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Ketosis
Other namesKetonemia
Ketone bodies: acetone, acetoacetic acid, and beta-hydroxybutyric acid
Pronunciation
SpecialtyEndocrinology

Ketosis is a metabolic state characterized by elevated levels of ketone bodies in the blood or urine. Physiological ketosis is a normal response to low glucose availability. 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, an uncontrolled production of ketones that occurs in pathologic states and causes a metabolic acidosis, which is a medical emergency. Ketoacidosis is most commonly the result of complete insulin deficiency in type 1 diabetes or late-stage type 2 diabetes. 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.[1]

Trace levels of ketones are always present in the blood and increase when blood glucose reserves are low and the liver shifts from primarily metabolizing carbohydrates to metabolizing fatty acids.[2] This occurs during states of increased fatty acid oxidation such as fasting, 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: pyruvate, acetoacetate, beta-hydroxybutyrate, and acetone.[1][2] These ketone bodies can function as an energy source as well as signalling molecules.[3] 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.[2]

When ketosis is induced by carbohydrate restriction, it is sometimes called nutritional ketosis. This may be done intentionally, as a low-carbohydrate diet for weight loss or lifestyle reasons. It may also be done medically, such as the ketogenic diet for refractory epilepsy in children or for treating type 2 diabetes.[4]

Definitions

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Normal serum levels of ketone bodies are less than 0.5 mM. Hyperketonemia is conventionally defined as levels in excess of 1 mM.[1]

Physiological ketosis

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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 medical ketogenic diet or the lifestyle "keto" diet.[5] In physiological ketosis, serum ketone levels generally remain below 3 mM.[1]

Ketoacidosis

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Ketoacidosis is a pathological state of uncontrolled production of ketones that results in a metabolic acidosis, 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, or isopropyl alcohol ingestion.[1][2] Ketoacidosis causes significant metabolic derangements and is a life-threatening medical emergency.[2] Ketoacidosis is distinct from physiological ketosis as it requires failure of the normal regulation of ketone body production.[6][5]

Causes

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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 and blood glucose reserves are low, a metabolic shift occurs in order to save glucose for the brain which is unable to use fatty acids 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.[2][3] 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.[1][2]

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.[7][8]

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.[1][9]

Biochemistry

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The precursors of ketone bodies include fatty acids from adipose tissue or the diet and ketogenic amino acids.[10][11] 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 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.[12] 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, where it undergoes an aldol condensation with oxaloacetate to form citric acid; citric acid then enters the tricarboxylic acid cycle (TCA), which harvests a very high energy yield per carbon in the original fatty acid.[13]

Biochemical pathway of ketone synthesis in the liver and utilization by organs
Biochemical pathway of ketone synthesis in the liver and utilization by organs

Acetyl-CoA can be metabolized through the TCA cycle in any cell, but it can also undergo ketogenesis in the mitochondria of liver cells.[1] 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 via thiolase. Acetoacetyl-CoA briefly combines with another acetyl-CoA via HMG-CoA synthase to form hydroxy-β-methylglutaryl-CoA. Hydroxy-β-methylglutaryl-CoA form the ketone body acetoacetate via HMG-CoA lyase. 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, 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.[11]

Measurement

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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

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Test for ketonuria using Bayer Ketostix reagent strips

Urine testing is the most common method of testing for ketones. Urine test strips utilize a nitroprusside 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.[1][8]

Serum testing

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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.[1]

Medical uses

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Epilepsy

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Ketosis induced by a ketogenic diet is a long-accepted treatment for refractory epilepsy.[14]

Obesity and metabolic syndrome

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Ketosis can improve markers of metabolic syndrome through reduction in serum triglycerides, elevation in high-density lipoprotein (HDL) as well as increased size and volume of low-density lipoprotein (LDL) particles. These changes are consistent with an improved lipid profile despite potential increases in total cholesterol level.[7][15]

Safety

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The safety of ketosis from low-carbohydrate diets is often called into question by clinicians, researchers and the media.[16][17][18] A common safety concern stems from the misunderstanding of the difference between physiological ketosis and pathologic ketoacidosis.[6][7] 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.[18] The counter-argument is that there is no physiological requirement for dietary carbohydrates, as adequate energy can be made via gluconeogenesis and ketogenesis indefinitely.[19] Alternatively, the switching between a ketotic and fed state has been proposed to have beneficial effects on metabolic and neurologic health.[3] 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.[20] However, literature on longer term effects of intermittent ketosis is lacking.[20]

Medication considerations

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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.[21] 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.[20]

Adverse effects

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There may be side effects when changing over from glucose metabolism to fat metabolism.[22] 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.[20] Breath may develop a sweet, fruity flavor via production of acetone that is exhaled because of its high volatility.[7]

Most adverse effects of long-term ketosis are reported among children because of its longstanding acceptance as a treatment for pediatric epilepsy. These include compromised bone health, stunted growth, hyperlipidemia, and kidney stones.[23]

Contraindications

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Ketosis induced by a ketogenic diet should not be pursued by people with pancreatitis because of the high dietary fat content. Ketosis is also contraindicated in pyruvate carboxylase deficiency, porphyria, and other rare genetic disorders of fat metabolism.[24]

Veterinary medicine

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Cattle

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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 most likely the result of an energy deficit when intake is inadequate to compensate for the increased metabolic demand of lactating.[25] The elevated β-hydroxybutyrate concentrations can depress gluconeogenesis, feed intake and the immune system, as well as have an impact on milk composition.[26] Point of care diagnostic tests can be useful to screen for ketosis in cattle.[27]

Sheep

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In sheep, ketosis, evidenced by hyperketonemia with beta-hydroxybutyrate in blood over 0.7 mmol/L, is referred to as pregnancy toxemia.[28][29] This may develop in late pregnancy in ewes bearing multiple fetuses and is associated with the considerable metabolic demands of the pregnancy.[30][31] In ruminants, because most glucose in the digestive tract is metabolized by rumen organisms, glucose must be supplied by gluconeogenesis.[32] 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.[29] 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.[33]

See also

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References

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Further reading

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Ketosis

View on Grokipedia
from Grokipedia
Ketosis is a physiological metabolic state in which the body shifts from using glucose as its primary energy source to utilizing ketone bodies, which are produced in the liver from fatty acids during periods of low carbohydrate availability or fasting. This process, known as ketogenesis, occurs primarily in the mitochondria of hepatocytes and results in elevated blood ketone levels, typically in the range of 0.5–3.0 mmol/L for nutritional ketosis, although in long-term keto-adapted individuals, circulating levels often stabilize at lower values (typically 0.5–1.5 mmol/L) due to increased efficiency in ketone utilization by tissues despite ongoing deep ketosis. These ketones provide an alternative fuel for tissues such as the brain, heart, and skeletal muscles when glycogen stores are depleted. Unlike pathological ketoacidosis, which involves dangerously high ketone levels leading to metabolic acidosis, ketosis is a regulated, adaptive response that supports energy homeostasis without significant pH disruption in healthy individuals. The of ketosis involves the breakdown of free fatty acids via beta-oxidation in the liver, yielding that is then converted into the acetoacetate, beta-hydroxybutyrate, and acetone. These ketones are water-soluble and can cross the blood-brain barrier, serving as an efficient energy substrate during prolonged energy deficits, thereby sparing glucose for essential functions like metabolism. Hormonal regulation plays a key role, with low insulin and elevated , , and catecholamines promoting and while suppressing glucose utilization. Common causes of ketosis include , , or adherence to a , which restricts carbohydrates to less than 50 grams per day to deplete hepatic and induce fat oxidation. It can also arise in conditions of increased availability, such as prolonged exercise or certain metabolic disorders, though it is most notably associated with therapeutic or weight-loss dietary interventions. In the initial adaptation phase to ketosis, often called the "keto flu," individuals may experience transient symptoms including fatigue, headache, irritability, nausea, dizziness, and muscle cramps due to electrolyte shifts and dehydration as the body adjusts to ketone metabolism. Additionally, some individuals report a sweet or fruity taste in the mouth or when drinking water, attributed to the production and buildup of ketones during this phase. Established nutritional ketosis is generally asymptomatic and may confer benefits like improved insulin sensitivity, reduced inflammation, and enhanced endurance in some contexts, though long-term effects require monitoring for potential nutrient deficiencies. Excessive or uncontrolled ketosis risks progression to ketoacidosis, particularly in diabetics, underscoring the importance of medical supervision.

