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==Overview==
==Overview==
Cystic fibrosis is an [[autosomal recessive]] disease that caused by [[Mutation|mutations]] in the [[CFTR (gene)|cystic fibrosis transmembrane conductance regulator (CFTR) gene]]. The genetic [[Mutation|mutation]] result in defective transport of [[chloride]], and secondarily [[sodium]] and eventually abnormal viscous [[Mucoid plaque|mucoid]] secretions mostly in [[Lung|lungs]] and [[Gastrointestinal tract|GI tract]]. [[Infertility]] due to [[atresia]]/absent [[Vas deferens|vasa deferentia]] and abnormal/absent [[Seminal vesicle|seminal vesicles]] is the associated condition of cystic fibrosis. Cystic fibrosis has to be [[Differentiate|differentiated]] from [[asthma]], [[bronchiolitis]], [[emphysema]] and [[primary ciliary dyskinesia]] ([[Kartagener's Syndrome|Kartagener syndrome]]). [[Immunoreactive trypsinogen]] (IRT) of [[serum]] is raised in newborns with cystic fibrosis and has been used as a [[Screening (medicine)|screening test]]. The most significant [[Complication (medicine)|complications]] are seen in [[Airway|airways]] and most common chronic pulmonary [[infection]] include ''[[Pseudomonas aeruginosa|P. aeruginosa]],'' ''[[Staphylococcus aureus|S. aureus]] and [[Haemophilus influenzae|H. influenzae]].'' [[Gastrointestinal tract|Gastrointestinal]] [[Complication (medicine)|complications]] include [[pancreatic insufficiency]], [[pancreatitis]], [[gastroesophageal reflux disease]], distal [[intestinal obstruction]] syndrome, [[constipation]] and [[small intestinal bacterial overgrowth]]. The [[Sweat test|sweat chloride test]] is the [[Gold standard (test)|gold standard test]] for the diagnosis of cystic fibrosis. Most common [[Symptom|symptoms]] include salty sweat, constant [[Cough|coughing]], [[diarrhea]] or [[Steatorrhea|greasy stools]], [[Abdominal pain|stomach pain]], [[constipation]] and poor weight gain. Also [[abdominal distension]] and [[Clubbing|digital clubbing]] may be detected. [[Respiratory examination|Lung examination]] may presents hyperresonant [[Lung|lungs]], [[Wheeze]] or [[crackles]]. Most common chest [[Computed tomography|CT scan]] findings include peribronchial thickening, [[Mucus|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 agent|mucolytic agents]] ([[dornase alfa]], [[Acetylcysteine|N-acetyl-L-cysteine]]), [[airway]] surface [[rehydration]], [[Antimicrobial|anti-infective agents]], [[Anti inflammatory medications|anti-inflammatory agents]] and potentiators of [[Cystic fibrosis transmembrane conductance regulator|CFTR protein]] defect.


==Historical Perspective==
==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 1989, the [[CFTR (gene)|CFTR gene]] was discovered first. In 1990, scientists successfully added cloned normal [[gene]] to cystic fibrosis cells which corrected the [[chloride]] transportion.
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)|CFTR gene]] was discovered first. In 1990, scientists successfully added [[Cloning|cloned]] normal [[gene]] to cystic fibrosis cells which corrected the [[chloride]] transportion


