Cystic Fibrosis
Disease Details
Family Health Simplified
- Description
- Cystic fibrosis is a genetic disorder that causes severe damage to the lungs, digestive system, and other organs due to the production of thick, sticky mucus.
- Type
- Cystic fibrosis is a genetic disorder. It is transmitted through an autosomal recessive pattern.
- Signs And Symptoms
- Cystic fibrosis typically manifests early in life. Newborns and infants with cystic fibrosis tend to have frequent, large, greasy stools (a result of malabsorption) and are underweight for their age. 15–20% of newborns have their small intestine blocked by meconium, often requiring surgery to correct. Newborns occasionally have neonatal jaundice due to blockage of the bile ducts. Children with cystic fibrosis lose excessive salt in their sweat, and parents often notice salt crystallizing on the skin, or a salty taste when they kiss their child.The primary cause of morbidity and death in people with cystic fibrosis is progressive lung disease, which eventually leads to respiratory failure. This typically begins as a prolonged respiratory infection that continues until treated with antibiotics. Chronic infection of the respiratory tract is nearly universal in people with cystic fibrosis, with Pseudomonas aeruginosa, fungi, and mycobacteria all increasingly common over time. Inflammation of the upper airway results in frequent runny nose and nasal obstruction. Nasal polyps are common, particularly in children and teenagers. As the disease progresses, people tend to have shortness of breath, and a chronic cough that produces sputum. Breathing problems make it increasingly challenging to exercise, and prolonged illness causes those affected to be underweight for their age. In late adolescence or adulthood, people begin to develop severe signs of lung disease: wheezing, digital clubbing, cyanosis, coughing up blood, pulmonary heart disease, and collapsed lung (atelectasis or pneumothorax).In rare cases, cystic fibrosis can manifest itself as a coagulation disorder. Vitamin K is normally absorbed from breast milk, formula, and later, solid foods. This absorption is impaired in some CF patients. Young children are especially sensitive to vitamin K malabsorptive disorders because only a very small amount of vitamin K crosses the placenta, leaving the child with very low reserves and limited ability to absorb vitamin K from dietary sources after birth. Because clotting factors II, VII, IX, and X are vitamin K–dependent, low levels of vitamin K can result in coagulation problems. Consequently, when a child presents with unexplained bruising, a coagulation evaluation may be warranted to determine whether an underlying disease is present.
- Prognosis
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The prognosis for cystic fibrosis has improved due to earlier diagnosis through screening and better treatment and access to health care. In 1959, the median age of survival of children with CF in the United States was six months.
In 2010, survival is estimated to be 37 years for women and 40 for men. In Canada, median survival increased from 24 years in 1982 to 47.7 in 2007. In the United States those born with CF in 2016 have a predicted life expectancy of 47.7 when cared for in specialty clinics.In the US, of those with CF who are more than 18 years old as of 2009, 92% had graduated from high school, 67% had at least some college education, 15% were disabled, 9% were unemployed, 56% were single, and 39% were married or living with a partner. - Onset
- Cystic fibrosis typically has an early onset, with symptoms often appearing in infancy or early childhood. However, it can sometimes be diagnosed later in life. The term "nan" (not a number) doesn't apply to the context of disease onset.
- Prevalence
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Cystic fibrosis is a genetic disorder most commonly found in people of Northern European descent. In the United States, the prevalence is approximately 1 in 3,500 live births. In Europe, it ranges from 1 in 2,000 to 1 in 3,000 live births. The disease is less common in other populations, such as African Americans (about 1 in 17,000) and Asian Americans (about 1 in 31,000).
