Cystic Fibrosis
Robert Guzy
Daniel B. Rosenbluth
General Principles
Definition
Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR), resulting in dysfunction in numerous exocrine organs.
Epidemiology
CF is the most common lethal inherited disease affecting the white population.
The incidence is ∼1 in 3300 white births but all races are affected. The incidence in nonwhite populations is estimated to be 1:9200 Hispanic births, 1:10,900 Native American births, 1:15,000 African American births, and 1:30,000 Asian births. Approximately 1000 new cases are diagnosed annually in the United States and the overall prevalence is just under 30,000 patients.1,2,3
Since newborn screening has been adopted by all states the proportion of new cases identified via newborn screening is increasing (62% in 2013).2 Early asymptomatic diagnosis may have better pulmonary function during early childhood.3,4
Aside from newborn screening most cases are identified in babies born with meconium ileus or young children who present with respiratory symptoms, most commonly recurrent pulmonary infections.
Up to 10% of patients are diagnosed at age 10 or older.2,5 These patients are more likely to present with nonclassic CF symptoms including bronchiectasis without pancreatic insufficiency, recurrent or chronic pancreatitis, or infertility (azoospermia with congenital absence of the vas deferens).
The median age of survival in the United States is 40.7 years (95% confidence interval 37.7–44.1).2
Pathophysiology
CF is a multisystem disease, with highly variable disease presentation.
Progressive lung disease and chronic respiratory tract infection, however, is the major cause of morbidity and mortality.3
Pulmonary disease is related to abnormal electrolyte transport in airways, resulting in decreased airway surface liquid and impaired mucociliary clearance. Infection, inflammation, and chronic airway obstruction ultimately result in bronchiectasis, chronic infection, and premature death.6,7
Thickened secretions in the pancreatic and biliary ducts result in malabsorption, maldigestion, diabetes, and occasionally liver disease.
A genetic mutation in the CFTR gene leading to an abnormal protein is the basic molecular defect responsible for CF.
The CFTR gene is located on chromosome 7.
CFTR is a cyclic AMP-regulated chloride ion channel on the apical surface of epithelial cells that primarily plays a role in chloride transport.
In CF, this protein is missing or malfunctioning, leading to abnormal chloride transport.
Abnormal function leads to decreased chloride secretion and increased sodium absorption on the apical surface of epithelial cells. This results in thickened secretions in airways, sinuses, pancreatic ducts, biliary ducts, intestines, sweat ducts, and reproductive tract.6,7
CFTR also plays a role in the regulation of other ion channels that may be important in the pathogenesis of CF.
Many of the specific mechanisms by which the molecular defect of CF leads to clinical disease remain unclear and are the subject of current investigations.
CFTR mutations can be divided into five classes, based on the effect of the mutation on CFTR protein production and function.2
Class I mutations lead to defective protein production. These are often nonsense, frameshift, or splicing mutations leading to complete absence of CFTR protein.
G542X, W1282X, R533X are examples.
Class I accounts for 2–5% of all CF cases.2
Class II mutations lead to defective protein processing. The CFTR protein is produced but is prevented from trafficking properly.
F508del, N1303K are examples.
The most common CFTR mutation is F508del, which is a deletion of three nucleotides which encode phenylalanine (F) at amino acid 508. This mutation is found in over 80% of patients with CF in the United States (46.5% homozygotes and 39.9% heterozygotes).2
Class III mutations lead to defective regulation of the CFTR protein. CFTR is present on the membrane; however, channel activity is diminished. G551D is the most common example.
Class IV mutations lead to defective conduction of the CFTR protein. CFTR is produced, localized, and regulated normally; however, ion conductance and channel opening are reduced. R117H is the most common example.
Class V mutations cause decreased numbers of normally functioning CFTR protein.
Information about specific mutations and reported phenotypes can be found at http://www.cftr2.org. Accessed 27/10/15.
Diagnosis
Clinical Presentation
Pulmonary
Nearly all patients have chronic sinusitis on radiographic studies. Nasal polyposis is common.
Chronic lower airway infections are characteristics of this disease.
Chronic infection causes inflammation, increased mucus secretion and obstruction, and direct destruction of pulmonary parenchyma.
Pulmonary infections with Haemophilus influenzae and Staphylococcus aureus are common early in the disease process.
Later, Pseudomonas aeruginosa becomes the dominant lung pathogen in a majority of CF patients. Progressive inflammation, lung damage, decline in lung function, and progressive dyspnea are most closely correlated with this organism.
Infection with other gram-negative organisms such as Burkholderia cepacia can lead to a fulminant course with a high mortality rate.
Colonization with Aspergillus fumigatus is common but invasive disease from this organism is relatively rare.
Acute exacerbation of CF is a common presentation of pulmonary disease.
The typical exacerbation presents with some combination of symptoms, including increased cough, changing sputum, increased shortness of breath, decreased exercise tolerance, and weight loss. Low-grade fever is common but not universal.
The specific factors causing exacerbations are unclear but viral infections have been implicated in some studies.10
Occasionally, a reduction in pulmonary function on spirometry may be the only abnormality noted.
CXRs are often unchanged during exacerbations but are useful to exclude other pulmonary complications of CF.
Pneumothorax is a relatively common pulmonary complication that presents in CF.
The incidence of pneumothorax rises with increasing age secondary to worsening lung disease. Approximately 3.4% of CF patients will experience pneumothorax (1 in 167 patients per year).11
Patients typically present with chest pain and dyspnea (but may present atypically) because of decreased compliance in the CF lung.
