Cystic Fibrosis

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Cystic Fibrosis : 

Cystic Fibrosis Dr S Sen Specialist Registrar Paediatrics North Western Deanery (Rochdale Infirmary)

Slide 2: 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 2 "Woe is the child who tastes salty from a kiss on the brow, for he is cursed, and soon must die.” - German Folklore

History : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 3 History 1905 Austrian Karl Landsteiner describes Meconium ileus 1938 Cystic fibrosis disease identified by Dorothy H. Andersen 1838 Carl von Rokitansky’s autopsy of infant with Meconium peritonitis

Overview : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 4 Overview Most common autosomal recessive disorder in Caucasians Affects 1 in 2500 with carrier hetrozygotes frequency approx 5% Less common in Asian and African population Characterised by chronic suppurative lung disease and chronic exocrine pancreatic insufficiency

Genetics & Pathophysiology : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 5 Genetics & Pathophysiology Defective gene is a cAMP-regulated chloride channel called cystic fibrosis transmembrane conductance regulator Gene is on long arm of 7 High concentration of Na and low concentration of Cl in exocrine secretions Most common defect – deletion of phenylalanine at position 508 (70%)

Gene Locus : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 6 Gene Locus Chromosome 7; Locus 7q31.2 The CFTR gene: is 250, 000 bp long contains 27 exons the protein has 1, 480 amino acids with a molecular mass of 168, 138 Da nucleotide of ~ 6,500

Mapping the gene for CF : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 7 Mapping the gene for CF 1989: Lap-Chee Tsui, at the Hospital for Sick Children in Toronto, clones the CFTR gene. Chromosome walking and jumping techniques were used to identify and sequence the 180,000 bp gene.

The ΔF508 Mutation : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 8 The ΔF508 Mutation The mutation results in the deletion of a single amino acid (Phe) at position 508. A 3 base pair deletion called ΔF508 is the most common mutation causing cystic fibrosis

Benefits of ΔF508 : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 9 Benefits of ΔF508 The ΔF508 mutation most likely occurred over 50,000 years ago in Northern Europe. Individuals with two copies of ΔF508 get cystic fibrosis and often cannot reproduce. Having one copy of ΔF508 reduces water loss during cholera, greatly increasing the chance of survival.

The Function of CFTR : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 10 The Function of CFTR CFTR encodes a 170 kDa, membrane-based protein with an active transport function

Slide 11: 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 11 The CFTR protein plays a vital role in mucus function The CFTR protein helps to keep mucus from becoming thick Role of CFTR Protein

Role of CFTR Protein : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 12 Role of CFTR Protein In CF, the CFTR cannot allow chloride ions to move out of the mucus-producing cells This means water doesn’t leave and it results in the mucus becoming thick This in turn blocks the passageways, and allow bacteria to feed off the mucus, which results in more infections

From Mutation to Disease : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 13 From Mutation to Disease The mutant form of CFTR prevents chloride transport, causing mucus build-up Mucus clogs the airways and disrupts the function of the pancreas & intestines.

CFTR Mutations : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 14 CFTR Mutations Over 1,000 mutations in CFTR have been found. ΔF508 accounts for just 70% of CF cases.

5 Classes of CFTR Mutations : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 15 5 Classes of CFTR Mutations CF Mutations can be classified by the effect they have on the CFTR protein.

5 Classes of CFTR Mutations : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 16 5 Classes of CFTR Mutations I Defective Production II Defective Processing III Defective Regulation IV Defective Conductance V Reduced Amounts

Presentation : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 17 Presentation Meconium ileus affects about 10% of newborns with cystic fibrosis, presenting as intestinal obstruction in the first day or so of life Respiratory problems, in particular recurrent respiratory infections Failure to thrive affects about 50% of CF patients in childhood and infancy; this is often as a result of pancreatic insufficiency Meconium ileus equivalent may occur in later life

Respiratory manifestations : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 18 Respiratory manifestations Bronchiectasis with progressive productive cough and green/brown sputum - multiple chest infections Pneumothorax Aspergillus fumigatus and allergic bronchopulmonary aspergillosis may occur in up to 20%. Colonisation of the lungs by pseudomonas, which is often a difficult problem Nasal polyposis Eventually pulmonary fibrosis may lead to death from cor pulmonale or respiratory failure

