Cystic fibrosis: Pathology review

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Case Study0:00–0:36

A newborn was delivered two days ago at home without any complications. Today, he was brought in for examination.
The baby has a fever and a distended abdomen that's rigid on palpation. The mother mentions her son started vomiting a green fluid and that he has yet to pass his first stool.
She also says she didn’t have access to prenatal care throughout the pregnancy. An x-ray was performed, and it showed air-fluid levels and dilated bowel loops, along with a “soap bubble” appearance.
A pilocarpine-induced sweat test was done which showed a Cl- level over 60.Now, the newborn seems to have cystic fibrosis.

Physiology0:36–1:52

But first, a little physiology. Normally, elements like ions and water come in and out of the cell through specific channels located on the cell’s membrane.
A very high yield fact you need to know is that there’s this particular channel called “cystic fibrosis transmembrane conductance regulator” or the CFTR protein, which is an ATP-gated channel, meaning it works by using ATP for energy.
It transports negatively charged Cl-. In cells that produce mucus, it secretes the ion out of the cell, and in cells of the sweat glands, it reabsorbs Cl- back into the cell.
Now, normally, cells in mucus membranes pump out chloride ions into the thick mucus, which helps attract water and make it less viscous.
This mucus will protect the lining of organs and tissues like the airways, digestive system, and reproductive system. For example, the mucus produced by the glands in the airways allows the tiny cilia to sweep back and forth.
This sweeping motion helps move the mucus and the bacteria or foreign particles trapped in it, out of the airways. Additionally, the CFTR protein also regulates the function of other channels, such as those that transport positively charged sodium ions.Now, cystic fibrosis, or CF, is an autosomal recessive disorder where there’s a mutation in the CFTR gene, and it is considered to be the most common lethal genetic disease in the Caucasian population.

Pathology1:52–3:58

Keep in mind that the defective gene is located on chromosome 7 and that the defect itself is usually represented by ∆F508, an abbreviation which indicates that there’s a deletion of three nucleotides that code for phenylalanine at amino acid position 508.
Another thing to know is that the ∆F508 mutation results in impaired post-translational processing. This means that the protein will be misfolded and it will not be glycosylated, so it’ll be retained in the endoplasmic reticulum, where it is degraded instead of being released to the cell membrane.
Without the CFTR protein on the epithelial surface, cells can’t transport chloride ions. In the mucus-secreting cells, the defect prevents chloride from being secreted, which causes intracellular levels to increase.
It also leads to a compensatory sodium reabsorption via the epithelial sodium channels, or ENaC, because the inhibitory effect of the CFTR protein on ENaC is missing.
Interestingly, this increase in sodium reabsorption causes a negative transepithelial potential difference, which basically means the epithelial surfaces with mucus producing glands have a significantly more negative electrical charge.
This is important because the negative transepithelial potential difference can be measured intranasally, and thus it can be used as a diagnosis test for CF.
Ok so going back to chloride ions, a high yield concept is that because they are trapped inside the cell, water won’t be attracted to the mucus to thin it out.
As a result, the mucus secreted by these cells will be abnormally thick, so it builds up and obstructs the organs where it is secreted, causing extensive damage.
In parallel, in sweat-producing cells, the defect prevents chloride ions from being reabsorbed, thus it accumulates in the sweat.Now, this leads to a wide range of signs and symptoms, which mostly depend on the individual’s age.

