Cystic fibrosis is an inherited disorder characterised by a defective CFTR gene, resulting in impairment of the body's ability to generate normal secretions like mucus and sweat. It's inherited in an autosomal recessive pattern, meaning both parents need to carry a faulty gene for the child to be affected, and it's estimated that around 1 in 25 Caucasian people are such carriers. The condition is life shortening, with median survival age in the US in 2021 being 33.9 years. And projections for those born between 2018 and 2022 to be 56 years. The CFTR gene is found on chromosome 7 and it codes for the protein CFTR, which stands for Cystic Fibrosis Transmembrane Conductance Regulator, that forms a cyclic AMP chloride channel that normally allows movement of chloride and bicarbonate across epithelial membranes and also, by extension, sodium and water. This protein is primarily expressed in the exocrine glands. Those are the glands that release secretions through a duct to an epithelial surface. And over 2000 defective variants to date have been found in this gene. But around 85% of cases are due to the variant F508 deletion that causes misfolding. The most commonly affected organs include the lungs, pancreas, sinuses, hepatobiliary system, intestines and sweat glands. Normally the CFTR channel helps move chloride and bicarbonate out of the cell, causing sodium to remain outside and overall to cause water to move out of the cells, forming normal secretions. The overall result of the variance in the gene, however, is decreased secretion of chloride out of the cells and consequently increased resorption of sodium into the cellular space. which therefore means more water tends to remain in the cell, this translates to thicker mucus on epithelial surfaces and more viscous secretions from exocrine glands, which generally predisposes them to becoming obstructed, leading to pathology. In sweat glands, the role of CFTR is actually reversed. The channel is meant to bring chloride in from the extracellular space to the intracellular space, and so encourage sodium and water to be reabsorbed. It's for this reason that in cystic fibrosis, chloride remains in the sweat and so does sodium, causing the sweat to be excessively salty, and excess sweating can also lead to significant dehydration. In the lungs, the CFTR dysfunction can mean stickier mucus that is more difficult to clear for the cilia, leading to mucus plugging and a breeding ground for recurrent infections, particularly Staphylococcus aureus early on in life and Pseudomonas aeruginosa, colonising 60% of adults later on. There is then inflammation with release of proteases and cytokines that perpetuate the lung injury. including release of interleukin-8 that can stimulate further mucous secretion, altogether giving episodic exacerbations and eventually dilatation and destruction of the airways, termed bronchiectasis, with progressively worsening lung function. The resulting hypoxemia can lead to pulmonary hypertension and eventually right-sided heart failure, or core pulmonale. In contrast to COPD, emphysema is not prominent and although the respiratory system may be normal at birth, respiratory disease can begin even in infancy. As we mentioned, the pancreas can be affected, the obstructed ducts can lead to early activation of the enzymes and subsequent autodestruction of the pancreas. Autodestruction then deteriorates, eventually causing insufficiency. The endocrine function of the pancreas is largely maintained, at least initially, but diabetes mellitus is present in 2% of affected children and 50% of adults. Involvement of the intrabiliary ducts leads to biostasis and eventually hepatic fibrosis in nearly one third of patients, with around 3% progressing to have biliary cirrhosis and portal hypertension by the age of 12. The intestines are also affected, particularly by having more viscous secretions, which can lead to meconium ileus in neonates, where there is an intestinal obstruction in neonates due to the increased viscosity of the meconium, and the viscous fluid may predispose to intestinal obstruction in adults. In males particularly, fertility is greatly impaired, with 98% of male patients being infertile due to poor or no development of the vas deferens, which are ducts that aid sperm transport from the epididymis to the ejaculatory ducts. In females, fertility can be impaired due to the viscous cervical secretions and may also be linked to nutrition deficits that we'll touch on shortly, with 15-30% of females estimated to be affected. Symptoms typically begin in infancy or in childhood, manifesting often as a failure to thrive. Respiratory symptoms can include recurrent respiratory tract infections with coughing and wheezing being common features, as well as disturbed sleep and gagging often related to the cough. During exacerbations, haemoptysis is more common, and as the disease