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?

Cystic fibrosis

Chapters:

Introduction0:00–0:24

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.

Pathology0:24–2:04

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.

Early childhood symptoms2:04–3:18

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.

Late childhood symptoms3:18–4:58

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. Examples of problematic bacteria include gram positive bacteria like Staphylococcus aureus, which is gram positive, and Pseudomonas aeruginosa, which is gram negative, both of which can be hard to treat if they are resistant to typical antibiotics.

In addition, the bacteria usually form a biofilm where individual bacterial cells are fixed in a matrix of slime which protects them from the immune system as well as antibiotics.

Chronic bacterial infection and inflammation can lead to bronchiectasis, which is airway wall damage causing permanent dilation of the bronchi.

Occasionally, if inflammation erodes into a blood vessel, there can even be hemoptysis, or coughing up of blood. Over time, the repeated CF exacerbations can ultimately lead to respiratory failure, the leading cause of death with CF.

Other CF-related issues include infertility in men who commonly lack the vas deferens which are the tubes that transport the sperm from the testes to the urethra in the penis.

Additional symptoms4:58–5:31

Men and women can also have digital clubbing where the fingernails begin to spoon around the fingertips, nasal polyps which are tissue growths in the nose, and allergic bronchopulmonary Aspergillosus (or ABPA), which is a hypersensitivity reaction to the fungus Aspergillus fumigatus which can live in a sinus or lung cavity.

For diagnosis, it’s possible to screen for CF in newborns, something that is done in some countries where CF is common and that helps treatment get started earlier.

Diagnosis5:31–6:17

The newborn screen detects a pancreatic enzyme called IRT, or immunoreactive trypsinogen, which is released into the fetal blood when there is pancreatic damage from CF.

And then if a sweat test then detects high levels of chloride in the sweat—CF is confirmed. Unlike in the lungs and pancreas where chloride can’t go out, when CFTR’s not working in the sweat glands, chloride can’t come in, or be reabsorbed, so there’s actually high chloride in the sweat.

In fact, parents of children with CF sometimes notice that, when kissing their baby, the baby tastes salty. In terms of treatment, a major goal is around nutrition and healthy weight gain.

Treatment6:17–7:55

Fortunately, fat-soluble vitamins (ADEK), extra calories, and replacement pancreatic enzymes, can all be supplemented to help boost nutrition and help the patient absorb nutrients.

In terms of pulmonary treatment, there’s chest physiotherapy, which to loosens the mucous by literally banging on the chest, as well as inhalers.

There are also medications like N-acetylcysteine which cleaves disulfide bonds in the mucus glycoproteins and dornase alfa which is a nuclease that cuts up nucleic acids in the mucus to thin it out.

CF lung disease is obstructive (like asthma and COPD), so pulmonary function tests are regularly used to monitor the disease.

Finally, because of the chronic infections and loss of pulmonary function over time, a lung transplant is sometimes needed.

A new hope for patients with CF has been the development of personalized treatments that target specific CFTR mutation types.

For example, lumacaftor is a chaperone that can bring the mutated ∆F508 CFTR to the cell membrane and is given in combination with ivacaftor.

Ivacaftor was originally designed against G551D mutations, but also improves function of mutated ∆F508 CFTR. Even though this isn’t a cure, these drugs are a good example of the potential of personalized medicine.

In addition, there are new genetic technologies on the horizon aimed at correcting specific gene mutations. Alright!

Time for a quick recap: cystic fibrosis is an autosomal recessive disorder involving the CFTR gene, which most notably causes issues with the lungs and the pancreas, but can also affect other organs.