**Cystic Fibrosis** Notes :

Transcription

1 **Cystic Fibrosis** Notes : - the slides are included in the lecture. - everything in Italic is just important things from the old lecture. - It s easy lecture, even it seems long.. GOOD LUCK Cystic fibrosis is the most common lethal genetic disease and it has autosomal recessive inheritance. Which means that we need 2 mutations to give us the full picture of the disease. One mutation predispose the person to have kids that are carriers but not affected with the disease. Mutations occur in cystic fibrosis transmembrane conductance regulator (CFTR) protein which functions as a chloride channel. Unfortunately, we don t have registry for cystic fibrosis patients in Jordan and the middle east so we don t have an exact life span for patients. But Median Predicted age of survival is 38 according to the US annual report in About 1500 mutations were identified in CFTR gene. but not all of them cause the disease, they may have different manifestations. The most common mutation that cause CF is delta f508, it accounts about 2/3 of mutations in Northern European and North American Population. * f508: - : deletion. - F : phenylalanine : the position of the deleted PA in the sequence of amino acids of CFTR. This map show the incidence of cystic fibrosis all over the world, is common in the white population (Caucasian) and least common in the African American. Also, the incidence is not known in our areas but it s less common. We are considered according to them Others, neither white nor black. 1

2 CFTR Protein (Chloride Channel ) The doctor showed a video about types of mutations in CFTR gene, but it s not present in the slide that she gave us. (Search it on youtube if you like ). You expect from having different mutations, that severity of the disease is different. The delta F508 mutation belongs to the trafficking mutation where the protein is synthesized but is not targeted to the surface of the cell membrane. The chloride channels are present in the epithelial cells mainly in the respiratory epithelium, GI tract, sweat glands and reproductive tract. ** Function Of CFTR protein. Look at this diagram, you can see that normal CFTR protein in the respiratory epithelium functions as Cl - channels ( Cl - excretion) and cause inhibition of Na absorption through the epithelial Na channels. Water will follow the electrolyte direction to the outside to keep the airway surface layer ASL well hydrated. 2

3 When mutation occurs, dysfunctional CFTR lead to 1 loss of Cl excretion, 2 Na and water absorption resulting in dehydration and retraction of ASL layer. Cilia need a good media to beat, so decrease in the water volume result in reduction in lubricating layer between epithelium and mucus layer (which become thick ) with compression of the cilia by mucus causing inhibition of normal ciliary and cough clearance of mucus. Diagnostic Criteria for CF We diagnose it according to CF Foundation Consensus Panel. We need either 1 one of the clinical manifestation of CF (Respiratory,GI or salt loss syndromes ) or 2 positive family history of CF or 3 +ve newborn screening PLUS we need a biochemical test to confirm the Dx which are 1 abnormal seat chloride test or 2 detection of genetic mutation or 3 abnormal Nasal Potential Difference (NPD is used for research purposes which measure the ve charge of nasal mucosa ). 3

4 Sweat chloride test The sweat test is the Gold Standard for testing for CF and it s painless, inexpensive and gives definite answers. The function of chloride channels in sweat glands is the absorption of chloride ions (opposite to that of respiratory epithelium) because we need to reserve the fluid and prevent dehydration. Once mutated, the chloride will be excreted and that will give the salty taste of skin in patients with CF. ** How the Sweat chloride test is done?? As you see in the figure, they hold the arm of the baby then, they apply pilocarpine iontophoresis that will stimulate sweating by cholinergic stimulation. Above the medication, they apply an electrode that help in the penetration of medication into the skin. Then they put a gauze of filter paper over the forearm to absorb the sweat and finally they take the gauze to test the sweat for chloride concentration. Sweat chloride concentration: - Normal: < 40 mmol/l 4

5 - Positive for CF : > 60mmol/L - Intermediate: mmol/l ( gray area that need further investigations). **We should repeat the test twice even it was +ve to diagnose CF. False Positive Sweat Test It occurs when the chloride test is positive but the patient is not having CF, it occurs in some endocrine abnormalities and others, which are : Adrenal insufficiency or stress Anorexia nervosa Ectodermal dysplasia Eczema Fucosidosis G6PD deficiency Glycogen storage disease type1 HIV infection Hypoparathyroidism Hypothyroidism Malnutrition Nephrogenic diabetes insipidus Psuedohypoaldosteronisim **Definitions of the some terms from wikipedia with modifications: (you can skip them if you want) Pseudohypoaldosteronism (PHA) is a condition that mimics hypoaldosteronism. However, the condition is due to a failure of response to aldosterone, and levels of aldosterone are actually elevated, due to a lack of feedback inhibition. 5

