Cystic Fibrosis - Pathogenesis and Treatment - Research Paper Example

Running Head: CYSTIC FIBROSIS Cystic Fibrosis Class Date Table of Contents Abstract 3 Introduction 4 Brief History 4 Cystic Fibrosis 6 Overview 6 Pathogenesis 6 The Animal Model 7 Treatment 9 Transplantation 11 Reflection 12 Conclusion 13 Resources 15 Abstract Cystic fibrosis is developed when the CFTR gene has mutated, disallowing proper balance of fluids in the organs. The sweat of a person with CF will be much saltier than that of the average person which lead to the first and still standard test for CF in which the sweat is tested for sodium and chloride levels. The effects of CF are devastating, but life expectancy in the last 70 years since it was first written about has increased from almost certain death in infancy to 37 years of age. The following paper discusses the nature of CF through a brief examination of the history of the research on the illness, to an overview of the pathology and an examination of treatment. Reflecting on the experiences of the patient who has CF provides deeper insight in to the illness and shows that it has a great impact on the lives of the child, family, and then the adult who must live with CF. Cystic Fibrosis Introduction Cystic fibrosis is an illness that only just 70 years ago was fatal for children within their first year. The illness was most often diagnosed during autopsy and an understanding of the illness had yet to emerge. Although increases in treatment improved the prognosis of CF, real knowledge about the illness came in the late 1980s when in 1989 the CFTR gene was discovered. Originally the sweat test was considered the definitive test to determine the presence of the illness derivations of the disease have emerged that defy the sweat test as the gold standard. The treatment for CF has improved to the point that instead of dying as infants, people are now living long into old age through management and care (Bush, 2006). The following paper will examine cystic fibrosis through looking at what is known about the disease in relationship to its pathology, through the developing knowledge that has increased life expectancy, and through the treatments and care that has extended the lives of those who suffer from the illness. The paper will discuss the experiences of those who suffer from the illness as well as how treatment has advanced throughout the last decade. Cystic fibrosis is a devastating disease that has taken the lives of many children, but with the advances that have been made in understanding the disease, people are now living much longer and more meaningful lives as they live with the condition. Brief History In 1938 Dr. Dorothy Andersen wrote a landmark medical report in which the illness of cystic fibrosis was differentiated as a separate and distinct illness. In 1953 Dr. Paul di Sant’Agnese and associates came to understand that losses in salt in the body were connected to the emergence of the disease. The Cystic Fibrosis Foundation was created in 1955 in order to focus on the illness so that growth in understanding how to approach the disease could be researched and the life expectancy of those suffering from CF could be improved. In 1962 the average life expectancy had increased to ten years of age. By 2005 the average life expectancy had increased to 37 years of age (Harrison, 2010). In the 1980s the effects of CF were tied together through research that measured electrical activity across mucous membrane in the nose. A marked difference was measured between those with cystic fibrosis and those without. The lining of other organs such as the pancreas and the lungs were then also measured and differences were measured in the electrical charges were observed. This single abnormality that was common in all CF patients led researchers to understand that he electrical charge that is created through the speed of sodium and chloride movement across the cells was affected in CF patients (Orenstein, Spahr, & Weiner, 2012). Understanding that it was a problem in fluid transport led to the discovery that the problem for CF patients was in the CFTR which when mutated could not provide the proper cell fluid transport, thus the affected organs could not be cleansed properly, leading to blockages through the mucous that would accumulate. Cystic fibrosis can be described as an autosomal recessive disease that is caused by the mutation of “gene encoding in the cystic fibrosis transmembrane conductance regulator anion channel” (Stolz et al, 2010, p. 29). CF can cause a series of other problems which include pancreatic issues, intestinal problems hepatic, vas derens, and lung disease. The influence of CF on these other organs has yet to be determined for how the illness works within the body. Pulmonary illness is the most common form of the disease which is characterized by infections and inflammation in the airways (Stolz et al, 2010). Cystic Fibrosis Overview There are approximately 25,000 patients with CF in the United States (Orenstien, Spahr & Weiner, 2012). Cystic fibrosis is primarily about fluids in the body, the chloride and bicarbonate not being able to pass through the cells normally. As well, too much sodium is transported into the cells contributing to the imbalance. Fluids in the lungs and the pancreas build up, blocking the ducts and airways through the reduction in proper fluids. As a result, the sweat of a person who has CF will be saltier than others, thus one of the basic tests for CF is testing the amount of salt in their sweat. There are a variety of mutations that can occur, creating