AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

In 1940, Dillon and colleagues first described alcoholic ketoacidosis (AKA) as a distinct syndrome. AKA is characterized by metabolic acidosis with an elevated anion gap, elevated serum ketone levels, and a normal or low glucose concentration.^{1, 2} The disorder typically occurs in people who chronically abuse alcohol and have a recent history of binge drinking, little or no food intake, and persistent vomiting.^{3, 4, 5} A concomitant metabolic alkalosis is common, secondary to vomiting and volume depletion.⁶

Related eMedicine topic:
Alcoholic Ketoacidosis [Emergency Medicine]

Related Medscape topic:
Resource Center Addiction

Pathophysiology

The pathogenesis of AKA is complex.⁷ Although the general physiological factors and mechanisms leading to AKA are understood, the precise factors have not been fully defined. The following are the 3 main predisposing events: 

• Delay and decrease in insulin and excess in glucagon secretion induced by starvation
• Elevated ratio of the reduced form of nicotinamide adenine dinucleotide (NADH) to nicotinamide adenine dinucleotide (NAD⁺) secondary to alcohol metabolism
• Volume depletion resulting from vomiting and poor oral intake of fluids

These inciting events result in the rapid accumulation of the metabolic acids hydroxybutyric acid and acetoacetic acid.^{4, 8}

Metabolism of ethanol

The metabolism of alcohol itself is a probable contributor to the ketotic state. Alcohol dehydrogenase metabolizes alcohol to acetaldehyde in the cytoplasm of hepatocyte mitochondria. Acetaldehyde is metabolized further to acetic acid by aldehyde dehydrogenase. Because alcohol dehydrogenase and aldehyde dehydrogenase require NAD⁺ as a cofactor, NAD⁺ is consumed and NADH is generated. The resulting increase in the NADH/NAD⁺ ratio inhibits hepatic gluconeogenesis and elevates the ratio of hydroxybutyric acid to acetoacetic acid.^{4, 8} Acetic acid is converted by coenzyme A to acetyl-coenzyme A, which in turn is used for the conversion to adipose tissue, in the formation of ketone bodies, and in the citric acid cycle.

Low insulin levels and increased glucagon, catecholamine, growth hormone, and cortisol levels inhibit the hepatic metabolism of acetyl-coenzyme A via the citric acid cycle and triglyceride synthesis, thereby further enhancing ketogenesis. Diminished pyruvate dehydrogenase activity as a result of decreased NAD⁺ availability and/or magnesium or thiamine deficiency inhibits utilization of pyruvate in the citric acid cycle.

Dehydration

All patients with severe AKA are dehydrated. Several mechanisms are responsible for dehydration, including protracted vomiting, decreased fluid intake, and inhibition of antidiuretic hormone secretion by ethanol. Volume depletion is a strong stimulus to the sympathetic nervous system and is responsible for elevated cortisol and growth hormone levels. Dehydration and volume constriction directly decrease the ability of the kidneys to excrete ketoacids. Profound dehydration can culminate in circulatory collapse and/or lactic acidosis.

Fasting

Energy (caloric) restriction secondary to abdominal pain, nausea, or vomiting usually occurs prior to the onset of AKA.⁶ Under conditions of starvation, the liver increases the production of ketones from fatty acids to supply the brain, kidney, and other peripheral tissues with a metabolic fuel that can replace glucose. Increased ketogenesis secondary to the utilization of hepatic glycogen stores, with subsequently increased lipolysis and a decreased insulin-to-glucagon ratio, causes starvation ketosis. Triglycerides stored in adipose tissue undergo lipolysis and are released into the circulation as free fatty acids bound ionically to albumin. Free fatty acids are removed by the liver, where they primarily undergo oxidation to hydroxybutyric acid and acetoacetate and subsequently are reesterified to triglyceride. Decreased insulin and elevated glucagon, cortisol, catecholamine, and growth hormone levels can increase the rate of ketogenesis.

