Cystic Fibrosis Research Paper
Cause of Cystic Fibrosis
Cystic Fibrosis is caused by a mutation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. The CFTR gene codes for the CFTR protein which is a chloride ion channel belonging to the ABC (what does it stand for) transporter superfamily of proteins. The CFTR proteins are normally located on the apical plasma membrane of epithelial cells in the airways, lungs, skin, digestive organs (E.g. - the pancreas and intestine) and reproductive tracts (E.g. - sperm duct). The CFTR ion channel allows the movement of chloride ions out of the cells, which then leads to the diffusion of sodium ions out of the cells. Since the electrolyte concentration increases outside the cell, water will also move out of the cell …show more content…
and into the mucus by osmosis, reducing the viscosity of the mucus. However, in individuals with the mutated CFTR gene, the movement of chloride ions cannot occur, preventing water from leaving the cells and leading to the build-up of thick, sticky mucus.
Genetics of Cystic Fibrosis
The CFTR gene is located on chromosome 7 and consists of around 250, 000 DNA nucleotides (reference).
There are “over a thousand” different mutations that could occur in the CFTR gene, these mutations have been organised in to 5 different classes:
(reference table)
Having said that, the most common mutation observed is the deletion of phenylalanine in position 508 (ΔF508), which is seen in around 90% of Cystic Fibrosis patients (reference).
Cystic Fibrosis is an autosomal recessive disease, which means the defective gene must be inherited from both parents in order to be affected. However, findings show that around 1 in 25 people are carriers of the defective gene (reference).
Although carriers of the faulty CFTR gene are not affected by cystic fibrosis, it is thought that they have a ‘heterozygote advantage’. For example, they are resistant to Typhoid and Cholera – diseases that involve the loss of body fluid (reference). This may explain why Cystic Fibrosis is most common in people of European descent, since in the past Cholera and Typhoid were prevalent in Europe. This meant that due to the selective pressures, the carriers of the mutated CFTR gene were more likely to survive and reproduce, resulting in the high frequency of this allele in the
population.
Pathophysiology
Cystic Fibrosis affects the respiratory, digestive and reproductive systems. Firstly, the thick mucus can obstruct the ducts of the pancreas, causing pancreatic enzymes to accumulate rather than being secreted into the duodenum. Unfortunately, this results in the digestion of the pancreatic tissue, which then leads to inflammation, known as pancreatitis. The lack of secretion of digestive enzymes into the small intestine also prevents the body from absorbing important nutrients, often leading to malnutrition and difficulties gaining weight.
(diabetes)
Cystic Fibrosis patients are also at high risk of suffering from lung infections. This is because the thick, sticky mucus cannot be carried away from the lungs by the cilia on the epithelial cells. This means that dust and microorganisms (eg - Staphylococcus aureus) that are trapped in the mucus remain within the lungs. (resp failure) Not only this, but the moist, thick mucus provides good conditions for bacteria to reproduce. (Macrophages?)
Furthermore, most males affected by cystic fibrosis are infertile since the mutations of the CFTR gene usually “cause absent or malformed vas deferens” (the duct that carries sperm to the urethra from the testicles). (98% of men infertile-reference) In women with cystic fibrosis, although not infertile, it is usually more difficult to become pregnant than those without cystic fibrosis due to the “build-up of thick cervical mucus, which decreases the movement of sperm” (reference). (period irregular etc)
Common Symptoms of Cystic Fibrosis are:
• Salty sweat
• Poor weight gain
• Persistent cough
• Shortness of breath
• Wheezing
• Formation of nasal polyps
• Recurring lung infections
• Fatigue
• Clubbed fingers
• Constipation
• Large, foul smelling stool
• Bowel obstruction
• Jaundice
Diagnostic Testing
There are four main diagnostic tests for Cystic Fibrosis: newborn testing, antenatal testing, sweat testing and genetic testing.
Newborn testing involves taking a blood sample from a baby which is around 5 days old using the heel prick method. The blood is then tested for cystic fibrosis and 8 other conditions, including: Congenital hypothyroidism, sickle cell disease, phenylketonuria, medium-chain acyl-CoA dehydrogenase deficiency, maple syrup urine disease, isovaleric acidaemia, glutaric aciduria type 1 and homocystinuria.
If the newborn tests are suggestive of cystic fibrosis, then the sweat test may be conducted. During this test a “very weak and painless electric current” is applied to the skin which triggers sweating. The sweat is then analysed for salt content – a very high salt concentration indicates cystic fibrosis (“a value higher than 60 mmol/L of chloride”). A genetic test can also be conducted, in which “a blood sample or a saliva sample taken from inside the cheek” is analyzed for the defective CFTR gene.
