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Cystic Fibrosis
Definition
Characterized by obstruction and infection of airways and by maldigestion and its consequences, cystic fibrosis (CF) is an
inherited multisystem disorder of children and adults; it is the most common life-limiting recessive genetic trait among white
persons. Dysfunction of the cystic fibrosis transmembrane conductance regulator protein (CFTR), the primary defect, leads to a
wide and variable array of presenting manifestations and complications.
CF is responsible for most cases of exocrine pancreatic insufficiency in early life and is the major cause of severe chronic lung
disease in children. It is also responsible for many cases of salt depletion, nasal polyposis, pansinusitis, rectal prolapse,
pancreatitis, cholelithiasis, and insulin-dependent hyperglycemia. CF may manifest as failure to thrive and, occasionally, as
cirrhosis or other forms of hepatic dysfunction. Therefore, this disorder enters into the differential diagnosis of many pediatric
conditions
.
Genetics
CF occurs in approximately 1/3,500 white live births and 1/17,000 black infants in US. Generally it is most prevalent among
Northern and Central Europeans and individuals who come from these areas.
It is inherited as an autosomal recessive trait and the mutated gene located on the long arm of chromosome 7.The CF gene codes
for a protein called CF transmembrane regulator(CFTR) which expressed largely in epithelial cells of airways, gastrointestinal
tract (including pancreas and biliary system), sweat glands, and genetourinary system and has ion channel and regulatory
function. The most prevalent mutation of CFTR is the deletion of a single phenylalanine residue at amino acid 508 (ΔF508).
Approximately 50% of individuals with CF who are of northern European ancestry are homozygous for ΔF508, and >80% carry
at least one ΔF508 gene. A few mutations(R117H) may substantially or even fully spare the lungs. Male gender and exocrine
pancreatic sufficiency are also associated with a slower rate of pulmonary function decline.
CF gene has been hypothetically ascribed to resistance to the morbidity and mortality associated with cholera. cultured CF
intestinal epithelial cells are unresponsive to the secretory effects of cholera toxin.
Pathogenesis
Four long-standing observations are of fundamental pathophysiologic importance:
Failure to clear mucous secretions.
Paucity of water in mucous secretions.
Elevated salt content of sweat and other serous secretions.
Chronic infection limited to the respiratory tract.
The membranes of CF epithelial cells are unable to secrete chloride ions in response to AMP-mediated signals and that, at least
in the respiratory tract, excessive amounts of sodium are absorbed through these membranes. These defects can be traced to a
dysfunction of CFTR, and clinical features correlate with the residual CFTR activity, so genotypes causing :
99% loss of CFTR activity cause lung disease and pancreatic insufficiency.
95% loss of CFTR activity retained pancreatic function.
90% loss of CFRT activity results in congenital bilateral absence of the vas deferens or idiopathic chronic pancreatitis.
Chronic infection in CF is limited to the endobronchial space of the airways. The most likely explanation for infection is a
sequence of events starting with failure to clear inhaled bacteria promptly and then proceeding to persistent colonization and an
inflammatory response in airway walls. Fatty acid deficiency have been implicated as predisposing factor for RTI, however
preservation of pancreatic function does not preclude development of typical lung disease. There is high prevalence of airway
colonization with Staph. aureus, Pseudomonas aeruginosa, and Burkholderia cepacia, organisms that are rarely infect the lung of
other individuals.
The immune system in CF appears to be fundamentally intact.
Pathology
Striking changes are observed in the organs that secrete mucus (respiratory system, GIT, GUT). Sweat and salivary glands
are not involved pathologically despite abnormalities in the electrolyte content of their secretory product. Generalized
amyloidosis has been reported rarely. The earliest pathologic lesion in the lung is that of bronchiolitis (mucous plugging and an
inflammatory response in the walls of the small airways); with time, mucus accumulation and inflammation extend to the larger
airways (bronchitis) . Goblet cell hyperplasia and submucosal gland hypertrophy become prominent pathologic findings, which
is most likely a response to chronic airway infection. Organisms appear to be confined to the endobronchial space; invasive
bacterial infection is not characteristic. With long-standing disease, evidence of airway destruction such as bronchiolar
obliteration, bronchiolectasis, and bronchiectasis
Clinical manifestations
Mutational heterogeneity and environmental factors appear responsible for highly variable involvement of the lung, pancreas,
and other organs.
*Respiratory system:
Cough is the most constant symptom of pulmonary involvement. At first, the cough may be dry, but eventually it becomes
productive. The cough is most prominent on arising on the morning or after activity.
Repeated pneumonia.
Extensive bronchiolitis is attended by wheezing.
As lung disease progresses, exercise intolerance, SOB, and failure to gain weight are noted.
Cor pulmonale.
Respiratory failure.
Atelectasis.
Hemoptysis.
Pneumothorax.
Bronchiectasis.
Nasal obstruction and rhinorrhea are common due to either inflamed mucous membrane or nasal polyp.
Although radiographically the paranasal sinuses are virtually always opacified, acute sinusitis is infrequent.
Mucoid impaction of the bronchi
Allergic bronchopulmonary aspergillosis
*GIT:
CF, the ileum is completely obstructed by meconium (meconium ileus).
In 15-20% of newborn infants with
Meconium peritonitis which results from intrauterine rupture of the bowel wall and detected radiographically by the presence of
peritoneal or scrotal calcifications.
Meconium plug syndrome which is less specific than Meconium ileus for this condition.
Meconium ileus equivalent which occurs in older patients due to ileal obstruction with fecal material, causing cramping
abdominal pain and abdominal distention.
Exocrine pancreatic insufficiency affected 85% of children and manifested as steatorrhea and failure to thrive even when food
intake appears to be large. Excessive flatus may be a problem.
