Understanding Cystic Fibrosis (Includes Pathophysiology & Diagnosis)
Summary
TLDRCystic fibrosis is an inherited disorder affecting the body's secretions due to a defective CFTR gene, causing life-shortening conditions with a median survival age of 33.9 years in the US as of 2021. The most common mutation, F508 deletion, leads to thick mucus and recurrent infections, particularly in the lungs and pancreas. Diagnosis involves newborn screening, sweat tests, and genetic analysis. Treatment focuses on symptom alleviation, with therapies including CFTR modulators, antibiotics, airway clearance techniques, and nutritional support. Lung and liver transplants are options for severe cases.
Takeaways
- 🧬 Cystic fibrosis is an autosomal recessive disorder caused by a defective CFTR gene, which affects the body's ability to produce normal secretions.
- 🧬 The CFTR gene is located on chromosome 7 and encodes a protein that regulates the movement of chloride and bicarbonate across epithelial membranes.
- 🌐 It is estimated that about 1 in 25 Caucasian individuals are carriers of the faulty gene, which is necessary for a child to be affected.
- 📉 The median survival age for cystic fibrosis patients in the US was 33.9 years in 2021, with projections for those born between 2018 and 2022 to reach 56 years.
- 🏥 The most commonly affected organs by cystic fibrosis include the lungs, pancreas, sinuses, hepatobiliary system, intestines, and sweat glands.
- 💧 The primary defect in CFTR function results in decreased chloride secretion and increased sodium absorption, leading to thicker mucus and more viscous secretions.
- 🫁 In the lungs, this leads to mucus plugging, recurrent infections, and eventually bronchiectasis, which causes a progressive decline in lung function.
- 🍽️ Pancreatic insufficiency due to CFTR dysfunction can cause malabsorption of nutrients, leading to poor growth and foul-smelling stools.
- 👶 Newborn screening is the primary method of diagnosis, looking for the level of immunoreactive trypsinogen and followed by sweat testing and CFTR gene analysis.
- 💊 Treatment aims to alleviate symptoms, prevent complications, and improve quality of life, including the use of CFTR modulators, antibiotics, and airway clearance techniques.
- 🍎 Nutrition support is crucial for patients, often requiring a 50% excess in calories and multivitamins, as well as enzyme replacement therapy for those with pancreatic insufficiency.
Q & A
What is cystic fibrosis?
-Cystic fibrosis is an inherited disorder characterized by a defective CFTR gene, which impairs the body's ability to generate normal secretions like mucus and sweat.
How is cystic fibrosis inherited?
-Cystic fibrosis is inherited in an autosomal recessive pattern, meaning both parents need to carry a faulty gene for the child to be affected.
What is the estimated carrier rate of the faulty CFTR gene among Caucasians?
-It is estimated that around 1 in 25 Caucasian people are carriers of the faulty CFTR gene.
What is the median survival age for individuals with cystic fibrosis in the US as of 2021?
-The median survival age in the US in 2021 was 33.9 years.
What does the CFTR gene code for and what is its function?
-The CFTR gene codes for the protein CFTR, which stands for Cystic Fibrosis Transmembrane Conductance Regulator. It forms a channel that allows the movement of chloride and bicarbonate across epithelial membranes, and by extension, sodium and water.
Which organ systems are most commonly affected by cystic fibrosis?
-The most commonly affected organs include the lungs, pancreas, sinuses, hepatobiliary system, intestines, and sweat glands.
How does the dysfunction of the CFTR protein affect the body's secretions?
-The dysfunction leads to decreased secretion of chloride out of the cells and increased resorption of sodium, resulting in thicker mucus and more viscous secretions that can obstruct exocrine glands.
What is the impact of CFTR dysfunction on the lungs and why is it problematic?
-CFTR dysfunction results in stickier mucus that is difficult to clear, leading to mucus plugging and recurrent infections, which can cause inflammation and lung injury over time.
How does cystic fibrosis affect the pancreas and what are the consequences?
-Obstructed ducts in the pancreas can lead to early activation and autodestruction of the enzymes, causing pancreatic insufficiency and eventually diabetes in some cases.
What is the role of newborn screening in diagnosing cystic fibrosis?
-Newborn screening is the primary method of diagnosis, initially looking for the level of immunoreactive trypsinogen in the blood, followed by sweat testing and CFTR gene analysis.
