Alcoholic ketoacidosis—A review

The Journal of Emergency Medune. Vol 5, pp 399-406. 1987

ALCOHOLIC

Pmted in the USA

CopyrIght 8~:1987 PergamonJON&

??

KETOACIDOSIS-A

Ltd

REVIEW

Kurt Duffens, MD, and John A. Marx, MD Emergency

MedIcal Serwces. Denver General Hospital, 777 Bannock Street, Denver, CO 80204.4507 Repr~ntaddress: John A. Marx, MD, (same address as above).

0 Abstract -Alcoholic ketoacidosis is a frequently encountered metabolic disturbance that follows a prolonged intake of ethanol. Following a brief duration of abstinence, patients typically present with vomiting, abdominal pain, and shortness of breath. Examination reveals Kussmaul breathing, variable volume loss, and coincident manifestations of chronic alcohol usage. Characteristic laboratory findings include anion-gap metabolic ketoacidosis, normal serum glucose, and zero ethanol levels. Phosphate measurements may be depressed, particularly after institution of therapy. Intravascular volume restitution, delivery of dextrose, attention to electrolytes, and discovery of alcohol-related illnesses are the mainstays of therapy.

drome in nondiabetic patients in 1940. All patients were chronic alcoholics, most experiencing vomiting and decreased food intake prior to admission. On presentation, the patients were found to have moderate to severe ketoacidosis with normal or slightly elevated blood glucose levels. All responded to glucose-containing intravenous fluids without insulin. Thus, the first nondiabetic cause of severe ketoacidosis in adults was described. The clinical presentation and management described by Dillon et al remain accurate today. In the past 15 years, this syndrome has been recognized with increasing frequency, its pathophysiology further explored, and its treatment clarified.

0 Keywords-alcohol; ketoacidosis; alcohol withdrawal; hypophosphatemia; acetoacetate; /3-hydroxybutyrate, bicarbonate

Pathophysiology

Inflaming wine, pernicious to mankind, Unnerves the limbs, and dulls the noble mind. -Homer, 850 BC The (AKA) holics ments.

The mechanisms giving rise to AKA are numerous. The syndrome arises through the various metabolic effects of alcohol (Table 1) in the fasted, volume-depleted alcoholic who has abruptly stopped his alcohol intake.2J The ketoacids responsible for AKA, @hydroxybutyrate (BOHB) and acetoacetate (AcAc), are in part formed because of

syndrome of alcoholic ketoacidosis is an often seen disorder in alcoat metropolitan emergency departDillon et all first described the syn-

Medicine in Review presents comprehensive surveys plus evaluation and critical interpretation of significant management problems in emergency medicine. Ann Harwood-Nuss, MD, of University Hospital of Jacksonville, Florida, coordinates Emergency

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this section.

