Cystic Fibrosis

Cystic fibrosis is an inherited disease that affects the exocrine glands, especially the gastrointestinal tract and the respiratory tract. It leads to chronic lung disease, exocrine pancreatic insufficiency, hepatobiliary disease and pathologically high sweat electrolyte. The diagnosis is made in patients with postiven newborn screening test by means of test welding or by identification of the two mutations in the cystic fibrosis gene (CFTR) or characteristic clinical findings. The treatment is supportive through aggressive multidisciplinary treatment with small molecule correctors and potentiators that target the CFTR defect.

Cystic fibrosis (CF) is the most common life-threatening genetic disease in Caucasians. The incidence in the US is at about 1/3300 in fair-skinned and 1 / 15,300 in the dark-skinned and 1 / 32,000 in the Asian population. Thanks to improved treatment and life expectancy is about 50% of patients with cystic fibrosis in the US adults.

Cystic fibrosis is an inherited disease that affects the exocrine glands, especially the gastrointestinal tract and the respiratory tract. It leads to chronic lung disease, exocrine pancreatic insufficiency, hepatobiliary disease and pathologically high sweat electrolyte. The diagnosis is made in patients with postiven newborn screening test by means of test welding or by identification of the two mutations in the cystic fibrosis gene (CFTR) or characteristic clinical findings. The treatment is supportive through aggressive multidisciplinary treatment with small molecule correctors and potentiators that target the CFTR defect. Cystic fibrosis (CF) is the most common life-threatening genetic disease in Caucasians. The incidence in the US is at about 1/3300 in fair-skinned and 1 / 15,300 in the dark-skinned and 1 / 32,000 in the Asian population. Thanks to improved treatment and life expectancy is about 50% of patients with cystic fibrosis in the US adults. Etiology The CF is an autosomal recessive disorder, which occurs in 3% of fair-skinned population. The gene responsible is found on the long arm of chromosome 7th It encodes a membrane-associated protein, the cystic fibrosis transmembrane conductance regulator (CFTR) is called. The most common mutation, F508del, occurs in approximately 86% of the ZF alleles; > 1,900 less frequent CFTR mutations were identified. CFTR is a cAMP-regulated chloride channel that regulates chloride and sodium transport along the epithelial membranes. A number of additional features are considered likely. The disease is manifested only in homozygotes. Heterozygous fine abnormalities of epithelial electrolyte transport can show are clinically but unobtrusive. The CFTR mutations were divided into five classes based on how the mutation affects the function or the processing of the CFTR protein. Patients are associated with mutations of class I, II or III, as such, with a heavier genotype, resulting in less or no CFTR function, while patients are with 1 or 2 mutations Class IV or V as those that have a milder genotype , resulting in residual CFTR results. However, there is no fixed relationship between specific mutations and manifestation of the disease, so that the clinical examination (eg. As organ function) a better assessment of the prognosis allowed as genetic testing. Pathophysiology Nearly all exocrine glands are affected in different distribution and severity. You can viscous or solid eosinophilic material stops his (pancreas, small intestine glands, intrahepatic bile ducts, gallbladder and submaxillary glands). be histologically striking and vast amounts of secretions (tracheobronchial and Brunner’s glands) produce appear histologically normal but excess sodium and chloride secrete (sweat, parotid, and small salivary glands). Respiratory Although the lung is usually at birth appears histologically normal, most patients develop lung disease in infancy or early childhood. Mucus and chronic bacterial infection, accompanied by a pronounced inflammatory response, damage the respiratory tract, which ultimately leads to bronchiectasis and respiratory failure. The typical course is characterized by episodic exacerbations with infections and increasing deterioration of lung function. The pulmonary damage will probably initially caused by a diffuse obstruction of the small airways by the pathologically thick secretions. Secondary occurs due to the obstruction and infection bronchiolitis and purulent airway obstruction. Respiratory changes are more common than parenchymal changes; Emphysema are not very frequent. About 50% of patients have a bronchial hyperreactivity, which responds to bronchodilators. In patients with advanced pulmonary disease chronic hypoxia causes muscular hypertrophy of the pulmonary arteries and right ventricular hypertrophy. Much of the pulmonary damage appears to be caused by inflammation due to the release of proteases and inflammatory cytokines of the cells in the airways. The lungs of most patients is colonized by pathogenic bacteria. In the early stages of the disease is detected as pathogens most commonly Staphylococcus aureus, when the disease progresses, Pseudomonas aeruginosa is frequently isolated. A mucosal variant of P. aeruginosa is always associated with CF and lead to a poorer prognosis than nichtmuköse Pseudomonas. The prevalence of methicillin-resistant S. aureus (MRSA) in the airways is now> 25%; Patients who are infected with MRSA, have a lower survival rate than those who are not. Colonization with Burkholderia cepacia occurs in about 2% of patients and may be associated with a more rapid pulmonary deterioration. Nontuberculous mycobacteria, including Mycobacterium Aviumkomplex and M. abscessus, are potential respiratory pathogens. The prevalence varies with age and geographical