Ketone testing past and present

It is often the case that the solution to a problem already exists. It is just a matter of knowing where to look. The diagnosis and monitoring of ketosis is a good example. Since 1949 the determination of urine ketones using Ketostix or Acetest has been standard practice for the diagnosis and monitoring of ketosis. The onset of ketosis requires changes in both adipose tissue metabolism and liver function.The primary substrates for ketone body formation are fatty acids from adipose stores. Ketone bodies are produced by the liver and used peripherally as an energy source when glucose is not readily available. Acetoacetate (AcAc) and 3-ß-Hydroxybutyrate(ßHB) are the two main ketone bodies; acetone is the third and least abundant. Strictly speaking ßHB is not chemically a ketone as it does not possess a keto structure. Ketone bodies are always present in the blood and their levels increase during fasting and prolonged exercise. Diabetes is the most common pathological cause of elevated ketones. In diabetic ketoacidosis (DKA), which occurs in poorly controlled diabetes, low insulin concentrations and high levels of counterregulatory hormones initiate a cascade of events that results in increased lipolysis and decreased reesterification, thereby increasing plasma fatty acids (see Fig. 1). In addition, the increased glucagon:insulin ratio enhances fatty acid oxidation in the liver. Increased counter regulatory hormones also increase lipolysis and ketogenesis in fat and liver respectively. The combination of increased hepatic ketone synthesis and decreased peripheral tissue metabolism leads to acetoacetate accumulation in the blood. A small fraction undergoes spontaneous decarboxylation to form acetone but the majority is converted to ßHB. In acute DKA the ketone body ratio (ßHB:AcAc) rises from normal (1:1) to as high as 10:1. In ketoacidosis ßHB levels are typically 78%- 80% of total ketone bodies. The classic method for the detection and determination of ketones utilises nitroprusside. The nitroprusside test is 10 times more sensitive to acetoacetic acid than to acetone and gives no reaction at all with ßHB because ßHB lacks a ketone ring. The fact that most of the commonly used methods for the determination of ketones measure only acetoacetate can produce a paradoxical situation. In a patient initially presenting in ketoacidosis the ketones, as measured by nitroprusside reaction, may be only weakly positive, whereas they are in fact high. This occurs because after initial treatment ßHB is converted to acetoacetate whichindicates a worsening condition.

Clinical significance

Excessive formation of ketone bodies results in increased blood ketone concentrations (ketonemia) and increased excretion of ketones in urine (ketonuria). This process is observed in conditions associated with decreased availability of carbohydrates such as starvation, frequent vomiting, diabetes mellitus, glycogen storage disease oralkalosis. High fat, low carbohydrate diets are ketogenic and increase ketone bodies in circulation. Ketogenic diets and prolonged exercise are also associated with physiological ketosis. Ketogenic diets, which are used in certain weightreduction programmes and which have been used to treat patients with refractory epilepsy, contain at least 50% of their calories as fat. This degree of fat content is nearly twice as high as that found in the typical diet of individuals in developed nations. Prolonged exercise is also associated with mild hyperketonemia, with ketone body levels not uncommonly rising to the range of 1-2 mmol/L. Diabetes mellitus and alcohol consumption are the most common causes of ketoacidosis in adults. Diabetic ketoacidosis (DKA) and the hyperglycemic hyperosmolar nonketotic state (HHNS) are two serious, acute metabolic complications of diabetes. Ketoacidosis can also be precipitated following binge drinking and withdrawal in chronic alcoholics. Ketosis can also occur following ingestion of isopropyl alcohol and salicylates. After DKA, alcoholic ketoacidosis is the most common cause of ketoacidosis in adults. It is a relatively common syndrome in chronic alcohol abusers and binge drinkers. Alcoholic ketoacidosis (AKA) is generally associated with a period of excessive alcohol consumption, followed by withdrawal and minimal food intake. Urine ketone tests are positive in approximately 30% of first morning specimens from pregnant women. During periods of glucose deficiency ketone bodies play a key role in sparing glucose utilisation and reducing proteolysis. Unlike most other tissues the brain cannot utilise fatty acids for energy when blood glucose levels become compromised. In this case ketone bodies provide the brain with an alternative source of energy, amounting to nearly two thirds of the brain’s energy requirements during prolonged fasting and starvation.1 Ketone bodies stimulate insulin release in vitro, generate oxygen radicals and cause lipid peroxidation. Lipid peroxidation and the generation of oxygen radicals may play a role in vascular disease in diabetes.