Cystic fibrosis overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
Overview
Cystic fibrosis is an autosomal recessive disease that caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The genetic mutation result in defective transport of chloride, and secondarily sodium and eventually abnormal viscous mucoid secretions mostly in lungs and GI tract. Infertility due to atresia/absent vasa deferentia and abnormal/absent seminal vesicles is the associated condition of cystic fibrosis. Cystic fibrosis has to be differentiated from asthma, bronchiolitis, emphysema and primary ciliary dyskinesia (Kartagener syndrome). Immunoreactive trypsinogen (IRT) of serum is raised in newborns with cystic fibrosis and has been used as a screening test. The most significant complications are seen in airways and most common chronic pulmonary infection include P. aeruginosa, S. aureus and H. influenzae. Gastrointestinal complications include pancreatic insufficiency, pancreatitis, gastroesophageal reflux disease, distal intestinal obstruction syndrome, constipation and small intestinal bacterial overgrowth. The sweat chloride test is the gold standard test for the diagnosis of cystic fibrosis. Most common symptoms include salty sweat, constant coughing, diarrhea or greasy stools, stomach pain, constipation and poor weight gain. Also abdominal distension and digital clubbing may be detected. Lung examination may presents hyperresonant lungs, Wheeze or crackles. Most common chest CT scan findings include peribronchial thickening, mucous plugging and Bronchiectasis. Medical treatments has targeted following consequences of the defect such as GI and pulmonary mucus plugging and infection. Treatment include mucolytic agents (dornase alfa, N-acetyl-L-cysteine), airway surface rehydration, anti-infective agents, anti-inflammatory agents and potentiators of CFTR protein defect.
Historical Perspective
In the late 1930s cystic fibrosis was first recognized as a disease. In 1949, Lowe and colleagues suggested this theory that cystic fibrosis must be caused by a defect in a single gene. In 1959, the measurement of sweat electrolyte concentrations was established as the mainstay of diagnosing CF. In 1989, the CFTR gene was discovered first. In 1990, scientists successfully added cloned normal gene to cystic fibrosis cells which corrected the chloride transportion
Classification
Cystic fibrosis may be classified according to CFTR protein function abnormality into 6 groups: lack of production (Class 1), failure to reach the site of action due to misfolding (class 2), defects in gating (class 3), reduced ion conductance (class 4), abnormally low channel numbers (class 5) and decreased half-life (class 6). Cystic fibrosis classes 1,2 and 3 are the most common types which have associated with pancreatic insufficiency.
Pathophysiology
Cystic fibrosis is an autosomal recessive disease that caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Substitution of a single amino acid is the most common type of CFTR gene mutation. CFTR gene functions as a chloride channel (pumps chloride from the intracellular space to the extracellular space) found on the surface of the epithelial cells. The genetic mutations result in defective transport of chloride, and secondarily sodium and eventually abnormal viscous mucoid secretions mostly in lungs (results in airway surface liquid depletion, decreased mucociliary transport, inflammation and infection) and GI tract (results in reduced volume of pancreatic secretion, pancreatic tissue destruction and fibrosis, malnutrition and poor growth). Infertility due to atresia/absent vasa deferentia and abnormal/absent seminal vesicles is the associated condition of cystic fibrosis.
Causes
Cystic fibrosis is caused by mutations in the CFTR gene. The genetic mutations result in defective transport of chloride, and secondarily sodium, by epithelial cells and eventually abnormal viscous mucoid secretions mostly in lungs and GI tract.
Differentiating cystic fibrosis from Other Diseases
Cystic fibrosis has to be differentiated from other conditions with similar presentation of cough and wheeze like common cold, asthma, bronchiolitis, emphysema, primary ciliary dyskinesia (Kartagener syndrome), bronchitis, bronchiectasis, foreign body aspiration, pneumoconiosis, interstitial lung disease, cardiogenic pulmonary edema, GERD and sarcoidosis.
Epidemiology and Demographics
The incidence of cystic fibrosis is approximately 1 in 2500 livebirths. It is a life-limiting disease (100% mortality rate), and a cure for the disease remains elusive. Most patients with cystic fibrosis are diagnosed in first 2 years of life. The onset of symptoms is before the first month of life in 12%, between 1-6 months of age in 75%, and between 6-12 months of age in 7% of patients. Although cystic fibrosis has been reported in all racial and ethnic groups, it mostly affects Caucasians of Northern European descent. It affects men and women equally.
Risk Factors
Every person inherits two CFTR genes, one from each parent. Children who inherit two mutated CFTR genes from both parents will have cystic fibrosis.
Screening
Newborn screening identified most of the children with cystic fibrosis before the symptoms develop. It offers this opportunity for early diagnosis and improved outcomes. Immunoreactive trypsinogen (IRT) of serum is raised in newborns with cystic fibrosis and has been used as a screening test. A raised IRT in the first week of life is a sensitive test but not specific for cystic fibrosis.
Natural History, Complications, and Prognosis
Malnutrition and poor growth (due to loss of pancreatic exocrine function) leads to death in the first decade of life for most untreated patients. The most significant complications are seen in airways (responsible for 80% of mortality) and most common chronic pulmonary infection include P. aeruginosa, S. aureus and H. influenzae. In cystic fibrosis 98% of men are infertile due to aspermia. Lung complications are currently the primary causes of morbidity and are responsible for 80% of mortality in these patients and gastrointestinal complications include pancreatic insufficiency, pancreatitis, gastroesophageal reflux disease, distal intestinal obstruction syndrome, constipation and small intestinal bacterial overgrowth. In cystic fibrosis, obstructive lung disease and other lung complications are currently the primary causes of morbidity and are responsible for 80% of mortality. At present time survival probability of children is 40-50 years. Women with cystic fibrosis have a shortened life expectancy compared to men.