Ketogenesis

Increased availability of free fatty acids, which provide the major substrate for ketone body formation, stimulates ketogenesis. Low insulin levels and elevated glucagon, catecholamine, growth hormone, and cortisol levels provide a hormonal milieu that inhibits the hepatic metabolism of acetyl-coenzyme A via the citric acid cycle and triglyceride synthesis, resulting in ketogenesis. In AKA, the increased ratio of NADH/NAD⁺ increases the proportion of beta hydroxybutyrate relative to acetoacetate.^{4, 8} Ketone body clearance is decreased by 2 major mechanisms, as follows:

• The low insulin level characteristic of AKA prevents ketone body utilization by insulin-sensitive tissues.
• Dehydration impairs the excretion of ketones by the kidneys.

Elevated cortisol levels can increase fatty acid mobilization and ketogenesis. Growth hormone can enhance precursor fatty acid release and ketogenesis during insulin deficiency. Catecholamines, particularly epinephrine, increase fatty acid release and enhance the rate of hepatic ketogenesis. Insulin release from the pancreatic beta cells might be abnormally sensitive to catecholamine inhibition. The pivotal variable appears to be a relative deficiency of insulin. Individuals with higher insulin levels are more likely to present with the syndrome of alcohol-induced hypoglycemia without ketoacidosis.⁹

Frequency

United States

In the United States, the prevalence of AKA in a given community correlates with the incidence and distribution of alcohol abuse in that community.

Mortality/Morbidity

• Mortality and morbidity are rare in uncomplicated AKA.
• Medical complications are secondary to concomitant medical conditions, such as gastrointestinal bleeding and alcohol withdrawal.^{1, 4, 10}
• Complications occur in less than 20% of patients. Markedly elevated beta hydroxybutyric acid could lead to death.^{4, 8}

Race

AKA has no race predilection.

Sex

AKA has no sex predilection.

Age

AKA can occur in adults of any age; however, it most often develops in persons aged 20-60 years who are chronic abusers of alcohol.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Patients almost always are alcoholics who, prior to the development of ketoacidosis, have engaged in a period of very heavy drinking, with subsequent abrupt cessation of alcohol consumption 1-2 days before presentation. Such presentations typically result from physical complaints, such as the following:
• • Nausea, vomiting, abdominal pain, and/or hematemesis
  • Dyspnea, tremulousness, and/or dizziness
  • Muscle pain, fever, diarrhea, syncope, seizure, and/or melena
• These symptoms usually are attributed to alcoholic gastritis or pancreatitis
• If the plasma glucose level is elevated above 300 mg/dL upon presentation, consider diabetic ketoacidosis.^{11, 12, 13, 14}

Related eMedicine topics:
Diabetic Ketoacidosis [Emergency Medicine]
Diabetic Ketoacidosis [Pediatrics: Cardiac Disease and Critical Care Medicine]
Pediatrics, Diabetic Ketoacidosis

Physical

• Physical examination may reveal a multitude of pathologic conditions.
• Typical characteristics of an alcohol abuser may be present, including rhinophyma, tremulousness, hepatosplenomegaly, peripheral neuropathy, gynecomastia, testicular atrophy, and palmar erythema. The patient might be tachycardic, tachypneic, profoundly orthostatic, or frankly hypotensive as a result of dehydration from decreased oral intake, diaphoresis, and vomiting.
• The patient's breath may carry the fruity odor of ketosis.
• A tachypnea in the form of the Kussmaul respiration varieties is usually present when the pH is less than 7.2.⁹
• Hypothermia is common in AKA; a fever can be a sign of an underlying infectious process.
• Symptoms of abdominal tenderness consistent with a diagnosis of alcoholic liver disease, pancreatitis, gastritis, or peptic ulcer disease may be revealed during abdominal examination and may mimic an abdominal emergency.
• Hemoccult-positive stools may be present.
• Mental status may be normal or slightly impaired as a result of derangements in electrolytes or vital signs.
• Severe obtundation; fixed, dilated pupils; and finally, death may occur.

