Cystic fibrosis

10,000,000 carriers in the U.S.

One in every 2000 newborns affected.

The incidence of CF is approximately one and 3500 to one in 5000 live births with, substantial regional variation.

CF affects more than 35,000 children and adults in the US and 90,000 people worldwide.

CF effects individuals of all races and ethnicities, and is most common in white individuals.

The most lethal genetic disease affecting Caucasians.

A life-shortening autosomal recessive disease.

Median survival for a child born in the 1990’s with cystic fibrosis is 40 years.

4% of persons with CF, receive a diagnosis after age of 18, and half of those receive a diagnosis after age 40.

Autosomal recessive pattern of inheritance and the most common fatal autosomal recessive disorder in Caucasians.

Caused by a mutation in a large gene on chromosome 7 that encodes a protein cystic fibrosis transmembrane conduction regulator (CFTR).

CFTR is responsible for salt transport across different tissues in the body.

CTFR encodes for an ion channel, CFTR, that is involved in regulation of the water, electrolyte balance on the surfaces of many organ systems, including upper and lower airways, intestine, pancreas, biliary tree, cervix, vas deferens, and sweat glands.

CFTR codes for an ion channel that transports both CL and HCO3 across epithelial services in the respiratory tract, pancreas, G.I. system, and sweat glands among other organs.

The number of CSTO a variants is more than 2000.

Itresults from biallelic mutations in the CFTR gene.

is the most common CFTR mutation that reduces the quantity of CFTR on the cell surface.

Phe508del is a processing and stress trafficking mutation.

In the sweat, glands, normal CFTR activity results in chloride ion absorption from primarily isotonic perspiration.

CFTR dysfunction in cystic fibrosis, causes impaired absorption in the sweat gland, ducts  , and consequently, elevated sweat chloride concentrations.

In CF the protein made by the abnormal CFTR gene is absent or dysfunctional, resulting and reduced salt transport and decreased water movement, resulting in thick mucus which accumulates in various parts of the body.
Loss of function of the CFTR proteins alters hydration and pH concentration in exocrine ducts, leading to obstructed and dilated endocrine glands in multiple organs.
The absence or dysfunction of CFTR in airway epithelium leads to decrease chloride and bicarbonate secretion at the apical membrane, the inability of alternative chloride channels to compensate and persistent sodium absorption through loss of CFTR mediated, inhibition of the epithelial sodium channel, which causes absorption of airway surface fluid.
The consequence of this fluid imbalance in the lungsare thickened, secretions and reduced mucociliary transport, resulting in mucous retention in plugging of airways.
Mucous retention favors recurrent and persistent bacterial infections with increased mucus production and inflammation, leading to the development of structural damage, bronchiectasis.
Chronic endobronchial infections and inflammation lead to a decline in lung function with decreased FEV1 and FVC on spirometry.

Most patients with CF develop an obstructive pattern on spirometry.

Patients with advanced CF may develop pulmonary hypertension. 

Adults in the US have increased risk of comorbidities, including diabetes, liver disease, with cirrhosis, and osteoporosis.

Patients with CF who have at least one copy of CFTR variant with residual function often have later onset of lung disease.

Of the 563 infants diagnosed with newborn screening in the US in 2000 21,88.3% were asymptomatic at the time of diagnosis. 

Reduced CFTR function in sweat gland leads to increased salt losses and higher chloride concentrations in sweat: the mucinous obstruction of pancreatic acini and ducts, biliary a’ducts and glandular obstruction of the vas deferens and submucosal glands in the airways leads to organ destruction and fibrosis.

Deficiencies in the cystic fibrosis transmembrane conductance regulator (CFTR) protein and epithelial anion channel, manifest is a complex multiorgan disease, including progressive respiratory impairment, exocrine pancreatic insufficiency, hepatobiliary disease, and abnormal sweat composition.

More than 2000 mutations have been identified of the transmembrane conduction regulator gene: approximately 700 have been shown to cause disease.

Deletion of three base pairs in CFTR lead to the loss of amino acid phenylalanine at position 508 (F508del) of the protein is the most common variant.

Approximately 85% of CF related alleles are F508del.1

There are five classes of mutations that lead to CFTR defects in the downstream consequences of abnormal CFTR channels include: bronchiectasis, exocrine and endocrine pancreatic insufficiency, colonic obstruction, and infertility.

Exocrine pancreatic insufficiency is present in an estimated 85% of patients with CF.

Pancreatic enzyme replacement is typically initiated for steatorrhea, which manifests as  diarrhea and abdominal pain.

