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MetabolicCpptx.rrpptx.pptx

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MetabolicCpptx.rrpptx.pptx

  1. 1. Tips on using my ppt. 1. You can freely download, edit, modify and put your name etc. 2. Don’t be concerned about number of slides. Half the slides are blanks except for the title. 3. First show the blank slides (eg. Aetiology ) > Ask students what they already know about ethology of today's topic. > Then show next slide which enumerates aetiologies. 4. At the end rerun the show – show blank> ask questions > show next slide. 5. This will be an ACTIVE LEARNING SESSION x three revisions. 6. Good for self study also. 7. See notes for bibliography.
  2. 2. Learning Objectives
  3. 3. Learning Objectives 1. Introduction & History 2. Relevant Anatomy, Physiology 3. Aetiology 4. Pathophysiology 5. Pathology 6. Classification 7. Clinical Features 8. Investigations 9. Management 10. Prevention 11. Guidelines 12. Take home messages
  4. 4. Introduction & History. •
  5. 5. Aetiology of Aetiology
  6. 6. Aetiology of Aetiology • Idiopathic • Congenital/ Genetic • Nutritional Deficiency/excess • Traumatic • Infections /Infestation • Autoimmune • Neoplastic (Benign/Malignant) • Degenerative / lifestyle • Iatrogenic • Psychosomatic • Poisoning/ Toxins/ Drug induced
  7. 7. Clinical Features •
  8. 8. Clinical Features • Demography • Symptoms • Signs • Prognosis • Complications
  9. 9. Demography
  10. 10. Demography • Incidence & Prevalence • Geographical distribution. • Race • Age • Sex • Socioeconomic status • Temporal behaviour
  11. 11. Demography • Incidence & Prevalence-
  12. 12. Demography • Geographical distribution.
  13. 13. Demography • Race.
  14. 14. Demography • Age
  15. 15. Demography • Sex
  16. 16. Demography • Socioeconomic status
  17. 17. Demography • Temporal behaviour
  18. 18. Signaling
  19. 19. Signaling • Humoral – inflammatory mediators in the circulation can induce fever and anorexia i.e. TNF-α • Neural – parasympathetic vagal stimulation attenuates the inflammatory response via Ach release – Reduces HR, increases gut motility, dilates arterioles, constricts pupils, and decreases inflammation – Reduces macrophage activation – Reduces macrophage release of pro-inflammatory mediators (TNF-α, IL-1, IL-18)
  20. 20. Adrenocorticotropic Hormone
  21. 21. Adrenocorticotropic Hormone • Synthesized anterior pituitary • Regulated by circadian signals • Pattern is dramatically altered in injured patients • Elevation is proportional to injury severity • Released by: pain, anxiety, vasopressin, angiotensin II, cholecystokinin, catecholamines, and pro-inflammatory cytokines • ACTH signals increase glucocorticoid production
  22. 22. Glucocorticoids
  23. 23. Glucocorticoids • Cortisol – elevated following injury, – duration of elevation depends on severity of injury • Potentiates hyperglycemia – Hepatic gluconeogenesis – Muscle and adipose tissue –> induces insulin resistance – Skeletal m.–> protein degradation, lactate release
  24. 24. Macrophage Inhibitory Factor
  25. 25. Macrophage Inhibitory Factor • Glucocorticoid antagonist • produced by anterior pituitary & T- lymphocytes • Reverses immunosuppressive effects of glucocorticoids • Potentiates G- and G+ septic shock • Experimentally improves survival
  26. 26. Growth Hormone
  27. 27. Growth Hormone • During stress -> protein synth, fat mobilization, and skeletal cartilage growth • 2˚ to release of insulin-like growth factor (IGF1) • Injury reduces IGF1 levels • IGF1 inhibited by pro-inflammatory cytokines – TNF-α, IL-1α, IL-6 • GH admin to pediatric burn patients shows improvement in their clinical course
  28. 28. Macrophage Inhibitory Factor
  29. 29. Macrophage Inhibitory Factor • Glucocorticoid antagonist • produced by anterior pituitary & T- lymphocytes • Reverses immunosuppressive effects of glucocorticoids • Potentiates G- and G+ septic shock • Experimentally improves survival
  30. 30. Growth Hormone
  31. 31. Growth Hormone • During stress -> protein synth, fat mobilization, and skeletal cartilage growth • 2˚ to release of insulin-like growth factor (IGF1) • Injury reduces IGF1 levels • IGF1 inhibited by pro-inflammatory cytokines – TNF-α, IL-1α, IL-6 • GH admin to pediatric burn patients shows improvement in their clinical course
  32. 32. Catecholamines
  33. 33. Catecholamines • Severe injury activates the adrenergic system • Norepi and Epi immed. increase 3-4 fold and remain elevated 24-48hrs after injury • Epinephrine – hepatic glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis – Decreases insulin and glucagon secretion – Peripheral- lipolysis, insulin resistance in skeletal m.
