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Cystic Fibrosis: Now a Multisystem Disease of Adolescence and Adulthood

Cystic Fibrosis: Now a Multisystem Disease of Adolescence and Adulthood. Andrew Bush MD FRCP FRCPCH Imperial School of Medicine & Royal Brompton Hospital. Email: a.bush@rbht.nhs.uk. CF: Multisystem, Adult Disease. How Has this come about? Late diagnosis of mild phenotypes

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Cystic Fibrosis: Now a Multisystem Disease of Adolescence and Adulthood

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  1. Cystic Fibrosis: Now a Multisystem Disease of Adolescence and Adulthood Andrew Bush MD FRCP FRCPCH Imperial School of Medicine & Royal Brompton Hospital Email: a.bush@rbht.nhs.uk

  2. CF: Multisystem, Adult Disease • How Has this come about? • Late diagnosis of mild phenotypes • Effective modern treatment • What are the consequences? • Disease issues • Iatrogenic issues • Summary and Conclusions

  3. Late diagnosis of CF – 15%

  4. CF Diagnosis in Adolescence and Adult Life - 1 • Bronchiectasis, atypical asthma, chronic productive cough • Atypical ‘asthma’ • Male infertility • Acute pancreatitis • Non-tuberculous mycobacterial infection

  5. CF Diagnosis in Adolescence and Adult Life - 2 • Nasal polyps, sinusitis (but ASA) • Diabetes • Screening (diagnosis in a relative) • Pseudo-Bartter’s syndrome • Hepatomegaly, splenomegaly, variceal haemorrhage

  6. Sweat electrolytes - CF, normal, borderline

  7. What is the pick-up? 2 known mutations -69.7% 1 mutation found only - 23.7% No mutations found - 6.6% (N=10,998 genotyped, 21,976 alleles) What mutations are found? DF508 - 68.2% G542X - 2.3% G551D - 2.0% W1282X - 1.3% N1303K - 1.2% R553X - 0.9% CF Genotype (> 1000 Known Mutations)

  8. Nasal potentials – normal, CF, PBA treated CF: more negative baseline, bigger deflection on blocking ENaC, no response to low chloride/isoprenaline

  9. Other Helpful Pointers • Stool elastase – pancreatic status • Sputum culture – esp Staph. Aureus, Ps. Aeruginosa, B. Cepacia • HRCT Scan – Bronchiectasis • BAL – Neutrophilic lavage • Semen analysis – azoospermia

  10. 100 P. aeruginosa 80 60 Percent S. aureus 40 H. influenza B. cepacia 20 S. maltophilia 0 0 to 1 2 to 5 6 to 10 11 to 17 18 to 24 25 to 34 35 to 44 45+ Age Infection: Common CF Bugs

  11. CF: Oral antibiotics • Prophylaxis • Need more work • Avoid cephalosporins • Treatment • 2-4 weeks for any isolate of St aureus, H Influenza • Continuous therapy if repeated isolates

  12. Nebulized antibiotics: Indications • Eradication 1st isolates Ps aer • Colistin/Ciprofloxacin • Tobi ™ • Chronic Ps aer infection: Suppressive • Colistin • Aminoglycosides (TOBI, iv preparations) • Other

  13. Treatment of Ps Aeruginosa Proposed Protocol Step 1: (1st isolation) - 3/52 ciprofloxacin (25-50 mg/kg/day) and colistin 1mU, bd Step 2: (>1 isolation) - double dose colistin tds; ciprofloxacin; 3/52 therapy Step 3: (3rd isolation in 6/12) - as Step 3, 3/12 therapy (TOBI?) Pediatr Pulmonol 1997; 23: 330-5

  14. N=60 patients randomised to prn or 3 monthly ivabs prn – mean 3 course/yr Underpowered study IV Antibiotics: Treatment When? Deaths: 4 in regular group vs. 1 in prn Thorax 2000; 55: 355-8

  15. Home Equal N=58 patient study Infection 2002; 30: 387-91 N=51 paired treatments Eur Respir J 1994; 7: 1640-4 Hospital Better N=63 patient study Pediatr Pulmonol 1997; 24: 42-7 N=140 patient study #336 Audit of experience Ir J Med Sci 1999; 168: 25-8 Treatment Where?

  16. Cystic Fibrosis: Nutrition (1) • High fat, high calorie diet • Ensure adequate salt and fluid intake • Give fat soluble vitamins (A,E,D,K) • Monitor height, weight, BMI

  17. Cystic Fibrosis: Nutrition (2) • Pancreatic enzymes (amount, timing) • Acid reduction strategies if necessary (H2 blockers, PPIs) • PEG feeds as needed

  18. CF: Multisystem, Adult Disease • How Has this come about? • Late diagnosis of mild phenotypes • Effective modern treatment • What are the consequences? • Disease issues • Iatrogenic issues • Summary and Conclusions

  19. Did God do it, or was it the Dr? • Insulin deficiency/diabetes • Bone disease • Liver disease • Urogenital problems

  20. CF Insulinopaenia with Normal OGTT • Four CF patients, age 15-23 yrs • Normal OGTT, HbA1c • All had abnormal random blood glucose • Trial of 6-12 units/insulin/day Arch Dis Child 2002; 87: 430-1

  21. CF-related Glucose Intolerance: Mechanisms • N=18 OGTT, n=14 ivGTT, age 9-15 years • N=4 (20%) impaired glucose tolerance • N=9 (65%) had impaired insulin secretion • No correlation with nutritional status, Shwachman score or lung function Clin Endocrinol 2002; 56: 383-9 See also: Diabet Med 2002; 19: 221-6