What are some treatment goals and approaches for cystic fibrosis?
-The goal is to alleviate symptoms, prevent complications, and improve quality of life. Treatments include airway clearance measures, CFTR modulators, antibiotics, bronchodilators, mucolytics, and nutrition support.
Outlines
🧬 Genetics and Impact of Cystic Fibrosis
Cystic fibrosis is an autosomal recessive genetic disorder caused by a defective CFTR gene, which is responsible for the production of a protein that regulates the movement of chloride and bicarbonate across epithelial membranes. This defect leads to the production of abnormal secretions, affecting the lungs, pancreas, and other organs. The most common mutation is the F508 deletion, which results in misfolding of the CFTR protein. Symptoms include life-shortening respiratory issues, with a median survival age in the US increasing due to advancements in treatment. The condition also impacts the pancreas, causing malabsorption and nutritional deficiencies, and can lead to infertility in males due to obstructed vas deferens development.
🌡 Clinical Presentation and Diagnosis of Cystic Fibrosis
Cystic fibrosis presents with a range of symptoms, often beginning in early childhood, such as failure to thrive, respiratory infections, and disturbances in sleep due to coughing. Newborn screening tests for immunoreactive trypsinogen levels, followed by sweat testing and CFTR gene analysis to confirm the diagnosis. Sweat tests measure chloride concentration, with abnormal levels indicating the disease. Pancreatic function is evaluated, and imaging techniques like CT scans are used to monitor lung health. Pulmonary function tests are conducted regularly to track changes in lung capacity and function over time.
🛡️ Treatment and Management of Cystic Fibrosis
While there is no cure for cystic fibrosis, treatment aims to alleviate symptoms and prevent complications, improving quality of life. This includes vaccines, airway clearance techniques, and aerobic exercise to enhance sputum clearance. CFTR modulators target the defective protein, with potentiators and correctors being key treatments. Antibiotics are used for infections, and bronchodilators and mucolytics improve lung function. Nutritional support is vital, with enzyme replacement therapy for those with pancreatic insufficiency. Surgical interventions and organ transplants are considered for severe cases, with lung transplantation showing promising survival rates.
Mindmap
Keywords
💡Cystic Fibrosis
💡CFTR Gene
💡Autosomal Recessive
💡Exocrine Glands
💡Chloride Channel
💡Mucus
💡Pancreatic Insufficiency
💡Bronchiectasis
💡CFTR Modulators
💡Newborn Screening
💡Pulmonary Function Tests
Highlights
Cystic fibrosis is an inherited disorder linked to a defective CFTR gene.
It is inherited in an autosomal recessive pattern, affecting Caucasians at a carrier rate of 1 in 25.
Median survival age in the US has increased from 33.9 years in 2021 to a projected 56 years for those born between 2018 and 2022.
The CFTR gene, located on chromosome 7, encodes a protein that regulates chloride and bicarbonate movement across epithelial membranes.
Over 2,000 defective CFTR gene variants have been identified, with 85% of cases due to the F508 deletion variant.
Affected organs include the lungs, pancreas, sinuses, hepatobilary system, intestines, and sweat glands.
CFTR dysfunction leads to thicker mucus and increased risk of infections, particularly with Staphylococcus aureus and Pseudomonas aeruginosa.
In the lungs, CFTR dysfunction results in mucus plugging, inflammation, and eventual bronchiectasis.
Cystic fibrosis can cause pancreatic insufficiency, leading to malabsorption of nutrients and the development of diabetes.
Intestinal complications include meconium ileus in neonates and intestinal obstruction in adults due to viscous secretions.
Male fertility is greatly impaired in cystic fibrosis, with 98% of patients being infertile due to vas deferens abnormalities.
Female fertility may also be affected by viscous cervical secretions and nutritional deficits.
Symptoms often manifest in infancy or childhood, with respiratory issues, poor growth, and malnutrition being common.
Diagnosis typically involves newborn screening, sweat testing, and CFTR gene analysis.
There is no cure for cystic fibrosis, but treatments aim to alleviate symptoms, prevent complications, and improve quality of life.
CFTR modulators are medications that target the defective protein, with two main classes: potentiators and correctors.
Nutrition support is crucial, often requiring a 50% excess in calories and multivitamins for those with pancreatic insufficiency.