RECEIVED: 4 September

1986; ACCEPTED: 2 December 399

1986

0736-4679/87

$3.00 + .OO

Kurt Duffens

400

Table 1. Metabolic Effects Associated With Development of AKA

and John A. Marx

outlined. It also occurs in response to starvation and the extracellular fluid volume depletion arising from vomiting, deHormonal Effects t Cortisol creased fluid intake, and inhibition of ant Growth hormone tidiuretic hormone (ADH) secretion by alt Glucagon coho1.2m4,6-9Moreover, dehydration and t Catecholamine release 1 Insulin volume contraction impair the excretion Inhibition of ADH of ketones by the kidneys, leading to furt Free fatty acid release ther elevation in ketone levels. Numerous t NADHlNAD Ratio hormonal changes in AKA, including elet jShydroxybutyrate/Acetocetate ratio vations in cortisol, growth hormone, glu1 Gluconeogenesis cagon, and catecholamines, mediate free 1 Citric acid cycle activity t Lactate production fatty acid (FFA) release through lipolysis. FFA concentrations, when measured at time of presentation, are markedly elethe metabolism of ethanol in the liver.3m5 vated.8*‘0-12These provide substrate for Ethanol is oxidized to acetaldehyde in the subsequent ketone body formation, with liver cytoplasm by alcohol dehydrogenase. the predominant ketones formed being In the liver mitochondria, acetaldehyde is BOHB and AcAc. oxidized to acetic acid by aldehyde dehyAnother effect of increased catecholadrogenase. These oxidative processes lead mines is inhibition of insulin secretion to an accumulation of reduced form of through an enhanced effect on CXdinucleotide nicotinamide-adenine adrenergic receptors. Low insulin levels (NADH), and resultant increased NADH/ impair insulin-dependent ketone metabonicotinamide-adenine dinucleotide (NAD) lism by peripheral tissues as well as utilizaratio. tion by insulin-responsive tissues. Increased endogenous insulin secretion by Aldehyde Alcohol the competent pancreas in response to gluDehydrogenase Dehydrogenase cose-containing fluids likely contributes to reversal of AKA with treatment.8 ETHANOLACETALDEHYDE-w ACETATE The metabolic derangement in AKA differs from that of diabetic ketoacidosis (DKA), where a more pronounced insulin NAbH NAD+ NADH NAD+ deficiency state exists. In DKA the underAcetic acid (acetate) is converted to lying insulin deficiency, coupled with inacetyl coenzyme A (CoA) which can enter creased glucagon levels, produces maxithe citric acid cycle, form ketone bodies, mal gluconeogenesis and impairment of or be converted to fat.5 peripheral utilization of glucose, leading to severe hyperglycemia. This is in conAdenosine triphosphate (ATP) trast to the normal to mildly elevated sew ACETYL CoAACETATE rum glucose levels seen in AKA. Coenzyme A NADH accumulation caused by the oxidation of ethanol leads to an increased CITRIC ACID CYCLE CO,, ATP NADH/NAD ratio. This causes a shift in FREE FATTY ACID SYNTHESIS the equilibrium between BOHB and AcAc, favoring BOHB. f KETONE

BODY FORMATION

Ketone body formation in AKA has several causes. An increase in production follows from the oxidation of ethanol as

Alcoholic Ketoacidosis

401 -_._

This accounts for the higher BOHB levels compared with AcAc in the serum of patients with AKA. A functional block in NADH reoxidation appears to exist, possibly mediated through mitochondrial acetaldehyde accumulation. In addition, an essential cofactor for phosphorus, NADH oxidation, may be deficient in alcoholics, also contributing to NADH buildup.8 With glucose treatment, NADH reoxidizes and the BOHB/AcAc ratio decreases.8,13 This may result from glucoseinduced transport of phosphorus into the hepatic cytosol with subsequent mitochondrial phosphorus uptake.8 An additional result of the increased NADH/NAD ratio is direct inhibition of hepatic gluconeogenesis and the citric acid cycle.J,‘3 Moreover, the conversion of pyruvate to lactate is favored, which may produce a mild elevation in serum lactate levels. A decreased rate of hepatic uptake of lactate secondary to alcohol also contributes to a small increase in lactate levels in AKA.14 Hypoglycemia can occur in any alcoholic in response to a prolonged fast, often within 20 hours of ethanol consumption.‘“,‘5s’6 The key to development of hypoglycemia appears to be glycogen depletion combined with the inhibitory effect of alcohol on gluconeogenesis.iO It has been proposed that alcohol-induced hypoglycemia and AKA can occur coincidentally in a predisposed alcoholic.‘7 Indeed, a few patients have been described with both marked hypoglycemia and AKA.‘~“~‘8However, a susceptible individual with chronically depleted glycogen stores will more often present with hypoglycemia earlier in the course of fasting, before the effects of prolonged vomiting and continued starvation lead to ketone body formation.‘6 Clinical Presentation