==Classification==
==Classification==
Cystic fibrosis may be classified according to [[Cystic fibrosis transmembrane conductance regulator|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 [[Ion channel|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]].
Cystic fibrosis may be classified according to [[Cystic fibrosis transmembrane conductance regulator|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 [[Ion channel|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==
==Pathophysiology==
Cystic fibrosis is an [[autosomal recessive]] disease that caused by [[Mutation|mutations]] in the [[CFTR (gene)|cystic fibrosis transmembrane conductance regulator (CFTR) gene]]. Substitution of a single [[amino acid]] is the most common type of [[CFTR (gene)|CFTR gene]] [[mutation]]. [[CFTR (gene)|CFTR gene]] functions as a [[chloride channel]] (pumps [[chloride]] from the [[intracellular]] space to the [[extracellular]] space) found on the surface of the [[Epithelium|epithelial cells]]. The genetic [[Mutation|mutations]] result in defective transport of [[chloride]], and secondarily [[sodium]] and eventually abnormal viscous [[Mucoid plaque|mucoid]] secretions mostly in lungs (results in airway surface liquid depletion, decreased mucociliary transport, [[inflammation]] and [[infection]]) and [[Gastrointestinal tract|GI tract]] (results in reduced volume of [[Pancreas|pancreatic]] secretion, [[Pancreas|pancreatic]] tissue destruction and [[fibrosis]], [[malnutrition]] and poor growth). [[Infertility]] due to [[atresia]]/absent [[Vas deferens|vasa deferentia]] and abnormal/absent [[Seminal vesicle|seminal vesicles]] is the associated condition of cystic fibrosis.
Cystic fibrosis is an [[autosomal recessive]] disease that caused by [[Mutation|mutations]] in the [[CFTR (gene)|cystic fibrosis transmembrane conductance regulator (CFTR) gene]]. [[Point mutation|Substitution of a single amino acid]] is the most common type of [[CFTR (gene)|CFTR gene]] [[mutation]]. [[CFTR (gene)|CFTR gene]] functions as a [[chloride channel]] (pumps [[chloride]] from the [[intracellular]] space to the [[extracellular]] space) found on the surface of the [[Epithelium|epithelial cells]]. The genetic [[Mutation|mutations]] result in defective transport of [[chloride]], and secondarily [[sodium]] and eventually abnormal viscous [[Mucoid plaque|mucoid]] secretions mostly in [[Lung|lungs]] (results in [[airway]] surface liquid depletion, decreased [[Mucociliary clearance|mucociliary transport]], [[inflammation]] and [[infection]]) and [[Gastrointestinal tract|GI tract]] (results in reduced volume of [[Pancreas|pancreatic]] secretion, [[Pancreas|pancreatic]] tissue destruction and [[fibrosis]], [[malnutrition]] and [[Delayed milestone|poor growth]]). [[Infertility]] due to [[atresia]]/absent [[Vas deferens|vasa deferentia]] and abnormal/absent [[Seminal vesicle|seminal vesicles]] is the associated condition of cystic fibrosis.


==Causes==
==Causes==
Cystic fibrosis is caused by [[Mutation|mutations]] in the [[CFTR (gene)|CFTR gene]]. The genetic [[Mutation|mutations]] result in defective transport of [[chloride]], and secondarily [[sodium]], by [[Epithelium|epithelial cells]] and eventually abnormal viscous mucoid secretions mostly in [[Lung|lungs]] and [[Gastrointestinal tract|GI tract]].


==Differentiating cystic fibrosis from Other Diseases==
==Differentiating cystic fibrosis from Other Diseases==
Cystic fibrosis has to be [[Differentiate|differentiated]] from other conditions with similar presentation of [[cough]] and [[wheeze]] like [[Acute viral nasopharyngitis (common cold)|common cold]], [[asthma]], [[bronchiolitis]], [[emphysema]], [[primary ciliary dyskinesia]] ([[Kartagener's Syndrome|Kartagener syndrome]]), [[bronchitis]], [[bronchiectasis]], [[Pulmonary aspiration|foreign body aspiration]], [[pneumoconiosis]], [[interstitial lung disease]], cardiogenic [[pulmonary edema]], [[Gastroesophageal reflux disease|GERD]] and [[sarcoidosis]].


==Epidemiology and Demographics==
==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 group|ethnic groups]], it mostly affects Caucasians of Northern European descent. It affects men and women equally.


==Risk Factors==
==Risk Factors==
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==Screening==
==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 (medicine)|screening test]]. A raised [[Immunoreactive trypsinogen|IRT]] in the first week of life is a [[Sensitivity (tests)|sensitive]] test but not [[Specificity (tests)|specific]] for cystic fibrosis.
[[Newborn screening]] identified most of the children with cystic fibrosis before the [[Symptom|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 (medicine)|screening test]]. A raised [[Immunoreactive trypsinogen|IRT]] in the first week of life is a [[Sensitivity (tests)|sensitive]] test but not [[Specificity (tests)|specific]] for cystic fibrosis.


