Extrapulmonary manifestations of Cystic Fibrosis

1. Extrapulmonary manifestations of Cystic Fibrosis Matt Dickson ST5

3. Introduction • Case study • CF related liver disease • CF related diabetes • CF related GI disease • And the rest…

4. Case study • 27 year old male • F508del/F508del – diagnosed aged 2 • Under care of Leeds CF team • Master’s Degree, Newcastle (started Sept 2017) • Care transferred (temporarily) to Newcastle

5. Case study • Background: • Stable lung function (FEV1 ~ 70% predicted) • Intermittent compliance with Acapella and Pulmozyme • Oral antibiotics annually, x1 course IVs in 12 years • CF related liver disease, splenomegaly and portal hypertension • Oesophageal varices (on propranolol) • Assessed for liver transplantation 2015 • On Ursodeoxycholic acid for “as long as I can remember” • CF related diabetes • CF related arthropathy • Distal intestinal obstructive syndrome 2005 • Osteopenia (T score spine -1.2)

6. Case study • Worsening abdominal distension September 2017 • Attended “Stag – do” beginning September • Ascitic drain placed (transudate) • 7 litres drained • Discharged with spironolactone 100mg OD • Reviewed following discharge • Re-admitted due to re-accumulation of ascites • Transferred care to Leeds CF Unit, for reassessment by local Liver team

7. Extrapulmonary disease • Multi-system disease • CFTR essential for water/solute movement • Present in epithelial cells of: • Lung • Liver • Pancreas • Gut • Reproductive tract • Skin • Inadequate hydration of mucous secretions, leading to organ dysfunction

9. CF related liver disease • Spectrum of disease • Raised transaminases (30-40%) → cirrhosis and portal hypertension (10%) • CFTR located in biliary epithelium, not hepatocyte • Associated with severe CFTR mutations • Risk factors – meconeum ileus, male, pancreatic insufficiency • Hepatic steatosis common (60%) – benign course • Neonatal cholestasis (10%) – does not predict later CFLD

11. Diagnosis Two or more of: • Hepatomegaly and/or splenomegaly, confirmed by ultrasound • Abnormalities of ALT, AST, and GGT above the laboratory upper limits of normal for >6 months, after excluding other causes of liver disease • Ultrasound evidence of coarseness, nodularity, increased echogenicity or portal hypertension • Liver biopsy showing focal biliary cirrhosis or multi-lobular cirrhosis

12. Screening • Physical examination • Laboratory testing: • Mild derangement in LFTs common • ALP often out of proportion to AST/ALT • Thrombocytopenia/drop in platelet count • Hypoalbuminaemia/coagulopathy • USS (+/- doppler)

13. Management • Nutrition • Risk reduction • Ursodeoxycholic acid • OGD • Beta blockers • TIPS • Liver transplantation • Liver-lung transplantation (4% children, 25% adults)

14. Indications for liver transplantation • Intractable variceal bleeding • Ascites and jaundice • Progressive hepatic dysfunction (hypoalbuminemia and coagulopathy) • Hepatopulmonary syndrome • Portopulmonary hypertension • Deteriorating pulmonary function, if this is thought to be a consequence of the liver disease (e.ghepatopulmonary syndrome) • Severe malnutrition, unresponsive to intensive nutritional support and treatment for cystic fibrosis-related diabetes, if present

15. Outcomes • Similar to those with other forms of liver disease • 1 year survival ~ 85% • 5 year survival 64-78% • Survival similar for liver/liver-lung transplantation

17. CF related diabetes • Separate to Type 1/Type 2 • Slowly progressive insulin deficiency • Insulin resistance • Postprandial hyperglycaemia → Fasting hyperglycaemia (HbAlc response) • Rarely associated with islet cell autoantibodies • Ketoacidosis rare • ~50% patients >40 years

18. Risk factors • Pancreatic insufficiency • Severe genotype • Increased age • Female gender • Lung function • Impaired nutrition/growth • Liver disease

19. Impact of CFRD • Lung function • Nutritional status • Vascular complications • Mortality

20. Screening • Annually, from 10 years • OGTT • HbA1c (low sensitivity for CFRD) • Interpretation of OGTT: • Normal glucose tolerance – fasting <5.6mmol/L and two hour glucose <7.8mmol/L • Impaired fasting glucose – fasting 5.6-7mmol/L • Indeterminate glycaemia – one hour peak >11.1mmol/L, normal two hour/fasting glucose (unique to CF) • Impaired glucose tolerance – two hour glucose 7.8-11.1mmol/L • CFRD: • Without fasting hyperglycaemia – two hour >11.1mmol/L, fasting <7mmol/L • With fasting hyperglycaemia – two hour >11.1mmol/L, fasting >7mmol/L

21. Treatment • Insulin • Remove catabolic effect • HbAlc <53mmol/mol (7%) • Maintain substantial calorie intake • Low glycaemic index • Monitoring for complications +/- primary prevention

22. Pancreatitis • 10% with pancreatic sufficiency • Rare in pancreatic insufficient • Late adolescence/early adulthood • ?CF related/Idiopathic pancreatitis

24. CF related GI disease • GORD • 30-40% symptomatic • 90% may silently aspirate • Meconeum Ileus • ~80% will have CF • Constipation • 25-50% • DIOS • Unique to CF • Pain • Right lower quadrant mass • “Foamy” gas pattern in right flank +/-dilated small bowel loops/fluid levels • Medical treatment

27. Musculoskeletal disorders • Osteopenia/osteoporosis • Vitamin D malabsorption • Poor nutritional status • Reduced physical activity • Steroids • Hypogonadism • DEXA scans >18yr • CF related arthropathy • Large joints • Non-erosive • Responds well to NSAIDs • 5% patients • Fever/erythema nodosum

29. Reproductive system • Men: • Normally infertile – failure of development/blockage of vas deferens • Testicular histology normal (sperm retrieval an option) • Women: • Subfertile (always offer contraception) • Physical state optimised prior to pregnancy • Risks to mother and baby • Risk of diabetes • PAH contraindication

30. Conclusion • Not just the lungs • Focus on other systems • Need to be vigilant of developing complications • Consider other differentials • New word of the day…Inspissated