Cystic Fibrosis

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Cystic Fibrosis. Dr. Daksh Jhim First Year Junior resident. introduction. Cystic fibrosis (CF) is a monogenic disorder that presents as a multisystem disease. was first described as a unique disease entity in 1938. Most common lethal genetic disease in Causasians . - PowerPoint PPT Presentation


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Dr. Daksh JhimFirst Year Junior residentCystic FibrosisintroductionCystic fibrosis (CF) is a monogenic disorder that presents as a multisystem disease.was first described as a unique disease entity in 1938.Most common lethal genetic disease in Causasians.lethal autosomal recessive disease.incidence: 1 in 2000-3000; predominantly Caucausian populations (carrier frequency 1 in 22-28).Woe to the child which when kissed on the forehead tastes salty. He is bewitched and soon will die - old proverb.

introductionPatients typically presented with intestinal obstruction or malnutrition and died from overwhelming pneumonia within the first year of life.Over the last 40 years, the median survival with CF has increased dramatically from 6 years in 1955 to 36 years in 2005.The improvement in CF outcomes has paralleled advances in antibiotic therapies, nutritional approaches, and the collection of clinical expertise into specialized treatment centers.

pathogenesisCF and geneticsCaused by mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

Anion channel

ATP Binding Cassette family

Regulates other ion channels (ENaC)

Plays crucial roles in absorption and secretion

Found mainly in wet epithelia

CFTR CFTR functions as a cAMP-activated ATP-gated anion channel.increasing the conductance for certain anions (e.g. Cl) to flow down their electrochemical gradient.ATP-driven conformational changes in CFTR open and close a gate to allow transmembrane flow of anions down their electrochemical gradient.found in the epithelial cells of many organs including the lung, liver, pancreas, digestive tract, reproductive tract, and skin.Mainly found in exocrine glands.Normally, the protein moves chloride and thiocyanate ions along the concentration gradient.

Sweat glandsMucusDigestive fluids

Sweat gland pathophysiology

Sweat gland pathophsiologyCFTR important for Cl- absorptionNa+ and Cl- generally reabsorbedCl- buildup = negative charge on luminal sideDecreased Na+ reabsorptionNaCl formation and secretion in sweatUsed as diagnostic factor

mutationsThe CFTR gene located on chromosome 7, on the long arm at position q31.2..The mutations in the CFTR gene fall into five major classes.Classes IIII mutations are considered "severe," as indexed by pancreatic insufficiency and high sweat NaCl values.Class IV and V mutations can be "mild," i.e., associated with pancreatic sufficiency and intermediate/normal sweat NaCl values.

mutationsOver 1900 mutations in the CFTR gene that can cause CF.Most common is F508.

LUNG PATHOPHYSIOLOGYCFTR plays a central role in the regulation of ion transport across airway epithelia.In CF, dysregulation of airway surface liquid (ASL) volume occurs as a consequence of ion transport dysfunction impairing mucociliary clearance and, therefore, lung defense.Airway surfaces are coatedwith a thin layer of liquid, the ASL, which is composed of a periciliary layer (PCL) more viscous mucus layer.LUNG PATHOPHYSIOLOGYThe mucus layer, which normally floats on top of the PCL, efficiently traps inhaled pathogens and particulates.The mucus layer, which normally floats on top of the PCL, efficiently traps inhaled pathogens and particulates.The underlying PCL layer, in turn, provides a low viscosity environment in which cilia can beat freely and thereby propel the mucus layer toward the mouth.The PCL also acts as a lubricant layer that prevents adhesion of the mucus layer to cell surfaces.proper regulation of ASL volume and the hydration of its component layers are critical to the maintenance of mucus clearance.LUNG PATHOPHYSIOLOGYAn adequate PCL height is necessary to allow ciliary beating.Adequate hydration of the mucus layer is a key determinant of its viscoelastic properties and transportability.

LUNG PATHOPHYSIOLOGYCFTR important for Cl- secretionCFTR also mediate ENaC activityNet decrease in Cl- secretion and increase in Na+ absorptionOsmotically surface mucous dehydratedBuildup compresses cilia resulting no mucous movementInfections.


