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Cystic Fibrosis. Paolo Aquino Internal Medicine-Pediatrics January 13, 2005. Outline. What is cystic fibrosis (CF)? What causes CF? What are the manifestations? How do you diagnose CF? How do you treat CF?. Cystic Fibrosis.

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Cystic fibrosis

Cystic Fibrosis

Paolo Aquino

Internal Medicine-Pediatrics

January 13, 2005


Outline

Outline

  • What is cystic fibrosis (CF)?

  • What causes CF?

  • What are the manifestations?

  • How do you diagnose CF?

  • How do you treat CF?


Cystic fibrosis1

Cystic Fibrosis

  • Inherited monogenic disorder presenting as a multisystem disease.

  • Typically presents in childhood

    • 7% of CF patients diagnosed as adults

  • Most common life limiting recessive trait among whites


Cystic fibrosis2

Cystic Fibrosis

  • Prognosis improving

    • >38% of CF patients are older than 18

    • 13% of CF patients are older than 30

  • Median survival

    • Males: 32 years

    • Females: 29 years


Genetics of cf

Genetics of CF

  • Autosomal recessive

  • Gene located on chromosome 7

  • Prevalence- varies with ethnic origin

    • 1 in 3000 live births in Caucasians in North America and Northern Europe

    • 1 in 17,000 live births of African Americans

    • 1 in 90,000 live births in Hawaiian Asians


Genetics of cf1

Genetics of CF

  • Most common mutation

    • Occurs in 70% of CF chromosomes

    • 3 base pair deletion leading to absence of phenylalanine at position 508 (DF508) of the CF transmembrane conductance regulator (CFTR)

  • Large number (>1000) of relatively uncommon muations (~2%)


Genetics of cf2

Genetics of CF

  • Difficult to use DNA diagnosis to screen for heterozygotes

  • No simple physiologic measurements yet available for heterozygote detection


Genetics of cf3

Genetics of CF

  • The CFTR protein

    • Single polypeptide chain, 1480 amino acids

    • Cyclic AMP regulated chloride channel

    • Regulator of other ion channels

    • Found in the plasma membrane of normal epithelial cells


Genetics of cf4

Genetics of CF

  • DF508 mutation leads to improper processing and intracellular degradation of the CFTR protein

  • Other mutations in the CF gene produce fully processed CFTR proteins that are either non-functional or partially functional


Mutation of cftr

Mutation of CFTR


Genetics of cf5

Genetics of CF

  • Epithelial dysfunction

    • Epithelia containing CFTR protein exhibit array of normal functions

      • Volume absorbing (airway, distal intestine)

      • Salt absorbing without volume (sweat ducts)

      • Volume secretory (proximal intestine, pancreas)

    • Dysfunction in CFTR gene leads to different effects on patterns of electrolyte and water transport


Persistence of cf

Persistence of CF

  • Is there a reason why CF mutations are so prevalent?

  • Hypothetical resistance to morbidity and mortality associated with cholera

  • Evidence shows intestinal epithelial cells homozygous for the DF508 mutation are unresponsive to the secretory effects of cholera toxin


Pathophysiology

Pathophysiology

  • Lung

    • Raised trans-epithelial electric potential difference

    • Absence of cAMP-dependent kinase and PKC-regulated chloride transport

    • Raised sodium transport and decreased chloride transport

    • Alternative calcium-regulated chloride channel in airway epithelia which is a potential therapeutic target


Cystic fibrosis

  • Normal airway epithelia

  • CF altered airway epithelia


Pathophysiology1

Pathophysiology

  • Lung

    • High rate of sodium absorption and low rate of chloride secretion reduces salt and water content in mucus, depletes peri-ciliary liquid

    • Mucus adheres to airway surface, leads to decreased mucus clearing

    • Predisposition to Staph and Pseudomonas infections


Pathophysiology2

Pathophysiology

  • Gastrointestinal

    • Pancreas

      • Absence of CFTR limits function of chloride-bicarbonate exchanger to secrete bicarbonate

      • Leads to retention of enzymes in the pancreas, destruction of pancreatic tissue.

    • Intestine

      • Decrease in water secretion leads to thickened mucus and dessicated intraluminal contents

      • Obstruction of small and large intestines


Pathophysiology3

Pathophysiology

  • Gastrointestinal

    • Biliary tree

      • Retention of biliary secretion

      • Focal biliary cirrhosis

      • Bile duct proliferation

      • Chronic cholecystitis, cholelithiasis

  • Sweat

    • Normal volume of sweat

    • Inability to reabsorb NaCl from sweat as it passes through sweat duct


Manifestations

Manifestations

  • Common presentations

    • Chronic cough

    • Recurrent pulmonary infiltrates

    • Failure to thrive

    • Meconium ileus


Manifestations1

Manifestations

  • Respiratory tract

    • Chronic sinusitis

      • Nasal obstruction

      • Rhinorrhea

      • Nasal polyps in 25%; often requires surgery

    • Chronic cough

      • Persistent

      • Viscous, purulent, green sputum


Manifestations2

Manifestations

  • Respiratory tract

    • Chronic cough

      • Exacerbations require aggressive therapy

        • Postural drainage

        • Antibiotics

        • Become more frequent with age

        • Progressive loss of lung function

    • Infection

      • Intially with H. influenzae and S. aureus

      • Subsequently P. aeruginosa

      • Occassionally, Xanthomonas xylosoxidans, Burkholderia gladioli, Proteus, E. coli, Klebsiella


