Cystic Fibrosis vs Kartagener syndrome

AR; chromosome 7

Classically caused by a deletion (ΔF508; deletion of phenylalanine) in the CFTR gene, which normally codes for CFTR protein (cystic fibrosis transmembrane regulator).

CF is the most common genetic disease leading to ↓ lifespan in the Caucasian population.

CFTR is a cAMP-regulated and ATP-gated chloride channel.

cAMP activates protein kinase A, which catalyzes the ATP hydrolysis.

CFTR has twelve transmembrane components; two domains, each with six segments (completely outrageous and ridiculous).

CFTR is a transmembrane chloride channel that normally absorbs Cl^– in sweat but secretes it everywhere else (i.e., pancreas, lungs).

Mechanism:

• CFTR is a transmembrane chloride channel that normally absorbs Cl^– in sweat but secretes it everywhere else (i.e., pancreas, lungs).
• Failure to secrete Cl^– from the pancreas and lungs leads to a buildup of Cl^– inside the pancreatic acinar cells and alveolar cells, respectively.
• Buildup of intracellular chloride means increased negative charge inside the cell.
• In order to balance charge, extracellular sodium within the pancreatic ducts and alveoli moves into the cell via ENaC to balance intracellular charge.
• Since H₂O follows Na⁺, ↑ H₂O reabsorption leads to viscous luminal secretions.
• This desiccation (drying up) is called inspissation.
• This is why there are thickened secretions in CF.

If you get a CF question and they simply ask you for which mechanism regarding ion shift occurs, the answer is ↑ activation of ENaC.

Once again:

• CFTR is a transmembrane chloride channel that normally absorbs Cl^– in sweat but secretes it everywhere else (i.e., pancreas, lungs).
• Failure to secrete Cl^– from the pancreas and lungs leads to a buildup of Cl^– inside the pancreatic acinar cells and alveolar cells, respectively.
• Buildup of intracellular chloride means increased negative charge inside the cell.
• In order to balance charge, extracellular sodium within the pancreatic ducts and alveoli, moves into the cell via ENaC to balance intracellular charge.
• Since H₂O follows Na⁺, ↑ H₂O reabsorption leads to viscous luminal secretions.
• This desiccation (drying up) is called inspissation.
• This is why there are thickened secretions in CF.

One of the highest yield points regarding cystic fibrosis is that mutated CFTR leads to the production of CFTR channel that is retained as a misfolded protein in the rough endoplasmic reticulum (RER).

The USMLE is obsessed with asking about this. “Defective chloride channel found in cell membrane” is 100% the WRONG answer.

Now clearly the RER is in the cytosol, so occasionally the answer might also be “misfolded protein sequestered in cytosol.” You get the point.

Comments:

• Whereas Cl^– is secreted in the pancreas and alveoli, it’s reabsorbed in the sweat glands.
• Normal sweat losses are hypotonic. In CF, they’re isotonic.
• This leads to ECF (extracellular fluid) contraction because failure of ↑ in ECF tonicity fails to draw out ICF (intracellular fluid) to compensate.
• The contraction stimulates RAAS (renin-angiotensin-aldosterone system).
• ↑ aldosterone-mediated distal renal K⁺ & H⁺ wasting can lead to contraction alkalosis.

Diagnosis is made via sweat chloride testing indicating > 60 mEq/L  of chloride in the sweat.

The sweat Cl^–test is more diagnostic of CF than genotyping.

Neonates can be screened for a positive blood immunoreactive trypsinogen.

If positive, the neonate requires a confirmatory sweat chloride test, where topical pilocarpine (muscarinic agonist) stimulates the sweat secretion.

Rarely in patients who have a non-diagnostic sweat chloride test and negative genotyping, a nasal transepithelial potential difference (TEPD) test can be performed.

In CF, there is a more negative transepithelial potential difference

• TEPD merely refers to the charge gradient between the external and internal cell surfaces of respiratory epithelium.
• Since Na⁺ is reabsorbed, less positive charge remains on the external cell surface, thereby causing the transepithelial potential difference to be more negative.
• Rarely in patients who have a non-diagnostic sweat chloride test and negative genotyping, a nasal transepithelial potential difference (TEPD) test can be performed. A nasal TEPD <40 mV is considered positive.

Cystic fibrosis is associated with increased frequency of pulmonary infections. Although various organisms can cause infection, Pseudomonas and Staph aureus infections are notably more common.