Antenatal testing is usually conducted on women who are over 10 weeks pregnant. It reveals whether her unborn child has cystic fibrosis. This test is mainly offered to women who have a family history of cystic fibrosis or who have previously had a child affected by the condition. It involves chorionic villus sampling during which cells of the placenta are removed and tested for the defective CFTR gene.
People can also be tested to see if they are a carrier of the allele for cystic fibrosis. A mouthwash is used to collect cells from the mouth, which are, again, tested for the presence of the faulty CFTR gene. (why Important)
Prognosis
There is currently no cure for cystic fibrosis. However, cystic fibrosis patients can live fairly normal lives with the help of treatment. (nhs video of girl) “The median predicted survival for someone with cystic fibrosis currently stands at 41 years old”. (IVF to have children and genetic counselling) Management
Managing the symptoms and preventing infections are very important for cystic fibrosis patients. One large aspect of their treatment is physiotherapy, which can improve breathing by helping to clear the thick mucus from the lungs. It is usually carried out daily. (Exercise)
Medication can also be used to clear mucus from the lungs. For example, Pulmozyme is an enzyme that breaks down the thick mucus, making it is easier to be coughed up(reference). If the Pulmozyme is not effective, patients are usually given hypertonic saline (“strong salt solution”) instead. Antibiotics must be taken to treat lung infections; these can be taken orally, via a nebuliser or intravenously.
In addition, due to the lack of pancreatic enzymes being passed into the small intestine, digestive enzymes are taken to break down food, allowing nutrients to be absorbed. As well as this, patients take vitamin supplements (Vitamin A, D, E and K). They are also expected to consume a high calorie diet that is rich in proteins and fats, to ensure that they get the most from their diet, as a lot of what they consume is not digested.
In some patients, lung transplants may be required.
Acid Base Balance
Maintaining pH
The body can use 3 different mechanisms to maintain the pH of the blood and surrounding tissues. They are:
1) Chemical buffers – These buffers usually consist of a weak acid and its conjugate base, and work to reverse the effect of small changes in pH. There are different chemical buffers in different body fluids. For example, in the blood plasma the bicarbonate buffer system is used, whereas in the intracellular fluid the protein, phosphate and bicarbonate buffers are used. There are also haemoglobin buffer systems in red blood cells.
H+ + HPO42- ↔ H2PO₄-
H+ + Hb ↔ HHb
CO2 + H2O ↔ H2CO3 ↔ H+ + HCO3-
2) Respiratory compensation – This involves the use of the lungs, and works by changing the rate and depth of breaths in order to gain or eliminate excess CO₂. This mechanism is quite rapid and takes within minutes to have an effect. (about chemoreceptors)
3) Renal compensation – The kidneys are slower to act, but are the long term regulators of pH. It can take days to have an effect. This mechanism works by excretion or retention of HCO₃⁻ or H⁺.
Acidosis and Alkalosis
There are 4 conditions that can cause deviation of pH from the normal range of 7.35-7.45, the first of which is respiratory acidosis. Respiratory acidosis is caused by hypoventilation (“insufficient ventilation leading to hypercapnia, which is an increase in the partial pressure of carbon dioxide”), which leads to the increase in formation of carbonic acid and therefore an increase in dissociation of H⁺ ions. In respiratory acidosis the PCO₂ will be greater than 45 mm Hg and the bicarbonate levels will be either normal, if compensation has not yet occurred or increased, if compensation has occurred. (depression of ..)
Metabolic acidosis can be caused by “an increase in metabolically derived acids, a loss of base (NaHCO₃) from the gut during diarrhea and a failure of the renal tubules to excrete hydrogen ions”. (lactic acidosis and diabetic ketoacidosis) It can be identified by the decreased levels of bicarbonate.
On the other hand, respiratory alkalosis is caused by hyperventilation, which results in too much CO₂ being lost and the decrease in H⁺ concentration. This can occur at high altitudes, in patients with liver or lung diseases (such as emphysema), during pregnancy, or due to extreme anxiety. As well as the pH rising above 7.45, the PCO₂ will be low.
Metabolic alkalosis occurs when there is excessive loss of acid from the body. For example, from repeated vomiting which leads to the loss of large amounts of Hydrochloric acid from the stomach. Other causes can be Cushing's syndrome, overuse of antacids and hyperaldosteronism.
Treatment of Acute Respiratory Acidosis
Acute respiratory acidosis is a medical emergency and must be treated as soon as possible, otherwise it could lead to coma or even death. If the cause is airway obstruction, a bronchodilator should be used to widen airways and ease breathing. In some cases a medical ventilator may be used, to artificially move air in and out of the lungs. In patients who experience acute respiratory acidosis due to smoking related problems, help should be provided to stop smoking.
