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Cystic Fibrosis (CF) - Coggle Diagram
Cystic Fibrosis (CF)
Pathogenesis
- The ΔF508 mutation, the deletion of phenylalanine at position 508 of the polypeptide, is present in 70% of CF chromosomes.
- In people with CF, mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause the CFTR protein to become dysfunctional.
- The ΔF508 mutation results in abnormal synthesis and premature degradation of CFTR protein by the cells, therefore an absence of this protein in CF epithelial cells. This results in a decreased permeability of chloride ions across these epithelial cells.
- Studies suggest that the absence of CFTR leads to a change in the composition of the airway surface liquid (ASL) and an increase in NaCl. This increased salt concentration inhibits the actions of a naturally secreted, salt-sensitive, antimicrobial protein (hBD-1), leaving CF epithelial cells susceptible to infection.
- The absence of CFTR protein in CF airway epithelium produces two defects in this process. First, the reduced permeability of CF epithelia to Cl- results in reduced Cl- secretion and less salt on the apical surface. The result is a reduced driving force for water to enter the lumen of the cells. Secondly, due to the lack of CFTR, ENaC activity is unregulated, which causes an inappropriate absorption of salt from airway surface liquid. The overlying mucus blanket becomes dehydrated and compresses the cilia, resulting in a lack of mucociliary clearance (MCC)
- It was shown that the mucus blanket expands with additional hydration, taking up water like a sponge, and as a result the height of the mucus layer increases.
- Airway hydration is crucial to maintain healthy flowing mucus. Mucus represents the main barrier between the airway epithelium and the external environment, so it is the primary defense mechanism of the airways.
- A healthy mucus layer consists of around 1% salt, 1% mucins and 98% water and is like a viscous liquid with a small elastic component.
- In contrast, the >8% mucus characteristic of CF patients displays highly elastic behavior and shear thickening, which is the thickening of mucus as force is applied to it.
- CF mucus is adhesive, and that property in combination with low viscosity and high elasticity makes CF mucus especially hard to clear, even during cough. These properties cause mucus stasis and adhesions.
- Normally hydrated mucus has a pore size of around 0.2-1 μm. In dehydrated CF-like 8% mucus, the pore size is <100 nm. The decreased pore size of CF mucus explains why the defense function of neutrophils is defective in CF because they cannot penetrate the mucus to capture and kill bacteria.
- Cystic fibrosis (CF) is a disease of exocrine gland function that involves multiple organ systems ultimately resulting in chronic respiratory infections and pancreatic enzyme insufficiency,
- End-stage lung disease is the primary cause of death for CF patients.
- Six classes of defects resulting from CFTR mutations include:
- Complete absence of CFTR protein synthesis
- Defective protein maturation and early degradation (caused by the most common mutation, ΔF508)
- Disordered regulation (diminished ATP binding and hydrolysis)
- Defective chloride conductance or channel gating
- Diminished transcription due to promoter or splicing abnormality
- Accelerated channel turnover from the cell surface
- CFTR mutations have poor penetrance. This means that the genotype does not predict the pattern or severity of disease.
- The CFTR protein produced by this gene regulates the movement of chloride and sodium ions across epithelial cell membranes.
- A combination of decreased mucociliary clearance and an altered ion transport allow for bacterial colonization of the respiratory tract, most commonly Pseudomonas, Haemophilus influenza, and Staphylococcus aureus. These pathogens cause an overwhelming inflammatory response. Ultimately, chronic infection and this repetitive inflammatory response can lead to airway destruction.
- The CFTR also affects the production of mucus, secretory granules and intracellular organelles. This defect affects cells in many organs, not all organs have similar clinical responses, and different organs may be affected.
- The obstruction of pancreatic canaliculi by mucous plugs prevents the release of enzymes into the duodenum, which causes poor digestion of fat, proteins and carbohydrates. Malabsorption is caused by pre-epithelial dysfunction, which occurs after the rejection of non-hydrolysable nutrients in the lumen.
- The endocrine pancreas also undergoes changes and the prevalence of CF related to glucose intolerance has increased proportionally with the rate of survival. The main cause of diabetes is damage caused to the pancreas, leading to a decrease in insulin secretion. Diabetes in CF patients results from microvascular and macrovascular complications associated with accelerated lung deterioration, consequently increasing the death rate.
- Early diagnosis and the treatment of complications of the respiratory and gastrointestinal tract in CF can lead to an improvement in the survival rate of CF patients. Those who live beyond the fourth decade have a higher risk of developing additional diseases associated with chronic manifestations. Patients with a higher risk of chronic diseases should be monitored closely to improve the chances of early diagnosis.
