Cystic Fibrosis - Pathophysiology and Pathogenesis - Literature review Example

Cystic Fibrosis Name Institutional Affiliation Cystic Fibrosis Introduction The realization of genetics as a field of study revolutionizes the medical discipline, especially about discovering the prevalence, spread, and cure of diseases. According to Cutting (2015), sequencing of the human genome provides an understanding of genes. Moreover, it provides an opportunity to examine the events leading to genetic disorders through identifying the science behind dysfunction gene. Cystic Fibrosis (CF) is an example of these diseases affecting the worldwide populations. Therefore, it is necessary to discuss the literature about the disease, through the topics of pathophysiology and pathogenesis, prevalence, clinical manifestation, diagnosis, treatment and making comparisons of the old and new studies. Pathophysiology and Pathogenesis Based on Stoltz, Meyerholz and Welsh (2015) draws an introduction to the nature of the CF describing it as an autosomal recessive disease resulting from the mutation of a specific gene. The gene in question is the cystic fibrosis transmembrane conductase regulator (CFTR). The effects of the mutation result into the abnormal secretion of viscous fluids in the areas of the lungs and pancreatic ducts. Cutting (2015) identifies the secretions as causing the obstructions of the passages leading to the conditions of inflammation, tissue and organ damages. Moreover, the disease attacks areas lined with the epithelial tissues interpreting to a higher risk in the secretory organs in the human body. Gibson-Corley, Meyerholz, and Engelhardt (2016) describe the CFTR functions as a protein channel controlling the flow of water and the chloride ions. Its function as a bicarbonate and chloride regulator influences the secretion of fluids from the epithelial cells present in the pancreas. In regards to Gibson-Corley et al. (2016), the lungs are the most affected organs owing to the importance of maintaining a mucus environment for efficient respiration. Currently, the morbidity and mortality regarding CF involve lung obstruction diseases resulting from the mutations in the CFTR gene (Cutting, 2015; Grubb & Boucher, 1999). Although several mutations may occur, Gibson, Burns and Ramsey (2003) explain that these mutations are present on chromosome 7 encoding the CFTR protein. Moreover, Gibson et al. (2003) provide that despite the advancement in technology, only 22 of these numerous mutations have successfully undergone identification. Common mutation involves the deletion mechanism of three base pairs coding for the phenylalanine. According to Gibson et al. (2003), the deletion follows the position 508 along the CFTR gene (ΔF508). The imperative is the classification of these mutation based on the consequences in the protein gene. Concerning the pathogenesis of CF in the lungs, Cantin, Harti, Konstan and Chmiel (2015) develop an understanding of the infections of the airways by the pathogens. Examples of these colonizing pathogens include Staphylococcus aureus and Pseudomonas aeruginosa producing severe inflammation to these tissues. Moreover, the absence of functional CFTR in these inflamed sites results in the deficiency in the cAMP-dependent sections of the chloride and bicarbonates in the airways (Cantin et al. 2015). The particular occurrence produces a sharp decline in the pH affecting the defense mechanism of the individual to the bacteria. More important it the tethering of the mucosa strands to the glands following the defects in secretion of the ions. Prevalence Cutting (2015) identifies approximately 70,000 people affected globally by the disease. However, the majority of the affected individuals are of the European descent with minimal cases in Asian and Africa. Similarly, Gibson et al. (2003) support its position as the most common genetic disorder among the populations of the whites. Focusing on the United States, the survival age of a person with CF falls on the average of 33.4 years. Contrastingly, Cutting (2015) speaks of an increase in the average survival age to 37 following the improved diagnosis and disease management. In discussing prevalence, it is important to recognize the greater contribution of lung and pulmonary related CF contributing about 80% of the mortality. Drawing on the statistics by De Boeck, Zolin, Cuppens, Olesen and Viviani (2014), every one of 25 people is a carrier of the gene ΔF508. Moreover, the class II mutations are more present in the European countries compared to the classes III, IV, and V. Clinical Manifestation The numerous and continuous studies on CF have progressively relied on its clinical characteristics in the quest to discover its cure. In regards to Stoltz et al. (2015), investigators identify the bronchiectasis as one of the early indicators of CF. Moreover; the study provides that both pulmonary infection and inflammation are found present in the CF patient way before the onset of other associated symptoms. The interesting factor concerning this information is the age of the CF sufferer where as young as the age of 3, the particular signs occur. Stoltz et al. (2015) provide a typical case of where a child of 3 months registers abnormal chest-X-ray through the Computed Tomography (CT) technology. Stoltz et al. (2015) discuss the prominent feature of CF at the clinical level. The examples of the symptoms include airway bacterial