Overall pathologySweat Glands :hypersecretion of saltLungs :mucous buildup + infectionPancreas :fibrous cysts + blockageGI Tract :blockage from thick fecesLiver : obstruction, possible cirrhosisMale Reproduction : sterile

Lung :secondary pathogenesisASL dehydration produces progressive mucostasis.Initiates a cascade of events that leads to clinically apparent CF lung disease.Firstly, thickened mucus secretions eventually become adherent to airway surfaces with the loss of PCL volume, and begin to obstruct small airway lumens.Mucus plugs and plaques not only provide a protected environment in which bacteria can escape mechanical and immune-mediated clearance, but also create a unique environment that drastically alters bacterial gene expression.

Lung :secondary pathogenesisParadoxically, the center of a mucus plug is in fact anaerobic (pO2 less than 2 Torr) due to a combination of an increased diffusion distance for O2 as well as increased oxygen consumption by CF epithelia (owing to heightened Na+ transport).Within this environment, P. aeruginosa converts to an anaerobic mode of metabolism, increases alginate production, and ultimately establishes a biofilm structure.Organisms growing within the biofilm possess increased resistance to secondary host defense mechanisms (e.g., neutrophils and soluble antimicrobials).Failure of neutrophils to clear this infection, accompanied by the release of proteases and other harmful substances destroying lung tissue, ultimately leads to bronchiectasis.

Lung pathogenesis

Clinical aspects ASL dehydration and mucus plugging, also develops chronic airway inflammation without readily identifiable bacterial infection.Current hypothesis to explain these findings include:a low burden of typical bacteria avoids eradication in the dehydrated mucus environment of the CF lung and drives the inflammatory process in very early disease.the presence of atypical, perhaps anaerobic, organisms are poorly identified with usual culture systems but dominate early disease and cause inflammation.intermittent events, including viral infections and/or gastric aspiration drive the inflammatory process early in life. Regardless, these observations point to the very early onset of lung disease, even in asymptomatic infants, and the need to develop and institute effective interventions in this population.Clinical aspectsOver a relatively short period of time, the CF lung becomes chronically infected with typical pathogens.In childhood, Haemophilus influenzae and Staphylococcus aureus are often identified first organisms to invade typically followed by the establishment of chronic Pseudomonas aeruginosa infection.Pseudomonas may take many morphologic forms, but mucoid phenotype signifies chronicity and the inability to eradicate this organism, even with aggressive antibiotic regimens.Other important pathogens that are encountered in CF include a variety of gram-negative bacteria, especially Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and the Burkholderia cepacia complex (Bcc).Clinical aspectsMycobacterial pathogens are also encountered in CF, including M. avium complex and M. abscessus.MAC is the most prevalent mycobacterial pathogen in CF, but often does not cause discernible clinical disease, as opposed to the much more problematic infection with M. abscessus.Viral infections, although probably not more frequent than in other populations, do appear to cause more morbidity and may be an important trigger of lung disease exacerbations.Fungi, particularly aspergillus species, are common colonizers but may cause allergic bronchopulmonary aspergillosis (ABPA).

The primary cause of morbidity and mortality in CF patients is bronchiectasis and obstructive lung disease.Pulmonary disease is present in 98% of patients with CF by the time they reach adulthood.A recurrent cough that becomes persistent is often the first manifestation.Airway hyperreactivity and wheezing are common in children.Pansinusitis with opacification of the paranasal sinuses is a universal finding in nearly 30% patients with CF.Acute exCerbationsExacerbations of CF lung disease are extremely important events in the life of a CF patient.These periodic illnesses often remove the patient from their usual work or school activities, are associated with significant reductions in quality of life, exact a large financial toll in terms of health care costs, and are associated with reduced survival.Exacerbations are typically acute to subacute events that are superimposed upon a previously stable clinical baseline.Patients usually report increased cough, sputum, fatigue, and weight loss during these episodes.

Fever, leukocytosis, chest pain, and new infiltrates on chest radiographs are less consistent findings with exacerbations.The inciting events that trigger an exacerbation have not been clearly defined, although acute respiratory viral infection may be one important cause in addition to inadequate use of preventative therapies.

Respiratory complicationsBronchiectasis: occurs as a result of destruction of lung tissue and erosion of the bronchial cartilage.Atelectasis: Lobar and segmental atelectasis occurs in about 5% of patients. This complication is most prevalent in the first 5 years of life and thereafter has a diminishing frequency. The right lung is the site of atelectasis in the majority of patients.Pneumothorax : is a more frequent complication .The overall incidence is about 1%/yr, and increases with age and disease severity, so that about 20% of CF adults will experience at least one pneumothorax. Lung complications4. Hemoptysis: is a common event in older CF patients. Minor to massive hemoptysis may occur .Massive hemoptysis