==Natural History, Complications, and Prognosis==
==Natural History, Complications, and Prognosis==


[[Malnutrition]] and [[Delayed milestone|poor growth]] (due to loss of [[Pancreas|pancreatic]] [[Exocrine|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 rate|mortality]]) and most common chronic pulmonary [[infection]] include ''[[Pseudomonas aeruginosa|P. aeruginosa]],'' ''[[Staphylococcus aureus|S. aureus]] and [[Haemophilus influenzae|H. influenzae]].'' In cystic fibrosis 98% of men are [[Infertility|infertile]] due to [[aspermia]]. Lung complications are currently the primary causes of [[morbidity]] and are responsible for 80% of [[Mortality rate|mortality]] in these patients and [[Gastrointestinal tract|gastrointestinal]] complications include [[pancreatic insufficiency]], [[pancreatitis]], [[gastroesophageal reflux disease]], distal intestinal obstuction 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 rate|mortality]]. At present time [[Survival rate|survival probability]] of children is 40-50 years.
[[Malnutrition]] and [[Delayed milestone|poor growth]] (due to loss of [[Pancreas|pancreatic]] [[Exocrine|exocrine function]]) leads to death in the first decade of life for most untreated patients. The most significant [[Complication (medicine)|complications]] are seen in [[Airway|airways]] (responsible for 80% of [[Mortality rate|mortality]]) and most common chronic pulmonary [[infection]] include ''[[Pseudomonas aeruginosa|P. aeruginosa]],'' ''[[Staphylococcus aureus|S. aureus]] and [[Haemophilus influenzae|H. influenzae]].'' In cystic fibrosis 98% of men are [[Infertility|infertile]] due to [[aspermia]]. [[Lung]] [[Complication (medicine)|complications]] are currently the primary causes of [[morbidity]] and are responsible for 80% of [[Mortality rate|mortality]] in these patients and [[Gastrointestinal tract|gastrointestinal]] [[Complication (medicine)|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]] [[Complication (medicine)|complications]] are currently the primary causes of [[morbidity]] and are responsible for 80% of [[Mortality rate|mortality]]. At present time [[Survival rate|survival probability]] of children is 40-50 years. Women with cystic fibrosis have a shortened [[life expectancy]] compared to men.
==Diagnosis==
==Diagnosis==
===Diagnostic study of choice===
===Diagnostic study of choice===
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===History and Symptoms===
===History and Symptoms===
Most common symptoms in cystic fibrosis include salty sweat, constant [[Cough|coughing]], [[diarrhea]] or [[Steatorrhea|greasy stools]], [[Abdominal pain|stomach pain]], [[constipation]] and poor weight gain. Less common symptoms include [[nasal polyp]], [[hemoptysis]] and skin irritation.
Most common [[Symptom|symptoms]] in cystic fibrosis include salty sweat, constant [[Cough|coughing]], [[diarrhea]] or [[Steatorrhea|greasy stools]], [[Abdominal pain|stomach pain]], [[constipation]] and poor weight gain. Less common [[Symptom|symptoms]] include [[nasal polyp]], [[hemoptysis]] and skin irritation.


===Physical Examination===
===Physical Examination===
In cystic fibrosis [[abdominal distension]] and [[Clubbing|digital clubbing]] may be detected. In HEENT [[Physical examination|examination]] there is [[Nasal polyp|nasal polyps]] and [[Medical sign|signs]] of [[rhinosinusitis]] ([[Pus|purulent]] nasal discharge, [[Mucous membrane|mucosal]] [[edema]], [[turbinate]] [[Hypertrophy (medical)|hypertrophy]] and [[tenderness]] on [[palpitation]] of the [[Paranasal sinus|sinuses]]). [[Respiratory examination|Lung examination]] may presents hyperresonant [[Lung|lungs]], [[Wheeze]] or [[crackles]] and Productive [[cough]] with mucoid or [[Pus|purulent]] [[sputum]].


===Laboratory Findings===
===Laboratory Findings===
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===Electrocardiogram===
===Electrocardiogram===
There are no electrocardiogram findings associated with cystic fibrosis.
There are no [[electrocardiogram]] findings associated with cystic fibrosis.


