10,000,000 carriers in the U.S.
One in every 2000 newborns affected.
CF affects more than 30,000 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.
CFTR codes for anion channel that transports both CL and HCO3 across epithelial services in the respiratory tract, pancreas, G.I. system, and sweat glands among other organs.
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.
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.
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 endo[bronchial bacterial infections associated with obstructive airway disease.
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.
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 go hands.
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.
Most common lethal autosomal recessive disorder in white people (Boyle MP).
Median survival increasing and now is older than 38 years.
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.
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
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.
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.