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Ketosis

Ketosis

Overview
Ketosis is a state of elevated levels of ketone bodies
Ketone bodies
Ketone bodies are three water-soluble compounds that are produced as by-products when fatty acids are broken down for energy in the liver and kidney. They are used as a source of energy in the heart and brain. In the brain, they are a vital source of energy during fasting...

 in the body. It is almost always generalized throughout the body, with hyperketonemia, that is, an elevated level of ketone bodies in the blood. Ketone bodies are formed by ketogenesis
Ketogenesis
Ketogenesis is the process by which ketone bodies are produced as a result of fatty acid breakdown.-Production:Ketone bodies are produced mainly in the mitochondria of liver cells. Its synthesis occurs in response to low glucose levels in the blood, and after exhaustion of cellular carbohydrate...

 when the liver glycogen
Glycogen
Glycogen is a molecule that serves as the secondary long-term energy storage in animal and fungal cells, with the primary energy stores being held in adipose tissue...

 stores are depleted. The ketone bodies acetoacetate and β-hydroxybutyrate are used for energy.


When glycogen
Glycogen
Glycogen is a molecule that serves as the secondary long-term energy storage in animal and fungal cells, with the primary energy stores being held in adipose tissue...

 stores are not available in the cells, fat (triacylglycerol) is cleaved to give 3 fatty acid
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...

 chains and 1 glycerol
Glycerol
Glycerol is a simple polyol compound. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol has three hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. The glycerol backbone is central to all lipids...

 molecule in a process called lipolysis
Lipolysis
Lipolysis is the breakdown of lipids and involves the hydrolysis of triglycerides into free fatty acids followed by further degradation into acetyl units by beta oxidation. The process produces Ketones, which are found in large quantities in ketosis, a metabolic state that occurs when the liver...

.
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Encyclopedia
Ketosis is a state of elevated levels of ketone bodies
Ketone bodies
Ketone bodies are three water-soluble compounds that are produced as by-products when fatty acids are broken down for energy in the liver and kidney. They are used as a source of energy in the heart and brain. In the brain, they are a vital source of energy during fasting...

 in the body. It is almost always generalized throughout the body, with hyperketonemia, that is, an elevated level of ketone bodies in the blood. Ketone bodies are formed by ketogenesis
Ketogenesis
Ketogenesis is the process by which ketone bodies are produced as a result of fatty acid breakdown.-Production:Ketone bodies are produced mainly in the mitochondria of liver cells. Its synthesis occurs in response to low glucose levels in the blood, and after exhaustion of cellular carbohydrate...

 when the liver glycogen
Glycogen
Glycogen is a molecule that serves as the secondary long-term energy storage in animal and fungal cells, with the primary energy stores being held in adipose tissue...

 stores are depleted. The ketone bodies acetoacetate and β-hydroxybutyrate are used for energy.

Metabolic pathways


When glycogen
Glycogen
Glycogen is a molecule that serves as the secondary long-term energy storage in animal and fungal cells, with the primary energy stores being held in adipose tissue...

 stores are not available in the cells, fat (triacylglycerol) is cleaved to give 3 fatty acid
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...

 chains and 1 glycerol
Glycerol
Glycerol is a simple polyol compound. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol has three hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. The glycerol backbone is central to all lipids...

 molecule in a process called lipolysis
Lipolysis
Lipolysis is the breakdown of lipids and involves the hydrolysis of triglycerides into free fatty acids followed by further degradation into acetyl units by beta oxidation. The process produces Ketones, which are found in large quantities in ketosis, a metabolic state that occurs when the liver...

. Most of the body is able to use fatty acids as an alternative source of energy in a process called beta-oxidation. One of the products of beta-oxidation is acetyl-CoA
Acetyl-CoA
Acetyl coenzyme A or acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions. Its main function is to convey the carbon atoms within the acetyl group to the citric acid cycle to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester...

, which can be further used in the Krebs cycle
Citric acid cycle
The citric acid cycle — also known as the tricarboxylic acid cycle , the Krebs cycle, or the Szent-Györgyi-Krebs cycle — is a series of chemical reactions which is used by all aerobic living organisms to generate energy through the oxidization of acetate derived from carbohydrates, fats and...