About 15% of adults over 35 years of age with CF also have pancreatic endocrine insufficiency with cystic fibrosis related diabetes.

CF related diabetes increases with age and affects approximately a quarter of persons with CF  older than 30 years of age.

Thickened secretions, cause pancreatic oral digestion, and fatty replacement of the pancreas.

Nearly 90% of patients with cystic fibrosis have at least one copy of the most common mutation, the Phe508del space CFTR mutation.

Phe508del CFTR Mutation causes defective intracellular processing and trafficking and decreased stability, which reduces the quantity CFTR protein at the surface of epithelial cells.

The most prevalent mutation in patients with CF causes a substitution of glycine for aspartic acid at amino acid 551 (G551D), and this mutation occurs in approximately 4-5% of patients with CF.

Mutations in the CFTR affect the quantity of protein that reaches the cell surface or that affect the function of the CFTR channels at the surface of the cell.

Fluctuations in the number of annual CF births have been reported repeatedly, suggesting a decrease in the birth incidence of this process.

Among whites 1 in 30 individuals is a carrier of a cystic fibrosis-related gene mutation, and the standard tests identify 80% of white carriers.

Recessive monogenic process with multi organ involvement and with clinical heterogeneity.

Transmembrane conductance regulator gene (CFTR).

CFTR protein is and epithelial ion channel that contributes to the regulation of absorption and secretion of salt and water in the lungs, sweat glands, pancreas, and G.I. tract.

CFTR protein is in anion channel that transports chloride and bicarbonate across the epithelium in many organs.

CTFR mutations can cause reduce CFTR protein expression, which subsequently results in a reduction in the number of CFTR anion channels present on the epithelial membrane.

CFTR mutations may result in abnormal channel function, causing impaired ion and fluid homeostasis, hyperviscous secretions, and multi system disease.

The clinical features of CS results from reduced or absent function of the CFTR proteins, a regulated anion channel located in the apical membrane of epithelia in multiple organs, including the lungs, liver, gastrointestinal, tract, and pancreas.

The clinical manifestations of CFTR dysfunction include: pancreatic insufficiency, biliary, cirrhosis, absence of the vas deferens, resulting in azoospermia, chronic sinusitis, and chronic endobronchial bacterial infections associated with obstructive airway disease.

More than 80% of people with cystic fibrosis and two severe gene variant have consequences of exocrine pancreatic insufficiency, including protein and fat, maldigestion, diarrhea, and poor growth.

Both upper and lower airway disease begin in infancy, with cough, increased respiratory rate, or wheezing or crackles on chest auscultation.

Patients become infected with pathogens, such as S aureus, and P aeruginosa and experience acute pulmonary exacerbations with cough, sputum production, and often requiring hospitalization

Cystic fibrosis related lung disease includes mucous plugging, chronic infection, airway remodeling, and progressive decline in lung function.

Adults with CF typically report respiratory symptoms and have a 0.5% decrease in the predicted force expiratory volume in one second (FEV1) per year on average after age 19.

Most adults with cystic fibrosis die of respiratory failure.

Gastrointestinal CFTR dysfunction results in chronic constipation and malnutrition due to viscous secretions in the intestinal tract and pancreatic ducts.

Additional findings include diabetes, azoospermia, and low bone mineral density

Agents that increase the ion-channel function of activated cell surface CFTR are referred to as potentiators.

Absence of functional CFTR at airway epithelium decreases chloride secretion and increased sodium absorption depleting airway surface water resulting in impared mucociliary clearance promoting inflammation, infection and lung destruction.

Patients exhibit wide range of lung disease and genetic variability in non-CFTR genes contribute to risk of severity of pulmonary disease.

Lungs of such patients have high levels of proteases that impair immune cell function.

Airways of patients are susceptible to infection, which creates an intense inflammatory response even in patients with modest pulmonary disease.

Patients with disease, often asymptomatic, have neutrophilic inflammation in the airways which can be protective and destructive, as well.

Abnormal or absent CFTR protein causes the accumulation of thick mucus, which blocks the airways and leads to repeat episodes of infection and inflammation with the resultant damage to the lungs.

Respiratory failure is the most common cause of death in patients with CF.

CF results in thick mucus in the pancreas, limiting release of digestive enzymes and leads to difficulty digesting food, malabsorption, and poor weight gain.

Damage to the pancreas may lead to the development of diabetes.

Patients with CF may develop chronic diarrhea and episodes of constipation.