===X-ray===
===X-ray===
In cystic fibrosis the [[Chest X-ray|chest radiographic]] features may overlap with many other disorders, particularly those characterized by [[Inflammation|inflammatory]] or destructive changes of the airways. [[Atelectasis]] is common in [[Infant|infancy]]. Most patients with CF demonstrate some of the classic [[Chest X-ray|chest radiographic]] findings that reflect chronic [[bronchiectasis]] include hyperinflation, [[Bronchiole|bronchial]] thickening and [[Dilation|dilatation]], [[peribronchial cuffing]], [[Mucoid plaque|mucoid impaction]], [[Cyst|cystic]] radiolucencies, increase in [[interstitial]] marking and cattered [[Nodule (medicine)|nodular]] densities.
In cystic fibrosis the [[Chest X-ray|chest radiographic]] features may overlap with many other disorders, particularly those characterized by [[Inflammation|inflammatory]] or destructive changes of the [[Airway|airways]]. [[Atelectasis]] is common in [[Infant|infancy]]. Most patients with CF demonstrate some of the classic [[Chest X-ray|chest radiographic]] findings that reflect chronic [[bronchiectasis]] include hyperinflation, [[Peribronchial cuffing|bronchial thickening]] and [[Dilation|dilatation]], [[peribronchial cuffing]], [[Mucoid plaque|mucoid impaction]], [[Cyst|cystic]] radiolucencies, increase in [[interstitial]] marking and cattered [[Nodule (medicine)|nodular]] densities.


===Ultrasound===
===Ultrasound===
In cystic fibrosis, [[ultrasound]] findings include small [[Cyst|cystic]] degeneration could be observed in the [[Tail of pancreas|pancreatic tail]]. Transabdominal [[ultrasound]] of the [[pancreas]] demonstrated a higher [[Pancreas|pancreatic]] [[echogenicity]], as a measure of [[Pancreas|pancreatic]] lipomatosis in [[Pancreas|pancreatic]] insufficient CF patients. [[Echogenicity|Echogenic]] bowel is found on [[ultrasound]] in 50% to 78% of [[Fetus|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 [[Pancreas|pancreatic]] [[enzyme]] secretion. The [[Ultrasound|sonographic]] findings include diffuse [[Echogenicity|echogenic]] bowel, focal [[Echogenicity|echogenic]] bowel with [[Calcification|calcifications]], hyperechoic mass and bowel dilation.


===CT scan===
===CT scan===
[[Computed tomography|Computed tomography (CT scan)]] findings in patients with cystic fibrosis are more [[Sensitivity (tests)|sensitive]] as compared to the [[Spirometry|pulmonary function tests]]. Most common chest CT scan findings include peribronchial thickening, [[Mucus|mucous]] plugging and [[Bronchiectasis]]. Less common findings include [[Abscess|abscesses]], emphysematous bullae, hyperinflation, collapse, [[Consolidation (medicine)|consolidation]], ground-glass opacities, [[Acinus|acinar]] nodules and thickening of interlobular and intralobular [[Septum|septa]]. Abdomen [[Computed tomography|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]].
[[Computed tomography|Computed tomography (CT scan)]] findings in patients with cystic fibrosis are more [[Sensitivity (tests)|sensitive]] as compared to the [[Spirometry|pulmonary function tests]]. Most common chest [[Computed tomography|CT scan]] findings include peribronchial thickening, [[Mucus|mucous]] plugging and [[Bronchiectasis]]. Less common findings include [[Abscess|abscesses]], emphysematous bullae, hyperinflation, collapse, [[Consolidation (medicine)|consolidation]], [[Ground glass opacification on CT|ground-glass opacities]], [[Acinus|acinar]] [[Nodule (medicine)|nodules]] and thickening of interlobular and intralobular [[Septum|septa]]. Abdomen [[Computed tomography|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===
[[Magnetic resonance imaging|MRI]] may be helpful in determining the cause of linear lung markings in cystic fibrosis. It is also helpful in [[Differentiating (disease name) from other diseases page|differentiating]] [[Mucoid plaque|mucous plugging]] and peribronchial thickening from normal [[Pulmonary blood vessel|pulmonary blood vessels]]. Because of [[Magnetic resonance imaging|MRI]] absence of [[Ionizing radiation|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.
[[Magnetic resonance imaging|MRI]] may be helpful in determining the cause of linear [[lung]] markings in cystic fibrosis. It is also helpful in [[Differentiating (disease name) from other diseases page|differentiating]] [[Mucoid plaque|mucous plugging]] and [[Peribronchial cuffing|peribronchial thickening]] from normal [[Pulmonary blood vessel|pulmonary blood vessels]]. Because of [[Magnetic resonance imaging|MRI]] absence of [[Ionizing radiation|ionising radiation]] and possibility for obtaining functional information, it is helpful for assessing [[Respiratory disease|lung disease]] in children who require repetitive follow up [[imaging]] for a long time. [[Magnetic resonance imaging|MRI studies]] of the [[pancreas]] have demonstrated different patterns of fatty infiltration, [[Duct (anatomy)|ductal]] changes, [[Pancreatic cyst|pancreatic cysts]], [[Calcification|calcifications]] and hypoechoic areas representing [[fibrosis]].