. During prolonged fasting or starvation, acetyl-CoA in the liver is used to produce ketone bodies
Ketone bodies
Ketone bodies are three water-soluble compounds that are produced as by-products when fatty acids are broken down for energy in the liver and kidney. They are used as a source of energy in the heart and brain. In the brain, they are a vital source of energy during fasting...

 instead, leading to a state of ketosis.

During starvation or a long physical training session, the body starts using fatty acids instead of glucose. The brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...

 cannot use long-chain fatty acids for energy because they are completely albumin-bound and cannot cross the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...

. Not all medium-chain fatty acids
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...

 are bound to albumin. The unbound medium-chain fatty acids are soluble in the blood and can cross the blood-brain barrier.http://www.ajcn.org/cgi/reprint/52/3/502.pdf The ketone bodies produced in the liver can also cross the blood-brain barrier. In the brain, these ketone bodies are then incorporated into acetyl-CoA and used in the citric acid cycle
Citric acid cycle
The citric acid cycle — also known as the tricarboxylic acid cycle , the Krebs cycle, or the Szent-Györgyi-Krebs cycle — is a series of chemical reactions which is used by all aerobic living organisms to generate energy through the oxidization of acetate derived from carbohydrates, fats and...

.

The ketone body acetoacetate will slowly decarboxylate into acetone
Acetone
Acetone is the organic compound with the formula 2CO, a colorless, mobile, flammable liquid, the simplest example of the ketones.Acetone is miscible with water and serves as an important solvent in its own right, typically as the solvent of choice for cleaning purposes in the laboratory...

, a volatile compound that is both metabolized as an energy source and lost in the breath and urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...

.

Ketoacidosis



Ketone bodies
Ketone bodies
Ketone bodies are three water-soluble compounds that are produced as by-products when fatty acids are broken down for energy in the liver and kidney. They are used as a source of energy in the heart and brain. In the brain, they are a vital source of energy during fasting...

 are acidic, but acid-base homeostasis
Acid-base homeostasis
Acid–base homeostasis is the part of human homeostasis concerning the proper balance between acids and bases, in other words, the pH. The body is very sensitive to its pH level, so strong mechanisms exist to maintain it...

 in the blood is normally maintained through bicarbonate buffering
Bicarbonate buffering system
The bicarbonate buffering system is an important buffer system in the acid-base homeostasis of living things, including humans. As a buffer, it tends to maintain a relatively constant plasma pH and counteract any force that would alter it....

, respiratory compensation
Respiratory compensation
Respiratory compensation is a mechanism by which plasma pH can be altered by varying the respiratory rate. It is faster than renal compensation, but has less ability to restore normal values....

 to vary the amount of CO2 in the bloodstream, hydrogen ion absorption by tissue proteins and bone, and renal compensation
Renal compensation
Renal compensation is a mechanism by which the kidneys can regulate the plasma pH. It is slower than respiratory compensation, but has a greater ability to restore normal values....

 through increased excretion of dihydrogen phosphate and ammonium
Ammonium
The ammonium cation is a positively charged polyatomic cation with the chemical formula NH. It is formed by the protonation of ammonia...

 ions. Prolonged excess of ketone bodies can overwhelm normal compensatory mechanisms, leading to acidosis
Acidosis
Acidosis is an increased acidity in the blood and other body tissue . If not further qualified, it usually refers to acidity of the blood plasma....

 if blood pH falls below 7.35.

There are two major causes of ketoacidosis:
  • Most commonly, ketoacidosis is diabetic ketoacidosis
    Diabetic ketoacidosis
    Diabetic ketoacidosis is a potentially life-threatening complication in patients with diabetes mellitus. It happens predominantly in those with type 1 diabetes, but it can occur in those with type 2 diabetes under certain circumstances...

     (DKA), resulting from increased fat metabolism due to a shortage of insulin
    Insulin
    Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....

    . It is associated primarily with type I diabetes
    Diabetes mellitus type 1
    Diabetes mellitus type 1 is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose...

    , and may result in a diabetic coma
    Diabetic coma
    Diabetic coma is a reversible form of coma found in people with diabetes mellitus. It is a medical emergency.Three different types of diabetic coma are identified:#Severe diabetic hypoglycemia...

     if left untreated.

