Ciammaichella M. M., Galanti A., Rossi C.
Dirigenti Medici
U.O.C. Medicina Interna I per l’Urgenza
(Direttore: Dott. G. Cerqua)
A.C.O. S. Giovanni - Addolorata - Roma, Italia


alcoholic ketoacidosis



Alcoholic ketoacidosis is characterized by an anion gap acidosis due to high levels of ketoacids. It occurs exclusively in relation to alcohol abuse but not just in chronic alcoholics. It has been reported in first-time drinkers whose food intake is minimal.
The true incidence is unknown, and the frequency is probably directly related to the incidence of alcoholism in a population.


Several mechanisms have been postulated. In one explanation, ketosis results from increased mobilization of free fatty acids from adipose tissue coupled with simultaneous enhancement of the liver's capacity to convert these substrates into acetoacetate and $-hydroxybutyrate.
During the metabolism of alcohol in the liver the rate of nicotinamide adenine dinucleotide (NAD) reduction exceeds the rate of mitochondrial NADH oxidation, causing a decrease in available NAD. This state persists for a few days in spite of no further alcohol consumption. An NAD-dependent step in the oxidation of fatty acids in the mitochondria of the hepatocyte is displaced in favor of ketone body formation.
During alcoholic ketoacidosis insulin levels are low, whereas levels of cortisol, growth hormone, glucagon, and epinephrine are increased, possibly as a result of alcohol-induced hypoglycemia. This hormonal milieu promotes lipolysis, which increases the levels of free fatty acids available for conversion to ketones.
Additional mechanisms that may contribute to ketosis include the conversion of acetate, an alcohol breakdown product, to ketones; alcohol-induced mitochondrial structural changes which enhance the rate of ketosis; and mitochondrial phosphorus depletion, which inhibits the utilization for NADH and increases ketone body formation. Finally, vomiting and starvation superimposed on chronic malnutrition also contribute to ketoacidosis.


The usual history is one of heavy alcohol consumption or binge drinking with decreased or absent food intake for several days. Food and alcohol intake are usually terminated by nausea, protracted vomiting, and abdominal pain occurring 24 to 72 h before presentation. It is during this period that ketoacidosis develops.
Clinically the patient appears acutely ill with dehydration, tachypnea, tachycardia, and diffuse abdominal pain. Most patients are alert, but they may be mildly disoriented or occasionally comatose.
There are no specific physical findings. Evidence of dehydration such as hypotension, orthostatic changes in blood pressure, tachycardia, and decreased urine output may be present. The temperature varies from hypothermia to mildly elevated. Abdominal pain due to non-specific causes or due to gastritis, pancreatitis, or hepatitis is common. Sepsis, meningitis, pyelonephritis, or pneumonia may be present, and delirium tremens may develop.


Alcohol levels are usually low or undetectable, as the alcohol intake is decreased or discontinued during the period of anorexia and vomiting. Essential to the diagnosis of alcoholic ketoacidosis is a large anion gap due to high levels of serum ketones. Most patients have a blood pH reflective of the underlying metabolic acidosis, but many may present with normal or alkalemic pH values.
Acid-Base Balance
Fulop and Hoberman compared typical laboratory data from patients with diabetic ketoacidosis with data from patients with alcoholic ketoacidosis. The alcoholic patients tended to have a higher blood pH, lower levels of serum K+ and Cl --, and a higher level of plasma HCO3-- than the diabetic patients. This difference is attributed to the severe recurrent vomiting experienced by the alcoholic patients. Vomiting causes chloride depletion and metabolic alkalosis. In addition, respiratory alkalosis may occur secondary to fever, sepsis, or alcohol withdrawal and further increases the blood pH.


