Alcoholic Ketoacidosis

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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]}

Although AKA most commonly occurs in adults with alcoholism, it has been reported in less-experienced drinkers of all ages. Patients typically 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 (see Workup). ^{[6, 7]}

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 ratio of the reduced form of nicotinamide adenine dinucleotide (NADH) to nicotinamide adenine dinucleotide (NAD⁺)

This goal can usually be achieved through the administration of dextrose and saline solutions (see Treatment).

The pathogenesis of AKA is complex. ^[8] Although the general physiological factors and mechanisms leading to AKA are understood, the precise factors have not been fully elucidated. The following are the 3 main predisposing events:

Delay and decrease in insulin secretion and excess glucagon secretion, induced by starvation and counter-regulatory hormones

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

During starvation there is decrease in insulin secretion and increases in production of counter-regulatory hormones such as glucagon, catecholamines, cortisol, and growth hormone. Hormone-sensitive lipase is normally inhibited by insulin, and, when insulin levels fall, lipolysis is up-regulated, causing release of free fatty acids from peripheral adipose tissue.

Free fatty acids are either oxidized to CO₂ or ketone bodies (acetoacetate, hydroxybutyrate, and acetone), or they are esterified to triacylglycerol and phospholipid. Carnitine acyltransferase (CAT) transports free fatty acids into the mitochondria and therefore regulates their entry into the oxidative pathway. The decreased insulin-to-glucagon ratio that occurs in starvation indirectly reduces the inhibition on CAT activity, thereby allowing more free fatty acids to undergo oxidation and ketone body formation.

Prolonged vomiting leads to dehydration, which decreases renal perfusion, thereby limiting urinary excretion of ketoacids. Moreover, volume depletion increases the concentration of counter-regulatory hormones, further stimulating lipolysis and ketogenesis.

The metabolism of alcohol itself is a probable contributor to the ketotic state. Alcohol dehydrogenase (ADH), a cytosolic enzyme, metabolizes alcohol to acetaldehyde in hepatocytes. Acetaldehyde is metabolized further to acetic acid by aldehyde dehydrogenase. This reaction takes place within the mitochondria. Both steps require the reduction of nicotinamide adenine dinucleotide (NAD⁺) to reduced nicotinamide adenine dinucleotide (NADH). Thus, 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. Acetic acid (an acyl group carrier) is linked with coenzyme A (a thiol) to produce Acetyl-CoA. This process is catalyzed by the enzyme acetyl-CoA synthetase.

The decreased ratio of NAD⁺ to NADH has the following implications:

Impaired conversion of lactate to pyruvate with an increase in serum lactic acid levels

Impaired gluconeogenesis because pyruvate is not available as a substrate for glucose production

A shift in the hydroxybutyrate (β-OH) to acetoacetate (AcAc) equilibrium toward β-OH

In contrast to diabetic ketoacidosis, the predominant ketone body in AKA is β-OH. Routine clinical assays for ketonemia test for AcAc and acetone but not for β-OH. Clinicians underestimate the degree of ketonemia if they rely solely on the results of laboratory testing.

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.

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.

Increased availability of free fatty acids, which provide the major substrate for ketone body formation. 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, 9]}

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. ^[10]

In a Japanese study of 1588 alcoholic men, risk factors for the development of ketosis included ADH1B*1/*1 genotype, whiskey or shochu (distilled alcoholic beverages with no carbohydrates) as the drink of choice, hypoglycemia, lower body mass index, and smoking. ^[11]

Most cases of AKA occur when a person with poor nutritional status due to long-standing alcohol abuse who has been on a drinking binge suddenly decreases energy intake because of abdominal pain, nausea, or vomiting. In addition, AKA is often precipitated by another medical illness such as infection or pancreatitis.

AKA results from the accumulation of the hydroxybutyric acid, and acetoacetic acid (true ketoacid), and acetone. ^{[4, 9]} Such accumulation is caused by the complex interaction stemming from alcohol cessation, decreased energy intake, volume depletion, and the metabolic effects of hormonal imbalance.

The 2015 National Survey on Drug Use and Health (NSDUH) stated that 15.1 million adults aged 18 years or older in the United States (equaling 6.2% of people in this age group) suffer from alcohol use disorder. The rate of US alcohol-related deaths is estimated to be 88,000 people per year. ^[12]

The prevalence of AKA in a given community correlates with the incidence and distribution of alcohol abuse in that community. No racial or sexual differences in incidence are noted.

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. Rarely, AKA occurs after a binge in persons who are not chronic drinkers. Recently, a case report was published of an 11 year-old boy who presented in AKA after drinking ethanol-based mouthwash. ^[13]

With timely and aggressive intervention, the prognosis for a patient with AKA is good. The long-term prognosis for the patient is influenced more strongly by recovery from alcoholism.

Mortality and morbidity are rare in uncomplicated AKA. The major cause of morbidity and mortality in AKA is not the acidosis itself but is instead the inadequate treatment of concurrent medical or surgical conditions, such as gastrointestinal bleeding and alcohol withdrawal. ^{[1, 4, 14]} Complications occur in less than 20% of patients

Mortality is rare; however, alcoholic ketoacidosis (AKA) has been reported as the cause of death in a number of alcoholics. Markedly elevated beta hydroxybutyric acid could lead to death. ^{[4, 9]}

Refer the patient for treatment of chronic alcohol abuse. For patient education information, see the Mental Health and Behavior Center, as well as Alcoholism and Alcohol Intoxication.

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George Ansstas, MD Assistant Professor of Medicine, Division of Medical Oncology, Washington University School of Medicine

George Ansstas, MD is a member of the following medical societies: American Medical Association

Disclosure: Nothing to disclose.

Irina Robinson, MD Fellow, Department of Endocrinology and Metabolism, University of New Mexico School of Medicine and Health Sciences Center

Irina Robinson, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians

Disclosure: Nothing to disclose.

Sofya M Rubinchik, MD Consulting Staff, Department of Behavioral Health, Lovelace Medical Center

Sofya M Rubinchik, MD is a member of the following medical societies: American Association for Geriatric Psychiatry, American Medical Association, American Psychiatric Association, American Neuropsychiatric Association

Disclosure: Nothing to disclose.

David S Schade, MD Chief, Division of Endocrinology and Metabolism, Professor, Department of Internal Medicine, University of New Mexico School of Medicine and Health Sciences Center

David S Schade, MD is a member of the following medical societies: American College of Physicians, American Diabetes Association, American Federation for Medical Research, Endocrine Society, New Mexico Medical Society, New York Academy of Sciences, Society for Experimental Biology and Medicine

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS Professor of Medicine (Endocrinology, Adj), Johns Hopkins School of Medicine; Affiliate Research Professor, Bioinformatics and Computational Biology Program, School of Computational Sciences, George Mason University; Principal, C/A Informatics, LLC

Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Nutrition, American Society for Bone and Mineral Research, International Society for Clinical Densitometry, American College of Endocrinology, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Informatics Association, Endocrine Society

Disclosure: Nothing to disclose.

Romesh Khardori, MD, PhD, FACP Professor of Endocrinology, Director of Training Program, Division of Endocrinology, Diabetes and Metabolism, Strelitz Diabetes and Endocrine Disorders Institute, Department of Internal Medicine, Eastern Virginia Medical School

Romesh Khardori, MD, PhD, FACP is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, Endocrine Society

Disclosure: Nothing to disclose.

Alcoholic Ketoacidosis

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