  • Alcoholic ketoacidosis (AKA) presents infrequently, but can occur with acute alcohol intoxication, most often following a binge in alcoholics
    Alcoholism
    Alcoholism is a broad term for problems with alcohol, and is generally used to mean compulsive and uncontrolled consumption of alcoholic beverages, usually to the detriment of the drinker's health, personal relationships, and social standing...

     with acute or chronic liver or pancreatic disorders. Alcoholic ketoacidosis occurs more frequently following methanol
    Methanol
    Methanol, also known as methyl alcohol, wood alcohol, wood naphtha or wood spirits, is a chemical with the formula CH3OH . It is the simplest alcohol, and is a light, volatile, colorless, flammable liquid with a distinctive odor very similar to, but slightly sweeter than, ethanol...

     or ethylene glycol
    Ethylene glycol
    Ethylene glycol is an organic compound widely used as an automotive antifreeze and a precursor to polymers. In its pure form, it is an odorless, colorless, syrupy, sweet-tasting liquid...

     intoxication than following intoxication with uncontaminated ethanol
    Ethanol
    Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...

    .


Ketoacidosis may also result from prolonged fasting or when following a ketogenic diet
Ketogenic diet
The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet that in medicine is used primarily to treat difficult-to-control epilepsy in children. The diet mimics aspects of starvation by forcing the body to burn fats rather than carbohydrates...

.

Diet


If the diet is changed from a highly glycemic
Glycemic index
The glycemic index, glycaemic index, or GI is a measure of the effects of carbohydrates on blood sugar levels. Carbohydrates that break down quickly during digestion and release glucose rapidly into the bloodstream have a high GI; carbohydrates that break down more slowly, releasing glucose more...

 diet to a diet that does not provide sufficient carbohydrate to replenish glycogen stores, the body goes through a set of stages to enter ketosis. During the initial stages of this process, blood glucose levels are maintained through gluconeogenesis
Gluconeogenesis
Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids....

, and the adult brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...

 does not burn ketones; however, the brain makes immediate use of ketones for lipid synthesis in the brain. After about 48 hours of this process, the brain starts burning ketones in order to more directly use the energy from the fat stores that are being depended upon, and to reserve the glucose only for its absolute needs, thus avoiding the depletion of the body's protein store in the muscles.

Ketosis is deliberately induced by use of a ketogenic diet
Ketogenic diet
The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet that in medicine is used primarily to treat difficult-to-control epilepsy in children. The diet mimics aspects of starvation by forcing the body to burn fats rather than carbohydrates...

 as a medical intervention in cases of intractable epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...

. Other uses of low-carbohydrate diet
Low-carbohydrate diet
Low-carbohydrate diets or low-carb diets are dietary programs that restrict carbohydrate consumption usually for weight control or for the treatment of obesity. Foods high in digestible carbohydrates are limited or replaced with foods containing a higher percentage of proteins and fats...

s remain controversial.

Diagnosis


Whether ketosis is taking place can be checked by using special urine test strips such as Ketostix. The strips have a small pad on the end which is dipped in a fresh specimen of urine. Within a matter of seconds, the strip changes color indicating the level of ketone bodies detected, which reflects the degree of ketonuria
Ketonuria
Ketonuria is a medical condition in which ketone bodies are present in the urine.It is seen in conditions in which the body produces excess ketones as an alternative source of energy. It is seen during starvation or more commonly in type I diabetes mellitus...

, which, in turn, can be used to give a rough estimation of the level of hyperketonemia in the body (see table below). Normal serum reference ranges for ketone bodies are 0.5-3.0 mg/dL, equivalent to 0.05-0.29 mmol/L.

Also, when the body is in ketosis, subjects often smell of acetone. Some find the smell offensive as acetone is the same chemical responsible for the smell in paint thinner and nail polish remover.
Urine
value
| Designation | Approximate serum concentration
mg/dL
Mass concentration
In astronomy or astrophysics mass concentration or mascon is a region of a planet or moon's crust that contains a large positive gravitational anomaly. In general, the word "mascon" can be used as a noun to describe an excess distribution of mass on or beneath the surface of a planet , such as Hawaii...

 
mmol/l
0 Negative Reference range
Reference range
In health-related fields, a reference range or reference interval usually describes the variations of a measurement or value in healthy individuals...

