Updated: 10/28/2020

Cystic Fibrosis

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Snapshot
  • A 3-year-old boy with a history of recurrent pneumonia and chronic diarrhea. His mother states that he has 6-8 four smelling stools per day. PE reveals a low grade fever, scattered rhonchi over both lung fields, crepitant rales at the left lung base and dullness to percussion. 
Introduction
  • Cystic fibrosis is a genetic disorder leading to excessive, viscous secretions that plug exocrine glands
    • autosomal recessive disorder
    • caused by mutations in CFTR gene (chloride channel) on chromosome 7
      • CFTR is a transmembrane cAMP-activated ion channel  
        • its normal function is to reabsorb chloride ions (lumen cell) in sweat glands and to secrete chloride ions (cell lumen) in other exocrine glands (e.g., pancreas and lungs 
        • movement of chloride creates a charge gradient that induces movement of sodium ions in the same direction as chloride to mitigate the gradient
        • movement of these ions drags solvent (water) with them
      • 3 nucleotide deletion
        • most common mutation is 508 Phe del 
      • result is instability of CFTR protein and premature degradation by Golgi apparatus
      • inability to alter ionic gradients of Cl- results in mucus dehydration 
  • Affects multiple organ systems with widespread exocrine gland dysfunction
    • pancreatic exocrine insufficiency is responsible for most of them
  • Epidemiology
    • most common genetic disease in the United States
    • mostly affects Caucasians
    • Newborn screening now routine in all states
Presentation
  • Symptoms
    • respiratory symptoms are more prominent in adulthood
      • recurrent pulmonary infections
        • Pseudomonal spp and S. aureus are most common
      • chronic sinusitis
      • chronic, productive cough
      • dyspnea on exertion
      • hemoptysis
    • gastrointestinal symptoms are more prominent in infancy
      • chronic, frequent diarrhea
        • greasy stool with flatulence from malabsorption secondary to pancreatic insufficiency
        • can lead to rectal prolapse
      • meconium ileus in infants (15%)
      • pancreatitis 
    • other symptoms
      • calcium oxalate kidney stones
        • secondary to fat malabosorption
  • Physical exam
    • failure to thrive (50%)
    • respiratory compromise (50%)
    • "salty taste"
    • cyanosis
    • digital clubbing
    • ronchi
    • rales
    • hyperresonance of chest to percussion
    • nasal polyposis
Evaluation
  • CXR
    • hyperinflation
    • prominent bronchovascular markings
      • bronchiectasis with "tram tracks" and peribronchial cuffing
      • diffuse bronciectactic changes
  • Sweat chloride test
    • historical diagnostic gold standard
    • >60 mEq/L in patients <20 years old
    • >80 mEq/L in adults
  • Genetic testing
    • confirms disease by identification of specific genetic mutation
  • Immunoreactive trypsinogen assay
  • Nasal transepithelial potential difference
  • Pulmonary function testing
    • often abnormal before first birthday
    • obstructive pattern with increased lung volumes (TLC and RV) over time from air trapping and hyperinflation
    • reduced diffusing capacity (DLCO)
    • reduced or normal FEV1:FVC ratio given obstructive pattern with possible late restrictive features (e.g., fibrosis, tissue destruction, and/or hyperinflation) 
Differential
  • Inherited immunodeficiency (SCID, CVID)
  • Primary ciliary dyskinesia
Treatment
  • Lifestyle
    • health maintenance
      • nutritional counseling
      • psychiatric/psychologic support indicated in most patients with or without mental instability
      • up-to-date immunizations indicated in all patients
  • Pharmacologic
    • respiratory therapy
      • indicated in all patients
      • includes several components including
        • chest physiotherapy (percussion, positive pressure, nebulizers)
        • bronchodilators
        • inhaled corticosteriods 
          • if asthmatic component or ABPA
        • DNA-ase and hypertonic saline
        • antibiotics 
          • chronic macrolide therapy common
          • IV antibiotics for acute exacerbations
        • anti-inflammatory agents (ibuprofen)
    • pancreatic enzymes and fat-soluble vitamins
      • indicated for malabsorption
  • Operative
    • lung and pancreas transplantation
      • indicated for most severe, but only if patient can tolerate surgery
Prognosis, Prevention, and Complications
  • Prognosis
    • while patients are living longer and more complete lives with modern medicine, rarely do CF patients live beyond 40 years of age without transplantation
  • Prevention
    • immunization for influenza and pneumococcus can prevent infections
    • embryonic selection, although controversial, has been used by known carriers or affected couples to prevent transmission of the disease to their children
  • Complications
    • chronic hypoxemia and hypercapnia lead to pulmonary hypertension
      • patients often develop cor pulmonale (RHF)
    • Recurrent, drug-resistent bacterial or fungal pneumonias 
      • classically Pseudomonas
    • idiopathic hyponatremia
    • CF-related diabetes mellitus
    • fat-soluble vitamin deficiency (low vitamin A, D, K, and E)  
    • esophageal varices
    • biliary cirrhosis and cholelithiasis
    • infertility (95%)  
      • absence/obliteration of the vas deferens 
    • heat exhaustion (poor sweating)
 