GI manifestations : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 19 GI manifestations Pancreatic insufficiency leading to malabsorption and failure to thrive. Gynaecomastia and other signs of chronic liver disease, for example,hepatosplenomegaly Liver cirrhosis, portal hypertension, hypersplenism - which may develop because of intrahepatic bile duct obstruction caused by abnormal inspissated bile Distal ileus obstruction syndrome - meconium ileus equivalent Rectal prolapse - due to bulky stools Biliary stricture,gallstones, cholecystitis Intussusception Acute pancreatitis

Other manifestations : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 20 Other manifestations Males are infertile Females are subfertile Diabetes mellitus - 10-20% of adult patients Vasculitis, purpura Hypertrophic pulmonary osteoarthropathy Cystic fibrosis arthropathy

Diagnosis : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 21 Diagnosis Immunoreactive trypsin Infants with CF 1-2/52 of age show ↑ levels of Immunoreactive trypsin in the plasma in the neonatal heal-prick test Positive if greater than 80 mcg/litre Immunoreactive trypsin is also raised in haemorrhagic shock and encephalopathy

Newborn Screening : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 22 Newborn Screening Infants can easily be screened on the Guthrie Card

Diagnosis : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 23 Diagnosis Sweat test Intra-dermal injection of pilocarpine If CF, Cl greater than 60 mmol/l & Na is greater than 70 mmol/l The mass of sweat should be greater than 100mg for an interpretable result

The Sweat Test : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 24 The Sweat Test Measures the concentration of chloride and sodium that is excreted in sweat. Two reliable positive results on two separate days is diagnostic for CF. Clinical presentation, family history and patient age must be considered to interpret the results.

Slide 25: 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 25 Baby with CF Normal carrier Normal carrier Normal non-carrier Carrier Mom Carrier Dad

Differential diagnosis : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 26 Differential diagnosis Hypogammaglobulinaemia Immotile cilia syndromes Asthma Coeliac disease Shwachmann-Diamond syndrome

Further investigations : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 27 Further investigations Sputum culture Skin test for aspergillus as 20% develop allergic bronchopulmonary aspergillosis Chest X Ray Pulmonary function tests: Obstructive : FEV1/VC ratio is reduced In severe cases arterial blood gas sampling shows chronic hypoxia and hypercapnia Glucose tolerance test Malabsorption screen

Management of Cystic Fibrosis : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 28 Management of Cystic Fibrosis

Respiratory Management : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 29 Bronchial clearance -Physiotherapy, with manual percussion, forced expiratory manoeuvres and vibration in a variety of positions Antibiotic treatment -Protection against Staph.aureus, the commonest childhood pathogen, Haemophilus influenzae and Pseudomonas aeruginosa Bronchodilators and Steroids may be beneficial especially in patients with allergic bronchopulmonary aspergillosis Mucolytics (DNAase) improve mucus expectoration Exercise - Anecdotal evidence that vigorous aerobic exercise slows lung deterioration heart-lung transplantation is a final possibility Respiratory Management

Nutritional management : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 30 Nutritional management Pancreatic replacement therapy in the form of granules or tablets Vitamin supplements Advice from dietician regarding special diets, for example high calorie content, high fat. The aim is to provide about 120% of the normal calorie requirements

Psychological & Genetic Management : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 31 Psychological & Genetic Management Counselling and emotional support prenatal diagnosis and genetic counselling. adult males with cystic fibrosis are normally sterile adult females with cystic fibrosis are subfertile Psychologist

Prognosis : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 32 Prognosis This is improving with most children reaching early adulthood. There are now cases where patients with cystic fibrosis are reaching their 4th or 5th decades The improvement in life-expectancy is likely to be a result of improved nutritional status, physiotherapy and antibiotic treatment. The variability in survival with this disease may reflect a variable expression of the condition and an environmental contribution to the development of clinical manifestations Patients may be a candidate for a heart-lung transplant operation

Summary : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 33 Summary Autosomal recessive condition Effects many systems of the body Good diagnostic tools Improving prognosis

Questions : 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 34 Questions

Slide 35: 

08/12/2009 Cystic Fibrosis/Dr S Sen/ST Teaching 35