Definitions and Overview

Physiological Ketosis

Physiological ketosis is a normal, adaptive metabolic state in which the liver converts fatty acids into —acetoacetate, beta-hydroxybutyrate, and acetone—to serve as an alternative energy source for the and other glucose-dependent tissues during periods of limited availability. This process enables the body to maintain by shifting from glucose metabolism to fat oxidation, particularly in scenarios such as overnight or moderate caloric restriction. In healthy individuals, blood ketone concentrations in nutritional (diet-induced) physiological ketosis typically range from 0.5 to 3.0 mmol/L, marking a transition from the baseline levels below 0.5 mmol/L observed in a carbohydrate-fed state. During prolonged , another form of physiological ketosis, levels can rise to 3-8 mmol/L and stabilize at elevated concentrations (often 4-7 mmol/L) without causing , underscoring ketosis as an efficient response to preserve glucose for critical functions like . From an evolutionary perspective, physiological ketosis conferred significant survival advantages by allowing humans to endure prolonged food scarcity, such as during periods of , through enhanced fat utilization and reduced reliance on finite stores. For instance, in human physiology, adapted ketosis supplies up to 70% of the brain's requirements, sparing limited glucose and minimizing muscle protein breakdown to maintain vital structures during extended . The metabolic phenomenon of ketosis was first recognized in the through observations in research, notably by Oskar Minkowski, who in 1889 noted in dogs following , highlighting production as a response to impaired glucose regulation.

Ketoacidosis

Ketoacidosis is a life-threatening metabolic condition characterized by the accumulation of excessive in the blood, resulting in severe . It is typically defined by elevated blood beta-hydroxybutyrate levels exceeding 3.0 mmol/L, arterial below 7.3, serum bicarbonate less than 18 mEq/L, and an elevated greater than 10–12 mEq/L. This state arises from an imbalance in and , where the body shifts to production as an alternative energy source, but the production overwhelms buffering mechanisms, leading to acidemia and potential if untreated. Unlike physiological ketosis, represents a pathological emergency requiring immediate medical intervention to prevent complications such as or cardiovascular collapse. The primary forms of ketoacidosis include (DKA), (AKA), and starvation ketoacidosis. DKA most commonly occurs in individuals with due to absolute insulin deficiency, though it can affect those with under stress, and is often a severe emergency. AKA develops in chronic alcohol users following and poor nutritional intake, often presenting after cessation of alcohol with or , and can be life-threatening. Starvation ketoacidosis emerges from prolonged or , where glycogen stores are depleted, prompting accelerated fat breakdown without sufficient availability; it is generally milder than DKA or AKA but can still require medical attention in severe cases. Each type shares the core feature of hyperketonemia but differs in precipitating factors and clinical context. Common symptoms of ketoacidosis reflect the underlying , , and shifts, including , , and , which may mimic an . Patients often exhibit rapid, deep Kussmaul respirations as a compensatory mechanism for , along with a characteristic fruity breath odor from acetone volatilization. Additional signs include , , , , and in severe cases, altered mental status or . These manifestations can progress rapidly, emphasizing the need for prompt recognition. The of centers on relative or absolute insulin deficiency coupled with excess counterregulatory hormones such as , , catecholamines, and . This hormonal imbalance inhibits glucose utilization in peripheral tissues while promoting hepatic , , and , exacerbating in DKA. Concurrently, unchecked in releases free fatty acids to the liver, where they undergo beta-oxidation to form (acetoacetate, beta-hydroxybutyrate, and acetone), overwhelming the body's acid-base . In AKA and starvation forms, similar mechanisms occur but without prominent , driven instead by nutritional deficits and alcohol-induced NADH excess that favors . Diagnosis of , particularly DKA, follows guidelines from the , which specify plasma glucose greater than 250 mg/dL (13.9 mmol/L), though recent consensus allows thresholds as low as 200 mg/dL (11.1 mmol/L) in euglycemic cases; ketonemia with beta-hydroxybutyrate above 3.0 mmol/L; and evidenced by less than 7.3 or below 18 mEq/L. calculation and or serum ketones support confirmation, with blood testing preferred for accuracy.

Causes and Mechanisms

Dietary and Lifestyle Triggers

Ketosis can be intentionally induced through dietary and lifestyle modifications that restrict availability, prompting the body to shift from glucose to fat as its source. Low- diets, particularly the , typically limit daily intake to less than 50 grams total, with most individuals maintaining ketosis at under 50 g total carbohydrates per day and a common range of 20–50 g net carbohydrates; stricter protocols for reliable ketosis often require under 20–30 g net, varying by individual factors such as activity level and metabolism, which can be verified using a blood ketone meter targeting levels above 0.5 mmol/L. This depletes hepatic stores and promotes hepatic while enhancing oxidation in the liver to produce . Protein-sparing modified fast (PSMF) diets, with their severe carbohydrate restriction, naturally induce and deepen ketosis. This metabolic adaptation usually occurs within 2 to 7 days, depending on adherence and individual factors, and results in nutritional ketosis characterized by blood beta-hydroxybutyrate levels of 0.5 to 3.0 mmol/L. Fasting protocols, including complete water fasting or regimens such as 16:8 (16 hours fasting, 8 hours eating window), accelerate ketosis by rapidly exhausting reserves. Liver is largely depleted after 12 to 24 hours of fasting, after which the body mobilizes free fatty acids from for beta-oxidation, leading to elevated production. sustains this state through repeated cycles of carbohydrate restriction, mimicking the metabolic effects of prolonged calorie deprivation without total abstinence. Prolonged endurance exercise, such as marathon running or lasting over 90 minutes, can also trigger ketosis by increasing energy demands that outpace replenishment, thereby boosting and mobilization. During such activities, especially in a fasted or low-carbohydrate state, muscle and hepatic ketone utilization rises, providing an source and potentially delaying . This exercise-induced shift is more pronounced in trained individuals, where adaptations enhance the of fat oxidation pathways. The originated in the 1920s as a therapeutic intervention for , pioneered by Russell Wilder at the , who observed that fasting's effects could be replicated through a high-fat, low-carbohydrate regimen to maintain ketosis. Modern adaptations, including the Atkins diet's induction phase (restricting carbohydrates to under 20 grams daily for 2 weeks) and certain paleo-inspired ketogenic variants emphasizing whole foods like meats, vegetables, and nuts while minimizing grains, have popularized these approaches for and metabolic health. The onset of ketosis varies based on individual , baseline levels influenced by prior high-carbohydrate diets, activity levels, and other factors such as insulin resistance. Most individuals achieve ketosis within 2 to 7 days, with some entering as quickly as 2 to 4 days under strict restriction; however, those transitioning from high-carbohydrate diets or with high insulin resistance may require up to a week or longer, occasionally several weeks. If nutritional ketosis (blood beta-hydroxybutyrate ≥0.5 mmol/L) is not achieved after two weeks of strict adherence to a ketogenic diet, common causes include consuming more net carbohydrates than realized (often exceeding 20–50 g daily due to hidden sources or inaccurate tracking), excessive protein intake that stimulates gluconeogenesis and inhibits ketosis, reliance on urine ketone strips which become unreliable after metabolic adaptation as the body utilizes ketones more efficiently, or individual variability such as severe insulin resistance. To troubleshoot and facilitate entry into ketosis, individuals should strictly track intake to limit net carbohydrates to under 20 g/day, prioritize high-quality fats to comprise approximately 55–60% of total calories, moderate protein consumption, employ a blood ketone meter for accurate confirmation of ketosis, incorporate intermittent fasting or exercise to further deplete glycogen stores, and consult a healthcare professional if ketosis remains elusive despite several weeks of strict adherence.

