Understanding Cystic Fibrosis (Includes Pathophysiology & Diagnosis)

Summary

Cystic 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

00:00

🧬 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.

05:02

🌡 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.

10:03

🛡️ 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.

Keywords

💡Cystic Fibrosis

Cystic fibrosis is an inherited disorder affecting the exocrine glands and characterized by the production of abnormally thick mucus. It is the main theme of the video, as it discusses the genetic basis, symptoms, and treatment of this condition. The video mentions that it is caused by a defective CFTR gene, leading to life-shortening complications, primarily in Caucasian populations.

💡CFTR Gene

The CFTR gene is responsible for coding the protein that regulates the movement of chloride and bicarbonate across epithelial membranes. In the context of the video, a defective CFTR gene results in the characteristic symptoms of cystic fibrosis, such as thick mucus and impaired secretions. The most common mutation mentioned is the F508 deletion.

💡Autosomal Recessive

Autosomal recessive inheritance means that an individual must inherit two copies of the mutated gene, one from each parent, to express the disease. The video explains that cystic fibrosis is inherited in this pattern, which is why carriers with one faulty gene typically do not show symptoms.

💡Exocrine Glands

Exocrine glands are glands that secrete substances through a duct to an epithelial surface. In the video, it is mentioned that the CFTR protein is primarily expressed in these glands, and their malfunction due to the defective gene leads to the thick mucus associated with cystic fibrosis.

💡Chloride Channel

The CFTR protein forms a chloride channel that allows the movement of chloride and bicarbonate ions across cell membranes. The video explains that in cystic fibrosis, this channel's function is impaired, leading to the buildup of thick mucus and other symptoms.

💡Mucus

Mucus is a thick fluid secreted by the exocrine glands, which helps to protect and moisten the epithelial surfaces of the body. The video describes how in cystic fibrosis, the mucus becomes excessively thick and sticky, leading to obstructions and infections, particularly in the lungs.

💡Pancreatic Insufficiency

Pancreatic insufficiency occurs when the pancreas does not produce enough digestive enzymes due to obstruction of the pancreatic ducts. The video explains that this is a common complication of cystic fibrosis, leading to malabsorption of nutrients and the need for enzyme replacement therapy.

💡Bronchiectasis

Bronchiectasis is a condition where the airways in the lungs become widened and damaged due to chronic inflammation and infection. The video describes it as a consequence of cystic fibrosis, where the thick mucus leads to recurrent infections and eventually lung damage.

💡CFTR Modulators

CFTR modulators are a class of medications that target the defective CFTR protein in cystic fibrosis. The video mentions two main types: potentiators, which enhance the channel function, and correctors, which address the misfolding of the protein, as part of the treatment strategy for the disease.

💡Newborn Screening

Newborn screening is a process used to identify certain genetic or metabolic disorders early in life. The video explains that for cystic fibrosis, this typically involves testing for immunoreactive trypsinogen levels and, if indicated, sweat testing and genetic analysis to confirm the diagnosis.

💡Pulmonary Function Tests

Pulmonary function tests are used to measure lung capacity and the efficiency of the respiratory system. The video mentions that these tests, including spirometry, are routinely performed in individuals with cystic fibrosis to monitor lung health and detect changes over time.

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