Ketosis

Ketosis is a state of elevated levels of ketone bodies 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 when liver glycogen stores are depleted. The ketone bodies acetoacetate and β-hydroxybutyrate are used for energy.

Metabolic pathways
When glycogen stores are not available in the cells, fat (triacylglycerol) is cleaved to provide 3 fatty acid chains and 1 glycerol molecule in a process known as lipolysis. 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, which can be further used in the citric acid cycle. During prolonged fasting or starvation, or as the intentional result of a ketogenic diet, acetyl-CoA in the liver is used to produce ketone bodies 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 cannot use long-chain fatty acids for energy because they are completely albumin-bound and cannot cross the blood–brain barrier. Not all medium-chain fatty acids are bound to albumin. The unbound medium-chain fatty acids are soluble in the blood and can cross the blood–brain barrier. 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.

The ketone body acetoacetate will slowly decarboxylate into acetone, a volatile compound that is both metabolized as an energy source and lost in the breath and urine.

Ketoacidosis
Ketone bodies are acidic, but acid-base homeostasis in the blood is normally maintained through bicarbonate buffering, respiratory compensation to vary the amount of CO2 in the bloodstream, hydrogen ion absorption by tissue proteins and bone, and renal compensation through increased excretion of dihydrogen phosphate and ammonium ions. Prolonged excess of ketone bodies can overwhelm normal compensatory mechanisms, leading to acidosis if blood pH falls below 7.35.

There are two major causes of ketoacidosis:
 * Most commonly, ketoacidosis is diabetic ketoacidosis (DKA), resulting from increased fat metabolism due to a shortage of insulin. It is associated primarily with type I diabetes, and may result in a diabetic coma if left untreated.


 * Alcoholic ketoacidosis (AKA) presents infrequently, but can occur with acute alcohol intoxication, most often following a binge in alcoholics with acute or chronic liver or pancreatic disorders. Alcoholic ketoacidosis occurs more frequently following methanol or ethylene glycol intoxication than following intoxication with uncontaminated ethanol.

A mild acidosis may result from prolonged fasting or when following a ketogenic diet or a very low calorie diet.

Diet
If the diet is changed from one that is high in carbohydrates to one 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, and the adult brain 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 as a medical intervention in cases of intractable epilepsy. Other uses of low-carbohydrate diets remain controversial. Induced ketosis or low-carbohydrate diet terms have very wide interpretation. Therefore Stephen S. Phinney and James S. Volek coined the term nutritional ketosis to avoid the confusion.

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, which, in turn, can be used to give a rough estimation of the level of hyperketonemia in the body (see table below). Alternatively, some products targeted to diabetics such as the Abbott Precision Xtra or the Nova Max can be used to take a blood sample and measure the ketone levels directly. 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, one's breath may smell of acetone. This is due to the breakdown of acetoacetic acid into acetone and carbon dioxide which is exhaled through the lungs. Acetone is the chemical responsible for the smell of nail polish remover and some paint thinners.

Controversy
Some clinicians regard restricting a diet from all carbohydrates as unhealthy and dangerous. However, it is not necessary to completely eliminate all carbohydrates from the diet in order to achieve a state of ketosis. Other clinicians (Jeff S. Volek, Stephen D. Phinney, Eric W. Westman to name a few) regard ketosis as a safe biochemical process that occurs during the fat-burning state. Ketogenesis can occur solely from the byproduct of fat degradation: acetyl-CoA. Ketosis, which is accompanied by gluconeogenesis (the creation of glucose de novo from pyruvate), is the specific state with which some clinicians are concerned. However, it is unlikely for a normal functioning person to reach life-threatening levels of ketosis, defined as serum beta-hydroxybutyrate (B-OHB) levels above 15 millimolar (mM) compared to ketogenic diets among non diabetics which "rarely run serum B-OHB levels above 3 mM." This is avoided with proper basal secretion of pancreatic insulin. People who are unable to secrete basal insulin, such as type 1 diabetics and long-term type II diabetics, are liable to enter an unsafe level of ketosis, causing an eventual comatose state that requires emergency medical treatment.

The anti-ketosis conclusions have been challenged by a number of doctors and advocates of low-carbohydrate diets, who dispute assertions that the body has a preference for glucose and that there are dangers associated with ketosis. The Inuit are an example of a culture that has lived for thousands of years on a ketogenic diet: traditional Inuit diets rely on fats and proteins for as much as 90% of total energy intake. Whether this diet is safe for non-Inuit is disputed: Nick Lane speculates that the Inuit may have a genetic predisposition allowing them to eat a ketogenic diet and remain healthy. According to this view, such an evolutionary adaptation would have been caused by environmental stresses. This speculation is unsupported, however, in light of the many arctic explorers, including John Rae, Fridtjof Nansen, and Frederick Schwatka, who adapted to native ketogenic diets with no adverse effects. Schwatka specifically commented that after a 2- to 3-week period of adaptation to the ketogenic diet of the native peoples he could manage "prolonged sledge journeys," including the longest sledge journey on record, relying solely on the Inuit diet without difficulty. Furthermore, in a comprehensive review of the anthropological and nutritional evidence collected on 229 hunter-gatherer societies it was found that, "Most (73%) of the worldwide hunter-gatherer societies derived >50% (≥56–65% of energy) of their subsistence from animal foods, whereas only 14% of these societies derived >50% (≥56–65% of energy) of their subsistence from gathered plant foods," suggesting that the ability to thrive on ketogenic diets is widespread and not limited to any particular genetic predisposition. 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. It seems appropriate that some clinicians refer to this period of keto-adaptation as the "Schwatka Imperative" after the explorer who first identified the transition period from glucose-adaptation to keto-adaptation.

Veterinary medicine
In dairy cattle, ketosis is a common ailment that usually occurs during the first weeks after giving birth to a calf. Ketosis is in these cases sometimes referred to as acetonemia. A study from 2011 revealed that whether ketosis is developed or not depends on the lipids a cow uses to create butterfat. Animals prone to ketosis mobilize fatty acids from adipose tissue, while robust animals create fatty acids from blood phosphatidylcholine (lecithin). Healthy animals can be recognized by high levels of milk glycerophosphocholine and low levels of milk phosphocholine.

In sheep, ketosis, evidenced by hyperketonemia with beta-hydroxybutyrate in blood over 0.7 mmol/L, occurs in pregnancy toxemia. This may develop in late pregnancy in ewes bearing multiple fetuses, and is associated with the considerable glucose demands of the conceptuses. In ruminants, because most glucose in the digestive tract is metabolized by rumen organisms, glucose must be supplied by gluconeogenesis, for which propionate (produced by rumen bacteria and absorbed across the rumen wall) is normally the principal substrate in sheep, with other gluconeogenic substrates increasing in importance when glucose demand is high or propionate is limited. Pregnancy toxemia is most likely to occur in late pregnancy because most fetal growth (and hence most glucose demand) occurs in the final weeks of gestation; it may be triggered by insufficient feed energy intake (anorexia due to weather conditions, stress or other causes), necessitating reliance on hydrolysis of stored triglyceride, with the glycerol moiety being used in gluconeogenesis and the fatty acid moieties being subject to oxidation, producing ketone bodies. Among ewes with pregnancy toxemia, beta-hydroxybutyrate in blood tends to be higher in those that die than in survivors. 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 ovine ketosis.