Ketoacidosis with Unexpected Serum Isopropyl Alcohol

Transcription

1 Clinical Chemistry 57: (2011) Clinical Case Study Ketoacidosis with Unexpected Serum Isopropyl Alcohol Peter L. Platteborze, 1 Petrie M. Rainey, 1 and Geoffrey S. Baird 1* CASE 1 Department of Laboratory Medicine, University of Washington Medical Center, Seattle, WA. * Address correspondence to this author at: Department of Laboratory Medicine, NW120, 1959 NE Pacific, Seattle, WA Fax ; [email protected]. Received October 22, 2010; accepted January 17, DOI: /clinchem A 34-year-old woman presented to the emergency department with a chief complaint of acutely worsening abdominal pain. The patient reported the abdominal pain to be in the left lower quadrant and of several months duration but noted that it had worsened substantially over the previous 10 days. She also reported diffuse muscle pain and nausea without emesis, no food intake over the previous 72 h, and only limited recent fluid intake consisting of ginger ale, water, Gatorade, and homemade liquor. Her last menstrual period was 2 weeks before admission. Her medical history was remarkable for posttraumatic stress disorder, bipolar disorder, gestational diabetes, a previous gastric bypass surgery, and an ambiguous history of injury to the liver and pancreas. She denied taking any medications or other illicit drugs, specifically denied binge drinking, and had recently received a tattoo from an unlicensed tattoo artist. She was homeless and resided in a tent city with her husband. The only remarkable findings of the physical examination were tachycardia and a mildly enlarged, nontender liver. She appeared ill and smelled of a campfire but was otherwise awake, alert, and cooperative. Selected laboratory results are shown in Table 1. Low urea nitrogen and albumin concentrations suggested probable malnutrition. The observed hypocalcemia of 7.4 mg/dl could be attributed only partly to the low albumin concentration, because the albumincorrected total Ca concentration which is equal to the measured total [Ca] 0.8 mg/dl (4.0 [Albumin]), where [Ca] is the calcium concentration in milligrams per deciliter and [Albumin] is the albumin concentration in grams per deciliter (1) was 8.8 mg/ dl, less than the institutional lower reference limit. Opiates and tricyclic antidepressants were identified in the patient s urine. The presence of opiates was not commented on in the medical record, so whether the clinical team was aware of this finding was unknown. The records of the hospital system did not have any prescriptions for tricyclic antidepressants for the patient, so the positive result for this analyte could be due to the use of a tricyclic antidepressant obtained illicitly or with an outside prescription; alternatively, it could be due to a cross-reacting substance. The attending physician in the emergency department requested assistance in interpreting the highly increased concentration of -hydroxybutyrate. Furthermore, the clinical team wanted to know if detecting isopropyl alcohol in the alcohol screen implied that the homemade liquor ingested by the patient contained isopropyl alcohol. DISCUSSION QUESTIONS TO CONSIDER 1. What are common causes of a combined high anion gap and increased osmolality? 2. What can cause ketoacidosis? 3. What is the appropriate approach to this patient with an increased serum isopropyl alcohol result? The initial arterial blood gas results showed a pattern consistent with metabolic acidosis (ph 7.28) that had been compensated for in part by hyperventilation, as suggested by the blood gas results. Additionally, the high -hydroxybutyrate concentration is indicative of ketoacidosis; however, because this patient s plasma was mildly hypoglycemic and because no history of type I diabetes could be ascertained, diabetic ketoacidosis (DKA) 2 was considered highly improbable (2). Rather, her medical history strongly suggested the ketoacidosis was due to alcohol consumption in conjunction with little or no nutritional intake, a condition known as alcoholic ketoacidosis (AKA) (3). Although commonly observed, AKA is often underdiagnosed in emergency departments that receive patients who are chronic alcohol abusers. It is estimated that 20% of patients presenting with ketoacidosis have AKA (4). The key factors leading to AKA include (a) star- 2 Nonstandard abbreviations: DKA, diabetic ketoacidosis; AKA, alcoholic ketoacidosis. 1361