(conclusion)
Cystic Fibrosis is caused by a mutation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. The CFTR gene codes for the CFTR protein which is a chloride ion channel belonging to the ABC (what does it stand for) transporter superfamily of proteins. The CFTR proteins are normally located on the apical plasma membrane of epithelial cells in the airways, lungs, skin, digestive organs (E.g. - the pancreas and intestine) and reproductive tracts (E.g. - sperm duct). The CFTR ion channel allows the movement of chloride ions out of the cells, which then leads to the diffusion of sodium ions out of the cells. Since the electrolyte concentration increases outside the cell, water will also move out of the cell …show more content…
and into the mucus by osmosis, reducing the viscosity of the mucus. However, in individuals with the mutated CFTR gene, the movement of chloride ions cannot occur, preventing water from leaving the cells and leading to the build-up of thick, sticky mucus.
Genetics of Cystic Fibrosis
The CFTR gene is located on chromosome 7 and consists of around 250, 000 DNA nucleotides (reference).
There are “over a thousand” different mutations that could occur in the CFTR gene, these mutations have been organised in to 5 different classes:
(reference table)
Having said that, the most common mutation observed is the deletion of phenylalanine in position 508 (ΔF508), which is seen in around 90% of Cystic Fibrosis patients (reference).
Cystic Fibrosis is an autosomal recessive disease, which means the defective gene must be inherited from both parents in order to be affected. However, findings show that around 1 in 25 people are carriers of the defective gene (reference).
Although carriers of the faulty CFTR gene are not affected by cystic fibrosis, it is thought that they have a ‘heterozygote advantage’. For example, they are resistant to Typhoid and Cholera – diseases that involve the loss of body fluid (reference). This may explain why Cystic Fibrosis is most common in people of European descent, since in the past Cholera and Typhoid were prevalent in Europe. This meant that due to the selective pressures, the carriers of the mutated CFTR gene were more likely to survive and reproduce, resulting in the high frequency of this allele in the
population.
Pathophysiology
Cystic Fibrosis affects the respiratory, digestive and reproductive systems. Firstly, the thick mucus can obstruct the ducts of the pancreas, causing pancreatic enzymes to accumulate rather than being secreted into the duodenum. Unfortunately, this results in the digestion of the pancreatic tissue, which then leads to inflammation, known as pancreatitis. The lack of secretion of digestive enzymes into the small intestine also prevents the body from absorbing important nutrients, often leading to malnutrition and difficulties gaining weight.
(diabetes)
Cystic Fibrosis patients are also at high risk of suffering from lung infections. This is because the thick, sticky mucus cannot be carried away from the lungs by the cilia on the epithelial cells. This means that dust and microorganisms (eg - Staphylococcus aureus) that are trapped in the mucus remain within the lungs. (resp failure) Not only this, but the moist, thick mucus provides good conditions for bacteria to reproduce. (Macrophages?)
Furthermore, most males affected by cystic fibrosis are infertile since the mutations of the CFTR gene usually “cause absent or malformed vas deferens” (the duct that carries sperm to the urethra from the testicles). (98% of men infertile-reference) In women with cystic fibrosis, although not infertile, it is usually more difficult to become pregnant than those without cystic fibrosis due to the “build-up of thick cervical mucus, which decreases the movement of sperm” (reference). (period irregular etc)
Common Symptoms of Cystic Fibrosis are:
• Salty sweat
• Poor weight gain
• Persistent cough
• Shortness of breath
• Wheezing
• Formation of nasal polyps
• Recurring lung infections
• Fatigue
• Clubbed fingers
• Constipation
• Large, foul smelling stool
• Bowel obstruction
• Jaundice
Diagnostic Testing
There are four main diagnostic tests for Cystic Fibrosis: newborn testing, antenatal testing, sweat testing and genetic testing.
Newborn testing involves taking a blood sample from a baby which is around 5 days old using the heel prick method. The blood is then tested for cystic fibrosis and 8 other conditions, including: Congenital hypothyroidism, sickle cell disease, phenylketonuria, medium-chain acyl-CoA dehydrogenase deficiency, maple syrup urine disease, isovaleric acidaemia, glutaric aciduria type 1 and homocystinuria.
If the newborn tests are suggestive of cystic fibrosis, then the sweat test may be conducted. During this test a “very weak and painless electric current” is applied to the skin which triggers sweating. The sweat is then analysed for salt content – a very high salt concentration indicates cystic fibrosis (“a value higher than 60 mmol/L of chloride”). A genetic test can also be conducted, in which “a blood sample or a saliva sample taken from inside the cheek” is analyzed for the defective CFTR gene.