===Other Imaging Findings===
===Other Imaging Findings===
There are no other specific imaging findings for cystic fibrosis.
There are no other [[imaging]] findings for cystic fibrosis.


===Other Diagnostic Studies===
===Other Diagnostic Studies===
Other diagnostic studies in patients with cystic fibrosis include [[Sweat test|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 [[Cystic fibrosis transmembrane conductance regulator|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.
Other diagnostic studies in patients with cystic fibrosis include [[Sweat test|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 [[Cystic fibrosis transmembrane conductance regulator|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 [[Spirometry|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 [[Sensitivity (tests)|insensitive]] to local or early damage.


==Treatment==
==Treatment==
===Medical Therapy===
===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 agent|mucolytic agents]] ([[dornase alfa]], N-acetyl-L-cysteine), airway surface [[rehydration]] (hypertonic [[Saline (medicine)|saline]], [[Osmosis|osmotic]] agents), [[Antimicrobial|anti-infective agents]] (for [[prophylaxis]], eradication of early infection and suppression of chronic infection), [[Anti inflammatory medications|anti-inflammatory agents]] ([[Non-steroidal anti-inflammatory drug|NSAIDs]], inhaled [[Corticosteroid|corticosteroids]], [[Leukotriene B4 receptor|LTB4 receptor]] antagonists and [[Azithromycin]]) and potentiators of [[Cystic fibrosis transmembrane conductance regulator|CFTR protein]] defect.
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 agent|mucolytic agents]] ([[dornase alfa]], [[Acetylcysteine|N-acetyl-L-cysteine]]), [[airway]] surface [[rehydration]] ([[hypertonic]] [[Saline (medicine)|saline]], [[Osmosis|osmotic]] agents), [[Antimicrobial|anti-infective agents]] (for [[prophylaxis]], eradication of early [[infection]] and suppression of chronic [[infection]]), [[Anti inflammatory medications|anti-inflammatory agents]] ([[Non-steroidal anti-inflammatory drug|NSAIDs]], inhaled [[Corticosteroid|corticosteroids]], [[Leukotriene B4 receptor|LTB4 receptor]] [[Receptor antagonist|antagonists]] and [[Azithromycin]]) and potentiators of [[Cystic fibrosis transmembrane conductance regulator|CFTR protein]] defect.


===Surgery===
===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.
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 [[Complication (medicine)|complications]] fails, [[lung transplantation]] is the only option.


===Primary Prevention===
===Primary Prevention===
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===Secondary Prevention===
===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.
In cystic fibrosis secondary prevention include [[airway]] clearance techniques, [[Dornase alfa|dornase alpha]], [[hypertonic]] [[Saline (medicine)|saline]], [[Antibiotic|antibiotics]], [[Vaccination|immunizations]], [[Physical exercise|physical activity]], nutritional support for [[pancreatic insufficiency]] and extra salt and water.


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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 asthmabronchiolitisemphysema 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 coldasthmabronchiolitisemphysemaprimary ciliary dyskinesia (Kartagener syndrome), bronchitisbronchiectasisforeign body aspirationpneumoconiosisinterstitial 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 airwaysAtelectasis 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 dilatationperibronchial cuffingmucoid impactioncystic 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 opacitiesacinar 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 pancreasFibrosis 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 alphahypertonic salineantibioticsimmunizationsphysical activity, nutritional support for pancreatic insufficiency and extra salt and water.