Cystic fibrosis is a hereditary systemic disease caused by
mutation of cystic fibrosis transmembrane regulator and characterized by exocrine
glands disorders, severe impaired function of the respiratory and gastro-intestinal
tract.
Cystic fibrosis is the most
common cause of chronic lung disease in children and young adults, and the most
common fatal hereditary disorder affecting Caucasians in the US.
Etiology and Pathogenesis
The disease is the result of gene
mutation. Pathological gene is localized in the middle of the long arm of
chromosome 7. Cystic fibrosis is inherited in an autosomal-recessive type and
is registered in most European countries with a frequency of 1:2000 - 1:2500
newborns. If both parents are heterozygous carriers of the mutated gene, the
risk of birth of the child with cystic fibrosis is 25%. According to studies
the frequency of heterozygous carriers of the pathological gene is 2-5%.
This chart can help you determine the genetic
probability of having a
child with cystic fibrosis
|
Parents
|
Chance of Unaffected Child
|
Chance of Child Carrier
|
Chance of Child with CF
|
|
Unaffected + Carrier
|
50%
|
50%
|
No Chance
|
|
Two Carriers
|
25%
|
50%
|
25%
|
|
Unaffected + CF Patient
|
No Chance
|
100%
|
No Chance
|
|
Carrier + CF Patient
|
No Chance
|
50%
|
50%
|
Currently, there are about
1000 identifiable gene mutations in cystic fibrosis. The consequence of gene
mutation is a disturbance of the structure and function of the protein, known
as the cystic fibrosis transmembrane regulator (CFTR). The result is a
thickening of the secrets of exocrine glands, difficulty in evacuation
secretion and changes in its physical and chemical properties, which, in turn,
causes the clinical picture. Changes in the pancreas, respiratory and
gastro-intestinal tract are recorded in the prenatal period and with the
patient's age are steadily increasing.
Isolation of a viscous exocrine
glands secretion leads to difficult output and stagnation with subsequent
expansion of the excretory ducts of glands, atrophy of glandular tissue and the
development of progressive fibrosis. Enzyme activity of the intestine and
pancreas is significantly decreased. Along with the formation of sclerosis in
the organs there is a violation of the functions of fibroblasts. It is
established that fibroblasts of patients with cystic fibrosis produce ciliary
factor, or M-factor, which has anticiliar activity - it disrupts the function
of ciliar epithelium.
Schematic
representation of proposed CFTR structure. CFTR is made up of five domains: two
membrane-spanning domains that form the chloride ion channel, two
nucleotide-binding domains that bind and hydrolyze ATP and a regulatory domain.
Pathological
anatomy.
Pathological changes in the lungs are
characterized by symptoms of chronic bronchitis with the development of
bronchiectasis and diffuse pneumosclerosis. In the bronchial lumen there is the
viscous mucous-purulent content. Often findings are atelectasis and areas of emphysema. In many
patients during the pathological process in the lungs there are complications
by joining the bacterial infection (pathogenic Staphylococcus aureus,
Haemophilus influenzae and Pseudomonas aeruginosa) and the formation of destruction.
In the pancreas there are revealed
diffuse fibrosis, thickening of the interlobular connective tissue, cystic
changes of small and medium-sized ducts. In the liver there are indicated focal
or diffuse fatty and protein dystrophy of liver cells, bile stasis in the
interlobular bile ducts, interlobular lymphohistiocytic infiltrates in
intralobular layers, fibrous transformation and development of cirrhosis.
At meconium ileus there is expressed
atrophy of the mucous layer, mucous glands of the intestinal lumen are enlarged,
filled with eosinophylic secretion masses, sometimes there is edema of
submucosal layer, the expansion of lymphatic slits. Often cystic fibrosis is combined
with various anomalies of gastrointestinal tract.
There are the following clinical forms of
cystic fibrosis:
Ø mostly pulmonary (respiratory,
bronchopulmonary)
Ø mostly enteric form
Ø mixed form with simultaneous involvement of
the gastrointestinal tract and
respiratory system
Ø meconium ileus
Ø atypical and abortive forms (edematous-anemic,
cirrhotic, and others).