Manifestations3

Manifestations

  • Respiratory tract

    • Lung function

      • Small airway disease is first functional lung abnormality

      • Progresses to reversible as well as irreversible changes in FEV1

      • Chest x-ray may show hyperinflation, mucus impaction, bronchial cuffing, bronchiectasis


Manifestations4

Manifestations

  • Respiratory tract

    • Complications

      • Pneumothorax ~10% of CF patients

      • Hemoptysis

      • Digital clubbing

      • Cor pulmonale

      • Respiratory failure


Manifestations5

Manifestations

  • Gastrointestinal

    • Meconium ileus

      • Abdominal distention

      • Failure to pass stool

      • Emesis

    • Abdominal flat plate

      • Air-fluid levels

      • Granular appearancemeconium

      • Small colon


Manifestations6

Manifestations

  • Gastrointestinal

    • Meconium ileus equivalent or distal intestinal obstruction syndrome

      • RLQ pain

      • Loss of appetite

      • Emesis

      • Palpable mass

      • May be confused with appendicitis


Manifestations7

Manifestations

  • Gastrointestinal

    • Exocrine pancreatic insufficiency

      • Found in >90% of CF patients

      • Protein and fat malabsorption

      • Frequent bulky, foul-smelling stools

      • Vitamin A, D, E, K malabsorption

      • Sparing of pancreatic beta cells

        • Beta cell function decreases with age

    • Increased incidence of GI malignancy


Manifestations8

Manifestations

  • Genitourinary

    • Late onset puberty

      • Due to chronic lung disease and inadequate nutrition

    • >95% of male patients with CF have azospermia due to obliteration of the vas deferens

    • 20% of female patients with CF are infertile

    • >90% of completed pregnancies produce viable infants


Diagnosis

Diagnosis

  • DNA analysis not useful due to large variety of CF mutations

  • Sweat chloride test >70 mEq/L

  • 1-2% of patients with clinical manifestations of CF have a normal sweat chloride test

    • Nasal transepithelial potential difference


Diagnosis1

Diagnosis

  • Criteria

    • One of the following

      • Presence of typical clinical features

      • History of CF in a sibling

      • Positive newborn screening test

    • Plus laboratory evidence for CFTR dysfunction

      • Two elevated sweat chloride concentrations on two separate days

      • Identification of two CF mutations

      • Abnormal nasal potential difference measurement


Treatment

Treatment

  • Major objectives

    • Promote clearance of secretions

    • Control lung infection

    • Provide adequate nutrition

    • Prevent intestinal obstruction

  • Investigation into therapies to restore the processing of misfolded CFTR protein


Treatment1

Treatment

  • Lung

    • >95% of CF patients die from complications of lung infection

    • Breathing exercises

    • Flutter valves

    • Chest percussion

    • ? Hypertonic saline aerosols


Treatment2

Treatment

  • Lung

    • Antibiotics

      • Early intervention, long course, high dose

      • Staphylococcus- Penicillin or cephalosporin

      • Oral cipro for pseudomonas

        • Rapid emergence of resistance

        • Intermittent treatment (2-3 weeks), not chronic

      • IV antibiotics for severe infections or infections resistant to orals


Treatment3

Treatment

  • Lung

    • Antibiotics

      • Pseudomonas treated with two drugs with different mechanisms to prevent resistance

        • e.g. cephalosporin + aminoglycoside

      • Use of aerosolized antibiotics

    • Increasing mucus clearance

      • N-acetylcysteine not clinically helpful

      • Long-term DNAse treatment increases time between pulmonary exacerbations


Treatment4

Treatment

  • Lung

    • Inhaled b-adrenergic agonists to control airway constriction

      • No evidence of long-term benefit

    • Oral glucocoticoids for allergic bronchopulmonary aspergillosis

    • Studying benefits of high dose NSAID therapy for chronic inflammatory changes


Treatment5

Treatment

  • Lung

    • Atelectasis

      • Chest PT + antibiotics

    • Respiratory failure and cor pulmonale

      • Vigorous medical management

      • Oxygen supplementation

      • Only effective treatment for respiratory failure is lung transplantation

        • 2 year survival >60% with lung transplatation


Treatment6

Treatment

  • Gastrointestinal

    • Pancreatic enzyme replacement

    • Replacement of fat-soluble vitamins- especially vitamin E & K

    • Insulin for hyperglycemia

    • Intestinal obstruction

      • Pancreatic enzymes + osmotically active agents

      • Distal- hypertonic radiocontrast material via enema


Treatment7

Treatment

  • Gastrointestinal

    • End-stage liver disease- transplantation

      • 2 year survival rate >50%

    • Hepatic and gallbladder complications treated as in patient without CF


Summary

Summary

  • CF is an inherited monogenic disorder presenting as a multisystem disease

  • Pathophysiology is related to abnormal ion transportation across epithelia

  • Respiratory, GI and GU manifestations

  • Treatment is currently preventative and supportive


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