High levels of proteases cleave the chemokine receptor CXCR1, which in the normal lung helps kill bacteria by IL-8 neutrophil stimulation via this receptor.

Neutrophil proteases, including elastase kill engulfed bacteria, but these same proteases can escape from neutrophils during phagocytosis and overwhelm anti protease defenses.

Neutrophil elastase may accumulate in the airways of patients, impair ciliary function, impair bacterial clearance, degrade structural proteins, all of which can lead to bronchiectasis.

Standard tests miss a carrier state in 20% of individuals.

Sweat test is the primary tool used in diagnosis.

Diagnosis is based on clinical presentation, family history, or a positive newborn screening test in addition to evidence of an abnormal CFTR protein or gene.

Most patients are now identified through newborn screening.

Universal neonatal screening for CF was adopted in the United States by 2009.

Newborn screening checks to see if infants have elevated levels of immunoreactive trypsinogen a pancreatic enzyme precursor, a sign of CF.
Diagnosis is established with a positive newborn screening and a sweat chloride level of at least 60 mmol per liter.
If the screen for elevated immunoreactive trypsinogen is found, DNA testing to check for a minimum of 23 common variations in the CF transmembrane conductance regulator (CFTR) gene that causes CF.

There are an increased number of late diagnoses, especially in adulthood, representing up to 7% of cases.

In combination with pulmonary disease, pancreatic malabsorption, positive family history of cystic fibrosis the sweat test is considered diagnostic.

Some patients with clinical signs or genetic evidence of cystic fibrosis may have a normal sweat test.

Prenatal diagnosis is increasingly common: recommending a carrier screening to all women who are considering pregnancy or are already pregnant.

in situations in which both parents are carriers of cystic fibrosis, testing can be performed on chorionic villi or amniocytes.

95% of men with CF are sterile.

80% have pancreatic insufficiency.

Women with CF have difficulty becoming pregnant.

Patients with CF may have chronic sinusitis.

Patients with CF or had increased risk for dehydration because of abnormal functioning of sweat glands.

Deficiency of fatty acids.

Low levels linoleic acid.

Fertility of women with CF is 20%.

30-64% of patients have liver disease.

Liver abnormalities reflect loss of CFTR function in the apical membrane of cholangiocytes.

CF related liver disease ranges from steatosis associated with increased ALT, AST and bilirubin levels to focal biliary fibrosis or to severe cholestasis and advanced liver cirrhosis with portal hypertension..

Most common lethal autosomal recessive disorder in white people (Boyle MP).

Median survival increasing and now is older than 50 years in the US.

Presently no cure exists.

Most common cause of death is respiratory failure from pulmonary infection.

Illness and death from CF are due primarily to progressive destructive lung diseases causing bronchiectasis and respiratory insufficiency.

CT scans can detect changes in the lungs associated with bronchiectasis and structural lung disease in children with CF as young as 10 weeks of age.

It is estimated that 50-70% of patients have CT evidence of bronchiectasis by age 3-5 years of age.

When bronchiectasis appears it persists in children and progresses in approximately 75% of patients despite best current therapy.

Progressive loss of lung function is the major source of illness in patients with CF.

Decreased FEV1 is associated with an increased risk of death and is used to evaluate therapies for CF.

Pseudomonas aeruginosa and Burkholderia cepacia are the most common pathogens associated with shorten survival.

Lactoferrin, is a component of innate immune system, and is decreased in CF.


Lactoferrin prevents bacterial biofilm development, and the loss of its microbicidal activity and increased formation of biofilm is observed in patients with cystic fibrosis.

MRSA prevalence in the respiratory tract of patients with CF is more than 20%.Bronchoalveolar lavage directed therapy does not lower prevalence of P aeruginosa infection among infants with cystic fibrosis, and does not lower cystic fibrosis computed tomography score when compared to standard therapy at age 5 years (Wainwright CE etal).

Lung function decline is faster in children and adolescents with persistent MRSA compared to those without MRSA (Dasenbrook EC), but it is not true in adults (Sawicki GS).

Inhaled tobramycin compared to placebo is associated with a 12% decrease in improvement from baseline of FEV1 (Ramsey BW et al).

In 137,819 patient-years of observation of CF patients the detection of MRSA in the respiratory tract was associated with worse survival (Dasenbrook EC).

Loss of CFTR (Cl channel) causes sluggish bile flow and inflammation , activation and proliferation of hepatic stellate cells, resulting in cholangitis and fibrosis in portal tracts.

Only 3 to 5% patients with this process developed severe liver disease, characterized by cirrhosis with portal hypertension.