Clinical
features in 70% of cases of cystic fibrosis is detected during the first
2 years of life.
The signs and symptoms of CF in children and young
adults may include:
§
Salty taste of the skin. People with CF
tend to have two to five times the normal amount of salt (sodium chloride) in
their sweat. This may be one of the first signs parents notice because they
taste the salt when they kiss their child.
§
Blockage in the bowel.
§
Foul-smelling, greasy stools.
§
Delayed growth.
§
Thick sputum. It's easy for parents to
overlook this symptom because infants and young children tend to swallow their
sputum rather than cough it up.
§
Coughing or wheezing.
§
Frequent chest and sinus infections with
recurring pneumonia or bronchitis.
§
Growths (polyps) in the nasal passages.
§
Cirrhosis of the liver due to inflammation
or obstruction of the bile ducts.
§
Displacement of one part of the intestine
into another part of the intestine (intussusception) in children older than age
4.
§
Protrusion of part of the rectum through
the anus (rectal prolapse). This is often caused by stools that are difficult
to pass or by frequent coughing.
§
Enlargement or rounding (clubbing) of the
fingertips and toes. Although clubbing eventually occurs in most people with
CF, it also occurs in some people born with heart disease and other types of
lung problems.
Meconium ileus
At 30-40% patients cystic
fibrosis is diagnosed in the early days of life in the form of meconium ileus.
This form of the disease is due to a lack of trypsin, which leads to
accumulation in the loops of the small intestine (usually in the ileocecal
region) of dense, viscous meconium.
A healthy newborn first feces
departs at first, less often - the second day after birth. In a sick child
meconium is absent. By the second day of life the child becomes restless,
abdomen is distended, regurgitation and vomiting are marked with an admixture
of bile. After 1-2 days the state of newborn becomes worse: skin is dry and pale,
expressed vascular pattern appears on the abdomen, tissue turgor is reduced,
anxiety is replaced by lethargy and adynamia, signs of intoxication and dehydration
occur.
An objective examination of patients reveals
dyspnea and tachycardia, at the percussion of the abdomen – tympanic sound.
Auscultation: peristalsis is not listening. Review radiograph of the abdominal
cavity reveals swollen loops of the small intestine and sleeping units in the
lower abdomen.
Complication meconium ileus
may be perforation of the intestine with the development of meconium
peritonitis. Frequently, the intestinal obstruction in cystic fibrosis patients
on the 3-4-th day of life is associated with pneumonia, which has a protracted
nature. Intestinal obstruction may also develop later.
A. Illustration of intestine blocked by meconium. B. Abdominal xray of a
newborn infant with meconium ileus showing dilated loops of bowel.
Pulmonary (respiratory) form
The first symptoms of
broncho-pulmonary forms of cystic fibrosis are fatigue, paleness of the skin,
lack of weight gain with satisfactory appetite. In some cases (severe course)
from the first days of life the patients have hacking cough, which gradually
increases and becomes like pertussis. The cough is accompanied by excretion of
the thick phlegm, which with presence of the bacterial flora is subsequently mucopurulent.
The increased viscosity of bronchial
secretion leads to the development mucostasis and occlusions of small bronchi
and bronchioles, which contribute to the development of emphysema, while the
total occlusion of the bronchi - the formation of atelectases. In very young
children lung parenchyma becomes quickly involved in the pathological process,
which leads to the development of severe, prolonged pneumonia with a tendency
to abscess formation. Lung affection is always bilateral.
An objective examination
indicated moist small-and medium bubbling rale, bandbox percussion sound.
Patients may have toxemia, and even clinical shock on the background of
diseases that occur with a high body temperature, or in the hot season in a
significant loss of sodium and chloride through sweat. Later chronic pneumonia
occurs with pneumosclerosis and bronchiectasis, symptoms of "cor
pulmonale", respiratory and cardiac failure.
