Alcoholic Ketoacidosis
Christopher R. Carpenter
KEY POINTS
• Alcoholic ketoacidosis accounts for up to 20% of cases
of ketoacidosis.
• The characteristic example is an alcoholic person who
abruptly abstains and has signs and symptoms such as
vomiting, abdominal pain, malnutrition, and an anion
gap metabolic acidosis, but no measurable alcohol
levels.
• Initial glucose levels may be low, normal, or high.
• A ratio of β-hydroxybutyrate to acetoacetate in excess
of 10 : 1 is pathognomonic for alcoholic ketoacidosis,
whereas a 3 : 1 ratio is more common in diabetic
ketoacidosis.
• Treatment emphasizes hydration with dextrosecontaining solutions and thiamine; resolution of the
acidosis usually occurs within 6 to 12 hours.
• Mortality from uncomplicated alcoholic ketoacidosis is
less than 1%.
DEFINITION AND EPIDEMIOLOGY
The diagnosis of alcoholic ketoacidosis (AKA) is established
when an alcoholic patient is found to have an anion gap metabolic acidosis without historical or laboratory evidence suggesting an alternative cause. AKA may develop after protracted
vomiting in malnourished, chronic alcoholics who consume a
daily average of 200 g of ethanol. AKA generally occurs with
equal frequency in adult men and women between 20 and 60
years of age. Its incidence and prevalence remain undefined.
Up to one half of patients are likely to suffer recurrence. It is
unclear whether these individuals have a genetic predisposition to AKA or whether they repeatedly reproduce the hormonal milieu that precipitates ketoacidosis. Almost one fifth
of cases of ketoacidosis are alcoholic ketoacidosis.1-3
PATHOPHYSIOLOGY
The term alcoholic acidosis describes a syndrome of four
types of metabolic acidosis that occur in alcoholics and vary
161 in severity: ketoacidosis, lactic acidosis, acetic acidosis, and
loss of bicarbonate in urine. AKA arises from a complicated
interplay of the metabolic effects of alcohol in fasted, dehydrated alcoholics who abruptly stop their intake of ethanol.4
β-Hydroxybutyrate is the predominant ketoacid.5 Metabolism of ethanol to acetaldehyde is catalyzed by alcohol dehydrogenase in the liver and results in accumulation of the
reduced form of nicotinamide adenine dinucleotide (NADH)
relative to the oxidized form of nicotinamide adenine dinucleotide (NAD+). The altered ratio of NADH/NAD+ is the
rate-limiting step in alcohol metabolism and favors the conversion of acetoacetate to β-hydroxybutyrate, as illustrated in
Figure 161.1.
Impaired insulin effects, dehydration, and hormonal
responses propagate the accumulation of ketoacid. Ethanol
consumption, acute starvation, and catecholamine release
cause a relative insulin insufficiency that acts to favor lipolysis
and limit glycogen storage. The formation of ketone bodies is
further promoted by a dehydration-induced stress response–
related release of cortisol, growth hormone, glucagons, and
catecholamines. It is unclear whether the elevated levels of
cortisol and growth hormone observed in patients with AKA
initiate or sustain this process. Ketone bodies in the form of
β-hydroxybutyrate are produced as a result of the NADH/
NAD+ ratio induced by ethanol metabolism, as well as the
lipolytic effect of counterregulatory hormones. Renal excretion of ketone bodies becomes impaired because of dehydration, volume contraction, and diminished renal clearance.
Accumulation of ketoacid ensues.
