Cystic Fibrosis: Clinical Manifestations and Pathophysiology
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What is the primary function of the CFTR protein in epithelial cells?

  • To regulate Na+ concentration in sweat
  • To stimulate the secretion of digestive enzymes in the GI tract
  • To facilitate anion transport, specifically Cl- and HCO3- (correct)
  • To maintain the integrity of the sweat gland epithelial layer

    • What is the locus of the CFTR gene?

  • 6q24.3
  • 7p21.2
  • 5p15.1
  • 7q31.2 (correct)

    • What is the normal range of Cl- concentration in sweat?

  • < 60 mM (correct)
  • < 40 mM
  • < 30 mM
  • No specific range is defined for Cl- in sweat

    • What is the purpose of pilocarpine in the sweat test?

    <p>To stimulate the secretion of sweat</p> Signup and view all the answers

    Which of the following is a characteristic of the CFTR protein?

    <p>It is activated by phosphorylation</p> Signup and view all the answers

    What is the primary organ affected by cystic fibrosis?

    <p>Lungs</p> Signup and view all the answers

    What is the inheritance pattern of cystic fibrosis?

    <p>Autosomal recessive</p> Signup and view all the answers

    What is the prevalence of cystic fibrosis in Europe?

    <p>1 in 3000-6000 live births</p> Signup and view all the answers

    What is the main feature of cystic fibrosis?

    <p>Progressive lung disease</p> Signup and view all the answers

    What is the term for the blockage of terminal ileum by dense meconium in newborns?

    <p>Meconium ileus</p> Signup and view all the answers

    What is the complication of cystic fibrosis that affects 40-50% of adult patients?

    <p>CF-related diabetes</p> Signup and view all the answers

    What is the genetic feature of cystic fibrosis that refers to the different expression of the disease in different individuals?

    <p>Variable expressivity</p> Signup and view all the answers

    What is the term for the failure of vas deferens to form before birth in male patients with cystic fibrosis?

    <p>Congenital bilateral absence of vas deferens (CBAVD)</p> Signup and view all the answers

    What is the test used for neonatal screening of cystic fibrosis?

    <p>Radioimmunologic test</p> Signup and view all the answers

    What is the characteristic of cystic fibrosis that affects the production of pancreatic enzymes?

    <p>Deficiency in the production of pancreatic enzymes</p> Signup and view all the answers

    What is the term for the long-lasting sinus inflammation and infection in cystic fibrosis?

    <p>Chronic sinusitis</p> Signup and view all the answers

    What is the primary goal of CFTR modulators in cystic fibrosis therapy?

    <p>To improve the opening time of the CFTR channel and enhance ion flow</p> Signup and view all the answers

    What is the current status of gene therapy in cystic fibrosis treatment?

    <p>It is still in the in vitro research stage</p> Signup and view all the answers

    What type of therapeutic strategy is focused on improving the expression or function of the defective CFTR protein?

    <p>Targeted/personalized drug therapy</p> Signup and view all the answers

    What is the mechanism of action of potentiators, a type of CFTR modulator?

    <p>They increase the opening time of the CFTR channel, resulting in higher ion flow</p> Signup and view all the answers

    What is the purpose of pancreatic enzymes in the treatment of cystic fibrosis?

    <p>To prevent malnutrition</p> Signup and view all the answers

    What is the current status of genome editing in cystic fibrosis treatment?

    <p>It is still in the in vitro research stage</p> Signup and view all the answers

    What is the function of Ivacaftor in the given context?

    <p>CFTR potentiator to increase Cl- transport</p> Signup and view all the answers

    In the Ussing chamber experiment, what is the purpose of forskolin?

    <p>To activate CFTR</p> Signup and view all the answers

    What is the effect of amiloride in the Ussing chamber experiment?

    <p>To block Na+ currents</p> Signup and view all the answers

    What is the difference in the effectiveness of Ivacaftor in bronchial epithelial cells?

    <p>Ivacaftor is more effective in G551D/F508del CFTR compared to homozygous F508del CFTR</p> Signup and view all the answers

    What is the type of cells used in the Ussing chamber experiment?

    <p>Bronchial epithelial cells</p> Signup and view all the answers

    In which publication was the study mentioned in the passage published?

    <p>Proc Natl Acad Sci USA</p> Signup and view all the answers

    What is the effect of lumacaftor on sweat Cl- levels in CF patients?

    <p>Significant reduction</p> Signup and view all the answers

    What type of cells were used in the lumacaftor in vitro studies?

    <p>Bronchial epithelium from CF patients homozygous for F508del CFTR</p> Signup and view all the answers

    What is the function of Ussing chambers in the lumacaftor studies?

    <p>To measure transepithelial chloride transport</p> Signup and view all the answers

    What is the effect of lumacaftor on F508del CFTR protein?

    <p>It increases F508del CFTR protein maturation</p> Signup and view all the answers

    What is the significance of the study showing lumacaftor's effect on non-CFTR misfolded proteins?

