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Cystic Fibrosis

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Cystic Fibrosis

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Cystic Fibrosis

  1. 1. CYSTIC FIBROSIS A Presentation by: Jayatheeswaran. Vijayakumar
  2. 2. CYSTIC FIBROSIS “Woe to the child which when kissed on the forehead tastes salty. He is bewitched and soon will die” – Old Proverb
  3. 3. CYSTIC FIBROSIS  Cystic fibrosis is a disease of exocrine gland function that involves multiple organ systems but chiefly results in chronic respiratory infections, pancreatic enzyme insufficiency, and associated complications in untreated patients  Is a lethal autosomal recessive disease  Has an incidence: 1 in 2000-3000; predominantly in Caucasian populations (carrier frequency 1 in 22-28)  Median age at diagnosis of cystic fibrosis is 6-8 months; two thirds of patients are diagnosed by 1 year of age.
  4. 4. CYSTIC FIBROSIS  The disease gene CFTR (cystic fibrosis transmembrane conductance regulator) is a regulated epithelial Cl- channel; influences other ion channels  The age at diagnosis, the clinical presentation, the severity of the symptoms, and the rate of disease progression in the organs involved varies widely.  Clinical manifestations vary with the patient's age at presentation. e.g. : patients diagnosed later in childhood or in adulthood are more likely to have pancreatic sufficiency and often present with chronic cough and sputum production
  5. 5. GENOTYPE & PHENOTYPE RELATIONSHIP  Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene which encodes a protein expressed in the apical membrane of exocrine epithelial cells.  This genotypic variation provides a rationale for phenotypic effects of the specific mutations. The extent to which various CFTR alleles contribute to clinical variation in CF is evaluated by genotype- phenotype studies.  The poor correlation between CFTR genotype and severity of lung disease strongly suggests an influence of environmental and secondary genetic factors (CF modifiers).
  6. 6. GENOTYPE & PHENOTYPE RELATIONSHIP  Several candidate genes related to innate and adaptive immune response have been implicated as pulmonary CF modifiers. In addition, the presence of a genetic CF modifier for meconium ileus has been demonstrated on human chromosome 19q13.2.  The phenotypic spectrum associated with mutations in the CFTR gene extends beyond the classically defined CF. Besides patients with atypical CF, there are large numbers of so- called monosymptomatic diseases such as various forms of obstructive azoospermia, idiopathic pancreatitis or disseminated bronchiectasis associated with CFTR mutations uncharacteristic for CF.
  7. 7. PATHOPHYSIOLOGY  Chloride channel.  Five domains:  2 membrane spanning domains (MSD)  2 nucleotide binding domains (NBD, for ATP hydrolysis)  1 regulatory domain (R).  Functions in lungs, liver, pancreas, digestive tract, reproductive tract & skin.
  8. 8. PATHOPHYSIOLOGY  In normal airway cells, there are two Cl- channels. One channel is regulated by cyclic AMP and ATP (CFTR), and the other is activated by Ca2+.  ATP binding and hydrolysis open CFTR, so that Cl- can move down its electrochemical gradient, into the mucus of the lungs.  Presence of Cl- in the mucus ensures its sufficient water content, required for mucus removal by the cilia of the airway cells
  9. 9. PATHOPHYSIOLOGY  In individuals with CF, the defect in CFTR protein causes decreased secretion of Cl- ions which cause a compensatory influx of Na+ ions to maintain the electro-neutrality of the cell.  Increase in the osmolarity inside the cell causes a water influx from outside the cell. This leads to the dehydration of the mucus membrane.  The now sticky mucus traps bacteria, is not remove by cilia of the lung epithelium. As the lungs have the perfect environment for bacterial propagation patients with CF typically get lung infections.
  10. 10. CLASSIFICATION  Class I: normal level of mRNA ; defective protein production (premature stop codon). No or little CFTR protein is produced.  Class II: Defective trafficking: the protein does not reach the membrane  Class III: defective regulation (opening/closing) of the CFTR channel  Class IV: defective conduction (Cl- doesn’t pass through the channel)  Class V: reduced synthesis of functional CFTR
  11. 11. CLASSIFICATION  The most common CFTR mutant ΔF508, is a class II defect.  The defective protein retains substantial chloride-channel function in cell-free lipid membranes.  When synthesized by the normal cellular machinery, however, the protein is rapidly recognized as misfolded and is degraded shortly after synthesis , via proteasome degradation pathway at endoplasmic reticulum (ER).