Lactic acidosis is a common, concurrent acid-base disorder,
in addition to ketoacidosis. Although lactic acidosis may
result from another cause such as sepsis or seizures, alcohol
consumption can cause mild accumulation of lactic acid by
two distinct mechanisms. First, the elevated NADH/NAD+
ratio can shift the pyruvate–lactic acid equilibrium in favor of
lactic acidosis. Second, the thiamine deficiency common in
chronic alcoholics prohibits the alternative oxidation of pyruvate to acetyl coenzyme A because thiamine is a coenzyme in
this reaction.6,7
PRESENTING SIGNS AND SYMPTOMS
AKA typically develops in severe alcoholics whose recent
binge drinking has abruptly and recently stopped. The sudden
alcohol cessation is often due to an alcohol-related disease
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METABOLIC AND ENDOCRINE DISORDERS
NAD+
NADH
Acetaldehyde
EtOH
Acetyl CoA
Acetate
↑NADH/NAD+
Concurrent illness
(gastritis, pancreatitis)
↓Insulin
Vomiting
Acute
starvation
↓Gluconeogenesis
↓Glycogen
Hypoglycemia
NAD+
NADH
Dehydration
†Fatty acid
release
Diminished
plasma volume
Shock
βOHB
Acetoacetate
Stress response
↑Catecholamine
↑Cortisol
↑Growth hormone
↑Glucagon
Pyruvate
Lactic acidosis
NAD+
NADH
Acetyl CoA
ATP + CO2
Thiamine deficiency
Fig. 161.1 Pathophysiology of alcoholic ketoacidosis. Alcohol dehydrogenase in hepatocyte cytosol metabolizes ethanol to
acetaldehyde, which is then transported into the mitochondria for metabolism to acetate. Acetate is activated by adenosine triphosphate
(ATP), coenzyme A (CoA), and acetate thiokinase to form acetyl CoA, which can (1) be oxidized to carbon dioxide (CO2) by the citric acid
cycle, (2) form ketone bodies, or (3) be converted to fat. Insulin depletion results from a number of influences, including endogenous
suppression from malnutrition, the direct suppressive effects of ethanol, and α-adrenergic suppression from catecholamines. Volume
depletion stimulates the counterregulatory release of catecholamines, cortisol, growth hormone, and glucagon. Glycogen depletion from
malnutrition and alcoholic liver disease stimulates enhanced fatty acid release, which is further promoted by catecholamines. The relative
increase in NADH over NAD+ resulting from the metabolism of ethanol drives several reactions to produce βOHB and lactate. Thiamine
deficiency favors the conversion of pyruvate to lactate rather than acetyl CoA. ATP, Adenosine triphosphate; EtOH, ethyl alcohol; NAD+,
oxidized form of nicotinamide adenine dinucleotide; NADH, reduced form of nicotinamide adenine dinucleotide; βOHB, β-hydroxybutyrate.
such as gastritis, pancreatitis, hepatitis, or pneumonia. Concurrent starvation, abdominal pain, and protracted vomiting
are common features.
Patients typically have a clear sensorium, are not confused,
and are able to provide a complete history, although there are
case reports of encephalopathic manifestations. Box 161.1
summarizes the sensitivity of signs and symptoms for AKA.
Tachycardia and tachypnea are typically the most remarkable findings on examination. Tachycardia results from volume
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depletion and early alcohol withdrawal, whereas tachypnea is
generally a physiologic response to the ongoing metabolic
acidosis. Hypotension and hypothermia are rare. Fever usually
indicates a separate, concurrent infectious process. Abdominal examination may reveal hepatomegaly, hepatic tenderness,
epigastric discomfort, or severe and diffuse tenderness. The
presence of hypotension, fever, peritoneal signs, bloody
stools, trauma, or altered mental status mandates a search for
alternative causes of these physical findings.
CHAPTER 161
BOX 161.1 Prevalence of Signs and Symptoms
of Alcoholic Ketoacidosis
Nausea (76%)
Vomiting (73%)
Abdominal pain (62%)
Dyspnea (20%)
Heart rate higher than 100 beats/min (58%)
Respiratory rate higher than 20 breaths/min (49%)
Abdominal tenderness (43%)
Altered mental status (18%)
Alcoholic Ketoacidosis
FACTS AND FORMULAS
Osmolar gap = [2 (Na) + (glucose/18) + (BUN/2.8) +
(EtOH/4.6)].
An osmolar gap greater than 25 mOsm/kg is specific for
methanol or ethylene glycol.
A β-hydroxybutyrate level greater than 386 µmol/L has been
proposed as a forensic pathology cutoff to identify “ketoalcoholic death.” Levels higher than 2500 µmol/L can be
fatal.
BUN, Blood urea nitrogen; EtOH, ethanol.