Pathophysiological Causes

Pathophysiological causes of ketosis primarily arise from conditions that disrupt normal glucose metabolism, leading to increased reliance on fat breakdown for energy and subsequent ketone production, often with severe complications such as ketoacidosis. The most common and critical example is diabetic ketoacidosis (DKA), which occurs in insulin-deficient states, particularly type 1 diabetes mellitus, where absolute or relative insulin deficiency prevents glucose utilization, prompting unchecked lipolysis and hepatic ketogenesis. This insulin shortfall is exacerbated by counterregulatory hormones like glucagon and cortisol, resulting in hyperglycemia, dehydration, and acidosis that can progress to life-threatening metabolic derangement. In type 1 diabetes patients, DKA incidence rates have been reported at approximately 5-6 per 1,000 person-years in community-based studies from the late 2010s, though rates vary by population and can reach higher in youth or those with poor glycemic control. Alcoholic ketoacidosis (AKA) represents another major pathophysiological trigger, typically in individuals with chronic alcohol dependence who experience acute binge drinking followed by abrupt cessation, compounded by malnutrition and dehydration. Heavy alcohol intake inhibits gluconeogenesis and depletes hepatic glycogen stores, while vomiting and poor nutritional intake further promote a catabolic state favoring ketone formation from fatty acids. Dehydration from gastrointestinal losses impairs renal ketone excretion, intensifying acidosis in this setting. AKA is particularly prevalent among malnourished chronic alcoholics, distinguishing it from isolated alcohol effects by the synergistic role of nutrient deficits. Starvation or severe , as seen in eating disorders like , can induce ketosis through prolonged caloric restriction that exhausts reserves and shifts metabolism to . In , extreme food avoidance leads to a fasting-like state, elevating free fatty acids and as the body compensates for energy needs, sometimes progressing to with pH below 7.0. This process is driven by adaptive hormonal changes, including reduced insulin and increased , mirroring physiological but with risks amplified by imbalances and refeeding vulnerabilities. Rarer pathophysiological causes include certain glycogen storage diseases (GSDs), such as GSD type VI (Hers disease), where defective glycogen breakdown impairs glucose release from liver stores, causing hypoglycemia and compensatory ketosis from fat metabolism. Prolonged vomiting, often from gastrointestinal disorders or as a symptom of other illnesses, can precipitate ketosis by inducing a state of effective starvation through fluid and nutrient losses, leading to glycogen depletion and ketone accumulation. Similarly, salicylate poisoning, as in aspirin overdose, stimulates uncoupled oxidative phosphorylation and lipolysis, directly promoting ketogenesis and potentially frank ketoacidosis alongside respiratory alkalosis. A prominent example in contemporary medicine is euglycemic diabetic ketoacidosis induced by SGLT2 inhibitors, a class of glucose-lowering agents used primarily in type 2 diabetes. These drugs promote glycosuria, reduce insulin levels, and enhance lipolysis and ketogenesis, leading to ketoacidosis with blood glucose often below 250 mg/dL, especially under stressors like illness or surgery. In contrast, in conditions characterized by severe insulin resistance with compensatory hyperinsulinemia, such as type 2 diabetes mellitus or metabolic syndrome, spontaneous ketosis is uncommon due to persistent inhibition of lipolysis and ketogenesis by elevated insulin. However, when ketosis is induced through strict dietary carbohydrate restriction, the onset may be delayed compared to individuals with normal insulin sensitivity, sometimes extending to several weeks due to slower reduction in insulin levels and impaired metabolic switching. These uncommon triggers highlight how metabolic stressors beyond diabetes or alcohol can disrupt ketone regulation, often requiring prompt intervention to avert complications.

Biochemistry

Ketone Body Production

are water-soluble metabolites produced primarily in the liver during states of low availability, serving as an alternative energy source to glucose. The three main are acetoacetate, which is the primary product of ; β-hydroxybutyrate (also known as 3-hydroxybutyrate), the most abundant form in circulation comprising approximately 78% of total in blood during ketosis; and acetone, a volatile formed in smaller quantities. Their chemical structures are as follows: acetoacetate (C₄H₅O₃), β-hydroxybutyrate (C₄H₇O₃⁻), and acetone (C₃H₆O). These undergo interconversion to maintain physiological balance. Acetoacetate and β-hydroxybutyrate are reversibly interconverted via the β-hydroxybutyrate (BDH1), which catalyzes the NAD⁺/NADH-dependent reaction in the . Additionally, acetoacetate can spontaneously decarboxylate to form acetone, though this process is non-enzymatic and contributes minimally to . Among the ketone bodies, β-hydroxybutyrate plays a prominent physiological role, particularly as the preferred fuel for the during prolonged or restriction, where it can supply up to 70% of the organ's needs. It efficiently crosses the blood-brain barrier via monocarboxylate transporters (MCT1 and MCT2), enabling rapid utilization by neurons and without the need for insulin. Beyond its role as an energy substrate, recent research has highlighted β-hydroxybutyrate's signaling functions, including its activity as a (HDAC) inhibitor that modulates and exerts effects. For instance, post-2020 studies have demonstrated that β-hydroxybutyrate inhibits HDACs in immune cells, suppressing pro-inflammatory production and M1 macrophage polarization, which may contribute to protective effects in conditions involving chronic inflammation.

Metabolic Pathways

Ketogenesis, the biochemical process responsible for ketone body synthesis, primarily occurs in the mitochondria of hepatocytes during states of low carbohydrate availability. It begins with the transport of free fatty acids into the via (CPT-I), followed by beta-oxidation, which sequentially cleaves the fatty chain to generate multiple molecules of . When the rate of production exceeds the capacity of the —due to diminished oxaloacetate availability from reduced —the excess is shunted into the pathway to prevent harmful accumulation and provide an alternative energy substrate. The core steps of ketogenesis involve the condensation of acetyl-CoA units. First, two molecules of acetyl-CoA are reversibly condensed by the enzyme acetoacetyl-CoA thiolase (also known as 3-ketoacyl-CoA thiolase) to form acetoacetyl-CoA and free coenzyme A: 2 acetyl-CoA⇌acetoacetyl-CoA+CoA-SH2 \text{ acetyl-CoA} \rightleftharpoons \text{acetoacetyl-CoA} + \text{CoA-SH} Next, mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMG-CoA synthase) catalyzes the addition of another acetyl-CoA to acetoacetyl-CoA, yielding 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). Finally, HMG-CoA lyase cleaves HMG-CoA to produce acetoacetate and acetyl-CoA, completing the synthesis of the primary ketone body. Acetoacetate can then be reduced to β-hydroxybutyrate or decarboxylated to acetone, though these conversions occur subsequent to the core pathway./02:_Unit_II-_Bioenergetics_and_Metabolism/17:_Fatty_Acid_Catabolism/17.03:_Ketone_Bodies) Regulation of ketogenesis is tightly controlled by hormonal signals and substrate availability to align with energy demands. A low insulin-to-glucagon ratio, characteristic of or low-carbohydrate states, promotes fatty acid mobilization and inhibits , thereby increasing flux into . enhances this by activating adenylate cyclase, leading to elevated cyclic AMP levels that inhibit ; this reduces production, relieving inhibition of CPT-I and facilitating entry into mitochondria. Conversely, high glucose levels stimulate insulin release, which promotes synthesis via activation, thereby suppressing CPT-I and inhibiting to favor glucose utilization.1520-7560(199911/12)15:6%3C412::AID-DMRR72%3E3.0.CO;2-8) In ketosis, the pathway integrates with via the , where lactate from peripheral tissues serves as a gluconeogenic precursor in the liver, sparing glucose for glucose-dependent tissues while s fuel others, thus optimizing energy distribution without excessive lactate accumulation. Additionally, futile cycles—such as simultaneous synthesis and utilization—are avoided in hepatocytes due to the absence of :3-ketoacid CoA-transferase (SCOT), the enzyme required for body re-activation, preventing energy-wasting recirculation. The energy yield from oxidation underscores their efficiency; complete oxidation of one acetoacetate in extrahepatic tissues generates approximately 22 ATP s through conversion to two units that enter the and .