  34. 34. Epinephrine – other effects
  35. 35. Epinephrine – other effects • Increase secretion of T3, T4, and renin • Reduces release of aldosterone • Enhances leukocyte demargination and lymphocytosis
  36. 36. Insulin
  37. 37. Insulin • Stress inhibited release + peripheral insulin resistance = hyperglycemia • Injury has 2 phases of insulin release – Within hours- release is suppressed – Later- normal/xs insulin production with peripheral insulin resistance • Activated lymphocytes have insulin receptors - > enhanced Tcell proliferation and cytotoxicity • Tight control of glucose levels esp. in diabetics significantly reduces mortality after injury
  38. 38. Acute Phase Proteins
  39. 39. Acute Phase Proteins • Nonspecific markers • Produced by hepatocytes • Response to injury, infection, inflammation • Induced by IL-6 • C-reactive protein best reflects inflammation – No diurnal variation, not affected by feeding – Affected only by preexisting hepatic failure
  40. 40. Inflammatory Mediators
  41. 41. Inflammatory Mediators • Heat Shock Proteins • Reactive Oxygen Metabolites • Eicosanoids • Fatty Acid Metabolites • Kallikrein-Kinin System • Serotonin • Histamine • Cytokines
  42. 42. Reactive Oxygen Metabolites
  43. 43. Reactive Oxygen Metabolites • Short-lived • Cause tissue injury by oxidation of unsaturated fatty acids within cell membranes • Produced by anaerobic glucose oxidation and reduction to superoxide anion in leukocytes • Further metabolized to hydrogen peroxide and hydroxyl radicals • Cells are protected by oxygen scavengers – glutathione and catalases • In ischemia- production of oxygen metabolites are activated but nonfunctional due to no oxygen supply. After reperfusion, large amounts are produced causing injury
  44. 44. Heat Shock Proteins
  45. 45. Heat Shock Proteins • Induced by hypoxia, trauma, heavy metals, and hemorrhage • Intracellularly modify and transport proteins – Steroids • Requires gene induction by a transcription factor • ACTH sensitive • Production seems to decline with age
  46. 46. Eicosanoids
  47. 47. Eicosanoids Phospholipids Arachadonic Acid Cyclic endoperoxidases (PGG2, PGH2) Prostaglandins PGD2, PGE2, PGF2α, PGI2 Thromboxane TXA2 Hydroperoxyeicosatetraenoic acid (HPETE) Hydroxyeicosatetraenoic Acid HETE Leukotrienes Cyclooxygenase 1 & 2 Lipoxygenase Phospholipase A2 Corticosteroids Glucocorticoids (Cortisol)
  48. 48. Eicosanoids • Secreted by nucleated cells (not lymphocytes) • Induced by hypoxic injury, direct tissue injury, endotoxin, norepinephrine, vasopressin, ang II, bradykinin, serotonin, ACh, cytokines, histamine • Diverse systemic effects • Adverse effects include acute lung injury, pancreatitis, renal failure • NSAIDs acetylate COX which reduce prostaglandin levels
  49. 49. Eicosanoid Effects
  50. 50. Eicosanoid Effects • Pancreas – glucagon secretion- PGD2, PGE2 • Liver – glucagon stimulated glucose production- PGE2 • Adipose – lipolysis- PGE2 • Bone – resorption- PGE2, PGF2α, PGI2 • Parathyroid – PTH secretion- PGE2 • Pulmonary – Bronchoconstriction- PGF2α, TXA2, LTC4, LTD4, LTE4 • Immune – suppress lymphocytes- PGE2 • Hematologic – platelet aggregation- TXA2 – Capillary leakage- PGE2, LT – PMN adherence and activation- LT • Pituitary – Prolactin- PGE1 – LH- PGE1, PGE2, 5-HETE – TSH- PGA1, PGB1, PGE1, PGE1α – GH- PGE1 • Renal – renin secretion- PGE2, PGI2 • GI – cytoprotective- PGE2
