Longitudinal Cystic Fibrosis Care
Sanja SINDJIC-ANTUNOVIC2012, Clinical Pharmacology & Therapeutics
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Abstract
state art nature publishing group Cystic fibrosis, also referred as mucoviscidosis, is a lifethreatening autosomal recessive genetic disorder affecting multiple organs, most critically the respiratory and digestive systems. The prognosis for cystic fibrosis has significantly improved as a result of earlier diagnosis, better treatment, and expanded access to specialized care. Modern cystic fibrosis care incorporates a longitudinal strategy that includes early prenatal detection, management of disease manifestations during infancy and childhood, and chronic treatment in the adult. Decoding the pathogenesis of cystic fibrosis has advanced personalized treatment algorithms. Most notable is the realization that cystic fibrosis is a generalized exocrinopathy with reduced chloride ion transport across cell membranes as a consequence of a primary genetic disorder within the long arm of chromosome 7 encoding the transmembrane conductance regulating protein (CFTR). In healthy duct epithelia, chloride is transported by plasma membrane channels. Opening of chloride channels is mediated by an agonist-induced increase in cyclic adenosine monophosphate, followed by activation of protein kinase A, which phosphorylates channel proteins. 1 The impact of defective chloride transport differs in various tissues. In sweat gland ducts, it leads to decreased reabsorption of sodium chloride from the lumen, resulting in an increased concentration of sweat chloride, the basis for clinical diagnosis of cystic fibrosis. In other epithelia, especially the respiratory and intestinal epithelia, as well as in the biliary and pancreatic ducts, chloride channel defects result in loss or reduction of chloride secretion. Active sodium absorption is also increased, and these concomitant ionic changes increase water reabsorption from the lumen. As a consequence, dehydration of the mucus layer leads to viscid secretions, resulting in lumen obstruction and predisposing over time to recurrent infection, inflammation, fibrosis, and organ failure. The pronounced improvement in life expectancy for patients with cystic fibrosis, which is experienced across global health systems, particularly in developed countries, is a result of early diagnosis and improved symptomatic treatment based on control of airway infections, intestinal function, mobilization of secretions, reduction of inflammation, and improved nutrition. 2 Treating the fundamental defect underlying cystic fibrosis through a gene-modifying therapy offers the prospect of potential cures. In this regard, encouraging results from early clinical trials with mutation-correcting drug and gene therapy pave the way to more efficient management in the future. 3 Prenatal Diagnosis Cystic fibrosis is a hereditary, autosomal recessive disease, passed on from parents to offspring, with the highest prevalences of 1 in 3,000 Caucasian children of northern European descent and from North America and 1 in 2,300 in the Ashkenazi Jewish population. Other ethnic and racial groups are less commonly affected, reflected in the prevalences of 1 in 10,000 in the Latino American population and 1 in 15,000 in African Americans. The disease is uncommon in Africa and Asia, with reported frequencies ranging from 1 in 35,000 to 1 in 350,000. The earliest manifestation of cystic fibrosis may be associated with bowel lesions identified at prenatal ultrasonography, especially
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Respirat01Y tract The apical surface of the epithelial eells of the alrways eontaln eilia that are covered with mucus, in which pathogenie and inhaled material is Smal! & large infesfine 2 ,132-134.136J37 villus high expressing ce lts apical membrane not in surface epithelium of colon reabsorptive duct Sweat gland 2. 13 1.l32 very liftle in seeretory eoil apical and baso!atera! membranes Liver l38 bile duel Salivary gland '32 intralobular duel apical membrane Kidney118.133 Tubules 1.8 The chloride channel lunction ol CFTR Before the discovery of the CF gene, functional studies were executed to determine the exact site for the abnormal electrolyte transport and to identify molecular entities responsible for the electrophysiological defect. By application of Cl-ehannel bloekers, Bijman et al showed that CI-transport in the sweat gland duct is through channels rather than paraeellularly,l44 The identification of different chloride channels in the epithelial tissues of the sweat gland 145,146 and airways147-150 supported these findings. 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Recent advances: Recent advances in cystic fibrosis
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