Diagnosis and Monitoring

Blood and Serum Testing

Blood and serum testing represents the most precise method for diagnosing and monitoring ketosis by quantifying beta-hydroxybutyrate (BHB), the primary ketone body circulating in the blood and the established gold standard for assessment. This approach utilizes point-of-care devices, such as fingerstick blood glucose and ketone meters like the Precision Xtra, which provide rapid results from a small capillary blood sample, or laboratory-based enzymatic assays that analyze serum or plasma specimens for higher accuracy in clinical settings. Interpretation of BHB levels relies on established reference ranges to differentiate physiological from pathological ketosis; concentrations between 0.5 and 3.0 mmol/L typically signify nutritional ketosis associated with ketogenic diets, whereas levels above 3.0 mmol/L indicate elevated risk for , particularly in patients. These thresholds guide clinical decision-making, with BHB offering a direct of production that correlates closely with metabolic state. In individuals adapted to a prolonged ketogenic diet or fasting (keto-adaptation), circulating BHB levels are often lower (typically 0.5–1.5 mmol/L) despite being in deep nutritional ketosis. This occurs because the body becomes highly efficient at utilizing ketones for energy, reducing circulating levels while maintaining ketosis. Other contributing factors may include individual metabolic variations, hormonal influences (e.g., elevated cortisol potentially suppressing ketogenesis), electrolyte imbalances, or insufficient fat mobilization in lean individuals. Blood testing remains the most reliable method for accurate assessment in such cases. Blood and serum BHB testing excels in delivering quantitative, that outperforms indirect alternatives in for detecting and tracking ketosis progression. Its advantages include reliable monitoring of therapeutic responses, such as reduced hospitalization rates in (DKA) cases when used over less precise methods. Nonetheless, drawbacks involve the procedure's relative invasiveness via or fingerstick, elevated costs for meters and disposable strips, and requirements for periodic device maintenance or calibration to ensure accuracy. In clinical protocols for DKA , serial BHB measurements are integral, performed every 2–4 hours to evaluate the efficacy of insulin therapy and confirm ketosis resolution before discontinuing treatment. This iterative testing helps titrate interventions precisely, avoiding over- or under-treatment based on dynamic ketone fluctuations. As of 2025, emerging advancements in continuous monitoring (CKM) systems are in development, featuring subcutaneous sensors that measure interstitial BHB in real time and integrate with continuous glucose monitors to prevent DKA in patients through proactive alerts. These innovations, exemplified by dual glucose-ketone biowearables such as Abbott's sensor—which received FDA device designation and is nearing commercial release following clinical trials—promise enhanced outpatient by providing uninterrupted data streams without repeated blood draws.

Urine and Breath Testing

Urine testing for ketosis primarily involves tests that detect acetoacetate, one of the main excreted in when levels exceed renal capacity. These strips employ a nitroprusside reaction, where acetoacetate reacts with in an alkaline medium to produce a color change, ranging from negative (no ketones) to large (high levels, typically >80 mg/dL or ~8 mmol/L acetoacetate). Users dip the strip in a sample, wait about 15-30 seconds, and compare the color to a provided for semiquantitative results, making it a simple at-home method. However, urine testing has notable limitations compared to blood testing, which is generally more reliable for real-time ketosis assessment. It lags behind blood ketone levels because acetoacetate appears in only after spillover, typically when blood acetoacetate exceeds 1.5 mmol/L, potentially missing early or mild ketosis. Additionally, the test primarily detects acetoacetate and acetone but not beta-hydroxybutyrate (β-HB), the predominant ketone in physiological ketosis and (DKA), leading to false negatives when β-HB dominates (up to 78% of total ketones in DKA). Furthermore, after keto-adaptation from prolonged ketogenic dieting or fasting, the body utilizes ketones more efficiently, resulting in reduced excretion of excess ketones in the urine. Consequently, urine strips often show low or negative results despite the presence of nutritional ketosis, further reducing their reliability for long-term monitoring in adapted individuals. Breath testing offers a non-invasive alternative by measuring exhaled acetone, a volatile ketone derived from acetoacetate , using portable devices such as the Ketonix analyzer. These devices often employ to detect acetone concentrations in breath samples, providing semiquantitative levels categorized as low, medium, or high ketosis without reagents or fluids. In terms of accuracy, urine strips show 70-90% sensitivity for detecting ketosis in diabetic or states, though specificity varies with strip type and hydration status; breath acetone correlates well with ketones, with studies reporting Pearson correlation coefficients around r=0.8-0.9 across total . Both methods are practically suited for daily in ketogenic diets, allowing users to track adherence and adjust intake, with urine strips being particularly cost-effective at under $0.20 per test and breath devices offering reusable, painless over hundreds of uses.

Therapeutic Applications

Epilepsy and Neurological Disorders

The ketogenic diet was first introduced as a treatment for in 1921 by Dr. Russell Wilder at the , who proposed it as a means to replicate the antiseizure benefits observed during by inducing a state of ketosis through a high-fat, low-carbohydrate regimen. This approach gained prominence in the early 20th century as an alternative for patients with drug-resistant , particularly before the widespread availability of antiseizure medications. Over time, variants such as the modified (MAD), which offers a less restrictive ratio of fats to carbohydrates, have been developed to improve adherence while maintaining ketosis and therapeutic effects. The antiepileptic mechanism of ketosis involves , particularly β-hydroxybutyrate (BHB), providing by enhancing gamma-aminobutyric acid (GABA) levels and the GABA/glutamate ratio in the brain, thereby reducing neuronal excitability and seizure susceptibility. This metabolic shift also promotes anaplerosis, replenishing intermediates in the tricarboxylic acid cycle to favor inhibitory neurotransmission over excitatory pathways. In clinical practice, the diet is particularly selected for children with refractory syndromes, such as Lennox-Gastaut syndrome (LGS), where traditional medications often fail, and ongoing monitoring of dietary compliance through blood measurements ensures sustained ketosis. Efficacy data from randomized controlled trials (RCTs) support the use of s in achieving substantial reduction; for instance, a 2008 multicenter RCT involving 145 children with intractable found that 38% of those on the classic experienced greater than 50% reduction after three months, compared to 6% in the control group receiving standard care. Broader evidence from Cochrane reviews indicates that approximately 50-70% of patients with drug-resistant achieve at least a 50% reduction in frequency with ketogenic therapies, with freedom rates ranging from 5-15% depending on the syndrome and diet variant. In LGS specifically, ketogenic diets yield greater than 50% reduction in over half of pediatric cases, highlighting their role as a targeted intervention when initiated early under multidisciplinary supervision.