6 Ectodermal dysplasias are described as "heritable conditions in which there are abnormalities of two or more ectodermal structures such as the hair, teeth, nails, sweat glands, cranial-facial structure, digits and other parts of the body." Glycogen storage disease (GSDs) is the result of defects in the processing of glycogen synthesis or breakdown within muscles, liver, and other cell types. Type I is the most common one (called von Gierke's disease). Lysosomal storage diseases (LSDs) are a group of approximately 50 rare inherited metabolic disorders that result from defects in lysosomal function. Mucopolysaccharidosis and fucosidosis belong to this group. I remember a case in my training, a kid that is presented with poor growth, he didn t have any respiratory problems and have normal lung function, he was 10 yr-old and have a hx of sinusitis, we did the sweat test it was 90 but the picture didn t go with CF, after investigations he is found to have adrenal insufficiency ( he had pigmentation on his skin also) and treated with cortisone and the sweat test becomes 30. Occurs when the patients has : Dilution of sample Malnutrition False Negative Sweat Test Peripheral edema due to hypoalbuminemia. Hypoproteinemia Dehydration ** These FALSE positives and negatives are good for MCQs. Memorize them. 6

7 Newborn Screening It s of high importance but unfortunately it s not done in Jordan. It s done in the USA and Europe. It s important to screen for CF because we want to initiate the treatment as early as possible. If the newborn get the appropriate treatment, nutrition and respiratory care, this will prevent the deterioration in the lung function and improve the life span. **How do they Screen For CF in newborns?? First, they take a blood sample and measure the Immunoreactive trypsinogen level (one of the pancreatic enzymes ) which will be elevated in CF because of the pancreatic injury. If it s elevated, sweat test is needed to confirm the diagnosis. But the screening could miss pancreatic sufficient patients. (10-15% ) Pancreatic insufficiency occur in 85-90% of patients with CF. Clinical Manifestations of Cystic Fibrosis 7

8 As you see in the figure there are different manifestations of CF involving different systems of the body. We will start one by one. Pulmonary involvement In CF Majority of morbidity and mortality is related to lung diseases. Respiratory failure accounts about 80% of deaths of CF. As we said, the cilia are not beating in an appropriate environment because the mucous is very thick (because of Airway surface liquid (ASL) depletion) so the cilia are not able to clear the bacteria when needed. Also, this thick mucous is a very good media for bacteria to grow. As bacteria colonize the lungs, they produce cytokines ( inflammatory mediators like IL-8) that cause inflammation. During the inflammatory process ASL becomes infiltrated with neutrophils that respond to IL-8 secretion. Neutrophils will 1 release elastase and hazardous enzymes that are harmful to the lungs. Also, as 2 they die they release their DNA (which is sticky ) which contribute to the viscosity of the mucus ( so using aerosolized Dnase (Dornase alpha ) will thin the mucus and improve the lung function ). So, One this vicious circle starts, it will never end unless you interfere with your treatment and medications. And lastly, we will end with end stage lung disease. At this stage, lung transplantation is the only option to prevent ultimate death. but the 5 years survival in lung transplantation patient is also not high <50%. 8

9 This diagram shows the microorganisms that colonize the airways according to age. First, the lungs of children are normal at birth, then they start to become infected and inflamed. Typically infants become rapidly colonized by Hemophilus influenza or Staph.aureus bacteria. After a while, P.aeruginosa becomes the predominant organism in the airways, It colonizes the airways for several reasons: - Permissive microenvironments within the hypoxic niches of adherent plaques. - Increased binding to the epithelium. - Decreased bacterial clearance via innate immune mechanism. ** This is a list of pathogens that colonize the lungs : Staphylococcus aureus : we have also the Methicillin-Resistant S aureus (MRSA) which colonizes 15-20% of CF patients and is associated with poorer lung function Haemophilus influenza Pseudomonas aeruginosa : by time it will be transformed from the nonmucoid to the mucoid form by acquiring a biofilm. and that s why it s very very resistant to medication ( it s very difficult to eradicate the mucoid P.aeruginosa and is associated with increased inflammatory burden and sputum volume). Non mucoid strain can be eradicated with aggressive antibiotic regimen. Burkholderia cepacia : they are very nasty bugs, once you see it, you don t expect a good outcome. It almost impossible to eradicate it because they are resistant to antibiotics and very virulent, and cause rapid decline in lung function and increased mortality. 9