- Further evidence came from multiple studies that demonstrated abnormal ion transport across other affected organs, including airways. pancreatic ducts, biliary ducts, and the colon.
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Incidence/Prevalence
- More than 30,000 people are living with cystic fibrosis in the United States (more than 70,000 worldwide).
- Approximately 1,000 new cases of CF are diagnosed each year.
- More than 75 percent of people with CF are diagnosed by age 2.
- More than half of the CF population is age 18 or older.
- The disease occurs in 1 in 2,500 to 3,500 white newborns.
- CF is less common in other ethnic groups, affecting about 1 in 17,000 African Americans and 1 in 31,000 Asian Americans.
- Its estimated heterozygote frequency in white people is up to 1 in 20. Each offspring of 2 heterozygote parents has a 25% chance of developing cystic fibrosis.
- The prevalence of CF varies throughout the fifty United States and the District of Columbia (Figure 2), ranging from 1.2/100,000 people in Hawaii to 24.6/100,000 in Vermont.
- In 2014, 93.9% of the individuals with CF were Caucasian, 4.6% were African American, 3.1% were other races and 8.2% were Hispanics. This is in contrast to the population of the United States that is 62% Caucasian, 12% African American and 17% Hispanic.
- Incidence rates for CF in Canada and the U.K. are similar to those seen in the U.S. Across the European Union, about 1 in 2,000 to 3,000 babies are diagnosed with CF at birth, slightly higher than the U.S.
- Worldwide, about 70,000 to 100,000 people have cystic fibrosis. It affects males and females at about the same rate.
Treatments
There is no cure for cystic fibrosis, but treatment can ease symptoms, reduce complications and improve quality of life.
Medications
- Medications that target gene mutations: Newer medications, cystic fibrosis transmembrane conductance regulator (CTFR) modulators, help improve the function of the faulty CFTR protein. They may improve lung function and weight, and reduce the amount of salt in sweat. Examples of these medications include: Kalydeco® (ivacaftor), Orkambi® (lumacaftor/ivacaftor), Symdeko® (tezacaftor/ivacaftor), and Trikafta® (elexacaftor/tezacaftor/ivacaftor). Side effects of these medications include Side effects of CFTR modulators vary according to the drug taken, but nausea and sinus congestion are common with these medications. The long-term risks of taking this new class of medications are unknown.
- Antibiotics: These medications are used to treat and prevent lung infections that result from a build up of secretions in the respiratory tract. Staphylococcus aureus and Hemophilus influenzae are the most common bacteria that cause infections in CF patients. Several classes of antibiotics help to treat staph infections including penicillins, cephalosporins, carbapenems, sulfas, tetracyclines, lincosamides, and oxazolidinone. Penicillins include amoxicillin and clavulanic acid (Augmentin®), dicloxacillin, nafcillin and oxacillin, and piperacillin/tazobactam. Cephalosporins include medications such as cephalexin, cefdinir, cefuroxime, and cefazolin. Next, carbapenems include meropenem, imipenem/cilastatin, doripenem, meropenem-avibactam, and ertapenem. Sufas include medications such as sulfamethoxazole and trimethoprim (Bactrim®). Tetracyclines include tetracycline, doxycycline, minocycline, and tigecycline. Lincosamides include clindamycin. Lastly, linezolid belongs to the class of oxazolidinone. On the other hand, there are two main classes that treat infections caused by Haemophilus influenzae: Penicillins (including amoxicillin/clavulanate) and cephalosporins (including cefdinir). Side effects of antibiotics include vomiting, nausea, diarrhea, bloating, indigestion, abdominal pain, and loss of appetite.
- Anti-inflammatory medications: These medications help to lessen swelling in the airways of the lungs due to the inability to function properly. Examples of anti-inflammatory medications that are common among CF patients include high doses of ibuprofen and steroids, such as prednisone. Ibuprofen belongs to the drug class called nonsteroidal anti-inflammatory drugs (NSAIDs). Prednisone is in a class of medications called corticosteroids. Side effects of ibuprofen include nausea, vomiting, stomach pain, tinnitus, constipation, dizziness, and drowsiness. On the other hand, side effects of prednisone include headache, dizziness, difficulty falling asleep or staying awake, extreme changes in mood, bulging eyes, and acne.
