Ketogenesis and ketolysis

MBBS Biochemistry

1. Dr Sohil Takodara Ketogenesis and Ketolysis

2. Headings Ketone bodies and their biological significance Ketogenesis and its regulation Utilization of ketone bodies Disorders associated with ketone bodies

3. Ketone bodies Ketone bodies are three water soluble compounds that are produced when the fats are broken down. They are Acetone Acetoacetate – hydroxybutyrate  

4. Ketone bodies

5. Ketone bodies as a fuel Ketone bodies are transported from the liver to other tissues, where oxaloacetate and – hydroxybutyrate can be reconverted into acetyl CoA to produce energy  

6. Ketone bodies as a fuel They are water soluble compounds They can be transported across inner mitochondrial membrane As well as they can cross the blood brain barrier Act as a source of energy for brain, heart and muscles Major source of energy for brain during starvation – 75%

7. Site – Liver mitochondria Occur only in liver because HMG-CoA lyase is present only in liver Ketogenesis

8. Acetyl CoA + Acetyl CoA Acetoacetyl CoA synthase Acetoacetyl CoA HMG CoA synthase HMG-CoA HMG CoA lyase Acetoacetate + Acetyl CoA Non enzymatic Dehydrogenase Acetone – hydroxybutyrate  

9. Acetoacetate is the primary ketone body Acetone and – hydroxybutyrate are the secondary ketone bodies  

10. Formation, utilization and excretion of ketone bodies Liver BLOOD Extrahepatic tissue Acetyl CoA Ketone bodies FFA Ketone bodies Acetone Ketone in lungs in urine Acetyl CoA Ketone bodies Citric acid cycle CO2

11. Hormonal

12. Occur in extrahepatic tissues Not in liver – Because the enzyme thiophorase is absent in liver Ketolysis

13. Ketolysis The formation of ketone bodies take place in liver mitochondria but the enzymes for its utilization are not present in the liver. Therefore, ketone bodies are released into circulation , and are taken up by tissues possessing the enzymatic machinery for their utilisation .

14. Ketolysis The first step is the activation of ketone bodies to acetoacetyl CoA. - Hydroxybutyrate is converted into acetoacetate which reacts with succinyl CoA to form succinate and acetoacetyl CoA Acetoacetyl CoA is converted into two molecules of acetyl CoA which are oxidised in the citric acid cycle  

15. This enzyme is absent in liver

16. Liver cannot use ketone bodies - Hydroxybutyrate is converted to acetoacetate for energy. For oxidation of acetoacetate, it has to be activated to Acetoacetyl CoA by “ Succinyl CoA acetoacetate CoA transferase ” or Thiophorase . This is absent in liver.  

17. Ketone bodies in plasma : 0.2 mmol /L In starvation : 3-5 mmol /L Diabetic Ketoacidosis : >12mmol/L Ketone bodies in urine : <1 mg/L

18. Ketosis Applied aspect

19. Ketosis Accumlation of ketone bodies in body due to increases synthesis than utilization - Ketonemia Also they are excreted in urine – Ketonuria With acetone in breath

20. DM Due to untreated hyperglycemia Is due to deficiency of Insulin So more and more breakdown of fats More fatty acids in the blood Oxidation of these fatty acids increases the acetyl CoA pool. Oxidation of acetyl-CoA by TCA cycle is reduced as the availability of oxaloacetate is reduced .

21. Starvation Supply of glucose to body is decreased. Oxaloacetate is directed to gluconeogenesis Lipolysis also takes place Excess acetyl CoA is converted to ketone bodies.

22. Pregnancy Due to elevated levels of circulating hCG in the blood in first trimester of pregnancy Causes vomiting (Morning sickness) Blood glucose level decreases Ketone bodies come as a source of fuel to body.

23. Explanation to ketogenesis

24. The Clinical Picture

25. Case study A 40 yrs old female is brought to the emergency department by her mother after being found unresponsive at home. She had been ill the day before with nausea and vomiting, but was not running a fever. Her parents had kept her home from school that day. When her mother came home at lunchtime to check on her, she was very lethargic and not responding coherently. When brought to hospital she shows diffuse abdominal tenderness with guarding. She appears pale, mucous membrane are dry and she only respond to painful stimulus.

26. Case study BP – 92/68 Respiratory rate – 30 Radial pulse - 126 Normal – 120/80 mm Hg Normal – 12 – 16 breath pm Normal – 60 – 90 beats pm

27. Questions

28. Important investigations Hct – 45% Creatine – 1.5 Glucose – 4+ in urine Ketone – 4+ in urine ( Rothra’s test + ve ) Increase anion gap Urea levels elevated – Pre renal failure Leucocytosis – marked feature Inc. lactate, dec HCO3- , Inc Anion gap

29. Diabetic Ketoacidosis Disorder

30. Pathophysiology

31. Diabetic Ketoacidosis Features- Mental confusion Abdominal pain Kussmaul Breathing with Tachypenia Dehydration Hypotension Increase osmotic load in blood Due to dehydration Due to ketoacidosis As ketone bodies can cross BBB so they in excess can cause CNS depression

32. Diabetic Ketoacidosis Tachycardia Fruity breathing Fever +/- If not treated timely it may lead to Coma and death Compensatory mechanism to adjust hypovolemia due to exhaled acetone Hyperosmolar coma

33. Other diseases that can have abdominal pain Inferior wall Myocardial infarction Porphyria Addisonian crisis Basal Pneumonia Appendicitis at the level of T10 Disseminated Intravascular coagulation

34. Differential Diagnosis Alcoholic ketoacidosis Hyperosmolar coma Hypothermia Metabolic acidosis MI Salicylate toxicity UTI In Pancreatitis both amylase and lipase are elivated but in DKA only amylase levels Increases Can lead to neurological disturbances, coma, semicoma

35. Complications Cerebral Edema Venous thrombosis MI in systole – due to elevated K+ level Acute gastric diarrhoea

36. Features Hyperglycemia – d/t inc gluconeogenesis, glycogenolysis Polyuria – Ketone and glucose are osmotically active Dehydration – due to polyuria Polydypsia – to compensate polyuria Pregnancy – In pregnancy can lead to gestational DM

37. Management Hyperventilate Blood glucose level monitor Normal saline solution – to prevent dehydration To check blood pH as due to hyperventilation acidosis may turn to alkalosis Bicarbonate levels Regular Insulin shot IV Electrolyte levels

38. Other Reports Urine and blood culture – infective organism like Helicobacter pylori Elevated amylase even in absence of pancreatitis Serum PO4 3-

39. Imaging Chest radiography to rule out pulmonary edema. MRI to detect cerebral edema which is very common in pediatric cases. If cerebral edema present – Mannitol or hypertonic saline to be administered immediately as it will cause osmotic diuresis while acting on Glomerulus. To see the levels of K+ in blood regular check, on ECG as it may result in cardiac arrest in systole

40. Drugs to be given Short acting insulin – Humalog Regular insulin IV Long acting insulin – Lantus Sulphonyl urea - Tolbutamide R

41. MOA Sulphonyl Urea GLUT - 2 ATP sensitive K+ channels Voltage gated Ca ++ channels Beta cell

42. Thank You