A second pulmonary complication is minor hemoptysis (<240 mL), which is common (9.1% of patients) and often occurs with acute exacerbations of this disease.12
Approximately 4% of CF patients will experience massive, life-threatening hemoptysis (>500 mL/24 hr) during their lifetime (1 in 115 patients per year).13
Hypertrophic bronchial arteries from chronic inflammation are the typical source of bleeding.
Patients presenting with hemoptysis should be treated with antibiotics.
Respiratory failure is the most concerning pulmonary presentation of CF. Unless reversible etiologies are responsible, this complication often indicates end-stage lung disease and carries a poor prognosis for recovery.
Gastrointestinal
Approximately 90% of CF patients exhibit exocrine pancreatic insufficiency.
Patients with pancreatic insufficiency have significantly lower life expectancies than those with pancreatic sufficiency.
Pancreatic sufficiency is more common in patients who present later in life.5
Pancreatic exocrine insufficiency can lead to steatorrhea, chronic malnutrition, edema secondary to hypoalbuminemia, and various vitamin deficiencies.
Fat-soluble vitamins A, D, E, and K are most commonly affected. Vitamin A deficiency can lead to visual deficiencies such as night blindness, and in severe cases xerophthalmia, keratomalacia, and complete blindness. Vitamin D deficiency can lead to poor bone mineralization. Vitamin E deficiency can lead to ataxia and absent deep tendon reflexes.
Gastroesophageal reflux disease is more common in CF patients than healthy control subjects and is possibly linked to worsening lung disease.14
Another presentation of GI disease is the distal intestinal obstruction syndrome (DIOS), which can be considered an adult equivalent of meconium ileus.
Colicky abdominal pain with a palpable mass is a typical presentation.
Radiographic patterns consistent with partial or complete obstruction can be seen on obstructive series.
Caution must be exercised, however, because these signs and symptoms are present in other abdominal conditions that present in CF patients. Empiric treatment of DIOS while evaluation is underway for other conditions is recommended.
Volvulus, intussusception, and rectal prolapse can occur.
Cholelithiasis and cholecystitis are seen.
CF can be associated with an asymptomatic increase in alkaline phosphatase and a mild transaminitis in up to one-third of patients, whereas biliary cirrhosis is much less common.
A small percentage of patients do have significant liver disease with about 3% of deaths in CF patients attributed to liver disease.2
Endocrine and Reproductive
Men are usually infertile secondary to obstructive azoospermia. Patients that are diagnosed at older ages may present with congenital absence of the vas deferens.
Women have reduced fertility because of thick cervical mucus as well as other, less understood factors.
Puberty is often late in onset owing to malnutrition.
Osteoporosis occurs in approximately one-third of adult CF patients.
Diabetes mellitus is common in CF, affecting more than 20% of adults.2
Diabetes in CF is primarily due to deficient insulin production, although insulin resistance may play a role as well.
CF patients may be dependent on insulin for glucose control but diabetic ketoacidosis is rare.
Diagnostic Criteria
The diagnosis of CF is based on clinical presentation coupled with confirmatory testing.
At least one criterion from each set of features is required to diagnose CF15:
Compatible clinical feature of CF (persistent colonization/infection with typical organisms, chronic cough and sputum production, persistent CXR abnormalities, airway obstruction, sinus abnormalities/polyps, clubbing, meconium ileus, DIOS, rectal prolapse, pancreatic insufficiency/pancreatitis, jaundice/biliary cirrhosis, malnutrition, acute salt depletion, chronic metabolic alkalosis, obstructive azoospermia) OR
Positive family history OR
Positive newborn screening test
AND
Elevated sweat chloride >60 mmol/L on two occasions OR
Presence of two disease-causing mutations in CFTR OR
Abnormal nasal transepithelial potential difference test
Differential Diagnosis
Primary ciliary dyskinesia: bronchiectasis, sinusitis, and infertility are common. Gastrointestinal (GI) symptoms are limited and sweat chloride levels are normal. Dextrocardia or situs inversus totalis can be seen.
Shwachman–Diamond syndrome: pancreatic insufficiency, cyclic neutropenia, and short stature are seen. Sweat chloride levels are normal.
Young syndrome: bronchiectasis, sinusitis, and azoospermia. Respiratory symptoms are mild, and there is a lack of GI symptoms. Sweat chloride testing is normal.
Immunoglobulin deficiency leads to recurrent sinus and pulmonary infections and can cause bronchiectasis. GI symptoms are absent and sweat chloride testing is normal.
Idiopathic bronchiectasis.
Chronic rhinosinusitis.
Chronic idiopathic pancreatitis.
Diagnostic Testing
Diagnosis of CF is usually made during childhood. Approximately 10% of patients are diagnosed after age 10.5 In 2013, over 60% of new diagnoses were made from newborn screening, which has increased the frequency of early diagnosis.2
Pilocarpine iontophoresis, or sweat testing, is the most common confirmatory test and is the gold standard for CF diagnosis.15
A quantitative test with a chloride value of >60 mmol/L on two occasions is consistent with CF.
Other conditions produce abnormal sweat tests but can usually be differentiated from CF based on their clinical presentation.
Borderline or nondiagnostic results should prompt repeat or additional testing depending on clinical suspicion.
Transepithelial potential difference can be used as confirmatory testing in the rare instance in which CF is suspected clinically but sweat testing is inconclusive. This testing is only available at specialized centers, and should be repeated on two separate days. Voltage across epithelial lining of the nose is measured at rest, after sodium channel inhibition, and after CFTR stimulation.
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