Diagnosis
Diagnostic study of choice
The sweat chloride test is the gold standard test for the diagnosis of cystic fibrosis. A sweat chloride value of more than 59 mmol/L is diagnostic for cystic fibrosis, 30-59 mmol/L needs more evaluation with CFTR genetic analysis and less than 30 is indicates that cystic fibrosis is unlikely.
History and Symptoms
Most common symptoms in cystic fibrosis include salty sweat, constant coughing, diarrhea or greasy stools, stomach pain, constipation and poor weight gain. Less common symptoms include nasal polyp, hemoptysis and skin irritation.
Physical Examination
In cystic fibrosis abdominal distension and digital clubbing may be detected. In HEENT examination there is nasal polyps and signs of rhinosinusitis (purulent nasal discharge, mucosal edema, turbinate hypertrophy and tenderness on palpitation of the sinuses). Lung examination may presents hyperresonant lungs, Wheeze or crackles and Productive cough with mucoid or purulent sputum.
Laboratory Findings
Immunoreactive trypsinogen (IRT) of serum is raised in newborns with cystic fibrosis and has been used as a screening test.
Electrocardiogram
There are no electrocardiogram findings associated with cystic fibrosis.
X-ray
In cystic fibrosis the chest radiographic features may overlap with many other disorders, particularly those characterized by inflammatory or destructive changes of the airways. Atelectasis is common in infancy. Most patients with CF demonstrate some of the classic chest radiographic findings that reflect chronic bronchiectasis include hyperinflation, bronchial thickening and dilatation, peribronchial cuffing, mucoid impaction, cystic radiolucencies, increase in interstitial marking and cattered nodular densities.
Ultrasound
In cystic fibrosis, ultrasound findings include small cystic degeneration could be observed in the pancreatic tail. Transabdominal ultrasound of the pancreas demonstrated a higher pancreatic echogenicity, as a measure of pancreatic lipomatosis in pancreatic insufficient CF patients. Echogenic bowel is found on ultrasound in 50% to 78% of fetuses affected with cystic fibrosis. It is thought to be caused by changes in the consistency of meconium in the small intestine as a result of abnormalities in pancreatic enzyme secretion. The sonographic findings include diffuse echogenic bowel, focal echogenic bowel with calcifications, hyperechoic mass and bowel dilation.
CT scan
Computed tomography (CT scan) findings in patients with cystic fibrosis are more sensitive as compared to the pulmonary function tests. Most common chest CT scan findings include peribronchial thickening, mucous plugging and Bronchiectasis. Less common findings include abscesses, emphysematous bullae, hyperinflation, collapse, consolidation, ground-glass opacities, acinar nodules and thickening of interlobular and intralobular septa. Abdomen CT scan in patients with cystic fibrosis may include these findings diffuse and complete fatty replacement of pancreas, Fibrosis of the pancreas and Intestinal obstruction.
MRI
MRI may be helpful in determining the cause of linear lung markings in cystic fibrosis. It is also helpful in differentiating mucous plugging and peribronchial thickening from normal pulmonary blood vessels. Because of MRI absence of ionising radiation and possibility for obtaining functional information, it is helpful for assessing lung disease in children who require repetitive follow up imaging for a long time. MRI studies of the pancreas have demonstrated different patterns of fatty infiltration, ductal changes, pancreatic cysts, calcifications and hypoechoic areas representing fibrosis.
Other Imaging Findings
There are no other imaging findings for cystic fibrosis.
Other Diagnostic Studies
Other diagnostic studies in patients with cystic fibrosis include sweat chloride test (measures the chloride content of the sweat) and nasal potential differences (performed by running different solutions through the nose) which used to detect changes in CFTR function. A sweat chloride value of more than 59 mmol/L is diagnostic for cystic fibrosis and less than 30 mmol/L indicates that cystic fibrosis is unlikely. Also Pulmonary function test (PFT) is important in monitoring lung function in patients with cystic fibrosis. However, it is only an indirect measure of lung structure and is insensitive to local or early damage.
Treatment
Medical Therapy
Medical treatments for patients with cystic fibrosis has targeted following consequences of the defect such as GI and pulmonary mucus plugging and infection. Treatment include mucolytic agents (dornase alfa, N-acetyl-L-cysteine), airway surface rehydration (hypertonic saline, osmotic agents), anti-infective agents (for prophylaxis, eradication of early infection and suppression of chronic infection), anti-inflammatory agents (NSAIDs, inhaled corticosteroids, LTB4 receptor antagonists and Azithromycin) and potentiators of CFTR protein defect.
Surgery
Cystic fibrosis patients with a large pneumothorax should undergo chest tube insertion and even surgical pleurodesis in case of recurrent large pneumothorax. When medical treatment for pulmonary complications fails, lung transplantation is the only option.
Primary Prevention
There is no known way for the primary prevention of cystic fibrosis.
Secondary Prevention
In cystic fibrosis secondary prevention include airway clearance techniques, dornase alpha, hypertonic saline, antibiotics, immunizations, physical activity, nutritional support for pancreatic insufficiency and extra salt and water.