Cystic fibrosis affects greater than 30,000 people in the US with patients having an average life expectancy of 37.5 years, making this genetic disease quite devastating to those afflicted with it. “Cyst” refers to fluid-filled pockets, and “fibrosis” refers to the formation of excess connective tissue, both of which tend to happen in the pancreas of patients with cystic fibrosis. Ultimately though, cystic fibrosis is a disease that deals with diffusion and osmosis. All cells have a membrane made of a phospholipid bilayer with outward-facing hydrophilic heads and inward-facing hydrophobic tails designed to separate the contents of the cell from the contents of the environment. Ions cannot pass through the cell membrane through simple diffusion, so they typically must go through channel proteins. In cystic fibrosis, issues with the CFTR (cystic fibrosis transmembrane regulator) channel protein arise, leading to ion imbalances that have severe consequences on the entire body.
Specifically, a genetic mutation in the CFTR gene is the cause of the channel protein issues. The mutations can be put into three groups. Class I and II mutations are characterized by the CFTR protein never making it to the cell membrane because the RNA is faulty or the protein is folded incorrectly, respectively. Class III and IV mutations are characterized by a channel protein that does not function properly and thus cannot serve its purpose. Class V and VI mutations see there not being enough CFTR channel protein because either enough is not made or the channel lacks stability, respectively. Nearly 90% of cystic fibrosis patients have a Class II mutation with the most common being the ∆F508 mutation. As cystic fibrosis is an autosomal recessive condition, if both parents are carrriers and thus unsymptomatic for the disease, it can be passed down to their child in one-fourth of cases.
CFTR is such a fundamentally important channel protein in the lungs because it transports chloride ions out into the mucous secretions. Typically, the increased concentration of chloride ions in these secretions leads them to pull in water through osmosis, hydrating and thinning these secretions out. This is important because the mucus is designed to trap bacteria that cilia (tiny hairs) subsequently push out the body. Without these chloride ions, however, the secretions become quite viscous, which leads to some airways being clogged altogether in cystic fibrosis patients. Furthermore, because of the thick, sticky mucus, the cilia cannot move the bacteria out of the lungs. The stagnant mucus thus becomes a breeding ground for inhaled bacteria, leading the patient to develop chronic respiratory infections in what is called cystic fibrosis exacerbation. While antibiotics can treat these infections, the repeated use for patients with cystic fibrosis tends to make the bacteria antibiotic-resistant, which can prove near impossible to treat. Eventually, due in large part to damage to the respiratory tract, the patient can develop respiratory failure, which is often fatal without a lung transplant.
While lung involvement is most characteristic of cystic fibrosis, the disease also often affects other parts of the body such as the pancreas and intestines. For similar reasons as in the lung, secretions in the pancreas become dehydrated and thickened, leading them to block the pancreatic ducts, which deliver vital digestive enzymes to the small intestine. Without these enzymes, the patient does not efficiently absorb protein and fat from their food; this is known as pancreatic insufficiency. When undigested food is combined with yet more thick mucus in the intestines, the patient can develop distal intestinal obstruction syndrome where there is a blockage in the small intestine. The obstruction is generally flushed out with laxatives or an enema but, sometimes, with surgery. This complication happens in about one-tenth to one-fourth of cystic fibrosis patients. One of the earliest diagnostic indications of cystic fibrosis is actually meconium ileus, which is when the infant’s first stool causes a similar type of blockage in the first part of their small intestine.
Blockages in the pancreatic ducts cause more complications than poor digestion though. In fact, the pancreatic enzymes, holed up in the pancreatic ducts, can begin to degrade the pancreas and cause pancreatitis, a severe case of inflammation of the organ. Eventually, the enzymes can even compromise the endocrine function of the pancreas, leading the patient to develop Type I diabetes because the glucose-producing beta cells are destroyed. Cystic-fibrosis related Type-1 diabetes occurs in 40% of these patients above the age of 30.
In the US, all newborns undergo testing for cystic fibrosis where blood obtained from a heel-prick is tested for immunoreactive trypsinogen (IRT), an enzyme indicative of pancreatic damage. In presence of high IRT, other testing may be used to help confirm the cystic fibrosis diagnosis. However, a significant portion of the population was not tested for cystic fibrosis as newborns because of the relative newness of this policy. A genetic test may be done to detect the presence of a mutation in the CFTR gene; however, a sweat chloride test is the standard to diagnose cystic fibrosis. A sweat chloride test is generally performed by using chemicals (pilocarpine) and electrodes to stimulate the patient’s sweat glands. The sweat is then collected and tested for its chloride content with a result higher than 60 mmol/L indicating a cystic fibrosis diagnosis.
Cystic fibrosis treatment usually falls into one of a few categories: airway clearance therapy, mucolytics, nutrition based therapy, anti-inflammatories/bronchodilators, and therapies to reverse the underlying abnormality. Airway clearance therapy, usually achieved through manual chest physiotherapy or a Vest device, seeks to shake the thick mucus out of place and make it easier for the patient to cough out. Mucolytics, such as hypertonic saline or dornase alfa, seek to help the patient thin out their mucus and thus more easily remove it from their body. Nutrition based therapy is focused on supplementing the patient with extra calories and fat-soluable vitamins to make up for their impaired digestive system as well as on giving them oral pancreatic enzymes to help them better absorb nutrients from their food. Anti-inflammatories and bronchodilators, such as symedko and albuterol respectively, seek to help keep the patient’s airways open so that they may more easily breathe. Lastly, therapies that seek to reverse the underlying abnormality have proven quite promising. Orkambi is a combination drug of lumacaftor and ivacaftor, which works in patinets with the ∆F508 mutation CFTR mutation by helping the protein properly fold and then ensuring that even the improperly folded channel proteins stay open so that chloride ions may pass through.
The recent development of Orkambi to treat the underlying cause of cystic fibrosis rather than its symptom sproves quite promising and indicative that greater awareness and research into cystic fibrosis provides tangible results. Much work is currently being done to create a gene therapy that would replace the defective CFTR gene with a properly functioning one, which would hopefully cure the patient of this devastating disease. Survival for patients with cystic fibrosis has doubled in the past half-century, so let us hope that one day, with more research and attention, patients with cystic fibrosis may live full lives without any fear of their disease.
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