Alcoholic Ketoacidosis Associated with Multiple Complications: Report of 3 Cases

□ CASE REPORT □

Masami TANAKA,Yasushi MIYAZAKI, Shinsuke ISHIKAWA and Kimihiko MATSUYAMA

Abstract abroad (2, 7–9), there is little Japanese literature on AKA (10–12). Considering that AKA is the causative factor in We report 3 patients with alcoholic ketoacidosis 20% of patients presenting with ketoacidosis (4, 13), AKA (AKA). All had a history of excessive intake and abrupt might be overlooked or confused with DKA and not uncom- termination of alcohol. They showed tachypnea, mon in Japan. Here, we report these three cases of AKA with tachycardia, abdominal tenderness, and epigastralgia. a review of the literature. Metabolic acidosis with an increased anion gap, decreased PaCO2 and ketonemia were present. One patient Case Report whose ratio of 3-hydroxybutyric acid to acetoacetic acid was 4.0 was associated with diabetic ketoacidosis. All pa- Case 1 tients were successfully hydrated with electrolyte, glucose The patient was a 50-year old woman. She had been a se- and thiamine. Complications such as liver dysfunction, vere alcoholic for the previous 10 years. She had been diag- lactic acidosis, acute pancreatitis, Wernicke’s encephalo- nosed with chronic alcoholic hepatitis. Nausea and vomiting pathy, rhabdomyolysis and heart failure were present. occurred on July 3, 2002. She kept vomiting overnight. The Attention should be paid to multiple complications in the following morning, she was admitted to Misato Kenwa treatment of AKA. Hospital. She was 151 cm tall and weighed 41 kg. Vital signs (Internal Medicine 43: 955–959, 2004) were body temperature of 37.3°C, blood pressure of 104/70 mmHg, respiratory rate of 24/min, and regular pulse of Key words: metabolic acidosis, anion gap, 3-hydroxybutyric 130/min with clear consciousness. Her palms were erythe- acid matous, and she had vascular spider. She complained of epigastralgia. Laboratory data on admission are summarized in Table 1. Urinalysis showed proteinuria (+), hematuria (+) and ketonuria (3+) without glycosuria. The white blood cell Introduction count (WBC) was 11,000/l, hemoglobin; 9.74 g/dl. Total bilirubin was 1.41 mg/dl, aspartate aminotransferase (AST); The entity of alcoholic ketoacidosis (AKA) was first de- 319 IU/l, alanine aminotransferase (ALT); 109 IU/l, - scribed by Dillon et al in 1940 (1). AKA affects only chronic glutamyltransferase (-GTP); 911 IU/l, and plasma glucose; alcoholics. It is characterized by a metabolic acidosis with an 73 mg/dl. The serum concentration of acetoacetic acid increased anion gap. The typical patient with AKA has a his- (AcAc) and 3-hydroxybutyric acid (3-OHB) were 1,400 tory of chronic alcohol abuse, and recent binge drinking fol- mol/l (normal range [NR]: <70) and 10,900 mol/l (NR: lowed by the abrupt cessation of alcohol consumption. The <70), respectively. The serum concentration of lactic acid clinical findings of AKA are very similar to those of diabetic and pyruvic acid were 98.6 mg/dl (NR: 3.3–15.6) and 1.5 ketoacidosis (DKA), but hyperglycemia and glycosuria are mg/dl (NR: 0.4–1.2), respectively. Arterial blood gas analy- usually absent. AKA has been rarely described in patients sis in room air showed pH 7.140, PaCO2 25.6 mmHg, PaO2 – with diabetes mellitus (DM), and there is no documented 117.7 mmHg, HCO3 8.5 mmol/l. She was diagnosed with connection between AKA and DKA (2–6). AKA and lactic acidosis. Endoscopic examination of the Recently we encountered 3 cases of AKA, 2 of which pre- upper digestive tract revealed esophagitis, erosive gastritis sented with DM. While there are several reviews of AKA and duodenitis. After hydration with 5% glucose solution

From the Department of Internal Medicine, Misato Kenwa Hospital, Misato Received for publication July 25, 2003; Accepted for publication May 14, 2004 Reprint requests should be addressed to Dr. Masami Tanaka, the Department of Internal Medicine, Misato Kenwa Hospital, 4-494-1 Takano, Misato, Saitama 341-8555

Internal Medicine Vol. 43, No. 10 (October 2004) 955 TANAKA et al

Table 1. Laboratory Data (Case 1, July 2002)

