Cystic Fibrosis:Cystic Fibrosis:

““Cystic fibrosis is an inherited Cystic fibrosis is an inherited multisystem disorder Characterized bymultisystem disorder Characterized by

obstruction & infection of airways & obstruction & infection of airways &

maldigestion & its consequencesmaldigestion & its consequences”.”.

Genetics:Genetics:

AR – 1/3500 live birthsAR – 1/3500 live births

Gene locus on long arm of chromosome 7Gene locus on long arm of chromosome 7

CF gene -CF transmembrane CF gene -CF transmembrane regulator(CFTR)regulator(CFTR)

CFTR- cAMP - regulated chloride channelCFTR- cAMP - regulated chloride channel

Expressed on ephitheial cells Expressed on ephitheial cells

>1500 mutations-most prevalent >1500 mutations-most prevalent ∆F508 ∆F508

The net ion flow across normal and cystic fibrosis cell

Pathophysiology (cont…)

1- Paucity of water in mucus secretions1- Paucity of water in mucus secretions

2- Failure to clear mucous secretions2- Failure to clear mucous secretions

3- Ch. infection limited to respiratory tract 3- Ch. infection limited to respiratory tract

4- Elevated salt content of sweat & other 4- Elevated salt content of sweat & other serous secretions serous secretions

Pathology:Pathology:

Lungs:Lungs: Bronchiolitis – Bronchitis-Bronchiolitis – Bronchitis- Bronchiectasis Bronchiectasis

Bronchiectatic cysts Bronchiectatic cysts

Pneumothorax Pneumothorax

Hemoptysis Hemoptysis Secondary pulmonary HTNSecondary pulmonary HTN

Paranasal sinuses:Paranasal sinuses:

Epithelial lining hyperplastic & Epithelial lining hyperplastic & hypertrophiedhypertrophied

Polypoid lesions, mucopyocele & erosion of Polypoid lesions, mucopyocele & erosion of bone may bone may occuroccur

Multiple polyps Multiple polyps

Pancreas:Pancreas:Small & cysticSmall & cystic

In 85-90% of cases replacement with In 85-90% of cases replacement with fibrous fibrous tissue & fattissue & fat

Foci of calcification may occurFoci of calcification may occur

Islets of langerhans – architectural Islets of langerhans – architectural disruption disruption

Intestinal Tract:Intestinal Tract:Minimal changesMinimal changes

Esophageal & duodenal glands are Esophageal & duodenal glands are distended with mucous secretionsdistended with mucous secretions

Crypts of appendix & rectum are Crypts of appendix & rectum are

distended with secretionsdistended with secretions

Biliary System:Biliary System:

Occasional prolonged NNJOccasional prolonged NNJ

Focal biliary cirrhosis in 25% casesFocal biliary cirrhosis in 25% cases

Fatty infiltration in 30% Fatty infiltration in 30%

Symptomatic multilobular biliary cirrhosisSymptomatic multilobular biliary cirrhosis

Gallbladder-hypoplastic Gallbladder-hypoplastic

Atresia of cystic duct & stenosis of Atresia of cystic duct & stenosis of distal common bile ductdistal common bile duct

Genitourinary Genitourinary system:system:

EndocervicitisEndocervicitis

In >95% males epididymis, vas In >95% males epididymis, vas deferens deferens & seminal vesicles are & seminal vesicles are obliteratedobliterated

Generalized amyloidosis rareGeneralized amyloidosis rare

Clinical Clinical Manifestations:Manifestations:Respiratory Tract:Respiratory Tract:

Symptoms Symptoms Cough, Wheezing, Shortness of breath Cough, Wheezing, Shortness of breath Exercise intolerance Exercise intolerance Rhinorhea, Nasal obstructionRhinorhea, Nasal obstruction

SignsSignsCyanosis, Digital clubbing, Cyanosis, Digital clubbing, Increased AP diameter of chestIncreased AP diameter of chestGen.hyper resonance, Coarse Gen.hyper resonance, Coarse

crackles, crackles, Expiratory wheeze Expiratory wheeze Acute sinusitis,Acute sinusitis, Nasal polyps Nasal polyps

Intestinal Tract:Intestinal Tract:

Meconium Ileus:Meconium Ileus:In 15-20% NewbornIn 15-20% Newborn

Meconium Plug Syndrome:Meconium Plug Syndrome:Less specific than meconium Less specific than meconium

ileus ileus Distal intestinal obstruction Distal intestinal obstruction with fecal material in older ptswith fecal material in older pts

Intestinal Tract:Intestinal Tract:

– Symptoms Symptoms Greasy stool, Excessive flatus Greasy stool, Excessive flatus Acid or bile reflux Acid or bile reflux Vit. Deficiencies- ADEKVit. Deficiencies- ADEK

– SignsSignsProtuberant abdomen Protuberant abdomen Intussusception Intussusception Fecal impaction of cecum Fecal impaction of cecum Subacute appendicitis,Subacute appendicitis,AnasarcaAnasarca

Biliary Tract:Biliary Tract:

Biliary cirrhosis 2-3% ptsBiliary cirrhosis 2-3% ptsBiliary colicBiliary colic

Icterus, Icterus,

Ascites Ascites Hematemesis Hematemesis Hypersplenism Hypersplenism Neonatal Hepatitis like picture Neonatal Hepatitis like picture HepatomegalyHepatomegaly

Pancreas:Pancreas:Exocrine pancreatic insufficiency Exocrine pancreatic insufficiency

Hyperglycemia, Hyperglycemia,

Glycosuria Glycosuria Polyuria Polyuria Weight loss Weight loss after 10 yrs of age after 10 yrs of age

when 8 % when 8 % acquire acquire diabetes diabetes

Recurrent acute pancreatitis Recurrent acute pancreatitis

Genitourinary system:Genitourinary system:

An average of 2 yrs delay in sexual An average of 2 yrs delay in sexual developmentdevelopment

MalesMales

>95% azoospermic >95% azoospermic Sexual function unimpaired Sexual function unimpaired

FemaleFemaleCervicitis Cervicitis

Secondary amenorrhea Secondary amenorrhea Decrease fertility Decrease fertility Pregnancy well toleratedPregnancy well tolerated

Sweat Glands: Sweat Glands:

Excessive loss of salt in sweatExcessive loss of salt in sweat

During gastroenteritis & warm weatherDuring gastroenteritis & warm weather

Hypochloremic alklosisHypochloremic alklosis

Diagnostic Criteria for Cystic FibrosisDiagnostic Criteria for Cystic Fibrosis

Presence of typical clinical featuresPresence of typical clinical featuresOROR

History of CF in a sibling History of CF in a sibling OROR

Positive newborn screening testPositive newborn screening test

PLUSPLUSLab evidence for CFTR dysfunctionLab evidence for CFTR dysfunction

Two elevated sweat Chloride testsTwo elevated sweat Chloride testsOROR

Identification of 2 CF mutations Identification of 2 CF mutations OROR

An abnormal nasal potential An abnormal nasal potential difference difference measurementmeasurement

Diagnosis:Diagnosis:

Sweat TestingSweat Testing

> 60mEq/L of chloride in sweat > 60mEq/L of chloride in sweat

Threshold levels of 40mEq/L have Threshold levels of 40mEq/L have been suggested been suggested

Values b/w 40-60mEq/L suggest Values b/w 40-60mEq/L suggest CF at all ages CF at all ages

Radiology Radiology

PulmonaryPulmonary Hyperinflation of lung, Hyperinflation of lung,

Atelactasis & Bronchiectasis Atelactasis & Bronchiectasis Dilated pulmonary artery segment Dilated pulmonary artery segment

Paranasal Sinuses Paranasal Sinuses Pan opacification Pan opacification Failure of frontal sinus to developFailure of frontal sinus to develop

Fetal USGFetal USGIleal obstruction with meconium in 2Ileal obstruction with meconium in 2ndnd

trimestertrimester

Pulmonary FunctionPulmonary Function

Not obtained till 5-6 yrs of ageNot obtained till 5-6 yrs of ageRV & FRC are increased (early)RV & FRC are increased (early)Declining total lung capacity & Declining total lung capacity &

VC(late) VC(late)