- Mucus-thinning drugs, such as hypertonic saline: These medications help produce a cough to clear the mucus, which can improve lung function. Hypertonic Saline belongs to a class of drugs called mucolytics. The adverse effects of mucolytics include headache, nausea, vomiting, gastric discomfort and bleeding, diarrhea, and rash.
- Inhaled medications called bronchodilators: These medications can help keep the airways open by relaxing the muscles around the bronchial tubes. Albuterol (Ventolin and Proventalin), Xopenex (levalbuterol), and Combivent, a combination of ipratropium bromide and albuterol, are examples of bronchodilators used by CF patients to treat bronchospasms. Side effects of bronchodilators include trembling, especially in the hands, headaches, dry mouth, sudden heart palpitations, muscle cramps, cough, nausea, vomiting, and diarrhea.
- Oral pancreatic enzymes: These medications help the digestive tract absorb nutrients, due to pancreatic insufficiency that occurs in CF patients. Creon®, Pancreaze®, Pertzye®, UltresaTM, and Zenpep® are the five main oral pancreatic enzymes used to treat this disease process. Side effects of this class of medications are diarrhea, constipation, headache, abdominal pain/cramps/bloating, gas, cough, nausea, and vomiting.
- Acid-reducing medications: These medications allow pancreatic enzymes to work better to absorb fat by lowering stomach acid. Proton pump inhibitors are found to be effective for CF patients. Some of these medications include Omeprazole (Prilosec®), Lansoprazole (Prevacid®), and Esomeprazole (Nexium®). H2 blockers are other common acid reducing medications used for CF. Some of the medications within this class include ranitidine (Zantac®), famotidine (Pepcid®), and nizatidine (Axid®). Side effects of proton pump inhibitors include headache, diarrhea, nausea, and vomiting. More serious side effects include kidney disease, fractures, infections, and vitamin deficiencies and are associated with long-term use. Side effects of H2 blockers include constipation, diarrhea, difficulty sleeping, dry mouth, dry skin, headaches, tinnitus, and a runny nose.
- Stool softeners: These medications are used to prevent constipation or bowel obstructions that can occur as a result of built up undigested nutrients. Polyethylene glycol electrolyte solutions (MiraLAX® or GoLYTELY®) are examples of stool softeners that are shown to be effective in CF patients. Side effects of polyethylene glycol electrolyte solutions include vomiting, stomach pain, indigestion, bloating, rectal pain or irritation, hunger, thirst, trouble sleeping, dizziness, and chills.
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Pulmonary Rehabilitation
- This is a long-term program to help improve long function and improve the CF patients' overall well-being. This is usually done in out-patient facilities and includes physical exercise, breathing techniques used to loosen the mucus and allow for better breathing, nutritional counseling along with other forms of counseling and support, and patient education about CF.
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Risk Factors
- Family History: A person is at high risk of developing CF if one or more of their parents has CF or is a carrier of a mutated CFTR gene. One is also at risk if their sibling, half-sibling, or first cousin has cystic fibrosis. The gene that causes CF is a recessive gene, so in order for one to get CF, a child must inherit two copies of the gene —one from each parent. If the child inherits only one copy of the gene, they will not get CF. However, this does make that individual a carrier, so they could pass CF on to their future children. Each time two CF carriers have a child, the chances are: 25 percent (1 in 4) the child will have CF, 50 percent (1 in 2) the child will be a carrier but will not have CF, and 25 percent (1 in 4) the child will not be a carrier and will not have CF.
- Race or ethnicity: CF is most common among individuals with a northern European ancestry. This disease is less common among Hispanics and African Americans. On the other hand, CF is uncommon in Asian Americans. Although CF occurs most often in the Caucasian population, it can occur in any ethnic group. Among caucasians, Cystic Fibrosis is the most common autosomal recessive disorder. The disease affects about 1 in 2,500 to 3,500 white newborns.
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Diagnostics
Newborns are screened for cystic fibrosis (CF) as part of each state's newborn screening program. More testing, however, is required to confirm positive results.
In addition to a full health history and and physical exam, other tests for CF include:
- Sweat (chloride) test: This test involves placing a solution on the forearm and attaching electrodes. Then, the skin is stimulated to sweat using a mild electric current. This stimulation helps to produce enough sweat to be absorbed into a special collector, which is then analyzed for the amount of chloride it contains. Kids with CF can have two to five times the normal amount of chloride in their sweat.
- Genetic tests: This test looks at a person's DNA in their cells. Blood, or cells taken from a cheek scraping, can be tested for mutations in the CFTR gene. About 2,000 different mutations on the gene have been found, but not all of them cause CF. Genetic tests for the disease are usually done in one of two ways:
- Panel test: This screen checks for the most common mutations that cause CF. If the result is “positive,” that means it’s 99% certain you have the gene mutation. A “negative” result could indicate a rare mutation that doesn’t show up on the test.