position and is probably over 10%. Sometimes it is difficult to distinguish infection from colonization. Other common respiratory pathogens are Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Aspergillus sp.Gastrointestinaltrakt The pancreas, the intestines and the hepatobiliary system are affected. Exocrine pancreatic function is impaired in 85-95% of patients. An exception is a subgroup of patients who have certain “weak” CF mutations, where the pancreatic function is not affected. Patients with pancreatic insufficiency have a malabsorption of fat (and fat soluble vitamins) and protein. Duodenal fluid pathologically viscous and shows an absence or a decrease in enzyme activity and a decreased HCO3 – concentration. Stuhltrypsin and chymotrypsin are missing or reduced. Endocrine pancreatic dysfunction is less common, but 2% of children, 20% of young people and at least 40% of adults suffer from impaired glucose tolerance or diabetes mellitus. Biliary involvement with biliary stasis and obstruction of the bile ducts resulting in 30% of patients asymptomatic liver fibrosis. Approximately 2-3% of patients the disease process progresses usually at an age of 12 years to irreversible multinodularer biliary cirrhosis with varices and portal hypertension. Hepatocellular failure is a rare and late event. There is an increased incidence of cholelithiasis, which is usually asymptomatic. Unusually sticky intestinal secretions often cause meconium ileus in newborns and sometimes a Mekoniumpropf in the colon. Older children and adults may also have intermittent or chronic constipation and bowel obstruction. Other problems of the gastrointestinal tract are intussusception, volvulus, rectal prolapse, perityphlitischer abscess, pancreatitis, an increased risk of cancer of the liver and gastrointestinal tract, gastroesophageal reflux and Ösophagitis.Weitere impact infertility occurs in 98% of adult men as a result of faulty development of the vas deferens or other species before obstructive azoospermia. In women, fertility is reduced slightly due to the viscous cervical secretions. Nevertheless, many women have pregnancies completely discharged. The outcome of pregnancy for both mother and child is related to the health of the mother. Other complications include osteopenia / osteoporosis, depression, kidney stones, dialysis-dependent chronic kidney disease (possibly also associated with treatment as with CF) one, iron deficiency anemia, and episodic arthralgia / arthritis. Symptoms and phlegm 50% of all patients who were not usually diagnosed by newborn screening, have pulmonary manifestations of chronic cough in infancy. Repeated or chronic infections with cough, phlegm and wheezing are common. The cough is the most disturbing symptom, often accompanied by sputum, gagging, vomiting and disturbed sleep. With progression of the disease occurs intercostal retractions, use of the respiratory muscles, fassförmigem thorax, drumstick fingers, cyanosis and decreasing motion tolerance. The involvement of the upper respiratory tract are a recurrent polyposis and chronic or recurrent sinusitis. Pulmonary complications are pneumothorax, infection with mycobacteria nontuberculous, hemoptysis, allergic bronchopulmonary aspergillosis and right heart failure as a result of pulmonary Hypertonie.Gastrointestinaltrakt A meconium ileus due to obstruction by the viscous meconium in the ileum can be the first symptom and is involved in 13-18% find newborns with CF. It typically manifests with abdominal distention, vomiting and ausbleibendem meconium. Some infants have a bowel perforation with symptoms of peritonitis and shock. Infants with meconium plug syndrome have delayed passage of meconium. You may have or similar symptoms as in an obstruction very mild and transient symptoms that go unnoticed. Elderly patients may be repeated episodes of constipation or chronic and potentially episodes of partial or complete small or large bowel obstruction have (distal intestinal obstruction syndrome). Symptoms include cramping abdominal pain, change in bowel habits, poor appetite and sometimes vomiting. In children without meconium ileus, the onset announces frequently on by a delayed re-achievement of birth weight and a failure to thrive at the age of 4-6 weeks. Occasionally, have especially when they get hypoallergenic formula, or soy processed foods children who are malnourished, generalized edema as a result of protein malabsorption. A pancreatic insufficiency is frequently found at an early stage and can run progressive. There are frequent, copious, foul-smelling and greasy stools. The abdomen to bulge. The growth rate, the subcutaneous fat and muscle mass are reduced in spite of a good appetite. The clinical signs may be related to a lack of fat-soluble vitamins. At 20% of untreated children it comes to rectal prolapse. Gastroesophageal reflux disease is relatively common in children and Erwachsenen.Weitere effects through excessive sweating can cause a hyponatremic or hypochloremic dehydration and circulatory failure. A dry climate can lead to chronic metabolic alkalosis in these children. Deposits of crystallized salt on the skin suggest the suspicion of CF. Adolescents show a delay of growth and delayed onset of puberty. Diagnosis General newborn screening, if possible Can also by a positive test result prenatal screening, family history or symptomatic manifestations are suspected. Confirmed by a welding test, exhibiting an elevated welding chloride levels in ? 