2 Table 1. Laboratory data. a Result Reference interval Arterial blood ph PCO 2, b mmhg PO 2, mmhg Calculated bicarbonate, meq/l Base deficit, meq/l Lactate, mg/dl Venous plasma Sodium, meq/l Potassium, meq/l Chloride, meq/l Carbon dioxide (total), meq/l Glucose, mg/dl Anion gap, meq/l Urea nitrogen, mg/dl Creatinine, mg/dl Calcium, mg/dl Albumin, g/dl Hydroxybutyrate, mg/dl Serum Osmolality, mosm/kg Osmolal gap (calculated c ), mosm/kg to 10 Serum alcohol screen (gas chromatography) Ethanol, mg/dl 128 Negative Acetone, mg/dl 37 Negative Isopropyl alcohol, mg/l 140 Negative Methanol, mg/l Negative Negative Ethylene glycol, mg/dl Negative Negative Urine drug screen (enzymatic immunoassay, Olympus AU400 EMIT) Opiates Positive Negative Tricyclic antidepressants Positive Negative Ethanol Positive Negative a Factors for converting conventional units of measure to SI units: bicarbonate, meq/l 1 mmol/l; lactate, mg/dl mmol/l; sodium, meq/l 1 mmol/l; potassium, meq/l 1 mmol/l; chloride, meq/l 1 mmol/l; carbon dioxide, meq/l 1 mmol/l; glucose, mg/dl mmol/l; anion gap, meq/l 1 mmol/l; urea nitrogen, mg/dl mmol/l; creatinine, mg/dl 88.4 mol/l; calcium, mg/dl 0.25 mmol/l; albumin, g/dl 10 g/l; -hydroxybutyrate, mg/dl mol/l; osmolality, mosm/kg 1 mmol/kg; osmolal gap, mosm/kg 1 mmol/kg; ethanol, mg/dl mmol/l; acetone, mg/dl mmol/l; isopropyl alcohol, mg/l mmol/l; methanol, mg/l mmol/l; ethylene glycol, mg/dl mmol/l. b PCO 2, partial pressure of CO 2 ; PO 2, partial pressure of O 2. c Osmolal Gap Measured Osmolality Calculated Osmolality. Calculated Osmolality (1.86 [Sodium]) ([Glucose]/18) ([Urea Nitrogen]/2.8) 9, where the sodium concentration is expressed in milliequivalents per liter and the glucose and urea nitrogen concentrations are expressed in milligrams per deciliter [Glasser (11)]. vation with glycogen depletion, (b) an increased intracellular NADH/NAD ratio secondary to the metabolism of alcohol, and (c) extracellular fluid volume depletion (3). The vast majority of AKA cases present with abdominal pain, nausea, and vomiting, all of which cause patients to suddenly stop eating and reduce their liquid consumption. Common physical findings on presentation include tachycardia, tachypnea, and abdominal tenderness. AKA is characterized in the clinical laboratory by increased serum ketones and a high anion gap. At its foundation is an underlying state of starvation that 1362 Clinical Chemistry 57:10 (2011)

3 causes hepatic glycogen depletion, insulin deficiency, and increased counterregulatory hormones (glucagon, cortisol, growth hormone, and catecholamines) (5). This hormonal imbalance leads to enhanced mobilization of free fatty acids from adipose tissue and a hepatic metabolic shift from lipogenesis to lipolysis and increased gluconeogenesis. Most of the free fatty acids that enter the liver are metabolized to so-called ketone bodies: acetoacetate, -hydroxybutyrate, and acetone. It is worth noting is that ketone body is partly a misnomer, because -hydroxybutyrate, usually the most prevalent ketone body, is not a ketone. AKA is particularly challenging to the patient s physiology because it has features of a positivefeedback loop. For example, patients with AKA typically present with a decreased blood volume due to prolonged emesis and/or ethanol-enhanced diuresis. This volume contraction limits the excretion of ketone bodies and organic acids, as well as increases the concentrations of lipolytic and ketogenic hormones. Although this patient appeared to have had a high anion gap metabolic acidosis with respiratory alkalosis, other acid base imbalances can occur in AKA. In one study, 30% of AKA patients had a coexisting metabolic alkalosis due to prolonged emesis (5). AKA can also be associated with other laboratory abnormalities, such as increased serum lactate and an osmolal gap, as well as reduced electrolyte concentrations. Both urea