10 Stenotrophomonas maltophilia : is commonly found in CF patients sputum but the literature didn t show that it s associated with poor lung function or decrease survival. Nontuberculois mycobacteria : they can cause lung injury, bronchiectasis and they are very difficult to treat. You should use 2-3 medications for almost a year. Pulmonary manifestations - Cough is the most constant symptom because they relay on cough to clear their airways. - Wheezing and tachypnea. - Increased upper airway secretions, they would have persistent congestion and rhinorrhea. (all CF patients). - Sinusitis. - Nasal polyposis which will lead to nasal obstruction (Surgical resection is needed ). And they are recurrent even with surgical repair. ** always when you find it, screen for CF. - Recurrent Chest infections. - Hemoptysis ( because of the inflammatory process and invasion of blood vessels ), atelectasis, pneumothorax and cor pulmolnale (late signs and symptoms). - Persistent airway infections and inflammation cause bronchiectasis which is irreversible destruction and dilatation of the airways. **Cor pulmonale: "enlargement of the right ventricle of the heart as a response to increased resistance or high blood pressure in the lungs." Wikipedia ** Respiratory symptoms can be misdiagnosed as asthma or recurrent LRTI and the diagnosis can be delayed. 10

11 Nasal Polyp (surgical resection) Bronchiectasis Look at these rings, in the CT of a patient with bronchiectasis which represent the dilated airways. The white points in the both figures represent the vessels. So the airways beside the vessels appears as rings ( signet sign). Bronchiectasis in CF patients mainly involves the upper lobes and then it could extend to other lobes. 11

12 Gastrointestinal Manifestations Thick secretions are everywhere and GIT has it s secretion so every organ in the GI system will be involved. The manifestations are : Meconium ileus (15% of CF newborns) : Means Delay of the passage of meconium >48 hours after birth because of the thick intestinal secretions, the baby will have thick meconium and the delay occurs. Protracted jaundice : Means prolonged neonatal jaundice because the bile will be thick in the liver, so they develop obstructive Jaundice. Cholestasis then will develop and prolonged cholestasis will lead to biliary cirrhosis. 5% of patients will get liver cirrhosis after the age of 15years. Intestinal atresia Pancreatic insufficiency : the pancreas secrete the enzymes that are needed for digestion and absorption. In CF patient the exocrine function of the pancreas will be affected and cystic changes occur and by time, fibrosis will happen. Once exocrine part is fibrosed, the endocrine functions will be also affected and they will develop diabetes after 10 years of age. ( Mixed type 1 & 2 diabetes as they also have resistance to insulin with deficiency of insulin ). You should think of it after the age of 10 years, because it won t manifest as the typical picture of polydipsia, polyuria and polyphagia but will present with poor weight gain and delayed puberty) % of CF develop pancreatic insufficiency, which will be present at birth or evolve over the first year of life Pancreatitis CF-related DM Rectal prolapsed :because of the chronic diarrhea. It could happen in any patient with Chr.Diarrhea. Happen in 1/5 of Patients with CF. 12

13 Chronic diarrhea : because we don t have the enzymes needed for the digestion of food. So we will have High fatty and osmotic content that drain water and cause the diarrhea. Constipation : because of the thick secretions. Distal intestinal obstruction syndrome (DIOS): because of the thick secretions we will have constipation and obstruction. It s meconium ileus equivalent : inspissated material in ileum, cecum, proximal colon. It would present with picture of intestinal obstruction: abdominal pain, distension, air fluid levels. Intussusception : telescoping of the small intestine. The fecal material because of being thick will work as a lead point. It will present as Colicky abdominal pain, vomiting ( because of the obstruction ). Malnutrition/Kwashiorkor Failure to thrive Focal biliary cirrhosis Malabsorption : manifests as abdominal distention, flatulence and chronic diarrhea. Meconium ileus It s small bowel obstruction in first days of life. We will see dilated proximal bowel with small distal obstructed bowel. Also,it may require surgical resection and ultimate reanastomosis. In mild cases we can use gastrograffin. 13

14 Rectal Prolapse Malnutrition/Kwashiorkor It occurs due to also hypoalbuminemia that cause edema. *Manifestations : Greasy stool (Steatorrhea) Flatulence Abdominal bloating Poor weight gain Fat-soluble-vitamin deficiency Pancreatic Insufficiency 14

15 (A,D, E, K) - Vit A deficiency leads to night blindness - Vit D deficiency leads to osteopenia and osteoporosis (Late). - Vit E deficiency leads to haemolytic anemia and neuropathy. - Vit K deficiency increase the bleeding tendency. Malnutrition Assessment of Pancreatic Function 10-15% of Patients have mild CFTR mutations that result in pancreatic sufficient CF. so the assessment of pancreatic function id done by : 1. Serum trypsinogen: doesn t have a good sensitivity hour fecal fat collection : the nutritionist will quantify the fat intake and the fat excreted in the stool which should be only 7% or less. So 93% of the fate should be absorbed. It s not practical because it s not pleasant to collect stool for 3 days and it s time-consuming. 3. Fecal elastase : is the gold standard: sensitivity and specificity is 100% in CF and isn t affected by the pancreatic enzyme replacement. It will be decreased in CF patients. Biliary Tract Manifestations Biliary cirrhosis : symptomatic in 2-3%. Jaundice: due to thick secretions in the liver (especially neonatal jaundice). Ascites, hematemesis and esophageal varices due to portal hypertension (all are late signs & symptoms). Neonatal hepatitis. 15

