of CFTR dysfunction by nasal potential difference.
How effective is newborn and infant screening?
Very. 71% of those born in 2021 were identified through newborn screening. The median age for diagnosis aged under 16 is 22 days. 70% are diagnosed by 12 months, and 90% by 12 yrs.
Only 14.6% of adults with CF were diagnosed after 16th birthday.
What are the 16 most commonly identified features/symptoms in cystic fibrosis? (Health conditions)
- Chronic sinusitis
- Nasal polyps
- Abnormal sweat secretions (high sodium and chloride)
- Pancreatic insufficiency
- Diabetes
- Finger clubbing
- Osteoporosis
- Male infertility
- Arthropathy/arthritis
- Steatorrhea
- Distal intestinal obstruction syndrome
- Liver disease
- Portal hypertension
- Gall stones
- Bronchiectasis
- Repeated lower respiratory tract infections
What condition accounts for 90% mortality in CF?
respiratory failure
What 8 clinical presentations are common in CF?
- Faltering growth
- Malabsorption of fat
- Pancreatic insufficiency
- Poor growth
- Wasting
- Steatorrhea
- Ravenous - always hungry
- Finger clubbing
Describe the pathogenesis of CF lung disease
Related directly to CFTR abnormality. Impaired salt and water secretion which reduces airway surface liquid, abnoramlly thick mucus causing impaired mucocilliary clearance and inactivation of defensins.
Thick mucus accumalation = increased infection recurrence and impaired immune response and chronic inflammation
Tissue damage occurs as a result (leading to scarring) leading to progressive lung disease and respiratory faiulre.
There is a depletion in the ability to oxygenate the blood
What is bronchopulmonary sepsis?
chronic sepsis influences the rate of decline of lung function. There is also inflammatory dysregulation, pro-inflammatory markers have bigger response which increases tissue damage and scarring.
What is bronchiectasis?
Permanent changes of the bronchi in the lungs.
Permanent dilation of the bronchi and is associated with clinical symptom of a cough, sputum production and recurrent respiratory infections.
CF leads to progressive bronchiectasis, bacterial infection and premature mortality.
Bronchiectasis is diagnosed when = an increase in diameter of the bronchus and failure of the bronchus to taper normally as it goes out towards the periphery of the lung.
What are treatment strategies for pulmonary infections in CF?
- sputum testing to identify most appropriate antibiotic and reduce chance of antibiotic resistance
- isolate and aggressive treatment
- nebulised antibiotics and/or IV antibiotics
- avoid cross infection by patient segregation
What is role of physio and exercise in CF chest infections management?
- chest physiotherapy
- self managed or with help of family/friends
- maintenance of lean body mass = super important and exercise can aid airway clearance.
What are the nebulised prescription drugs used in CF chest infections?
Mucolytics - facilitate expectoration by reducing sputum viscosity
(RhDNase) = Uses a recombinant deoxyribonuclease (enzyme) that reduces sputum viscosity in lungs and promotes secretion clearance.
saline nebulisers are also mucolytics.
Long term maintenance treatment aims
- improve FEV1 (forced expiratory volume)
- reduce exacerbation frequency (helps avoidp ermanent lung scarring)
- suppress bacterial burden (hygiene, avoid cross contamination, avoiding crowded spaces)
- improve quality of life
What GI diseases are associated with CF?
Gastrointestinal:
1. malabsorption (pancreatic insufficiency)
- inadequate pancreatic enzymes diagnosed by fecal elastase treated with PERT (pancreatic enzyme replacement therapy)
- deficiency of fat soluble vitamins ADEK
- steatorrhea (fat malabsorption)
2. Distal intestinal obstruction (DIOS)
- constipation is main feature; management = GI review, diet and exercise. laxatives. increased fibre and fluid.
3. Gastroesophagul reflux disease (GERD)
- Causes = COPD; GI dysmotility; physio.
- clinical features = apnoea; cough, nausea, vomiting, epigastric pain, wheeze, dyspepsia, faltering growth, halitosis. Can lead to respiratory tract infections from aspiration of gastric acid
4. intusseption
5. volvulus
6. fibrosing colonopathy
Liver, billiary and pancreatic:
1. CF related liver disease
2. gallstones
3. pancreatitis
- more frequent in pancreatic insufficient patients; severe or recurrent. Normal pancreatitis presentation: vomiting, epigastric pain; distended and tender abdomen.
What liver disease are associated with CF? (CFLD) and what is the treatment
Cystic fibrosis Liver Disease - most important non-pulmonary cause of death
caused by impaired liver function and an increase in liver enzymes
- fatty infiltration of the liver
- cirrhosis
- gallstones
- pancreatitis
- billiary obstruction
- progressive periportal fibrosis
- focal billiary fibrosis/cirrhosis
- portal hypertension
Treatment = ursodeoxycholic acid (destoys cholesterol to prevent build up)
Tested for by liver function tests
What are CFLD complications?
- portal hypertension and oesophagul varices; variceal bleeding; regular screening and close follow up with hepatologist
- impact on nutritional status = impaired appetite and malnutrition implications
- liver failure
- liver transplantation
Why is CFRD a thing (cystic fibrosis related diabetes)
a combination of destruction of pancreatic duct, increased inflammation causing reduced insulin sensitivity and steroids that also increase insulin resistance
When thick secretions block pancreatic ducts - a fatty infiltration and fibrosis of islet cells leads to decreased insulin secretionleading to hyperglycaemia.
Insulin reistance can be transient and occur only during infection, or be permanent.
CFRD is associated with an accelerated decrease in lung function and weight (FEV1)
Impact of CRFD on morbidity?
- poorer pulmonary function
- more severe lung disease
- more exacerbations - nutritional status
- lower weight
- lower BMI - Chronic diabetic complications
- retinopathy
- nephropathy
- neuropathy
Treatment is similar to typical diabetes.
What are the 3 main aims of CF treatment?
- Maintaining lung functrion as near to normal as possible by controlling respiratory infection and clearing airways of mucus
- administering nutritional therapy to maintain adequate growth and lean muscle mass
- enzyme supplements
multivitamins and mineral supplements
- BMI correlates directly with lung function: lower BMI = less lung function. - Manging complications
What is medication Kalydeco used for in CF?
action: increases ion channel function of activated cell surface CFTR
a “potentiator”
Greatest effect on cells with G551D-CFTR mutation
Benefits of Ivacaftor:
improves FEV1
- sweat chloride levels drop by almost 50%
What is Orkambi medication used for in CF?
Available for all CF patients. It works on deltaF509 homozygous CF.
What are the reasons for improved survival of CF patients?
- aggressive approach to therapy : physio, nutritional, antibiotic and immunosuppressant
- Improved tailored antibiotic administration
- development of medications that negate the CFTR mutation causing CF and therefore reducing disease burden on people so young.