The prevalence refers to the proportion of individuals within a population who have cystic fibrosis at any given time. This term encompasses both new and existing cases. - Epidemiology
- Cystic fibrosis is the most common life-limiting autosomal recessive disease among people of European heritage. In the United States, about 30,000 individuals have CF; most are diagnosed by six months of age. In Canada, about 4,000 people have CF. Around 1 in 25 people of European descent, and one in 30 of white Americans, is a carrier of a CF mutation. Although CF is less common in these groups, roughly one in 46 Hispanics, one in 65 Africans, and one in 90 Asians carry at least one abnormal CFTR gene. Ireland has the world's highest prevalence of CF, at one in 1353.Although technically a rare disease, CF is ranked as one of the most widespread life-shortening genetic diseases. It is most common among nations in the Western world. An exception is Finland, where only one in 80 people carries a CF mutation. The World Health Organization states, "In the European Union, one in 2000–3000 newborns is found to be affected by CF". In the United States, one in 3,500 children is born with CF. In 1997, about one in 3,300 white children in the United States was born with CF. In contrast, only one in 15,000 African American children have it, and in Asian Americans, the rate was even lower at one in 32,000.Cystic fibrosis is diagnosed equally in males and females. For reasons that remain unclear, data have shown that males tend to have a longer life expectancy than females, though recent studies suggest this gender gap may no longer exist, perhaps due to improvements in health care facilities. A recent study from Ireland identified a link between the female hormone estrogen and worse outcomes in CF.The distribution of CF alleles varies among populations. The frequency of ΔF508 carriers has been estimated at one in 200 in northern Sweden, one in 143 in Lithuanians, and one in 38 in Denmark. No ΔF508 carriers were found among 171 Finns and 151 Saami people. ΔF508 does occur in Finland, but it is a minority allele there. CF is known to occur in only 20 families (pedigrees) in Finland.
- Intractability
- Cystic fibrosis is considered intractable, meaning it is currently a lifelong condition without a cure. Treatment focuses on managing symptoms and improving quality of life. Advances in medical research have led to better management strategies and therapies, but the disease remains incurable.
- Disease Severity
- The severity of cystic fibrosis varies widely among individuals. It is primarily determined by the specific mutations in the CFTR gene, the organ systems affected, and the response to treatment. Some people may have mild symptoms and a near-normal life expectancy, while others may have severe respiratory and digestive issues, significantly impacting their quality of life and longevity.
- Healthcare Professionals
- Disease Ontology ID - DOID:1485
- Pathophysiology
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The CFTR gene regulates the transport of salts and water through cell membranes, providing instructions for creating a pathway that allows the passage of chloride ions. A mutation in the CFTR gene can impair the normal function of chloride channels, leading to abnormal transport of chloride ions and water, resulting in the formation of thick and abnormal mucus.Several mutations in the CFTR gene can occur, and different mutations cause different defects in the CFTR protein, sometimes causing a milder or more severe disease. These protein defects are also targets for drugs which can sometimes restore their function. ΔF508-CFTR gene mutation, which occurs in >90% of patients in the U.S., creates a protein that does not fold normally and is not appropriately transported to the cell membrane, resulting in its degradation.Other mutations result in proteins that are too short (truncated) because production is ended prematurely. Other mutations produce proteins that do not use energy (in the form of ATP) normally, do not allow chloride, iodide, and thiocyanate to cross the membrane appropriately, and degrade at a faster rate than normal. Mutations may also lead to fewer copies of the CFTR protein being produced.The protein created by this gene is anchored to the outer membrane of cells in the sweat glands, lungs, pancreas, and all other remaining exocrine glands in the body.
The protein spans this membrane and acts as a channel connecting the inner part of the cell (cytoplasm) to the surrounding fluid. This channel is primarily responsible for controlling the movement of halide anions from inside to outside of the cell; however, in the sweat ducts, it facilitates the movement of chloride from the sweat duct into the cytoplasm. When the CFTR protein does not resorb ions in sweat ducts, chloride and thiocyanate released from sweat glands are trapped inside the ducts and pumped to the skin.
Additionally hypothiocyanite, OSCN, cannot be produced by the immune defense system. Because chloride is negatively charged, this modifies the electrical potential inside and outside the cell that normally causes cations to cross into the cell. Sodium is the most common cation in the extracellular space. The excess chloride within sweat ducts prevents sodium resorption by epithelial sodium channels and the combination of sodium and chloride creates the salt, which is lost in high amounts in the sweat of individuals with CF. This lost salt forms the basis for the sweat test.Most of the damage in CF is due to blockage of the narrow passages of affected organs with thickened secretions. These blockages lead to remodeling and infection in the lung, damage by accumulated digestive enzymes in the pancreas, blockage of the intestines by thick feces, etc. Several theories have been posited on how the defects in the protein and cellular function cause the clinical effects. The most current theory suggests that defective ion transport leads to dehydration in the airway epithelia, thickening mucus. In airway epithelial cells, the cilia exist in between the cell's apical surface and mucus in a layer known as airway surface liquid (ASL). The flow of ions from the cell and into this layer is determined by ion channels such as CFTR. CFTR not only allows chloride ions to be drawn from the cell and into the ASL, but it also regulates another channel called ENac, which allows sodium ions to leave the ASL and enter the respiratory epithelium. CFTR normally inhibits this channel, but if the CFTR is defective, then sodium flows freely from the ASL and into the cell.As water follows sodium, the depth of ASL will be depleted and the cilia will be left in the mucous layer. As cilia cannot effectively move in a thick, viscous environment, mucociliary clearance is deficient and a buildup of mucus occurs, clogging small airways. The accumulation of more viscous, nutrient-rich mucus in the lungs allows bacteria to hide from the body's immune system, causing repeated respiratory infections. The presence of the same CFTR proteins in the pancreatic duct and sweat glands in the skin also cause symptoms in these systems. - Carrier Status
- Carrier status for cystic fibrosis refers to individuals who have one copy of the mutated CFTR gene but do not exhibit symptoms of the disease. These carriers can pass the mutated gene to their offspring. If two carriers have a child, there is a 25% chance the child will have cystic fibrosis, a 50% chance the child will be a carrier, and a 25% chance the child will have two normal CFTR genes.