The anion gap Na+--Cl-- + HCO3--) = 12 +/-4 mEq/L] in the patient groups is very similar and is due primarily to high levels of $-hydroxybutyrate and to a lesser extent to lactic acid accumulation. The principal ketones are acetoacetate and $-hydroxybutyrate. These ketones are intermediates in the oxidation of fatty acids; they are normally produced in equal amounts and are not normally detectable in the serum. Acetoacetate and $-hydroxybutyrate are a redox pair and are interconverted by an oxidation-reduction reaction with NAD and NADH as cofactors. In alcoholic ketoacidosis, perhaps because of lack of NAD, $-hydroxybutyrate accumulates to levels several times higher than the levels of acetoacetate. Acetone is a volatile, neutral ketone that is formed from acetoacetate by irreversible spontaneous decarboxylation. Its presence reflects the level and duration of acetoacetate elevation and is indicative of a sustained, severe acidosis.

Nitroprusside Test

The nitroprusside test is used to detect the presence of ketones in serum and urine. This is a semiquantitative test that gives a reaction with acetoacetate, is less sensitive to acetone, and does not detect $-hydroxybutyrate at all. There is no practical test that measures $-hydroxybutyrate levels. In most series on alcoholic ketoacidosis, the nitroprusside test has shown moderate or large ketonemia or ketonuria. But in a significant minority of patients, the reaction may be weakly positive or negative even though ketoacidosis, because of high levels of $-hydroxybutyrate, is pronounced. Reliance on this test alone as a measure of ketoacidosis may lead to failure to recognize the presence of ketoacidosis or to an underestimation of the severity of the ketoacidosis.


The blood glucose level in alcoholic ketoacidosis varies from hypoglycemia to mild elevation. In most series it is normal or slightly increased. Glucosuria is usually mild or absent. A subset of alcoholic patients in whom hypoglycemia and ketoacidosis are coexistent has been described.
The pathogenesis of alcohol-induced hypoglycemia includes acute starvation, depletion of liver glycogen stores because of chronic malnutrition, and inhibition of gluconeogenesis because of alcohol-induced alteration of the NAD/NADH ratio. Alcohol also causes decreased peripheral utilization of glucose, and this acts to balance the glucose-depleting processes. Devenyi asks if alcoholic hypoglycemia and alcoholic ketoacidosis are sequential events of the same process. He theorizes that alcohol-induced hypoglycemia occurs first, causing increased levels of cortisol, growth hormone, glucagon, and epinephrine; this may correct the hypoglycemia and mobilize free fatty acids, which are converted to ketones. If this theory is correct, the diagnosis of alcoholic hypoglycemia or alcoholic ketoacidosis may depend upon the point in this process at which the disorder is detected.


The diagnosis of alcoholic ketoacidosis is easily established in those patients with an antecedent history of alcohol intake, decreased food intake, vomiting, and abdominal pain, and laboratory findings of metabolic acidosis, a positive nitroprusside test, and a low or mildly elevated glucose level.
Several factors may contribute to the failure to recognize this metabolic disorder. The blood alcohol level may be zero, and, in the absence of a history of alcohol intake, this diagnosis may not be considered. The nitroprusside test may be weakly positive or negative in spite of significant ketoacidosis. The pH may be mildly acidotic, normal, or even alkalemic in the face of pronounced metabolic acidosis. There are no specific physical findings which suggest the diagnosis of alcoholic ketoacidosis. Alcoholic patients may have a variety of alcohol-induced associated illnesses which may obscure or distract from this diagnosis. Mental confusion or coma may be incorrectly attributed to alcoholic intoxication or other causes if the appropriate laboratory studies are not performed or if they are incorrectly interpreted.
Soffer and Hamburger's criteria to define alcoholic ketoacidosis are a serum glucose level less than 300 mg/dL, a recent history of alcohol intake with a relative or absolute decline in ethanol consumption 24 to 72 h before hospitalization, a history of vomiting, and a metabolic acidosis for which other causes, such as diabetic ketoacidosis, lactic acidosis, renal failure, or drug ingestion, are excluded by clinical observations or laboratory studies. A positive serum nitroprusside test, because of its limitations, is not a criterion for diagnosis.

