Ketoacidosis

biochimistry of ketoacidosis

1. Biochemistry of Ketoacidosis By Ali Faris

2.  Normally, total body needs of energy (ATP) is met by various fuels . 1 . Carbohydrates (glucose) 70%. 2 . Fat (fatty acids) 25%. 3 . Proteins (Amino acids) 5%. 4 . Ketone bodies normally negligible %. In a normal well fed person ketone body concentration is only < 1mg/dl. In prolonged starvation its concentration may increase up to 500mg/dl

3. WHAT IS KETOACIDOSIS?? Ketoacidosis : increase acidity of the blood due to presence of high concentration of keton bodies. While… ketosis : high level of ketone bodies than normal in blood ( ketonemia) in urine ( ketonuria). Ketones They are soluble in aqueous solution (don't need to be incorporated into lipoproteins or carried by albumin like lipid) .

4. Ketoacidosis: Develops when the body does not have enough insulin. The body can’t break down sugar so it breaks down fat instead. Ketones are what is left from this process . The body does not tolerate ketones and tries to pass them out of the body.

5. • Carbohydrates are essential for the metabolism of fat or FAT is burned under the fire of carbohydrates. • Acetyl CoA formed from fatty acids can enter & get oxidized in TCA cycle only when carbohydrates are available. • During starvation & diabetes mellitus, acetyl CoA takes the alternate route of formation of ketone bodies.

6. • Acetone, acetoacetate & β - hydroxybutyrate ( or 3-hydroxybutyrate ) are known as ketone bodies • β - hydroxybutyrate does not possess a keto (C=O ) group. • Acetone & acetoacetate are true ketone bodies. • Ketone bodies are water-soluble & energy yielding . • Acetone, it cannot be metabolized

7. Ketogenesis • Acetoacetate is the primary ketone body. • β - hydroxybutyrate & acetone are secondary ketone bodies . • Site: • Synthesized exclusively by the liver mitochondria. • The enzymes are located in mitochondrial matrix. • Precursor: • Acetyl CoA, formed by oxidation of fatty acids, pyruvate or some amino acids

8. W hy ketone bodies synthesized by the liver: The production and export of ketone bodies from the liver to extrahepatic tissues allow continued oxidation of fatty acids in the liver when acetyl-CoA is not being o xidized in the citric acid cycle. Liver can't utilize ketone bodies as a fuel because [can not reconvert acetoacetate to acetyl CoA]. In extrahepatic tissues, acetoacetate is activated to acetoacetyl -CoA by succinyl CoA - acetoacetate CoA transferase which transfer CoA portion from succinyl -CoA to acetoacetate to form acetoacetyl -CoA

9. Utilization of ketone bodies • The ketone bodies, are easily transported from the liver to various tissues. • Acetoacetate & β - hydroxybutyrate serve as important sources of energy for the peripheral tissues such as skeletal muscle, cardiac muscle, renal cortex etc.

10. • The tissues which lack mitochondria ( eg . erythrocytes ) cannot utilize ketone bodies. • The production & utilization of ketone bodies is more significant when glucose is in short supply to the tissues. • During starvation & diabetes mellitus ketone bodies production & utilization is more significant

11. ketosis • The rate of synthesis of ketone bodies by the liver is such that they can be easily metabolized by extrahepatic tissues. • Blood level of ketone bodies is <1 mg/dl. • Ketonemia : • When the rate of synthesis of ketone bodies exceeds the rate of utilization, their concentration in blood increases - ketonemia .

12. • Ketonuria: • The term ketonuria represents the excretion of ketone bodies in urine • Ketosis : • Ketonemia , ketonuria & smell of acetone in breath. • All these three together known as ketosis.

13. Types of Ketoacidosis: 1-Fasting Ketoacidosis ( ketotic hypoglycemia): Ketosis occurs in starvation due to depletion of available carbohydrate coupled with mobilization of free fatty acids. a- During starvation glycogenolysis & gluconeogenesis increased, leads to : 1) depletion of citric acid cycle intermediates, diverting acetyl-CoA to ketone body production. 2)Low secretion of insulin increasing ketones synthesis

14. b- During starvation lipolysis increased & lipogenesis decreased due to decreased insulin secretion, increase glucagon secretion .fatty acids used to produce keton bodies(source of energy) c-Brain may tolerate ketotic hypoglycemia better than insulin- induced hypoglycemia because: in ketotic hypoglycemia , brain adapts to ketone bodies metabolism ,while in insulin induced hypoglycemia,ketone concentration are low .

