1. Metabolic Pathways for Lipids.
Ketogenesis and Ketone Bodies.

2. Ketogenesis and Ketone Bodies
In ketogenesis:
Body fat breaks down to meet energy needs.
Keto compounds called ketone bodies form.

3. Ketogenesis What is it and What For
Ketogenesis What is it and What For ? Ketogenesis is the conversion of long chain FA to the Four- carbon acetoacetate and 3 hydroxy butyrate (Ketone Bodies). The primary utility of ketogenesis is to provide a universally accepted * fuel for energy production… ( an adaptive response in starvation) *The Brain oxidizes KB but not Fat. *Other Tissues oxidize KB and Fat.

4. Ketone bodies are a major fuel in some tissues
Ketone bodies diffuse from the liver mitochondria into the blood and are transported to peripheral tissues.
Heart muscle and the renal cortex use acetoacetate in preference to glucose in physiological conditions.
The brain adapts to the utilization of acetoacetate during starvation and diabetes. 4

5. Ketogenesis and Ketone Bodies
In ketogenesis:
Two acetyl CoA molecules combine to form acetoacetyl CoA.
Acetoacetyl CoA hydrolyzes to acetoacetate.
Acetoacetate reduces to -hydroxybutyrate or loses CO2 to form acetone, both ketone bodies.

6. KETOGENESIS
It occurs when there is a high rate of fatty acid oxidation in the liver.
These three substances are collectively known as the ketone bodies (also called acetone bodies or acetone). Enzymes responsible for ketone bodies formation are associated with mitochondria.

7. 3-Hydroxybutyrate is formed by the reduction of acetoacetate by 3-hydroxybutyrate dehydrogenase.
Acetoacetate also undergoes a slow, spontaneous decarboxylation to acetone.
The odor of acetone may be detected in the breath of a person who has a high level of acetoacetate in the blood. 7

10. Ketone bodies are a water-soluble, transportable form of acetyl units
Acetoacetate is activated by the transfer of CoA from succinyl CoA in a reaction catalyzed by a specific CoA transferase.
Acetoacetyl CoA is cleaved by thiolase to yield two molecules of acetyl CoA (enter the citric acid cycle).
CoA transferase is present in all tissues except liver.
Ketone bodies are a water-soluble, transportable form of acetyl units 10

12. KETOGENESIS IS REGULATED AT THREE CRUCIAL STEPS:
1. Adipose tissue: Factors regulating mobilization of free fatty acids from adipose tissue are important in controlling ketogenesis
2. Liver: After acylation, fatty acids undergo ß-oxidation or esterified to triacylglycerol or ketone bodies.
a. CPT-1 regulates entry of long-chain acyl groups into mitochondria prior to ß-oxidation. Its activity is low in the fed state, and high in starvation.

13. Fed state: Malonyl-CoA formed in the fed state is a potent inhibitor of CPT-1. Under these conditions, free fatty acids enter the liver cell in low concentrations and are nearly all esterified to acylglycerols and transported out as VLDL.
Starvation: Free fatty acid concentration increases with starvation, acetyl-CoA carboxylase is inhibited and malonyl-CoA decreases releasing the inhibition of CPT-I and allowing more ß-oxidation.
These events are reinforced in starvation by decrease in insulin/glucagon ratio. This causes inhibition of acetyl-CoA carboxylase in the liver by phosphorylation.

14. In short, ß-oxidation from free fatty acids is controlled by the CPT-I gateway into the mitochondria, and the balance of free fatty acid uptake not oxidized is esterified.
3. Acetyl-CoA formed from ß-oxidation of fatty acids is either oxidized in TCA cycle or it forms ketone bodies.