    <p>It demonstrates lumacaftor's selectivity for correcting CFTR processing</p> Signup and view all the answers

    What is the outcome of the lumacaftor-ivacaftor clinical trial in CF patients?

    <p>Combined treatment with lumacaftor and ivacaftor improves lung function</p> Signup and view all the answers

    What is the difference between lumacaftor and other CFTR correctors, such as VRT-325 and Corr-4a?

    <p>Lumacaftor is more selective than VRT-325 and Corr-4a</p> Signup and view all the answers

    What is the duration of the lumacaftor-ivacaftor treatment in the clinical trial?

    <p>24 weeks</p> Signup and view all the answers

    What is the characteristic of cystic fibrosis that affects the production of viscous mucus?

    <p>Multisystem disease affecting exocrine glands</p> Signup and view all the answers

    What is the major difference between classical and non-classical cystic fibrosis?

    <p>Number of organs affected</p> Signup and view all the answers

    What is the genetic feature of cystic fibrosis that refers to the different expression of the disease in different individuals?

    <p>Variable expressivity</p> Signup and view all the answers

    What is the complication of cystic fibrosis that affects 40-50% of adult patients?

    <p>CF-related diabetes</p> Signup and view all the answers

    What is the purpose of the radioimmunologic test in neonatal screening of cystic fibrosis?

    <p>To detect high levels of serum immunoreactive trypsin (IRT)</p> Signup and view all the answers

    What is the main goal of genetic therapeutic strategies in cystic fibrosis?

    <p>Correcting the defective gene through genome editing</p> Signup and view all the answers

    What is the mechanism of action of potentiators in cystic fibrosis therapy?

    <p>Increasing the opening time of the CFTR channel</p> Signup and view all the answers

    What is the current status of gene therapy in cystic fibrosis treatment?

    <p>It has limited effectiveness in clinical trials</p> Signup and view all the answers

    What is the primary goal of CFTR modulators in cystic fibrosis therapy?

    <p>Improving the function of the defective CFTR protein</p> Signup and view all the answers

    What is the purpose of glucocorticoids in cystic fibrosis therapy?

    <p>Treating bronchial inflammation</p> Signup and view all the answers

    What is the frequency of CF carriers in a population?

    <p>1 in 25</p> Signup and view all the answers

    What is the effect of the F508del mutation on CFTR function?

    <p>Deletion of Phe at aa 508, resulting in decreased CFTR activity</p> Signup and view all the answers

    What is the association between the 5T variant and CFTR function?

    <p>The 5T variant is associated with decreased CFTR activity</p> Signup and view all the answers

    What is the correlation between genotype and pancreatic function in CF patients?

    <p>Good correlation, with mild alleles associated with pancreatic sufficiency</p> Signup and view all the answers

    What is the benefit of having a mutant CFTR allele in terms of infectious diseases?

    <p>Resistance to cholera and typhoid fever</p> Signup and view all the answers

    What is the primary effect of Ivacaftor on Cl- transport?

    <p>It potentiates the activation of CFTR by forskolin</p> Signup and view all the answers

    What is the reason for the greater effect of Ivacaftor on G551D-CFTR compared to F508del-CFTR?

    <p>G551D-CFTR has higher cell surface density</p> Signup and view all the answers

    What is the purpose of incubating F508del-CFTR cells at 27°C overnight?

    <p>To improve the cell surface density of mutant channels</p> Signup and view all the answers

    What is the role of forskolin in the Ussing chamber experiment?

    <p>Activates CFTR</p> Signup and view all the answers

    What can be inferred about the effect of Ivacaftor on F508del-CFTR and G551D-CFTR?

    <p>Ivacaftor has a greater effect on G551D-CFTR</p> Signup and view all the answers

    What is the effect of ivacaftor on the airway surface liquid in patients with cystic fibrosis?

    <p>Increases the volume of airway surface liquid</p> Signup and view all the answers

    What is the purpose of the VIP stimulation in the experiment shown in Figure 5?

    <p>To activate the CFTR protein</p> Signup and view all the answers

    What is the outcome of the clinical trial in cystic fibrosis patients treated with ivacaftor for 48 weeks?

    <p>Improvement in lung function</p> Signup and view all the answers

    What is the method used to measure the ciliary beating frequency in Figure 5?

    <p>Measurement of light intensity on the ciliary surface</p> Signup and view all the answers

    What is the type of cells used in the experiment shown in Figure 5?

    <p>Bronchial epithelial cells</p> Signup and view all the answers

    Study Notes

    Cystic Fibrosis

    • Cystic fibrosis (CF) is an autosomal recessive (AR) inheritance disorder, affecting 1 in 3000-6000 live births in Europe.
    • It is a multisystem disease affecting exocrine glands, resulting in the production of viscous mucus, leading to obstruction and chronic inflammation.
    • Main features include progressive lung disease, pancreatic insufficiency, malnutrition, and susceptibility to infections.

