Cystic Fibrosis: Epidemiology and Pathophysiology

00:00 Welcome back.

00:02 Today we're taking a deep dive into cystic fibrosis, a condition that begins with one specific faulty chloride channel, but has broad repercussions for nearly every organ system.

00:12 Basically, cystic fibrosis, or CF, is an autosomal recessive disorder that plays out most critically in the lungs, with patients developing thick respiratory mucus secretions, hence the British name, mucoviscidosis.

00:27 Those secretions are poorly cleared from the airways, leading in turn to recurrent respiratory infections and the major cause of morbidity and mortality for CF-afflicted individuals.

00:38 Outside of the lung, the same defective chloride channels lead to pancreatic insufficiency and increased salinity and sweat, as we'll discuss shortly.

00:48 Now let's take a look at the disease in more detail.

00:51 We'll talk about its epidemiology first.

00:53 We start with the scale of the problem.

00:57 Cystic fibrosis remains the most common life-limiting autosomal recessive disease among people of Northern European ancestry, appearing in roughly 1 out of 3,400 births in the United States.

01:08 It's also important to emphasize that although CF is classically associated with white European populations, cases can occur in all ethnic groups.

01:17 Something interesting to also note is that universal newborn screening now flags more than three-quarters of patients before they turn two, giving us a crucial head start in care.

01:28 Now for the pathophysiology.

01:31 Here, we need to remember that both parents must contribute a mutant allele of the CFTR gene.

01:37 CFTR stands for Cystic Fibrosis Transmembrane Conductance Regulator.

01:40 The gene codes for a chloride channel that is normally inserted into the plasma membrane of specific cell types.

01:47 Over 1,500 different mutations have been described, potentially leading to either deficient amounts or deficient activities of the channel.

01:56 Of the various mutations, a deletion of a single phenylalanine, position 508 in the amino acid sequence, called F508del, is responsible for roughly 70% of cases of CF worldwide.

02:11 That loss of a single amino acid causes the protein to misfold in the endoplasmic reticulum of cells and results in its premature degradation by the unfolded protein response long before the protein can ever reach the cell surface.

02:28 In the lungs, CFTR is synthesized by a few rare cells called ionocytes, which constitute only 1% of the epithelium lining the upper airways.

02:38 They use the CFTR protein to control the salt balance, which is essential to keep mucus watery and at the proper pH.

02:46 In pancreatic ducts, CFTR-driven fluid flow ensures digestive enzymes reach the duodenum before they get activated and can cause pancreatic injury.

02:55 And in sweat glands, CFTR normally reclaims chloride.

03:00 So without a functioning CFTR, there is extreme sweat hypersalinity.

03:04 Indeed, before we had more specific testing, as we will discuss later, moms would often make the diagnosis in their newborns because they were so salty when they kissed them.

03:13 On the screen, you can see a flow chart that walks from DNA transcription to the plasma membrane, illustrating six mutation classes.

03:21 Class 1 stops synthesis cold, meaning simply no CFTR protein is made.

03:27 Class 2 allows the protein to be made, but it's misfolded, so it's degraded and thrown away.

03:33 Class 3 locks the channel shut, so chloride ions can't get through to help hydrate the mucus.

03:39 Class 4 narrows the pore, restricting the flow of ions.

03:42 Class 5 is a quantity problem that throttles down production, so too little protein is made.

03:48 And finally, Class 6 creates a stability issue, where the protein works but is removed from the surface too quickly.

03:54 So plasma membrane CFTR endocytosis is accelerated, thus reducing CFTR density and chloride movement.

04:01 Here you see the domino effect of a broken CFTR.

04:06 Once that chloride channel is absent or dysfunctional, chloride transport grinds to a halt, and sodium and water follow suit, leaving secretions thick and sticky.

04:16 Over in the sweat gland, the same traffic jam plays out in reverse, with no CFTR to reclaim chloride.

04:24 Sodium and water stay in the lumen, pouring out as sweat rich in salt, staying at the microscopic level.

04:30 On the left, you see the normal setup.

04:33 CFTR channels at the surface secrete chloride into the lumen, while the epithelial sodium channel, called the ENAC, fine-tunes the sodium to maintain electro-neutrality with all of the other charged proteins in the extracellular space.

04:46 Water ultimately follows the salt concentrations to maintain normal osmolarity, and produce a thin, well-lubricated layer that lets those cilia beat like little oars to sweep mucus out of the airways.

05:00 Flip to the right panel, and you get cystic fibrosis in a nutshell.

05:04 That pink X across the CFTR shows that no chloride is being released due to the mutation, so ENAC storms on unchecked, yanking sodium and water back into the cell.

05:15 The fluid in the airspace becomes dehydrated and really viscous, with the cilia stalling against the sticky overlay.

05:21 Not only is this mucus plugging a rich medium for the growth of inhaled microbes, but the lower pH can also impact microorganism survival and immune responses.

05:32 In this last final frame, you can see the airway surface is coated in a dense, unmoving mucus blanket.

05:38 No ciliary clearance, no self-cleaning, just a breeding ground for infection.

05:44 And with each bout of infection, there is lower airway destruction, and overall causing pulmonary scarring.

05:50 In simple terms, the normal mucociliary escalator has been defeated and filled up with vicid, microbe-supporting mucus.