Less common GI manifestations include intussusceptions, fecal impaction of the caecum, epigastric pain due to duodenal
inflammation, reflux eosophagitis, subacute appendicitis and periappendicular abscess, rectal prolapsed, and hypoproteinemia
with anasarca.
Fat-soluble vitamin deficiencies manifested as neurologic dysfunction (dementia and peripheral neuropathy) and hemolytic
anemia (vit E deficiency), bleeding diathesis (vit K deficiency), decreased bone density (vit D deficiency), and night blindness
(vit A deficiency).Rickets is rare.
*Biliary tract:
Biliary cirrhosis.
Neonatal hepatitis-like picture.
Cholelithiasis.
*Pancreas:
Exocrine pancreatic insufficiency (as mentioned above).
Diabetes mellitus evident after 10 years of age and affected 8% of individuals.
Recurrent, acute pancreatitis.
*GUT:
Sexual development is often delayed by an average of 2 years.
More than 95% of males are azoospermic, but sexual function is generally unimpaired.
Adolescent females may have secondary amenorrhea and the female fertility rate is diminished. Pregnancy is tolerated well by
women with good pulmonary function.
*Sweat gland:
Excessive loss of salt in sweat predisposes young children to salt depletion episodes, especially during the time of gastroenteritis
and during warm weather and present with hypochloremic alkalosis. parents notice salt frosting of the skin or salty taste when
they kiss the child. A few genotypes are associated with normal sweat chloride values.
Diagnosis
Diagnostic criteria for CF include:
Presence of typical clinical features( respiratory, gastrointentestinal, or genitourinary)
OR
A history of CF in a sibling
OR
A positive newborn screening test
PLUS
Laboratory evidence for CFTR dysfunction:
Two elevated chloride concentration obtained on separate days
OR
Identification of two CF mutations
OR
An abnormal nasal potential difference measurement
*Sweat test: At least 50 mg and preferably 100 mg of sweat should be collected. Reliable testing may be difficult in the first few
weeks of life because of low sweat rate. Positive results should be documented; a negative result should be repeated if suspicion
of the diagnosis remains.
Sweat test considered positive if sweat chloride level > 60 mEq/L, value between 40 and 60 mEq/L is suggestive, and value <
40 mEq/L is negative.
condition associated with false negative results

1. Dilution
2. Malnutrition
3. Edema
4. Insufficient sweat quantity
5. Hyponatremia
6. Cystic fibrosis transmembrane conductance regulator (CFTR) mutations with preserved sweat duct function
Conditions associated with false positive results
Eczema (atopic dermatitis)
Ectodermal dysplasia
Malnutrition/failure to thrive/deprivation
Anorexia nervosa
Congenital adrenal hyperplasia
Adrenal insufficiency
Glucose-6-phosphatase deficiency
Mauriac syndrome
Fucosidosis
Familial hypoparathyroidism
Hypothyroidism
Nephrogenic diabetes insipidus
Pseudohypoaldosteronism
Klinefelter syndrome
Familial cholestasis syndrome
Autonomic dysfunction
Prostaglandin E infusions
Munchausen syndrome by proxy
Newborn screening
Most algorithms utilize a combination of immunoreactive trypsinogen results and limited DNA testing on blood spots,
•
which are then coupled with confirmatory sweat analysis. This screening test is ≈95% sensitive.
DNA testing
•
Several commercial laboratories test for 30-96 of the most common CFTR mutations. This testing identifies ≥90% of
•
individuals who carry 2 CF mutations. Some children with typical CF manifestations are found to have 1 or no
detectable mutations by this methodology. Some laboratories perform comprehensive mutation analysis screening for
all of the >1,500 identified mutations.
Other
Diagnostic Tests
Pancreatic Function
Radiology
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Pulmonary Function
Microbiologic Studies
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Treatment
General approach to care.
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Pulmonary therapy.
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Nutritional therapy.
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Treatment of intestinal complication.
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General approach:
Education of patient and parents.
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Follow-up evaluations every 2-3 months, and in each visit the following should be obtained: an interval history and
physical examination and sputum or lower pharyngeal swab for culture and antibiotic susceptibility even in
asymptomatic patients because irreversible loss of pulmonary function can occur gradually .
Vaccination against measles, pertussis, and influenza.
•
Attention in early childhood to oral hydration, especially during warm weather or with acute GI, and early initiation
of IV therapy for dehydration.
Monitoring for complications of therapy.
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Pulmonary therapy:
•
•
The object is to clear secretions from airways and to control infection. It includes:
Inhalation therapy: 0.45- 0.9% normal saline, B-agonists, cromolyn sodium, steroids.
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Antibiotic therapy: indicated when there is respiratory tract symptoms and pathogenic organisms in the respiratory
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tract cultures. The usual course is 2 weeks or more and maximum doses are recommended.
Anti-inflammatory agents: Steroids used for severe reactive airway disease, ibuprofen used chronically for patients >4
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years with mild lung disease to slow disease progression.
Endoscopy and lavage if there is airways obstruction.
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Expectorant: not effective.
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Treatment of pulmonary complications.
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Nutritional therapy
Diet: In the past low-fat, high-protein, high-calorie was recommended, but with the advent of improved
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pancreatic enzyme products, normal amounts of fat are tolerated and preferred to avoid essential FA deficiency.
Pancreatic enzyme replacement: Should not exceed 2500 lipase units/kg/meal to avoid colonic constriction.
•
Vit. and mineral replacement: including fat-soluble Vit., zinc, and iron.
•
Prognosis
Median life span is 32 years. Male survival is better than female for unknown reasons. Poor socioeconomic state
associated with poorer prognosis. Children with CF have good school attendance.