Obesity and Metabolic Syndrome

Ketogenic diets have been employed to induce ketosis as a strategy for in , leveraging the metabolic shift to fat utilization for energy. The primary mechanism of involves appetite suppression mediated by elevated , which reduce levels—the hormone associated with hunger—while enhancing signals through increased cholecystokinin and . Additionally, the high-fat and moderate-protein composition promotes greater compared to carbohydrate-rich diets, contributing to reduced caloric intake. Initial rapid , often observed in the first week, stems from depletion in liver and muscle tissues, which releases bound and leads to , accounting for 1-2 kg of loss primarily from fluid rather than . In individuals with and , ketosis confers benefits by improving insulin sensitivity, as the low-carbohydrate intake minimizes postprandial glucose spikes and insulin demand, allowing beta cells to recover function. Clinical trials demonstrate reductions in HbA1c levels, typically by 0.5-1.0%, alongside lowered fasting glucose and improved glycemic control. levels also decline significantly, often by 20-50 mg/dL, due to decreased hepatic and increased oxidation during ketosis, which mitigates common in . Long-term adherence to ketogenic diets yields sustained superior to low-fat alternatives, with meta-analyses from the indicating 2-4 kg greater reductions at 12 months, attributed to preserved lean mass and metabolic adaptations. Protocols such as very low-calorie ketogenic diets (VLCKD), restricting carbohydrates to under 50 g/day, protein to 1-1.5 g/kg ideal body weight, and fats to 15-30 g/day for 600-800 kcal total, are effective for severe , often combined with supervised exercise like to enhance fat loss and preserve muscle. For , ketosis promotes reversal of non-alcoholic (NAFLD), with pilot studies showing histologic improvements in , , and in a of patients, though larger trials are needed to confirm rates of resolution, linked to reduced intrahepatic accumulation. These outcomes underscore ketosis as a targeted intervention for endocrine dysregulation, though monitoring for deficiencies remains essential.

Emerging Uses in Other Conditions

Research into the therapeutic potential of ketosis extends beyond established applications in epilepsy and metabolic disorders, with emerging evidence suggesting benefits for neurodegenerative conditions such as . In , ketones serve as an source for the , potentially bypassing glucose impairments associated with neurodegeneration. Clinical trials from 2022 to 2025 have demonstrated cognitive stabilization in patients using (MCT) oil to induce ketosis; for instance, a 2022 study found that 80% of participants with experienced stabilization or improvement in cognition after nine months of continual MCT supplementation. A 2024 review further indicated that MCTs exert beneficial effects on in Alzheimer's and , though measurable clinical improvements are not always observed. These findings highlight ketosis as a promising adjunctive strategy, yet larger randomized controlled trials are needed to confirm efficacy. However, in conditions like advanced cancer, ketosis may be contraindicated due to risks of ; ongoing 2025 trials stress supervised implementation. In cancer adjunct therapy, ketosis is being investigated for its ability to reverse the Warburg effect, whereby tumor cells preferentially rely on for energy. Preclinical studies, particularly in models, show that ketogenic diets inhibit tumor growth by limiting glucose availability and promoting utilization, which normal tumor cells can adapt to but cancer cells struggle with. A 2024 analysis of preclinical models across various cancers reported predominantly favorable survival-prolonging effects with ketogenic diets in monotherapy. For specifically, animal studies have demonstrated reduced lactate generation and tumor progression under ketogenic conditions. While these results support ketosis as a metabolic intervention to enhance standard therapies, human data remain limited to small feasibility trials, underscoring the need for robust clinical validation. Ketosis also shows potential in improving cardiovascular health markers, including increases in high-density lipoprotein (HDL) cholesterol and reductions in inflammation. Cohort studies from 2024 have linked ketogenic diets to favorable changes in serum biomarkers, such as elevated HDL and lowered triglycerides, without adverse impacts on overall cardiovascular risk. A 2025 study in patients with psoriatic arthritis—a condition with elevated cardiovascular risk—reported that strict ketogenic adherence improved lipid profiles, insulin resistance, and blood pressure, thereby mitigating inflammation-driven risks. These effects are attributed to ketosis-induced shifts in lipid metabolism and anti-inflammatory pathways, though long-term outcomes require further investigation in diverse populations. Preliminary evidence suggests ketosis may alleviate symptoms, including reductions in frequency, through stabilization of cerebral and mitigation of hyperexcitability. A 2023 and found that metabolic ketogenic therapies reduced frequency and severity in small human trials, with benefits emerging within weeks of intervention. Similarly, for conditions like , ketogenic diets have demonstrated mood stabilization in pilot studies; a 2024 pilot trial reported positive correlations between blood levels and improvements in daily mood and energy among participants. A 2025 process evaluation of a ketogenic intervention in further supported feasibility and preliminary mood benefits, potentially via enhanced mitochondrial function and reduced . Despite these promising developments, the evidence for ketosis in these emerging applications is predominantly derived from models, case reports, or small-scale trials, limiting generalizability. Comprehensive reviews emphasize the necessity for larger, well-designed randomized controlled trials to establish causality, optimal dosing, and long-term across diverse patient groups.

Safety and Risks

Adverse Effects

Induced ketosis, particularly through ketogenic diets or , can lead to a range of acute adverse effects, most notably the "keto flu," which typically manifests in the first week as the body adapts to restriction. Symptoms include , , , , and , primarily resulting from shifts such as losses of sodium, , and magnesium due to increased and reduced insulin levels. Some individuals also report a sweet taste in the mouth or when drinking plain water, attributed to elevated levels of ketones such as acetone during the onset of ketosis. Gastrointestinal disturbances are common during ketosis induction and maintenance. Constipation arises frequently from low dietary fiber intake inherent to high-fat, low-carbohydrate regimens, affecting up to 33% of individuals in some cohorts. Nausea and diarrhea may also occur as the gut microbiota adjusts to altered macronutrient ratios, while halitosis, often described as a fruity odor, stems from acetone—a ketone body—being exhaled through the lungs. Long-term adherence to strict ketogenic diets raises concerns for nutrient deficiencies, particularly of vitamins such as B vitamins, vitamin C, and folate, due to restricted intake of fruits, vegetables, and grains without supplementation. In children using ketogenic diets for epilepsy management, the risk of kidney stones is substantially elevated, occurring in approximately 5-6% of cases—up to 5 times higher than in the general pediatric population—linked to chronic dehydration, acidosis, and altered urinary chemistry. Musculoskeletal effects include muscle cramps, often tied to ongoing and imbalances, which can persist beyond the initial adaptation phase if and are inadequate. Additionally, some animal studies suggest prolonged ketogenic diets may impair bone health and contribute to loss, potentially through mechanisms like increased acid load or , though human evidence remains limited and mixed, with no significant changes in density observed in available studies. Adverse effects contribute to variable dropout rates in ketogenic diet trials, ranging from 13% to 84% across studies, with side effects often cited as a primary reason for discontinuation among participants pursuing or metabolic benefits. Emerging research as of 2025, primarily from animal models, indicates potential long-term risks including hepatic dysfunction such as , which may increase the risk of cardiovascular issues such as heart disease, and metabolic complications with extended use; human studies are needed to confirm these findings. During extended fasting or prolonged adherence to zero-carbohydrate diets such as the carnivore or Lion diet, ketone production increases as glucose stores are depleted and the body relies on fat for fuel, leading to deeper nutritional ketosis with blood ketone levels typically rising to 1-5 mmol/L or higher. This is normal and generally safe for healthy individuals. However, very prolonged fasts or severe caloric restriction can risk progression to starvation ketoacidosis in some cases, particularly with comorbidities or other predisposing factors. Monitoring levels and ensuring adequate hydration can help mitigate some of these risks.

