Inherited disorders: Cystic fibrosis
CFTR protein
Cystic fibrosis (CF) is a disorder usually diagnosed at birth through newborn screening programmes. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene result in faulty production of the CFTR protein. This protein regulates the movement of chloride and bicarbonate ions and water across membranes. This means that secretions in certain parts of the body such as the lungs, pancreas and gut, become very thick and are difficult to clear.The CFTR protein is shaped like a channel with a gate. The gate needs to be present at the cell surface and open for chloride to flow through it. Around 85% of patients with CF in Europe can make the CFTR protein but it does not fold into shape correctly and so cannot move to the cell surface. The most common variant causing this is F508del. Other patients have gene variants which result in the gate of the channel not opening, or mean the channel is completely absent.
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| A computer generated image of the CFTR protein. On the left-hand side the channel is closed and chloride and bicarbonate cannot pass. On the right-hand side the channel is open and the ions can move across the cell membrane. |
CFTR modulators
The introduction of CFTR modulators has significantly improved the quality of life and health outcomes for many patients with CF.
There are 4 CFTR modulators currently approved for use in the NHS;
• Kaftrio (ivacaftor, tezacaftor, elexacaftor – sometimes referred to as ‘triple therapy’)
• Orkambi (ivacaftor, lumacaftor)
• Symkevi (ivacaftor, tezacaftor)
• Kalydeco (ivacaftor)
Ivacaftor is called a ‘potentiator’ which means it holds the gate of the CFTR channel open so chloride can flow through the cell membrane. Tezacaftor, elexacaftor and lumacaftor are called ‘correctors’. They act by helping the CFTR protein form the correct shape, get to the cell surface and stay there longer. Correctors and potentiators are used in combination to optimise their efficacy.
In practice, in the UK, most eligible adults and children over 2 years are given triple therapy (ivacaftor, tezacaftor, elexacaftor) in the morning with single agent ivacaftor given in the evening. Patients are required to have specific gene mutations to qualify as outlined by NHS England.
Chronic respiratory complications
Mucus accumulates in the lungs which become infected by bacteria (most commonly Pseudomonas aeruginosa). Recurrent, intermittent infections occur and can become chronic, which may accelerate a decline in respiratory function. Preventing chronic chest infection is therefore a key element in increasing survival. Airways clearance techniques such as physiotherapy help to reverse the build-up of mucus, and medicines such as inhaled dornase alfa or hypertonic saline reduce the viscosity of lung secretions. Infections may be managed with inhaled antibiotics such as tobramycin or colistimethate sodium, or a variety of oral medication depending on the bacteria present in sputum samples.
Damage to the pancreas results in its digestive enzymes not reaching the bowel in sufficient quantity, and this can give rise to malnutrition. This dietary deficiency can affect growth. Patients with CF often take pancreatic enzyme supplements orally (pancreatin) and sometimes the doses may be higher compared to that used in other indications (e.g. 40 capsules daily of the 25 000 unit strength). In addition they may need nutritional supplements to boost their calorific intake and to ensure they receive adequate fat-soluble vitamins. Some patients suffer from liver impairment, and patients with CF can develop diabetes type 3c because of ongoing damage to the pancreas which may need to be treated pharmacologically.
Medicines optimisation
Patients with CF may handle medicines differently, but it's difficult to make generalisations as the effects of cystic fibrosis vary widely between patients. All cystic fibrosis specialist centres in the UK have pharmacist team members, who can provide advice on medication, while lung transplant centres manage these specialist medicines, including interpreting therapeutic drug monitoring.
The absorption of medicines may be reduced because of the effects that CF has on the gut.
Many patients with CF are children and the special care required with medicines in this age group is discussed in our children’s tutorial.
As above, some patients with cystic fibrosis have CF-related liver disease, and the principles discussed in our liver tutorial are useful for considering the impact of any liver dysfunction.
Patients with CF may need medicines that are not commonly used in other patient groups, and so pharmacists have a particular role to ensure that prescribed regimens are safe and correct. The medicines concerned may be unlicensed, given via an unlicensed route, or be taken at larger than expected doses. Pharmacists also counsel patients on the benefits and risks of taking their medicines including their CFTR modulators, and the importance of adherence even if symptoms improve and patients feel relatively well.
Read the most recent UK Cystic Fibrosis Registry summary to see how health outcomes have changed from 2018 to 2023.