Introduction
Cystic Fibrosis (CF) is the most prevalent genetic disorder in the Caucasian population, with an incidence of 1 in 2500 births. CF is a disease that affects many organs including the upper and lower respiratory tracts, pancreas, intestines and reproductive system. Over the past 20 years, our understanding of the manifestation and management of the disease has progressed dramatically. CF was once considered a condition of childhood and there was very little expectation that children would enter adult life. However, CF has become a multisystem adult disease with the increased survival attributable to advancements in standardized treatment, introduction of newborn screening and continuing research into new therapeutic approaches. The drastic increase in life expectancy is not only an improvement noted in North America but is a phenomenon changing the lives of CF patients worldwide. In an international study by Fogarty, et al. (Fogarty et al. 2000), results demonstrated that the median age of death from cystic fibrosis increased from 8 years in 1974 to 21 years in 1999. This paper will review the history and development of CF and discuss current issues and obstacles in the transitioning process.
Disease
Mutations in the CFTR gene directly influence chloride permeability and have an effect on sodium and bicarbonate (Cutting 2005). CFTR is expressed in the apical membrane of pancreatic duct cells where it supports pancreatic secretion. Damaged pancreatic secretion of bicarbonate and chloride is characteristic of CFTR impairment. Mutations in the CFTR gene lead to an alteration in the composition of these secretions, creating blockage of the ducts, development of excessive fibrous connective tissue in the pancreas and ultimately organ failure. Exocrine pancreatic insufficiency is seen in 85-90% of CF patients, requiring pancreatic enzyme supplementation for proper nutrient absorption. Failure to thrive is a common presentation in individuals with CF, as reduced secretion of pancreatic enzymes in the small intestine causes malabsorbtion and slows down digestion of fat and protein (Ibid.). Some individuals with CF suffer from recurrent occurrences of pancreatitis associated with CFTR dysfunction (Bush 2006). In the normal airway, CFTR absorbs chloride ions and regulates the absorption of sodium through epithelial sodium channels (ENaC). In CF, inhibition of ENaC in the apical epithelial membrane is distorted, leading to hyper-absorption of sodium. Chloride flows through alternative chloride channels and water follows, leading to shrinkage of the airway surface liquid and hyperpolarization of the epithelial surface, dehydration of mucous 5 secretions and collapse of epithelial cilia (Bush 2006).
In healthy individuals, the mucus layer is a gel-forming mucin-type glycoprotein consisting of approximately 95% water. Between the mucus layer and epithelial cell membrane lies a thin liquid layer that provides a low viscosity solution in which the cilia can beat rapidly, and prevents adhesion of mucus to epithelial surface, lubricating the movement of mucus during cough clearance (Derrien et al. 2010). In CF, unregulated absorption of ions and water across the airway and epithelia continuously absorb surface liquid, causing the cilia to collapse onto the cell surface. This leads to mucus plugging and airway obstruction, promoting bacterial infection, inflammation and airway damage (Bush 2006). 95% of mortality in CF patients is attributed to respiratory illness. Thickened secretions, limited mucociliary clearance, and a weakened defense mechanism affect patients' ability to remove lingering and harmful bacteria from airways, resulting in severe damage to the lungs (Salvatore et al. 2002). A person with cystic fibrosis will have up to 10 times more inflammation than a healthy person with a lower respiratory tract infection. In most individuals with CF, the outcome of these abnormalities is permanent airway damage with bronchiectasis and respiratory failure (Davies et al. 2007). The intestine epithelium is responsible for regulating the movement of electrolytes, nutrients and water to the bloodstream. CFTR is found in large quantities in the intestinal membrane and is essential for secretion of intestinal fluid and lubrication, which is achieved through chloride transport and regulation of sodium channels. In addition, CFTR regulates the pH of the intestine; chloride secreted via CFTR is replaced by bicarbonate ions, provided by the pancreas, biliary system, duodenal glands and intestinal glands. Bicarbonate-rich secretions are necessary for neutralizing acid that enters the duodenum from the stomach. In CF patients, duodenal pH has unusually high acid levels due to the lack of CFTR. Loss of fluid coupled with abnormal acid levels modifies electrolyte transport, causing dehydration of fetal intestine, inflammation and intestinal damage, including a high incidence of gastroesophageal reflux in children, meconium ileus/bowel obstruction (15-20%), rectal prolapse (20%), obstruction of the small intestine (15%) and distal intestinal obstruction (20%) (Cutting 2005). Chronic liver disease is found in 25% of patients with CF and liver failure accounts for approximately 2.5% of CF mortality. Liver disease generally begins before puberty, is most often asymptomatic and progresses gradually.
