Cystic fibrosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Castro Molina, M.D.

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.

Over the past decade, CFTR modulator therapies have transformed the natural history of cystic fibrosis for many patients, with improvements in lung function, pulmonary exacerbations, nutritional status, and quality of life, particularly with highly effective triple therapy (elexacaftor/tezacaftor/ivacaftor) in people with at least one Phe508del allele.^[1] As a result, the cystic fibrosis population is increasingly adult, with evolving care needs and a growing focus on comorbidities, treatment burden, and long-term outcomes.^[2][3]

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.

The era of disease-modifying therapy began with CFTR modulators, including ivacaftor (a CFTR potentiator) for gating mutations such as G551D, followed by combination modulator regimens for Phe508del (including lumacaftor/ivacaftor and tezacaftor/ivacaftor) and highly effective triple therapy (elexacaftor/tezacaftor/ivacaftor).^{[4][5][6][7][1]}

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.

Eligibility for CFTR modulators depends on CFTR genotype and functional consequences of the variant(s). Curated resources (e.g., CFTR2) support genotype interpretation and guide therapy selection in clinical practice and newborn screening follow-up.^[8][9]

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.

Experimental and translational studies support airway surface liquid depletion and impaired mucociliary clearance as early drivers of cystic fibrosis lung disease, including evidence from large-animal (porcine) models that demonstrate reduced airway surface liquid and impaired bacterial clearance associated with CFTR dysfunction.^[10] Reviews of early lung disease and pathogenesis emphasize that airway obstruction, infection, and inflammation begin early in life and contribute to progressive structural lung injury.^[11]

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.

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.

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.

Contemporary registry and population-based analyses demonstrate improved survival and an increasing proportion of adults living with cystic fibrosis, with differences by region and health system. Cystic fibrosis population trends and survival estimates are frequently monitored through national registries and comparative cohort analyses.^[3][12][2]

Every person inherits two CFTR genes, one from each parent. Children who inherit two mutated CFTR genes from both parents will have cystic fibrosis.

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.

In many screening programs, elevated IRT is followed by CFTR variant testing, and in some algorithms, a sequencing tier is used to improve diagnostic yield and reduce false positives and inequities across ancestry groups. Screening approaches vary by region and program design.^[13]

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.

As CFTR modulators have become widely used, outcomes and complications are changing, including improvements in nutritional status and lung function in many treated individuals. Emerging clinical questions include how to safely reduce treatment burden in selected patients receiving highly effective CFTR modulators.^[14][2]

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.

Cystic fibrosis diagnostic criteria and guidance for ambiguous or intermediate sweat chloride results incorporate CFTR genotyping, functional testing when needed, and careful clinical correlation. Expert guidelines also address CFTR-related disorders and diagnostic uncertainty.^[15][8]

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.

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.

Immunoreactive trypsinogen (IRT) of serum is raised in newborns with cystic fibrosis and has been used as a screening test.

There are no electrocardiogram findings associated with cystic fibrosis.

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.

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.

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 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.

There are no other imaging findings for cystic fibrosis.

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.

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.

CFTR modulators are genotype-directed therapies that include potentiators (e.g., ivacaftor) and correctors (e.g., lumacaftor, tezacaftor, elexacaftor) used alone or in combination. These therapies improve CFTR function and have been associated with improved lung function, reduced pulmonary exacerbations, and improved nutritional parameters in eligible patients.^[9]

• Ivacaftor for gating mutations such as G551D was associated with clinically meaningful improvements in outcomes in pivotal trials.^[4]
• Combination corrector-potentiator therapies for Phe508del (including lumacaftor/ivacaftor and tezacaftor/ivacaftor) expanded modulator eligibility and provided more modest benefits than later triple therapy.^[5][6][7]
• Elexacaftor/tezacaftor/ivacaftor (highly effective triple therapy) provides substantial improvements in patients with at least one Phe508del allele and is expected to influence long-term outcomes across respiratory and extrapulmonary domains.^[1]

As modulator use increases, clinical trials and observational data are evaluating how to safely reduce treatment burden (e.g., discontinuation of hypertonic saline or dornase alfa) in selected patients receiving highly effective modulators.^[14]

Airway clearance therapies remain foundational for many patients and are supported by guideline-based recommendations.^[16] Dornase alfa and hypertonic saline have evidence of benefit in selected populations and are often used to reduce mucus plugging and exacerbations.^[17][18]

Chronic airway infection and inflammation are major drivers of morbidity. Guidance supports early eradication and chronic suppressive therapy for Pseudomonas aeruginosa infection, and inhaled antibiotics are a cornerstone of management.^[19][20] Opportunistic pathogens (including nontuberculous mycobacteria and fungi) can complicate management and may require specialized evaluation and therapy.^[21]

CFTR modulators may alter extrapulmonary manifestations, including reports of improved pancreatic function in selected individuals treated with ivacaftor.^[22] CF-related diabetes and other metabolic complications remain important in adult care; registry analyses provide updated estimates of prevalence and trends.^[23] Mental health screening and management are increasingly emphasized, including clinician guidance and observational studies evaluating symptom changes after initiation of highly effective modulators.^[24][25]

For patients not eligible for current modulators or with persistent disease burden, investigational approaches include antisense oligonucleotide therapies for specific splicing mutations, respiratory gene therapy, and inhaled mRNA-based therapies.^[26][27][28]

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.