    Clinical Manifestations

    • Classical CF: severe phenotype, multiple organs affected.
    • Non-classical/atypical CF: milder phenotype, affects 1 or 2 organs, normal pancreatic function.
    • Chronic sinusitis: long-lasting sinus inflammation and infection.
    • Pancreatic insufficiency: deficiency in pancreatic enzyme production, compromising food digestion and leading to malnutrition and impaired growth.
    • CF-related diabetes: reduced insulin release and elevated blood sugar (40-50% of adult patients).
    • Obstructive lung disease: airflow blockage causing difficulty breathing, deterioration of pulmonary capacity, and the leading cause of death.
    • Liver disease: obstruction of bile ducts, inflammation, and fibrosis.
    • Meconium ileus: blockage of the terminal ileum by dense meconium (first feces of newborn), life-threatening.
    • Congenital bilateral absence of vas deferens (CBAVD): vas deferens fail to form before birth, leading to sterility (97-98% of male patients).
    • Pancreatitis: inflammation of the pancreas.

    Neonatal Screening

    • Worldwide implementation of cystic fibrosis newborn screening as of 2020.
    • Mandated by law in many countries, including Italy (Ministero della Salute, Articolo 6, legge quadro 5 febbraio 1992, n.104).
    • Radioimmunologic test: serum immunoreactive trypsin (IRT) measures high IRT levels in CF cases.
    • Sweat test: measurement of Cl- and Na+ in sweat following stimulation with pilocarpine, with CF cases showing [Cl-] > 60 mM.

    Cystic Fibrosis Conductance Regulator (CFTR)

    • Gene: CFTR, locus 7q31.2.
    • Protein: CFTR, an anion channel for Cl- and HCO3-.
    • Expressed on apical surface of epithelial cells of exocrine organs: respiratory tract, pancreatic duct, GI tract, sweat glands, salivary gland, reproductive tract, and bile duct.
    • Member of ABC transporter family (ATP-binding cassette protein).
    • Consists of: 2 membrane spanning domains (MSD1 and MSD2), 2 intracellular nucleotide-binding domains (NBD 1 and NBD2), and 1 intracellular regulatory domain (R domain).

    Therapeutic Strategies

    • Symptomatic drug therapy: antibiotics, glucocorticoids, bronchodilators, mucolytics, and pancreatic enzymes.
    • Genetic therapy: gene therapy (direct delivery of CFTR gene to airways), and genome editing to correct defective gene (e.g., CRISPR/cas9).
    • Targeted/personalized drug therapy: CFTR modulators to improve expression/function of defective protein based on molecular defect.

    CFTR Modulators

    • Potentiators: increase the opening time of the CFTR channel, resulting in higher ion flow.
    • Ivacaftor (VX-770): a CFTR potentiator that increases Cl- transport.
    • Lumacaftor (VX-809): a CFTR corrector that increases F508del CFTR maturation and chloride secretion.
    • Combination of lumacaftor and ivacaftor: improves lung function in CF patients bearing homozygous F508del CFTR.

    Cystic Fibrosis (CF)

    • AR inheritance, most common lethal AR disease in Europe, affecting 1 in 3000-6000 live births
    • Multisystem disease affecting exocrine glands, characterized by production of viscous mucus, leading to obstruction, chronic inflammation, and damage to multiple organs
    • Main features: progressive lung disease, pancreatic insufficiency, malnutrition, susceptibility to infections, and phenotypic variability (affected organs, severity, age of onset)

    Clinical Manifestations

    • Classical CF: severe phenotype, multiple organs affected
    • Non-classical/Atypical CF: milder phenotype, affects 1 or 2 organs, normal pancreatic function
    • Chronic sinusitis, pancreatic insufficiency, CF-related diabetes, obstructive lung disease, liver disease, meconium ileus, congenital bilateral absence of vas deferens (CBAVD), pancreatitis

    Genetics

    • Heterozygote advantage: protection against infectious diseases, resistance to cholera and typhoid fever
    • Allelic heterogeneity, variable expressivity, and genetic modifiers
    • >2000 CFTR variants, of which ~380 are CF-causing, most frequent variant being F508del (ΔF508)
    • Global distribution of CF patients, with varying prevalence per 100,000 habitants

    Targeted Therapy

    • CFTR modulators to improve expression/function of defective protein based on molecular defect
    • Ivacaftor (VX-770) acts as a CFTR potentiator to increase Cl- transport
    • Improves hydration of airway surface and ciliary beating, and lung function in CF patients bearing G551D CFTR

    Testing and Diagnosis

    • Neonatal screening, radioimmunologic test, serum immunoreactive trypsin (IRT)

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    Description

    This quiz covers the clinical manifestations, pathophysiology, and genetics of cystic fibrosis, a lethal autosomal recessive disease affecting exocrine glands. Learn about its features, such as progressive lung disease, pancreatic insufficiency, and susceptibility to infections.

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