Pathophysiology of acute and long term complications - Student Copy.pptx

Acute and Chronic Diabetic Pathophysiology BSMS203: Theme 1, Lecture 17 Oliver G. Steele [email protected] Join at slido.com #1696072 Lecture in Context This lecture will build on … • Glucose homeostasis • Pathophysiolo gy of diabetes mellitus … by introducing and covering … Introduction to...

Acute and Chronic Diabetic Pathophysiology BSMS203: Theme 1, Lecture 17 Oliver G. Steele [email protected] Join at slido.com #1696072 Lecture in Context This lecture will build on … • Glucose homeostasis • Pathophysiolo gy of diabetes mellitus … by introducing and covering … Introduction to Endocrinolog y • Pathophysiology Series of of acute diabetic Endocrin emergencies e • Pathophysiology Physiolo of chronic gy diabetic Lectures You are complications here! 2 Intended Learning Outcomes To understand the pathophysiology of Diabetic Ketoacidosis and Hyperosmolar Hyperglycaemic State, to understand the macro- and microvascular complications associated with DM 3 Outline 1. Hyperosmolar Hyperglycaemic State • Pathophysiology associated with HHS 2. Diabetic Ketoacidosis • Pathophysiology associated with DKA • Treatment strategy and presentation 3. Microvascular Complications of Diabetes • Pathophysiology of diabetic retinopathy, diabetic nephropathy and diabetic neuropathy 4. Macrovascular Complications of Diabetes • Accelerated atherosclerosis and general treatment strategy 4 Hyperosmolar hyperglycaemic state Section 1 of 4 5 Brief recap of the glucose homeostasis Insulin Blood Glucose 3.9-5.6 mmol/L (fasting) Glucagon Glycolysis (promoted) - Glucose oxidation in tissue Blood Glucose Glycogen & fat synthesis (promoted) - Conversion of glucose into either glycogen or fat Pancrea ticα cell Gluconeoge nesis Glucag on Lipolysis (inhibited) - Breakdown of fat into availably energy Net effect: Decreased blood glucose through storage and use Liver 6 Net effect: Increased blood glucose levels in between meals Glycogenoly sis What is the hyperosmolar hyperglycaemic state? Hyperosmolar Hyperglycaemic = = 330-400 mOsm/kg Severity & symptoms Low blood water Normal Blood Osmolarity 275-295 mOsm/kg 44.4-133.2 mmol/L Severity & symptoms High blood glucose Complication arising from RELATIVE insulin deficiency and unchecked diabetic pathology Normal Blood Glucose Usually occurring in patients who have milder diabetes or are much older 7 3.9-5.6 mmol/L Pathophysiology of HHS Hyperglycaemia enhances osmotic diuresis, which is characterized by increased urination (polyuria) Glomerulu s If uncontrolled polyuria will lead to severe dehydration leading to an overall decreased blood volume Glucos e H2O (From blood in veins surrounding collecting ducts Urinary Excretion and tubules) (Glycosuria = Glucose in the urine) Renal function drops as blood flow to kidneys decreases and hyperosmolarity worsens further 8 Pathophysiology of HHS Death Dehydration leads to increased thirst and drinking (polydipsia) Hyperosmolarity and poor glucose utilization often lead to craving of sugary drinks which can exacerbate symptoms H2O Severe hyperosmolarity is highly correlated with nervous system depression and coma Coma 330 mOsm/kg Stupor 300 mOsm/kg Normal Blood Osmolarity 275-295 mOsm/kg 9 Presentation & Treatment Strategy Treatment Strategy Patient presentation • Days to weeks of polyuria and polydipsia • Lack of ketosis due to presence of small amounts of insulin • If ketosis present, other underlying issue must be searched for and treated separately (renal failure, 1. Fluid replacement to reduce hyperosmolarity 2. Electrolyte replacement follows alleviation of hyperglycaemia and hyperosmolarity has been restored 3. Insulin treatment (aggressive insulin treatment in the case of insulin resistant patients) but only if glucose levels persist 10 Normal blood osmolarity is 275-295 mmol/L. Beyond which number will nervous system depression begin? A. B. C. D. 295 300 330 400 Move to reveal correct answer Correct Answer: B - 300 11 Pathophysiology Death Dehydration leads to increased thirst and drinking (polydipsia) Hyperosmolarity and poor glucose utilization often lead to craving of sugary drinks which can exacerbate symptoms H2O Severe hyperosmolarity is highly correlated with nervous system depression and coma Coma 330 mOsm/kg Stupor 300 mOsm/kg Normal Blood Osmolarity 275-295 mOsm/kg 12 Diabetic Ketoacidosis Section 2 of 4 13 What is diabetic