Cystic Fibrosis

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Basics

Description

  • Cystic fibrosis (CF) is an autosomal recessive genetic mutation (CFTR gene) that most prominently affects the pulmonary and pancreatic systems. The gastrointestinal (GI), endocrine, and reproductive systems as well as the liver, sinuses, and skin can all be involved.
  • Initially a pediatric disease, CF has become a chronic pediatric and adult medical condition as improvements in medical care have led to a dramatic increase in long-term survival, resulting in adults living with the disease outnumbering children in 2014.

Epidemiology

Although CF is the most common lethal inherited disease in Caucasians, it is found in every racial group.

Incidence

Number of infants born with CF in relation to the total number of live births in the United States

  • 1 in 3,200 Caucasians
  • 1 in 10,000 Latin Americans
  • 1 in 10,500 Native Americans
  • 1 in 15,000 African Americans
  • 1 in 30,000 Asian Americans

Prevalence
More 30,000 patients with CF living in the United States and 70,000 worldwide. The median predicted survival for CF patients in the U.S. was 39.3 years (95% CI, 37.3–41.4).

Etiology and Pathophysiology

  • Primary defect is abnormal function of an epithelial chloride channel protein encoded by the CFTR (CF transmembrane conductance regulator) gene on chromosome band 7q31.2. CTFR functions as a regulated chloride channel, which may regulate the activity of other chloride and sodium channels at the cell surface. Abnormal CFTR function leads to abnormally viscous secretions that alter organ functions.
  • The lungs: Obstruction, infection, and inflammation negatively affect lung growth, structure, and function.
    • Decreased mucociliary clearance
    • Infection is accompanied by an intense neutrophilic response.
    • Degradation of supporting tissues causes bronchiectasis and eventual failure.

Genetics
CF is a single-gene disorder. CFTR gene has >1,500 mutations that can cause varying severity of phenotypic CF, all of which are recessively inherited. Most common is loss of the phenylalanine residue at 508th position (deltaF508), which accounts for 8.7% of affected alleles in the CF population in the United States. G551D mutation accounts for 4.3% of affected alleles.The severity of the phenotype can be affected by the specific CFTR mutation (most predictive of pancreatic disease), other modifier genes (CFTM1 for meconium ileus), gastroesophageal reflux disease (GERD), severe respiratory virus infection, and environmental factors such as tobacco smoke exposure.

General Prevention

Preconception counseling

  • American Congress of Obstetricians and Gynecologists (ACOG) recommends preconception or early (1st/2nd trimester) genetic analysis for all North American couples planning a pregnancy, with appropriate counseling to identified carriers and genetic analysis of siblings of known CF patients.
  • Universal newborn screening (NBS) has been integral in early diagnosis (64% of new CF diagnosis in 2014 were found by NBS). Patients diagnosed prior to onset of symptoms have better lung function and nutritional outcomes and should receive referral and early intervention services by an accredited regional CF center.

Commonly Associated Conditions

  • CF-related diabetes (CFRD)
    • May present as steady decline in weight, lung function, or increased frequency of exacerbation
    • Leading comorbid complication (20.7%)
    • Result of progressive insulin deficiency
    • Early screening and treatment may improve reduced survival found in CFRD.
  • Upper respiratory
    • Rhinosinusitis is seen in up to 100% of patients with CF.
    • Nasal polyps are seen in up to 86% of patients.
  • The GI tract
    • Pancreatic exocrine insufficiency (85–90%)
    • Malabsorption of fat, protein, and fat-soluble vitamins (A, D, E, and K)
    • Hepatobiliary disease (12.6%)
    • Focal biliary cirrhosis
    • Cholelithiasis
    • Meconium ileus at birth (10–15%)
    • Distal intestinal obstruction syndrome (DIOS): intestinal blockage that typically occurs in older children and adults (5.3%)
    • GERD (32.7%)
  • Endocrine
    • Bone mineral disease (16.6%)
    • Joint disease (3.0%)
    • Hypogonadism
    • Frequent low testosterone levels in men
    • Menstrual irregularities are common.
  • Reproductive organs
    • Congenital bilateral absence of the vas deferens: obstructive azoospermia in 98% of males
  • Depression (12.8%)

Pregnancy Considerations

  • Pulmonary disease may worsen during pregnancy.
  • CF may cause increased incidence of preterm delivery, IUGR, and cesarean section.
  • Advances in fertility treatments now allow men with CF to father children.