AKA was thought to occur predominantly in women but this has not been shown in more recent studies.8J’~‘2J9J0 It has been

described in pregnancy.2’ AKA has been rarely described in diabetics, and there is no documented link between the two conditions.“J’J8 Although AKA may occur at any age, it typically occurs between ages 20 and 60 years. I6 Recurrences are seen in up to one half of patients.?O The frequency of the illness is likely directly proportional to the incidence and severity of alcoholism in a population. Investigators have estimated that AKA is the causative factor in 20% of patients presenting with ketoacidosis.12JZ The clinical picture of AKA has been well described.* Patients are severe alcoholics with a recent history of heavy alcohol intake several days to weeks prior to the episode. Usually the alcohol consumption is markedly decreased or completely stopped for 24 to 72 hours before presentation. Thus, these patients frequently have no measureable blood alcohol levels when seen in the emergency department. A period of starvation for one to three days following abstinence is also seen. Moderate to severe upper abdominal pain with nausea and protracted vomiting often accompany the cessation of drinking. These symptoms are likely related to one or more existing alcohol-induced diseases, namely alcoholic gastritis, pancreatitis, hepatitis, alcohol withdrawal, fatty liver infiltration, or aspiration pneumonia. Shortness of breath in the 24 hours preceding admission may reflect a Kussmaul breathing pattern compensatory for the ketoacidosis. Physical examination usually reveals signs of intravascular volume depletion secondary to prolonged vomiting, gastrointestinal blood loss, or another serious intercurrent condition. Normotension with moderate to severe orthostatic changes or frank hypertension is detected. Patients often exhibit tachycardia as a reflection of their volume status or alcohol withdrawal. Tachypnea, often in the form

*References

1, 8, 10, 12, 16, 18-21, 23-27.

402

of Kussmaul respiration, is commonly present. Fever is usually absent, but if present should signal a search for intercurrent infection or signs of alcohol withdrawal. Hypothermia has been reported.” Patients are normally conscious and are able to give an accurate history. If confused or comatose, causes of an altered sensorium should be considered. Tremulousness and diaphoresis may be due to alcohol withdrawal. Peripheral stigmata of chronic alcohol abuse may be present, including spider angiomata and signs of chronic malnutrition. The detection of acetone on the breath is variable. Pulmonary examination normally reveals tachypnea without localized findings. Tachycardia is the prominent cardiovascular finding. Patients with AKA often have abnormal abdominal examination findings. Hepatomegaly and hepatic tenderness may be present. Diffuse or localized abdominal tenderness is usually found. Examination mimicking an acute abdomen necessitating laparotomy has been described in a patient with AKA.27 Hemoccult positive stools are often evident. Neurological examination may reveal signs of alcohol withdrawal.

Laboratory Characteristics The complete blood count analysis is often abnormal. Patients usually have a mild nonspecific leukocytosis and may be anemic. Associated conditions such as gastrointestinal bleeding, alcohol-induced bone marrow depression, nutritional anemia, or hemolytic anemia may be responsible for a lowered hematocrit. The platelet count may also be lowered secondary to the toxic effects of chronic ethanol on platelet production. As the hallmark of AKA is ketoacidosis without marked hyperglycemia, electrolyte, glucose, and arterial blood gas measurements are essential in securing the diagnosis. The acid-base abnormality in

Kurt Duffens and John A. Marx

this disorder is an elevated anion gap metabolic acidosis. The anion gap is calculated from electrolyte analysis and derived as follows: Na+ - (HCO,- + Cl-). In AKA, the anion gap averages 29 (normal 12 f 2 mEq/L) (Table 2). Bicarbonate ion, used as a buffer for the increased unmeasured acids, is lowered, and ranges from 6 to 21 mEq/L in various studies (Table 2). Hypokalemia and hypochloremia may be found secondary to prolonged vomiting. A low initial serum potassium is uncommon, since there is a shift from the intracellular fluid to the extracellular fluid caused by metabolic acidosis, and insulin deficiencyS5However, potassium stores are often depressed owing to poor dietary intake and vomiting. With therapy for AKA, serum potassium levels often become low and must be monitored. In general, the serum glucose is normal to slightly elevated. Variations in the serum glucose levels ranging from marked hypoglycemia to mild hyperglycemia can be seen (Table 2). Blood urea nitrogen (BUN) levels are variable; depending on the degree of starvation, intravascular volume depletion, malnutrition, presence of blood in the gastrointestinal tract, and chronic liver disease, the BUN may be low, normal, or elevated. Arterial blood gas studies help to determine the severity of metabolic acidosis in AKA. The pH is variable, with reported values ranging from 6.96 to 7.61.1L,19More pronounced acidemia with pH below 6.70 is consistent with this disease.28 Patients may have a significant respiratory alkalosis as a compensatory response to their metabolic acidosis or through direct respiratory stimulation owing to alcohol withdrawal or other associated illnesses. In addition, protracted vomiting can give rise to a primary metabolic alkalosis. Hence, the pH in AKA may be acidemic, normal, or even alkalemic when several primary acidbase disturbances coexist. Initial arterial pH and bicarbonate levels have not shown a correlation with eventual outcome.ll