nitrogen and creatinine concentrations are usually increased, as are markers of liver or pancreatic injury (e.g., enzymes, bilirubin). These latter findings are most commonly due to comorbid illnesses, such as alcohol-induced hepatitis and pancreatitis. This patient exhibited all of these laboratory derangements, except for having a very low value for urea nitrogen, which was likely decreased because of the malnutrition. In the pathophysiology of AKA, oxidative metabolism of ethanol to acetaldehyde and acetate occurs in the liver, causing a greatly increased NADH/ NAD ratio. This abnormal NADH/NAD ratio has important metabolic ramifications, because to regenerate NAD requires that the pyruvate produced by gluconeogenesis and other pathways be converted to lactate, or else acetoacetate must be converted to -hydroxybutyrate. Thus, the altered intracellular redox potential induced by ethanol is critical in explaining why AKA patients exhibit increased lactate and -hydroxybutyrate concentrations. Patients diagnosed with AKA should be treated immediately with 50 g/l glucose in normal saline to address the starvation state and lack of glucose. Insulin concentrations will consequently increase, and glucagon and other counterregulatory hormones will decrease. Eventually, this treatment stimulates the oxidation of NADH by reactivating the normal oxidative metabolism of carbohydrates, simultaneously reducing the NADH/NAD ratio and halting ketogenesis. Insulin therapy is not recommended unless underlying DKA is present. Thiamine is often given with glucose to ensure adequate cofactor concentrations for the enzymes involved in aerobic carbohydrate metabolism, such as pyruvate dehydrogenase. An added benefit is that thiamine can prevent Wernicke encephalopathy (4). Finally, intravenous hydration is a mainstay of therapy for AKA. Replenishing the extracellular fluid promotes normal renal function, removal of excess acids, and the return to normal bicarbonate concentrations. The increased osmolal gap observed in this case could not be explained by ethanol alone. In such cases, it is useful to directly test for other commonly ingested, osmotically active small molecules, such as small organic alcohols. Furthermore, a suspicion of a toxic ingestion as an etiology warrants research into the identity of the ingested matter, such as consultation with the local poison center about the contents of commercial products, or even soliciting a sample of the unknown material for analysis. The homemade liquor in question was unavailable for analysis in this case, but a gas chromatography analysis of the patient s serum identified acetone (37 mg/dl) and isopropyl alcohol (14 mg/dl). The calculated osmolal gap of 56 mosm/kg was above the upper limit of the reference interval by approximately 46 mosm/kg, a difference that could be mostly explained by approximating the additive contributions of ethanol (34 mosm/kg, using [Ethanol] in mg/dl mosm/kg (6)), acetone (6 mosm/kg, using [Acetone] in mg/dl mosm/kg), and isopropyl alcohol (2 mosm/kg, using [Isopropyl Alcohol] in mg/dl 6 1 mosm/kg). Although it is possible that the homemade liquor reportedly consumed by this patient contained isopropyl alcohol, there is another possible explanation for its presence. Previous studies involving acetonemic diabetic patients and acetonemic cows and rats illustrated that a highly reduced intracellular environment could cause some acetone to be biotransformed into isopropyl alcohol and concomitantly regenerate NAD (7, 8). None of the individuals described in these studies were exposed to isopropyl alcohol, yet all had evidence of serum isopropyl alcohol. These findings corroborated previous reports of isopropyl alcohol present in the blood of autopsy patients not previously exposed to isopropyl alcohol, as well as in vitro enzymatic studies involving alcohol dehydrogenase (9). In summary, AKA is an often underdiagnosed condition in the US. Although its pathophysiology can be complex, the condition can be resolved rapidly with therapy, resulting in a low mortality (10). Although the clinical findings of AKA are very similar to DKA, differentiation is based on the patient s history of diabetes Clinical Chemistry 57:10 (2011) 1363

