Chapter 226: Alcoholic Ketoacidosis

Alcoholic ketoacidosis is a wide anion gap metabolic acidosis, most often associated with acute cessation of alcohol consumption after chronic alcohol abuse, and is typically associated with nausea, vomiting, and vague GI complaints.¹ Metabolism of alcohol combined with little or no glycogen reserves results in elevated ketoacid levels. Although alcoholic ketoacidosis is usually seen in chronic alcoholics, it has been described in first-time binge drinkers. Repeated episodes can occur.² Although with proper treatment this illness is self-limited, death has been reported from presumed excessive ketonemia.^2,5,4

Ethanol metabolism requires nicotinamide adenine dinucleotide (NAD) and the enzymes alcohol dehydrogenase and aldehyde dehydrogenase to convert ethanol to acetyl coenzyme A. Acetyl coenzyme A may be metabolized directly, resulting in ketoacid production; used as substrate for the Krebs cycle; or used for free fatty acid synthesis (Figure 226-1).

Alcoholic ketoacidosis occurs when NAD is depleted by ethanol metabolism, resulting in inhibition of the aerobic metabolism in the Krebs cycle, depletion of glycogen stores, ketone formation, and lipolysis stimulation. Ethanol metabolism results in NAD depletion manifesting as a higher ratio of the reduced form of nicotinamide adenine dinucleotide (NADH) to NAD. When glycogen stores are depleted in a patient stressed by concurrent illness or volume depletion, insulin secretion is also suppressed. Under these same conditions, glucagon, catecholamine, and growth hormone secretion are all stimulated. This hormonal milieu inhibits aerobic metabolism in favor of anaerobic metabolism and stimulates lipolysis. Acetyl coenzyme A is metabolized to the ketoacids, β-hydroxybutyrate (βHB) and acetoacetate.

NAD is used in the conversion of βHB to acetoacetate (AcAc + NADH βHB + NAD). Due to the depletion of NAD, βHB is the predominant ketone product formed. Normally, the ratio of acetoacetate to βHB is 1:1; however, in alcoholic ketoacidosis, the ratio can be 1:7 or higher.⁵ Once the NADH:NAD returns to normal, lactate levels decrease and acetoacetate increases.¹ The ratio of βHB to acetoacetate is also much higher in alcoholic ketoacidosis than in diabetic ketoacidosis.¹ The high NADH:NAD ratio also results in increased lactate production, so lactate levels are higher than normal in alcoholic ketoacidosis but not as high as in shock or sepsis. Acetoacetate is metabolized to acetone so that acetone and its metabolites are elevated and may cause an osmolal gap.

Ketone production can be further stimulated in malnourished, vomiting patients or in those who are hypophosphatemic.⁶ Both conditions are seen commonly in alcoholic patients with alcoholic ketoacidosis.

The typical history is an episode of heavy drinking followed by vomiting and an acute decrease in alcohol consumption. The most common symptoms are nausea, vomiting, and nonspecific abdominal pain.² Associated gastritis or pancreatitis may occur. Mental status changes are typically secondary to other causes, such as toxic ingestion, hypoglycemia, alcohol-withdrawal seizures, postictal state, or unrecognized head injury.

Diagnosis is made in the appropriate clinical setting and is based on laboratory evaluation. Laboratory evaluation should include CBC; electrolyte panel with calcium, phosphate, and magnesium; ethanol, methanol, and isopropyl alcohol levels; hepatic enzymes; lipase; and serum ketones. Determination of serum lactic acid level and serum osmolality also may be helpful. Diagnosis is made by the criteria listed in Table 226-1, with metabolic acidosis, positive serum ketones, elevated anion gap, and a low or mildly elevated serum glucose level. Patients frequently have hypophosphatemia, hyponatremia, and/or hypokalemia. Most patients also will have elevated bilirubin and liver enzyme levels due to liver disease from a long history of chronic ethanol use. BUN levels frequently are elevated due to relative volume depletion. The nitroprusside reagent used to measure urine and serum ketones measures acetoacetate. Acetone is weakly reactive, and βHB is not detected at all. So, the initial ketone levels may be low or negative in alcoholic ketoacidosis. With recovery, acetoacetate increases and assays become positive.¹ A small to moderate anion gap is invariable in alcoholic ketoacidosis. Without routine evaluation of the anion gap in every patient at risk for alcoholic ketoacidosis, the diagnosis can be easily missed. The anion gap is usually 16 to 33, with a mean of 21,² and is due to ketonemia, primarily from βHB. The osmolal gap may be slightly elevated because acetone and its metabolites cause an osmolal gap (<20 mmol/kg).¹ Consider co-ingestions or other causes of anion gap acidosis if the anion gap fails to close with ongoing treatment. Mild lactic acidosis may be present due to a shift to pyruvate metabolism toward lactate¹.