Alcoholic

Ketoacidosis

403

Table 2. Summary of Laboratory

No. of Episodes Arterial pH (mean) Bicarbonate mEqlL (mean) Anion gap mEq/L (mean) Glucose mg% (mean) fl-Hydroxybutyrate mEq/L’ Acetoacetate mEq/Lt Lactate mEq/L* Urinary ketones

Data in Alcoholic

Ketoacidosislo

Miller et al*

Platia Platia Hsuls

Soffer & Hambuergerno

Halperin et al5

Jenkins et allo

24

18

5

30

13

24

7.25

7.33

7.14

7.19

7.46

7.29

7.06-7.21

6

9

14

6

15

21

14

9-14

40

33

25

21

28

160

143

100

87

23

120

134

10.8

8.7

8

7.54

7.9

2.5 7.0 O-3+

2.1 1.1

6 o-4+

3.64

2.4 3/5d

Levy et alI1

Cooperman et alI2

6

7

7.16

Fulop & Hoberman

80-205

2

7 2115

‘Normal c 0.05 mEq/L tNormal
Serum phosphate levels are often decreased in alcoholics.29 Initial levels in AKA may be low, normal, or elevated.*J”J9 In one study, hyperphosphatemia on admission was followed by a rapid drop to low levels in 24 hours with administration of glucose and water.8 Although not routinely measured, absolute values of serum ketones are markedly elevated. AcAc levels greater than 2 mEq/L (nL: <0.05) and BOHB levels greater than 10 mEq/L (normal: ~0.05) have reported (Table 2). There is, moreover, an increase in the BOHB/AcAc (normal, 1 : 1) ratio. The average BOHB/ AcAc ratio in AKA (5-10 : 1) tends to be higher than that in diabetic ketoacidosis (3 : 1).3 Testing for urine or serum ketones must be interpreted with caution. The nitroprusside reaction, utilized in routine ketoacid determination, measures urine 01 serum acetoacetate and acetone but not

BOHB. Hence the test may be weakly positive or even negative at presentation when levels of BOHB are highest.3.“*12s’9With treatment of the disorder, BOHB is oxidized to AcAc and later to acetone, thus the nitroprusside test may paradoxically worsen as the patient improves. Urinalysis is helpful in the initial assessment of these patients. The finding of ketonuria without glycosuria suggests AKA. As noted above, the urine dipstick may be negative for ketones, reflecting the predominance of BOHB as the primary ketoacid in the urine. Hence, AKA cannot be ruled out by a negative urinalysis. Serum lactate levels, if measured, may be slightly to moderately elevated. The mean value reported from several series was 4.3 mEq/L (normal, 0.5-1.5 mEq/L). Lactate contributes minimally to the metabolic acidosis in AKA and to a much lesser degree than the ketoacids. Severe lactic

404

Kurt Duffens and John A. Marx

acidosis should suggest another serious underlying disorder such as hypoxemia or hypoperfusion. Serum amylase and liver enzyme values may be abnormal depending on the severity of concomitant alcohol-associated diseases.