Symptoms3:58–10:31

In a newborn baby, the thick secretions can affect the baby’s meconium or first stool. The meconium can get so thick and sticky that it gets stuck in the baby’s intestines and can cause small bowel obstruction.
This is called a meconium ileus, and it is considered a surgical emergency because the obstruction can lead to bowel perforation and peritonitis.
On examination, babies initially present a distended and rigid abdomen, and they might look mottled and lethargic. Another sign of obstruction is bilious vomiting, which is when the vomit has a green color due to a high bile content.
If bowel perforation occurs, it can lead to septic shock, which can ultimately cause organ failure and death. If a baby is septic, the vital signs might show temperature instability, either a fever or hypothermia, tachycardia, tachypnea, and hypotension.
Something to keep in mind is if a newborn survives meconium ileus, without proper management, they will most likely die of cardiorespiratory complications like pneumonia or bronchiectasis, which account for more than 80% of deaths due to CF.In early childhood, the most prominent and high yield complication of CF is pancreatic insufficiency.
This happens because thick secretions block the pancreatic ducts, preventing digestive enzymes from making it into the small intestine.
Without those pancreatic enzymes, fat isn’t absorbed, causing steatorrhea or an abnormal amount of fat in a person’s stools.
Over time, this can lead to poor weight gain and failure to thrive because most of the nutrients and fat-soluble vitamins like vitamin A, D, E, and K, are lost through stool.
Something that you might encounter on your test is avitaminosis A, which is important since it leads to squamous metaplasia of the epithelial lining of pancreatic exocrine ducts.
This is particularly problematic because there’s already pancreatic damage, usually from the backed-up digestive enzymes that will start digesting the pancreas, causing pancreatitis.
Sometimes, the destruction of pancreatic tissue can also reduce the endocrine function of the pancreas, causing insulin-dependent diabetes mellitus.
As the child grows, their lungs can also be affected, usually because the mucus in their airways are so thick that the cilia can’t move them out.
So they get repeatedly colonized by bacteria, which causes chronic bacterial infection and inflammation. Sometimes, the mucus can get compacted and it starts acting as a mucus plug, which alongside chronic bacterial infection and inflammation, leads to bronchiectasis.
Bronchiectasis represents damage to the airway walls that causes permanent dilation of the bronchi. This causes respiratory symptoms like cough with lots of sputum, and if the damage extends to the blood vessels, it can lead to hemoptysis.
Individuals can also develop recurrent pneumonia, especially when there’s chronic lower respiratory infections. There are a couple of high yield bacteria you need to remember!
In infants and children, the pneumonia-causing pathogens are often gram positive bacteria, like Staphylococcus aureus or methicillin-resistant Staphylococcus aureus, whereas in teens and adults, it’s usually gram negative bacteria, like Pseudomonas aeruginosa.
The recurrence of Pseudomonas aeruginosa pneumonia in CF has been linked, in part, to the bacteria’s ability to form biofilms.
Biofilms are defined as communities of microorganisms that are attached to a surface, and in Pseudomonas cases, this is possible due to its mucoid polysaccharide capsule which makes it sticky.
Another thing to look out for is and allergic bronchopulmonary aspergillosis, or ABPA, which is a hypersensitivity reaction to the fungus Aspergillus fumigatus that can live in the sinus or lung cavity.
Sometimes pulmonary symptoms can increase rapidly, causing a CF exacerbation. This usually includes worsening productive cough with sputum, dyspnea with exertion, fatigue, decreased appetite, and fever.
Over time, repeated cystic fibrosis exacerbations can lead to irreversible respiratory failure and death. Sometimes, the liver and the bile can be affected too.
It is thought that the abnormal CFTR protein in the biliary system leads to the impaired secretion and deposition of thick, viscous bile with reduced alkalinity.
The abnormal bile increases the activity of free radicals, and its stagnation increases the liver’s susceptibility to infectious and toxic agents, which end up damaging the hepatocyte directly.
In addition, the thick biliary secretion can also obstruct the small bile ducts, damaging the liver and the biliary tract even more.
In time, hepatic stellate cells, the main “culprits” of hepatic fibrosis, are activated and start to produce collagen, as well as stimulating the epithelium of bile ducts to release cytokines, which accelerates the fibrotic process.
This process, over a number of years, leads to the development of biliary cirrhosis.Other frequently-tested complications associated with CF are hypokalemia and contraction alkalosis, which is alkalosis associated with hypovolemia, caused by water and sodium losses via sweating and with concomitant renal potassium and hydrogen losses.
Clinically, these individuals develop symptoms suggestive of hypovolemia like dehydration, hypotension, tachycardia, and even cardiovascular collapse.
In adulthood, a common cystic fibrosis-related issue is the bilateral absence of vas deferens in biological males. Because the sperm transportation is impaired, they are infertile but not sterile since spermatogenesis is typically unaffected.
In biological females, cystic fibrosis could cause subfertility, meaning these women are fertile, but can’t get pregnant because of the abnormally thick cervical mucus that makes it harder for sperm to successfully penetrate the cervix.
Poor nutrition secondary to malabsorption can also lead to irregular ovulation and amenorrhea. Although the fertility issues might be the only signs of cystic fibrosis in adults, individuals can also develop digital clubbing, which describes how the fingernails begin to spoon around the fingertips; and nasal polyps, which are mucosal epithelial growths in the nose.
Ok, for diagnosis, screening can be done at birth via a heel prick test that detects pancreatic enzyme called immunoreactive trypsinogen or IRT, which is released into the fetal blood when there’s pancreatic damage from CF.