Lung transplantation is considered for individuals with advanced lung disease, with median survival rates of approximately 9 years post-transplant.
Liver transplant is also an option for some patients with hepatic fibrosis or biliary cirrhosis.
Transcripts
[Music]
cystic fibrosis is an inherited disorder
characterized by a defective CFT Gene
resulting in impairment of the body's
ability to generate normal secretions
like mucus and sweat it's inherited in
an autosomal recessive pattern meaning
both parents need to carry a faulty Gene
for the child to be affected and its
estim ated that around 1 in 25 Caucasian
people are such carriers the condition
is life shortening with median survival
age in the US in 2021 being
33.9 years and projections for those
born between 2018 and 2022 to be 56
years the CFT Gene is found on
chromosome 7 and it codes for the
protein CFT which stands for Cystic
Fibrosis transmembrane conductance
regulator that forms a cyclic chloride
channel that normally allows movement of
chloride and bicarbonate across
epithelial membranes and also by
extension sodium and water this protein
is primarily expressed in the exocrine
glands those are the glands that release
secretions through a duct to an
epithelial surface and over 2,000
defective VAR variants to date have been
found in this Gene but around 85% of
cases are due to the variant f508
deletion that causes misfolding the most
commonly affected organs include the
lungs pancreas sinuses hepatobilary
system intestines and sweat glants
normally the cftr channel helps move
chloride and bicarbonate out of the cell
causing sodium to remain outside and and
overall to cause water to move out of
the cells forming normal secretions the
overall result of the variance in the
gene however is decreased secretion of
chloride out of the cells and
consequently increased resorption of
sodium into the cellular space which
therefore means more water tends to
remain in the cell this translates to
thicker mucus on epithelial surfaces and
more viscous secretions from exocrine
glands which generally predisposes them
to becoming obstructed leading to
pathology in sweat glands the role of
CFT is actually reversed the channel is
meant to bring chloride in from the
extra cellular space to the
intracellular space and so encourage
sodium and water to be reabsorbed it's
for this reason that in cystic fibrosis
chloride remains in the sweat and so so
does sodium
causing the sweat to be excessively
salty and excess sweating can also lead
to significant
dehydration in the lungs the CFT
dysfunction can mean stickier mucus that
is more difficult to clear for the cyia
leading to mucus plugging and a breeding
ground for recurrent infections
particularly staf cus orius early on in
life and ponus arenosa colonizing 60% of
adults later on there is then
inflammation with release of proteases
and cyto that perpetuate the lung injury
including release of interlukin 8 that
can stimulate further mucus secretion
altogether giving episodic exacerbations
and eventually dilation and destruction
of the Airways termed bronchiectasis
with progressively worsening lung
function the resulting hypoxemia can
lead to pulmonary hypertension and
eventually right-sided heart failure or
core
pulmonal in contrast to COPD empyema is
not prominent and although the
respiratory system may be normal at
Birth respiratory disease can begin even
in
infancy as we mentioned the pancreas can
be affected the obstructed ducts can
lead to early activation of the enzymes
and subsequent autodestruction of the
pancreas pancreatic function then
deteriorates eventually causing
insufficiency the endocrine function of
the pancreas is largely maintained at
least initially but diabetes malius is
present in 2% of affected children and
50% of adults involvement of the
intrabiliary ducts leads to biostasis
and eventually hepatic fibrosis in
nearly onethird of patients with around
3% progressing to have bilary ceros and
portal hypertension by the age of 12 the
intestines are also affected
particularly by having more viscous
secretions which can lead to meconium
IAS in neonates where there is an
intestinal obstruction in neonates due
to the increased viscosity of the
meconium and the viscous fluid May
predispose to intestinal obstruction in
adults in males particularly fertility
is greatly impaired with 98% of male
patients being infertile due to poor or
no development of the vast Defence which
adducts that Aid sperm transport from
the epidermis to the ejaculatory ducts
in females fertility can be impaired due
to the viscous cervical secretions and
may also be linked to nutrition deficits
that we'll touch on shortly with 15 to
30% of females estimated to be
affected symptoms typically begin in
infancy or in childhood manifesting
often as a failure to thrive respiratory
symptoms can include recurrent
respiratory tract infections with
coughing and wheezing being common
features as well as Disturbed sleep and
