Tuesday, April 2, 2013

Hereditary Polyorganic Diseases Mainly Affecting The Respiratory System

Cystic fibrosis  
             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
Chance of Unaffected Child
Chance of Child Carrier
Chance of Child with CF
Unaffected + Carrier 


   No Chance
Two Carriers
Unaffected + CF Patient

   No Chance

      No Chance
Carrier + CF Patient

      No Chance



                     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.

                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 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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