Cystic fibrosis
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Transcript of Cystic fibrosis
Cystic
Fibrosis
More than mucus
dr. ravindra k. SharmaPediatric specialist
Fujairah hospital UAE
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Notable History
1905Austrian Karl Landsteiner describes Meconium ileus
1938Cystic fibrosis disease identified by American Dorothy H. Andersen
1838
Carl Von Rokitansky’s autopsy of infant withMeconium peritonitis
Objectives
Know the clinical features of cystic fibrosis.
Know how CF is inherited. Be familiar with criteria to diagnose
CF. Become aware of the myriad of
treatments used in CF.
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What is cystic fibrosis (CF)?
A multisystem disease Autosomal recessive inheritance Cause: mutations in the cystic
fibrosis transmembrane conductance regulator (CFTR) gene chromosome 7 codes for a c-AMP regulated chloride
channel
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Hallmarks of CF
Very salty-tasting skin Appetite, but poor growth & weight gain Coughing, wheezing ,at
times with phelgum & shortness of breath Lung infections, e.g. pneumonia/bronchitis greasy, bulky stools or
difficulty in bowel movements
Presentation : CF PANCREAS
C Chronic respiratory disease F Failure to thrive P Polyps A Alkalosis, metabolic N Neonatal intestinal obstruction C Clubbing of fingers R Rectal Prolapse E Electrolyte in sweat A Aspermia / absent vas deferens S Sputum – S.aureus/P.aeruginosa
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Burden of CF
Most common “life-shortening” recessive disease in Caucasians 1:3,200 in the northern Europian US 1:15,000 population in blacks 1 :10,500 Native Americans 1 :9,200 Hispanics 1 :31,000 Asian Americans 1 :90,000 Asians
(Ref : emedicine medscape) 1,000 new cases diagnosed / year. More than 70% diagnosed by age two. More than 45% of CF population is 18 Y or older. predicted median age of survival is more than 36.9 years.M>F
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Protein Function and Biochemistry
CFTR controls chloride ion movement in and out of the cell.
Cystic fibrosis transmembrane conductance regulator (CFTR) gene
The CFTR gene is located on the long arm of chromosome 7.
There are 1604 mutations in CFTR listed on the CFTR mutation database
The most common mutation is Δ F508---70% CF alleles in caucasians.
Pathogenesis
Defects in (CFTR), - encodes for a protein that functions as chloride channel & regulated by (cAMP).
Abnormalities of cAMP-regulates chloride transport
Defective CFTR - decreased secretion of chloride and increased re-absorption of sodium and water
Reduced height of epithelial lining fluid Decreased hydration of mucus - that is
stickier to bacteria Result in viscid secretions
CFTR and Airway Surface Liquid
Types of mutations in CFTR
Class I Defective protein production
Class II Defects in processing
ΔF508 Class III
CFTR reaches cell surface but regulation is defective (channel not activated)
Class IV CFTR in membrane with
defective conduction
Class V Decreased synthesis of CFTR
Class VI Accelerated turnover from cell
surface
CF: Clinical Signs
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Clinical Aspects
Cystic fibrosis affects entire body
• Lungs and sinuses
• GI, liver and pancreas
• Reproductive system
•Nutritional
Chronic Sino-Pulmonary Disease
Endobronchial disease Cough / sputum production Air obstruction---wheezing; evidence of
obstruction on PFTs Chest x-ray anomalies Digital Clubbing
Sinus disease Nasal Polyps / sinusitis/ hemoptysis
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Endobronchial disease
Hyperinflation Peribronchial
cuffing Bronchiectasis Diffuse fibrosis Atelectasis
Mucous in the airways cannot be easily cleared from the lungs.