gagging often related to the cough
during exacerbations hemoptisis is more
common and as the disease progresses
shortness of breath or reduced exercise
tolerance become more prominent
pancreatic insufficiency leads to
malabsorption of nutrients particularly
fats resulting in poor growth despite a
good appetite and it can also cause foul
smelling stools Laden with lipids that
are difficult to flush called
Storia malnutrition and vitamin
deficiency particularly in vitamins a d
e and K which are the fat soluble
vitamins are common we mentioned
meconium IAS that can present with
vomiting abdominal distension and
failure to pass the m conium with
similar symptoms involving stool in
intestinal obstruction in adults other
systemic features include salty tasting
skin or formation of salt crystals on
the skin itself and there can also be
excess sweating in response to heat or
fever that can predispose to
dehydration a diagnosis is typically
made when there is clinical suspicion of
cystic fibrosis for example a positive
newborn screening an affected sibling or
all clinical
manifestations and evidence of
dysfunctional CFT genes newborn
screening is the way in which most cases
are diagnosed which initially looks for
the level of immunoreactive trp cinogen
in the blood taken from a heel prick
followed by sweat testing and CFT Gene
analysis a sweat test can be done as
early as 48 hours after birth and
involves inducing localized sweat
typically using pylo carpine and then
evaluating the volume of sweat produced
and the concentration of chloride in the
sweat levels below 30 mm per liter are
considered normal while those of 60 mm
or above are considered abnormal this
should then be confirmed with a repeat
test or genetic testing identifying two
disease causing cystic fibrosis variance
the values between 30 and 59 are
considered intermediate and then if
repeats do not suggest cystic fibrosis
and two disease-causing variants and not
found genetically then it may be a
diagnosis of cftr related metabolic
syndrome pancreatic function is
evaluated looking at pancreatic elastase
in stool which may involve serial
measurements to identify progression to
insufficiency Imaging can involve the
use of CT typically done routinely every
1 to 2 years but also at times of
exacerbations with findings ranging from
hyperinflation and bronchial wall
thickening to
bronchiectasis pulmonary function tests
involve spirometry done routinely four
times a year in those Beyond 5 years of
age there is typically a reduction in
forced vital capacity and forced
expiratory volume in 1 second as well as
the fv1 to fvc ratio
while there is no cure the goal is to
alleviate symptoms prevent complications
and improve the overall quality of life
from a respiratory point of view this
involves vaccines such as the annual
influenza and more recently covid-19
vaccines Airway clearance measures
involves movements to encourage
expulsion of the thicker secretions such
as chest
physiotherapy active cycle of breathing
and other methods like vest therapy may
also be an option to Aid this and
aerobic exercise is also encouraged this
helps increase the volume of sputum
cleared and helps with disp near CFT
modulators are medications that Target
the defective protein there are two main
classes called the potentiators such as
ivacaftor that potentiates the Ion
channel function and correctors that
correct the defective misfolding CFT
protein such as l umor teaor and
elexacaftor antibiotics are used both in
exacerbations and prophylactically for
example severe exacerbations or
pseudomonas colonizers will have
intravenous toyin with the addition of
anomy and lenalid ifmsa positive
prophylactic antibiotics include inhaled
toyin every other month along with
continuous oral
aiyin which can make maintain pulmonary
function and decrease the frequency of
pulmonary
exacerbations Bronco dilators can Aid in
reversing some Airway obstruction and
mucco litics like Dorise alpha help
improve lung function and reduce
exacerbations non-steroidal
anti-inflammatory drugs like ibuprofen
have been shown to slow deterioration in
lung function but is not used routinely
due to the associated GI risks like
peptic ulcer disease nutrition support
plays a large role which may involve a
50% excess in calories and multivitamins
in order to meet requirements for growth
in those with pancreatic insufficiency
enzyme replacement therapy is used
cystic fibrosis patients can experience
frequent partial obstructions that may
be relieved by the use of enemas and
prevented by laxatives especially stool
softeners surgery is an option in some
instances such as nasal polyps or
localized atelectasis or
bronchiectasis while lung
transplantation may be considered for
individuals with Advanced lung disease
which is now becoming more routine with
median survival rates of approximately 9
years post transplant liver transplant
is also an option in some
cases
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