- Gene sequencing: This test studies all 250,000 pairs that make up the CFTR gene. It spots rare mutations. However, this test is expensive, so it is not as common as the panel test.
Other tests may include:
- Blood tests: A few drops of blood are drawn from the baby’s heel and sent to a lab. It is then checked for a chemical made by the pancreas called immunoreactive trypsinogen (IRT).The IRT-based test is a just a screening test and is not meant to be used to make a diagnosis. Most babies who “fail” the IRT screen don’t have cystic fibrosis. Instead, they have a higher risk and need another test to confirm. If results from the second test are normal, there’s no further risk or need for more testing.
- Chest x-rays: This exam uses a small dose of ionizing radiation to produce images to evaluate for dilated airways containing mucus and also to evaluate lung infections that need to be treated with antibiotics. Chest x-rays are used periodically to observe changes in patients with cystic fibrosis and rule out other respiratory conditions such as pneumonia or a collapsed lung. Most patients with CF demonstrate some of the classic chest radiographic findings that reflect chronic bronchiectasis, including hyperinflation and mucoid impaction.
- Pulmonary function tests: Pulmonary function tests (PFT) measure both the capacity (size) of the lungs and how well the air flows in and out of the lungs. These numbers also measure long-term damage to the lungs and progression of CF.The two most common types of pulmonary function tests that people with CF take are:
- Spirometry: A spirometer is a machine that measures how well the lungs are working. It records how much air the lungs can take in on a full breath or inspiration. This number is used to monitor the progression of CF and the effectiveness of any treatments.
- Diffusion capacity: This PFT measures how the lungs move oxygen through the air sacs into the rest of the body.
- Sputum cultures: This test is done on the material that is coughed up from the lungs and into the mouth. A sputum culture is often done to find out if an infection is present and to prescribe the most effective antibiotics to target a specific infection.
- Stool evaluations: This test measures the amount of elastase in your stool. Elastase is an enzyme made by special tissue in the pancreas, an organ in your upper abdomen. Elastase helps break down fats, proteins, and carbohydrates after you eat. If little or no elastase is found in the stool, it can mean this enzyme is not working as it should. These tests are also done to measure the amount of fat in a stool sample. Too much fat may mean the digestive system is not working correctly.
Clinical Manifestations
Respiratory
- A persistent cough that produces thick mucus (sputum): In CF, the mucus is too thick for the cilia to move it, which causes coughing in order to help the lungs remove the mucus.
- Wheezing: The thick and sticky mucus associated with CF clogs the tubes that carry air in and out of the lungs, which causes high-pitched, whistling sounds from the labored breathing.
- Exercise intolerance: Bronchial obstruction due to the thick mucus produced by CF causes exertional dyspnea because of dysfunctional gas exchange, which can make it hard for CF patients to engage in physical activity.
- Repeated lung infections: Bacteria that are normally cleared from the lungs get trapped in the thickened mucus caused by CF. This allows the bacteria to thrive and multiply, causing an infection.
- Inflamed nasal passages and or a stuffy nose: The thick, sticky mucus builds up in the sinuses, which are the cavities around the nasal passages. This can lead to infections of the sinuses.
- Recurrent sinusitis: Chronic blocking of the sinuses, preventing them from draining, leads to consistent infections of the sinuses because of the mucus buildup caused by CF. This mucus can trap bacteria in the sinuses, making an infection very likely.
Digestive
- Foul-smelling, greasy stools: The thick mucus can also block tubes that carry digestive enzymes from the pancreas to the small intestine. Without these digestive enzymes, the intestines aren't able to completely absorb the nutrients in the food you eat.
- Poor weight gain and growth: The lack of digestive enzymes caused by CF cause malabsorption of food and nutrients, which leads to a deficit in the necessary nutrients to gain weight and grow.
- Intestinal blockage, particularly in newborns (meconium ileus): Because mucus builds up along the intestinal tract, this slows down the emptying of food. This results in the build-up of stool behind the mucus-filled area, causing a blockage.
- Chronic or severe constipation, which may include frequent straining while trying to pass stool, eventually causing part of the rectum to protrude outside the anus (rectal prolapse): The intestines in CF make thick mucus. If this thick mucus is present but there is not enough fluid in the intestines, you can get constipated or even develop a bowel obstruction due to the buildup of undigested nutrients.