  12. 12. THE MOST COMMON CFTR MUTATION Around 75% of mutations observed in CF patients result from a deletion of three base pairs in CFTR's nucleotide sequence. This deletion causes loss of the amino acid phenylalanine located at position 508 in the protein; therefore, this mutation is referred to as delta F508 or ΔF508.
  13. 13. CLINICAL PRESENTATION Manifestations Respiratory Tract Urogenital Tract Gastrointestinal Tract Atypical
  14. 14. CLINICAL PRESENTATION  Nose examination may reveal the following:  Rhinitis  Nasal polyps  Findings related to the pulmonary system may include the following:  Tachypnea  Respiratory distress with retractions  Wheeze or crackles  Cough (dry or productive of mucoid or purulent sputum)  Increased anterior-posterior diameter of chest  Clubbing  Cyanosis  Hyperresonant sound heard upon chest percussion (crackles are heard acutely in associated pneumonitis or bronchitis and chronically with bronchiectasis)
  15. 15. CLINICAL PRESENTATION  Findings related to the GI tract include the following:  Abdominal distention  Hepatosplenomegaly (fatty liver and portal hypertension)  Rectal prolapse  Dry skin (vitamin A deficiency)  Cheilosis (vitamin B complex deficiency)  Findings related to the Urogenital tract include the following:  Hydrocele  Undescended testicles  Amenorrhea  Sterility  In males: due to the absence of the vas deferens  In females: fertility is maintained although it is severely decreased
  16. 16. CLINICAL PRESENTATION  Examination of other systems may reveal the following:  Scoliosis  Kyphosis  Swelling of submandibular gland or parotid gland  Aquagenic wrinkling of the palms (AWP)  One study reported an association between AWP and cystic fibrosis.Among patients with cystic fibrosis, a greater degree of AWP is observed in patients who are homozygous for the ΔF508 mutation.
  17. 17. CLINICAL PRESENTATION Atypical Manifestations  Clinical variants have been described, such as adult males with bilateral absence of the vas deferens who have little other clinical involvement. Absence of the vas deferens is considered an atypical presentation of cystic fibrosis, and 80% of men with this presentation have at least one CFTR gene mutation. Zielenski et al reported that the most common of these mutations is the IVS8/5T mutation.  Another atypical manifestation of cystic fibrosis is polyuria and polyphagia in an infant. Despite not having any initial intestinal symptoms, such as diarrhea, an infant in Belgium with failure to thrive was initially treated for diabetes insipidus before being diagnosed with cystic fibrosis. Although a sweat test result may be abnormal in diabetes insipidus, cystic fibrosis must be excluded upon any positive sweat test result.
  18. 18. CLINICAL PRESENTATION Complications  The following are potential complications of cystic fibrosis:  Nasal polyps  Chronic and persistent sinusitis with complications such as mucopyocele formation  Bronchiectasis  Atelectasis  Pneumothorax  Hemoptysis  Hypertrophic pulmonary osteoarthropathy  Allergic bronchopulmonary aspergillosis (ABPA)  Gastroesophageal reflux  Pulmonary hypertension  End-stage lung disease  Cor pulmonale  Pancreatitis  Cystic fibrosis–related diabetes mellitus  Meconium ileus  Distal intestinal obstruction syndrome  Rectal prolapse  Vitamin deficiency (especially fat- soluble vitamins)  Fatty liver  Focal biliary cirrhosis  Portal hypertension  Liver failure  Cholecystitis and Cholelithiasis  Rickets  Osteoporosis
  19. 19. THE RELATIONSHIP BETWEEN CLINICAL PRESENTATIONS & RESIDUAL CFTR FUNCTION % of Normal CFTR Function Clinical Presentations < 1 Pancreatic insufficiency and below < 4.5 Pulmonary infection and below < 5 Positive sweat test and symptoms below < 10 Congenital absence of vas deferens 10-49 None 50-100 None  34% of patients reach adulthood 10% live past age of 30 Average Life Expectancy •Male : 31 •Female: 28
  20. 20. TREATMENT • The major goal in treating CF is to clear the abnormal and excess secretions, control infections in the lungs and to prevent obstruction in the intestines. • For patients with advanced stages of the disease, a lung transplant operation may be necessary. • Although treating the symptoms does not cure the disease, it can greatly improve the quality of life for most patients.
  21. 21. TREATMENT  Modified Diet Due to pancreatic disorders, children with CF require a modified diet, including vitamin supplements (vitamins A, D, E, and K) and pancreatic enzymes. Maintaining adequate nutrition is essential. The diet calls for a high-caloric content (twice what is considered normal for the child's age), which is typically low in fat and high in protein. Patients or their caregivers should consult with their health care providers to determine the most appropriate diet.

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