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

• 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 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

• • • 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 CF

• Most common mutation – Occurs in 70% of CF chromosomes – 3 base pair deletion leading to absence of phenylalanine at position 508 ( D F 508 ) of the CF transmembrane conductance regulator (CFTR) • Large number (>1000) of relatively uncommon muations (~2%)

Genetics of CF

• Difficult to use DNA diagnosis to screen for heterozygotes • No simple physiologic measurements yet available for heterozygote detection

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 CF

• D F 508 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

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

• • • 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 D F 508 mutation are unresponsive to the secretory effects of cholera toxin

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

• Normal airway epithelia • CF altered airway epithelia

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

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

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

• Common presentations – Chronic cough – Recurrent pulmonary infiltrates – Failure to thrive – Meconium ileus

Manifestations

• Respiratory tract – Chronic sinusitis • • • Nasal obstruction Rhinorrhea Nasal polyps in 25%; often requires surgery – Chronic cough • • Persistent Viscous, purulent, green sputum

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

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

Manifestations

• Respiratory tract – Complications • • • • • Pneumothorax ~10% of CF patients Hemoptysis Digital clubbing Cor pulmonale Respiratory failure

Manifestations

• Gastrointestinal – Meconium ileus • • • Abdominal distention Failure to pass stool Emesis – Abdominal flat plate • • • Air-fluid levels Granular appearance  meconium Small colon

Manifestations

• Gastrointestinal – Meconium ileus equivalent or distal intestinal obstruction syndrome • • • • • RLQ pain Loss of appetite Emesis Palpable mass May be confused with appendicitis

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

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

• • • 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

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

• 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

Treatment

• Lung – >95% of CF patients die from complications of lung infection – Breathing exercises – Flutter valves – Chest percussion – ? Hypertonic saline aerosols

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

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

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

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

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

Treatment

• Gastrointestinal – End-stage liver disease- transplantation • 2 year survival rate >50% – Hepatic and gallbladder complications treated as in patient without CF

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