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, 3] The diagnosis of AKA requires arterial blood gas (ABG) measurement and serum chemistry assays.
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.[4, 5, 6] A concomitant metabolic alkalosis is common, secondary to vomiting and volume depletion (see Workup).[7, 8]
Generally, the physical findings relate to volume depletion and chronic alcohol abuse. Typical characteristics of the latter may include 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. Tachypnea in the form of the Kussmaul respiration varieties is usually present when the pH is less than 7.2.[9]
The diagnosis of alcoholic ketoacidosis (AKA) requires arterial blood gas (ABG) measurement and serum chemistry assays. Usual laboratory findings include the following[10] :
All patients with AKA have ketonuria and most have ketonemia. In AKA, the average ratio of hydroxybutyric acid (β-OH) to acetoacetic acid (5:1) tends to be higher than that which occurs in diabetic ketoacidosis (3:1).[5, 12, 11]
The hallmark of AKA is ketoacidosis without marked hyperglycemia; the serum glucose level may be low, normal, or slightly elevated.[4] This finding can help to distinguish AKA from diabetic ketoacidosis (DKA).
Treatment of alcoholic ketoacidosis (AKA) is directed toward reversing the three major pathophysiologic causes of the syndrome, which are:
This goal can usually be achieved through the administration of dextrose and saline solutions.[5]
In alcoholics, thiamine (100 mg IV or IM) should be administered prior to any glucose-containing solutions. This will decrease the risk of precipitating Wernicke encephalopathy or Korsakoff syndrome.[13]
The pathogenesis of AKA is complex.[14] Although the general physiologic factors and mechanisms leading to AKA are understood, the precise factors have not been fully elucidated. The following are the 3 main predisposing events:
During starvation, there is a decrease in insulin secretion and an increase in the 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:
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.[7] 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.[5, 12]
Ketone body clearance is decreased by 2 major mechanisms, as follows:
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]
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.[15]
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, acetoacetic acid (true ketoacid), and acetone.[5, 12] 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 National Survey on Drug Use and Health (NSDUH) stated that almost 29 million persons aged 12 years or older in the United States suffered from alcohol use disorder in 2023.[16]
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. A case report was published of an 11 year-old boy who presented in AKA after drinking ethanol-based mouthwash.[17]
A retrospective study by Milroy et al of 9332 autopsies found that 82 deaths (0.9%) were known to be from DKA, and 48 deaths (0.5%) were known to be from AKA, with more male than female deaths occurring in both DKA and AKA. The median ages at death for DKA and AKA were 51 and 55 years, respectively, and the median body mass indexes (BMIs) at death were 21.9 kg/m2 and 20.2 kg/m2, respectively. A higher mean concentration of the ketone body acetone was seen in DKA deaths than in those from AKA (33.7 mg/100 mL vs 16.9 mg/100 mL, respectively).[18]
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, 5, 19] Complications occur in less than 20% of patients
AKA has nonetheless been reported as the cause of death in a number of alcoholics. Markedly elevated beta hydroxybutyric acid could lead to death.[5, 12]
Patients with alcoholic ketoacidosis (AKA) 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:
These symptoms usually are attributed to alcoholic gastritis or pancreatitis.
Example case of alcoholic ketoacidosis: A 35-year-old man who chronically abuses alcohol presents with abdominal pain and intractable emesis for the past 2 days. The pain and emesis developed after 5 days of heavy drinking. Since their onset, he stopped eating and drinking altogether. He complains of epigastric pain that radiates through to his back. He is afebrile, tachycardic, and borderline hypotensive. He is sleepy, but awakens easily to verbal stimuli.
Generally, the physical findings relate to volume depletion and chronic alcohol abuse. Typical characteristics of the latter may include 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. 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.
Abdominal tenderness consistent with a diagnosis of alcoholic liver disease, pancreatitis, gastritis, or peptic ulcer disease may be found on 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.
Complications associated with AKA include the following:
Diagnosis of alcoholic ketoacidosis (AKA) requires arterial blood gas (ABG) measurement and serum chemistry assays. Usual laboratory findings include the following[10] :
Arterial blood gas (ABG) measurement may show a low pCO2 level, low bicarbonate level, and normal partial pressure of oxygen (pO2) level. The pattern is consistent with a metabolic acidosis with a respiratory compensation.
Serum pH levels may be misleading because the patient with AKA often has a mixed acid-base disorder. In addition to metabolic acidosis due to ketone formation, a metabolic alkalosis may be present due to vomiting and volume depletion.[7] A respiratory alkalosis may be present secondary to hyperventilation. The possibility of a double or triple acid-base disorder means serum pH levels may be near normal despite a severe acid-base disturbance.
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.
Venous blood gas measurements correlate very well with arterial measurements. One should consider using venous blood gas measurements in lieu of arterial blood gas measurements.[24]
All patients with AKA have ketonuria and most have ketonemia. In AKA, the average ratio of hydroxybutyric acid (β-OH) to acetoacetic acid (5:1) tends to be higher than that which occurs in diabetic ketoacidosis (3:1).[5, 12, 11] The nitroprusside reaction (Acetest) may be negative or only weakly positive for serum ketones in AKA because nitroprusside reacts with acetone and acetoacetic acid, but not with β-OH.[5, 25] Direct serum measurements of β-OH should be used when available.