ketoacidosis (DKA)? Hyperosmola r >300 mOsm/kg Severity & symptoms Diabetic Ketoacidosis = = Insulin Deficient Ketosis and Blood acidification Hyperglycae mic 14.9-50 mmol/L Severity & symptoms Complication arising from acute ABSOLUTE insulin deficiency and unchecked diabetic pathology Normal Blood Osmolarity Normal Blood 275-295 Acidity mOsm/kg pH 7.35-7.45 14 Normal Blood Glucose Severity & symptoms Acidotic pH 6.9-7.2 3.9-5.6 mmol/L Pathophysiology of DKA Drop in insulin promotes lipolysis as an alternate source of energy 8-10.0 mmol/L 6.9-7.2 pH Lipolysis introduces large amounts of amino acids and free fatty acids into the blood Ketone levels This is further worsened by the action of glucagon, as insulin is no longer preventing the release of glucagon Ketone body Liver converts amino acids to glucose and free fatty acids to ketones Acidity Normal Blood Ketone and Acidity Levels < 0.6 mmol/L 7.35-7.45 pH 15 Pathophysiology of DKA Death Insulin drop and glucagon rise also leads to hyperglycaemia Concurrent with becoming acidotic, the body is also being pushed into hyperglycaemia and hyperosmolarity Glomerulu s H2O Glucos e (From blood in collecting ducts and Renal function begins tubules) to drop … Urinary Excretion (Glycosuria = Glucose in the urine) 16 Coma 330 mOsm/kg Stupor 300 mOsm/kg Normal Blood Osmolarity 275-295 mOsm/kg Pathophysiology of DKA As renal function drops, acidosis is exacerbated, and a patient begins to vomit due to the high blood acidity Ketosis Acidotic blood Vomiting further decreases the blood volume and worsens the hyperosmolarity Higher levels of acidosis then perturb cardiovascular function (cardiovascular collapse) and generate excess lactic acid further worsening acidosis! Hyperosmolarity Hyperglycaemia 17 Presentation & Treatment Strategy Patient presentation • Often first presentation of Type 1 Diabetes, triggered by infection/trauma • Associated with patients using and insulin pump that breaks • ~24 hours of polydipsia and polyuria, onset of vomiting and abdominal pain Treatment Strategy 1. Fluid replacement to reduce hyperosmolarity 2. Insulin treatment urgently (aggressive insulin treatment in the case of insulin resistant patients) 3. Electrolyte replacement follows alleviation of hyperglycaemia and hyperosmolarity has been restored 18 Diabetic ketoacidosis arises from deficiency of which hormone? A. B. C. D. Relative glucagon deficiency Absolute glucagon deficiency Relative insulin deficiency Absolute insulin deficiency Correct Answer: D - Absolute Move to reveal correctinsulin answerdeficiency 19 Answer slide Hyperosmola r >300 mOsm/kg Severity & symptoms Diabetic Ketoacidosis = = Insulin Deficient Ketosis and Blood acidification Hyperglycae mic 14.9-50 mmol/L Severity & symptoms Complication arising from acute ABSOLUTE insulin deficiency and unchecked diabetic pathology Normal Blood Osmolarity Normal Blood 275-295 Acidity mOsm/kg pH 7.35-7.45 20 Normal Blood Glucose Severity & symptoms Acidotic pH 6.9-7.2 3.9-5.6 mmol/L Microvascular Complications of Diabetes Mellitus Section 3 of 4 21 Microvascular complications Neuropath y Nephropat hy Retinopath y Microvascular complications are chronic complications of hyperglycaemia and take years to develop, however may be present at diagnosis in Type 2 patients 22 Sorbitol induced osmotic damage The Polyol Pathway Excess glucose is metabolized to sorbitol which becomes stuck in cells inducing osmotic damage and promoting oxidate stress and Glucose Sorbitol Polyol Pathwa y Osmotic Damage 23 Basemement membrane thickening AGEs Formation Hyperglycaemia produces advanced glycation end products (AGEs) which lead to basement membrane thickening and damage to blood vessel wall components Healthy Blood Vessel 24 Thickened Basement Membrane and Endothelial Cell Loss Vascular endothelial growth factor DAG PKC Activation One of the end products of glycolysis is DAG, which activates Protein Kinase C (PKC). PKC promotes Vascular Endothelial Growth Factor (VEGF) expression which drives the formation of new blood vessels PKC VEG F VEGF Expression 25 Angiogenes is Retinal Microvasculature Blood vesse ls Optic Disk Fovea Healthy Retina 26 Endothelial Cell Basement Pericyte Membrane s Diabetic Retinopathy Minor bleed Endothelial Cell Loss New vessel formati on New vess els Protei n deposi ts Diabetic Retinopathy 27 Basement Membrane Thickening Diabetic Nephropathy Podocyte cell loss and loss of