Lung transplantation remains an important option for advanced lung disease, and contemporary registry studies describe outcomes in cystic fibrosis recipients.^[29]

There is no known way for the primary prevention of cystic fibrosis.

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.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shaghayegh Habibi, M.D.[2]

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.

• In the late 1930s, cystic fibrosis was first recognized as a disease. This term was used to describe the characteristic cyst formation and fibrosis observed in the pancreas.^[1][2][3]
• In 1949, Lowe and colleagues suggested that cystic fibrosis must be caused by a defect in a single gene, based on autosomal recessive pattern of inheritance.
• In 1959, the measurement of sweat electrolyte concentrations was established as the mainstay of diagnosing CF.
• In the late 1980s, the first articles described the application of computed tomography in patients with cystic fibrosis.
• In 1989, the CFTR gene was discovered.
• Till 1996, approximately 500 different mutations for cystic fibrosis had been detected.^[4]

• In 1990, scientists successfully added cloned normal gene to cystic fibrosis cells in the laboratory, which corrected the chloride transportion. The gene therapy technique was then tried on a limited number of CF patients.^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shaghayegh Habibi, M.D.[2]

Cystic fibrosis may be classified according to CFTR protein function abnormality into 6 classes and includes 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 commonly associated with pancreatic insufficiency.

Cystic fibrosis may be classified according to CFTR mutation type:^[1][2][3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shaghayegh Habibi, M.D.[2]

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.

• Cystic fibrosis (CF) is an autosomal recessive disease that caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.^[1][2][3]
• 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, that line multiple organs especially lungs and GI tract.
• 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.
• Other organs containing epithelia such as the sweat glands, biliary duct, the male reproductive tract, and the intestine are also affected.
• Two mechanisms which cause airway-surface-liquid depletion are as follow:

• In patients with cystic fibrosis abnormal chloride conductance of epithelial cells results in airway surface liquid depletion and decreased mucociliary transport (airway surface liquid is essential to support ciliary function).
• The consequence of cystic fibrosis is a vicious circle of inflammation, tissue damage and infection.^[3]
• Also, exaggerated, generalized, and prolonged inflammatory response of lungs to bacterial and viral pathogen is observed.
• The inflammatory response is characterized by neutrophilic dominated airway inflammation which is present even in clinically stable patients and in young infants diagnosed by neonatal screening.^[3][4]
• Breakdown of accumulated neutrophils in the infected lungs of patients with cystic fibrosis leads to the release of large amounts of DNA.
• Accumulated DNA causes high viscosity of the infected sputum, followed by decreased ciliary transport and function.^[5]

• In cystic fibrosis, approximately 90% of patients present with exocrine pancreatic insufficiency.
• Pancreatic disease results from a reduced volume of pancreatic secretion with low concentrations of bicarbonate, followed by retained and prematurely activated digestive proenzymes in pancreatic ducts, resulting in tissue destruction and fibrosis.^[6]
• Abnormally viscous secretions in the ducts of the pancreas, followed by loss of pancreatic exocrine function results in malnutrition and poor growth.^[4]

• One third of patients with cystic fibrosis have abnormal results on liver function tests.
• Fatty infiltration is reported in up to 70% of older patients and in nearly 10% of these progresses to biliary cirrhosis.
• Histological evaluation shows duct dilatation and intraluminal concretions.
• Bile-duct epithelium becomes hyperplastic with periductal inflammation and fibrosis.
• Up to one third of patients with cystic fibrosis, a small and poorly functioning gallbladder is detected.^[6]

Cystic fibrosis is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. This gene codes for a chloride transporter regulated by cyclic AMP (cAMP)-dependent phosphorylation. There are almost 2,000 variants of CFTR gene mutations:^[4]

• Substitution of a single amino acid (40%)
• Alter RNA processing including nonsense, frameshift and missplicing (36%)
• Large rearrangements of CFTR (3%)
• Promoter regions (1%)
• Neutral variants (14%)
• The effect of the remaining 6% is unclear.
• Children who inherit one mutated CFTR gene and one normal CFTR gene are “CF carriers“. CF carriers usually have no symptoms of cystic fibrosis but they can pass the mutated CFTR gene to their children.^[7]

In Caucasian populations, the frequency of mutations is as follows:^[9]Template:Entête tableau charte alignement ! Mutation ! Frequency
worldwide |—– | ΔF508 | 66.0% |- | G542X | 2.4% |—– | G551D | 1.6% |- | N1303K | 1.3% |—– | W1282X | 1.2% |}

• In cystic fibrosis, 98% of men are infertile. The causes of aspermia include:^[10]
  • Atresia or absent vasa deferentia
  • Abnormal or absent seminal vesicles

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shaghayegh Habibi, M.D.[2]

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.

