The true cost of inpatient obesity impact on inflammatory stress and morbidity.

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1 The true cost of inpatient obesity impact on inflammatory stress and morbidity. Professor Bob Grimble, Institute of Human Nutrition, Institute of Developmental Sciences Building, University of Southampton Medical School

2 One of the first indications that the immune system had a role in mortality from chronic diseases Serum albumin is a negative acute phase reactant and is reduced when levels of inflammatory stress become raised Phillips et al Lancet

3 The inflammatory response is purposeful, focussed, powerful and dangerous. The perfect response. -"And the lion and the lamb shall lie down together, but the lamb won't get much sleep." Woody Allen

4 Normal host response to trauma/infection/burns Immune system activation Pro-inflammatory cytokines T and B cells Oxidants Pathogen killing Tissue damage Hostile environment

cells Oxidants Glucose Pathogen killing Tissue damage Nutrient

5 Normal host response to trauma/infection/burns Pro-inflammatory cytokines Immune system activation Immunonutrition T and B cells Oxidants Glucose Pathogen killing Tissue damage Nutrient release from host tissues Glutamine Hostile environment Appetite loss

6 Normal host response to trauma/infection/burns Pro-inflammatory cytokines Immune system activation Immunonutrition Oxidants Antiox defence Glucose T and B cells Pathogen killing Hostile environment - Tissue damage Nutrient release from host tissues Appetite loss Sulphur amino acids Glutamine Glutathione synthesis Antioxidant defences strengthened

7 Normal host response to trauma/infection/burns Pro-inflammatory cytokines Oxidants Antiox defence Immune system activation - Feedback systems IL10, Heat shock proteins Glucose Immunonutrition T and B cells Pathogen killing Hostile environment - Tissue damage Nutrient release from host tissues Appetite loss Sulphur amino acids Glutamine Glutathione synthesis Antioxidant defences strengthened

8 The inflammatory response is designed so species can combat pathogens and survive injury Aggression Appropriate Inappropriate

9 Downside of the inflammatory response. The lamb gets a little stressed!

10 Inflammatory stimuli pathogens, environmental factors, damaged tissue Insulin insensitivity Pathogen killing Inflammation Hyperlipidemia

11 Inflammatory stimuli pathogens, environmental factors, damaged tissue Diabetes mellitus Insulin insensitivity Pathogen killing Inflammation Hyperlipidemia Atherosclerosis Mortality and morbidity Myocardial infarction

12 The human race is diverse and thus risk factors influencing the inflammatory response are diverse. What are the key variables which influence the strength and outcome of the response?

13 Key factors influencing inflammatory stress:- Poor anti-oxidant defences Polymorphisms (SNP) in cytokine genes Obesity Gender Aging

14 Key factors influencing inflammatory stress:- Poor anti-oxidant defences Polymorphisms (SNP) in cytokine genes Obesity Gender Aging

15 Oxidants and cytokines are partners in crime Inflammatory cells Oxidants Cytokines Cell membrane NFkB IkB

16 Oxidants and cytokines are partners in crime Inflammatory cells Oxidants Cytokines Cell membrane Oxidised cell components NFkB IkB NFkB

17 Oxidants and cytokines are partners in crime Inflammatory cells Oxidants Cytokines Cell membrane Oxidised cell components NFkB IkB NFkB DNA transcription Inflammatory mediator production

18 Oxidants and cytokines are partners in crime Inflammatory cells Oxidants Cytokines Cell membrane Antioxidants Oxidised cell components NFkB IkB

19 Key factors influencing inflammatory stress:- Poor anti-oxidant defences Polymorphisms (SNP) in cytokine genes Obesity Gender Aging

20 Polymorphisms in the promoter region of genes Single nucleotide base change From Father From Mother Bioactivity of normal increased greatly increased protein produced;

21 Cytokine gene polymorphisms associated with altered levels of production Polymorphism TNF-α -308 LT-α +252 IL-1β -511 IL IL Genotype associated with raised inflammatory stress or poor disease outcome TNF2 allele (A) TNFB2:2 (AA) TT G allele AA

22 Key factors influencing inflammatory stress:- Poor anti-oxidant defences Polymorphisms (SNP) in cytokine genes Obesity Gender Aging

24 AND I AM SUFFERING FROM CHRONIC INFLAMMATION

25 Adipose tissue becomes an inflammatory site Wellen & Hotamisligil 2003 JCI 112: 1785

26 Inflammatory stimuli pathogens, environmental factors, damaged tissue Diabetes mellitus Insulin insensitivity Pathogen killing Inflammation Hyperlipidemia Obesity + Atherosclerosis Mortality and morbidity Myocardial infarction

27 Effects of a 10week hypocaloric diet (-600kcal) on in vitro cytokine production by 400mg subcutaneous adipose tissue of obese women 160 ng* protein secreted n=40. before After weight loss 0 TNF-α IL-6 IL-8 Leptin * Value X0.01 for TNF, X0.1 for IL-6 Arvidsson et al Diabetes 2004; 53:

28 Combined influence of Body Mass Index and LT-α +252 SNP on fasting plasma triglyceride concentrations in healthy men (mmol/l). Values mean±sem Significant effect of BMI Jonckheere-Terpstra test (n)= subject s per subgroup Influence of BMI p=0.003 LT-α+252 GG 0.8 LT-α+252 AG 0.6 LT-α+252 AA (12) (24) (17) (7) (30) (16) (7) (31) (15) Tertile of BMI Lowest Middle Highest (21.1±1.4) (23.8±0.6) (27.7±2.3) Normal weight Overweight

29 Influence of TNF-α-308 and IL SNPs and being overweight on C-reactive protein concentrations in Peripheral vascular disease patients 12 TNF-308 A allele or IL G allele 10 8 Normal weight Overweight p=0.036 Mann Whitney Neither present One present 6 Both present

30 Impact of obesity and overweight status on diseases with an underlying inflammatory aeteology and outcome from operative procedures.

31 Influence of overweight and obese status on mortality from diseases All cause mortality Stroke Coronary disease Relative risk Type 2 diabetes Men Visscher TL, Seidell JC Annu Rev Public Health. 2001;22: BMI kg/m 2

32 (Chest. 2001;120: ) 2001 American College of Chest Physicians Morbid Obesity in the Medical ICU* Ali El-Solh, MD; Pawan Sikka, MD; Erkan Bozkanat, MD; Wafaa Jaafar, MS and Joan Davies, RN * From the Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, James P. Nolan Clinical Research Center, University at Buffalo School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY. Organ Failures Morbidly Obese Nonobese Patients Mortality Patients Mortality (5) (6) 26 1 (4) (34) 54 6 (11) (65) 25 5 (20) (86) 11 7 (64) (100) 3 3 (100)

33 (Chest. 2001;120: ) 2001 American College of Chest Physicians Morbid Obesity in the Medical ICU* Ali El-Solh, MD; Pawan Sikka, MD; Erkan Bozkanat, MD; Wafaa Jaafar, MS and Joan Davies, RN * From the Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, James P. Nolan Clinical Research Center, University at Buffalo School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY. Organ Failures Morbidly Obese Nonobese Patients Mortality Patients Mortality (5) (6) 26 1 (4) (34) 54 6 (11) (65) 25 5 (20) (86) 11 7 (64) (100) 3 3 (100)

34 Obesity Is an Independent Risk Factor of Mortality in Severely Injured Blunt Trauma Patients Angela L. Neville, MD; Carlos V. R. Brown, MD; Janie Weng, BS; Demetrios Demetriades, MD, PhD; George C. Velmahos, MD, PhD Arch Surg. 2004;139:

35 Obesity Is an Independent Risk Factor of Mortality in Severely Injured Blunt Trauma Patients Angela L. Neville, MD; Carlos V. R. Brown, MD; Janie Weng, BS; Demetrios Demetriades, MD, PhD; George C. Velmahos, MD, PhD Arch Surg. 2004;139:

36 Obesity is not always a risk factor in all clinical situations in which inflammation is exerting a deleterious effect.

37 The impact of obesity on outcomes following pancreatectomy for malignancy. Benns M, Woodall C, Scoggins C, McMasters K, Martin R. Ann Surg Oncol Sep;16(9): Epub 2009 Jun 26

38 Mediators (adipokines) secreted by adipose tissue Adiponectin Resistin Leptin Cytokines TNF-α,IL-1α,β,IL-6 Adipocyte IL-4, IL-10 Adipsin Vistatin Estrogens Pro-inflammatory Anti-inflammatory Unclear effect on inflammation

39 Interactions between genotype and overweight status and nutrient modulation of the consequences of obesity induced inflammation

40 Healthful effects of fish oil Anti-inflammatory Lipid lowering

41 Influence of combined TNF-α -308 A allele CD GG genotype and overweight on ability of fish oil to lower fasting plasma triglycerides in healthy middle aged men Change in TGs (mmol/l) Nn= Overweight No No Yes Yes Genotypes One Both One Both

42 Influence of TNF-α-308 genotype and body weight on the effects of fish oil supplementation on the ratio of LPS stimulated TNF to IL-10 production by monocytes of peripheral vascular disease patients * Significantly Ratio of TNF-α to IL-10 production by monocytes different from overwt patients without TNF-308A allele Raised inflammatory stress * n= TNF-308 A allele Yes Yes No No Overweight No Yes No Yes p=0.039 Mann-Whitney

43 The future- gaining a greater understanding of the influence of phenotype and genotype on the variable impact of immunonutrition on the inflammatory stress caused by obesity. Thanks for your attention

TPN and lipid. RCT of 57 patients. TPN with lipid vs TPN without lipid. TPN associated with increased infectious complications

TPN and lipid. RCT of 57 patients. TPN with lipid vs TPN without lipid. TPN associated with increased infectious complications TPN and lipid RCT of 57 patients TPN with lipid vs TPN without lipid TPN associated with increased infectious complications * * * * Battistella FD, et al. J Trauma 1997; 43:52. Data Needed 1. New TPN trials