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Basics

Description

  • Cystic fibrosis (CF) is an autosomal recessive genetic mutation (CFTR gene) that most prominently affects the pulmonary and pancreatic systems. The gastrointestinal (GI), endocrine, and reproductive systems as well as the liver, sinuses, and skin can all be involved.
  • Initially a pediatric disease, CF has become a chronic pediatric and adult medical condition as improvements in medical care have led to a dramatic increase in long-term survival, resulting in adults living with the disease outnumbering children in 2014.

Epidemiology

Although CF is the most common lethal inherited disease in Caucasians, it is found in every racial group.

Incidence

Number of infants born with CF in relation to the total number of live births in the United States

  • 1 in 3,200 Caucasians
  • 1 in 10,000 Latin Americans
  • 1 in 10,500 Native Americans
  • 1 in 15,000 African Americans
  • 1 in 30,000 Asian Americans

Prevalence
More 30,000 patients with CF living in the United States and 70,000 worldwide. The median predicted survival for CF patients in the U.S. was 39.3 years (95% CI, 37.3–41.4).

Etiology and Pathophysiology

  • Primary defect is abnormal function of an epithelial chloride channel protein encoded by the CFTR (CF transmembrane conductance regulator) gene on chromosome band 7q31.2. CTFR functions as a regulated chloride channel, which may regulate the activity of other chloride and sodium channels at the cell surface. Abnormal CFTR function leads to abnormally viscous secretions that alter organ functions.
  • The lungs: Obstruction, infection, and inflammation negatively affect lung growth, structure, and function.
    • Decreased mucociliary clearance
    • Infection is accompanied by an intense neutrophilic response.
    • Degradation of supporting tissues causes bronchiectasis and eventual failure.

Genetics
CF is a single-gene disorder. CFTR gene has >1,500 mutations that can cause varying severity of phenotypic CF, all of which are recessively inherited. Most common is loss of the phenylalanine residue at 508th position (deltaF508), which accounts for 8.7% of affected alleles in the CF population in the United States. G551D mutation accounts for 4.3% of affected alleles.The severity of the phenotype can be affected by the specific CFTR mutation (most predictive of pancreatic disease), other modifier genes (CFTM1 for meconium ileus), gastroesophageal reflux disease (GERD), severe respiratory virus infection, and environmental factors such as tobacco smoke exposure.

General Prevention

Preconception counseling

  • American Congress of Obstetricians and Gynecologists (ACOG) recommends preconception or early (1st/2nd trimester) genetic analysis for all North American couples planning a pregnancy, with appropriate counseling to identified carriers and genetic analysis of siblings of known CF patients.
  • Universal newborn screening (NBS) has been integral in early diagnosis (64% of new CF diagnosis in 2014 were found by NBS). Patients diagnosed prior to onset of symptoms have better lung function and nutritional outcomes and should receive referral and early intervention services by an accredited regional CF center.

Commonly Associated Conditions

  • CF-related diabetes (CFRD)
    • May present as steady decline in weight, lung function, or increased frequency of exacerbation
    • Leading comorbid complication (20.7%)
    • Result of progressive insulin deficiency
    • Early screening and treatment may improve reduced survival found in CFRD.
  • Upper respiratory
    • Rhinosinusitis is seen in up to 100% of patients with CF.
    • Nasal polyps are seen in up to 86% of patients.
  • The GI tract
    • Pancreatic exocrine insufficiency (85–90%)
    • Malabsorption of fat, protein, and fat-soluble vitamins (A, D, E, and K)
    • Hepatobiliary disease (12.6%)
    • Focal biliary cirrhosis
    • Cholelithiasis
    • Meconium ileus at birth (10–15%)
    • Distal intestinal obstruction syndrome (DIOS): intestinal blockage that typically occurs in older children and adults (5.3%)
    • GERD (32.7%)
  • Endocrine
    • Bone mineral disease (16.6%)
    • Joint disease (3.0%)
    • Hypogonadism
    • Frequent low testosterone levels in men
    • Menstrual irregularities are common.
  • Reproductive organs
    • Congenital bilateral absence of the vas deferens: obstructive azoospermia in 98% of males
  • Depression (12.8%)

Pregnancy Considerations

  • Pulmonary disease may worsen during pregnancy.
  • CF may cause increased incidence of preterm delivery, IUGR, and cesarean section.
  • Advances in fertility treatments now allow men with CF to father children.

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