- Mechanism
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Cystic fibrosis (CF) is primarily caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene. The most common mutation is ΔF508, leading to a defective CFTR protein. This protein functions as a chloride channel in the epithelial cells lining organs such as the lungs, pancreas, and intestines.
**Mechanism:**
1. **Defective Ion Transport:** The faulty CFTR protein disrupts chloride and bicarbonate ion transport across cell membranes.
2. **Dehydrated Mucus:** The ion imbalance leads to thick, sticky mucus production, particularly in the lungs and digestive system.
3. **Obstruction and Infection:** This viscous mucus clogs airways and ducts, creating environments prone to bacterial infections and causing chronic inflammation.
**Molecular Mechanisms:**
1. **Protein Misfolding:** Mutations like ΔF508 cause the CFTR protein to misfold, leading to its degradation before it reaches the cell membrane.
2. **Altered Channel Function:** Even if the protein reaches the membrane, some mutations affect the channel's functionality or regulatory processes, impairing chloride ion movement.
3. **Disrupted Cellular Homeostasis:** The defective chloride transport affects cellular hydration and ion balance, further exacerbating symptoms and leading to damage in multiple organ systems. - Treatment
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Cystic fibrosis treatment focuses on managing symptoms, reducing complications, and improving quality of life. Common treatments include:
1. Medications:
- Antibiotics to treat and prevent lung infections
- Mucus-thinning drugs to help clear mucus from the lungs
- Bronchodilators to help keep airways open
- CFTR modulators that target the defective protein caused by the CF gene mutation
2. Airway Clearance Techniques:
- Chest physical therapy to loosen and expel mucus
- Mechanical devices like vests that vibrate the chest
3. Nutritional Support:
- High-calorie diet and pancreatic enzyme supplements to aid digestion
- Vitamins and minerals to address nutritional deficiencies
4. Pulmonary Rehabilitation:
- Exercise programs to improve lung function and overall health
In advanced cases, lung transplantation might be considered. Regular follow-up with a specialized care team is essential. - Compassionate Use Treatment
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Cystic fibrosis (CF) is a genetic disorder affecting the lungs, pancreas, and other organs. Compassionate use treatment for CF allows patients access to investigational drugs when no comparable or satisfactory alternative treatment options are available.
Off-label or experimental treatments for CF include:
1. **Gene Therapy**: Targets the underlying genetic defect in CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene.
2. **CFTR Modulators**: Therapies like ivacaftor, lumacaftor, tezacaftor, and elexacaftor can be used to improve the function of mutated CFTR proteins.
3. **Inhaled Antibiotics**: While primarily approved for specific uses, inhaled antibiotics like tobramycin are sometimes used off-label.
4. **Anti-inflammatory Drugs**: Agents like azithromycin are used off-label to reduce lung inflammation.
5. **Ivacaftor**: While typically approved for specific CFTR mutations, it's sometimes prescribed off-label for other mutations based on emerging evidence.
It's crucial for patients to discuss these options with their healthcare providers to consider potential benefits and risks. - Lifestyle Recommendations
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Lifestyle recommendations for individuals with cystic fibrosis typically include:
1. **Medication Adherence**: Regularly taking prescribed medications to manage symptoms and prevent complications.
2. **Nutritional Support**: High-calorie, high-fat diet, along with pancreatic enzyme supplements to aid digestion. Vitamins and mineral supplements may also be needed.
3. **Hydration**: Ensuring adequate fluid intake to help thin mucus.