At long course of disease there is
involving in the pathological process nasopharynx: sinusitis, adenoidal
vegetation, nasal polyps, chronic tonsillitis. Radiological examination of the lungs at cystic
fibrosis reveals widespread peribronchial, infiltrative, sclerotic changes and
atelectasis on the background of marked emphysema. At bronchography there is the presence of
drop-shaped bronchiectasis, bronchial abnormalities and a decrease in the
number of small branches, the bronchi 3-6-th calibre are in the form of beads. At bronchoscopy there is
often found a small amount of thick viscous sputum, which resides in the form
of threads in the lumens of the major bronchi.
Microbiological examination of sputum in cystic
fibrosis patients can identify Staphylococcus aureus, Haemophilus influenzae
and Pseudomonas aeruginosa. The presence of Pseudomonas aeruginosa in sputum is
a poor prognostic sign for the patient.
There is specific appearance
of the patient: pale-gray skin, acrocyanosis, general cyanosis, shortness of
breath at rest, barrel chest, sternum deformation of type "wedge" and
deformation of terminal phalanges of the type "drumsticks ",limitation
of motor activity, decreased appetite and weight loss.
Symptom of "drumsticks
" and "watch glasses" at cystic fibrosis.
CT gram
Ultrasound of the chest.
Bronchiectasis in a vacuum section of lung at cystic fibrosis.
Frontal chest X ray in CF shows diffuse interstitial disease with
bronchiectasis and nodular densities of mucoid impaction.CF = cystic fibrosis.
At bronchography of
the left lung in left lateral projections shows the decrease of the lower lobe
of the left lung, convergence and expressed deformation of the bronchial tree,
cylindrical bronchiectasis, lack of filling in small bronchial branches.
The rare complications of cystic fibrosis are
pneumo- and pyopneumothorax, pulmonary hemorrhage. In a more favorable course
of cystic fibrosis, at which onset of the disease is observed at older age,
bronchopulmonary pathology manifests slowly with progressive deforming
bronchitis with moderate pneumosclerosis.
Intestinal form
Clinical symptoms of the intestinal form are
caused by secretory insufficiency of the gastrointestinal tract. Violation of
the enzymatic activity of the gastrointestinal tract is particularly pronounced
after the transfer of the child to bottle-feeding or complementary feeding and
manifest lack of splitting and absorption of proteins, fats and carbohydrates. Putrefactive
processes is dominated in intestine, accompanied by the accumulation of gases,
which leads to bloating. Frequent bowel movements, polifecalia (daily amount of
feces 2-8 times exceed the age limit). In elder patiens with cystic fibrosis there
is often marked prolapse of the rectum (in 10-20% of patients).
Patients complain of dry mouth, due to the high
viscosity of saliva. Patients with difficulty chew dry food, and during meals drink
a significant amount of fluid. Appetite in the first months is normal or even
increased, but due to the violation of the digestive processes in patients hypotrophy
and polyhypovitaminosis rapidly occur.
Muscle tone and tissue turgor are reduced.
Patients complain of abdominal pain of various
kinds: cramping - with meteorism, muscle - after coughing, pain in right
hypochondrium - the presence of right heart failure, pain in epigastric region
due to the lack of neutralization of gastric juice into the duodenum at a
reduced secretion of pancreatic bicarbonates.
Violation of neutralization of gastric juice may cause the
development of duodenal ulcer or ulcerative process in the small intestine.
Intestinal complications of the cystic fibrosis may be secondary disaccharidase
failure, intestinal obstruction, secondary pyelonephritis and urolithiasis on
the background of metabolic disorders, latent diabetes in lesions of insular
apparatus of the pancreas. Violation of protein metabolism leads to
hypoproteinemia, which becomes the cause of development in some cases, infants
edema.
Hepatomegaly (liver enlargement) occurs due
to cholestasis. When clinical picture of biliary cirrhosis is present there may
be observed jaundice, itching, signs of portal hypertension, ascites. Cirrhosis
of the liver in some patients may develop without cholestasis.