: 0.5-3.0
0.05-0.29
1+ 5 (interquartile range
Interquartile range
In descriptive statistics, the interquartile range , also called the midspread or middle fifty, is a measure of statistical dispersion, being equal to the difference between the upper and lower quartiles...

 
(IQR): 1-9)
0.5 (IQR: 0.1–0.9)
2+ Ketonuria 7 (IQR: 2-19) 0.7 (IQR: 0.2–1.8)
3+ 30 (IQR: 14-54) 3 (IQR: 1.4–5.2)
4+ Severe ketonuria - -

Controversy


Some clinicians regard ketosis as a dangerous and potentially life-threatening state that stresses the liver. Ketogenesis can occur solely from the byproduct of fat degradation: acetyl-CoA
Acetyl-CoA
Acetyl coenzyme A or acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions. Its main function is to convey the carbon atoms within the acetyl group to the citric acid cycle to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester...

. Ketosis, which is accompanied by gluconeogenesis
Gluconeogenesis
Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids....

 (the creation of glucose de novo from pyruvate), is the specific state with which clinicians are concerned.

The anti-ketosis conclusions have been challenged by a number of doctors and advocates of low-carbohydrate diet
Low-carbohydrate diet
Low-carbohydrate diets or low-carb diets are dietary programs that restrict carbohydrate consumption usually for weight control or for the treatment of obesity. Foods high in digestible carbohydrates are limited or replaced with foods containing a higher percentage of proteins and fats...

s, who dispute assertions that the body has a preference for glucose and that there are dangers associated with ketosis. It has been argued that the Inuit
Inuit
The Inuit are a group of culturally similar indigenous peoples inhabiting the Arctic regions of Canada , Denmark , Russia and the United States . Inuit means “the people” in the Inuktitut language...

 lived for thousands of years on a diet that would have been ketogenic, and there are many documented cases of modern humans living in these societies for extended periods of time. On the other hand, it is speculated by Nick Lane
Nick Lane
Nick Lane is a British biochemist. He holds the post of honorary reader and is the first Provost's Venture Research Fellow at University College London and was formerly strategic director at Adelphi MediCine, a medical multimedia company. He is the author of three popular science books and many...

  that the Inuit may have a genetic predisposition allowing them to healthfully eat a ketogenic diet. According to this view, such an evolutionary adaptation would have been caused by environmental stresses. While it is believed that carbohydrate intake after exercise is the most effective way of replacing depleted glycogen stores , studies have shown that, after a period of 2–4 weeks of adaptation, physical endurance (as opposed to physical intensity) is unaffected by ketosis, as long as the diet contains high amounts of fat.

See also

  • Ketoacidosis
    Ketoacidosis
    Ketoacidosis is a metabolic state associated with high concentrations of ketone bodies, formed by the breakdown of fatty acids and the deamination of amino acids. The two common ketones produced in humans are acetoacetic acid and β-hydroxybutyrate....

  • Ketogenic diet
    Ketogenic diet
    The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet that in medicine is used primarily to treat difficult-to-control epilepsy in children. The diet mimics aspects of starvation by forcing the body to burn fats rather than carbohydrates...

  • Ketonuria
    Ketonuria
    Ketonuria is a medical condition in which ketone bodies are present in the urine.It is seen in conditions in which the body produces excess ketones as an alternative source of energy. It is seen during starvation or more commonly in type I diabetes mellitus...

  • Low-carbohydrate diet
    Low-carbohydrate diet
    Low-carbohydrate diets or low-carb diets are dietary programs that restrict carbohydrate consumption usually for weight control or for the treatment of obesity. Foods high in digestible carbohydrates are limited or replaced with foods containing a higher percentage of proteins and fats...

  • Fasting
    Fasting
    Fasting is primarily the act of willingly abstaining from some or all food, drink, or both, for a period of time. An absolute fast is normally defined as abstinence from all food and liquid for a defined period, usually a single day , or several days. Other fasts may be only partially restrictive,...

  • Ketogenesis
    Ketogenesis
    Ketogenesis is the process by which ketone bodies are produced as a result of fatty acid breakdown.-Production:Ketone bodies are produced mainly in the mitochondria of liver cells. Its synthesis occurs in response to low glucose levels in the blood, and after exhaustion of cellular carbohydrate...


External links