Ketones, such as 3-hydroxybutyric and acetoacetic acids, are the end-products of rapid or excessive fatty acid breakdown.
3-Hydroxybutyric acid is a typical partial-degradation product of branched-chain amino acids (primarily valine) released from muscle for hepatic and renal gluconeogenesis. This acid metabolizes by 3-hydroxybutyrate dehydrogenase—the enzyme functions in nervous tissues and muscles, enabling circulating hydroxybutyrate as a fuel. In the liver mitochondrial matrix, the enzyme can also catalyze the reverse reaction, a step in ketogenesis. Like the other ketone bodies (acetoacetate and acetone), levels of 3-hydroxybutyrate in blood and urine are raised in ketosis. In humans, 3-hydroxybutyrate is synthesized in the liver from acetyl-CoA and can be used as an energy source by the brain when blood glucose is low.
Blood levels of 3-hydroxybutyric acid levels may be monitored in diabetic patients to look for diabetic ketoacidosis. Persistent mild hyperketonemia is a common finding in newborns. Ketone bodies serve as an indispensable energy source for extrahepatic tissues, especially the brain and lung of developing mammals. Another important function of ketone bodies is to provide acetoacetyl-CoA and acetyl-CoA to synthesize cholesterol, fatty acids, and complex lipids. During the early postnatal period, acetoacetate (AcAc) and beta-hydroxybutyrate are preferred over glucose as substrates for the synthesis of phospholipids and sphingolipids accord with requirements for brain growth and myelination.
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Acetoacetic acid and 3-hydroxybutyric acid, respectively, are ketones. Ketones in themselves are breakdown products of fatty acid metabolism. When fat is used as an energy source, it is converted into ketones in the liver through ketogenesis. First, free fatty acids are released and converted into acetyl CoA via beta-oxidation in the liver’s mitochondria. Two of these acetyl-CoA molecules are then combined to make ketone bodies. These ketones then leave the liver and make their way to extrahepatic tissues via the bloodstream. In the cell, ketones are broken down into acetyl CoA via beta-oxidation to enter the Citric Acid Cycle. This process is always occurring on some level in the body.
In times of elevated urinary ketones, this means that beta-oxidation has been upregulated, as it is our primary pathway for fatty acid metabolism. In times of increased ketogenesis, more ketones are being formed, and the turnover into acetyl CoA is not keeping up with ketone production. This is due to more ketones being produced than the energy needed by the body, so ketones will build up and be excreted into the urine, leading to an increase in Acetoacetic acid and 3-hydroxybutyric acid.
Possible reasons for elevation:
There are many biologic processes that lead to this phenomenon. Some common, more purposeful, processes are mainly common dietary changes. Ketogenic diets, low carb inspired diets, and also 12-18 hour fasting are all purposeful reasons for elevated ketones. Due to the surge in low carb eating and intermittent fasting, elevations in Acetoacetic acid and 3-hydroxybutyric acid are common. These markers can come in handy when monitoring someone on a keto or low carb eating plan. Whenever elevations are present, it is a good idea to rule out dietary changes that could impact these values.
Other, more concerning reasons for these elevations in ketones include a myriad of processes:
- A common reason in those with G.I. upset is vomiting and diarrhea. The purging associated with these processes leads to an increase in ketogenesis as all sources of energy are being purged, and fat must be used to continue biological processes.
- B12 deficiency is another cause of increased ketones. Due to the requirement of B12 as a cofactor for the enzyme methylmalonyl CoA reductase needed for beta-oxidation of odd chain fatty acids, B12 deficiency can cause a buildup of urinary ketones. This enzyme converts methylmalonyl CoA to succinyl CoA for the incorporation into the CAC or gluconeogenesis for ATP production. Due to a buildup of methylmalonyl CoA and a decrease in succinyl CoA, the body upregulates ketogenesis to meet our energy needs. To determine B12 deficiency is a possible cause be sure to review the marker methylmalonic acid.
- Another possibility is an eating disorder. This could be due to diagnosed or undiagnosed anorexia or bulimia. When the system is malnourished or going through a prolonged fast or purging, the body will upregulate fatty acid metabolism and ketogenesis for adequate energy production.
- Situations, where the body cannot utilize carbohydrates for energy production, will also lead to increased ketones. One common cause is insulin resistance. In times of blood sugar dysregulation, due to a lack of insulin production or insulin resistance, the body must rely on fat metabolism to make ATP. This leads to an increase in ketones in the urine. Potentially this leads to a life-threatening state of ketoacidosis. In an individual consuming carbs in their diet, but also has ketones elevated, insulin resistance should be ruled out. This phenomenon can happen in relation to diabetes type 1 and type 2. An additional culprit for urinary ketones is fungal overgrowth. The fungus can readily absorb and metabolize carbohydrates. When in our intestinal tract, these organisms come into contact with the carbs we eat. In an overgrowth, more fungus is present and can potentially absorb and metabolize enough of the carbs eaten to switch the body into glycogenolysis and eventually ketogenesis. In absence of a low carb diet, all possible causes of elevation should be assessed.
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Common causes of elevated ketones, such as 3-hydroxybutyric and acetoacetic acids, are:
- prolonged fasting
- protein malnutrition
- high-fat diet
- vitamin B12 deficiency
- severe GI Candida overgrowth
- pulmonary infections.
Potential treatment option (please discuss with your doctor):
Regardless of the cause, supplementation with L-carnitine or acetyl-L-carnitine (500-1000mg per day) may be beneficial.
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I have been using Healthmatters.io since 2021. I travel all over the world and use different doctors and health facilities. This site has allowed me to consolidate all my various test results over 14 years in one place. And every doctor that I show this to has been impressed. Because with any health professional I talk to, I can pull up historical results in seconds. It is invaluable. Even going back to the same doctor, they usually do not have the historical results from their facility in a graph format. That has been very helpful.
Karin
Advanced Plan Member since 2020
What fantastic service and great, easy-to-follow layouts! I love your website; it makes it so helpful to see patterns in my health data. It's truly a pleasure to use. I only wish the NHS was as organized and quick as Healthmatters.io. You've set a new standard for health tracking!
Paul
Healthmatters Pro Member since 2024
As a PRO member and medical practitioner, Healthmatters.io has been an invaluable tool for tracking my clients' data. The layout is intuitive, making it easy to monitor trends and spot patterns over time. The ability to customize reports and charts helps me present information clearly to my clients, improving communication and outcomes. It's streamlined my workflow, saving me time and providing insights at a glance. Highly recommended for any practitioner looking for a comprehensive and user-friendly solution to track patient labs!
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