a differences in the way that the disease is manifested (Orenstein, Spahr, & Weiner, 2012). Infection in CF was once thought to be because of the stickier and dryer regions that were affected. It is now clear to researchers that infection comes from a lack of salt in the fluids of the lining of organs, making the region dehydrated and lacking the proper ability of the body to move the mucas up and into the stomach where it is disposed of by the digestive system. In other words there is just not enough movement to flush out the bacteria that can then take hold in the system. The mechanism that results in the average individual to clear their throat is a part of the process that gets that fluid out of the lungs and swallowed into the stomach. When the cilia cannot beat the mucus up and out of the lungs, as an example, so that this clearage takes place, the lungs are more susceptible to what is held within them (Orenstein, Spahr, & Weiner, 2012). Pathogenesis CF occurs where there is a genetic mutation in the CFTR protein which regulates the fluid balance across epithelial cells. Odze and Goldblum (2009) write that “Under physiologic conditions, cyclic AMP-stimulated chloride secretion through the low conductance CFTR channels imposes a negative luminal potential and an osmotic gradient that triggers passive secretion of NA and water”. In other words, stimulation of fluids within the body creates imbalances that will cause damage and ineffective performance in the organs. Bicarbonite (HCO3) extrusion into the lumen is facilitated by the apical chloride gradient through the C1/HCO exchange. The dysfunction of the chloride exchange that occurs within the transepithelial fluid system, all epithelial cells involved in the exchange of water have the potential to be affected when there is a defective CFTR functioning. The bronchopulmonary tree, the hepetobiliary duct system, the pancreatic ducts, and the intestines are specifically affected with an inability to maintain normal fluid secretion. Any of the systems that are dependent on the cellular mechanism that transports chloride to the plasma membrane will be affected by the mutated CFTR protein. This leads to the imbalance within the fluids of the cells (Odze and Goldblum, 2009). The lungs, as an example, will develop a secretion of fluids, leading to bacterial infections and inflammation in the lungs because of the imbalance within the cells. One of the key features of CF in infants is a failure to thrive. The illness may produce effects in the lungs, pancreas, sweat glands, liver or intestines. One of the major complications of CF is liver failure. Infants have elevated serum levels of alkaline phosphate, ALT, ALT, and GGT in the liver. Neonates and infants will also experience cholestasis and hepatomegaly (Odze and Goldblum, 2009). The Animal Model Stolz et al (2010) examined the nature of CF through creating an animal model with the use of pigs as the subject to their inquiry. The research paper lists two problems that hindered investigation into the pathogenesis of the lung disease associated with CF. The first problem is that it is not possible to investigate the emerging respiratory tract abnormalities in their beginning because they occur at birth at which time treatment is begun before the natural state of the illness can be examined. The second is concerned with the development of an animal model in which the CFTR gene alterations manifested the same as typical human forms of CF. Until the research by Stolzt et al (2010) mice had been used which had not led to a successful model. Pigs developed the same “intestinal lesions (meconium ileus and microcolon), exocrine pancreatic destruction, gallbladder abnormalities, and early focal biliary cirrhosis similar to that seen in human CF. Like the lungs of human infants, porcine CF lungs lacked cellular inflammation and submucosal gland change” (p. 29). Although a form of animal research which is still highly suspect as necessary in research, the development of an animal model could provide insight into the early stages of the illness that cannot be accessed through the examination of human examples. Just like in humans with the illness, CF pigs need to circumvent the meconium ileus so that the intestinal obstruction that is common in CF could find relief. Surgeries for CF pigs included ileostomy or cecostomy on newborns. Segregated from other pigs in order to prevent porcine bacterial and viral contamination, the surviving five pigs with CF exhibited similar associated pathologies, but also common complications for pigs such as gastric ulcers which was exacerbated by the addition of pulmonary disease and stress from CF. The necropsy of the pigs that were used for the development of the model revealed that the fibrosis that was described by Dr. Dorothy Andersen created distended pancreatic ducts with periodic intervening fibrosis. This pancreatic parenchymal loss had been a continuing problem since the birth of the pigs. At the same time, the microcolon which had been seen at the birth of the pigs had reduced back to its normal size with a normal structure. As well, the “micro gall bladder with mucinous changes and the hetorgeneous focal biliary cirrhosis” had not shown any increases since the time the pigs had been newly born (Stolz et al, 2010, p. 30). One of the first observations in the pigs was that at birth they had inflation in the lungs along with infection. Within hours of birth the pig was already exhibiting difficulty in eradicating bacteria, with marked similarities that could not be observed in