Mixed
form
Mixed form of cystic fibrosis is the most severe and includes clinical
symptoms of pulmonary and intestinal forms. Usually the first week of life the
patient has severe recurrent bronchitis and pneumonia with protracted,
persistent cough, bowel syndrome, eating disorders and expressed dyspeptic
syndrome. Clinical features of cystic fibrosis differ by considerable
polymorphism, which determines the clinical variants of the disease. Severity of
cystic fibrosis depends on the onset of the first symptoms. For the younger
child the disease manifestation are severer and prognosis is more unfavorable. Taking into
account the polymorphism of clinical manifestations of cystic fibrosis severity
is determined in most cases by the nature and extent of lesions of the broncho-pulmonary
system.
There are 4 stages of pathological changes in the
bronchopulmonary system in cystic fibrosis:
• 1-stage - the
stage of non-permanent functional changes, which is characterized by a dry
cough without sputum, low or moderate dyspnea during physical exertion.
Duration of this stage may be up to 10 years.
• 2-stage - stage
of development of chronic bronchitis, which is characterized by the presence of
cough with phlegm excreation, moderate dyspnea (increases with tense), the formation
of the deformation of the terminal phalanges. Auscultation reveals moist,
"booming" rales on the hard breathing. The duration of this stage may
range from 2 to 15 years.
• 3-stage - stage
of the progression of bronchopulmonary process with the development of
complications. There are forming a zone of diffuse pulmonary fibrosis and focal
pneumosclerosis, bronchiectasis, cysts and severe respiratory failure in
combination with RV heart failure (cor pulmonale). The duration of the stage is
from 3 to 5 years.
• 4-stage is
characterized by severe cardio-respiratory insufficiency, which in the months is
leading to the death of the patient.
Diagnosis
The diagnosis
of cystic fibrosis is determined by the data of clinical and laboratory
examination of a patient.
For the diagnosis of
the disease four basic criteria are necessary:
chronic bronchopulmonary process bowel syndrome cases of cystic fibrosis in sibs positive results of sweat test.
Sweat for the study is collected after
electrophoresis with pilocarpine. The minimum amount of sweat required to
obtain reliable results, is 100 mg. The difference between the sodium and
chlorine in the sample should not exceed 20 mmol / l, otherwise the study is
repeated. At an acceptable methodology the determination of one of the ions is
possible. In healthy children the concentration of sodium and chloride in the
sweat can not exceed 40 mg / dl. Diagnostic criteria for cystic fibrosis is a
reliable content of chloride ions more than 60 mmol / l and sodium – more than 70 mmol / liter. To
confirm the diagnosis there is required three positive sweat test s with
chloride more than 60 mmol / liter.
Important in the diagnosis of cystic
fsbrosis has coprological
study. In patients with cystic
fibrosis in coprogram the most characteristic feature is the high content of
neutral fat, but perhaps the presence of muscle fibers, cellulose and starch
grains, which allows determine the degree of impairment of the enzymatic
activity of the gastrointestinal glands. Under the supervision of data coprological
research the dose of pancreatic enzymes is correcting.
Approximate methods for the diagnosis of cystic fibrosis
are the identification of the proteolytic activity of feces by X-ray test,
enzyme activity of the pancreas in the duodenal contents, the concentration of
sodium in nails and salivary gland secretion. As a screening test in the
neonatal period the method of determining the high content of albumin in
meconium - meconium test is used (normal albumin content does not exceed 20 mg
per 1g of dry weight).
A special place in the
diagnosis is molecular
genetic testing. Today, the presence of known mutations is available
identifying in 65-75% of patients with cystic fibrosis, which makes it
impossible to use for verification of the diagnosis of the disease only by molecular-genetic
examination.
Differential diagnosis
The differential diagnosis of
cystic fibrosis is conducted with whooping cough, obstructive bronchitis,
bronchial asthma, congenital and acquired bronchiectasis, pulmonary fibrosis nonpancreatic
origin. In the presence of a high rate of electrolytes in sweat cystic fibrosis
is differentiated with such diseases as diabetes insipidus, adrenal
insufficiency, hereditary ectodermal dysplasia, glycogenic disease, lack of
glucose-1-phosphatase, hypoparathyreoidism, malnutrition, gargoilism, fucozidosis,
dehydration, edema.
Treatment
Treatment of cystic fibrosis is symptomatic.
