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Cystic fibrosis





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Autosomal trisomies: Pathology review
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Cystic fibrosis


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High Yield Notes
13 pages

Cystic fibrosis

19 flashcards

USMLE® Step 1 style questions USMLE

13 questions

A 14-year-old boy is brought to the clinic by his parent for a routine checkup. The patient has cystic fibrosis and has had multiple hospitalizations in the past for pulmonary infections. The patient is currently on albuterol, inhaled N-acetylcysteine, oral ibuprofen, and a combination of lumacaftor and ivacaftor. The patient states he feels fine today. Vital signs are within normal limits. Weight is at the 10th percentile for age and height is at the 10th. Digital clubbing is present. The patient’s parent recently read about the medication dornase alfa that is supposedly effective in treating cystic fibrosis. The mechanism of action of which of the following medications is most similar to dornase alfa?  

External References


You’re probably aware that cystic fibrosis, or CF, is a genetic disorder that affects the lungs, but that’s only part of the story.

In fact, the name “cystic fibrosis,” refers to the disease’s effects on the pancreas, where it can lead to cysts, which are fluid-filled sacs wrapped in a membrane and fibrosis—excess deposition of connective tissue that can replace or infiltrate normal tissue in an organ.

CF is an autosomal recessive disorder involving the CFTR gene, which stands for “cystic fibrosis transmembrane conductance regulator,” and this gene codes for the CFTR protein.

CF develops when there’s a mutation in the CFTR gene, but because it’s autosomal recessive, you need to inherit two mutated CFTR genes, one from mom and one from dad.

Now if mom and dad both have one copy of the mutated gene and one normal gene, they’re considered carriers and don’t have the disease.

Inheriting CF is more common in people of European descent.

The CFTR protein is a channel protein that pumps chloride ions into various secretions, those chloride ions help draw water into the secretions, which ends up thinning them out.

The most common mutation is the “∆F508” mutation.

Delta means a deletion, and the F (which can also be written as “Phe”) is short for phenylalanine, and the 508 is the five hundred and 8th amino acid in the CFTR protein.

So, the ∆F508 mutation is where the 508th amino acid out of 1480, phenylalanine, is deleted and missing.

This CFTR protein with the ∆F508 mutation gets misfolded and can’t migrate from the endoplasmic reticulum to the cell membrane, meaning there’s a lack of CFTR protein on the epithelial surface, and this means that it can’t pump chloride ions out, which means water doesn’t get drawn in, and the secretions are left overly thick.

In a newborn, thick secretions can affect the baby’s meconium, or first stool, or, which can get so thick and sticky that it might get stuck in the baby’s intestines and not come out, and this is called a meconium ileus and is a surgical emergency.

In early childhood, pancreatic insufficiency is the most prominent effect of CF.

This happens because thick secretions jam up the pancreatic ducts, not allowing digestive enzymes to make it to the small intestine.

Without those pancreatic enzymes, protein and fat aren’t absorbed.

And over time this can lead to poor weight gain and failure to thrive.

Fat malabsorption can lead to steatorrhea, or fat-containing stools.

Eventually the pancreas gets damaged, because backed-up digestive enzymes degrade the cells lining the pancreatic ducts, causing local inflammation.

This can lead to acute pancreatitis and—with repeated episodes—chronic pancreatitis, with the development of cysts and fibrosis like we talked about, giving the disease it’s name.

Finally, the destruction of pancreatic tissue can also compromise of the endocrine function of the pancreas, causing insulin-dependent diabetes.

It’s usually not until later in childhood that lung problems start to crop up.

Normally the cilia, these hair-like projections lining the airways, do a pretty good job of keep the them clean by moving mucus, which catches things like debris and bacteria, toward the pharynx, called mucociliary action.

With thick mucus, though, it gets a lot harder to clear and the mucociliary action becomes defective, which means bacteria is allowed to chronically colonize the lungs.

If the bacterial load suddenly increases, it causes symptoms like cough and fever, a decrease in lung function, and sometimes changes on a chest X-ray, and this is called a CF exacerbation and usually prompts a round of antibiotics.

Pneumonia is one example of a CF exacerbation which requires antibiotic treatment.

  1. "Robbins Basic Pathology" Elsevier (2017)
  2. "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2)" McGraw-Hill Education / Medical (2018)
  3. "Pathophysiology of Disease: An Introduction to Clinical Medicine 8E" McGraw-Hill Education / Medical (2018)
  4. "CURRENT Medical Diagnosis and Treatment 2020" McGraw-Hill Education / Medical (2019)
  5. "Cystic Fibrosis: Lessons from the Sweat Gland" Physiology (2007)
  6. "Infection Control in Cystic Fibrosis" Clinical Microbiology Reviews (2004)
  7. "Pharmacological approaches for targeting cystic fibrosis nonsense mutations" European Journal of Medicinal Chemistry (2020)