Cystic fibrosis and general facts or info.pptx

Cystic fibrosis and brief information about it by my wonderful teacher Teona

1. Cystic fibrosis Teona Iremadze

2. Cystic  fibrosis  (CF) is an  autosomal recessive  disorder that is common in individuals of European descent. It is caused by mutations in the  CFTR   gene , which encodes the CF transmembrane conductance regulator ( CFTR ) protein. These mutations result in defective  chloride  (Cl - ) channels. 

3. General considerations The CFTR gene encodes the CFTR protein, which is an important component of the ATP-gated chloride channel in cell membranes. Mutated CFTR gene → misfolded protein → retention for degradation of the defective protein in the rough endoplasmic reticulum ( rER ) → absence of ATP-gated chloride channel on the cell surface of epithelial cells throughout the body (e.g., intestinal and respiratory epithelia, sweat glands, exocrine pancreas, exocrine glands of reproductive organs)

4. In sweat glands The chloride channel is responsible for transporting Cl- from the lumen into the cell (reabsorption). Defective ATP-gated chloride channel → inability to reabsorb Cl- from the lumen of the sweat glands → reduced reabsorption of Na+ and H2O → excessive loss of salt and elevated levels of NaCl in sweat

5. In all other exocrine glands (e.g., in the GI tract or lungs) The chloride channel is responsible for transporting Cl- from the cell into the lumen (secretion). Defective ATP-gated chloride channel → inability to transport intracellular Cl- across the cell membrane → reduced secretion of Cl- and H2O → accumulation of intracellular Cl- → ↑ Na+ reabsorption (via ENaC) → ↑ H2O reabsorption → formation of hyperviscous mucus → accumulation of secretions and blockage of small passages of affected organs → chronic inflammation and remodeling → organ damage (see “Clinical features” below

6. !!! A mutation in the CFTR gene results in defective protein synthesis and the absence of the ATP-gated chloride channel in the cell surface of epithelial cells throughout the body (intestinal and respiratory epithelia, sweat glands, exocrine pancreas, exocrine glands, and reproductive organs). Chloride and sodium are normally in equilibrium , but the accumulation of intracellular chloride due to the absence of a transporter results in the retention of intracellular sodium and water (due to osmosis ). This ultimately results in hyperviscous mucus , which causes blockages of small organs and airways, inflammation, and end-organ damage.

7. Clinical features Gastrointestinal Gastrointestinal symptoms are common in children. The presence of these features during infancy should raise suspicion for CF. Meconium ileus (in newborns) Failure to thrive (due to malabsorption) Pancreatic disease Pancreatitis Exocrine pancreatic insufficiency Foul-smelling steatorrhea (fatty stools) may occur. Malabsorption Abdominal distention Diarrhea Hypoproteinemia Deficiency of fat-soluble vitamins

8. Meconium ileus is a bowel obstruction that occurs when the meconium in child's intestine is even thicker and stickier than normal meconium, creating a blockage in a part of the small intestine called the ileum. Most infants with meconium ileus have a disease called cystic fibrosis.

9. CF-related diabetes mellitus (CFRD) Liver and bile duct abnormalities Cholecystolithiasis, cholestasis Fatty metamorphosis of the liver, eventually progressing to liver cirrhosis Biliary cirrhosis with portal hypertension, jaundice, and/or esophageal varices Intestinal obstruction: abdominal distention, pain, and a palpable mass Rectal prolapse (rare) - Photo

10. Respiratory  Respiratory symptoms are common in adulthood. CF should be considered in individuals with the following features: Chronic obstructive lung disease with bronchiectasis Chronic sinusitis: nasal polyps may eventually develop Recurrent or chronic productive cough and pulmonary infections S. aureus is the most common cause of recurrent pulmonary infection in infancy and childhood. P. aeruginosa is the most common cause of recurrent pulmonary infections in adulthood.

