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Internal Medicine

Cystic Fibrosis

Cystic fibrosis (mucoviscidosis) is a multisystemic disorder due to the mutations in both copies of the gene for the cystic fibrosis transmembrane conductance regulator (CFTR) protein (chloride channel of exocrine glands).

Cystic fibrosis (mucoviscidosis) is a multisystemic disorder due to the mutations in both copies of the gene for the cystic fibrosis transmembrane conductance regulator (CFTR) protein (chloride channel of exocrine glands).

The name ‘cystic fibrosis’ refers to the characteristic fibrosis and cysts that form within the pancreas
  • Autosomal recessive (AR) inheritance
  • M/C lethal genetic disease in Caucasians (> Blacks > Asians)
  • M/C cause of pancreatic insufficiency in children (can lead to malnutrition)
Chromosome (7) long arm (q) region (3) band (1)
Chromosome (7) long arm (q) region (3) band (1)

History

Dorothy Hansine Andersen
Dorothy Hansine Andersen first described cystic fibrosis in 1938 (photo at National Library of Medicine)
dorothy_hansine_andersen
Dorothy Hansine Andersen first described cystic fibrosis in 1938 (photo at National Library of Medicine)

Pathophysiology

CFTR gene (Cystic fibrosis transmembrane conductance regulator) mutation:

Deficiency/mutation of CFTR gene (Cystic fibrosis transmembrane conductance regulator) on Chromosome 7 which encodes ATP-gated Cl⁻-channel (secretes Cl⁻ in lungs & GI tract and reabsorbs Cl⁻ in sweat gland).
CFTR protein
The CFTR protein is a channel protein that controls the flow of H2O and Cl- ions in and out of cells inside the lungs. When the CFTR protein is working correctly, ions freely flow in and out of the cells. However, when the CFTR protein is malfunctioning, these ions cannot flow out of the cell due to a blocked channel. This causes cystic fibrosis, characterized by the buildup of thick mucus in the lungs. | De Boeck, K. and Amaral, M. D. (2017) ‘Progress in therapies for cystic fibrosis’, The Lancet Respiratory Medicine. Elsevier, 4(8), pp. 662–674. doi: 10.1016/S2213-2600(16)00023-0.
The cystic fibrosis (CF) pathogenesis cascade in the lung
The cystic fibrosis (CF) pathogenesis cascade in the lung. The mechanism of CF dysfunction starts with the primary CFTR gene defect and ultimate leads to severe lung deficiency. CFTR, cystic fibrosis transmembrane conductance regulator; ASL, airway surface liquid; ENaC, epithelial Na+ channel. | Amaral, M. (2014) Novel personalized therapies for cystic fibrosis: Treating the basic defect in all patients, Journal of Internal Medicine. doi: 10.1111/joim.12314.

Mutation types:

  • Class 1: Nonsense, frameshift, or splice-site mutation which leads to premature termination of the mRNA sequence.
  • Class 2: Abnormal post-translational processing of the CFTR protein (essential for the proper intracellular transit of the protein). As a result, CFTR is unable to be moved to the correct cellular location.
    • ΔF508/Phe508 mutation (M/C, 70% cases)
      • Δ: Deletion
      • F: Phenylalanine
      • 508: 508th amino acid
  • Class 3: Diminished protein activity in response to intracellular signalling. The result is a fully formed protein channel in the cellular membrane that is non-functional.
  • Class 4: Protein is produced and correctly localized to the cell surface. However, the rate of chloride ion flow and the duration of channel activation after stimulation is decreased from normal.
  • Class 5: Net decreased concentration of CFTR channels in the cellular membrane as a result of rapid degradation by cellular processes.

Presentation

Variable presentation.

Cystic fibrosis
The Calgary Guide | http://calgaryguide.ucalgary.ca/

Complications:

Complications of CF
Complications of CF according to the American CF registry | CF Foundation

Diagnosis

Newborn screening:

  • IRT (immunoreactive trypsinogen) detection:
    • Pancreatic damage → ↑ Blood IRT
Neonatal screening CF
Neonatal screening (cutoff value of PAP depends on the test kit used and corresponds to the 87.5th percentile in the normal population) | Gemeinsamer Bundesausschuss. Kinder-Richtlinie: Formale und inhaltliche Überarbeitung (Neustrukturierung) – Neufassung. www.g-ba.de/informationen/beschluesse/2287/ (last accessed on 10 September 2016)

Pilocarpine-induced sweat test:

  • ↑ Cl in sweat > 60 mEq/l
  • Skin tastes salty
Child’s arm during sweat test with the macroduct system
Child’s arm during sweat test with the macroduct system. After pilocarpine iontophoresis to stimulate sweating, the closed capillary collecting system is applied to the skin of the forearm. Sweat can be seen entering the tubing (blue); electrolyte analysis can be reliably performed on as little as 50 μl of sweat | Davies, J. C., Alton, E. W. F. W., & Bush, A. (2007). Cystic fibrosis. BMJ (Clinical Research Ed.), 335(7632), 1255–1259. https://doi.org/10.1136/bmj.39391.713229.AD

Imaging:

Cystic fibrosis
The Calgary Guide | http://calgaryguide.ucalgary.ca/

X-ray:

CT-scan:

  • Contrast enema
    • Meconium ileus:
      • “Soap bubble” appearance
      • Microcolon

Management

Main pathophysiological dysfunctions and treatment modalities for CF
The main pathophysiological dysfunctions and treatment modalities for CF patients. Inner trapezoid boxes depict the pathophysiological abnormalities and outer rectangular boxes depict the main treatments. The texts connecting the outer boxes show non-pharmacological management | Rafeeq, M. M., & Murad, H. A. S. (2017). Cystic fibrosis: current therapeutic targets and future approaches. Journal of Translational Medicine, 15(1), 84. https://doi.org/10.1186/s12967-017-1193-9

Nutrition supplementation:

  • Fat-soluble vitamins (A, D, E, K)
  • Extra calories
  • PERT (Pancreatic enzyme replacement therapy)

Medical management:

  • Facilitate mucus clearance:
    • Albuterol, aerosolized ornase alfa (DNase), hypertonic saline, chest physiotherapy
    • N-acetylcysteine: Cleaves disulfide bonds in mucus glycoproteins
  • Azithromycin (anti-inflammatory)
  • Ibuprofen (slows disease progression)

Newer treatments cases with Phe508 deletions):

  • Lumacaftor (corrects misfolded proteins and improves transport to cell surface)
  • Ivacaftor (opens Cl⁻ channels for improved chloride transport)
  • Genetic treatments

Summary

Cystic fibrosis
‘Cystic fibrosis’ (2015). Macmillan Publishers Limited, 1, p. 15049. Available at: http://dx.doi.org/10.1038/nrdp.2015.49.

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