MONITORING KETOSIS
Ketone testing past and present
CRAIG FOREBACK and GARY DOWTHWAITE review alternative ways to diagnose and monitor ketoacidosis using assays for the major ketone body, 3-ß-Hydroxybutyrate, which have been available on automated analysers since 1987.
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 re- esterification, 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
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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.
Figure 1: Schematic of pathways involved in diabetic ketoacidosis.
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
NOVEMBER 2012
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