1. FATIGUE Dr Cathryn Edwards D.Phil FRCP

2. Question? ■Who’s tired? ■Who’s fatigued?

3. Definitions Fatigue can be described as an overwhelming sense of continuing tiredness which is not relieved after rest or sleep…. Results from …. ‘a complex interaction between biological, psychosocial and behavioural processes…’

4. Talk Outline - Fatigue The Hitchhiker’s Guide to Fatigue! What is it and what can we do about it? Fatigue and gut inflammation Anaemia, Iron and Fatigue Other aspects of Fatigue

5. Fatigue Multidimensional concept of Fatigue Physical Cognitive Affective Subjective: perceived weakness; inability to finish a task Objective: measurable decrease in physical ability /performance Subjective: difficulty concentrating Objective: measurable decrease in memory Subjective: decreased motivation low mood no energy

6. Fatigue ■Wide range of diseases/conditions report association with Fatigue Chronic Fatigue Syndrome Irritable Bowel Syndrome Primary biliary Cirrhosis Multiple sclerosis Rheumatoid arthritis Ankylosing spondylitis Cancer Inflammatory Bowel Disease Fatigue Impact Scale

7. Fatigue - is the link inflammation? ■There appears to be a correlation between fatigue and inflammatory disease in various conditions, bowel joints or multisystem diseases ■We know that certain circulating substances known a pro- inflammatory cytokines such as tumour necrosis factor alpha IL-1 and IL-6 can induce fatigue in diseases such as cancer influenza and inflammatory bowel disease Treatment with anti TNF- alpha improves fatigue

8. Inflammation the Gut and Fatigue Chronic Fatigue Syndrome ■IBS type symptoms are common ■Leaky gut theory ■Changes in microbiota ? Link between the gut and the brain ■Low grade inflammation in CFS Other conditions where gut inflammation has been described ■Ankylosing Spondylitis ■SLE ■Auto Immune disease Wegner’s PAN Rheumatoid Arthritis

9. Treating inflammation in IBD – improves fatigue Fatigue is seen in ■Up to 86% of patients with active Crohn’s Disease But also in ■41% - 48% of patients in remission Crohn’s disease is inflammation of the intestinal tract anywhere from the mouth to the anus

10. What else is happening to produce fatigue? ■Central nervous system involvement through the stress hormone ‘cortisol’ pathways ■Altered transmission of chemicals important in depression serotonin and noradrenaline ■The possible connection between decreased levels of tryptophan ( a precursor of serotonin) in the presence of TNF alpha

11. Tryptophan- serotonin Important in mood Stress hormones Hypothalamus Pituitary axis Sleep disturbance and immune function Fatigue TNF Alpha IL - 1 IL- 6 inflammation Bugs

12. Muscle weakness – what’s the evidence? ■Physical fatigue commonly reported – part of the global fatigue phenomenon. Muscle mass seems to be a predictor of muscle strength /function and in CD some evidence that 60% of CD patients had a reduced muscle mass. ■Data is not clear about direct associations but areas of interest are micronutrients selenium zinc and magnesium deficiency vitamin D vitamin B12 and essential fatty acids

13. How does Fatigue affect people? Details from the Crohn’s and Colitis survey ■Reduction of physical activities such as sport, or daily activities such as driving housework etc ■Memory and concentration ■Social activities travel hobbies interest ■Emotions, anger isolation loneliness ■Impact on family relationships ■Work and education challenges www.fatigueinIBD.co.uk

14. Anaemia how important is this? ■Not just blood loss ( iron deficiency) but the anaemia of chronic disease in which the utilisation of iron is impeded – (TNF alpha, acute phase proteins, peptides such as hepcidin) ■This functional iron deficiency has been associated with fatigue in other conditions including cancer 30% of IBD sufferers have Anaemia Other contributory factors B12 folate deficiencies ‘Treatment associated’ anaemia

15. Fatigue – what else can we do? Study in IBD to look at screening tests in fatigue Blood count, renal and liver profiles Iron studies Magnesium Testosterone zinc and selenium Vitamin B12, folate, Vitamin D3 Thyroid function Cortisol Coeliac blood test Screening for diabetes

16. Chronic Fatigue is associated with anaemia in IBD and in Cancer ■Changes in Quality of life were studied in Crohn’s disease patients treated with Iron sucrose and Erythropoietin ■improved mood, well being physical ability and social activities

17. Fatigue – what else can we do? Omega 3 fatty acids (fish oils) Can I change my diet doctor? ■Omega 3 has been useful for fatigue in other conditions – for example in breast cancer survivors not studied in IBD ■Omega 3 fatty acids may improve physical performance of trained and untrained individuals by increasing blood flow to active muscles and reducing muscle soreness and inflammation after exercise. Other reported effects include a reduction in heart rate and oxygen consumption during exercise.

18. What else can we be doing – the role of exercise ■Recent research to study the mechanism by which exercise acts on the brain and it appears to enhance the effects of omega 3 fatty acids (DHA). The evidence to date would suggest that the combined effects of increasing omega-3 and exercise on fatigue could be more effective than exercise or omega- 3 intake alone. ■Programmed exercise has been shown to be beneficial in other chronic conditions ( with and without gut involvement) cancer MS diabetes heart failure ■CCUK are studying the role of programmed regular exercise in IBD

19. Summary Fatigue – what we can do to make a difference?

20. Tryptophan- serotonin Important in mood Stress hormones Hypothalams Pituitary axis Sleep disturbance and immune function Fatigue TNF Alpha IL - 1 IL- 6 inflammation Bugs Summary Fatigue – what can we do to make a difference?

21. Summary Fatigue – what we can do to make a difference? Gut inflammation in chronic conditions – treat and remove from the equation Exclude other contributory factors especially Anaemia – using iron infusions to treat iron deficiency Look for other contributory factors hormonal / Vitamin deficiencies

22. Summary Fatigue – what we can do to make a difference? Diet – ?Omega 3 Programmed Exercise

23. THANK YOU Questions?