Presentation of Disease in lung
Nasal Polyps
Benign lesions in nasal airway(5-20 yrs)
If large - associated with nasal obstruction, drainage, headaches, snoring
associated with chronic inflammation
need surgical intervention High recurrence rate
GI disease
Intestinal abnormality Meconium ileus (15-20% of newborn with CF) Distal intestinal obstruction syndrome (DIOS) Intussusception / Rectal prolapse Volvulus / atresia / meconium peritonitis
Hepatobiliary disease steatorrhea Focal biliary cirrhosis Multilobular cirrhosis
Pancreatic endocrine dysfunction Cystic fibrosis related diabetes
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liver disease……..
Focal inspissation of bile Obstructs biliary ductules
Second leading cause of death in CF Prevalence 9-37% Spectrum of disease
increased liver enzymes biliary cirrhosis portal hypertension GB stones
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Nutritional deficiency
Pancreatic insufficiency “cystic fibrosis of the pancreas”---mucus
plugging of glandular ducts Chloride impermeability affects HCO3-
secretion and fluid secretion in pancreatic ducts
Pancreatic enzymes stay in ducts and are activated intraductally
Autolysis of pancreas Inflammation, calcification, plugging of ducts, fibrosis
Malabsorption Failure to thrive Fat soluble vitamin deficiency(ADEK)C
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Infertility
Men Abnormal embryologic development of
the epididymal duct and vas deferens-- incomplete or absent
Congential bilateral absence of vas deferens—97-98% of men with CF
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Infertility…….
Women Lower fertility rate than non-CF women Viscid mucoid cervical secretions of low
volume in women with CF Pregnancy and CF:
Goss et al, 2003---no significant difference in survival in women who became pregnant with CF compared to women who did not become pregnant (after adjusting for disease severity)
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Electrolyte abnormality---history
Dr. Paul di Sant’ Agnese 1949 NYC heat wave----noted CF infants
to have a higher rate of heat prostration than non-CF
Showed that sodium and chloride concentration in CF patients’ sweat was 5 times higher than in non-CF
Became basis for sweat chloride test(1953)
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CF: Diagnostic Methods
Diagnostic Criteria of CF
One or more clinical features of CF OR A history of CF in a sibling OR A positive newborn screening test Plus Laboratory evidence for CFTR dysfunction:
Two elevated sweat chloride concentrations obtained on separated days
ORIdentification of two CF mutations
ORAn abnormal nasal potential difference measurement
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Diagnosis-Sweat chloride
First described by Gibson and Cooke,1950
Chemical that stimulates sweating placed under electrode pad; saline under other electrode pad on arm
Mild electric current is passed between electrodes
Sweat collected(75-100gm)
Wescor macroduct procedure
Sweat chloride test. Positive Sweat chloride:
60-165 meq/L Borderine sweat
chloride: 40-60 meq/L Normal sweat chloride:
0-40
False positives: Hypothyroidism Addison disease Ectodermal dysplasia Glycogen storage
disease Edema Malnutrition Lab error (evaporation
or contamination of sample)
False negatives: Edema Malnutrition Some CF mutations Sample dilutedC
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Other Diagnostic Test
DNA testing- 30–80 of CFTR mutations. This identifies ≥90% who carry 2 CF mutations
increased potential differences across nasal epithelium with reference to forearm
loss of potential difference with topical amiloride application is more in CF
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Diagnosis…
Pancreatic function Fat estimation in stool OGTT
Pulmonary radiologic finding Pulmonary function Microbiologic studies
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Prenatal screening
American College of Obstetricians and Gynecologists recommended offering prenatal screening for CF Carrier testing of 23 most common
mutations Sensitivity of prenatal screening for CF
among the white population <78% lower than that for newborn screening sensitivity of prenatal testing in racial and
ethnic minority populations is lowerCy
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Genotyping
More than 1604 mutation identified
2 CFTR mutations in association with symptom is diagnostic
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Newborn Screening for CF
Goal: early diagnosis may be associated with better nutritional outcome Immunoreactive trypsinogen usually
first followed by either sweat or DNA testing
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CF: Treatment
Cystic fibrosis-Treatment …
Pulmonary Therapy Inhalation Therapy Airway Clearance Therapy Infection-Antibiotic Therapy—
Oral Aerosolized IV
Bronchodilator Antiinflammatory Endoscopy & lavageC
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CF: Treatment…
Nutrition Diet Pancreatic enz replacement Vitamins
Gastrointestinal & Rx of complication
Infertility Others-
Nasal polyp Rhinosinusitis Salt depletion Growth & maturation
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Treatment: Complication
Atelactasis Hemomptysis Pneumothorax Allergic aspergilosis Nontuberculous mycobactria
infection Bone & joint complication Sleep-Disordered Breathing Acute Respiratory Failure Chronic Respiratory Failure
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Rx:Complication..