11. bronchiectasis

12. Pulmonary obstruction and airway hyperreactivity may manifest with expiratory wheezing and/or dyspnea. Barrel chest , moist rales (indicate pneumonia), hyperresonance to percussion Hemoptysis Signs of chronic respiratory insufficiency : digital clubbing associated with chronic hypoxia (photo1)

13. Musculoskeletal Frequent fractures due to osteopenia Kyphoscoliosis Urogenital Nephrolithiasis, nephrocalcinosis Frequent urinary tract infections Genital Men: usually infertile Obstructive azoospermia is common, spermatogenesis may be intact The vas deferens may be absent. Undescended testicle Women: reduced fertility Viscous cervical mucus can obstruct fertilization. Menstrual abnormalities (e.g., amenorrhea) Delayed development of secondary sexual characteristics

14. Vas deferens The vas (ductus) deferens is a muscular tube that is located within the spermatic cord and is a major component of the male reproductive system . It is a continuation of the epididymis and is involved in transporting spermatozoa from the epididymis to the ejaculatory ducts.

15. Newborn screening (NBS) Newborn screening (NBS) for CF is essential for early detection and treatment, which can improve health outcomes. In many countries, including the US, it is mandatory to screen for CF Immunoreactive trypsinogen (IRT ) : initial screening test An immunofluorescence assay that measures levels of IRT Normal IRT levels: CF unlikely Elevated IRT levels: CF possible; additional screening tests require IRT levels are thought to become elevated due to mucus plugs, which cause pancreatic duct obstruction, preventing the conversion of trypsinogen to trypsin. This can occur in neonates with or without pancreatic insufficiency.

16. Any of the following findings are evidence of CFTR protein dysfunction: Sweat chloride testing with a chloride value ≥ 60 mmol/L Evidence of two CF-causing CFTR gene mutations and a sweat chloride test result ≥ 30 mmol/L Positive physiologic CFTR testing with abnormal nasal potential difference test or intestinal current measurement CFTR mutation analysis

17. Sweet chloride test

18. General principle of treatment All patients with CF require periodic follow-up with a multidisciplinary team for specialized management.  Management should include the following goal-directed interventions: Preservation of  lung function Pharmacological and nonpharmacological interventions Prevention of infection and reduction of exacerbations Optimization of nutrition Screening and monitoring for comorbidities and complications Patients with certain mutations may benefit from treatment with  CFTR modulators . Acute pulmonary exacerbations require rapid and effective treatment

19. Treatment A relatively new therapy for the long-term management of CF that targets specific defects in the CFTR protein to improve its function. Indications Approved for patients with specific CFTR mutations (e.g., ΔF508, G511D mutations) Their use can potentially reduce CF complications and comorbidities Mechanism of action: improve CFTR protein function by targeting underlying protein defects Potentiators (e.g., ivacaftor): increase CFTR Cl- channel gate opening and conductance and improve Cl- transport Correctors (e.g., lumacaftor, tezacaftor , elexacaftor ): improve protein folding, protein stability, and the transport of functional CFTR protein to the cell surface

20. Prognosis Median life expectancy: 39 years  [43] Individuals with CF who have  pancreatic  sufficiency tend to present with mainly pulmonary symptoms in late childhood/early adulthood and generally have a milder course of disease  The main determinant of life expectancy is the severity of pulmonary disease: chronic respiratory infections and mucus plugging →  bronchiectasis  (irreversible) → progressive respiratory failure →  death

21. Prevention Annual influenza vaccine for all affected individuals > 6 months with inactivated influenza vaccine Pneumococcal vaccine (see ”Immunization schedule”) Palivizumab: antibody against the respiratory syncytial virus (RSV) for infants < 24 months Long-term treatment with azithromycin may be used to prevent recurrent pulmonary infections.

22. Thank you! https://www.youtube.com/watch?v=CqFsAwCFvCM https://next.amboss.com/us/article/ZI0ZYh?m=mxbVCD