Causes

• The alcoholic patient who has been on a drinking binge suddenly decreases energy intake because of abdominal pain, nausea, or vomiting.
• AKA results from the accumulation of the ketoacids, hydroxybutyric acid, and acetoacetic acid.^{4, 8} Such accumulation is caused by the complex interaction stemming from alcohol cessation, decreased energy intake, volume depletion, and the metabolic effects of hormonal imbalance.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to Be Considered

Ethylene glycol intoxication
Methanol intoxication
Salicylate intoxication

It can be difficult at presentation to distinguish between ethanol, methanol, and ethylene glycol toxicity in an alcoholic patient with a high–anion gap metabolic acidosis and an osmolal gap. Additional possibilities, which may be concurrent abnormalities, include lactic acidosis and diabetic ketoacidosis. Thus, the diagnostic evaluation should include a careful history, an assessment for ketonemia or ketonuria, a urinalysis (eg, an evaluation for calcium oxalate crystals), and a measurement of serum levels of suspected toxins.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Usual laboratory findings include the following¹⁵:
• • The arterial pH is less than 7.3, and the serum bicarbonate level is less than 15 mEq/L.
  • The calculated anion gap is greater than 14 mmol/L.
  • The partial pressure of carbon dioxide is decreased secondary to compensatory hyperventilation.
  • In some patients, severe vomiting results in chloride depletion and metabolic alkalosis, with consequently higher pH values than those found in patients with diabetic ketoacidosis.^{3, 11}
• In AKA, the average ratio of hydroxybutyric acid to acetoacetic acid (5:1) tends to be higher than that which occurs in diabetic ketoacidosis (3:1).^{4, 8, 11}
• Because the nitroprusside reaction measures acetoacetate but not beta hydroxybutyrate, serum ketones estimated by this method may be only weakly positive or may even be negative.^{4, 16}
• • Use reagent strips that measure only beta hydroxybutyrate.
  • The hallmark of AKA is ketoacidosis without marked hyperglycemia.³
  • Serum glucose levels above 300 mg/dL usually indicate diabetic ketoacidosis, unless AKA has developed in a diabetic patient.¹¹
• Free fatty acid levels are usually markedly elevated, which is secondary to increased lipolysis.
• Insulin levels are low, glucagon levels are high.
• Cortisol and catecholamine levels are markedly elevated, and modest elevations of growth hormone are common.
• Because many of these patients are alcoholics and may have intercurrent or chronic disease, a variety of other laboratory parameters can be present, including elevated liver function test results, an increased amylase level, a decreased hemoglobin/hematocrit value, a decreased white blood cell (WBC) and thrombocyte count, macrocytosis (MCV 100-110 fL), and an abnormal BUN-to-creatinine ratio.
• Hyponatremia and hypokalemia are common laboratory findings. Vomiting and extracellular volume depletion may cause hyponatremia. Hypokalemia is often associated with hypomagnesemia.
• Phosphate levels may be low, normal, or elevated.
• An elevated lactate level (usually does not exceed 3 mmol/L) may result from dehydration or seizure or could be the direct metabolic effect of alcohol.
• Hyperuricemia is commonly observed; it results from decreased renal perfusion, tissue catabolism, competitive inhibition of renal uric acid excretion by ketone bodies, and direct ethanol enhancement of adenine nucleotide degradation.
• True hypocalcemia associated with hypomagnesemia may be present. Concomitant pancreatitis also may contribute to true hypocalcemia. Factitious hypocalcemia can result from a markedly decreased serum albumin level following prolonged malnutrition with alcoholism.