Feeding is very
important to the patient. Daily calories must be 10-30% higher than the age
limit due to an increase in dietary protein component. Protein requirements are
satisfied by the consumption of meat, fish, eggs, cottage cheese. Fat intake is
significantly reduced. It is possible to use the fat, composed of fatty acids
with an average size of the chain, because their digestion does not dependent
on the activity of pancreatic lipase.
At deficiency of
disaccharidases in the small intestine the corresponding sugar (usually
lactose) must be excluded from the diet. It is necessary to add salt to food,
especially in the hot season and at high temperature, because of the large
losses of salt through sweat.
A sufficient intake of
fluids is provided to the patient. In the food should be included products
containing vitamins, fruit and vegetable juices, butter.
It is obligatory to carry out correction of pancreatic
function through the use of pancreatin or combined preparations
containing pancreatin, along with other intestinal enzymes and lipotropics (Creon,
Polizim, panzinorm, meksaza, etc.). The dose of enzyme preparations is picked
individually, focusing on data of coprological study.
Indicators of the optimal
selection of a dose are normalization of stool and the disappearance of neutral
fat in feces. The initial dose is 2-3grams a day. Dose is gradually raised
until a positive effect. To liquefy the secrets of the gastrointestinal tract
and improve their excreation the acetylcysteine is used in tablets and
granules, which is indicated at cholestasis, viscous duodenal contents, impossibility
of probe.
Treatment of pulmonary syndrome includes a complex
of measures aimed at thinning of the sputum and removing it from the bronchi.
For this purpose physical, chemical and instrumental methods are applied.
Mucus-thinning therapy is carried out daily
throughout the patient's life. The effectiveness of treatment increases with
the simultaneous use of aerosol inhalation, exercise therapy, vibratory massage
and postural drainage. The number and duration of inhaled medicines depend on
the severity of the patient. As a mucus-thinning drugs may be used saline-alkaline
mixture (1-2% solution– saline chloride and sodium carbonate), bronchodilators
drugs acetylcysteine (one inhalation of 2-3 ml of 7-10% solution), pulmozim
(dornaza alpha). Postural drainage is carried out every morning, vibrating
massage - at least 3 times a day.
Therapeutic bronchoscopy with bronchial lavage with acetylcysteine
and isotonic sodium chloride solution is indicated as emergency procedure in
the absence of the effect of the previous therapy. During periods of
exacerbation, in the presence of acute pneumonia or acute respiratory viral
infection there are indications for the
using of antibacterial therapy.
Antibacterial drugs are injected parenterally
(semi-synthetic penicillins, cephalosporins of second and third generation,
aminoglycosides, Chinolones) and in the form of aerosols (aminoglycosides:
gentamicin, tobramicin). As the pneumonia at cystic fibrosis has a prolonged
duration, a course of antibiotics is not less than one month and sometimes
more.
In severe pneumonia, corticosteroids are used
for 1,5-2 months. Prednisolone is prescribed in dose of 1,0-1,5 mg / kg / day
for 10 - 15 days. Then the dose is gradually reduced.
Antibiotics are used during the
course of corticosteroid therapy. In addition to antibacterial and mucus-thinning therapy there are
carried out a full range of therapeutic measures aimed to liquidate hypoxia,
cardiovascular disorders, acid-base changes.
The organization of dispensary observation of
patients with cystic fibrosis in an outpatient setting it is necessary to
monitor a feces and a patient's body weight, regular (1 every 3 months) to
conduct coprological study for correction of doses of the pancreatic enzymes, in the spring
and during exacerbation of the process to assign courses of vitamins (it is justified
the appointment of double dose of fat-soluble vitamins A, E, D in water
solutions).
Relatives of the patient should
be taught techniques of postural drainage, vibration massage and care for the
patient. Along with exercise therapy, physical therapy recommends dosing
exercise and sports. At sustained remission for 6 months there is allowed
preventive vaccinations.
The prognosis for cystic fibrosis
remains serious. Mortality is 50-60% among young children. Late diagnosis of
disease and inadequate therapy significantly worsen the prognosis. Currently
there is available the diagnostic of the disease in early pregnancy, and
therefore becomes important medico-genetic counseling of families in which
there are patients with cystic fibrosis.
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