  51. 51. Fatty Acid Metabolites
  52. 52. Fatty Acid Metabolites • Omega 6 FA – precursors of inflammatory mediators (LT, PG, platelet activating, factor) – found in enteral nutrition formulas • Substituting Omega 3 FA attenuate the inflammatory response – Reduces TNFα, IL6, PGE2 – Reduces the metabolic rater, normalizes glucose metabolism, attenuates weight loss, improves nitrogen balance, reduces endotoxin induced acute lung injury, minimizes reperfusion injury to the myocardium, small intestine, and skeletal muscles.
  53. 53. Kallikrein-Kinin System
  54. 54. Kallikrein-Kinin System • Bradykinins are potent vasodilators • Stimulated by hypoxic and ischemic injury – Hemorrhage, sepsis, endotoxemia, tissue injury – Magnitude proportional to severity of injury • Produced by kininogen degradation by kallikrein • Kinins increase capillary permeability (edema), pain, inhibit gluconeogenesis, renal vasodilation, incr bronchoconstriction • In clinical trials, bradykinin antagonists help reverse G- sepsis, but do not improve survival
  55. 55. Serotonin
  56. 56. Serotonin • Present in intestinal chromaffin cells & platelets • Vasoconstriction, bronchoconstriction, platelet aggregation • Myocardial chronotrope and ionotrope • Unclear role in inflammation
  57. 57. Cytokines
  58. 58. Cytokines • Most potent mediators of inflammation • Local- eradicate microorganisms, promote wound healing • Overwhelming response- hemodynamic instability (septic shock) or metabolic derangements (muscle wasting) • Uncontrolled- end-organ failure, death • Self-regulatory production of anti-inflammatory cytokines, but inappropriate release may render the patient immunocompromised and susceptible to infection
  59. 59. Tumor Necrosis Factor α
  60. 60. Tumor Necrosis Factor α • Secreted from monocytes, macrophages, Tcells • Responds early, T ½ < 20min • Potent evocation of cytokine cascade • Induces muscle catabolism/cachexia, coagulation, PGE2, PAF, glucocorticoids, eicosanoids • Circulating TNF receptors compete with cellular receptors and may act as a counter regulatory system to prevent excessive
  61. 61. Interleukin-1 • Released by activated macrophages, endothelial cells • IL1α- cell membrane associated • IL1β- circulation • Synergistic with TNF- α • T ½ = 6 min • Induces febrile response by stimulating PG activity in the anterior hypothalamus • Release of β-endorphins after surgery reduce perception of pain
  62. 62. Interleukin-2 • Promotes T-lymphocyte proliferation, Ig production, gut barrier integrity • T ½ < 10 min • Major injury or perioperative blood transfusions reduce IL-2 activity leading to a transient immunocompromised state • Regulates lymphocyte apoptosis
  63. 63. Interleukin-6 • Induced by IL-1 and TNF-α • Levels are detectable within 60 min of injury, peak 4-6 hours, and persist up to 10 days • Levels are proportional to extent of tissue injury • Pro-inflammatory – Mediates hepatic acute phase response during injury and convalescence – Induces and prolongs neutrophil activity • Anti-inflammatory – Attenuate TNF-α and IL-1 activity – Promote release of circulating TNF- α receptors & IL-1 antagonists