Differential Diagnosis

A positive nitroprusside test and a very low plasma bicarbonate concentration suggest ketosis with a high level of $-hydroxybutyrate. The combination of a barely positive nitroprusside test and a low plasma bicarbonate concentration signifies either a very reduced state with high concentrations of $-hydroxybutyrate or else a coincidental lactic acidosis. The measurement of serum lactate levels aids in this differential diagnosis.
The entity with which alcoholic ketoacidosis is most often confused is diabetic ketoacidosis. The magnitude of ketoacidosis is equal in these two disorders. It is important to make the proper distinction, as the treatment of each entity is different. In diabetic ketoacidosis, hyperglycemia and glucosuria are present. The serum glucose level in alcoholic ketoacidosis varies from hypoglycemia to mild elevation, and glucosuria is usually mild or absent. This differential diagnosis can be made in the emergency department.


Therapy of alcoholic ketoacidosis is simple and effective and consists of the intravenous administration of a glucose and saline solution. Patients given only saline improve, but not as rapidly as those who are also given glucose. Thiamine, 50 to 100 mg intravenously, should be given before the glucose to prevent precipitation of Wernicke's disease. Reversal of ketoacidosis usually occurs in 12 to 18 h.
Restoration of intravascular volume is best accomplished by alternating infusions of glucose-containing normal and half-normal saline. Volume repletion is necessary to correct insulin-release inhibition by adrenergic nerve endings in the islets of Langerhans as well as by circulating catecholamines. Glucose infusion stimulates insulin release, and insulin inhibits lipolysis and terminates ketoacid production. Glucose may inhibit further ketoacid production by increasing oxidation of accumulated NADH via glucose-induced uptake of phosphorus by the hepatic mitochondria.
Exogenous administration of insulin is not indicated in treatment of alcoholic ketoacidosis; this aspect of therapy differs from therapy of diabetic ketoacidosis. Inappropriate administration of insulin to a patient with a normal or low glucose level could be dangerous.
Administration of sodium bicarbonate is usually not required. As ketoacid levels fall, plasma bicarbonate levels increase, and the pH returns to normal. A small amount of bicarbonate may be indicated if the pH is less than 7.1 or if the patient is clinically deteriorating as evidenced by a weak, rapid pulse, hypotension, or inability to compensate by hyperventilation because of weakness. The role of phosphorus replenishment in therapy of alcoholic ketoacidosis is not clear.
With recovery and reversal of the acidosis, $-hydroxybutyrate is converted to acetoacetate. As this process occurs, the nitroprusside test becomes more positive because of higher levels of acetoacetate. This factitious hyperketonemia may cause the uninformed clinician unnecessary concern, as it appears that the ketoacidosis is worsening. Clinical improvement of the patient and increasing blood pH values are more reliable parameters of recovery than the nitroprusside test.
The survival rates of patients with alcoholic ketoacidosis are good. Those patients that die usually do so because of other complications of chronic alcoholism. A thorough search for and treatment of associated alcoholic disorders is essential. Recurrent episodes of alcoholic ketoacidosis after subsequent alcoholic debauch are not uncommon.


1)Fulop M, Ben-Ezra J, Bock J: Alcoholic ketosis. Alcoholism: Clin Exp Res 10:610, 1986.
2)Fulop M, Hoberman HD: Alcoholic ketosis. Diabetes 24:785, 1975.
3)Levy LJ, Duga J, Girgis M, et al: Ketoacidosis associated with alcoholism in nondiabetic subjects. Ann Intern Med 78:213, 1973.
4)Miller PD, Heinig RE, Waterhouse C: Treatment of alcoholic acidosis—The role of dextrose and phosphorus. Arch Intern Med 138:67, 1978.
5)Soffer A, Hamburger S: Alcoholic ketoacidosis: A review of 30 cases. J Am Med Wom Assoc 37:106, 1982.