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(M1.PL.15.72) A 1-year-old child who was born outside of the United States is brought to a pediatrician for the first time because she is not gaining weight. Upon questioning, the pediatrician learns that the child has had frequent pulmonary infections since birth, and on exam the pediatrician appreciates several nasal polyps. Genetic testing is subsequently ordered to confirm the suspected diagnosis. Testing is most likely to show absence of which of the following amino acids from the protein involved in this child's condition? Tested Concept

QID: 106523
1

Histidine

6%

(2/34)

2

Leucine

3%

(1/34)

3

Lysine

0%

(0/34)

4

Valine

3%

(1/34)

5

Phenylalanine

76%

(26/34)

M 1 C

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(M1.PL.15.72) A newborn is found to have cystic fibrosis during routine newborn screening. The parents, both biochemists, are curious about the biochemical basis of their newborn's condition. The pediatrician explains that the mutation causing cystic fibrosis affects the CFTR gene which codes for the CFTR channel. Which of the following correctly describes the pathogenesis of the most common CFTR mutation? Tested Concept

QID: 106514
1

Insufficient CFTR channel production

14%

(6/42)

2

Defective post-translational glycosylation of the CFTR channel

50%

(21/42)

3

Excess CFTR channel production

0%

(0/42)

4

Defective post-translational hydroxylation of the CFTR channel

19%

(8/42)

5

Defective post-translational phosphorylation of the CFTR channel

14%

(6/42)

M 1 C

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(M1.PL.14.0) A 1-year-old male with a history of recurrent pseudomonal respiratory infections and steatorrhea presents to the pediatrician for a sweat test. The results demonstrate a chloride concentration of 70 mEq/L (nl < 40 mEq/L). Which of the following defects has a similar mode of inheritance as the disorder experienced by this patient? Tested Concept

QID: 106978
1

Trinucleotide repeat expansion of CAG on chromosome 4

8%

(3/39)

2

Accumulation of glycogen in the lysosome

49%

(19/39)

3

Inability to convert carbamoyl phosphate and ornithine into citrulline

23%

(9/39)

4

Abnormal production of type IV collagen

13%

(5/39)

5

Mutated gene for mitochondrial-tRNA-Lys

3%

(1/39)

M 1 D

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(M1.PL.14.91) A 27-year-old female presents to general medical clinic for a routine checkup. She has a genetic disease marked by a mutation in a chloride transporter. She has a history of chronic bronchitis. She has a brother with a similar history of infections as well as infertility. Which of the following is most likely true regarding a potential vitamin deficiency complication secondary to this patient's chronic illness? Tested Concept

QID: 104731
1

It may result in wound healing defects

15%

(7/47)

2

It may result in corneal vascularization

23%

(11/47)

3

It may result in the triad of confusion, ophthalmoplegia, and ataxia

11%

(5/47)

4

It may be exacerbated by excessive ingestion of raw eggs

4%

(2/47)

5

It may manifest itself as a prolonged PT

43%

(20/47)

M 4 D

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(M1.PL.13.79) A child with which of the following diseases would have the highest morbidity from being outside during a hot summer day? Tested Concept

QID: 100882
1

Tay-Sachs disease

2%

(1/56)

2

Cystic fibrosis

80%

(45/56)

3

Cerebral palsy

0%

(0/56)

4

Down syndrome

0%

(0/56)

5

Asthma

14%

(8/56)

M 4 E

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(M1.PL.13.3) A 4-year-old Caucasian girl previously diagnosed with asthma presents with recurrent sinusitis, otitis media, and clubbing of the nail bed. Family history is significant for a distant cousin with cystic fibrosis. A "sweat test" is performed and comes back normal. What additional diagnostic test would be helpful in establishing a diagnosis? Tested Concept

QID: 100806
1

Nasal transepithelial potential difference

60%

(61/102)

2

Chest radiograph

19%

(19/102)

3

Skeletal survey

1%

(1/102)

4

Complete blood cell count

13%

(13/102)

5

Urinalysis

7%

(7/102)

M 2 E

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