• 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.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shaghayegh Habibi, M.D.[2], Karina Zavaleta, MD [3], Anmol Pitliya, M.B.B.S. M.D.[4]

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.

Cystic fibrosis must be differentiated from other diseases presenting with cough and wheeze include:

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shaghayegh Habibi, M.D.[2]

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.

• The incidence of cystic fibrosis is approximately 40 in 100,000 live births worldwide.
• The incidence of cystic fibrosis is approximately 25 in 100,000 newborns in the US.^[1][2]

• Cystic fibrosis affects more than 30,000 people in the United States and 80,000 people worldwide.^[3]

• Cystic fibrosis is a life-limiting disease (100% mortality rate), and a cure for the disease remains elusive.^[4]

• 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.^[5]

• Although cystic fibrosis has been reported in all racial and ethnic groups, it mostly affects Caucasians of Northern European descent.
• Cystic fibrosis is the most lethal genetic disease among Caucasians
• Cystic fibrosis is approximately reported in different ethnic groups as follow:^[6][7]

• Cystic fibrosis affects men and women equally. Women with cystic fibrosis have a shortened life expectancy compared to men.^[8]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shaghayegh Habibi, M.D.[2]

Every individual with cystic fibrosis inherits two CFTR genes, one from each parent. Children who inherit two mutated CFTR genes from both parents will have cystic fibrosis.

• Every individual with cystic fibrosis inherits two CFTR genes, one from each parent. Children who inherit two mutated CFTR genes from both parents will have cystic fibrosis.^[1]
• Children with only one gene will act as a carrier for next generations.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shaghayegh Habibi, M.D.[2]

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.

• In almost all of the Western countries, newborn screening for cystic fibrosis (CF NBS) has been introduced that identified most of the children with cystic fibrosis before the symptoms develop.
• It offers this opportunity for early diagnosis and improved outcomes in patients with cystic fibrosis.^[1][2]
• 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 (b-IRT) is a sensitive test but not specific for cystic fibrosis. A second IRT test within 6 weeks of life is used in some screening protocols to avoid excessive numbers of sweat chloride test.^[3][4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Shaghayegh Habibi, M.D.[2]

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 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. At present time survival probability of children is 40-50 years. Women with cystic fibrosis have a shortened life expectancy compared to men.

• If patients with cystic fibrosis left untreated, they would present with failure to thrive and/or steatorrhea during infancy. Also this would typically progress to hypoproteinemia, edema, and severe cachexia.^[1]
• Malnutrition and poor growth (due to loss of pancreatic exocrine function) leads to death in the first decade of life for most untreated patients.^[2]

In patients with cystic fibrosis the most significant changes and complications are seen in the airways. The primary genetic defect eventually causes chronic pulmonary infections. P. aeruginosa is the most common infection, followed by S. aureus and H. influenzae.^[3][4]

• Infancy: the most common bacteria cultured is S. aureus along with H. influenzae recently increased during childhood
• Adolescence and young adulthood: the commonest pathogen cultured is P. aeruginosa

Other lung complications of cystic fibrosis include:^[5]

• Sinusitis
• Airway obstruction
• Bronchiectasis
• Hemoptysis
• Pneumothorax
• Respiratory failure

In cystic fibrosis, approximately 90% of patients present with exocrine pancreatic insufficiency. Pancreatic insufficiency leads to maldigestion and malabsorption of nutrients, followed by sequelae of malnutrition include permanent stunting of stature, cognitive dysfunction (due to vitamin E deficiency) and more rapid decline in pulmonary function. Other gastrointestinal complications related to cystic fibrosis include:^[5][6][7]

• Pancreatitis
• Gastroesophageal reflux disease
• Distal intestinal obstuction syndrome
• Obstipation/constipation
• Small intestinal bacterial overgrowth
• Steatosis
• Cholelithiasis
• Meconium ileus
• Malabsorption (vitamin malabsorption may cause hemolytic anemia and defective coagulation)

Endocrine complications related to cystic fibrosis include:^[5]

• Diabetes mellitus
• Osteoporosis
• Delayed sexual development
• Hypogonadism

• Salt-loss syndromes (acute salt depletion, chronic metabolic alkalosis, and/or hyponatremic hypochloremic dehydration)
• Hemolytic anemia and defective coagulation due to vitamin malabsorption ^[8]

• Life expectancy of patients with cystic fibrosis has been increased over past decades because of better symptomatic treatment strategies.
• In patients with cystic fibrosis, obstructive lung disease and other lung complications are currently the primary causes of morbidity and are responsible for 80% of mortality.^[2][9]
• At present, the survival probability of children is 40-50 years.^[10]
• Women with cystic fibrosis have a shortened life expectancy compared to men. Women also become colonized with certain common CF pathogens earlier and have a lower life expectancy in the setting of respiratory infections.^[11]