Nasal polyps

Exocrine pancreas insufficiency causes fat-soluble vitamin malabsorption

Failure to thrive can be seen with intestinal malabsorption. Bowing of the tibias is a typical finding in rickets.

• Since the pancreatic secretions are inspissated, pancreatic enzyme secretion is less efficient and signs of malabsorption are common.
• Fat-soluble vitamin (A, D, E, K) and B12 deficiencies are common. (All of those blue vitamins link to unique posts btw)
• So be on the lookout for any symptoms of those nutrient deficiencies, e.g., nyctalopia (A), rickets (D), hemolysis (E), ↑ PT/aPTT (K), megaloblastic anemia (B12), and neurological findings (E and B12).

Normal fasting glucose is 72-99 mg/dL. Impaired fasting glucose (pre-diabetic) is 100-125 mg/dL. Diabetes mellitus is diagnosed if two fasting sugars 126 mg/dL or greater are measured. In CF, we could theoretically say glucose would be at least 100-126 or greater by adolescence.

Endocrine pancreas insufficiency can cause diabetes mellitus

• Diabetes mellitus is one of the most common morbidities of CF, occurring in ~20% by adolescence and ~40-50% by adulthood.
• (Obtained those %s from this highly cited American Diabetes Association article here)

Failure to pass meconium in the first 24 hours of life is super HY and most commonly due to cystic fibrosis (and less commonly Hirschsprung disease).

In CF, this failure to pass meconium is given a special name called meconium ileus, where inspissated meconium plugs the ileum.

N-acetylcysteine softens mucous (N-acetylcysteine has an –SH that reacts with -S–S- bonds in mucous).

Guaifenesin ↑ expectoration / clearance of mucous.

Dornase-α is a recombinant deoxyribonuclease that breaks down DNA left over from leukocytic debris within mucous. It’s important to associate CF with lots of nucleic acid plugging the airways.

Ivacaftor is a special drug you must know

• One type of mutation leading to CF, the G551D missense mutation, leads to a glycine that is replaced by an aspartic acid at position 551.
• This enables the CFTR channel to make it to the cell surface, in contrast to sequestration in the RER/cytosol.
• The CFTR channel is still defective; it’s just merely at the correct location on the cell surface.
• Ivacaftor is a CFTR modulator that binds to this misfolded channel and increases the probability it will open.

The USMLE wants you to know that if a phenotypically normal patient has a sibling with an AR condition (e.g., CF) when both parents are carriers, his or her chance of being a carrier is TWO-THIRDS.

And further, two people in this category mating would have a one-ninth chance of having a child with an AR condition.

If someone who is phenotypically normal (i.e., does not have the disease) has a sibling with an AR disorder (e.g., CF), there is a 2/3 chance he or she is a carrier because it’s impossible he or she is “aa” if phenotypically normal. Got it?

If you get a question where they tell you someone with CF has two copies of an “exceedingly rare” mutation no one’s ever heard of, and they want to know the mechanism for disease, the answer = uniparental isodisomy.

This means the individual somehow got two copies of the same allele from the same parent.

They will also list uniparental heterodisomy as an answer (receiving two different alleles from the same parent), but this can’t be correct because if this were the case, the parent would also have the disease.

If you have two copies of an allele that is “one in ten-million,” it’s absurdly unlikely each parent carried that allele and passed it.

CBAVD and CF

• Another really important point is cystic fibrosis in relation to infertility.
• Cystic fibrosis is known to cause congenital bilateral absence of the vas deferens (CBAVD) in men.
• Even asymptomatic carriers have an increased likelihood of CBAVD and infertility.
• Because the vas deferens is absent bilaterally, there are NO sperm seen in a sample of ejaculate.

The USMLE is obsessed with the contrast between Kartagener syndrome and cystic fibrosis in regard to infertility

Kartagener is a disorder characterized by immotile, dysfunctional cilia, resulting in sperm immotility and defective fallopian tube-mediated ovum transport. This leads to male and female infertility, as well as increased risk of ectopic pregnancy.

USMLE gets pedantic about cilia in relation to Kartagener

• The cilia are immotile because of a dynein arm defect.
• Dynein is a protein that enables proper ciliary motility.
• A cilium is composed of a 9+2 arrangement of microtubules.
• In other words, a cilium is larger than a microtubule.

Kartagener is associated with situs inversus

• You need to know that Kartagener syndrome is associated with situs inversus, where the internal organs are on the opposite side of the body.
• They might tell you the apex beat is palpated in the 5^th intercostal space, just medial to the right midclavicular line.