experimentation with mice. The researchers concluded that studies with animals were a viable form of research and this was not exclusive to primates. On e of the key aspects of CF lung destruction is inflammation. The question that is persistent about CF is whether inflammation comes first or bacteria, Stoltz et al (2010) citing the debate about which coming first, the chicken or the egg, being the example of how to think about the dilemma. According to the research done on the pigs, the lungs with CF continued to have an impaired ability in eliminating bacteria even in the absence of inflammation. This can suggest that low levels of bacteria create the inflammation which is explanatory of the data for infants and children with CF which was conflicting in relationship to cause and effect. While inflammation appears to be spontaneous, the research on the pigs suggests that it is caused by the presence of the low levels of bacteria that cannot be eradicated in the CF lung. The research does not explain whether or not the inflammatory response is exaggerated (Stoltz et al, 2010). Treatment Treatment for cystic fibrosis most often includes targeting the secondary effects of the dysfunction in the CFTR. The life expectancy of patients with CF is still below the normal and the burden of treatment on CF conditions is still very high. There is a need for better therapies, but the progress of treatment therapy research has still been slow (Accurso et al, 2010). Because there is a decline in lung function with acute episodes of symptoms, treatment for the lungs is the most common forms of treatment that patients with CF will have to undergo. Exacerbations will include increased coughing, sputum production, a persistent shortness of breath, pain in the chest, a loss of appetite with losses of weight, and a general decline of lung function. This will have a serious impact on the quality of life for the CF patient (Flume et al, 2009). The most common form of treatment for CF patients is to intervene with intravenous antibiotic therapy. Through research on the use of inpatient versus outpatient use of antibiotic therapies, it was determined that inpatient therapy had the best hope of effective treatment. This is because of some socio-economic factors, but also due to the need for capacities of auxiliary treatment such as clearance of the lungs. During exacerbation nutritional needs are increased thus inpatient treatment allows for nutrients to be given in whatever form is best for the patient, including through IV interventions. Diabetes is exacerbated which may mean that an increase in insulin is needed during these episodes. Outcomes for patients treated in hospital settings are higher than those who try to treat at home (Flume et al, 2009). Airway clearance therapy involves an individualized formation of therapy that must take into consideration age, level of physical activity possible, and basically, what will work best. Everything from cupped pounding on the back of the individual to blowing games intended to release the excess mucus in the airway can be used to help clear the lungs. Aerobic exercise is a good method of dislodging mucus and clearing the airways, but must be done only when the patient can endure the stress. Everything from postural positioning to clear the airways to handheld devices can be used for the benefit of the patient (Hess, Macintyre, Mishoe & Galvin, 2011). There are a great many investigations into more effective treatments for CR. One strategy that has some potential is through improving the defective CFTR function systemically so that lung damage can be affected through a reduction of manifestations of extrapulmonary disease. In CFTR protein transport of chloride, the most often seen mutation is a subsdtitution of glycine for aspartic acid in amino acid 551 which occurs in 4-5% of all persons with cystic fibrosis. VX-770 is an agent that increases the ion-channel function of the activated cell surface and is considered to be a potentiator. VX770 has been given orally in order to increase the activity of the CFTR proteins with wild-type and defective cell surfaces in vitro, having the greatest effect on the G551D-CFTR. Improvement of CFTR mediated ion transport as well as pulmonary status was observed (Accurso, 2010). Transplantation One of the treatments for CF is transplantation of the lungs. Transplantation is a precarious proposal as 70% of the people who have a lung transplant with CF live for only a year after, with 50-60% living 2 to 3 years longer. Liver transplants are more successful with children who receive these transplants living 3-5 years longer. Transplantation occurs when the organ has been damaged beyond the point where quality of life can be maintained and it is likely that a short life expectancy has been established. Lung transplants are needed far more often than liver transplants. In 2009 there were 212 lung transplants for patients with CF with only 15 receiving liver transplants (Orenstein, Spahr, & Weiner, 2012). Lung transplantation is done at the end stages of CF when the disease has caused damage to the organs through repeated stress and infection. According to Hofer et al (2009) there is a debate about the effectiveness of lung transplantation in extending the lives of recipients with CF. In a longitudinal study of 5 years in which post-transplant survival was calculated against those with and without lung transplantation, of the 80 patients that were observed of which 13.8% were children, survival benefits were seen through the use of lung transplantation. The median age