Cystic Fibrosis: Clinical Manifestations and Pathophysiology

Questions and Answers

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?

To stimulate the secretion of sweat Signup and view all the answers

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

It is activated by phosphorylation Signup and view all the answers

What is the primary organ affected by cystic fibrosis?

Lungs Signup and view all the answers

What is the inheritance pattern of cystic fibrosis?

Autosomal recessive Signup and view all the answers

What is the prevalence of cystic fibrosis in Europe?

1 in 3000-6000 live births Signup and view all the answers

What is the main feature of cystic fibrosis?

Progressive lung disease Signup and view all the answers

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

Meconium ileus Signup and view all the answers

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

CF-related diabetes 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?

Variable expressivity 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?

Congenital bilateral absence of vas deferens (CBAVD) Signup and view all the answers

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

Radioimmunologic test Signup and view all the answers

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

Deficiency in the production of pancreatic enzymes Signup and view all the answers

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

Chronic sinusitis Signup and view all the answers

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

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

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

It is still in the in vitro research stage Signup and view all the answers

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

Targeted/personalized drug therapy Signup and view all the answers

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

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

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

To prevent malnutrition Signup and view all the answers

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

It is still in the in vitro research stage Signup and view all the answers

What is the function of Ivacaftor in the given context?

CFTR potentiator to increase Cl- transport Signup and view all the answers

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

To activate CFTR Signup and view all the answers

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

To block Na+ currents Signup and view all the answers

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

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

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

Bronchial epithelial cells Signup and view all the answers

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

Proc Natl Acad Sci USA Signup and view all the answers

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

Significant reduction Signup and view all the answers

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

Bronchial epithelium from CF patients homozygous for F508del CFTR Signup and view all the answers

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

To measure transepithelial chloride transport Signup and view all the answers

What is the effect of lumacaftor on F508del CFTR protein?

It increases F508del CFTR protein maturation Signup and view all the answers

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

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

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

Combined treatment with lumacaftor and ivacaftor improves lung function Signup and view all the answers

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

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

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

24 weeks Signup and view all the answers

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

Multisystem disease affecting exocrine glands Signup and view all the answers

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

Number of organs affected 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?

Variable expressivity Signup and view all the answers

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

CF-related diabetes Signup and view all the answers

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

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

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

Correcting the defective gene through genome editing Signup and view all the answers

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

Increasing the opening time of the CFTR channel Signup and view all the answers

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

It has limited effectiveness in clinical trials Signup and view all the answers

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

Improving the function of the defective CFTR protein Signup and view all the answers

What is the purpose of glucocorticoids in cystic fibrosis therapy?

Treating bronchial inflammation Signup and view all the answers

What is the frequency of CF carriers in a population?

1 in 25 Signup and view all the answers

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

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

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

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

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

Good correlation, with mild alleles associated with pancreatic sufficiency Signup and view all the answers

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

Resistance to cholera and typhoid fever Signup and view all the answers

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

It potentiates the activation of CFTR by forskolin Signup and view all the answers

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

G551D-CFTR has higher cell surface density Signup and view all the answers

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

To improve the cell surface density of mutant channels Signup and view all the answers

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

Activates CFTR Signup and view all the answers

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

Ivacaftor has a greater effect on G551D-CFTR Signup and view all the answers

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

Increases the volume of airway surface liquid Signup and view all the answers

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

To activate the CFTR protein Signup and view all the answers

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

Improvement in lung function Signup and view all the answers

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

Measurement of light intensity on the ciliary surface Signup and view all the answers

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

Bronchial epithelial cells 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.

Cystic Fibrosis: Clinical Manifestations and Pathophysiology

Questions and Answers

What is the primary function of the CFTR protein in epithelial cells?

What is the locus of the CFTR gene?

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

What is the purpose of pilocarpine in the sweat test?

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

What is the primary organ affected by cystic fibrosis?

What is the inheritance pattern of cystic fibrosis?

What is the prevalence of cystic fibrosis in Europe?

What is the main feature of cystic fibrosis?

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

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

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

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

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

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

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

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

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

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

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

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

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

What is the function of Ivacaftor in the given context?

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

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

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

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

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

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

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

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

What is the effect of lumacaftor on F508del CFTR protein?

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

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

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

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

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

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

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

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

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

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

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

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

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

What is the purpose of glucocorticoids in cystic fibrosis therapy?

What is the frequency of CF carriers in a population?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Study Notes

Cystic Fibrosis

Clinical Manifestations

Neonatal Screening

Cystic Fibrosis Conductance Regulator (CFTR)

Therapeutic Strategies

CFTR Modulators

Cystic Fibrosis (CF)

Clinical Manifestations

Genetics

Targeted Therapy

Testing and Diagnosis

Studying That Suits You

Description

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