The SERPINA1 Z allele is a risk factor for living disease and patients who carry this allele are at greater risk of developing severe liver disease with portal hypertension.

The SERPINA1 Z allele occurs in about 2.2% of CF carrier patients.

VX-770 is a potentiator that increases the ion-channel function of activated cell surface CFTR and has experimentally been shown to increase pulmonary function in CF (Accurso FJ et al).

Most patients require inhaled medications to thin mucus and use mechanical devices to dislodge mucus from the airways.


Oral and inhaled antibiotics help control infections, while intravenous antibiotics are used to treat flares.

Most patients in CF require a high calorie diet with fat soluble vitamin supplements in pancreatic enzyme replacement medication.

CFTR modulators, are aimed to treat underlying cause of of CF: they affect abnormal CTFR proteins within cells to improve salt transport.

CFTR modulators restore some level of CFTR function, and lead to improvements in respiratory dynamics, reductions in pulmonary exacerbations, and increases in body mass index.

CFTR modulators increase the possibility of opening the channel and is lead to improvements and respiratory outcomes, including lung function, the risk of pulmonary exacerbation and respiratory symptoms, as well as nutritional status, and other manifestations of cystic fibrosis.

CFTR modulators delay, disease, manifestations, and have positive effects in the care of adults with cystic fibrosis.

CFTR modulators reduce the risk of acute pulmonary exacerbations.

Only approximately 5% of patients with CF carry disease causing variants that respond to Ivacafor monotherapy.

Ivacafor (VX-770), a CFTR potentiator in a randomized, double blind, placebo controlled trial in subjects 12 years or older with CF and at least one G551D-CFTR mutation: associated with improvements in lung function at 2 weeks and sustained through 48 weeks, with improvement in pulmonary exacerbations, respiratory symptoms, (Ramsey BW et al).weight and sweat chloride concentration.

In patients with gating mutations,Ivacafor improves lung function, nutritional status and quality of life and decreases pulmonary exacerbations.

Ivacaftor, a CFTR potentiator, augments gating of mutant CFTR proteins.

Kaylydeco (ivacaftor) available for the treatment of cystic fibrosis, tripling the number of rare gene mutations that the drug is indicated to treat from 10 to 33.

Combination treatment with the cystic fibrosis transmembrane conductance regulator (CFTR) modulators tezacaftor and ivacaftor are designed to target the underlying cause of disease in patients with cystic fibrosis.

In patients with F580del, the most common variant, combination therapy with corrected drugs that ameliorate the protein, folding defect, allowing transport of the channel to the cell surface, and ivacaftor to improve channel gating can achieve clinical benefit.

Receive either 100 mg of tezacaftor once daily and 150 mg of ivacaftor twice daily.

The rate of pulmonary exacerbation was 35% lower in the tezacaftor-ivacaftor group than in the placebo group.

Fewer patients in the tezacaftor group than in the placebo group had respiratory adverse events, none of which led to discontinuation.

The combination of tezacaftor and ivacaftor was efficacious and safe in patients 12 years of age or older who had cystic fibrosis and were homozygous for the CFTR Phe508del mutation.

Elexavaftor-tezacaftor-ivacaftor in combination is efficacious and patients with cystic fibrosis patients with Phe508del-minimal function genotypes, and whom previous CFTR modulator regimens were ineffective.

Highly effective modulated therapy in treating CF is employed as early as possible.

Studies indicate that CF manifestations can be prevented, or rescued with antenatal initiation of highly effective modulator therapy.

Nutritional management includes high calorie, high fat diet and pancreatic enzyme replacement in patients with pancreatic insufficiency.

Management includes preventing pulmonary exacerbations, mucus plugging and mucus clearance are important components of maintenance therapy.

Inhalation of the mucolytic drug dornase alpha, improves lung function, and reduces the frequency of pulmonary exacerbations.

Dornase alpha, lowers the viscosity of secretions by breaking down, free DNA strands, mainly derive from neutrophils entering the airways as part of the inflammation.

Nebulized inhaled, hypertonic saline ameliorates dehydration of airway secretions and improves lung function, and reduces exacerbations.

Acute and chronic infections of the airways with cystic fibrosis is caused by a large variety of gram-positive and gram-negative organisms and regular microbiology testing secretions is performed to detect new infections and to guide treatment decisions.

Pulmonary exacerbations treated with antibiotics, increase the risk of fungal infections.

Bilateral lung transplantation is a surgical option for patients with advanced cystic fibrosis and profound lung disease.


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