Heart Failure Nutritional therapy.
Follow nutrition parameters closely Pancreatic enzymes Vitamin supplementation Other nutritional supplementation Tube feedings High calorie supplemental shakes,
formulas
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Rx:Intestinal Complication..
Meconium Ileus. Distal Intestinal Obstruction Syndrome Gastroesophageal Reflux Rectal Prolapse Heptobiliary Disease Pancreatitis Hyperglycemia. Nasal Polyps Rhinosinusitis. Salt Depletion Growth and Maturation Surgery.
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Treatment: Nutrition
Follow nutrition parameters closely Pancreatic enzymes
Porcine extract, 2000U/kg/meal TheraCLEC-Total, micro derived under trial
Vitamin supplementation- ADEK
Other nutritional supplementation Tube feedings High calorie supplemental shakes, formulas
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Treatment: Infertility
Microsurgical epididymal sperm aspiration coupled plus in vitro technology
Percutaneous epididymal sperm aspiration
Testicular sperm extraction Maternal genetic testing
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Psychosocial issues
Quality of life Frequent hospitalizations Time spent on therapies Morbidity from disease Restrictions secondary to disease
Adherence to therapies Family planning End of life issues
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Treatment…
Mucolytic- Pulmozyme -to thin mucus Dornase alfa- enzyme hydrolyse DNA-
improve airway clearance Antibiotics- Inhaled TOBI
Cayston- Aztreonam, monobactem AB inhaled for p. aeruginosa
Antioxidant
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Rx: Airway Clearance Therapy
ACTs loosen thick, sticky lung mucus move mucus from small to large airways to be coughed or
huffed out. Coughing is the most basic ACT. Huffing is a type of cough. involves taking a breath
in and actively exhaling. It is more like “huffing” onto a mirror or window to steam it up
Chest Physio Therapy Oscillating Positive Expiratory Pressure
(Oscillating PEP) an ACT where the person blows all the way out many times through a device named FlutterTM, AcapellaTM, CornetTM and Intrapulmonary Percussive Ventilation (IPV). Breathing with devices vibrate & dislodge.
ACT….
High-frequency Chest Wall
Oscillation
Positive Expiratory Pressure (PEP)
Active Cycle of Breathing Technique
(ACBT) It gets air behind mucus, lowers
airway spasm and clears mucus.
ACT….
Thoracic expansion exercises – deep breaths in. done with chest clapping or vibrating,
followed by breathing control. Forced expiration technique – huffs of varied
lengths with breathing control. Autogenic Drainage (AD) means “self-
drainage.” uses varied airflows to move mucus. aims to reach very high airflows in different
lung parts. This moves mucus from small to large airways.
New Therapy
Lung Transplant 900 LT /year in USA 1600 received LT from 1991 2003– 17 pts received from living
donor & 126 from cadaveric lung transplant
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Gene Therapy
Gene therapy is the use of normal DNA to "correct" for the damaged genes that cause disease.
In the case of CF, gene therapy involves inhaling a spray that delivers normal DNA to the lungs.
The goal is to replace the defective CF gene in the lungs to cure CF or slow the progression of the disease.
ThankYou!