4 or alcoholism and the plasma glucose concentration on admission. Patients with AKA will usually present with normal or low glucose concentrations and a history of substantial alcohol use. FOLLOW-UP Approximately 1 month after discharge from this hospitalization, the patient was readmitted for multiple subcutaneous abscesses consistent with sequelae of injection drug use. She developed sepsis and pneumonia after surgical drainage of these abscesses, which were complicated by stroke, and died 1 week later. POINTS TO REMEMBER AKA occurs in alcoholics who binge drink but have little to no intake of any nonalcohol calories. This leads to glycogen depletion, ketosis, an increased NADH/NAD ratio, and severe dehydration. Treatment of AKA involves simple fluid replacement with fluids containing glucose, electrolytes, and thiamine. Patients with AKA will present with an increased anion gap in combination with an increased osmolal gap. The crucial differential diagnoses for an increase in both the anion and osmotic gaps are DKA, lactic acidosis, or ingestion of methanol or ethylene glycol. Although AKA and DKA share a common symptomology, a patient history of substantial alcohol use along with a normal or below-normal plasma glucose concentration will indicate AKA. References 1. Endres DB, Rude RK. Mineral and bone metabolism. In: Burtis CA, Ashwood ER, Bruns DE, eds. Tietz textbook of clinical chemistry and molecular diagnostics. St. Louis: Elsevier Saunders; p McGuire LC, Cruickshank AM, Munro PT. Alcoholic ketoacidosis. Emerg Med J 2006;23: Yip L. Ethanol. In: Flomenbaum NE, Goldfrank LR, Hoffman RS, Howland MA, Lewin NA, Nelson LS, eds. Goldfrank s toxicologic emergencies. 8th ed. New York: McGraw-Hill; p Tanaka M, Miyazaki Y, Ishikawa S, Matsuyama K. Alcoholic ketoacidosis associated with multiple complications: report of 3 cases. Intern Med 2004; 43: Umpierrez GE, DiGirolamo M, Tuvlin JA, Isaacs SD, Bhoola SM, Kokko JP. Differences in metabolic and hormonal milieu in diabetic- and alcoholinduced ketoacidosis. J Crit Care 2000;15: Geller RJ, Spyker DA, Herold DA, Bruns DE. Serum osmolal gap and ethanol concentration: a simple and accurate formula. J Toxicol Clin Toxicol 1986; 24: Bailey DN. Detection of isopropanol in acetonemic patients not exposed to isopropanol. Clin Toxicol 1990;28: Jones AE, Summers RL. Detection of isopropyl alcohol in a patient with diabetic ketoacidosis. J Emerg Med 2000;19: Davis PL, Dal Cortivo LA, Maturo J. Endogenous isopropanol: forensic and biochemical implications. J Anal Toxicol 1984;8: Wrenn KD, Slovis CM, Minion GE, Rutkowski R. The syndrome of alcoholic ketoacidosis. Am J Med 1991;91: Glasser DS. Utility of the serum osmol gap in the diagnosis of methanol or ethylene glycol ingestion. Ann Emerg Med 1996;27: Commentary Jeffrey A. Kraut 1,2,3,4* High anion gap metabolic acidosis and an increased serum osmolal gap in patients with a history of alcoholism can be due to methanol or ethylene glycol intoxication, lactic acidosis, and alcoholic or diabetic ketoacidosis. Isopropyl alcohol intoxication occurring in this 1 Medical and Research Services, Veterans Health Administration Greater Los Angeles (VHAGLA) Healthcare System, 2 UCLA Membrane Biology Laboratory, 3 Division of Nephrology, VHAGLA Healthcare System, and 4 David Geffen School of Medicine, Los Angeles, CA. * Address correspondence to the author at: Division of Nephrology, VHAGLA Heathcare System, Wilshire Blvd., Los Angeles, CA [email protected]. Received February 16, 2011; accepted February 24, DOI: /clinchem context is also associated with an osmolal gap, but acidosis is uncommon in the absence of sufficient hypoperfusion to produce lactic acidosis. It is important to be able to correctly identify the cause and to initiate appropriate treatment. Unfortunately, a history of exposure to these substances is not always obtained, and such clinical clues as blindness in methanol intoxication or urinary crystals in ethylene glycol intoxication are not always present. The metabolic acidosis and increased serum osmolal gap are also not always present together. For example, with methanol and ethylene glycol intoxication, an increased serum osmolality is present early after exposure, but metabolic acidosis is absent. As the parent alcohol is metabolized, the serum osmolality decreases, 1364 Clinical Chemistry 57:10 (2011)