vascular wall integrity Basement Membrane thickening and subsequent leakage of protein into the urine Glomerular scarring and impaired renal function Glomerular Apparatus Net effect: Progressive loss of renal function 28 SEM of a Glomerular Apparatus Diabetic Neuropathy Damage to the microvasculature can cause ischaemia to neurons and lack of nerve function accordingly Schwann cells are sensitive to hyperglycaemia so can be damaged in diabetic patients Schwann cells Muscle weakness and impaired signaling of pain, touch and temperature are common Diabetic Foot (charcot’s and ulcers) arise from chronic neuropathy Diabetic Foot 29 What is the fovea of the retina? A. B. C. D. Entry point of the blood vessels Entry point of the optic nerves Blind spot Greatest concentration of rods and cones Correct Answer: D - Greatest concentration of Move to reveal correct answer rods and cones 30 Answer Slide Blood vesse ls Optic Disk Fovea Healthy Retina 31 Endothelial Cell Basement Pericyte Membrane s Macrovascular Complications of Diabetes Mellitus Section 4 of 4 32 Macrovascular Complications Macrovascular Disease • Strokes • Myocardial infarction • Ischaemia/hypoxia to limbs Patients with Type 2 Diabetes have multiple risk factors for the development of macrovascular disease Risk Factors • Waist circumference • Sedentary lifestyle • High fat/sugar diet • Diabetes alone is almost as bad as smoking 33 Disrupted Glucose Metabolism Much of the damage occurring in the small vessels, is also occurring in the larger blood vessels Polyol pathway and sorbitol Glucose Polyol Pathwa y Sorbitol Thickened basement membrane 34 Osmotic Damage Thickened Basement Membrane and Endothelial Cell Loss Accelerated atherosclerosis Macrovascular Disease is largely considered to be a form of accelerated atherosclerosis however the precise mechanisms/caus es are not entirely clear 1. Endothelial dysfunction and/or small lesion like the microvascular complications 2. Fatty streak deposition and the beginnings of lipid deposition Clinically sile 3. Fibrotic scarring and invasion of macrophages Clinically silent or overt 4. Rupture and thrombosis, or possibly an aneurysm 35 Treatment Strategies EARLY DETECTION & PREVENTION Many of the macrovascular complications can be life threatening or severely life altering Management of lifestyle and blood glucose and delay or prevent further pathogenesis Diabetes costs the NHS £10,000,000,000 p/a (roughly 10% of it’s entire budget) 36 What are the consequences of accelerated atherosclerosis to large blood vessels? A. B. C. D. Increase risk of blockages Decrease available blood supply Increase risk of bursts (aneurysms) Increased blood pressure Correct Answer: ALL OF THE ABOVE! Move to reveal correct answer 37 Answer Slide Macrovascular Disease is largely considered to be a form of accelerated atherosclerosis however the precise mechanisms/caus es are not entirely clear 1. Endothelial dysfunction and/or small lesion like the microvascular complications 2. Fatty streak deposition and the beginnings of lipid deposition Clinically sile 3. Fibrotic scarring and invasion of macrophages Clinically silent or overt 4. Rupture and thrombosis, or possibly an aneurysm 38 What you need to know • Understand the pathophysiology that causes diabetic patients to develop polyuria, polydipsia and glycosuria • Understand how the hyperosmolar hyperglycaemic state arises from a relative lack of insulin • Understand how diabetic ketoacidosis arises from an absolute lack of insulin • Appreciate the pathophysiological processes leading to both macrovascular and microvascular complications of diabetes mellitus 39 Suggested Additional Reading Greenspan’s Basic and Clinical Endocrinology. “Chapter 17 is very good here, and goes into much more clinical detail on the management of these complications.” Tenth Edition. Gardner & Shoback. McGraw-Hill Medical; 2018. ISBN: 978-0071622431. “Chapter 15 is helpful here in providing a more concise view of the concepts.” Integrated Endocrinology First Edition. Laycock & Meeran. Wiley-Blackwell; 2013. ISBN: 978-0470688120. 40 Feedback Opportunity If you have any feedback for me on this lecture, please either scan the QR code or follow the link below Questionnaire is short (~2 mins) and anonymous All feedback helps me to improve, and as a result improve the quality of your teaching. https://universityofsussex.eu.qualtrics.com/jfe/form/SV_3wVeRAhOFt bXjee 41