Urinalysis Blood chemistry Arterial blood gas analysis (room air/rest) Glucose (–) Total bilirubin 1.41 mg/dl pH 7.140

Protein (+) AST 319 IU/l PaCO2 25.6 mmol/l

Occult blood (+) ALT 109 IU/l PaO2 117.7 mmol/l – Ketone (3+) LDH 427 IU/l HCO3 8.5 mmol/l -GTP 911 IU/l Anion gap 33.5 mEq/l Hematology CPK 215 IU/l Ketone body WBC 11,000/l Amylase 168 IU/l AcAc 1,400 mol/l Hb 9.74 g/dl BUN/Cr 18/0.8 mg/dl 3-OHB 10,900 mol/l Plt 27.7×104/l Na/K/Cl 131/4.4/89 mEq/l Lactic acid 98.6 mg/dl Plasma glucose 73 mg/dl Pyruvic acid 1.5 mg/dl CRP 0.6 mg/dl

Table 2. Treatment within 24 Hours after Arrival at Our Hospital for Our 3 Cases

Case 1 Case 2 Case 3

Volume of intravenous drip (ml) 2,500 3,500 3,500 Sodium (mEq) 135.5 314.5 166 Potassium (mEq) 42 38 24 Glucose (g) 86 64.5 43 Thiamine (mg) 100 50 100 Insulin (units) – 24 –

containing electrolyte and thiamine (Table 2), her metabolic blood gas analysis in room air showed pH 7.179, PaCO2 12.2 – acidosis was improved quickly. Subsequently, she had 2 re- mmHg, PaO2 119.4 mmHg, HCO3 5.8 mmol/l. The anion – current episodes of AKA. gap (Na-[Cl+HCO3 ]) was 35.2 mEq/l. Abdominal CT revealed swelling of the pancreas. He was diagnosed with Case 2 DKA because of hyperglycemia, acidemia, decreased bicar- The patient was a 62-year-old man. He had been diag- bonate, positive urinary ketones, increased serum ketones nosed with type 2 DM when he was 48 years old. Insulin and increased anion gap. In addition, acute pancreatitis was therapy had been introduced using biphasic isophane insulin present. Initial treatment consisted of intravenous infusion of (10 units in the morning and 6 units in the evening). Diabetic regular insulin (8 units injection followed by 8 units/hour) retinopathy was absent, but intermittent proteinuria and dia- and a large volume of saline (mainly 0.9% NaCl 1 l/first 2 betic neuropathic pain in his legs were present. He had been hours) containing thiamine (Table 2). Two hours later, his consuming excessive alcohol for years. Gastric pain occurred plasma glucose became as low as 91 mg/dl. Therefore, insu- and worsened after binge drinking. He could not drink alco- lin infusion was reduced and 0.9% NaCl was replaced by 5% hol because of severe epigastralgia for 3 days and was admit- glucose solution. At that time, we diagnosed him as having ted to our hospital on July 3, 2002. He was 165 cm tall and AKA concomitantly. Acute pancreatitis was treated simulta- weighed 40 kg. Vital signs were body temperature of 35.3 neously with gabexate mesilate and antibiotics (cefmetazole °C, blood pressure of 166/90 mmHg, respiratory rate of sodium). His metabolic acidosis and pancreatitis were cured. 28/min, and regular pulse of 105/min. His consciousness was However, his drowsiness persisted. Brain computed tomo- drowsy and palms were erythematous. Abdominal examina- graphy revealed slight brain atrophy. Although vitamin B1 tions revealed tenderness in the epigastrium. Laboratory data was not measured, the cause of his consciousness distur- on admission are summarized in Table 3. Urinalysis showed bance might be Wernicke’s encephalopathy considering the glycosuria (4+), proteinuria (2+), hematuria (2+) and clinical course. ketonuria (2+). The platelet count was 3.9×104 /l. Total bilirubin was 2.09 mg/dl, AST; 244 IU/l, ALT; 134 IU/l, lac- Case 3 tate dehydrogenase (LDH); 497 IU/l, -GTP; 3,246 IU/l, The patient was a 53-year-old man. He was admitted to a amylase; 1,308 IU/l and plasma glucose; 428 mg/dl. His he- hospital due to alcoholic hepatitis and had never been diag- moglobin A1c was 7.3 %. The serum concentration of AcAc nosed with DM. He had been consuming excessive alcohol. and 3-OHB were 3,100 mol/l and 10,900 mol/l, respec- Vomiting because of gastric irritation occurred and worsened tively. The serum concentration of lactic acid and pyruvic on November 18, 2001. He kept vomiting frequently for 2 acid were 29.1 mg/dl and 1.6 mg/dl, respectively. Arterial days, and then, was transferred to our hospital on November

