Ketosis is a metabolic state characterized by elevated levels of
ketone bodies
Ketone bodies are water-soluble molecules that contain the ketone groups produced from fatty acids by the liver ( ketogenesis). Ketone bodies are readily transported into tissues outside the liver, where they are converted into acetyl-CoA (acet ...
in the blood or urine. Physiological ketosis is a normal response to low
glucose
Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...
availability, such as
low-carbohydrate diets or
fasting
Fasting is the abstention from eating and sometimes drinking. From a purely physiological context, "fasting" may refer to the metabolic status of a person who has not eaten overnight (see " Breakfast"), or to the metabolic state achieved after ...
, that provides an additional energy source for the brain in the form of ketones. In physiological ketosis, ketones in the blood are elevated above baseline levels, but the body's
acid–base homeostasis is maintained. This contrasts with
ketoacidosis
Ketoacidosis is a metabolic state caused by uncontrolled production of ketone bodies that cause a metabolic acidosis. While ketosis refers to any elevation of blood ketones, ketoacidosis is a specific pathologic condition that results in changes ...
, an uncontrolled production of ketones that occurs in pathologic states and causes a
metabolic acidosis
Metabolic acidosis is a serious electrolyte disorder characterized by an imbalance in the body's acid-base balance. Metabolic acidosis has three main root causes: increased acid production, loss of bicarbonate, and a reduced ability of the kidneys ...
, which is a medical emergency. Ketoacidosis is most commonly the result of complete
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism ...
deficiency in
type 1 diabetes
Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar f ...
or late-stage
type 2 diabetes
Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urinatio ...
. Ketone levels can be measured in blood, urine or breath and are generally between 0.5 and 3.0
millimolar (mM) in physiological ketosis, while ketoacidosis may cause blood concentrations greater than 10 mM.
Trace levels of ketones are always present in the blood and increase when blood glucose reserves are low and the
liver
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...
shifts from primarily metabolizing carbohydrates to metabolizing fatty acids.
This occurs during states of increased fatty acid oxidation such as fasting, starvation, carbohydrate restriction, or prolonged exercise. When the liver rapidly metabolizes
fatty acids into
acetyl-CoA, some acetyl-CoA molecules can then be converted into ketone bodies:
acetoacetate
Acetoacetic acid (also acetoacetate and diacetic acid) is the organic compound with the formula CHCOCHCOOH. It is the simplest beta-keto acid, and like other members of this class, it is unstable. The methyl and ethyl esters, which are quite stab ...
,
beta-hydroxybutyrate
β-Hydroxybutyric acid, also known as 3-hydroxybutyric acid or BHB, is an organic compound and a beta hydroxy acid with the chemical formula CH3CH(OH)CH2CO2H; its conjugate base is β-hydroxybutyrate, also known as 3-hydroxybutyrate. β-Hydroxy ...
, and
acetone
Acetone (2-propanone or dimethyl ketone), is an organic compound with the formula . It is the simplest and smallest ketone (). It is a colorless, highly volatile and flammable liquid with a characteristic pungent odour.
Acetone is miscibl ...
.
These ketone bodies can function as an energy source as well as signalling molecules.
The liver itself cannot utilize these molecules for energy, so the ketone bodies are released into the blood for use by peripheral tissues including the brain.
When ketosis is induced by carbohydrate restriction, it is sometimes referred to as nutritional ketosis. A low-carbohydrate, moderate protein diet that can lead to ketosis is called a
ketogenic diet. Ketosis is well-established as a treatment for
epilepsy
Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrica ...
and is also effective in treating type 2 diabetes.
Definitions
Normal serum levels of ketone bodies are less than 0.5 mM. ''Hyperketonemia'' is conventionally defined as levels in excess of 1 mM.
Physiological ketosis
Physiological ketosis is the non-pathological (normal functioning) elevation of ketone bodies that can result from any state of increased
fatty acid oxidation including fasting, prolonged exercise, or very low-carbohydrate diets such as the
ketogenic diet.
In physiological ketosis, serum ketone levels generally remain below 3 mM.
Ketoacidosis
Ketoacidosis
Ketoacidosis is a metabolic state caused by uncontrolled production of ketone bodies that cause a metabolic acidosis. While ketosis refers to any elevation of blood ketones, ketoacidosis is a specific pathologic condition that results in changes ...
is a pathological state of uncontrolled production of ketones that results in a
metabolic acidosis
Metabolic acidosis is a serious electrolyte disorder characterized by an imbalance in the body's acid-base balance. Metabolic acidosis has three main root causes: increased acid production, loss of bicarbonate, and a reduced ability of the kidneys ...