Imaging Studies

• Chest radiography - Because of the high risk of aspiration pneumonia in people with alcoholism, consider obtaining a chest radiograph. Esophageal rupture may occur with prolonged retching, resulting in pneumomediastinum or in subdiaphragmatic air.
• Urgent abdominal series - Consider obtaining an urgent abdominal series in patients with significant vomiting and abdominal pain, because these symptoms may indicate obstruction, perforation of a viscus, and/or pancreatitis.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Treatment of AKA is directed toward reversing the 3 major pathophysiologic causes of the syndrome, which are:
• • Extracellular fluid volume depletion
  • Glycogen depletion
  • An elevated NADH/NAD⁺ ratio
• In AKA, this goal can usually be achieved through the administration of dextrose and saline solutions.⁴ Carbohydrate and fluid replacement reverse the pathophysiologic derangements that lead to AKA by increasing serum insulin levels and suppressing the release of glucagon and other counterregulatory hormones. Dextrose stimulates the oxidation of NADH and aids in normalizing the NADH/NAD⁺ ratio. Fluids alone do not correct AKA as quickly as do fluids and carbohydrates together.
• In alcoholics, thiamine (100 mg IV or IM) should be administered prior to any glucose-containing solutions in order to decrease the risk of precipitating Wernicke encephalopathy or Korsakoff syndrome.¹⁷
• Phosphate depletion is also commonly present in alcoholics. The plasma phosphate concentration may be normal on admission; however, it typically falls to low levels with therapy as insulin drives phosphate into the cells. When present, severe hypophosphatemia may be associated with marked and possibly life-threatening complications, such as myocardial dysfunction, in these patients.
• Bicarbonate therapy should be considered only in the face of severe, life-threatening acidosis (ie, pH <7.1) that is unresponsive to fluid therapy. 
• Evaluate the patient for signs of alcohol withdrawal syndrome, which may include tremors, agitation, diaphoresis, tachycardia, hypertension, tremors, agitation, seizures, or delirium. Exclude other causes of autonomic hyperactivity and altered mental status. If the diagnosis of alcohol withdrawal syndrome is established, consider the judicious use of benzodiazepines, which should be titrated to clinical response.

Consultations

• The underlying severity of the disease process and of the underlying diseases associated with AKA determines the role of the consultant.
• Patients with uncomplicated AKA may need nothing more than appropriate treatment and observation until their metabolic and systemic abnormalities are resolved.
• Patients with an acute abdomen need consultation with a surgeon.
• Patients with underlying medical problems may need to consult with the appropriate specialist.
• If indicated, provide follow-up with AKA patients to assess the problem of alcohol abuse, with possible referral to a counselor at an alcohol treatment center.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Potassium repletion is indicated in hypokalemic patients and normokalemic patients with acidemia.

Magnesium repletion is indicated in all patients to help restore calcium and potassium homeostasis and to prevent alcohol withdrawal.

Phosphate repletion is recommended only if severe hypophosphatemia is present.

Thiamine repletion is indicated routinely to provide prophylaxis against the development of Wernicke encephalopathy.¹⁷

Drug Category: Electrolyte supplements, parenteral

Used to replenish electrolyte levels that have been depleted.

Drug Category: Vitamins

Essential for normal DNA synthesis and cell function.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Institute appropriate treatment for serious, coexisting, acute illnesses.

Further Outpatient Care

• Arrange follow-up to evaluate patients after the resolution of symptoms, in order to detect other complications of chronic alcohol abuse.
• The patient may benefit from an alcohol rehabilitation program.

Transfer

• Patients generally do not need to be transferred to special facilities.
• Always assess the patient's stability for transfer.
• Appropriately evaluate the patient for any life-threatening complications before a transfer is considered.

Deterrence/Prevention

• Treatment of chronic alcohol abuse

Complications

• Seizure
• Sudden cardiac arrest^{17, 18}
• Life-threatening arrhythmias
• Shock
• Infection
• Pulmonary edema
• Delirium tremens

Prognosis

• The major cause of morbidity and mortality is not the acidosis itself but is instead the inadequate treatment of concurrent medical or surgical conditions.^{1, 4, 10}

Patient Education

• Refer the patient for treatment of chronic alcohol abuse.
• For excellent patient education resources, visit eMedicine's Mental Health and Behavior Center. Also, see eMedicine's patient education articles Alcoholism and Alcohol Intoxication.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to recognize underlying diseases associated with AKA
• Failure to inform patients and families about the possibility of treatment at an alcohol rehabilitation center
• Failure to recognize and treat a major alcohol withdrawal or delirium tremens
• Failure to recognize and treat hypoglycemia in patients presenting with altered mental status and/or seizure.