  22. CF Insulopaenia: Prevalence • 335 CF patients; 9 diabetic (2.7%) • OGTT performed in 94, age 10-18, normal fasting glucose • 16/94 (17%) impaired glucose tolerance • 4/94 (4.3%) CFRD without fasting hyperglycaemia • Impaired GT only with PI, severe mutations J Pediatr 2003; 142: 128-32

  23. CF Insulopaenia: Consequences • CFRD is an adverse prognostic feature • Pediatr Pulmonol 2001; 32: 343-50 • Pediatr Pulmonol 2002; 33: 483-91 • Clinical deterioration may precede CFRD by 2-4 years • Eur J Pediatr 1992; 151: 684-7 • BlueJ 2000; 162: 891-5

  24. CF, Sugar and Insulin: Conclusions • Insulinopaenia not peripheral insulin resistance is the problem; insulin has important anabolic functions • Insulinopaenia is common; suspect in PI, severe mutations • Look for evidence of insulinopaenia in those with decline in nutrition or PFTs • Do not be deceived by a normal OGTT • The treatment of insulin deficiency/CFRD is insulin, not oral hypoglycaemics

  25. Dem Bones, Dem Bones..Dem Dry Bones • One third of adults have osteopaenia or a pathological fracture • Osteopaenia at best makes transplant more problematic

  26. CF Bone Disease: Risk Factors • Vit D, Vit K, Calcium malabsorption • Systemic inflammatory response • Lack of exercise (pathological, physiological) • Delayed puberty, hypogonadism • Inhaled and oral steroid therapy

  27. CF Bone Histomorphometry • N=20 CF adults • Iliac crest bone biopsies after double tetracycline labelling (n=19) Results • Low cancellous bone volume, due to low bone formation at tissue and cellular level BlueJ 2002; 166: 1470-4

  28. CF CF Normal Normal Normal and CF Bone biopsies

  29. CF: Change in BMD • Subjects: 114 CF adults and children, bone densitometry • Results: • Age < 24, decrease instead of increase • Age > 24, decrease instead of stability Results (n=114 adults) * * *significant decline in BMD, p<0.05 Thorax 2002; 57: 719-23

  30. Milk and Bones: Normal Adolescent Girls • Design: 18 month, open randomised trial in 82 girls • Subjects: extra pint of milk; controls, normal diet • Outcome: incl. BMD, bone mineral content BMJ 1997; 315: 1255-60 • Follow-up: changes still present 3.5 years later Lancet 2001; 358: 1208-12

  31. Pathology of CF liver disease • Mucus plugs cirrhosis • CFTR is expressed in apical membrane of cholangiocytes • CFTR controls fluid and electrolytes in bile • Secondary inflammation (cytokines and Oxygen radicals) • Modifier genes

  32. EpidemiologyRisk Factors • Meconium ileus: Odds Ratio 5.5 (3-11) • Male sex: Odds Ratio 2.5 (1.3-4.9) • “Severe mutations”: Odds Ratio 2.4 (1.2-4.8)

  33. EpidemiologyIncidence and prevalence • 177 patients followed for median 14yrs • CF Liver Disease defined as 2 of the following • Hepatomegaly • Abnormal liver enzymes • USS abnormalities (excluding fatty liver) • Cirrhosis defined on ultrasound scan

  34. Outcomes • 41% with no liver disease had abnormal liver enzymes • Those with CF Liver Disease wide range of abnormal enzymes (14% normal) • 48/177 developed CF Liver Disease. All<20yrs • 17 cirrhosis, 13 portal hypertension • 1 decompensation, 1 transplant • No overall effect on survival Colombo et al 2002

  35. Clinical features • Neonatal jaundice (not related to later cirrhosis) • Rarely a presenting feature (1.5%, USA) • Usually diagnosed due to abnormal enzymes, palpable liver and liver ultrasonography • Portal hypertension • Acute decompensation of cirrhosis (jaundice, ascites) • Biliary strictures (?)

  36. Regular assessment • Abdominal exam ?hepatosplenomegaly - every visit • Liver enzymes- annually • Ultrasound of abdomen- 2-3 yearly • Magnetic Resonance Imaging (MRI) cholangiography (specialist hepatologists)

  37. Portal Hypertension & Oesophageal Varices • No specific data for CF • Varices develop in almost all cirrhotics • Cause of death in 1/3 of cirrhosis • First bleed 20% mortality • Who to screen?

  38. Screening for varices • Who? – splenomegaly, low platelet count, spiders, all predictive but screen all with cirrhosis • When? • No varices – every 3 years • Small varices – every 2 years • Medium – treat and assess every 6-12 months

  39. Treatment for oesophageal varices (Drugs) • Beta-blockers – reduce incidence from 25% to 15% (40% Relative Risk reduction) • Isosorbide Mononitrate no effect • Beta-blockers + Isosorbide Mononitrate: ?? • Beta-blockers contraindicated in CF?

  40. Treatment for primary OVs(Interventional) • Sclerotherpy • Band ligation • First line therapy • 20% reduction in first bleed • 16% reduction in mortality • More effective than Beta-blocker

  41. Options for long term management • Repeated endoscopic treatment • Long term Beta- blockers • Surgical shunt or Transjugular intrahepatic shunt • Liver transplantation (not often best option for varices)

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