Lecture 63: Pulmonary Clinical Correlations, Dr.

Rao

• Cystic Fibrosis
○ Multisystem, autosomal recessive disease caused by a defective CF gene
(CFTR) on chromosome 7
○ Affects > 30,000 children and adults in the US (55,000 worldwide)
○ Caucasians have 5-7% carrier rate
• History of CF
○ First clinical description, 1938: life expectancy < 1 yr
○ CFTR cloned in 1989: life expectancy 27 years
○ Current life expectancy > 33 yrs
• CFTR Gene
○ Located on long arm of chr 7
○ Consists of 27 exons that encode the 1480 amino acid CFTR protein
○ Member of ABC family of transporters
○ Six classes of mutations all w/ variable disease severity
– I : No synthesis
– II : Defective processing
– III : Disordered regulation
– IV : Abnormal conduction
– V: Reduced synthesis
– VI: Accelerated turnover
○ ΔF508 mutation accounts for 70% of alleles
○ Mutational analysis has 90% sensitivity for Caucasians
○ CFTR activity results from genotype
○ Individual organ systems require different levels of CFTR activity
○ Environmental factors involved in phenotypic expression
○ Modifier genes also thought to play a role
• Diagnosis of CF
○ Requires one of the following:
– >1 typical phenotypic feature of CF
– Sibling w/ CF
– Positive newborn screening test
○ Plus one of the following:
– Elevated sweat chloride on 2 occasions
– 2 identified CFTR mutations
– Abnormal nasal potential difference
○ Classical triad for CF is pancreatic insufficiency, chronic pulmonary disease
and abnormal sweat chloride test
○ Most often there is a h/o CF in the sibling or first cousin
• Primary Manifestations
○ Respiratory tract
– Susceptible to bacterial infections
– Mucus which lines airways is thicker than normal serving as a host for
bacteria and obstruction of the airway
– Mucus is poorly hydrated due to CFTR failure
 – Abnormal glycoproteins present in mucus
– Most prevalent infection is pseudomonas (Pa)
– Respiratory complications include pneumothorax, hemoptysis and
respiratory failure
– Leading cause of death in CF
– Damage begins early in life
○ Digestive tract
– Pancreas produces enzymes that aid in digestion
– In CF thick mucus plugs the pancreas so that these enzymes are not
secreted
– Digestion and absorption of nutrients (including vit ADEK) are affected
– Results in conjunctivitis, rickets, ataxia, anemia, hemorrhage
– Testing for pancreatic deficiency include testing for fecal elastase and a
72 hour fecal fat balance study
– The backed up enzymes cause severe damage over time and diabetes
is commonly seen
• Clinical Case #1
○ 3 month old presents w/ loose foul smelling, greasy stools and cannot gain
weight
○ Failure to thrive
• Clinical Case #2
○ 5 y.o. w/ h/o chronic sinusitis, frequent wheezing, and a chronic cough w/ thick
green sputum occasionally w/ blood
– Diagnosed w/ asthma but no improvement
– On clinical exam clubbing of fingers, nasal polyps and wheezing
– Lung tests reveal obstructive lung disease
– Sweat chloride test abnormal
• Managing CF
○ Early screening
○ Nutrition : pancreatic enzyme replacement, high calorie requirements and
vitamin supplementation
○ Infections : antibiotics
○ Inflammation : anti-inflammatory meds
• Current Treatments
○ Airway clearance
– 10% improvement
○ Mucolytics including Dornase Alpha (Pulmozyme) and Hypertonic Saline
○ Corticosteroids
○ Long-term high-dose ibuprofen
○ Azithromycin
○ Recurrent chest xrays
○ Lung transplants