Special Concerns

• The AKA differential diagnosis includes all metabolic conditions that can cause an increased–anion gap metabolic acidosis in a person who abuses ethanol.
• All patients with AKA have ketonuria and most have ketonemia. A normal, or even high, blood pH does not exclude the diagnosis, because patients with AKA may have a concomitant metabolic alkalosis due to vomiting or may have a compensatory respiratory alkalosis.⁶
• • A compensatory respiratory alkalosis alone cannot correct the pH to normal, because the drive for compensation decreases as the pH approaches normality.
  • This implies that a significant noncompensatory metabolic alkalosis also must be present if the pH is near the normal range.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Adams SL. Alcoholic ketoacidosis. Emerg Med Clin North Am. Nov 1990;8(4):749-60. [Medline].
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3. Fulop M. Alcoholic ketoacidosis. Endocrinol Metab Clin North Am. Jun 1993;22(2):209-19. [Medline].
4. Palmer JP. Alcoholic ketoacidosis: clinical and laboratory presentation, pathophysiology and treatment. Clin Endocrinol Metab. Jul 1983;ID - AM17047/AM/NIADDK(2):381-9. [Medline].
5. Al-Sanouri I, Dikin M, Soubani AO. Critical care aspects of alcohol abuse. South Med J. Mar 2005;98(3):372-81. [Medline].
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9. Marinella MA. Alcoholic ketoacidosis presenting with extreme hypoglycemia. Am J Emerg Med. May 1997;15(3):280-1. [Medline].
10. Ngatchu T, Sangwaiya A, Dabiri A, et al. Alcoholic ketoacidosis with multiple complications: a case report. Emerg Med J. Nov 2007;24(11):776-7. [Medline].
11. Umpierrez GE, DiGirolamo M, Tuvlin JA, et al. Differences in metabolic and hormonal milieu in diabetic- and alcohol-induced ketoacidosis. J Crit Care. Jun 2000;15(2):52-9. [Medline].
12. Samaha FF, Iqbal N, Seshadri P, et al. A low-carbohydrate as compared with a low-fat diet in severe obesity. N Engl J Med. May 22 2003;348(21):2074-81. [Medline].
13. Wootton-Gorges SL, Buonocore MH, Kuppermann N, et al. Cerebral proton magnetic resonance spectroscopy in children with diabetic ketoacidosis. AJNR Am J Neuroradiol. May 2007;28(5):895-9. [Medline]. [Full Text].
14. Ferreri R. Treatment practices of diabetic ketoacidosis at a large teaching hospital. J Nurs Care Qual. Apr-Jun 2008;23(2):147-54. [Medline].
15. Kugelberg FC, Jones AW. Interpreting results of ethanol analysis in postmortem specimens: a review of the literature. Forensic Sci Int. Jan 5 2007;165(1):10-29. [Medline].
16. Pounder DJ, Stevenson RJ, Taylor KK. Alcoholic ketoacidosis at autopsy. J Forensic Sci. Jul 1998;43(4):812-6. [Medline].
17. Diltoer MW, Troubleyn J, Lauwers R, et al. Ketosis and cardiac failure: common signs of a single condition. Eur J Emerg Med. Jun 2004;11(3):172-5. [Medline].
18. Yanagawa Y, Sakamoto T, Okada Y. Six cases of sudden cardiac arrest in alcoholic ketoacidosis. Intern Med. 2008;47(2):113-7. [Medline]. [Full Text].

Article Last Updated: Jun 5, 2008