DIFFERENTIAL DIAGNOSIS

Table 226-2 and chapter 15, Acid-Base Disorders, list the most important causes of metabolic acidosis that should be excluded to diagnose alcoholic ketoacidosis.

Alcoholic ketoacidosis should be differentiated from other alcohol ingestions. Methanol and ethylene glycol ingestions do not produce ketosis, and acidosis tends to be severe. Isopropyl alcohol ingestion results in production of ketones. The presence of a large osmolal gap suggests acute isopropyl, ethanol, methanol, or ethylene glycol ingestion. If the blood alcohol level is known, then its contribution to any osmolal gap can be calculated. Each 100 milligrams/dL (21.7 mmol/L) of ethanol raises the osmolal gap by 22. Details of osmolal gap are discussed in chapter 17, Fluids and Electrolytes.

The presence of a mixed acid-base disturbance suggests a comorbid disorder. Common concurrent illnesses are dehydration and electrolyte disturbances from vomiting and reduced intake, pancreatitis, gastritis or upper GI bleeding, seizures, alcohol withdrawal, pneumonia, sepsis, and hepatitis.

Starvation ketosis occurs in patients with diminished carbohydrate intake, resulting in lipolysis and ketonuria. Ketone bodies appear after about 3 days of fasting but can appear earlier in the presence of stress and dehydration. Metabolic acidosis and ketonemia are rare in starvation ketosis, but ketonuria is common.⁷

Therapy consists of both glucose administration and volume repletion (Table 226-3). Fluids alone do not correct the ketoacidosis as fast as fluids and glucose administered together. Glucose stimulates insulin production, which stops lipolysis and halts further ketone formation. Glucose also increases oxidation of NADH to NAD, thereby further stopping ketone production. The fluid of choice is 5% dextrose in normal saline. Once fluid and electrolyte losses are replaced, change fluids to 5% dextrose in half normal saline until oral intake is assured.¹ Patients with alcoholic ketoacidosis are not hyperosmolar. Unlike treatment of diabetic ketoacidosis, cerebral edema is of little concern with large volumes of fluid administration. Even with vigorous fluid resuscitation, in our review of the literature, cerebral edema has not been reported among those being treated for alcoholic ketoacidosis.

Insulin is of no proven benefit and can even be dangerous, as patients often have depleted glycogen stores and normal or low glucose levels. Sodium bicarbonate is not indicated unless patients are severely acidemic, with a pH <7.0. Severe acidemia is unlikely to be explained by alcoholic ketoacidosis alone. Mildly elevated osmolal gaps can exist, but it is important to consider co-ingestions, or other causes of anion gap acidosis, if the gap fails to close with ongoing fluid and carbohydrate treatment. Hypophosphatemia is common in alcoholics and can retard the resolution of acidosis because phosphorus is necessary for mitochondrial utilization of glucose for oxidation of NADH. However, phosphate replacement generally is unwarranted in alcoholic ketoacidosis unless levels are very low (<1.0 milligram/dL or <0.323 mmol/L).⁶ Serum ketone levels correlated with clinical status may be used to help guide therapy because an increasingly positive reaction signifies improvement.

The prevalence of key vitamin deficiencies in alcohol-dependent patients is unknown but is probably low.⁸ Some feel that the practice of routine administration of IV thiamine or multivitamins in the ED is necessary to prevent the theoretical precipitation of Wernicke's disease,⁹ whereas others feel that vitamin supplementation in the ED should be reserved for those with confirmed deficiencies or who are truly at high risk for such deficiencies.¹⁰ If vitamins are given, they can be provided concurrently with, or after, the administration of glucose.¹¹ Oral vitamin supplementation has also been described, with IM thiamine added to the oral regimen.⁸ Administration of magnesium sulfate should be guided by laboratory results. Acidosis should clear within 12 to 24 hours.

Patients with an uncomplicated ED course may be safely discharged home if there is resolution of acidosis and the patient is able to tolerate oral fluids. Patients should receive counseling on alcohol dependence, be encouraged to use multivitamins, and be offered treatment in an alcohol detoxification program. Patients with a complicated course, underlying illnesses, or persistent acidosis should be admitted for further evaluation and treatment (Table 226-3).