For medical staffs

For Medical staffs

I already wrote chapters for beta-ketothiolase deficiency and SCOT deficiency in Orphanet. Please read these articles.

I am very happy if you have any questions and discussions in the contents,

Beta-ketothiolase deficiency

SCOT deficiency


Herein I would like to describe ketones and their importance.



In general, acetoacetate, 3-hydroxybutyrate and acetone are called as ketones. Acetone is produced by decarboxylation from acetoacetate and metabolically non-active and causes acetonemic smell in breath. Acetoacetate and 3-hydroxybutyrate are short chain carboxylic acids, strong acids, so accumulation of ketones causes ketoacidosis.


Production and utilization of ketones


Ketone bodies are important substitute energy vectors to save glucose.  Ketones are produced in the liver to keep blood glucose level.  Most tissues except for the liver can use ketones as an energy source, and especially for brain  ketones are the only substitute for glucose.

Ketone body synthesis in the liver

1) Free fatty acids moves from adipose tissues to the liver,

2) Free fatty acids are  subjected to beta-oxidation in the liver.

3) Plenty of acetyl-CoA and acetoacetyl-CoA  are produced  via beta-oxiation.

4) HMG-CoA is produced from them by mitochondrial HMG-CoA synthase.

5) Acetoacetate is produced from HMG-CoA by HMG-CoA lyase.

6) Large part of acetoacetate is converted into 3-hydroxybutyrate by 3-hydroxybutyrate dehydorgenase.

7) Acetoacetate and 3-hydroxybutyrate are excreted into blood stream


Keotne body usilization  in extrahepatic tissues

1) 3-hydroxybutyrate is converted into acetoacetate by 3-hydroxybutyrate dehydrogease.

2) Acetoacetate is activated inrto acetoacetyl-CoA by SCOT.

3) Acetoacetyl-CoA is converted into acetyl-CoA by T2.

4) Acetyl-CoA is used for energy production via the citric cycle.



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.



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.

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.

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.

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.