infection, mucus-obstruction, neutrophilic inflammation, and bronchiectasis. Similarly, Gibson-Corley et al. (2016), presents the manifestation of the pancreatic CF including decreased pH, reduction in volumes of the secretion, increased protein content and obstruction of ducts and acini cells. In the chronic stages, the pancreas may undergo complete destruction following its inflammation. Moreover, the later stages present the characteristics of increase in zymogen secretion. Rosenstein and Cutting (1998) discuss the outcomes of the CFTR mutation through identifying primary factors that closely link with CF. First, there are the acute respiratory symptoms that are persistent and recurring is one of the manifestations present in all age groups, malnutrition especially in developing children, abnormal stools, electrolyte imbalances, obstruction of the intestines and lungs, and sinuses. In a similar response is the discussion by Rowe et al. (2014) explaining of the obstruction of the small airways and infections by pathogens as the contributing clinical manifestation during the progressive stages of CF. Moreover, salt loss as a technique contributes to identifying symptoms of CF. Diagnosis According to Gibson et al. (2003), the diagnosis of CF follows the clinical setting since the genetic manipulations of its onset is difficult to manage. However, Gibson et al. (2003) present that the advancement of research through availing data on mutations and inclusion of bioelectric characteristics significantly contributes to the expansion of the diagnosis spectrum. The imperative is the realization of the newborn screening technique allowing for an earlier diagnosis of the disease. Based on Munck et al. (2015), the screening requires the analysis of the immunoreactive trypsinogen in the blood sample of the infant. The screen also follows a Deoxyribonucleic Acid (DNA) analysis whose results follow a comparison with the clinical assessment. Rosenstein and Cutting (1998) identifies that appropriate diagnosis follows the presence of clinical symptoms or phenotypic features which link with the clinical manifestation. Examples of the features include salt loss syndrome, male urogenital obstruction presenting the case of azoospermia, gastrointestinal abnormalities, malnutrition, and chronic pulmonary diseases. Rosenstein and Cutting (1998) supports the relevance of the sweat chloride testing as a diagnosis test. The test follows the guidelines of the National Committee for Clinical Laboratory Standards. According to the standards, the significant factors to consider include the volume of the chloride with respect to the age of the individual. Measurement of the nasal potential difference (PD) through an in-vivo technique is a part of the diagnosis relating to the patterns of the PD which identifies with the ion transport (Rosenstein and Cutting, 1998). Specific features associating with CF involve the feature of raised basal PD patterns, increased PD inhibition, and a PD pattern exhibiting no change following the perfusion of the respiratory epithelia with corresponding solutions. Moreover, carrying out of microbiological tests provides sufficient mechanism towards the effective diagnosis of CF (Gibson et al. 2003; Rosenstein and Cutting, 1998). Treatment Owing to the numerous possible mutations of the CFTR gene, Rowe et al. (2014) present the acceptance of the potentiator ivacaftor model in the treatment of the CF patients. In particular, the model works for patient above the age of 6 having a G551D- CFTR type of mutation. Research on its effectiveness provides the significant improvement in weight, lung function, and the volume of the sweat chloride. Similar to these findings is the study by Boyle et al. (2014) presenting evidence of repaired defects of CFTR following the utilization of the CFTR potentiator ivacaftor. In regards to Boyle et al. (2014), the sole use of the ivacaftor fails to provide efficient clinical benefits to homozygous patients for the ΔF508 mutant. The imperative in this treatment is the dominance of the ΔF508 mutation among the populations of the CF patients. Therefore, as a result of the inefficiency of the potentiation, researchers developed the lumacaftor (Boyle et al. 2014). The technique of the new model involves the improvement in the presentation of the ΔF508 CFTR to the cell surface as well as the in the transport of chloride mediated by the CFTR (Boyle et al. 2014). Consequently, its administration to patient saw an improvement of the sweat chloride levels with minimum effects on lung function. Following the outcome, appropriate treatment would involve the combination of both the ivacaftor and lumacaftor. Moreover, Tosco et al. (2016) support the evidence of improvement in a patient following the combination of treatments. Cantin et al. (2015) discuss a broad category of treatment mainly involving the anti-inflammatory therapies. The treatment follows the administration of anti-inflammatory drugs such as ibuprofen. The drugs are manufactured with components that manage to target specific inflammatory mediators. Moreover, Cantin et al. (2015) examine antibacterial therapies as an important segment within anti-inflammation management. In this case, the administration of antibiotics such as Azithromycin suppresses the prevalence of the pathogens. Comparison of the old and new Studies The appropriate comparison of the earlier research on CF and the contemporary issues includes