Ketosis

Ketosis is a metabolic state marked by elevated concentrations of ketone bodies in the blood or urine, typically arising when glucose availability is limited and fatty acids become the primary substrate for energy production. Trace ketone levels are always detectable in healthy individuals, but during periods of fasting, prolonged exercise, or carbohydrate restriction, the liver increases ketone synthesis as part of normal metabolic adaptation. This state, known as physiological ketosis, maintains the body’s pH balance and contrasts sharply with ketoacidosis, a pathological condition associated with excessive, uncontrolled ketone production leading to metabolic acidosis and clinical instability. Ketone levels in physiological ketosis generally remain between 0.5 and 3.0 mM, whereas ketoacidosis often involves concentrations above 10 mM.

Definitions and Types

Hyperketonaemia is defined conventionally as serum ketone levels exceeding 1 mM. In normal physiology, ketone levels rarely surpass 0.5 mM except when carbohydrate availability is restricted. Physiological ketosis may arise following an overnight fast, where ketones can provide more than a quarter of the body’s energy, increasing to 30–40 per cent during extended fasting. Nutritional ketosis, induced by very low-carbohydrate diets such as the ketogenic diet, shares these metabolic characteristics and typically keeps serum ketones below 3 mM.
Ketoacidosis, by contrast, is a medical emergency resulting from uncontrolled ketone production. It is most commonly linked to absolute insulin deficiency in type 1 diabetes but may also occur in the later stages of type 2 diabetes, during heavy alcohol use, or following the ingestion of certain toxins such as salicylates or isopropyl alcohol. Ketone production is no longer regulated appropriately, causing acid–base imbalance, dehydration, electrolyte disturbances, and a life-threatening fall in blood pH.

Causes and Physiological Context

Elevations in ketone concentrations primarily reflect increased ketone synthesis in the liver, though exogenous ketones or their precursors can also contribute. When glycogen stores and circulating glucose fall, metabolic pathways prioritise glucose conservation for organs unable to metabolise fatty acids directly, most notably the brain. In this context the liver accelerates fatty acid oxidation, converting acetyl-CoA into ketone bodies—acetoacetate, β-hydroxybutyrate, and acetone—which are then released into the bloodstream for use by the brain, heart, kidneys, and skeletal muscles.
The carbohydrate intake threshold required to induce ketosis varies, influenced by factors such as activity level, insulin sensitivity, age, and genetic predisposition. In most individuals, consuming fewer than 50 grams of carbohydrates per day for several consecutive days will initiate ketosis. Particular populations, including neonates, pregnant women, and lactating women, enter ketosis more rapidly due to their metabolic demands, limited glycogen reserves, and reliance on high-fat nutrition.

Biochemistry of Ketone Production

Ketogenesis takes place in the mitochondrial matrix of hepatocytes. Its substrates include free fatty acids mobilised from adipose tissue and ketogenic amino acids derived from dietary protein or muscle catabolism. Fatty acids reach the liver in states of high glucagon and catecholamine activity and low insulin, which signal low glucose availability.
Once inside hepatic mitochondria, fatty acids undergo β-oxidation, yielding acetyl-CoA. Under normal conditions acetyl-CoA combines with oxaloacetate to enter the tricarboxylic acid (TCA) cycle. However, when glucose is scarce, oxaloacetate is diverted into gluconeogenesis, making it unavailable to condense with acetyl-CoA. This metabolic bottleneck promotes ketogenesis.
The pathway begins with the condensation of two acetyl-CoA molecules by thiolase to form acetoacetyl-CoA. A further condensation with another acetyl-CoA forms HMG-CoA, which is then cleaved by HMG-CoA lyase to generate acetoacetate. Acetoacetate can be reduced to β-hydroxybutyrate or spontaneously decarboxylate to acetone. The liver cannot use ketones for its own energy needs, so they are exported to peripheral tissues. Ketogenic amino acids also contribute to the TCA cycle intermediates and enhance ketone production.

Measurement of Ketone Levels

Ketone levels can be assessed through urine, blood, or breath testing, with each method detecting different ketone bodies.

• Urine testing is the most accessible method, using nitroprusside-based strips that measure acetoacetate semiquantitatively. Because β-hydroxybutyrate predominates in circulation and renal ketone excretion varies markedly with hydration and kidney function, urinary ketones may not accurately correlate with blood levels.
• Blood testing provides direct measurement of β-hydroxybutyrate via fingerstick meters or laboratory assays. This method offers the most reliable indicator of ketotic status, particularly in clinical contexts.
• Breath testing detects acetone, which correlates with fat oxidation rates but is less commonly used in medical practice.

Medical Applications

The induction of ketosis through dietary manipulation or fasting has several established clinical uses:

• Epilepsy: Ketogenic diets have long been employed in the management of refractory epilepsy, particularly in children who do not respond adequately to antiepileptic medications.
• Obesity and metabolic syndrome: Ketosis has been shown to improve several metabolic markers, including reductions in serum triglycerides, increases in high-density lipoprotein (HDL) cholesterol, and favourable shifts in the size and volume of low-density lipoprotein (LDL) particles, contributing to an improved lipid profile.
• Type 2 diabetes: Low-carbohydrate diets and nutritional ketosis can improve glycaemic control and insulin sensitivity in individuals with type 2 diabetes.

Safety Considerations

Despite its long-term therapeutic use, ketogenic nutrition remains subject to debate regarding safety and physiological appropriateness. Misconceptions often arise from conflating physiological ketosis with ketoacidosis. Physiological ketosis is tightly regulated, maintains normal blood pH, and poses no risk of metabolic acidosis in healthy individuals.
Arguments against long-term ketosis suggest that humans evolved to avoid frequent ketotic states, whereas counterarguments emphasise that the body has no essential requirement for dietary carbohydrates, with glucose production and ketone utilisation capable of sustaining long-term energy balance. Some researchers propose that alternating between fed and ketotic states may provide metabolic and neurological benefits.