956 Internal Medicine Vol. 43, No. 10 (October 2004) 3 Cases of Alcoholic Ketoacidosis

Table 3. Laboratory Data (Case 2, July 2002)

Urinalysis Blood chemistry Arterial blood gas analysis (room air/rest) Glucose (4+) Total bilirubin 2.09 mg/dl pH 7.179

Protein (2+) AST 244 IU/l PaCO2 12.2 mmol/l

Occult blood (2+) ALT 134 IU/l PaO2 119.4 mmol/l – Ketone (2+) LDH 497 IU/l HCO3 5.8 mmol/l -GTP 3,246 IU/l Anion gap 35.2 mEq/l Hematology CPK 43 IU/l Ketone body WBC 8,600/l Amylase 1,308 IU/l AcAc 3,100 mol/l Hb 11.6 g/dl BUN/Cr 15.1/1.1 mg/dl 3-OHB 12,400 mol/l Plt 3.9×104/l Na/K/Cl 131/4.7/90 mEq/l Lactic acid 29.1 mg/dl Plasma glucose 428 mg/dl Pyruvic acid 1.6 mg/dl CRP 0.3 mg/dl Hemoglobin A1c 7.3%

Table 4. Laboratory Data (Case 3, November 2001)

Urinalysis Blood chemistry Arterial blood gas analysis (room air/rest) Glucose (3+) Total bilirubin 2.74 mg/dl pH 6.934

Protein (2+) AST 98 IU/l PaCO2 12.6 mmol/l

Occult blood (3+) ALT 29 IU/l PaO2 157.6 mmol/l – Ketone (3+) LDH 785 IU/l HCO3 2.6 mmol/l -GTP 506 IU/l Anion gap 48.4 mEq/l Hematology CPK 1,046 IU/l Ketone body WBC 20,400/l Amylase 93 IU/l AcAc 360 mol/l Hb 12.8 g/dl BUN/Cr 12.1/2.4 mg/dl 3-OHB 4,400 mol/l Plt 9.8×104/l Na/K/Cl 129/4.8/78 mEq/l Lipase 92 U/l Plasma glucose 286 mg/dl Elastase-1 545 ng/dl CRP 0.3 mg/dl Hemoglobin A1c 7.0%

20. He was 163 cm tall and weighed 49 kg. Vital signs were the color of urine changed into dark brown, oliguria devel- body temperature of 33.8°C, blood pressure of 110/72 oped and his potassium rose to 5.8 mEq/l. Acute renal failure mmHg, respiratory rate of 36/min, and regular pulse of due to rhabdomyolysis was strongly suspected, because CPK 108/min. His consciousness was drowsy and palms were on admission was very high. Subsequently, hypoxia and erythematous. The bulbar conjunctiva showed icterus. acute heart failure developed, then mechanical ventilation Abdominal examinations revealed tenderness and slight de- and hemodialysis were introduced. Subsequently, his general fense in the right hypochondriac region. Laboratory data on condition was improved, but his drowsiness, probably due to admission are summarized in Table 4. Urinalysis showed Wernicke’s encephalopathy, persisted. glycosuria (3+), proteinuria (2+), hematuria (3+) and ketonuria (3+). The WBC and platelet count were 20,400/l Discussion and 9.8×104/l, respectively. Total bilirubin was 2.74 mg/dl, AST; 98 IU/l,ALT;29IU/l, LDH; 785 IU/l, -GTP; 506 IU/ All 3 patients presented in this paper shared a common l,creatine phosphokinase (CPK); 1,046 IU/l,amylase; 93 IU/ clinical picture of massive alcoholic intake, which had been l, blood urea nitrogen; 12.1 mg/dl, creatinine; 2.4 mg/dl, po- terminated a few days before admission by repeated vomit- tassium; 4.8 mEq/l and plasma glucose; 286 mg/dl. His he- ing or abdominal pain, resulting in acute starvation and se- moglobin A1c was 7.0%. The levels of lipase and elastase-I vere dehydration. For these patients, alcohol is almost the were 92 IU/l (NR: <45) and 545 IU/l (NR: 100–400), respec- only source of calorie intake, so the cessation of alcohol tively. The serum concentration of AcAc and 3-OHB were caused starvation. Pathophysiologically, acute starvation, 360 mol/l and 4,400 mol/l, respectively. Arterial blood ethanol abuse and dehydration were direct causes of AKA, gas analysis in room air showed pH 6.934, PaCO2 12.6 leading to the accumulation of ketone bodies (8, 14, 15). – mmHg, PaO2 157.6 mmHg, HCO3 2.6 mmol/l. Abdominal Taking the history of not only excessive intake but also CT revealed swelling of the pancreas. The patient was diag- abrupt cessation of alcohol is very important for the correct nosed with AKA, acute pancreatitis and DM. He was treated diagnosis of AKA. Recurrence of AKA as in Case 1 is re- with a large volume of saline containing thiamine (Table 2), ported to be common (8, 16). gabexate mesilate and antibiotics (cefmetazole sodium). His The precise pathogenesis of AKA is not clear. In Cases 2 metabolic ketoacidosis was improved quickly. Nevertheless, and 3, DM was diagnosed. In Case 1, her casual blood

