Cystic fibrosis

Cystic fibrosis (CF) is an autosomal recessive condition leading to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) present on chromosome 7.

🏘️ ⚠️ Epidemiology and risk factors

If both parents carry the mutation:

• There is a 1/4 chance of the child having CF.
• There is a 1/2 chance of the child being a carrier but not having CF.
• There is a 1/4 chance of the child neither having CF nor being a carrier.

Approximately 1 in 25 have the CFTR protein mutation, meaning the likelihood of a child with CF is 1 in 2500 (1/25 x 1/25 x 1/4).

The life expectancy of CF was about 30 years old 30 years ago. Nowadays, due to advancements in treatment, the life expectancy is about 48 years old (with many patients living longer).

The prevalence is higher in Europe. This is due to an interesting theory - seeing as the CFTR mutation is protective against the cholera toxin. As cholera was very prevalent in Europe the protection against cholera allowed for passage from generation to generation.

Pathophysiology

The CFTR protein is an ion channel that allows for the transport of chloride and bicarbonate ion.

It is made up of 5 segments:

• 2 transmembrane domains - TMD1 and TMD2.
• 2 nucleotide binding domains - NBD1 and NBD2.
• 1 regulatory domain - R domain.

When protein kinase A (PKA) phosphorylates the R domain, it causes activation and binding of ATP to the nucleotide binding domains. Activation of these domains allows for the chloride channel to be opened, leading to chloride conductance. Osmosis then causes water to follow the chloride ion and the secretions that are on the other side are then thinned out (as opposed to being thick and stick).

The CFTR protein is located on the apical surface of secretory membranes in the following locations:

• Pancreas
• Lungs
• Intestines
• Sweat ducts

The mutation of the transporter leads to thick and sticky secretions that can impact these organs in different ways, which we will take a look at in the presentation section.

😷 Presentation

Pancreas:

The pancreas both endocrine and exocrine functions. However, the CFTR protein is located on the ductal cells of the exocrine glands. These exocrine glands release digestive enzymes into the intestines. In cystic fibrosis, the pancreatic juices become thicker and thicker. Eventually this leads to obstruction of the pancreatic duct.

The result of this is:

• Autodestruction of the exocrine glands as the digestive enzymes have early activation within the ducts and glands themselves. Autodestruction leads to fibrosis and cyst formation.
• Malabsorption and nutritional deficiencies as the intestines are deficient of the enzymes necessary for digestion and breakdown into smaller molecules that can be absorbed. This leads to the subsequent nutritional deficiencies.

Lungs:

The effect that cystic fibrosis has on the lungs is the leading cause of mortality relating to CF.

The CFTR protein is responsible for chloride secretion from the epithelial cells that line the bronchi, while the epithelial sodium channel (ENaC) is responsible for letting the Na+ into the airway. Water follows the Cl- into the airway but also follows the Na+ back into the cells. This balance is well maintained in order to maintain sufficient airway surface liquid homeostasis (ASL homeostasis). This ASL is important to clear mucus from the airways.

In CF, the absence of Cl- secretion leads to an imbalance with the ENaC continuously drawing fluid into the cells through Na+ influx. This leads to mucus build-up in the airways and a dehydrated ASL.

The result of this is:

• Chronic mucus in the bronchioles - this leads to an obstructive lung disease pattern with a reduced FEV1.
• Bacterial colonisation and recurrent respiratory tract infections
• The most common pathogens are staphylococcus aureus and pseudomonas aeruginosa.

Intestines:

As nutrients are not getting absorbed and there is impaired fluid to hydrate the intestinal contents, we end up with bulky and thick stool. This leads to what is known as a meconium ileus in neonates. Meconium ileus is the earliest presentation in about 20% of infants with CF.

In adults it can cause distal intestinal obstructive syndrome (DIOS) which is very similar to intestinal obstruction of other aetiologies.

Liver:

CFTR proteins are also present on the apical surfaces of the intrahepatic bile ducts. 10% of children with CF develop some form of liver disease due to clogging of the ducts.

Skin:

Normally, the CFTR protein is on the apical surface of sweat ducts to facilitare chloride ion outflow into the dermis. The amount of chloride ion remaining in the duct and reaching the skin is lower than that in the sweat glands (i.e. it is hypotonic).

However, in CF, the Cl- remains in the duct and accumulates, meaning the amount of Cl- that ends up in the gland is more and the skin subsequently too. This results in salty sweat.

Let’s now discuss the signs and symptoms of these issues that we have discussed:

In neonates:

• Meconium ileus - not passing stool within the first 48 hours of life. 99% of healthy, term babies pass meconeum within the first 24 hours and 100% of them should pass within the first 48 hours.

In infancy and childhood:

• Salty sweat
• Chronic cough
• Failure to thrive
• Recurrent chest infections
• Finger clubbing
• Delayed onset of puberty
• Nasal polyps - thought to be due to chronic infections and nasal congestion.
• Malabsorption:
• Steatorrhoea
• Abdominal pain and bloating

🔢 Classification

There 6 classes of CFTR mutations based on the functionality, cell membrane, production of CFTR protein and RNA production:

1. Class I - Protein synthesis defects

Little/no functional CFTR protein is produced. The most common mutation in this class is the ΔF508 mutation, where a deletion of three nucleotides results in the loss of the phenylalanine at position 508 of the CFTR protein. Due to this the protein cannot be folded properly and is not transported to the cell membrane.

2. Class II - Protein processing defects

The most common type is once again the ΔF508 mutation. It results in misfolded proteins that get stuck in the endoplasmic reticulum and is targeted for degradation rather than being transported to the cell surface.

3. Class III - Gating/regulation defects

These mutations produce CFTR proteins that form a channel on the cell membrane, but the channel does not open properly.

4. Class IV - Permeation defects

In this kind, the CFTR proteins are produced and present on the cell membrane. The channel also does open, but its ability to transport chloride ions is reduced.

5. Class V - Reduced synthesis

In this class there is CFTR protein made, just not in sufficient quantities.

6. Class VI - Protein stability defects

The CFTR protein is present on the cell membrane and functions normally. It is just degraded more rapidly, reducing its overall effectiveness.

🔍 Investigations

Cystic fibrosis is one of the conditions that is tested in with Guthrie testing (newborn heel prick test).

• 🥇 Immunoreactive trypsinogen - this is elevated in CF. Trypsinogen is a pro enzyme made by the pancreas’ exocrine cells. If it is elevated in the blood then it means that there is defects in its passage into the intestines, which may indicate CF.
• 🏆 Sweat test - this measures the concentration of chloride excreted in sweat. If it is >60mmol/L this confirms the diagnosis.

Genetic testing can be done during pregnancy through amniocentesis or chorionic villous sampling. It can also be done through blood testing after birth.

Gastrograffin enema is done to assess a meconium ileus.

🧰 Management

Other treatments may include:

• Bilateral lung transplant or liver failure - for terminal respiratory failure or liver failure.
• Fertility treatments - such as testicular sperm extraction.
• Genetic counselling
• High calorie diet
• Monitoring - such as monitoring of sputum, diabetes, liver failure, osteoporosis.

🚨 Complications

• Male infertility
• Female subfertility
• Rectal prolapse
• Osteoporosis - due to vitamin D deficiency.
• Arthritis
• Hypertrophic pulmonary osteoarthropathy
• Diabetes mellitus