Disease development and variability in terms of severity suggests a multifactorial pathogenesis, caused by environmental as well as genetic influences. In the liver, CFTR controls the fluid and electrolyte content of bile. Abnormalities of chloride transport due to CFTR dysfunction or deficiency cause defective secretion of mucin necessary for hydration and lubrication. In addition, increased bile viscosity leads to bile duct blockage, and an increased propensity to damage from toxic compounds excreted into the bile. Damage interferes with liver function and eventually leads to cirrhosis (Colombo 2007). Approximately 97-98% of men with Cystic Fibrosis are infertile, the result of structural abnormalities of the reproductive tract. The most common defect is congenital bilateral absence of the vas deferens (CB AVD), which blocks the transport of spermatozoa, resulting in azoospermia. Other abnormalities include reduced quantity, increased acidity and absent or decreased fructose concentrations of sperm (Lewis-Jones et al. 2000). However, with the combination of new aggressive therapy and intervention, survival has progressed, and marriage and reproduction have become an option for many individuals with CF. In the last few years, techniques to obtain viable sperm from the male reproductive tract, for example, microsurgical epididymal sperm aspiration (MESA), or testicular biopsy, have allowed men with CF to attain biological paternity. The most common technique used to assist in fertilization is intracytoplasmic sperm injection (ICSI), a process where the egg and the sperm are fertilized in the laboratory, via direct injection of a single sperm into each egg and then transferred into the uterus (McCallum et al. 2000).
Genetic Background
Mutations in the CFTR gene have been classified into 6 groups according to the mechanism by which they disrupt gene performance and cause functional consequences of the CFTR protein (Appendix B). Such classification is useful in providing logic for predicting phenotypic effects (Zielenski 2000). The CF phenotype is complex, involving multiple organs and variability in symptom manifestation. Phenotypic expression is site specific, ranging from asymptomatic (affecting the sweat glands), to mild (affecting pancreatic function) to severe (affecting the lungs, pancreas and male reproductive tract). In addition, the severity of clinical presentation in each system may vary from one individual to another; variability is more common in respiratory performance, and to a lesser degree pancreatic function, and less common for sweat gland involvement and male infertility (CBAVD). The CF phenotype is extremely heterogeneous. Siblings who have the same CFTR mutation often show great variability between symptom manifestations, suggesting that there may be other factors contributing to the severity of the disease. Severe or class I mutations are often associated with absence of functional CFTR protein; these are also associated with early diagnoses (less than 1 year), pancreatic insufficiency, high sweat chloride concentration, and meconium ileus. CF is a disorder that results in a complex spectrum of disease phenotypes. The amount of CFTR necessary by each organ involved in the disease to remain phenotypically healthy differs; likewise, the extent to which each organ plays a role in the CF phenotype varies significantly (Bush 2006).
Treatment
Phenotype-genotype correlation is an important aspect of research and treatment development. The efficacy of each new drug developed, is dependent on the type of mutation and the unique nature of how the disease manifests itself in each individual. As investigational therapies, mutation specific treatment and therapy may contribute to increased survival among individuals with CF; health care providers need to develop a plan on how to deliver care to a new and evolving population of CF patients.
CF is a multi-system disease and treatment requires a multi-disciplinary approach. The cystic fibrosis team consists of doctors, nurses, dietitians, respiratory therapists, physical therapists, social workers and pharmacists. The goal of treatment is to prevent and control lung infections, loosen and remove the thick, sticky mucus from the lungs, provide sufficient nutrition and prevent intestinal blockage. Chest physical therapy/postural drainage, done multiple times throughout the day, involve clapping or pounding the chest and back to dislodge the thick mucus from the lungs. There are devices that can help with this therapy such as a mechanical percussor, therapy vest, "flutter" device (creates vibrations which remove mucus), and positive expiratory pressure mask (PEP-helps break up mucus from airway), as well as breathing techniques such as the forced expiration technique (FET) and active cycle breathing (ACB).
Babies and young children have to rely on their caregivers for these treatments, and breathing modalities and devices are generally used as the child gets older and more independent. Individuals with cystic fibrosis are encouraged to lead active lives, maintain a consistent exercise regimen and get involved in sports and aerobic activity. Inhaled medications and treatments are recommended for CF care as they have the ability to travel to the airway quickly. Nebulizers are a device used to release medication in an aerosol form through a mouthpiece or facemask. Like an inhaler, it can deliver medication straight into the lungs by creating a medication mist propelled by an air compressor. Inhaled medications include mucolytics, including Pulmozyme, which thins mucus so that individuals can cough it up more easily, as well as hypertonic saline, a watersalt solution which contains a greater concentration of salt than our body fluids and draws water from the cells into the airway. The water mixes with the thick mucus in the airway, causing it to become thinner and easier to cough out. Antibiotics are utilized to combat lung infections that can lead to hospitalization and can become chronic and life threatening if not treated aggressively. They can be administered orally, intravenously, or as an aerosol. Some individuals who suffer from recurrent lung infections can be helped by the use of a port or PICC line, an implanted device that allows long term antibiotic administration (Cystic Fibrosis Foundation, 2015). Treatment for pancreatic insufficiency is important in assisting with digestion of fats and proteins, and facilitating vitamin absorption. Oral pancreatic enzymes are taken before meals and snacks to aid in proper digestion. Vitamin supplements/multivitamins are taken to substitute for the fat soluble vitamins that the intestines have difficulty absorbing. Some individuals are advised to take acid reducing medication in order to improve the efficacy of the oral pancreatic enzymes (Cystic Fibrosis Foundation, 2015). It is recommended that individuals adopt a high calorie and high salt diet in order to provide extra nutrients.
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