Contraindications and Precautions

Ketosis induction via ketogenic diets is absolutely contraindicated in individuals with without rigorous medical monitoring, as it significantly elevates the risk of (DKA) due to impaired insulin production and increased ketone production; even mildly elevated ketones (e.g., trace/small in urine or blood levels 0.6–1.5 mmol/L) warrant caution, particularly when combined with hyperglycemia, to prevent escalation. While some guidelines permit light activity with trace ketones if blood glucose is not extremely high, the consensus recommends avoidance of exercise until ketones resolve. Similarly, active represents an absolute , given that high-fat intake can exacerbate pancreatic and lead to necrotizing complications. Liver also prohibits ketosis induction, as the diet's demands on hepatic fat metabolism can worsen liver dysfunction and . Relative contraindications include , where elevated ketones may impair fetal growth and increase risks of defects and other developmental anomalies due to potential deficiencies and metabolic stress. Patients with active eating disorders face heightened risks, as the diet's restrictive limits may intensify behaviors and nutritional imbalances, necessitating professional oversight. , including gallstones, is another relative , since rapid fat mobilization can trigger or by overstimulating bile production. Precautions are essential for older adults with , where ketosis may support fat loss but requires monitoring to prevent unintended muscle alongside age-related declines in protein synthesis. Athletes engaged in high-intensity or activities should proceed cautiously, as restriction can impair glycogen-dependent and recovery, potentially leading to reduced power output and . Adequate hydration and electrolyte management are critical across all users to mitigate risks like and imbalances; guidelines recommend 3–5 g of sodium intake daily, alongside potassium and magnesium supplementation, to counteract urinary losses induced by low insulin levels. Professional guidelines, such as those from the (ADA), advise against unsupervised ketogenic diets in diabetic patients due to the need for insulin adjustments and monitoring to avoid or DKA. Pre-diet screening for comorbidities, including renal function, lipid profiles, and nutritional status, is recommended to identify risks and tailor interventions. In special cases, post-bariatric surgery patients exhibit higher susceptibility to acidosis, as surgical alterations in nutrient absorption combined with ketosis can precipitate severe metabolic derangements like euglycemic DKA. Individuals experiencing persistent failure to enter physiological ketosis (blood ketone levels ≥0.5 mmol/L) after several weeks of strict adherence to a ketogenic diet should consult a healthcare professional to rule out underlying issues or complications, ensure accurate dietary implementation, or identify any unrecognized contraindications. Given these potential risks and contraindications, individuals considering ketosis induction, particularly through ketogenic diets, should seek professional medical supervision to ensure safety and appropriateness for their health status.

Medication Interactions

Ketosis, particularly when induced therapeutically through ketogenic diets, can interact with various medications, potentially altering their efficacy or increasing risks of adverse effects such as toxicity or metabolic imbalances. Patients on antidiabetic agents require careful monitoring, as sodium-glucose cotransporter 2 (SGLT2) inhibitors like canagliflozin and empagliflozin have been associated with an elevated risk of diabetic ketoacidosis (DKA), even at euglycemic levels, prompting the U.S. Food and Drug Administration (FDA) to issue label warnings in 2015 based on post-marketing reports. Similarly, insulin requirements often decrease substantially in individuals with diabetes adopting ketogenic diets due to reduced carbohydrate intake and improved insulin sensitivity, necessitating proactive dose adjustments to prevent hypoglycemia. In the context of epilepsy management, the can enhance the antiseizure efficacy of antiepileptic drugs (AEDs) by synergizing with their mechanisms to reduce frequency, but specific interactions pose risks; for instance, valproic acid () combined with ketosis has been linked to idiosyncratic in case reports, potentially requiring discontinuation or close liver function monitoring. Although earlier concerns about routine hepatotoxicity were not consistently substantiated in larger reviews, clinicians should remain vigilant for elevated liver enzymes in patients on this combination. Diuretics, such as loop or agents, and laxatives can exacerbate the dehydration and imbalances inherent to ketosis, as the diet promotes and fluid loss through ketone-induced , amplifying risks of , , or hypomagnesemia when these drugs are used concurrently. For other medications, statins may indirectly benefit from ketosis-related improvements, including reduced triglycerides and smaller LDL particle sizes, potentially allowing dose reductions or discontinuation in some patients without compromising cardiovascular risk management. , often consumed as or supplements, can potentiate ketone production by stimulating and beta-oxidation, leading to dose-dependent increases in plasma beta-hydroxybutyrate levels by up to 116% in acute studies. Effective management of these interactions emphasizes individualized dose adjustments and multidisciplinary oversight; endocrine guidelines recommend reducing basal insulin by 20-30% initially when initiating therapeutic ketosis in diabetic patients to mitigate , with frequent to guide further . For AEDs and other agents, serial laboratory assessments, including electrolytes and hepatic panels, are essential to detect and address imbalances promptly.

Ketosis in Veterinary Medicine

Occurrence in Animals

Ketosis, also known as acetonemia in ruminants, is a prevalent metabolic disorder in dairy cattle, primarily occurring during the early postpartum period of lactation when cows experience a negative energy balance due to insufficient feed intake relative to the high demands of milk production. Subclinical ketosis affects approximately 20-40% of dairy cows in early lactation, with clinical cases occurring in about 3-10% and often following subclinical episodes characterized by elevated blood ketone levels. In affected cattle, the body mobilizes fat reserves for energy, leading to excessive ketone body production, which can manifest as reduced appetite, weight loss, and decreased milk yield if untreated. In companion animals such as dogs and cats, ketosis typically arises spontaneously in the context of uncontrolled diabetes mellitus, resembling (DKA) in humans, where insulin deficiency prompts fat breakdown and ketone accumulation. It can also be induced by prolonged or , particularly in obese individuals predisposed to . Common symptoms include , weakness, , , and rapid breathing, often requiring urgent veterinary intervention to prevent progression to or death. Among other species, ketosis presents as pregnancy toxemia in sheep, a condition triggered by the high energy demands of late , especially in ewes carrying multiple fetuses, leading to and ketonemia if nutritional intake is inadequate. In horses, ketosis is less common and typically mild, with small elevations in observed post-exercise during activities, though the equine plays a minor role compared to glucose utilization. Key risk factors for ketosis in include favoring high milk production, which exacerbate negative energy balance in early , as well as environmental stressors like cold weather or poor feeding management. In pets, is a significant predisposing factor, increasing the likelihood of and subsequent ketosis by promoting and pancreatic beta-cell dysfunction. The economic impact of ketosis in is substantial, with affected cows experiencing milk yield losses of up to 500 kg per , alongside increased veterinary costs and higher rates, contributing to overall profitability declines.