Microbiological StudiesMicrobiological Studies Staph aureus, Staph aureus,

pseudomonas aeruginosa, B. cepaciapseudomonas aeruginosa, B. cepacia

Newborn ScreeningNewborn Screening Immunoreactive trysinogen in blood spots Immunoreactive trysinogen in blood spots Confirmatory sweat & DNA testingConfirmatory sweat & DNA testing

Other Investigations as IndicatedOther Investigations as Indicated Cardiac: ECG, EchocardiographyCardiac: ECG, EchocardiographyGIT: S. proteins, LFTs, coagulationGIT: S. proteins, LFTs, coagulation

studies, x-ray abdomen, USG abdomen, studies, x-ray abdomen, USG abdomen, hepatobiliary Tc-99 Scintigraphy, PTC, hepatobiliary Tc-99 Scintigraphy, PTC, ERCP, pancreatic function testsERCP, pancreatic function testsOther: urea & electrolytes Other: urea & electrolytes

Management of CF:Aims:

1. Ensure optimal growth & development2. Delaying progress of pulmonary disease3. Preventing & treating complications4. Normal life style5. Patient & family education6. Recognition & treatment of psychological complications

Multidisciplinary approach

Treatment:Treatment:

1- Treatment of Lung disease1- Treatment of Lung disease

2- Treatment of Gastrointestinal disease 2- Treatment of Gastrointestinal disease

3- Nutritional therapy 3- Nutritional therapy

4- Treatment of Complications 4- Treatment of Complications

Treatment of lung disease:

1. Antibiotics2. Chest physiotherapy3. Nebulized treatment4. Bronchodilators5. Anti inflamatory treatment6. Mucolytic treatment7. Management of allergic pulm.Aspergilosis8. Hemoptysis9. Pneumothorax10. Cor- Pulmonale

11. Immunization- influenza

Antibiotic therapy:Antibiotic therapy:Staph aureus, H. influenzae, Staph aureus, H. influenzae, P. aeruginos, Burkholderia cepacia P. aeruginos, Burkholderia cepacia

Intermittent oral Antibiotic Therapy Intermittent oral Antibiotic Therapy Continous oral Antibiotic TherapyContinous oral Antibiotic TherapyI/V antibiotic therapy I/V antibiotic therapy

Important points to remember are-Important points to remember are-Sputum cultures do reflect lung floraSputum cultures do reflect lung floraDouble doseDouble doseAdult dose from 7yrsAdult dose from 7yrs

Chest Physio TherapyChest Physio Therapy

Postural drainagePostural drainage

Percusion & vibrationPercusion & vibration

10-20 min, One to 4 time a day10-20 min, One to 4 time a dayRoutine aerobic exercises Routine aerobic exercises

Nebulized Treatment:Nebulized Treatment:

Hypertonic saline Hypertonic saline

Bronchodilators Bronchodilators MucolyticsMucolyticsAntibioticsAntibioticsCromolynCromolynCorticosteroidsCorticosteroids

Dornase Alpha Dornase Alpha Nebulized amiloride(Na+channel Nebulized amiloride(Na+channel

blocker)blocker)

Bronchodilator Treatment:Increased bronchial activity in 40-75 % ptsStandard asthma treatment

Anti- Inflamatory treatment:Long term corticosteroids & Ibuoprofen – Slow the progres of CF

Hemoptysis:

Minor hemoptysis- No specific treatment

Hemoptysis > 15-20mlAdmit in WardO2 InhalationVit. KBlood transfusionAntibioticsStop chest physiotherapy

Treatment of GIT disease:

1. PERT2. Salt3. Management of meconium ileus4. DIOS5. Rectal prolapse6. Liver & biliary tract disease7. Fibrosing Colonopathy8. Abd. Pain

P E R T: (Lipase, Amylase, Proteases)P E R T: (Lipase, Amylase, Proteases)

Fat absorption improves from 60% Fat absorption improves from 60% without without therapy to 85-90% with therapytherapy to 85-90% with therapy

An upper limit of 10,000 units An upper limit of 10,000 units lipase/kg/daylipase/kg/day

PERT for infants 500-1000 U lipase/g of PERT for infants 500-1000 U lipase/g of dietary fatdietary fat

PERT for children 500-4000 U lipase/g of PERT for children 500-4000 U lipase/g of dietary fatdietary fat