  64. 64. Interleukin-8 • Released from monocytes, macrophages, T lymphocytes • Activity similar to IL-6 • Chemoattractant for PMNs, basophils, eosinophils, and lymphocytes, activates PMNs • Proposed biomarker for risk of multiple organ failure
  65. 65. Interleukin-10 • Anti-inflammatory • Released from T lymphocytes • Down-regulates TNF-α activity • Also attenuates IL-18 mRNA in monocytes • Studies in animal sepsis and ARDS models suggest induced IL-10 decreases the systemic inflammatory response and reduces mortality
  66. 66. Interleukin-12 • Promotes differentiation of type 1 T Helper cells • Promotes PMN and coagulation activation • In primate studies, IL-12 induces inflammatory responses independent of TNF-α and IL-1 • In animal studies of fecal peritonitis and burns, IL-12 administration increases survival, whereas IL-12 neutralization
  67. 67. Interleukin-13 • Similar to IL-4, overall anti-inflammatory • Modulates macrophage function • Unlike IL-4, has no effect on T lymphocytes • Inhibits NO production • Inhibits pro-inflammatory cytokines • Attenuates leukocyte interaction with activated endothelial surfaces
  68. 68. Interleukin-13 • Similar to IL-4, overall anti-inflammatory • Modulates macrophage function • Unlike IL-4, has no effect on T lymphocytes • Inhibits NO production • Inhibits pro-inflammatory cytokines • Attenuates leukocyte interaction with activated endothelial surfaces
  69. 69. Interleukin-15 • Derived from macrophages • Shares receptor components with IL-2, and shares promoting lymphocyte activation/prolif. • In neutrophils, it induces IL-8 and nuclear factor кB -> enhanced phagocytosis against fungal infections
  70. 70. Interleukin-18 • Formerly IFN-γ-inducing factor • Produced by macrophages • Pro-inflammatory, similar to IL-12 • Increased levels are pronounced (especially in G- sepsis) and can last up to 21 days
  71. 71. Signs
  72. 72. Signs • General Examination • Systemic Examination • Local Examination
  73. 73. Signs • General Examination
  74. 74. Signs • Systemic Examination
  75. 75. Signs • Local Examination
  76. 76. Prognosis
  77. 77. Prognosis • Morbidity • Mortality rate • 5 year survival in Malignancy
  78. 78. Investigations
  79. 79. Investigations • Laboratory Studies – Routine – Special • Imaging Studies • Tissue diagnosis – Cytology • FNAC – Histology – Germ line Testing and Molecular Analysis • Diagnostic Laparotomy.
  80. 80. Investigations in Malignancy •
  81. 81. Investigations in Malignancy • For diagnosis • For staging • For Screening • For Monitoring
  82. 82. Diagnostic Studies
  83. 83. Diagnostic Studies Imaging Studies • X-Ray • USG • CT • Angiography • MRI • Endoscopy • Nuclear scan
  84. 84. Prevention
  85. 85. Prevention • Screening • Risk reduction
  86. 86. Mythbusters Myths Facts
  87. 87. Get this ppt in mobile 1. Download Microsoft PowerPoint from play store. 2. Open Google assistant 3. Open Google lens. 4. Scan qr code from next slide.
  88. 88. Get this ppt in mobile
  89. 89. Get my ppt collection • https://www.slideshare.net/drpradeeppande/ edit_my_uploads • https://www.dropbox.com/sh/x600md3cvj8 5woy/AACVMHuQtvHvl_K8ehc3ltkEa?dl =0 • https://www.facebook.com/doctorpradeeppa nde/?ref=pages_you_manage

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