Definition and Epidemiology

The diagnosis of alcoholic ketoacidosis (AKA) is established when an alcoholic patient is found to have an anion gap metabolic acidosis without historical or laboratory evidence suggesting an alternative cause. AKA may develop after protracted vomiting in malnourished, chronic alcoholics who consume a daily average of 200 g of ethanol. AKA generally occurs with equal frequency in adult men and women between 20 and 60 years of age. Its incidence and prevalence remain undefined. Up to one half of patients are likely to suffer recurrence. It is unclear whether these individuals have a genetic predisposition to AKA or whether they repeatedly reproduce the hormonal milieu that precipitates ketoacidosis. Almost one fifth of cases of ketoacidosis are alcoholic ketoacidosis.^1–3

Pathophysiology

The term alcoholic acidosis describes a syndrome of four types of metabolic acidosis that occur in alcoholics and vary in severity: ketoacidosis, lactic acidosis, acetic acidosis, and loss of bicarbonate in urine. AKA arises from a complicated interplay of the metabolic effects of alcohol in fasted, dehydrated alcoholics who abruptly stop their intake of ethanol.⁴

β-Hydroxybutyrate is the predominant ketoacid.⁵ Metabolism of ethanol to acetaldehyde is catalyzed by alcohol dehydrogenase in the liver and results in accumulation of the reduced form of nicotinamide adenine dinucleotide (NADH) relative to the oxidized form of nicotinamide adenine dinucleotide (NAD⁺). The altered ratio of NADH/NAD⁺ is the rate-limiting step in alcohol metabolism and favors the conversion of acetoacetate to β-hydroxybutyrate, as illustrated in Figure 161.1.

Fig. 161.1 Pathophysiology of alcoholic ketoacidosis.

Alcohol dehydrogenase in hepatocyte cytosol metabolizes ethanol to acetaldehyde, which is then transported into the mitochondria for metabolism to acetate. Acetate is activated by adenosine triphosphate (ATP), coenzyme A (CoA), and acetate thiokinase to form acetyl CoA, which can (1) be oxidized to carbon dioxide (CO₂) by the citric acid cycle, (2) form ketone bodies, or (3) be converted to fat. Insulin depletion results from a number of influences, including endogenous suppression from malnutrition, the direct suppressive effects of ethanol, and α-adrenergic suppression from catecholamines. Volume depletion stimulates the counterregulatory release of catecholamines, cortisol, growth hormone, and glucagon. Glycogen depletion from malnutrition and alcoholic liver disease stimulates enhanced fatty acid release, which is further promoted by catecholamines. The relative increase in NADH over NAD⁺ resulting from the metabolism of ethanol drives several reactions to produce βOHB and lactate. Thiamine deficiency favors the conversion of pyruvate to lactate rather than acetyl CoA. ATP, Adenosine triphosphate; EtOH, ethyl alcohol; NAD⁺, oxidized form of nicotinamide adenine dinucleotide; NADH, reduced form of nicotinamide adenine dinucleotide; βOHB, β-hydroxybutyrate.

Impaired insulin effects, dehydration, and hormonal responses propagate the accumulation of ketoacid. Ethanol consumption, acute starvation, and catecholamine release cause a relative insulin insufficiency that acts to favor lipolysis and limit glycogen storage. The formation of ketone bodies is further promoted by a dehydration-induced stress response–related release of cortisol, growth hormone, glucagons, and catecholamines. It is unclear whether the elevated levels of cortisol and growth hormone observed in patients with AKA initiate or sustain this process. Ketone bodies in the form of β-hydroxybutyrate are produced as a result of the NADH/NAD⁺ ratio induced by ethanol metabolism, as well as the lipolytic effect of counterregulatory hormones. Renal excretion of ketone bodies becomes impaired because of dehydration, volume contraction, and diminished renal clearance. Accumulation of ketoacid ensues.