progresses, shortness of breath or reduced exercise tolerance become more prominent. Pancreatic insufficiency leads to malabsorption of nutrients, particularly fats, resulting in poor growth despite a good appetite. And it can also cause foul-smelling stools laden with lipids that are difficult to flush, called steatorrhea. Malnutrition and vitamin deficiency, particularly in vitamins A, D, E and K, which are the fat soluble vitamins, are common. We mentioned meconium ileus, that can present with vomiting, abdominal distension and failure to pass the meconium, with similar symptoms involving stool and intestinal obstruction in adults. Other systemic features include salty tasting skin or formation of salt crystals on the skin itself. There can also be excess sweating in response to heat or fever that can predispose to dehydration. A diagnosis is typically made when there is clinical suspicion of cystic fibrosis, for example a positive newborn screening, an affected sibling or clinical manifestations, and evidence of dysfunctional CFTR genes. Newborn screening is the way in which most cases are diagnosed, which initially looks for the level of immunoreactive trypsinogen in the blood, taken from a heel prick, followed by sweat testing and CFTR gene analysis. A sweat test can be done as early as 48 hours after birth, and involves inducing localised sweating, typically using pilocarpine. and then evaluating the volume of sweat produced and the concentration of chloride in the sweat. Levels below 30 mmol per litre are considered normal, while those of 60 mmol or above are considered abnormal. This should then be confirmed with a repeat test or genetic testing identifying two disease causing cystic fibrosis variants. The values between 30 and 59 are considered intermediate and then if repeats do not suggest cystic fibrosis and two disease-causing variants are not found genetically then it may be a diagnosis of CFTR-related metabolic syndrome. Pancreatic function is evaluated looking at pancreatic elastase in stool, which may involve serial measurements to identify progression to insufficiency. Imaging can involve the use of CT, typically done routinely every 1-2 years but also at times of exacerbations, with findings ranging from hyperinflation and bronchial wall thickening to bronchiectasis. Pulmonary function tests involve spirometry, done routinely 4 times a year in those beyond 5 years of age. There is typically a reduction in forced vital capacity and forced expiratory volume in 1 second, as well as the FEV1 to FVC ratio. While there is no cure, the goal is to alleviate symptoms, prevent complications and improve the overall quality of life. From a respiratory point of view, this involves vaccines such as the annual influenza and more recently COVID-19 vaccines. Airway clearance measures involves movements to encourage expulsion of the thicker secretions, such as chest physiotherapy. Active cycle of breathing and other methods like vest therapy may also be an option to aid this. and aerobic exercise is also encouraged. This helps increase the volume of sputum cleared and helps with dyspnea. CFTR modulators are medications that target the defective protein. There are two main classes called the potentiators, such as Ivacaftor, that potentiates the ion channel function, and correctors that correct the defective misfolding CFTR protein, such as Lumacaftor, Tezacaftor, and Alexacaftor. Antibiotics are used both in exacerbations and prophylactically. For example, severe exacerbations or pseudomonas colonizers will have intravenous tobramycin with the addition of vancomycin and linezolid if MRSA positive. Antibiotic antibiotics include inhaled tobramycin every other month along with continuous oral azithromycin. which can maintain pulmonary function and decrease the frequency of pulmonary exacerbations. Bronchodilators can aid in reversing some airway obstruction, and mucolytics like Dornay's Alpha help improve lung function and reduce exacerbations. Non-steroidal anti-inflammatory drugs like Ibuprofen have been shown to slow deterioration in lung function, but is not used routinely due to the associated GI risks like peptic ulcer disease. Functional support plays a large role. which may involve a 50% excess in calories and multivitamins in order to meet requirements for growth. In those with pancreatic insufficiency, enzyme replacement therapy is used. Cystic fibrosis patients can experience frequent partial obstructions that may be relieved by the use of enemas and prevented by laxatives, especially stool softeners. Surgery is an option in some instances, such as nasal polyps or localised atelectasis or bronchiectasis. While lung transplantation may be considered for individuals with advanced lung disease, which is now becoming more routine, with median survival rates of approximately 9 years post-transplant, liver transplant is also an option in some cases.