Antenatal testing is usually conducted on women who are over 10 weeks pregnant. It reveals whether her unborn child has cystic fibrosis. This test is mainly offered to women who have a family history of cystic fibrosis or who have previously had a child affected by the condition. It involves chorionic villus sampling during which cells of the placenta are removed and tested for the defective CFTR gene.
People can also be tested to see if they are a carrier of the allele for cystic fibrosis. A mouthwash is used to collect cells from the mouth, which are, again, tested for the presence of the faulty CFTR gene. (why Important)
Prognosis
There is currently no cure for cystic fibrosis. However, cystic fibrosis patients can live fairly normal lives with the help of treatment. (nhs video of girl) “The median predicted survival for someone with cystic fibrosis currently stands at 41 years old”. (IVF to have children and genetic counselling) Management
Managing the symptoms and preventing infections are very important for cystic fibrosis patients. One large aspect of their treatment is physiotherapy, which can improve breathing by helping to clear the thick mucus from the lungs. It is usually carried out daily. (Exercise)
Medication can also be used to clear mucus from the lungs. For example, Pulmozyme is an enzyme that breaks down the thick mucus, making it is easier to be coughed up(reference). If the Pulmozyme is not effective, patients are usually given hypertonic saline (“strong salt solution”) instead. Antibiotics must be taken to treat lung infections; these can be taken orally, via a nebuliser or intravenously.
In addition, due to the lack of pancreatic enzymes being passed into the small intestine, digestive enzymes are taken to break down food, allowing nutrients to be absorbed. As well as this, patients take vitamin supplements (Vitamin A, D, E and K). They are also expected to consume a high calorie diet that is rich in proteins and fats, to ensure that they get the most from their diet, as a lot of what they consume is not digested.
In some patients, lung transplants may be required.
Acid Base Balance
Maintaining pH
The body can use 3 different mechanisms to maintain the pH of the blood and surrounding tissues. They are:
1) Chemical buffers – These buffers usually consist of a weak acid and its conjugate base, and work to reverse the effect of small changes in pH. There are different chemical buffers in different body fluids. For example, in the blood plasma the bicarbonate buffer system is used, whereas in the intracellular fluid the protein, phosphate and bicarbonate buffers are used. There are also haemoglobin buffer systems in red blood cells.
H+ + HPO42- ↔ H2PO₄-
H+ + Hb ↔ HHb
CO2 + H2O ↔ H2CO3 ↔ H+ + HCO3-
2) Respiratory compensation – This involves the use of the lungs, and works by changing the rate and depth of breaths in order to gain or eliminate excess CO₂. This mechanism is quite rapid and takes within minutes to have an effect. (about chemoreceptors)
3) Renal compensation – The kidneys are slower to act, but are the long term regulators of pH. It can take days to have an effect. This mechanism works by excretion or retention of HCO₃⁻ or H⁺.
Acidosis and Alkalosis
There are 4 conditions that can cause deviation of pH from the normal range of 7.35-7.45, the first of which is respiratory acidosis. Respiratory acidosis is caused by hypoventilation (“insufficient ventilation leading to hypercapnia, which is an increase in the partial pressure of carbon dioxide”), which leads to the increase in formation of carbonic acid and therefore an increase in dissociation of H⁺ ions. In respiratory acidosis the PCO₂ will be greater than 45 mm Hg and the bicarbonate levels will be either normal, if compensation has not yet occurred or increased, if compensation has occurred. (depression of ..)
Metabolic acidosis can be caused by “an increase in metabolically derived acids, a loss of base (NaHCO₃) from the gut during diarrhea and a failure of the renal tubules to excrete hydrogen ions”. (lactic acidosis and diabetic ketoacidosis) It can be identified by the decreased levels of bicarbonate.
On the other hand, respiratory alkalosis is caused by hyperventilation, which results in too much CO₂ being lost and the decrease in H⁺ concentration. This can occur at high altitudes, in patients with liver or lung diseases (such as emphysema), during pregnancy, or due to extreme anxiety. As well as the pH rising above 7.45, the PCO₂ will be low.
Metabolic alkalosis occurs when there is excessive loss of acid from the body. For example, from repeated vomiting which leads to the loss of large amounts of Hydrochloric acid from the stomach. Other causes can be Cushing's syndrome, overuse of antacids and hyperaldosteronism.
Treatment of Acute Respiratory Acidosis
Acute respiratory acidosis is a medical emergency and must be treated as soon as possible, otherwise it could lead to coma or even death. If the cause is airway obstruction, a bronchodilator should be used to widen airways and ease breathing. In some cases a medical ventilator may be used, to artificially move air in and out of the lungs. In patients who experience acute respiratory acidosis due to smoking related problems, help should be provided to stop smoking.
(conclusion)