AKA occurs in the setting of a large quantity of alcohol ingestion and relative starvation. Starvation decreases glycogen and insulin stores and increases catecholamines, glucagon, growth hormone, and cortisol. As glycogen stores decrease, insulin production is retarded, resulting in increased lipolysis, increased hepatic ketogenesis, and peripheral use of ketones. Elevated levels of catecholamines, glucagon, growth hormone, and cortisol also stimulate lipolysis and hepatic ketogenesis. Both of these metabolic pathways lead to ketoacidosis.

Three types of ketones are produced in varying amounts: b-hydroxybutyrate (bHB), acetoacetate, and acetone ( Fig.^204-1). Acetone, a metabolite of acetoacetate and a nonacidotic ketone, is rapidly excreted in urine. bHB and acetoacetate are the predominant primary ketones producing the acidosis seen in this illness, with bHB usually in greater concentration. The usual ratio of these ketones in healthy patients is 1:1. The ratio of these ketones is 5:1 to 10:1 in patients with AKA. The lack of nicotinamide adenosine dinucleotide (NAD), a necessary cofactor used to form acetoacetate from bHB, is thought to be the principle cause of this disparity.

The enzyme alcohol dehydrogenase metabolizes alcohol to acetaldehyde and acetate. Acetaldehyde is metabolized by the enzyme aldehyde dehydrogenase to acetyl coenzyme A, which forms free fatty acids, ketone bodies, and enters the Krebs cycle for glucose metabolism (Fig.204-1). Under normal metabolic conditions, the majority of acetyl coenzyme A enters the Krebs cycle, and few ketone bodies are produced. NAD is a necessary cofactor for this step and is continually renewed through mitochondrial oxidation.

Under conditions of relative starvation, as seen in AKA, there is a relative insulin deficiency, whose release is further inhibited by the a-adrenergic response to volume contraction. Thus, glucose is not available for utilization in the Krebs cycle and the equation shifts to production of ketone bodies. In addition, the rate of NAD oxygenation by mitochondria also declines, resulting in a deficiency of this cofactor to metabolize alcohol and acetaldehyde, which further stimulates ketone body production (Fig, 2.04.-1). The resulting deficiency of NAD can persist for several days after alcohol consumption has ceased. Hepatic gluconeogenesis is also decreased, due to the lack of available NAD cofactor for metabolism, along with decreased glycogen stores. Thus, AKA occurs in the setting of increased ketone production and an increased ratio of NADH (the reduced form of NAD) to Nad.

Additional mechanisms that contribute to ketone production include alcohol-induced mitochondrial structural changes and mitochondrial phosphorus depletion. Hypophosphatemia also inhibits the utilization of NADH and increases ketone body formation. Finally, acute vomiting and starvation superimposed on chronic malnutrition also contributes to the ketoacidosis state.

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