of the study participants was 26.2. The estimated survival of all in the study was 5 years. The only participants that did not do well with the transplant were those with diabetes. Being a child did not have a negative impact on the survival rate of those observed. Reflection While the clinical examination of CF is detrimental, it has an even harsher impact on those who must live with the illness. Living with the illness includes members of the family, the community, as well as the individual. When the breath is restricted it is a frustrating state for both the individual and the family as they are helpless to do much but wait through the episode. Therapies for the illness require waiting and each one means that the lung or organ affected has deteriorated a little bit more. Waiting is almost as bad as the illness effects as the wait to see if recovery will occur of if something more will be needed can be excruciating. People living with CF are often waiting on a time table with their quality of life measured out before them in a much more acute way than most people. Waiting for a transplant is something that is also stressful on the family and the individual who must wait for someone to die in order to receive the gift of a few more years. In order to be viable for transplant, a lung must have belonged to a person who has died in such a manner that harvesting the organ is possible, which most often means dying in the hospital. The family of the deceased must be willing to donate the organs of their loved one. This is often an emotional decision to make in the wake of a recent death. The lungs must be healthy, which also means that death is often the result of an accident which increases the emotional shock of the family who must agree to the donation. The decision is made while the patient seems alive, because they are brain dead, and this is often a deciding factor as people hope for a miracle of return for their loved ones (Orenstein, Spahr, & Weiner, 2009). Waiting on an opportune death can be a painful existence until such a time as a transplant organ becomes available, leaving the family drained and hopeful, a state of conflict that wears on the family. CF means that the individual will lead a life that is intrinsically connected to medical care. Although there might be periods of apparent wellness, the effects of the illness will always be of concern and the episodes that require more care will take its toll on a family. It is even worse for individuals without meaningful or substantive connections to other people to facilitate their care. While the illness is no longer an immediate death sentence for an infant, the quality of life and the length of life are dependent upon socio-economic factors, family support, and the ability for the individual to contribute to their own care. Cystic fibrosis is a devastating illness that has yet to be cured, but it is the hope of the Cystic Fibrosis Foundation that a cure will come through gene therapy or something that has yet to occur to researchers (Accurso et al, 2010). Conclusion The nature of cystic fibrosis has only been understood within the last 30 years. While there are 25,000 people in the United States diagnosed with the illness, the treatment for the disease is primarily for the symptoms rather than the cause. The cause of CF is a mutation of the CFTR protein which facilitates the movement of fluid through the cells. The movement of chloride and sodium is specifically affected, which creates difficulties in the lungs which is the most common manifestation of CF, although other organs can be involved in the symptoms of the illness. While antibiotics and airway clearance are two of the most often used treatments for the lungs during an episode, sometimes the lungs will deteriorate until they need transplantation. Sometimes the liver will also suffer to the point that it must be replaced. Transplantation requires waiting on a list and this can take some time. Waiting is the worst part of CF as the individual and the family is always waiting for the results of the next episode or the time when the organs have gone too far beyond repair. While life expectancy and quality of life have improved, the illness is ever present in the patient which promotes the hope for a cure to this difficult and devastating disease. Resources Accurso, F. J. et al (18 November 2010). Effects of VX-770 in person with cystic fibrosis and the G551D-CFTR mutation. The New England Journal of Medicine. 363, 1991-2003. Bush, A. (2006). Cystic fibrosis in the 21st century: 47 tables. Basel: Karger. Flume, P. A. et al (3 September 2009). Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. The American Thoracic Society. 1-93. Harrison, E. A. (2010). Neonatal respiratory care handbook. Sudbury MA: Jones and Bartlett Publishers. Hess, D. R., Macintyre, N. R., Mishoe, S. C. & Galvin, W. F. (2011). Respiratory care: principles and practice. Sudbury MA: Jones & Bartlett. Hofer, M. et al (2009). True survival benefit of lung transplantation for cystic fibrosis patients; the Zurich experience. The Journal of Heart and Lung Transplantation. 28(5), 334-339. Odze, R. D., & Goldblum, J. R. (2009). Surgical pathology of the GI tract, liver, biliary tract, and pancreas. Philadelphia, PA: Saunders/Elsevier. Orenstein, D. M., Spahr, J. E. & Weiner, D. J. (2012). Cystic fibrosis. Philadelphia PA: Lippincott Williams & Wilkins. Stoltz, D. et al (28 October 2010). Cystic fibrosis pigs develop lung disease and exhibit defective bacterial eradication at birth. Science Translational Medicine. 2(29), 29-31. Read More