Cystic Fibrosis Chris Kingsnorth

Before We Begin

Overview Epidemiology Pathophysiology Clinical features Diagnosis Management Prognosis

Epidemiology Most common cause of suppurative lung disease in childhood 1 in 2,500 babies affected Autosomal recessive 1 in 25 people carriers Most common mutation = ∆F508

Pathophysiology: ∆F508 Mutation Affects gene coding for cystic fibrosis transmembrane conductance regulator (CFTR) Defective protein cannot escape endoplasmic reticulum

Pathophysiology: CFTR Protein Controls Na and Cl transport across membrane of secretory epithelial cells Defect leads to thick secretions and high salt content of sweat https://www.youtube.com/watch?v=YzjnxegMWfk

Pathophysiology https://www.youtube.com/watch?v=YzjnxegMWfk

Clinical Features: Presentation At birth: Meconium ileus During infancy: Diarrhoea and failure to thrive During childhood: Chronic, persistent respiratory Sx (cough, wheeze, recurrent infections) CF is screened for on Guthrie heel-prick blood test; if +ve will have sweat test at 2-4 weeks of age (see below)

Clinical features are highly variable Chronic cough with sputum +/- wheeze Sputum colonisation with Haemophilus spp., S. aureus or Pseudomonas aeruginosa Recurrent chest infections Clubbing CXR typically shows overinflation with patchy collapse and consolidation Cor pulmonale Pancreatic exocrine insufficiency (blocked ducts)  malabsorption Leads to poor weight gain, stunted growth and frequency of bulky, greasy stools Abdominal distension Diabetes in 10% http://www.memrise.com/s3_proxy/?f=uploads/mems/4547212000130920095706.jpg Clinical features are highly variable

Clinical features are highly variable High salt losses in sweat Can lead to salt-losing crises in hot weather Male infertility in 98% (congenital malformation of vas deferens) Females suffer delay in puberty (secondary to poor growth and development) and often suffer from amenorrhoea, however fertility largely unaffected Fatty liver/ cirrhosis http://www.memrise.com/s3_proxy/?f=uploads/mems/4547212000130920095706.jpg Osteoporosis (secondary to poor exercise tolerance, chronic illness and steroid use) Clinical features are highly variable

Diagnosis: Chloride Sweat Test Sweat collected by ‘pilocarpine electrophoresis’ Low voltage current carries pilocarpine (parasympathomimetic) into skin (usually forearm) Stimulates sweat secretion Collected on filter paper and analysed for Na and Cl concentration >60mmol/L Na diagnostic of CF

Diagnosis: Sweat Test https://youtu.be/8UCWoz6gUp8

Management

Management: Airway Clearance Coughing and huffing techniques loosen mucus, promoting expectoration May require help from family members, friends or respiratory therapists ‘Vest’ therapy (high frequency chest wall oscillation) also used

Management: Inhaled Medications Bronchodilators (e.g. salmeterol) Anticholinergics (e.g. ipratropium) Antibiotics (not long-term beyond 3 years) Steroids Mucolytics (e.g. DNase)

Management: Pancreatic Enzyme Replacement Capsules containing mixtures of pig-derived pancreatic amylase, lipase, and chymotrypsin (protease) Taken with every meal +/- snacks Brands include Creon and Pancreaze Often taken alongside multivitamins

Management: CFTR Modulators Ivacaftor (Kalydeco): For patients >2yrs with rare gating mutations (protein in membrane, but defective), not common ∆F508 mutation. Binds to transporter and improves function. Lumacaftor + Ivacaftor (Orkambi): For patients >12yrs with 2 copies of common ∆F508 mutation. Lumacaftor moves defective CFTR to cell membrane; once there, Ivacaftor increases CFTR activity. Approved by FDA (USA), awaiting European approval. CFTR modulators https://youtu.be/7WTjQY0V4qI

Management: Lung Transplant Considered when lung function <30% 1/3 of patients on waiting list will die before donor becomes available 5 year mortality post-transplant = 50% http://www.webmd.com/children/lung-transplantation-for-cystic-fibrosis

Management: Support Patients with CF should not meet (risk of infection) Internet forums and message boards Cystic Fibrosis Trust (UK) http://www.webmd.com/children/lung-transplantation-for-cystic-fibrosis

Prognosis Life-limiting Life expectancy 30-40 yrs; median survival 41 yrs Cause of death is generally respiratory failure and cor pulmonale Survival and quality of life expected to improve with advent of CFTR modulators http://www.cysticfibrosis.org.uk/about-cf/frequently-asked-questions#na

What Now? Download slides/ notes pages Online MCQ: https://www.goconqr.com/en-GB/p/3931332-Cystic-Fibrosis-quizzes Request a Podcast/ ask a question

References CFTR render: ‘Protein CFTR PDB 1xmi’ by Emw - Own work. Licensed under CC BY-SA 3.0 via Commons - https://commons.wikimedia.org/wiki/File:Protein_CFTR_PDB_1xmi.png#/media/File:Protein_CFTR_PDB_1xmi.png Blood spot form: http://webarchive.nationalarchives.gov.uk/20100415090301/newbornbloodspot.screening.nhs.uk/bloodspotcard Body:http://www.memrise.com/s3_proxy/?f=uploads/mems/4547212000130920095706.jpg

References Lung transplant statistics: http://www.webmd.com/children/lung-transplantation-for-cystic-fibrosis Survival statistics: http://www.cysticfibrosis.org.uk/about-cf/frequently-asked-questions#na