DIFFERENTIAL DIAGNOSIS
Alcoholic patients are predisposed to a variety of complications that may precipitate AKA, including gastritis, peptic
ulcer disease, Boerhaave syndrome, pancreatitis, and hepatitis. In addition, intoxicated patients are at increased risk for
infectious complications such as aspiration pneumonia. Evaluation for alcohol-related conditions should occur in parallel
with evaluation and management of presumed AKA.
DIAGNOSTIC TESTING
AKA is one of the many conditions that cause an anion gap
metabolic acidosis, which is partly summarized by the mnemonic CAT-MUDPILES, as shown in the Tips and Tricks box.
When an anion gap is present, an osmolar gap can help distinguish between these various entities. Additional rare causes
of an anion gap metabolic acidosis include sulfuric acidosis,
short bowel syndrome, formaldehyde, nalidixic acid, methenamine mandelate, rhubarb ingestion, and inborn errors of
metabolism such as the methylmalonic acidemias.
TIPS AND TRICKS
“CAT-MUDPILES” Mnemonic
C = Carbon monoxide, Cyanide
A = Alcoholic ketoacidosis
T = Toluene
M = Methanol*
U = Uremia
D = Diabetic ketoacidosis
P = Paraldehyde, Phenformin
I = Iron, Isoniazid
L = Lactic acidosis
E = Ethylene glycol*
S = Salicylates, Strychnine, Starvation
*Osmolar gap, greater than 25 mOsm/kg.
The acid-base disorder in AKA is usually a mixed anion
gap metabolic acidosis and respiratory alkalosis. pH ranges
from 6.7 to 7.6, and the anion gap ranges from 20 to 40.
Hypoalbuminemia is common in alcoholics and may lower
the observed anion gap.
Glucose levels may be low, normal, or elevated. Diabetic
alcoholics with modest elevations in glucose (>250 mg/dL)
pose a particular diagnostic challenge because they may have
diabetic ketoacidosis (DKA) or concurrent DKA and AKA.
A useful distinguishing feature in these cases is the
β-hydroxybutyrate–acetoacetate ratio, which is 1 : 1 normally,
3 : 1 with DKA, and 10 : 1 with AKA.
Because the nitroprusside reaction used in a urine dipstick
tests for DKA, a negative urine dipstick test for “ketones”
does not exclude AKA. In such instances, the dipstick may
show paradoxic worsening of urine ketones as AKA resolves
with treatment and β-hydroxybutyrate is converted to
acetoacetate.8,9
Hypokalemia and hypophosphatemia are common with
AKA, particularly as treatment progresses. Alcohol levels are
generally zero, although case reports have noted the presence
of AKA even when ethanol is detectable.10-12
TREATMENT
Treatment of AKA is directed at correcting three deficits:
volume depletion, glycogen depletion, and the elevated
NADH/NAD+ ratio. Intravenous fluid and glucose are highly
effective treatments. Administration of dextrose-containing
solutions to hypoglycemic or euglycemic patients stimulates
NADH oxidation and replaces glycogen stores, which results
in more rapid correction of acidosis than with saline alone.
Antiemetics should be provided.
Initially normal levels of magnesium, potassium, and phosphorus decrease during treatment and require repletion. Intravenous thiamine supplementation (100 mg) provides theoretic
prophylaxis against Wernicke encephalopathy and may help
reverse the lactic acidosis. Exogenous insulin and bicarbonate
therapy is rarely indicated.12-14
DISPOSITION
Mortality in patients with AKA is less than 1%. Adverse
outcomes are typically associated with concurrent alcoholrelated complications rather than with the ketoacidosis it­­
self. Admission for uncomplicated AKA is indicated for
patients with intractable vomiting or abdominal pain of un­­
clear cause.
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If a thorough evaluation fails to reveal additional acute
health issues, the acidosis can be treated and resolved within
6 to 12 hours. Discharged patients should have appropriate
follow-up to address issues of chronic alcohol abuse. Patients
may also benefit from an alcohol rehabilitation program (see
Chapter 199). Discharge instructions should advise patients
of their predisposition for recurrent episodes of AKA, as well
as the potentially detrimental effect of alcohol abuse on other
aspects of their health. Return precautions should include
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intractable vomiting, caloric starvation, and increasing
abdominal pain.
REFERENCES
References can be found
www.expertconsult.com.
on
Expert
Consult
@
CHAPTER 161
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Alcoholic Ketoacidosis
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