15. 2-Diabetic Ketoacidosis DKA: 1- insulin deficiency increases lipolysis and therefore free fatty acid delivery to the liver. 2- glucagon stimulates the adipose tissue to release fatty acids stored in triglycerides, the free fatty acids enter the circulation and are taken up by the liver where they undergo β-oxidation to acetyl CoA.

16. 3- Hydroxybutyrate is quantitatively the predominant ketone body present in the blood & urine in ketosis . In uncontrolled DM, extrahepatic tissues cannot take up glucose efficiently from the blood (as a fuel ) so that patients becomes hyperglycemic, as a result of lack of insulin & because of increased gluconeogenesis.

17. The resultant hyperglycemia produces an osmotic diuresis that leads to loss of water and electrolytes in the urine. The ketones are also excreted in the urine and this result in an obligatory loss of Na+ and K+. Ketone bodies in the blood of uncontrolled diabetes can reach [90 mg/100 mL compared with a normal level of 3 mg/100 mL]. Urinary excretion is [ 5g/24 hr compared with a normal rate of 0.125 mg/ 24 hr ]. Measurement of the ketonemia , not the ketonuria , is the preferred method of assessing the severity of ketosis. Diabetic ketoacidosis (DKA) is rare in people with type 2 diabetes. It is more commonly occurs in Missing one or more insulin doses can cause DKA in people with type 1 diabetes .

18. Diagnosis of diabetic ketoacidosis Tests of blood sugar and acidity levels are the first steps of diagnosis. Testing for ketones in a sample of urine is also done. Other test is: -a basic blood panel, including potassium and sodium, to assess metabolic function Symptoms of diabetic ketoacidosis, include: -frequent urination(osmotic diuresis) -extreme thirst(dehydration) -high blood sugar levels(insulin deficiency) -high levels of ketones in the urine

19. Treatment: Correction of hyperglycemia with insulin Correction of fluid loss with intravenous fluids Correction of electrolyte disturbances, particularly potassium loss Correction of acid-base balance

20. Alcohol ketoacidosis Metabolism of ethanol: -The metabolism of alcohol itself is a probable contributor to the ketotic state. -Alcohol dehydrogenase (ADH), a cytosolic enzyme, metabolizes alcohol to acetaldehyde in hepatocytes. - Acetaldehyde is metabolized further to acetic acid by aldehyde dehydrogenase - This reaction takes place within the mitochondria. - Both steps require the reduction of nicotinamide adenine dinucleotide (NAD+) to reduced nicotinamide adenine dinucleotide (NADH). - Thus, NAD+ is consumed and NADH is generated. - The resulting increase in the NADH/NAD+ ratio inhibits hepatic gluconeogenesis and elevates the ratio of hydroxybutyric acid to acetoacetic acid . Acetic acid is linked with coenzyme A (a thiol ) to produce Acetyl-CoA. This process is catalyzed by the enzyme acetyl-CoA synthetase.

21. Treatment of alcoholic ketoacidosis (AKA) Directed toward reversing the 3 major pathophysiologic causes of the syndrome, which are: Extracellular fluid volume depletion Glycogen depletion An elevated ratio of the reduced form of nicotinamide adenine dinucleotide (NADH) to nicotinamide adenine dinucleotide (NAD  + ). This goal can usually be achieved through the administration of dextrose and saline solutions. Carbohydrate and fluid replacement reverse the pathophysiologic derangements that lead to AKA by increasing serum insulin levels and suppressing the release of glucagon. Dextrose stimulates the oxidation of NADH and aids in normalizing the NADH/NAD +  ratio .

22. References: Netter’s Physiology Flash Cards NETTER’S ESSENTIAL PHYSIOLOGY Davidsons Principles and practice of medicine_22Ed Lippincott's Illustrated Reviews Biochemistry 5th edition Guyton_and_Hall_Textbook_of_Medical Gannon's Review of Medical Physiology Medscape website Lippincott Illustrated Reviews: Pharmacology Sixth Edition W ebMD website