Cystic fibrosis: What is it and why is it so deadly?

Cystic fibrosis, a dreaded disease that affects one in every 2,500 children born. It is characterised by the accumulation of thick, sticky mucus. What I longed to understand was the cause and the pathophysiology of this disease.

In one of our autosomal genes, there lies a gene called the CFTR gene. This gene codes for a channel protein which serves as a chloride ion pump. This protein pump is situated in glandular cells, where they transport these chloride ions into the lumen of the ducts, ie from inside to outside the cell. These glands are responsible for the production of sweat, digestive juices and mucus. This increases the solute concentration and inevitably lowers the water potential of the solution in the ducts. Thus, water naturally follows via osmosis, constituting to the normal consistency of mucus.

However, in people with Cystic Fibrosis, there are several different mutation of the CFTR gene. Such mutations can cause either the protein pump to not be correctly shaped (it doesnt’ fold properly thus does not have the precise tertiary structure which is vital to its function); the protein is too short due to premature termination of its production; ATP is not used properly so it cannot actively transport the halogen ions into/out of the lumen or not enough CFTR genes are produced. In any case, the choride ions are not secreted effectively, so less water moves via osmosis to soften the consistency of the mucus, resulting in the thick mucus typical of a sufferer.

People with cystic fibrosis have sweat tests: what is the basis of this test?

In the proportion of the population without cystic fibrosis, sweat is produced via a well understood mechanism. The body has found an ingenious way to get somehow force water out of sweat glands, since usually water likes to remain inside the body. It does this by a process of salt secretion and succeeding re-absorption. Firstly, sodium chloride is secreted by sweat glands into the lumen of the sweat duct. This increases the solute concentration of the solution in the duct, thus lowering the water potential. Here water moves out of the cells by osmosis, leaving a salty solution. However these lost ions must be reabsorbed, otherwise the body would now be able to continually sweat. The sodium and chloride ions are taken back in via ion channels (sodium and chloride ion channels)… and the chloride channel is called ‘CFTR’. Do you remember this protein? This is where we link sweating back to cystic fibrosis; in people with defective CFTR channels, chlorine is not successfully reabsorbed, so the chlorine remains in the ducts. Re-absorption relies on a well balanced concentration of sodium and chlorine ions. If this harmonious balance is disrupted, the sodium too won’t be properly reabsorbed. Both ions have opposite charges, so the sodium will remain in the sweat with to keep the solution electrically neutral, in spite of the sodium channels working proficiently. This leaves a heavily concentrated salt solution forming the basis of sweat in suffers of CF. Thus, as you can see, one way to diagnose CF is through a sweat test: A test to measure the concentration of salt in sweat.

So why is it so deadly?

1) Sticky lungs

Mucus is secreted by goblet cells in the airways of the lungs. Since the mucus produced is so thick and sticky, it builds up in copious amounts. Mucus has the function of trapping the invading dirt and bacteria which happens to permeate our lungs. This is great for us: bacteria can’t cause infections as the pathogen-filled mucus is swiftly disposed of in the stomach or out the trachea. However for someone who can’t waft the mucus up the trachea and out of the airways, these bacteria can wreak havoc. Pathogens build up, irritating the bronchi and trachea, resulting in excessive inflammation. This can lead to bronchitis, pneumonia, difficulty breathing due to restricted airways (from mucus and inflammation). The surface area of the lungs will inevitably decrease due to the inflammation and repair of alveoli (so the new alveoli are larger and less numerous). This will both result in hypoxia (the supply of oxygen doesn’t meet the demand) and high blood pressure. The reason for high blood pressure is quite fascinating: The thin, delicate capillaries surrounding the alveoli become damaged due to the irritation from bacteria, but also from the macrophages in the blood (pathogen destroying white blood cells) secreting enzymes called elastase. Elastase has the property of breaking down elastic fibres in the capillary walls, thus capillaries are broken down. Eventually the number of capillaries will decrease. To pump the same amount of blood around a smaller volume of capillaries requires a lot more pressure, thus the cardiac muscle needs to pump more powerfully to push the blood round the pulmonary circuit (lungs). Therefore, a CF sufferer will experience pulmonary hypertension.

2) Sticky pancreatic juices; Gastrointestinal effects 

Likewise with the lungs, the secretions of other organs are severely thickened. In the pancreas, the duct becomes full of this sticky mucus which blocks the digestive enzymes from being secreted onto food in the duodenum. Food can’t be broken down, so a sufferer will have difficulty absorbing nutrients. This is known as malabsorption, leading to poor growth and development and severe weight loss.

The liver is too effected: the bile duct which secretes bile onto your food becomes blocked, leading to scarring (cirrhosis) and the inability of the liver to remove toxins from the blood.

The disaster doesn’t stop there. The pancreas has role of secreting Insulin to maintain blood glucose levels. A group of cells called islets of Langerhans are responsible for secreting this insulin. Damage to the pancreas leads to the loss of these cells, meaning that suffers usually develop a cystic-fibrosis related diabetes.

Finally, the other main horrifying consequence of having such disease is infertility. Men born with CF usually are missing a structure called the Vas Defrens. This connects the testes to the ejaculatory ducts of the penis. Thus, around 97% of male suffers are infertile.

Are there any potential cures to this disease?

There have been attempts to alleviate some of the symptoms, such as ingesting tablets containing digestive enzymes to help with the breakdown of food. Recently I read an article in the new scientist describing attempts to use liposomes to carry healthy CFTR genes into the cells of the lungs.

Read the full article here: https://www.newscientist.com/article/dn27832-gene-therapy-works-in-cystic-fibrosis-for-the-first-time/ 

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