Internal Medicine Vol. 43, No. 10 (October 2004) 957 TANAKA et al glucose became 163 mg/dl when AKA was cured, indicating tions could happen. Therefore, it is prudent to treat hyper- that she had glucose intolerance. Considering that all of the glycemic AKA patients with insulin under careful monitor- present 3 cases possessed glucose intolerance, it might be an ing of plasma glucose, because DKA could be fatal. important factor for the onset of AKA. It was reported that During the treatment of Case 2, 24 units of insulin low- insulin secretion is delayed and decreased in untreated AKA ered his plasma glucose from 428 mg/dl to 91 mg/dl in only and that insulin secretion is normalized when AKA was 2 hours. The reason for this phenomenon is not clear. treated (11). This suggests the possibility that hormonal im- Malnutrition, glycogen depletion in the liver and decrease in balance (relative deficiency in insulin, relative surplus in glyconeogenesis might be involved. Ohshiro et al reported an counter-regulatory stress hormones including glucagon) AKA case whose plasma glucose was very changeable (11). might be an important mechanism underlying this disorder. In their report, only 6.7 grams of glucose raised the patient’s Plasma insulin concentration should have been measured in plasma glucose from 30 mg/dl to 280 mg/dl in 40 minutes. these 3 cases to better understand the pathophysiology of Considering the above, blood glucose might be changeable AKA. and should be monitored carefully during the treatment of Physical examinations revealed that all 3 patients showed AKA. tachypnea, tachycardia and erythematous palm. Tachypnea In uncomplicated AKA, the prognosis is reported to be often in the form of Kussmaul respiration, is commonly pre- very good (2, 7–9). But multiple complications as in our sent in AKA (8, 9), compensating for metabolic acidosis. cases could be present. All 3 cases in this paper showed liver Tachycardia reflects intravenous dehydration. Erythematous dysfunction. Lactic acidosis was found in Case 1. Acute palm is a typical characteristic of an alcohol abuser. In Cases pancreatitis and suspected Wernike’s encephalopathy were 2 and 3, tense, tender abdomen and epigastralgia were pre- present in Cases 2 and 3. Rhabdomyolysis and heart failure sent. Diffuse or localized abdominal tenderness and probably due to beriberi heart were present in Case 3. AKA epigastralgia, caused by acute pancreatitis as in Cases 2 and is far from a simple disease. We should pay attention to pos- 3, or acute gastritis as in Case 1, are usually found (2, 7, 8, sible multiple organ failure in the treatment of AKA. 14). Hypothermia as in Cases 2 and 3 could occur (2, 17). In conclusion, awareness of this syndrome and taking a Metabolic acidosis with an increased anion gap (Case 1; typical history of drinking are essential for the correct diag- 33.5, Case 2; 35.2, Case 3; 48.4, respectively), decreased nosis of AKA. AKA is an important differential diagnosis