4. **Physical Activity**: Regular exercise to help clear mucus from the lungs and improve overall health.
5. **Airway Clearance Techniques**: Using devices or performing techniques such as chest physiotherapy to clear mucus from the lungs.
6. **Infection Prevention**: Avoiding contact with people who have respiratory infections, practicing good hand hygiene, and staying up-to-date with vaccinations.
7. **Routine Check-Ups**: Regular visits to a cystic fibrosis clinic for monitoring and management of the condition.
8. **Mental Health Support**: Seeking psychological support or counseling to manage the emotional and mental burden of the disease.
Individuals should always consult with their healthcare team to tailor these recommendations to their specific needs. - Medication
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Medications for cystic fibrosis typically include:
1. **CFTR Modulators**: These target the defective CFTR protein in cystic fibrosis. Examples include Ivacaftor (Kalydeco), Lumacaftor/Ivacaftor (Orkambi), Tezacaftor/Ivacaftor (Symdeko), and Elexacaftor/Tezacaftor/Ivacaftor (Trikafta).
2. **Mucolytics**: Help thin and clear mucus from the lungs. Examples are Dornase alfa (Pulmozyme) and hypertonic saline.
3. **Antibiotics**: Used to treat and prevent lung infections. They can be taken orally, inhaled, or through IVs. Tobramycin and azithromycin are common examples.
4. **Bronchodilators**: These help open the airways. Examples include Albuterol.
5. **Anti-inflammatory Medications**: Help reduce inflammation in the lungs. Ibuprofen and corticosteroids like prednisone are examples.
6. **Digestive Enzymes**: Taken with meals to help digest food properly. Pancrelipase (Creon, Pancrease) is commonly prescribed.
7. **Vitamins**: Fat-soluble vitamins (A, D, E, K) supplements are often necessary due to malabsorption.
Treatment plans should always be tailored to the individual and managed by healthcare professionals specializing in cystic fibrosis. - Repurposable Drugs
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**Repurposable Drugs for Cystic Fibrosis:**
1. **Ivacaftor**: Originally developed for specific mutations in cystic fibrosis, it has potential uses in other variations.
2. **Lumacaftor/Ivacaftor (Orkambi)**: A drug initially intended for CF patients homozygous for the F508del mutation.
3. **Tezacaftor/Ivacaftor (Symdeko)**: Another combination therapy repurposing existing CF drugs for broader mutation groups.
4. **Elexacaftor/Tezacaftor/Ivacaftor (Trikafta)**: Designed for patients with at least one F508del mutation; it exhibits benefits that might extend to other mutations.
Research into other medications traditionally used for different conditions is ongoing to see their efficacy in cystic fibrosis management, particularly concerning inflammation and infection management. - Metabolites
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In cystic fibrosis, certain metabolites can be altered due to the disease's impact on various organs, primarily the lungs and pancreas. These metabolites may include:
1. **Chloride and Sodium Ions**: Levels are typically abnormal in sweat due to defective CFTR channels.
2. **Thickened Mucus**: Elevated levels of DNA and mucus proteins in respiratory secretions.
3. **Fatty Acids**: Changes in essential fatty acid levels in cell membranes.
4. **Glucose**: Risk of cystic fibrosis-related diabetes, altering glucose metabolism.
5. **Amino Acids**: Malabsorption can lead to altered amino acid levels.
Monitoring these metabolic changes can be crucial for managing the disease. - Nutraceuticals
- Nutraceuticals have been explored as supplementary treatments for cystic fibrosis (CF) to enhance general health and potentially improve disease outcomes. Popular nutraceuticals for CF include antioxidants like vitamins E and C, omega-3 fatty acids, curcumin, and certain probiotics. These can support overall health, reduce inflammation, and improve gut microbiota balance. While nutraceuticals can offer benefits, they should complement prescribed medical treatments rather than replace them. It is essential for patients to consult healthcare providers before adding any nutraceutical to their regimen.
- Peptides
- Peptides and nanoparticle-based therapies are emerging areas of research in cystic fibrosis treatment. Peptides can be designed to modulate the function of defective CFTR (cystic fibrosis transmembrane conductance regulator) proteins or to serve as antimicrobial agents to combat chronic lung infections. Nanoparticles can be used for targeted drug delivery, enhancing the efficacy and reducing the side effects of existing treatments. These advanced approaches aim to improve the quality of life and clinical outcomes for individuals with cystic fibrosis.