Differential

Diagnosis

All causes of an increased anion gap metabolic acidosis deserve consideration. Included in this differential diagnosis are conditions causing ketoacidosis, those causing lactic acidosis, toxic exposures, and uremia30 (Table 3). In general, severe elevations of the anion gap (>30 mEq/L) are found in ketoacidosis, hyperosmolar coma, lactic acidosis, and ingestion of ethylene glycol or methanol.3’ The causes of ketoacidosis are AKA, DKA, and starvation. Patients with DKA often report polyuria, polydipsia, and usually are already diagnosed as suffering from diabetes mellitus. However, subjective symptoms of nausea, vomiting, and abdominal pain may be confused with presenting symptoms of AKA. DKA can usually be excluded by urine dipstick testing for glucose and ketones, dextrostick testing, and ultimately serum glucose determinations. Diabetic alcoholics may present with AKA, or coincident AKA and DKA. The distinction is difficult to make if the blood sugar is only mildly to moderately elevated, since 159’0 of patients with DKA have very modest elevations of serum glucose.23 Starvation ketosis, alone, usually causes a mild ketoacidosis and will normally not lower the bicarbonate level below 18 mEq/L. The clinical presentation of AKA should distinguish it from simple starvation ketosis. Lactic acidosis may be caused by shock states, seizures, and toxic poisonings. Careful history taking and physical examination, along with an elevation in serum

Table 3. Differential Diagnosis of Increased Anion Gap Metabolic Acidosis Ketoacidosis Alcoholic ketoacidosis Diabetic ketoacidosis Starvation Lactic acidosis Hypoperfusion Hypoxemia Other Toxicologic Salicylate Ethylene glycol Methanol Iron Phenformin Paraldehyde Agents that cause seizures Agents that interfere with intermediary metabolism Uremia

help to distinguish these causes from AKA. Seizures cause a moderate metabolic acidosis that normally resolves within 15 minutes if there is no further seizure activity.32 A classic postictal state, known history of seizure disorder, and spontaneous improvement in the patient’s acidosis help to define this as the cause of metabolic acidosis. Imbibed toxins, particularly in alcoholics, that cause metabolic acidosis include ethylene glycol and methanol.33*34In addition, salicylates,35 iron,36 and substances that cause seizures (eg, isoniazid) may also cause an anion gap metabolic acidosis. Less commonly, toxins that interfere with intermediary metabolism (carbon monoxide, cyanide, hydrogen sulfide) may produce a metabolic acidosis. lactate,

Management

Successful treatment of AKA is accomplished through complete correction of the volume depletion and by administration of glucose. To correct the moderate-

Alcoholic Ketoacidosis

to-severe volume depletion in these patients, a solution of normal saline with dextrose appears to provide optimal rehydration. The rate of administration depends upon the degree of depletion present. When the volume deficit is corrected, as evidenced by resolution of orthostatic blood pressure and pulse measurements, one-half normal saline with dextrose may be continued. Intravenous fluid therapy should be continued until the serum bicarbonate reaches 18 to 20 mEq/L, signs of orthostasis have resolved, and oral fluids are well tolerated. Patients usually respond to therapy within 12 hours. To date, only one study has evaluated intravenous fluid treatment regimens in AKA.* The clinical effect of saline alone compared with intravenous glucose with water was measured in 18 patients with AKA. Intravenous glucose was administered, at a rate of 7.0 to 7.5 g/h (D,W at 150 mL/H), to 13 patients while normal saline was given to five patients at a rate of 100 to 125 mL/h. A significantly more rapid improvement in acidosis was seen in the dextrose-treated group. This correlated with a significant drop in the BOHB/ AcAc ratio. All patients in the dextrosetreated group normalized their acid-base status within 8 to 16 hours compared with a somewhat slower response in the salinetreated group. Serum phosphate levels dropped markedly with treatment in both groups, being more pronounced in the glucose-treated group. The authors concluded that glucose-containing solutions provide the fastest and most effective means of treating AKA. One study suggests that empiric phosphate repletion is indicated in AKA.8 Close monitoring of serum potassium and phosphorus levels (every four to six hours) is important as hypokalemia and hypophosphatemia may develop during treatment. Potassium supplementation should be given if serum potassium levels are less than 4.0 mEq/L, as a further de-