, with serum ketone levels typically in excess of 3 mM. Ketoacidosis is most commonly caused by a deficiency of insulin in type 1 diabetes or late stage type 2 diabetes but can also be the result of chronic heavy alcohol use,
salicylate poisoning
Salicylate poisoning, also known as aspirin poisoning, is the acute or chronic poisoning with a salicylate such as aspirin. The classic symptoms are ringing in the ears, nausea, abdominal pain, and a fast breathing rate. Early on, these may be su ...
, or isopropyl alcohol ingestion.
Ketoacidosis causes significant metabolic derangements and is a life-threatening medical emergency.
Ketoacidosis is distinct from physiological ketosis as it requires failure of the normal regulation of ketone body production.
Causes
Elevated blood ketone levels are most often caused by accelerated ketone production but may also be caused by consumption of exogenous ketones or precursors.
When
glycogen
Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. The polysaccharide structure represents the main storage form of glucose in the body.
Glycogen functions as one of ...
and blood glucose reserves are low, a metabolic shift occurs in order to save glucose for the brain which is unable to use
fatty acid
In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, f ...
s for energy. This shift involves increasing fatty acid oxidation and production of ketones in the liver as an alternate energy source for the brain as well as the skeletal muscles, heart, and kidney.
Low levels of ketones are always present in the blood and increase under circumstances of low glucose availability. For example, after an overnight fast, 2–6% of energy comes from ketones and this increases to 30–40% after a 3-day fast.
The amount of carbohydrate restriction required to induce a state of ketosis is variable and depends on activity level,
insulin sensitivity, genetics, age and other factors, but ketosis will usually occur when consuming less than 50 grams of carbohydrates per day for at least three days.
Neonates, pregnant women and lactating women are populations that develop physiological ketosis especially rapidly in response to energetic challenges such as fasting or illness. This can progress to ketoacidosis in the setting of illness, although it occurs rarely. Propensity for ketone production in neonates is caused by their high-fat breast milk diet, disproportionately large central nervous system and limited liver glycogen.
Biochemistry
The precursors of ketone bodies include fatty acids from
adipose tissue or the diet and
ketogenic amino acids.
The formation of ketone bodies occurs via
ketogenesis in the
mitochondrial matrix of liver cells.
Fatty acids can be released from adipose tissue by
adipokine
The adipokines, or adipocytokines (Greek ', fat; ', cell; and ', movement) are cytokines (cell signaling proteins) secreted by adipose tissue. Some contribute to an obesity-related low-grade state of inflammation or to the development of metabolic ...
signaling of high
glucagon and
epinephrine levels and low insulin levels. High glucagon and low insulin correspond to times of low glucose availability such as fasting. Fatty acids bound to
coenzyme A allow penetration into mitochondria. Once inside the mitochondrion, the bound fatty acids are used as fuel in cells predominantly through
beta oxidation, which cleaves two carbons from the acyl-CoA molecule in every cycle to form
acetyl-CoA. Acetyl-CoA enters the
citric acid cycle
The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and prot ...
, where it undergoes an
aldol condensation with
oxaloacetate to form
citric acid
Citric acid is an organic compound with the chemical formula HOC(CO2H)(CH2CO2H)2. It is a colorless weak organic acid. It occurs naturally in citrus fruits. In biochemistry, it is an intermediate in the citric acid cycle, which occurs in ...
; citric acid then enters the
tricarboxylic acid cycle (TCA), which harvests a very high energy yield per carbon in the original fatty acid.
Acetyl-CoA can be metabolized through the TCA cycle in any cell, but it can also undergo ketogenesis in the mitochondria of liver cells.
When glucose availability is low, oxaloacetate is diverted away from the TCA cycle and is instead used to produce glucose via
gluconeogenesis. This utilization of oxaloacetate in gluconeogenesis can make it unavailable to condense with acetyl-CoA, preventing entrance into the TCA cycle. In this scenario, energy can be harvested from acetyl-CoA through ketone production.