2 tests. Can also through the identification of two CF mutations (one on each chromosome) can be confirmed, often in atypical cases are confirmed by the detection of abnormal ion transport across the nasal mucosa A generalized neonatal screening for CF is now in the United States common; more than 90% of cases are first identified by newborn screening, but up to 10% are not diagnosed until adolescence or early adulthood. Despite advances in the genetic testing of the weld chloride test remains in most cases the standard for the confirmation of a CF diagnosis due to its sensitivity and specificity, simplicity and availability. Sweat test In this test localized sweating is using stimulated by pilocarpine. Then, the amount is measured at the welding and the chloride concentration was determined (see Table: sweat chloride concentration ranges in cystic fibrosis (CF)). The results are significant already after the first 48 hours of life, but it may be difficult to collect in front of the 2nd week of life, a sufficient weld sample (> 75 mg on a filter paper or> 15 .mu.l in a microbore header). False-negative results are rare, but may occur at welding collected in the presence of edema and hyperproteinaemia or insufficient amounts. False-positive results are usually due to technical errors. A temporary increase of the welding chloride concentration of psychosocial impairment (z. B. Child Abuse and Neglect) result and occur in patients with anorexia nervosa. Although the chloride concentration increases with age, the test at all ages is valid. A positive sweat test result should be confirmed by a second welding test or by the detection of 2 CF mutations. Sweat chloride concentration ranges in cystic fibrosis (CF) Age Normal (mmol / l) * means (mmol / l) † Abnormal (mmol / L) ‡ * These concentrations that CF is unlikely. † These concentrations that CF is possible. ‡ These concentrations are consistent with CF. ? 6 months ? 29 30 to 59 ? 60> 6 months ? 39 40 to 59 ? 60 Average welding test results A small subset of patients have a weak or partial CF phenotype and sweat chloride values ??that are constantly in the middle or even the normal range are. In addition, there are patients who have a single organ manifestation such as pancreatitis, bronchiectasis or congenital bilateral absence of the vas deferens caused by a partial CFTR protein dysfunction. In some patients, the diagnosis of CF through the identification of two CF mutations can be placed in each chromosome. 1 If no two CF mutations are identified, additional evaluations as pancreatic function tests, images of the pancreas, high-resolution chest CT, sinus CT, pulmonary function tests, urogenital study in men and bronchoalveolar lavage, including an assessment of the microbial flora be useful can. Other potentially useful diagnostic tests are an expanded genetic CFTR analysis and measurement of nasal transepithelial potential difference (based on the observation of the increased sodium reabsorption by the epithelium, which is relatively impermeable to Cl in patients with CF) .CFTR-dependent metabolic syndrome infants, wherein which is an indication of CFTR dysfunction are present, but do not meet the diagnostic criteria for CF, have a CFTR-related metabolic syndrome (CRMs). CRMS is at 3 to 4% of children who have a positive neonatal ultrasound diagnosed. To be diagnosed, children must be asymptomatic and have one of two of the following: his sweat chloride concentrations in the intermediate area at least two separate occasions and <2 known CF-causing mutations sweat chloride concentrations within the normal range and two CFTR mutations ? 1, the CF-causing mutation can. Some children with CRMS develop over time symptoms of CF, but most stay healthy. Such patients should be regularly evaluated in a CF-care clinic and observed werden.Pankreaskrebstests An evaluation of pancreatic function should be performed at the time of diagnosis. It is customary to measure the fat excretion within 72 h and the concentration of human pancreatic elastase in the feces. The latter test is also possible in presence of exogenous pancreatic enzymes. In infants who initially have sufficient pancreatic function and have two "severe" mutations, serial measurements should be made to the progression of pancreatic insufficiency to erkennen.Respiratorische assessing chest x-rays are in times of pulmonary deterioration or exacerbation and routinely every 1-2 to make years. A high-resolution chest computed tomography may be helpful to define the extent of damage to the lungs and respiratory system more accurately and to detect subtle abnormalities. Both imaging techniques can show hyperinflation and a thickening of the bronchial wall as the first findings. This is followed infiltrates, atelectasis and adenopathy of Hilusdrüsen. With progressive disease leads to segmental and lobar atelectasis, cystic changes, bronchiectasis and hypertrophy of the pulmonary artery and the right ventricle. Branched, finger-like shadows are caused by mucus accumulations in the dilated bronchi. They are characteristic. CT scans of the sinuses are in patients with significant sinus symptoms or nasal polyps, in which an endoscopic surgery is considered necessary. These shots almost always show a persistent shadowing of the paranasal sinuses. Cystic fibrosis (chest radiograph) with permission of the publisher. For Berman L .: Atlas of Anesthesia Critical Care. Edited by R. Miller (Series Editor) and R. R. Kirby. Philadelphia, Current Medicine, 1997. var model = {thumbnailUrl: '/-/media/manual/professional/images/cystic_fibrosis_chest_xray_high_de.jpg?la=de&thn=0&mw=350' imageUrl: '/ - / media / manual / professional / ? images / cystic_fibrosis_chest_xray_high_de.jpg lang = en & thn = 0 ', title:' Cystic fibrosis (chest radiograph) 'description:' u003Ca id = "v37897675 " class = ""anchor "" u003e u003c / a u003e u003cdiv class = ""para "" u003e u003cp u003eDieser chest x-ray shows the collapse of the right lower lobe. Findings are typical for CF

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