15. The main factors which control Ketogenesis in the liver
Availability of the substrate (Long Chain Fatty Acids) : from increased production by lipolysis with increased delivery of FA to the liver.
The level of Malonyl Co A in the liver, with its influence to inhibit the Carnitine Palmitoyl Transferase I (CPT I)
The Glucagon / Insulin Ratio : a high ratio increases lipolysis and activation of oxidative ketogenesis , a low ratio counteracts ketogenisis

18. Ketosis or Keto-Acidosis
A large accumulation of KB is dangerous, because it leads to profound metabolic acidosis.
The physiologic Ketogenesis of fasting and
the adaptive ketosis in starvation never progress to life threatening acidosis

19. Ketosis Ketosis occurs:
In diabetes, diets high in fat, and starvation.
As ketone bodies accumulate.
When acidic ketone bodies lowers blood pH below 7.4 (acidosis).

20. CLINICAL ASPECTS:
1. Carnitine-deficiency: can occur in newborn or preterm infants owing to inadequate biosynthesis or renal leakage. Losses can also occur in hemodialysis.
Symptoms: hypoglycemia due to reduced gluconeogenesis resulting from impaired fatty acid oxidation, resulting in muscle weakness (Reye's syndrome).
Carnitine is supplemented with diet.

21. CLINICAL ASPECTS (cont):
2. Deficiency of Carnitine palmitoyltransferase-I and -II:
I Deficiency– affects only liver, resulting in reduced fatty acid oxidation and ketogenesis with hypoglycemia.
II Deficiency– skeletal muscle
Sulfonylureas (glyburide and tolbutamide) inhibit CPT and reduce fatty acid oxidation

22. CLINICAL ASPECTS (cont):
3. Inherited defects in the ß-oxidation lead to nonketotic hypoglycemia, coma, and fatty liver. Defects in long-chain 3-hydroxyacyl-CoA dehydrogenase, short-chain 3-hydroxyacyl-CoA dehydrogenase and 3-ketoacyl-CoA thiolase, HMG-CoA lyase are known.
4. Jamaican vomiting sickness: It is caused by eating unripe fruit of the akee tree which contains a toxin, hypoglycin, that inactivates medium-and short-chain acyl-CoA dehydrogenase, inhibiting ß-oxidation resulting in hypoglycemia with excretion of medium- and short-chain mono- and dicarboxylic acids.

23. CLINICAL ASPECTS (cont):
5. Dicarboxylic aciduria: It is characterized by excretion of C6-C10 w-dicarboxylic acids and by nonketotic hypoglycemia due to deficiency of medium-chain acyl-CoA dehydrogenase. This impairs ß-oxidation but increases w-oxidation which are then shortened by ß-oxidation to medium-chain dicarboxylic acids, which are excreted.
6. Refsum's disease: A rare neurologic disorder caused by accumulation of phytanic acid, formed from phytol, a constituent of chlorophyll. Phytanic acid contains a methyl group on carbon 3 that blocks ß-oxidation. Normally, an initial a-oxidation removes the methyl group, but person's with this disease have an inherited deficiency in a-oxidation.

24. CLINICAL ASPECTS (cont):
7. Zellweger's (cerebrohepatorenal) syndrome: Due to rare inherited absence of peroxisomes in all tissues. They accumulate C26-C38 polynoic acids in brain tissue owing to inability to oxidize long-chain fatty acids in peroxisomes.
Ketoacidosis results from prolonged ketosis:
Ketonemia- higher than normal quantities of ketone bodies in blood 
Ketonuria- higher than normal quantities of ketone bodies in urine. 
Ketosis: the overall condition is called ketosis.

25. Ketone Bodies and Diabetes
The blood glucose is elevated within 30 min following a meal containing carbohydrates
The elevated level of glucose stimulates the secretion of insulin, which increases the flow of glucose into muscle and adipose tissue for synthesis of glycogen (+ stimulates glycolysis)
As blood glucose levels drop, the secretion of glucagon increases, which stimulates the breakdown of glycogen in the liver to yield glucose

26. Ketone Bodies and Diabetes
In diabetes:
Insulin does not function properly.
Glucose levels in muscle, liver, and adipose tissue are insufficient for energy needs.
As a result, liver cells synthesize
glucose from non-carbohydrate
sources (gluconeogenesis) and fats are broken down to acetyl CoA.
The level of acetyl CoA is elevated.
Excess acetyl CoA undergoes ketogenesis.
Ketogenesis produces ketone bodies.
Ketone bodies accumulate in the blood.