In ketogenesis, two acetyl-CoA molecules condense to form
acetoacetyl-CoA
Acetoacetyl CoA is the precursor of HMG-CoA in the mevalonate pathway, which is essential for cholesterol biosynthesis. It also takes a similar role in the ketone bodies synthesis (ketogenesis) pathway of the liver. In the ketone bodies digestion ...
via
thiolase. Acetoacetyl-CoA briefly combines with another acetyl-CoA via
HMG-CoA synthase
In molecular biology, hydroxymethylglutaryl-CoA synthase or HMG-CoA synthase is an enzyme which catalyzes the reaction in which acetyl-CoA condenses with acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). This reaction comprise ...
to form
hydroxy-β-methylglutaryl-CoA. Hydroxy-β-methylglutaryl-CoA form the ketone body acetoacetate via
HMG-CoA lyase
3-Hydroxy-3-methylglutaryl-CoA lyase (or HMG-CoA lyase) is an enzyme ( that in human is encoded by the HMGCL gene located on chromosome 1. It is a key enzyme in ketogenesis (ketone body formation). It is a ketogenic enzyme in the liver that ca ...
. Acetoacetate can then reversibly convert to another ketone body—
D-β-hydroxybutyrate—via D-β-hydroxybutyrate dehydrogenase. Alternatively, acetoacetate can spontaneously degrade to a third ketone body (acetone) and
carbon dioxide
Carbon dioxide ( chemical formula ) is a chemical compound made up of molecules that each have one carbon atom covalently double bonded to two oxygen atoms. It is found in the gas state at room temperature. In the air, carbon dioxide is t ...
, which generates much greater concentrations of acetoacetate and D-β-hydroxybutyrate. The resulting ketone bodies cannot be used for energy by the liver so are exported from the liver to supply energy to the brain and peripheral tissues.
In addition to fatty acids, deaminated
ketogenic amino acids can also be converted into intermediates in the citric acid cycle and produce ketone bodies.
Measurement
Ketone levels can be measured by testing urine, blood or breath. There are limitations in directly comparing these methods as they measure different ketone bodies.
Urine testing
Urine testing is the most common method of testing for ketones. Urine test strips utilize a
nitroprusside
Sodium nitroprusside (SNP), sold under the brand name Nitropress among others, is a medication used to lower blood pressure. This may be done if the blood pressure is very high and resulting in symptoms, in certain types of heart failure, and ...
reaction with acetoacetate to give a semi-quantitative measure based on color change of the strip. Although beta-hydroxybutyrate is the predominant circulating ketone, urine test strips only measure acetoacetate. Urinary ketones often correlate poorly with serum levels because of variability in excretion of ketones by the kidney, influence of hydration status, and renal function.
Serum testing
Finger-stick ketone meters allow instant testing of beta-hydroxybutyrate levels in the blood, similar to
glucometers. Beta-hydroxybutrate levels in blood can also be measured in a laboratory.
Medical uses
Epilepsy
Ketosis induced by a ketogenic diet is a long-accepted treatment for refractory
epilepsy
Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrica ...
.
Obesity and metabolic syndrome
Ketosis can improve markers of
metabolic syndrome through reduction in serum
triglyceride
A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''tri-'' and ''glyceride'').
Triglycerides are the main constituents of body fat in humans and other vertebrates, as ...
s, elevation in
high-density lipoprotein (HDL) as well as increased size and volume of
low-density lipoprotein
Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall densi ...
(LDL) particles. These changes are consistent with an improved lipid profile despite potential increases in
total cholesterol level.
Safety
The safety of ketosis from low-carbohydrate diets is often called into question by clinicians, researchers and the media.
A common safety concern stems from the misunderstanding of the difference between physiological ketosis and pathologic ketoacidosis.
There is also continued debate whether chronic ketosis is a healthy state or a stressor to be avoided. Some argue that humans evolved to avoid ketosis and should not be in ketosis long-term.
[ The counter-argument is that there is no physiological requirement for dietary carbohydrate as adequate energy can be made via gluconeogenesis and ketogenesis indefinitely.] Alternatively, the switching between a ketotic and fed state has been proposed to have beneficial effects on metabolic and neurologic health. The effects of sustaining ketosis for up to two years are known from studies of people following a strict ketogenic diet for epilepsy or type 2 diabetes; these include short-term adverse effects leading to potential long-term ones. However, literature on longer term effects of intermittent ketosis is lacking.