5 and a high anion gap metabolic acidosis becomes evident. When all of the parent alcohol has been metabolized, the high anion gap metabolic acidosis will be present alone (1). Moreover, in alcoholic or diabetic ketoacidosis, the serum osmolal gap can be normal or increased, depending not only on the ethanol concentration in the blood (in alcoholic ketoacidosis) but also on the concentration of other osmotically active metabolites arising in the course of these disorders, such as acetone (or isopropyl alcohol, as in this case) (2). Given the potentially serious consequences of methanol and ethylene glycol intoxication, or lactic acidosis and alcoholic ketoacidosis, these disorders need to be recognized very early in their course. There is a need for simple and rapid tests to exclude these disorders, and various laboratories are working toward that goal (3). The case presented underscores the challenges faced by the clinician investigating patients with serious acid base disorders and the value of understanding their pathophysiology in making an appropriate diagnosis. References 1. Kraut JA, Kurtz I. Toxic alcohol ingestions: clinical features, diagnosis, and management. Clin J Am Soc Nephrol 2008;3: Davidson DF. Excess osmolal gap in diabetic ketoacidosis explained. Clin Chem 1992;38: Shin J, Sachs G, Kraut JA. Simple diagnostic tests to detect toxic alcohol intoxications. Transl Res 2008;152: Commentary Nikola A. Baumann * Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN. * Address correspondence to the author at: Mayo Clinic, 200 First St. SW, Hilton 3-70, Rochester, MN [email protected]. Received March 15, 2011; accepted March 21, DOI: /clinchem The typical biochemical findings in patients with alcoholic ketoacidosis (AKA) include increased anion gap metabolic acidosis, increased serum ketones, a low or normal plasma glucose concentration, an increased plasma lactate concentration, and normal or increased values for blood urea nitrogen and serum creatinine. There are a few caveats to the laboratory findings described in this Clinical Case Study that are important to discuss. As mentioned in the case report, mixed acid base imbalances can occur in patients with AKA owing to concurrent disease processes. Therefore, the serum ph will reflect the final balance of these factors and may not necessarily be low. Increased serum ketones are a trademark of AKA; however, the ratio of -hydroxybutyrate to acetoacetate is markedly higher in patients with AKA than in those with diabetic ketoacidosis. Many laboratories use semiquantitative nitroprusside-based assays to rapidly measure ketones (e.g., Acetest). Nitroprusside-based tests are most sensitive for detecting acetoacetate and do not detect -hydroxybutyrate. These tests may yield a low to moderate result in patients with AKA even when the -hydroxybutyrate concentration is markedly increased. Electrolyte abnormalities, including hyponatremia and hypokalemia, are often present in patients with AKA, and hypokalemia is a strong indicator of hypomagnesemia. Potassium and magnesium replacement may be required as part of treatment, and serum potassium should be monitored. Finally, ethanol may be low or undetectable in the serum of patients with AKA because of decreased consumption in the days preceding presentation. In addition, evidence of alcoholic hepatitis is common in these patients, and serum transaminase activities and bilirubin are frequently increased. The clinical case described by Platteborze and colleagues is an excellent teaching case that discusses the clinical and laboratory findings of a patient presenting to the emergency department with AKA. Laboratorians and clinicians must be able to recognize patients with AKA and be aware of the complexity of these cases and the impact of coexisting conditions on laboratory results. Clinical Chemistry 57:10 (2011) 1365