Fibrosing colonopathyFibrosing colonopathy

Nutritional Therapy:Nutritional Therapy:

*CF pts require 120% of normal energy*CF pts require 120% of normal energy

requirement requirement *Liberal diet containing *Liberal diet containing

Fats, SugarFats, SugarMilk products, Protein foodsMilk products, Protein foods

*Salt*Salt

< 6m< 6m 0.5g/d0.5g/d

6-12m6-12m 1.0g/d1.0g/d

1-5yrs1-5yrs 2.0g/d2.0g/d

>5yrs>5yrs 3.0g/d3.0g/d

Treatment of other Complications:

1. Diabetes Mellitus- DKA rare

2. Musculoskeletal problems- Pulmonary care & NSAID

3. Lung transplantation- Life expectancy <2yrs Quality of life impaired Frequent life threatening

hemoptysis

Prognosis:Median survival 40 yrs

> 90 % mortality is due to lung disease

Cirrhosis is second life threatening complication

Poor prognosis factors includeFemale sexMultiple organ involvementAbnormal chest x- ray 12m after diagnosisPoor growthRecurrent hemoptysisPneumothoraxCorpulmonale

Thank You

Pulmonary Treatment (Cont…)Pulmonary Treatment (Cont…)Bronchodilator TreatmentBronchodilator Treatment

Inhaled B2 agonistsInhaled B2 agonistsAnticholinergics, Oral theophyllineAnticholinergics, Oral theophylline

Anti Inflammatory TreatmentAnti Inflammatory TreatmentLong term use of oral corticosteroids & Long term use of oral corticosteroids &

ibuprofenibuprofenMucolytic Treatment: Mucolytic Treatment:

Dornase Alpha Dornase Alpha (Recombinant (Recombinant Human Human Deoxyribonuclease 1)Deoxyribonuclease 1)

Cleaves extracellular DNA & decreases Cleaves extracellular DNA & decreases viscoelasticity of purulent secretionsviscoelasticity of purulent secretionsUsed in chronic suppurative disease or Used in chronic suppurative disease or

obstructive obstructive disease disease Dose: 2.5 mg ODDose: 2.5 mg OD

Pulmonary Treatment Pulmonary Treatment (Cont…)(Cont…)

Aerosolized Antibiotic TherapyAerosolized Antibiotic Therapy

Inhaled tobramycin, 300mg twice Inhaled tobramycin, 300mg twice daily daily on alternate months for 6 on alternate months for 6 monthsmonths

Ticarcillin, 0.5g, BD OR QIDTicarcillin, 0.5g, BD OR QIDColistin, 20-40mg, BD OR QIDColistin, 20-40mg, BD OR QID

Pulmonary Treatment (Cont…)Pulmonary Treatment (Cont…)

Intravenous Antibiotic TherapyIntravenous Antibiotic TherapyIndicated in pts. Who have Indicated in pts. Who have

progressive progressive or unrelenting symptoms or or unrelenting symptoms or signs signs despite intensive home despite intensive home measures measures

Period of treatment is 14 daysPeriod of treatment is 14 daysPseudomonas requires 2 drug Pseudomonas requires 2 drug

therapy therapy

The net ion flow across normal and cystic fibrosis

Other Diagnostic TestsOther Diagnostic Tests

potential difference across nasal potential difference across nasal epitheliumepithelium

Loss of this difference with topical amiloride Loss of this difference with topical amiloride applicationapplication

Absence of voltage response to B–Absence of voltage response to B–

adrenergic adrenergic agonistagonist

Failure to sweat when a combination of Failure to sweat when a combination of isoproterenol and atropine is injected in isoproterenol and atropine is injected in skinskin

PathophysiologyCFTR mutation

In airways cells can’t excrete Cl- from cells into the lumen through cAMP mediatedCFTR channels

In sweat glands cAMP mediated conductance ofCl- in to the cells is defective

Cl- is trapped inside the cells

sodium follows chloride & water follows sodium

secretions in the lumenbecome viscous & elastic & are harder to clear

so Cl- can’ t be absorbed from the sweat

sodium follows chloride

salt is lost in sweat

Secretions are Retained & obstruct airway