Medication considerations
Some medications require attention when in a state of ketosis, especially several classes of diabetes medication. SGLT2 inhibitor medications have been associated with cases of euglycemic ketoacidosis- a rare state of high ketones causing a metabolic acidosis with normal blood glucose levels. This usually occurs with missed insulin doses, illness, dehydration or adherence to a low-carbohydrate diet while taking the medication. Additionally, medications used to directly lower blood glucose including insulin and sulfonylureas may cause hypoglycemia if they are not titrated prior to starting a diet that results in ketosis.
Adverse effects
There may be side effects when changing over from glucose metabolism to fat metabolism. These may include headache, fatigue, dizziness, insomnia, difficulty in exercise tolerance, constipation, and nausea, especially in the first days and weeks after starting a ketogenic diet. Breath may develop a sweet, fruity flavor via production of acetone that is exhaled because of its high volatility.
Most adverse effects of long-term ketosis reported are in children because of its longstanding acceptance as a treatment for pediatric epilepsy. These include compromised bone health, stunted growth, hyperlipidemia, and kidney stones.
Contraindications
Ketosis induced by a ketogenic diet should not be pursued by people with pancreatitis
Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormones. There are two main types: acute pancreatitis, and chronic p ...
because of the high dietary fat content. Ketosis is also contraindicated in pyruvate carboxylase deficiency
Pyruvate carboxylase deficiency is an inherited disorder that causes lactic acid to accumulate in the blood. High levels of these substances can damage the body's organs and tissues, particularly in the nervous system. Pyruvate carboxylase defic ...
, porphyria, and other rare genetic disorders of fat metabolism.
Veterinary medicine
In dairy cattle, ketosis commonly occurs during the first weeks after giving birth to a calf and is sometimes referred to as ''acetonemia''. This is the result of an energy deficit when intake is inadequate to compensate for the increased metabolic demand of lactating. The elevated β-hydroxybutyrate concentrations can depress gluconeogenesis, feed intake and the immune system, as well as have an impact on milk composition. Point of care diagnostic tests can be useful to screen for ketosis in cattle.
In sheep
Sheep or domestic sheep (''Ovis aries'') are domesticated, ruminant mammals typically kept as livestock. Although the term ''sheep'' can apply to other species in the genus '' Ovis'', in everyday usage it almost always refers to domesticate ...
, ketosis, evidenced by hyperketonemia with beta-hydroxybutyrate
β-Hydroxybutyric acid, also known as 3-hydroxybutyric acid or BHB, is an organic compound and a beta hydroxy acid with the chemical formula CH3CH(OH)CH2CO2H; its conjugate base is β-hydroxybutyrate, also known as 3-hydroxybutyrate. β-Hydroxy ...
in blood over 0.7 mmol/L, is referred to as ''pregnancy toxemia''.[Pugh, D. G. 2002. Sheep and goat medicine. Saunders, Philadelphia. 468 pp.][Kimberling, C. V. 1988. Jensen and Swift's diseases of sheep. 3rd Ed. Lea & Febiger, Philadelphia. 394 pp.] This may develop in late pregnancy in ewes bearing multiple fetuses and is associated with the considerable metabolic demands of the pregnancy. In ruminants, because most glucose in the digestive tract is metabolized by rumen
The rumen, also known as a paunch, is the largest stomach compartment in ruminants and the larger part of the reticulorumen, which is the first chamber in the alimentary canal of ruminant animals. The rumen's microbial favoring environment al ...
organisms, glucose must be supplied by gluconeogenesis. Pregnancy toxemia is most likely to occur in late pregnancy due to metabolic demand from rapid fetal growth and may be triggered by insufficient feed energy intake due to weather conditions, stress or other causes. Prompt recovery may occur with natural parturition, Caesarean section or induced abortion. Prevention through appropriate feeding and other management is more effective than treatment of advanced stages of pregnancy toxemia.
See also
*Bioenergetics
Bioenergetics is a field in biochemistry and cell biology that concerns energy flow through living systems. This is an active area of biological research that includes the study of the transformation of energy in living organisms and the study of ...
* Ketonuria
* Ketogenic diet
*Very-low-calorie diet
A very-low-calorie diet (VLCD), also known as semistarvation diet and crash diet, is a type of diet with very or extremely low daily food energy consumption. Often described as a fad diet, it is defined as a diet of per day or less. Modern medica ...
* Inuit cuisine
References
Further reading
*
*
*
External links
*
NHS Direct: Ketosis
* The Merck Manual —
{{Lipid metabolism
Metabolism