Diagnosis10:31–13:07

The confirmatory test you might come across is the quantitative pilocarpine iontophoresis, better known as the pilocarpine-induced sweat test, which checks for high levels of chloride in the sweat.
So if chloride levels are over 60 millimoles per litre, CF diagnosis is very likely, while intermediate levels, from 30 to 59 millimoles per litre in infants below 6 months or 40 to 59 mmol/L in older infants, children, and adults, mean CF diagnosis is possible.
DNA testing can also be done in all age groups to detect the most common cystic fibrosis-related mutations. If two or more mutations are detected, one in each chromosome, then the diagnosis of CF is confirmed.
Another test that might help you diagnose CF, especially in cases where the sweat test was negative, is the nasal potential difference test, which is used to detect the negative voltage across the nasal epithelium associated with CF.
Now, CF is rarely diagnosed by itself, which means further testing is necessary to diagnose any of the complications associated with the disease.
For example, meconium ileus is diagnosed by a combination of clinical and x-ray findings. Typical abdominal x-ray signs include dilated bowel loops and air-fluid levels proximal to the obstruction, along with a “soap bubble” or “ground glass” appearance at the site of obstruction due to small air bubbles mixed in with the meconium.
Another complication is bronchiectasis, which is diagnosed by pulmonary function tests, or PFTs, showing an obstructive pattern, meaning a decrease in the forced expiratory volume in one second or FEV1, and the ratio of FEV1 to forced vital capacity.
Chest x-ray is also needed, and it might show might show tram-track lines radiating from the hila and ring shadows which represent clusters of cysts, typically in the upper lobes.
And finally, a CF exacerbation can be diagnosed if there are new or increased symptoms. If pulmonary function tests are done, there’s usually a 10-15% decrease in FEV1.
On a chest x-ray, CF exacerbations typically present as bilateral lower lobe infiltrates. Sputum cultures are usually sent to identify the pathogens that are responsible.
Finally, a blood test can show hypokalemia and contraction alkalosis in those with symptoms suggestive of hypovolemia. Treatment is multifactorial.
Clearing out the mucus helps with breathing, and it can be done with chest physiotherapy as well as medications. Medications include bronchodilators, such as beta-2 adrenergic agonists like albuterol; anticholinergic drugs; and theophylline which help keep the airways open.

Treatment13:07–14:35

Also remember that it can include mucolytics, like nebulized N-acetylcysteine, which cleaves disulfide bonds in the mucus glycoproteins, or dornase alfa, which is a nuclease that cuts up nucleic acids in the mucus to thin it out.
Sometimes anti-inflammatory agents, like ibuprofen, and oral or inhaled glucocorticoids, are used to suppress excessive inflammation.
Long-term use of the antibiotic azithromycin is also sometimes used to diminish airway inflammation and slow disease progression and prevent CF exacerbations.
In addition, some individuals with chronic hypoxemia are given supplemental oxygen. Finally, there are medications called CFTR modulators, like ivacaftor, tezacaftor, and lumacaftor, which work on specific CFTR mutations and act by boosting production, intracellular processing, or function of the mutated CFTR protein.
For example, the best choice can be a combination of lumacaftor, which is a chaperone that can correct the misfolded protein and bring it to the cell membrane, and ivacaftor, which opens the chloride channels and improves the ion’s transport.
All right, as a quick recap, cystic fibrosis is an autosomal recessive disorder involving the CFTR gene. The misfolded protein it encodes causes chloride transport impairment in the mucus and sweat-producing cells, resulting in an abnormally thick mucus.

Review14:35–15:45

This causes obstruction-related issues with the lungs and pancreas, as well as other organs and tissues. CF complications vary from one age group to another but they can include digestive issues, like meconium ileus and liver disease; respiratory complications, such as bronchiectasis, recurrent pneumonia, and nasal polyps; peritonitis; failure to thrive; and pancreatic disease.
Other features include male infertility and female subfertility. In a newborn, it can be screened for with a positive immunoreactive trypsinogen test.
It can be confirmed by either an abnormal sweat chloride test, DNA testing, or an abnormal nasal potential difference test.
Chronic treatment includes chest physiotherapy, bronchodilators, mucolytics, and in some cases anti-inflammatory agents, azithromycin, supplemental oxygen, or CFTR modulators.Now back to our case.

Summary15:45–16:23

The newborn showed signs of bowel obstruction: fever, a distended and rigid abdomen, and bilious vomiting. His history also revealed that he hadn’t had his first stool yet, which was supposed to occur within the first day after delivery.
This suggests meconium ileus, so an X-ray was ordered, which confirmed the diagnosis based on the dilated bowel loops and air-fluid levels proximal to the obstruction, along with a “soap bubble” or “ground glass” appearance at the site of obstruction.
The newborn’s clinical picture is highly suggestive of cystic fibrosis, and a sweat test showing highly elevated Cl- confirmed the diagnosis.
chloride ions confirmed, the diagnosis.
Cystic fibrosis: Pathology Review: Video, Causes | Osmosis