405

cline is expected with correction of the acidosis. If serum phosphorus levels are low, intravenous supplementation should be given since levels less than 1 mEq/L have adverse effects on oxygen delivery to tissues, cardiac output, muscle strength, neutrophil function, and respiratory function.29 As in DKA, sodium bicarbonate administration is usually not necessary except in severe cases of acidosis (pH < 7. l).” Although serum insulin levels are low to low-normal, insulin therapy is not recommended in treatment of AKA unless DKA is thought to coexist. In AKA, an increase in endogenous insulin concentration occurs as a direct response to intravenous glucose infusion.* In light of the chronic nutritional deficiencies present in alcoholics, thiamine (So-100 mg) should routinely be given to prevent development of the Wernicke-Korsakoff syndrome. Magnesium and multivitamins should also be considered in the treatment of these patients. Morbidity and mortality in patients with AKA are not related to the ketoacidosis, but rather to intercurrent processes such as a severely reduced extracellular fluid volume, alcohol withdrawal, hypokalemia-induced dysrythmias, or other underlying conditions prompting the patient to seek medical care, such as acute pancreatitis, gastritis, gastrointestinal hemorrhage, and aspiration pneumonia. Along with the primary treatment of AKA, early treatment of these associated conditions is important. The decision to admit patients with AKA to the hospital depends on the severity of these associated illnesses. Treatment of AKA can be successfully achieved within 8 to 16 hours and can be accomplished in an emergency department observation unit if available. Efforts to treat the patient’s chronic alcoholism should be attempted in light of the recurrence rate of this syndrome and of the long-term devastating effects of alcohol abuse.

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Kurt Duffens and John A. Marx

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1775-1782. 8. Miller PD, Henig RE, Waterhous C: Treatment of alcoholic ketoacidosis. Arch Intern Med 1978; 138~67-72. 9. Schade DS, Eaton

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Med 1979; 131:270-276. 19. Fulop M, Hoberman HD: Alcoholic ketoacidosis. Diabetes 1975; 24:785-790. 20. Soffer A, Hambuerger S: Alcoholic ketoacidosis: A review of 30 cases. J Am Med Worn Assoc

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RP: Differential diagnosis and therapy of hyperketonemic state. JAMA

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10. Jenkins DW, Eckel RE, Craig JW: Alcoholic ketoacidosis. JAMA 1971; 217:177-183. 11. Levy LJ, Duga J, Dirgis M, et al: Ketoacidosis associated with alcoholism in nondiabetic subjects. Ann Intern Med 1973; 78:213-219. 12. Cooperman MT, Davidoff F, Spark R, et al: Clinical studies of alcoholic ketoacidosis. Diubetes 1974; 23:433-439.

13. Kreisberg RA, Siegal AM, Owen WC: Glucoselactate inter-relationships: effect of alcohol. J Clin Invest 1971; 50:175anl85. 14. Ibid: JClin Invest 1971; 50:166-174. 15. Pierce JR: Stuporous alcoholics: metabolic considerations. South Med J 1982; 75~463-469. 16. Larremore T: Alcohol-induced ketoacidosis and hypoglycemia in alcohol-related emergencies. Top Emerg Med 1984; 6~48-57. 17. Deveny P: Alcoholic hypoglycemia and alcoholic

ketoacidosis: sequential events of the same process? Can MedAssoc 1982; 15:513. 18. Platia EV, Hsu TH: Hypoglycemic coma with

297~796-799. 33. Parry MF, Wallach R: Ethylene glycol poisoning. Am JMed 1974; 143-150. 34. Becker C: Acute methanol poisoning: “the blind drunk.” West JMed 1981; 135:122-128.

35. Done AK: Aspirin overdosage: incidence, diagnosis and management. Pediuks 1978; 62(Supp1):890-897. 36. Stein M, Blayney D, Feit T, et al: Acute iron poisoning in children. West JMed 1976; 76:289297.