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Cystic fibrosis

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

One in every 2000 newborns affected.

The most lethal genetic disease affecting Caucasians.

A life-shortening autosomal recessive disease.

Approximately 80,000 cases worldwide.

Estimated to affect 30,000 children and adults in United States.

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

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 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 1200 mutations have been identified of the transmembrane conduction regulator gene.

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.

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

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.

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.

Newborn screening checks to see if infants have elevated levels of immunoreactive trypsinogen a pancreatic enzyme precursor, a sign of CF.

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.

95% of men with CF are sterile.

80% have pancreatic insufficiency.

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).

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.

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