Clinical Management

Clinical management of ketosis in veterinary practice focuses on early , prompt treatment, preventive strategies, and monitoring for complications, primarily in ruminants such as cows where the condition is most prevalent. typically involves cow-side tests for . Urine ketone tests, using strips to detect acetoacetate, provide a quick initial assessment in cows, though they are less sensitive than analysis. The gold standard is measuring beta-hydroxybutyrate (BHB) levels, with concentrations exceeding 1.2 mmol/L indicating subclinical ketosis and over 3.0 mmol/L signaling clinical disease. Treatment aims to restore glucose availability and reduce ketone production. For mild to moderate cases in ruminants, oral drenching with is the mainstay, administered at 300 g per cow daily for 3 days in mild instances or up to 5 days in severe ones, as it serves as a glucogenic precursor fermented in the . In severe cases with profound or recumbency, intravenous administration of glucose or dextrose (250–500 mL of 50% solution) is recommended to provide immediate energy support, often combined with . Supportive care, including fluid therapy and monitoring, is essential to address and secondary issues. Prevention strategies emphasize nutritional management during the transition period around calving. Providing balanced rations with adequate energy from carbohydrates and sufficient fiber promotes health and prevents negative energy balance, which predisposes cows to ketosis. Regular monitoring of body condition scores (BCS) in herds is critical, targeting a score of 3.0–3.5 on a 5-point scale at calving to avoid overconditioning (BCS >3.75), which increases and ketosis risk. Prognosis is generally favorable with early intervention, with recovery rates approaching 100% in mild bovine cases treated promptly in studied groups. However, untreated or severe ketosis can lead to complications such as , characterized by hepatic accumulation, reduced feed intake, and increased mortality risk. Recent approaches include supplementation with rumen-protected choline, which enhances hepatic export and reduces . Studies from the 2020s have shown that it significantly reduces the incidence of hyperketonemia in multiparous cows when administered during the periparturient period.