16 Other CF Manifestations 1- CF-related Diabetes Mellitus (CFRD) : we mention it previously and 30% of CF patients will have it after the age of 25years. 2- Male infertility: Because of 1 Obstructive azoospermia (98%), 2 congenital bilateral absence of the vas deference (CBAVD) - Azoospermia: is the medical condition of a man not having any measurable level of sperm in his semen." Wikipedia 3- Salt depletion, metabolic alkalosis (Especially in hot areas because of excessive sweating ). 4- Digital clubbing : obliterated nail angle. Digital Clubbing Management Modalities the Dr slides and the record was so much not organized in the management part, so I put many things from the old lecture with some modifications. 16

17 1. Management of Pulmonary manifestations 2. Management of GI manifestations. 3. Preventive therapy. Management of Pulmonary manifestations A) Airway clearance : Is done mainly by Chest Physiotherapy which is is important and should be encouraged at home and at the hospital. Most of its practice involves 1 postural drainage (see figure below) and 2 positive expiratory pressure. During postural drainage, the child should try to keep his head and face down to get rid of secretions. Young children in general can't produce sputum and they tend to swallow normal secretions. B) Agents to promote airway secretion clearance: We put patients on nebulizers to liquefy the thick secretion in the airway. So we give: ** Inhaled Mucolytics : - Inhaled recombinant DNAse (dornase alfa) : it breaks the DNA of neutrophils and it s expensive medication. It s trade name is Pulmozyme and it s not available in Jordan that s why we use other medications. 17

18 - N-acetyl-L-cysteine ** Inhaled Hypertonic saline 7% : ( Also not available in Jordan, we have just the 2.7% concentration ). It acts as an osmotic agent ( high content of Na ) to drag water to the pericellular layer, thus improving the lung function test and reduce lung exacerbation. C) Antibiotic Therapy : To treat the infections. - Nebulized antibiotics. - IV antibiotics. For P.aeruginosa, we need at least 2 antibiotics and we need higher doses than the regular doses ( because we need high concentrations to reach the thick mucous layer ). Cystic fibrosis has higher incidence of asthma. Therefore, we have to give them bronchodilators and anti-inflammatory drugs. D) Anti-Inflammatory therapy High doses of ibuprofen proved to be beneficial but practically they are not used because they cause severe side effects like GI side effects : peptic ulcers and renal impairment. We can use also CS for bronchopulmonary aspergillosis. E) Bronchodilator therapy: Beta2 agonist. F) Macrolide antibiotics The Prototype that is used in CF patients is the azithromycin. It s used for its anti-inflammatory effect and It s indicated for P.arueginose-positive patients ( 3 times/week and we leave the patients on it even if they are asymptomatic ) because it reduces biofilm production (conversion of non-mucoid to mucoid ) and reduces virulence of P.aeruginosa (Bactericidal effect). It improves lung function and decreases exacerbations. 18

19 Pulmonary Exacerbations When do I said that this patient is getting an exacerbation? When : Increased cough, change in sputum colour or quantity Decreased appetite and weight Change in RR, presence of new crackles or wheezing Decline in lung function (FEV1 : if low, it reflect an abstructive disease ) Rx: Aggressive treatment (we give IV antibiotics at least 2, used with higher doses than usual for days ) : - Antibiotics - Increase airway clearance - Improve nutrition The Doctor showed a video about High frequency chest wall oscillation (trade name vest, cost 15000$ ) which is used for airways clearance. They wear it for 30minutes twice daily, then they enhance the patient to cough to clear the secretions. It s used also for neuromuscular diseases. Management of GI manifestations It s mainly By nutrition which should include : 1. High energy and calorie diet They need more than the regular amount of calories ( kcal/kg/day), they should take extra snacks and extra meals and they should take the enzymes with EVERY meal. We also encourage the high protein intake also food with high fat content. 2. Pancreatic enzyme replacement which are Enteric coated PH-resistant microsphere preparations to protect them from degradation by the stomach pepsin and this allow the release of the enzymes at ph of which is in the small intestine. 19

20 3. Fat-soluble vitamin supplementation and minerals. Vit A,D, E, K. and we should provide them with high energy and high calorie diet. Preventive Care -Annual influenza vaccine - Pneumococcal vaccine - RSV prophylaxis < 2 years (this summary from illustrated textbook of Pediatrics ) THANK YOU **Done By : Bara Al-Zu bi 20