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INTRODUCTION

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Ketones form a viable energy source used daily by the body in response to variations in carbohydrate intake and energy demand. There are several conditions that may result in excessive production of ketoacids that can result in a significant metabolic acidosis. The challenge for the clinician is to differentiate states of excessive, uncontrolled ketoacidosis from physiologic ketonemia, from states where excessive ketones may be produced, or from conditions or a toxin altering normal metabolism.1 The pathophysiology of ketoacidosis is poorly understood. Authors speculate about the hormonal milieu and pre-existing glycogen stores that, under some circumstances, will tip certain patients into pathologic ketoacidosis.

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The benefits of controlled metabolic access to ketones (i.e., ketogenic diet) have been recently advocated for several conditions. Unfortunately, the timing and triggers for the exact tipping point from controlled to uncontrolled ketone production are not well understood. This chapter will discuss important conditions of uncontrolled ketone production and treatment of this pathologic state.

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PATHOPHYSIOLOGY

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Ketones may be produced through metabolism of long-chain fatty acids for energy within cells or made within the perivenous hepatocytes and then displaced into the serum for use by cells without mitochondria (i.e., red blood cells). Serum ketones are also used as an energy source for the brain because long-chain fatty acids cannot cross the blood–brain barrier and neurons cannot generate their own ketones. Once generated, ketones can be used as an additional energy source, entering the citric acid cycle as acetyl coenzyme A and taking the place of pyruvate generated through glucose metabolism. Ketone production is typically tightly regulated to prevent excessive ketoacid production and metabolic acidosis. Lower serum levels of insulin and ketones coupled with higher levels of cortisol and epinephrine may trigger an increase in ketone production.2 Regulation of ketone production is complex and incompletely understood. Additionally, the rate of ketone consumption can vary over time (minutes, hours, days) for unknown reasons.3 In general, with the exception of DKA, low levels of insulin are not found in ketoacidotic syndromes.

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To understand ketone metabolism, first remember that ketones are made daily by the body for energy, and that production is tightly regulated to limit serum levels (Figure 226-1). The normal blood ketone level is about 1 milligram/dL. Ketones are metabolized as rapidly as they are formed. Pathologic states arise when production exceeds metabolism or consumption, resulting in metabolic acidosis. Second, it is important to understand the ketone forms normally present in the human body. Acetyl coenzyme A, an energy source that can enter the citric acid cycle for metabolism, is produced in the liver and then converted to the ketones β-hydroxybutyrate and acetoacetate. These ketones spontaneously decay to acetone, which is a volatile chemical and thus exhaled and detected on the breath. Finally, the ratio of ketone production may vary. Typically, in most conditions (pathologic or normal physiology), the balance of β-hydroxybutyrate and acetoacetate is ...

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