Cystic Fibrosis - Flashcards
Definition of cystic fibrosis
Cystic fibrosis is an inherited multi-system disorder of children and adults, characterized chiefly by obstruction and infection of the airways, and mal-digestion and its consequences.
This is the most common life-limiting recessive genetic trait among whites. Lower life expectancy for women.
A dysfunction of epithelial cells of the airways, GI tract, the swat glands and the genitourinary system is the predominant pathogenic process.
CF is the major cause of severe chronic lung disease in children, and is responsible for most exocrine pancreatic insufficiency during early life.
Genetics of CF
Autosomal recessive- on chromosome 7. CFTR (cystic fibrosis transmembrane conductance regulator protein) gene product. Channelopathy. CFTR- Membrane protein, ATP depended epithelial chloride channel, regulator of ENAc, endosomal pH and other cellular proteins. P aeruginosa receptro.
Overview of ion channels in CF in airway and sweat ducts
Na follows Cl and both accumulate in lumen in sweat ducts.
Na overcompensates for Cl accumulation in airway cell by also accumulating in cell, water follows and mucus becomes dehydrated.
What is the isotonic concentration of sodium and cholride in blood and sweat?
Blood: Na: 140mM, Cl: 100 mM
Sweat: 40mM (>60 is a positive sweat test)
What is the Airway Surface Layer (ASL) made of?
PCL + Mucus layer
PCL (Peri-Ciliary Liquid) = 7 micron
Hydration of ASL is the dominant variable governing MCC-Muco-ciliary clearance .
What are the most common mutations in CFTR and classes of mutations?
One common mutation (DF508) accounts for about 70% of CF alleles in Northern CP population.
10-20 less common mutations account for 2-15% of CF alleles depending upon ethnic group.
Remainder of mutations are rare.
Severe:
- Defective CFTR production- Stop mutation at level of the nucleus, mRNA truncated (G542X). No synthesis
- Defective CFTR processing and trafficking to the apical membrane (Delta F508). Defective maturation and premature degredation.
- Defective regulation of Cl- channel function from mutations in CFTR phosphorylation of ATP binding sites or hydrolysis (G551D).
Other:
- Defective Cl- conductance or channel gating (R347P).
- Abnormal splicing of CFTR or promoter (3849 C-T), fewer transcriptions
Respiratory Presentations of CF
Chronic Cough
Recurrent\Chronic Bronchitis or Pneumonia
Severe Wheezing\ hyperinflation
Forced expiratory flow is low: obstruction
Tachypnea \ retractions
Bronchiectasis (more in upper lobe)
Staph\Pseudomonas Colonization in the respiratory tract
Nasal Polyposis
Chronic Pansinusitis
Clubbing
Arterial PCO2 is high: indication for lung transplant
Presenting clinical manifestations
Acute or persistent respiratory symptoms 50%
Failure to thrive, malnutrition 43%
Abnormal stools 35%
Meconium ileus (at birth), intestinal obstruction 19%
Family history of CF 17%
Electrolyte, acid base abnormality 5%
Rectal prolapse 3.5%
Nasal polyps, sinus disease 2.0%
Hepatobiliary disease 0.9%
Other 1-2%
How is clubbing diagnosed?
Ratio of thickness at first knuckle (IPD) to thickness at nailbed (DPD) In normal individuals, the DPD:IPD ratio is <1. However, in clubbed fingers, the distal portion is thicker and thus, the ratio of DPD:IPD is >1.
Diamond appears in normal fingers when index fingers are placed with nailbeds against each other. In clubbing, they are flush with a triangle.
What is the most common pathogen in CF?
Up until age 10: S aureus
After age 10: Pseudomonas aeruginosa (worsen survival, especially mucoid)
GI presentation of CF
Meconium Ileus
Prolonged Neonatal Jaundice
Steatorrhea
Rectal Prolapse
Mucoid Impacted Appendix
Recurrent Intussusception
Recurrent Pancreatitis (caused by backup of exocrine enzymes from blockage of lumen, 85% born with pancreatic insufficiency, endocrine replaced by fatty tissue)
Cirrhosis, Portal Hypertension
Distal Intestinal Obstruction Syndrome (DIOS: abdominal pain manifestation, not enough adherence to enzyme -treatment: enema to open small intestine)
Metabolic Presentations of Cystic Fibrosis
Failure to Thrive
Hypoproteinemia, edema (from malabsorption and hypoalbuminuria)
Hemolytic anemia - Vitamin E deficiency
Salt depletion – Metabolic alkalosis
Vitamin A, E D deficiency (fat soluble)
Salty Taste
Aspermia/CBAVD
Biliary problems cause liver cirrhosis
Diagnostic criteria for CF
Presence of typical clinical features (respiratory, gastroentestinal, or genitourinary)
or
A history of CF in a sibling
or
A positive newborn screening test
PLUS
Laboratory evidence for CFTR dysfunction:
2 elevated sweat tests, OR
identification of 2 CF mutations, OR
an abnormal nasal PD measurement.
1% of CF patients have normal sweat test (atypical)
CF Typical Phenotype
Chronic sinusitis, severe chronic infection, severe hepatobiliary disease, pancreatic insufficiency, meconium ileus at birth, elevated sweat Cl values, Obstructive azoospermia
Atypical CF Phenotype
Chronic sinusitis, chronic infection, normal hepatobiliary function, pancreatic sufficiency, no meconium ileus at birth, normal or borderline sweat chloride values, obstructive azoospermia
