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)

Fertility is mildly impairedCy

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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!