References

  1. https://pubmed.ncbi.nlm.nih.gov/10634967/
  2. https://pubmed.ncbi.nlm.nih.gov/38934469/
  3. https://pubmed.ncbi.nlm.nih.gov/23651522/
  4. https://pmc.ncbi.nlm.nih.gov/articles/PMC3625904/
  5. https://www.ncbi.nlm.nih.gov/books/NBK554523/
  6. https://www.ncbi.nlm.nih.gov/books/NBK493179/
  7. https://pubmed.ncbi.nlm.nih.gov/14769483/
  8. https://www.ncbi.nlm.nih.gov/books/NBK499830/
  9. https://pmc.ncbi.nlm.nih.gov/articles/PMC6472268/
  10. https://www.medicalnewstoday.com/articles/320292
  11. https://pmc.ncbi.nlm.nih.gov/articles/PMC11978633/
  12. https://pmc.ncbi.nlm.nih.gov/articles/PMC7082414/
  13. https://pubmed.ncbi.nlm.nih.gov/27475046/
  14. https://my.clevelandclinic.org/health/body/25177-ketones
  15. https://www.healthline.com/nutrition/ideal-ketosis-level-for-weight-loss
  16. https://pmc.ncbi.nlm.nih.gov/articles/PMC4617363/
  17. https://pmc.ncbi.nlm.nih.gov/articles/PMC9459968/
  18. https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-021-02185-0
  19. https://ccforum.biomedcentral.com/articles/10.1186/cc10020
  20. https://pmc.ncbi.nlm.nih.gov/articles/PMC9581824/
  21. https://www.ncbi.nlm.nih.gov/books/NBK534848/
  22. https://www.ncbi.nlm.nih.gov/books/NBK560723/
  23. https://diabetesjournals.org/care/article/47/8/1257/156808/Hyperglycemic-Crises-in-Adults-With-Diabetes-A
  24. https://pmc.ncbi.nlm.nih.gov/articles/PMC10289692/
  25. https://www.mayoclinic.org/diseases-conditions/diabetic-ketoacidosis/symptoms-causes/syc-20371551
  26. https://my.clevelandclinic.org/health/articles/24003-ketosis
  27. https://pmc.ncbi.nlm.nih.gov/articles/PMC7080885/
  28. https://pmc.ncbi.nlm.nih.gov/articles/PMC2129159/
  29. https://www.ncbi.nlm.nih.gov/books/NBK534877/
  30. https://pmc.ncbi.nlm.nih.gov/articles/PMC5783752/
  31. https://pmc.ncbi.nlm.nih.gov/articles/PMC5407977/
  32. https://pmc.ncbi.nlm.nih.gov/articles/PMC9244428/
  33. https://pubmed.ncbi.nlm.nih.gov/19049574/
  34. https://pmc.ncbi.nlm.nih.gov/articles/PMC3929267/
  35. https://pmc.ncbi.nlm.nih.gov/articles/PMC4389034/
  36. https://pmc.ncbi.nlm.nih.gov/articles/PMC5987302/
  37. https://www.medicalnewstoday.com/articles/326484
  38. https://diabetesjournals.org/care/article/41/9/1839/40740/Increasing-Hospitalizations-for-DKA-A-Need-for
  39. https://medlineplus.gov/ency/article/000323.htm
  40. https://emedicine.medscape.com/article/116820-overview
  41. https://www.emra.org/emresident/article/understanding-alcoholic-ketoacidosis
  42. https://www.sciencedirect.com/science/article/pii/S204908012200783X
  43. https://www.medicalnewstoday.com/articles/starvation-ketoacidosis
  44. https://pmc.ncbi.nlm.nih.gov/articles/PMC4880580/
  45. https://pmc.ncbi.nlm.nih.gov/articles/PMC3633328/
  46. https://medlineplus.gov/genetics/condition/glycogen-storage-disease-type-vi/
  47. https://pmc.ncbi.nlm.nih.gov/articles/PMC6883983/
  48. https://www.merckmanuals.com/professional/injuries-poisoning/poisoning/aspirin-and-other-salicylate-poisoning
  49. https://www.ncbi.nlm.nih.gov/books/NBK554570/
  50. https://pmc.ncbi.nlm.nih.gov/articles/PMC7244089/
  51. https://onlinelibrary.wiley.com/doi/full/10.1002/%28SICI%291520-7560%28199911/12%2915:6%253C412::AID-DMRR72%253E3.0.CO%253B2-8
  52. https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/ketone-bodies
  53. https://pubchem.ncbi.nlm.nih.gov/compound/Acetoacetate
  54. https://pubmed.ncbi.nlm.nih.gov/34116232/
  55. https://smpdb.ca/view/SMP0000071
  56. https://pmc.ncbi.nlm.nih.gov/articles/PMC7699472/
  57. https://pubmed.ncbi.nlm.nih.gov/27826689/
  58. https://www.nature.com/articles/s41419-024-07268-3
  59. https://www.sciencedirect.com/science/article/pii/S2405844023083068
  60. https://pmc.ncbi.nlm.nih.gov/articles/PMC8488448/
  61. https://joslin.org/news-stories/all-news-stories/education/2019/11/ketone-testing-0
  62. https://www.diazyme.com/other-markers/hydroxybutyrate-bhb-assay/
  63. https://www.webmd.com/diabetes/what-is-ketosis
  64. https://pmc.ncbi.nlm.nih.gov/articles/PMC7394730/
  65. https://pubmed.ncbi.nlm.nih.gov/23330615/
  66. https://journals.physiology.org/doi/10.1152/ajpendo.00454.2019
  67. https://bestpractice.bmj.com/topics/en-us/162/monitoring
  68. https://emcrit.org/ibcc/dka/
  69. https://pubmed.ncbi.nlm.nih.gov/39314201/
  70. https://www.abbott.com/corpnewsroom/strategy-and-strength/abbotts-biowearable-one-sensor-for-glucose-ketones.html
  71. https://pubmed.ncbi.nlm.nih.gov/40761614/
  72. https://pmc.ncbi.nlm.nih.gov/articles/PMC7556427/
  73. https://www.accessdata.fda.gov/cdrh_docs/pdf5/k051727.pdf
  74. https://www.ncbi.nlm.nih.gov/books/NBK247/
  75. https://pmc.ncbi.nlm.nih.gov/articles/PMC11089855/
  76. https://diabetesjournals.org/care/article/45/2/267/140906/Controversies-Around-the-Measurement-of-Blood
  77. https://emedicine.medscape.com/article/2087982-overview
  78. https://pmc.ncbi.nlm.nih.gov/articles/PMC7835940/
  79. https://shop.ketonix.com/pages/faq
  80. https://www.aafp.org/pubs/afp/issues/2000/0201/p800.html
  81. https://pubmed.ncbi.nlm.nih.gov/35868249/
  82. https://pmc.ncbi.nlm.nih.gov/articles/PMC6963753/
  83. https://www.mdpi.com/1424-8220/18/11/3655
  84. https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.15921
  85. https://pubmed.ncbi.nlm.nih.gov/31677579/
  86. https://www.hopkinsmedicine.org/neurology-neurosurgery/specialty-areas/epilepsy/keto-diet-timeline
  87. https://jamanetwork.com/journals/jamapediatrics/fullarticle/2800777
  88. https://www.nature.com/articles/s41421-023-00636-x
  89. https://www.sciencedirect.com/science/article/pii/S2590139724000590
  90. https://pmc.ncbi.nlm.nih.gov/articles/PMC9740154/
  91. https://pubmed.ncbi.nlm.nih.gov/18456557/
  92. https://pubmed.ncbi.nlm.nih.gov/33883420/
  93. https://pubmed.ncbi.nlm.nih.gov/32193016/
  94. https://pubmed.ncbi.nlm.nih.gov/30128963/
  95. https://pubmed.ncbi.nlm.nih.gov/34233255/
  96. https://pubmed.ncbi.nlm.nih.gov/35469570/
  97. https://pubmed.ncbi.nlm.nih.gov/33163300/
  98. https://pubmed.ncbi.nlm.nih.gov/32640608/
  99. https://pubmed.ncbi.nlm.nih.gov/36064937/
  100. https://pubmed.ncbi.nlm.nih.gov/34912453/
  101. https://pubmed.ncbi.nlm.nih.gov/33317019/
  102. https://pubmed.ncbi.nlm.nih.gov/33882506/
  103. https://pubmed.ncbi.nlm.nih.gov/36245515/
  104. https://pubmed.ncbi.nlm.nih.gov/17219068/
  105. https://onlinelibrary.wiley.com/doi/10.1111/obr.13024
  106. https://pubmed.ncbi.nlm.nih.gov/31705259/
  107. https://pmc.ncbi.nlm.nih.gov/articles/PMC11433106/
  108. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0321140
  109. https://www.health.harvard.edu/blog/what-is-keto-flu-2018101815052
  110. https://www.verywellhealth.com/keto-flu-8680770
  111. https://www.healthline.com/nutrition/10-signs-and-symptoms-of-ketosis
  112. https://www.psychiatrist.com/pcc/advances-ketogenic-diet-therapies-pediatric-epilepsy-systematic-review/
  113. https://www.virtahealth.com/blog/what-is-keto-breath
  114. https://pmc.ncbi.nlm.nih.gov/articles/PMC8322232/
  115. https://publications.aap.org/pediatrics/article/124/2/e300/72343/Empiric-Use-of-Potassium-Citrate-Reduces-Kidney
  116. https://pubmed.ncbi.nlm.nih.gov/17621514/
  117. https://science.drinklmnt.com/low-carb/leg-cramps-on-keto
  118. https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2025.1508695/full
  119. https://pmc.ncbi.nlm.nih.gov/articles/PMC9932495/
  120. https://pmc.ncbi.nlm.nih.gov/articles/PMC6371871/
  121. https://onlinelibrary.wiley.com/doi/10.1111/epi.18657
  122. https://www.science.org/doi/10.1126/sciadv.adx2752
  123. https://pmc.ncbi.nlm.nih.gov/articles/PMC5452247/
  124. https://pmc.ncbi.nlm.nih.gov/articles/PMC11206495/
  125. https://pcna.net/news/ketosis-vs-ketoacidosis-whats-the-difference/
  126. https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-023-02874-y
  127. https://www.nhs.uk/conditions/diabetic-ketoacidosis/
  128. https://diabetes.org/health-wellness/fitness/exercise-and-type-1
  129. https://pmc.ncbi.nlm.nih.gov/articles/PMC6908414/
  130. https://pmc.ncbi.nlm.nih.gov/articles/PMC7539910/
  131. https://www.sciencedirect.com/science/article/pii/S2667268523000566
  132. https://www.pcrm.org/news/news-releases/most-comprehensive-review-yet-keto-diets-finds-heart-risks-cancer-risk-dangers
  133. https://www.tandfonline.com/doi/full/10.1080/17446651.2022.2089112
  134. https://www.diabetes.co.uk/keto/keto-diet-safety.html
  135. https://pmc.ncbi.nlm.nih.gov/articles/PMC8838342/
  136. https://pmc.ncbi.nlm.nih.gov/articles/PMC11212571/
  137. https://ketogenic.com/importance-electrolytes-ketogenic-diet/
  138. https://diabetesjournals.org/spectrum/article/33/2/133/32999/Low-Carbohydrate-and-Very-Low-Carbohydrate-Diets
  139. https://pmc.ncbi.nlm.nih.gov/articles/PMC5664869/
  140. https://pmc.ncbi.nlm.nih.gov/articles/PMC6340926/
  141. https://www.fda.gov/drugs/drug-safety-and-availability/fda-revises-labels-sglt2-inhibitors-diabetes-include-warnings-about-too-much-acid-blood-and-serious
  142. https://pmc.ncbi.nlm.nih.gov/articles/PMC10448543/
  143. https://www.neurology.org/doi/10.1212/WNL.84.14_supplement.P4.278
  144. https://www.sciencedirect.com/science/article/pii/S1059131106000021
  145. https://www.everydayhealth.com/ketogenic-diet/diet/keto-diet-dangers-you-need-know/
  146. https://pubmed.ncbi.nlm.nih.gov/32864246/
  147. https://pubmed.ncbi.nlm.nih.gov/28177691/
  148. https://www.healio.com/news/endocrinology/20190814/ketogenic-lowcarb-diets-require-diabetes-medication-adjustments
  149. https://medcraveonline.com/JDVAR/JDVAR-07-00230.pdf
  150. https://extension.psu.edu/subclinical-ketosis-types-impacts-and-risk-factors
  151. https://vcahospitals.com/know-your-pet/diabetic-ketoacidosis-in-dogs
  152. https://www.merckvetmanual.com/endocrine-system/the-pancreas/diabetes-mellitus-in-dogs-and-cats
  153. https://www.petmd.com/cat/conditions/endocrine/c_ct_diabetes_with_ketoacidosis
  154. https://extension.oregonstate.edu/animals-livestock/sheep-goats/causes-prevention-pregnancy-ketosis-small-ruminants
  155. https://pubmed.ncbi.nlm.nih.gov/7043686/
  156. https://pmc.ncbi.nlm.nih.gov/articles/PMC8304442/
  157. https://www.vet.cornell.edu/departments-centers-and-institutes/cornell-feline-health-center/health-information/feline-health-topics/feline-diabetes
  158. https://pubmed.ncbi.nlm.nih.gov/10068950/
  159. https://www.merckvetmanual.com/metabolic-disorders/hyperketonemia-in-cattle/hyperketonemia-in-cattle
  160. https://heatherwhite.webhosting.cals.wisc.edu/wp-content/uploads/sites/164/2015/01/F-08872-15-Ketosis-Understanding-the-Biology1.pdf
  161. https://afs.mgcafe.uky.edu/files/treatments_for_dairy_cows_with_ketosis_2.pdf
  162. https://dairy.extension.wisc.edu/articles/the-fresh-cow-ketosis/
  163. https://extension.psu.edu/body-condition-scoring-as-a-tool-for-dairy-herd-management
  164. http://www.ijvets.com/pdf-files/Volume-3-no-3-2014/147-150.pdf
  165. https://www.mdpi.com/2076-2615/14/7/1016
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