27. The absence of insulin in diabetes mellitus
KETOSIS
The absence of insulin in diabetes mellitus
liver cannot absorb glucose
inhibition of glycolysis
activation of gluconeogenesis
activation of fatty acid mobilization by adipose tissue
deficit of oxaloacetate
large amounts of acetyl CoA which can not be utilized in Krebs cycle
large amounts of ketone bodies (moderately strong acids)
severe acidosis (ketosis)
Impairment of the tissue function, most importantly in the central nervous system 27

28. Ketone body metabolism and its defects
Clinical correlations

29. Acetoacetate (AcAc) and 3-hydroxybutyrate (3HB), the two main ketone bodies of humans, are important vectors of energy transport from the liver to extrahepatic tissues, especially during fasting, when glucose supply is low. Blood total ketone body (TKB) levels should be evaluated in the context of clinical history, such as fasting time and ketogenic stresses. Blood TKB should also be evaluated in parallel with blood glucose and free fatty acids (FFA). The FFA/TKB ratio is especially useful for evaluation of ketone body metabolism.

30. Insulin suppresses and glucagon and catecholamine induces the following three steps: 1) free fatty acid production in adipose tissues, 2) mitochondrial entry of free fatty acids via malonyl-CoA, 3) ketone body synthesis at the HMG-CoA syntase. Hence insulin-dominant conditions such as postprandial state or hyperinsulinism, ketone production is strongly suppressed. On the other hand, glucagon and catecholamine-dominant conditions, such as fasting,  febrile,  and/or stress conditions, ketone production is induced.

31. Ketosis
Ketosis means a condtion in which blood ketone level is equal or more than 0.2mM(200μmol/L). Ketoacidosis is defined as  a condition in which blood ketone level  is equal or more than 7 mM. Blood ketone level decreases to about 0.05~0.1 mM in postprandial condition, and increases up to 6mM after 24-hour fast in young children.  This means ketone levels increases 100-fold after fasting.

32. Clinical symptoms for ketosis and ketoacidosis are not specific but patients may have acetone smelling.  If ketoacidosis is severe, patients may have polypnea and  various degrees of unconsciousness.
Blood gas data is important to evaluate severity of ketoacidosis.
Is blood pH less than 7.3?  Non-physiological (pathogenic) ketoacidosis  has lower pH because of  insufficient respiratory compensation. For evaluation of ketone body metabolism, simultaneous measurement of blood glucose and free fatty acid, together with blood ketone bodies, is essential.

33. Clinical judgment  is also important to evaluate ketone body metabolism.
What condition does your patient have ?  for example, two hours after meal, after 15hour-fasting,  frequent vomiting and appetine loss for 10 hours, two days febrile, etc. Since fasting, febrile, and/or stress induce ketone body production, the ketone body level in your child should be evaluated clinically to be physiological or lower or higher than you expected.

34. Acetonemic vomiting and  ketotic hypoglycemia  are common causes of ketosis and their symptoms includes vomiting and lethargy. Hence if patients with such conditions look serious, especially at the first attack, sufficient metabolic tests should be done. Onsets of acetonemic vomiting and ketotic hypoglycemia are usually after the age of 1 and half years. The onsets of inborn errors of ketone body utilization are much earlier than those of acetonemic vomiting and ketotic hypoglycemia. If you see a 1-year old patient who is suspected to have severe acetonemic vomiting or ketotic hypoglycemia, you should consider underlying  metabolic disorders.