PCO2 and increased level of serum ketone bodies were pre- among heavy drinkers with metabolic acidosis. Attention sent in these 3 cases. The ratio of 3-OHB to AcAc of Case should be paid to complications involving multiple organs. 2 was lower than that of Cases 1 and 3 (Case 1; 7.8, Case 2; DKA is not only an important differential diagnosis but also 4.0, Case 3; 12, respectively). Considering that Case 2 was a possible complication of AKA. associated with DKA, this has clinically important signifi- cance. References It has been reported that the ratio of 3-OHB to AcAc is higher in patients with AKA than in those with DKA. In 1) Dillon ES, Dyer WW, Smelo LS. Ketone acidosis in nondiabetic adults. AKA patients, this ratio averages 7.2 (3) or 5.2 (4), com- Med Clin North Am 24: 1813–1822, 1940. pared with an average of 3 (16) or 2.85 (18) among the DKA 2) Duffens K, Marx JA. Alcoholic ketoacidosis—a review. J Emerg Med 5:399–406, 1987. patients. If a patient with AKA is presenting with hypergly- 3) Levy LJ, Duga J, Dirgis M, Gordon EE. Ketoacidosis associated with cemia and whose 3-OHB/AcAc ratio is less than 5, the co- alcoholism in nondiabetic subjects. Ann Intern Med 78: 213–219, 1973. existence of DKA must be considered. 4) Cooperman MT, Davidoff F, Spark R, Pallotta J. Clinical studies of al- Treatment within 24 hours after arrival at our hospital for coholic ketoacidosis. Diabetes 23: 433–439, 1974. these 3 cases is shown in Table 2. As mentioned above, alco- 5) Platia EV, Hsu TH. Hypoglycemic coma with ketoacidosis in nondiabetic alcoholics. West J Med 131: 270–276, 1979. hol abuse, starvation and dehydration play a crucial role in 6) Halperin ML, Hammeke M, Josse RG, Jungas RL. Metabolic acidosis the pathogenesis of AKA. Consequently, hydration with in the alcoholic: A pathophysiologic approach. Metabolism 32: 308– electrolytes and administration of glucose and thiamine are 315, 1983. the fundamental treatments of AKA. Glucose is essential to 7) Fulop M. Alcoholism, ketoacidosis, and lactic acidosis. Diabetes Metab stop ketogeneis and to replete glycogen stores in the liver (2, Rev 5: 365–378, 1989. 8) Fulop M. Alcoholic ketoacidosis. Endocrinol Metab Clin North Am 7). Thiamine is necessary because some patients have 22:209–219, 1993. thiamine deficiency, which could be the cause of lactic aci- 9) Adams SL. Alcoholic ketoacidosis. Emerg Med Clin North Am 8: 749– dosis and Wernicke’s encephalopathy (4, 7–9). 760, 1990. Theoretically, AKA patients without DM do not require 10) Yokoyama M, Hori S, Aoki K, et al. Alcoholic ketoacidosis in the insulin. Furthermore, there are opinions that insulin should emergency room. JJNE 13: 59–62, 2000. 11) Ohshiro Y, Komiya I, Takasu N, Taira N, Kawajiri A. Changes in insu- be contraindicated because of the risk of hypoglycemia (8, lin secretion during the treatment of severe alcoholic ketoacidosis. J 14, 19, 20). It has been reported that most patients with AKA Japan Diab Soc 41: 711–716, 1998. do not have concomitant DM (6, 9) and it has been consid- 12) Yano T, Yano M. Report of 4 cases of alcoholic ketoacidosis. ICU & ered that the co-existence of AKA and DKA is exceptional CCU 18: 493–500, 1994. (14). As in Case 2, however, the co-existence of both condi- 13) Kreisberg RA. Diabetic ketoacidosis: New concepts and trends in

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pathogenesis and treatment. Ann Intern Med 88: 681–695, 1978. JAmMed Womens Assoc 37: 106–110, 1982. 14) Hojer J. Severe metabolic acidosis in the alcoholic: differential diagno- 18) McGarry JD, Foster DW. Diabetic ketoacidosis. in: Diabetes Mellitus. sis and management. Hum Exp Toxicol 15: 482–488, 1996. Rifkin H, Raskin P, Eds. American Diabetes Association, Alexandria, 15) Jenkins DW, Eckle RE, Craig JW. Alcoholic ketoacidosis. JAMA 1981: 185–193. 217: 177–183, 1971. 19) Wrenn KD, Slovis CM, Minion GE, Rutkowski R. The syndrome of al- 16) Palmer JP. Alcoholic ketoacidosis: Clinical and laboratory presenta- coholic ketoacidosis. Am J Med 91: 119–128, 1991. tion, pathophysiology and treatment. Clin Endocrinol Metab 12: 381– 20) Miller PD, Heinig RE, Waterhouse C. Treatment of alcoholic 389, 1983. ketoacidosis. The role of dextrose and phosphorus. Arch Intern Med 17) Soffer A, Hambuerger S. Alcoholic ketoacidosis: A review of 30 cases. 138: 67–72, 1978.

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