With initial therapy, ketone formation shifts toward the production of acetoacetic acid. Measured ketone levels rise, although β-OH levels decrease.
A study by Ahlström et al found beta-hydroxybutyrate analysis to be an important element in determining death by AKA. The investigators determined that after Sweden introduced such analysis on a more widespread basis in the practice of forensic autopsy, the number of deaths in the autopsy population that were attributed to AKA rose from 3-10 cases annually between 2013 and 2015 to 66 cases in 2019.[26]
The hallmark of AKA is ketoacidosis without marked hyperglycemia; the serum glucose level may be low, normal, or slightly elevated.[4] This finding can help to distinguish AKA from diabetic ketoacidosis (DKA). Serum glucose levels above 300 mg/dL usually indicate DKA, unless AKA has developed in a diabetic patient.[11]
The anion gap is elevated. Lactate levels may be 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.
Hyponatremia and hypokalemia are common laboratory findings in patients with AKA. Vomiting and extracellular volume depletion may cause hyponatremia. Hypokalemia is often associated with hypomagnesemia.
Hypomagnesemia may be caused by poor nutrition, decreased renal absorption of magnesium, or nasogastric suctioning. Serum magnesium levels are not reliable indicators of total body magnesium stores, however. Due to the linked excretion between potassium and magnesium, the presence of hypokalemia is a strong indicator of hypomagnesemia and can be used as a surrogate test to determine if magnesium replacement is needed.
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.
Phosphate levels may be low, normal, or elevated. Ethanol-enhanced urinary excretion, emesis, and antacid use may contribute to hypophosphatemia in people who have chronic alcoholism.
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. In a study of Japanese men aged 40 years or older with alcoholism, Yokoyama et al suggested that the development of hyperuricemia was associated with quicker ethanol and acetaldehyde metabolism by those who had both the ADH1B*2 allele and the ALDH2*1/*1 genotype and with greater levels of ketosis.[27]
Anemia may be present secondary to nutritional deficiencies, alcoholic bone marrow suppression, or gastrointestinal (GI) bleeding. The hematocrit (Hct) may be falsely elevated from hemoconcentration in the presence of intravascular volume depletion. Other findings are a decreased white blood cell (WBC) macrocytosis (mean corpuscular volume [MCV] 100-110 fL). Thrombocytopenia may be present due to chronic liver disease.
Liver and pancreatic function test results, including hepatic enzymes (eg, serum glutamic-oxaloacetic transaminase [SGOT], lactate dehydrogenase [LDH], alkaline phosphatase), total bilirubin, and pancreatic amylase and lipase levels, may be elevated because of associated illnesses (eg, alcohol-induced hepatitis, pancreatitis).
The alcohol level may be low or zero due to anorexia and decreased drinking in the preceding 1-3 days. Blood alcohol levels do not typically change the management of AKA and are therefore not often necessary.
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.
A study by Kim et al indicated that in males with AKA, a high delta neutrophil index (DNI) value predicts poor outcomes. The cumulative survival rates for patients with an initial DNI level of 4.5% or greater were lower than for those whose DNI value was less than 4.5%.[28]
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.
Consider obtaining an urgent abdominal series in patients with significant vomiting and abdominal pain. These symptoms may indicate obstruction, perforation of a viscus, and/or pancreatitis.
Treatment of alcoholic ketoacidosis (AKA) is directed toward reversing the three major pathophysiologic causes of the syndrome, which are:
This goal can usually be achieved through the administration of dextrose and saline solutions.[5]
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. Indeed, evidence-based guidelines by Flannery et al on the management of intensive care unit patients with a chronic alcohol disorder, including symptoms that mimic or mask Wernicke encephalopathy, recommend that in cases of suspected AKA, dextrose-containing fluids be used in place of normal saline during the first day of admission.[29]
In alcoholics, thiamine (100 mg IV or IM) should be administered prior to any glucose-containing solutions. This will decrease the risk of precipitating Wernicke encephalopathy or Korsakoff syndrome.[13]
Phosphate depletion is also common in people with alcoholism. 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.
Institute appropriate treatment for serious, coexisting, acute illnesses. These may include pancreatitis, hepatitis, heart failure, or infection.
Prevention of AKA involves the treatment of chronic alcohol abuse.
Patients generally do not need to be transferred to special facilities. Appropriately evaluate the patient for any life-threatening complications before a transfer is considered. Always assess the patient's stability for transfer.
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 the following:
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.
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. Consider referral to a counselor at an alcohol treatment center.
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.
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.[13]
Clinical Context: Potassium is essential for transmission of nerve impulses, contraction of cardiac muscle, maintenance of intracellular tonicity and skeletal and smooth muscles, and maintenance of normal renal function. Gradual potassium depletion occurs via renal excretion through GI loss or because of low intake.
Clinical Context: Magnesium is a cofactor in enzyme systems involved in neurochemical transmission and muscular excitability.
Clinical Context: Response to IV phosphorus supplementation is highly variable and is associated with hyperphosphatemia and hypocalcemia. Base the rate of infusion and the choice of initial dosage on the severity of the hypophosphatemia and on the presence of symptoms. IV preparations are available as sodium or potassium phosphate.
These agents are used to replenish electrolyte levels that have been depleted.
Clinical Context: This vitamin is indicated for thiamine deficiency, including Wernicke encephalopathy syndrome.