both significant and vital areas that develop an understanding of the trend. One of these fields involves the use of animal models in the research. Based on Cutting (2015) five animals including the mouse, rat, zebrafish, pig, and ferret are already part of the research. However, the tradition studies utilized small animals owing to the efficiency in their management (Cutting, 2015). Comparatively, current research focuses on larger animals such as the pigs following their comparable anatomical features to humans. The field of diagnosis provides a significant contribution in contrasting the old and the new. According to Gibson et al. (2003), the traditional diagnosis relied on clinical criteria of stipulated clinical manifestation. However, the advancement in technology realizes in-depth knowledge of the underlying genetics of the CF disease. As Rosenstein and Cutting (1998) explain about the shortcomings of the traditional clinical method, its disadvantage mainly stems from its inability to account for all the possible possibilities of CF manifestation. Moreover, the challenges become more pronounced with the increasing mutations. Therefore, the rise of technology and its application in CF researchers realizes a deeper understanding and the development of more comprehensive techniques such as the infant screening, DNA analysis, and molecular analysis occur (Gibson et al. 2003). The greater benefit today is the ability of the physician to detect possibilities of CF in a child as young as the age of 3 months through the CT X-rays and scans. Conclusion In summary, the research regarding the CF disease continues to experience great success, especially about the detection and treatment segments. The relevance of genetic disorders remains vital in today’s society, particularly regarding their mutations. CF being one of these disorders significantly reduces the survival rate of the patient, necessitating the need to involve more knowledge through technology in discovering its treatment. The imperative is its peculiar pathophysiology and pathogenesis involving particular mutations in the CFTR gene. The magnitude of its effects to the sufferer involves the importance of the gene in managing the movement of ions across cell and tissues. The defecting of the gene through mutations results into lethal inflammation of tissues which becomes more pronounced through the presence of pathogens. Through research, scientists manage to diagnose the disease with the use of clinical settings, screening, microbiology, and sweat chloride testing. Following the diagnosis, current treatment includes the use of antibiotics, anti-inflammatory drugs, and a combination of the lumacaftor and ivacaftor. Nevertheless, the disease continues to trouble the global population, particularly the European people where prevalence is relatively higher compared to the continents of Asian and Africa. It is with great sadness that despite the research, there is currently no cure for CF. References Boyle, M. P., Bell, S. C., Konstan, M. W., McColley, S. A., Rowe, S. M., Rietschel, E., & VX09-809-102 study group. (2014). A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial. The Lancet Respiratory Medicine, 2(7), 527- 538. Cantin, A. M., Harti, D., Konstan, M. W., & Chmiel, J. F. (2015). Inflammation in cystic fibrosis lung disease: pathogenesis and therapy. Journal of Cystic Fibrosis, 14(4), 419- 430. Cutting, G. R. (2015). Cystic fibrosis genetics: from molecular understanding to clinical application. Nature Reviews Genetics, 16(1), 45- 56. De Boeck, K., Zolin, A., Cuppens, H., Olesen, H. V., & Viviani, L. (2014). The relative frequency of CFTR mutation classes in European patients with cystic fibrosis. Journal of Cystic Fibrosis, 13(4), 403- 409. Gibson, R. L., Burns, J. L., & Ramsey, B. W. (2003). Pathophysiology and management of pulmonary infections in cystic fibrosis. American journal of respiratory and critical care medicine, 168(8), 918- 951. Gibson-Corley, K. N., Meyerholz, D. K., & Engelhardt, J.F. (2016). Pancreatic pathophysiology in cystic fibrosis. The Journal of pathology, 238(2), 311- 320. Grubb, B. R., & Boucher, R. C. (1999). Pathophysiology of gene-targeted mouse models for cystic fibrosis. Physiological reviews, 79(1), S 193- S214. Munck, A., Mayell, S. J., Winters, V., Shawcross, A., Derichs, N., Parad, R., & Southern, K. W. (2015). Cystic fibrosis screen positive, inconclusive diagnosis (CFSPID): a new designation and management recommendations for infants with an inconclusive diagnosis following newborn screening. Journal of Cystic Fibrosis, 14(6), 706- 713. Rosenstein, B. J., & Cutting, G. R. (1998). The diagnosis of cystic fibrosis: a consensus statement. The Journal of pediatrics, 132(4), 589- 595. Rowe, S. M., Heltshe, S. L., Gonska, T., Donaldson, S. H., Borowitz, D., Gelfond, D., & Joseloff, E. (2014). Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. American journal of respiratory and critical care medicine, 190(2), 175- 184. Stoltz, D. A., Meyerholz, D. K., & Welsh, M. J. (2015). Origins of cystic fibrosis lung disease. New England Journal of Medicine, 372(4), 351- 362. Tosco, A., De Gregorio, F., Esposito, S., De Stefano, D., Sana, I., Ferrari, E., & Grassia, R. (2016). A novel treatment of cystic fibrosis acting on-target: cysteamine plus epigallocatechin gallate for the autophagy-dependent rescue of class II-mutated CFTR. Cell Death & Differentiation, 23(8), 1380- 1393. Read More