Clinical features and diagnosis of diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults Author Abbas E Kitabchi, PhD,

MD, FACP, MACE Section Editor David M Nathan, MD Deputy Editor Jean E Mulder, MD Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Mar 2014. | This topic last updated: dic 20, 2013. INTRODUCTION Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS, also known as nonketotic hyperglycemia) are two of the most serious acute complications of diabetes. They are part of the spectrum of hyperglycemia and each represents an extreme in the spectrum. The clinical features and diagnosis of DKA and HHS will be reviewed here. The epidemiology, pathogenesis, and treatment of these disorders are discussed separately. (See "Epidemiology and pathogenesis of diabetic ketoacidosis and hyperosmolar hyperglycemic state" and "Treatment of diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults".) DEFINITIONS DKA and HHS differ clinically according to the presence of ketoacidosis and usually the degree of hyperglycemia [1-4]. The definitions proposed by the American Diabetes Association for DKA and HHS are shown in a table, along with criteria for classification of DKA as mild, moderate, or severe, based on the patient's arterial pH, serum bicarbonate, and mental status (table 1). In HHS, there is little or no ketoacid accumulation, the serum glucose concentration frequently exceeds 1000 mg/dL (56 mmol/L), the plasma osmolality may reach 380 mosmol/kg, and neurologic abnormalities are frequently present (including coma in 25 to 50 percent of cases) [2,3,5]. Most patients with HHS have an admission pH >7.30, a serum bicarbonate >20 meq/L, a serum glucose >600 mg/dL (33.3 mmol/L), and test negative for ketones in serum and urine, although mild ketonemia may be present. DKA is characterized by the triad of hyperglycemia, anion gap metabolic acidosis, and ketonemia. Metabolic acidosis is often the major finding. The serum glucose concentration is usually greater than 500 mg/dL (27.8 mmol/L) and less than 800 mg/dL (44.4 mmol/L) [2,6]. However, serum glucose concentrations may exceed 900 mg/dL (50 mmol/L) in patients with DKA who are comatose [7]. In certain instances, such as DKA in the setting of starvation or pregnancy, or treatment with insulin prior to arrival in the emergency department, the glucose may be only mildly elevated. Factors that contribute to the lesser degree of hyperglycemia in DKA, compared with HHS, are discussed below. (See 'Serum glucose' below.) Significant overlap between DKA and HHS has been reported in more than one-third of patients [8-11]. The typical total body deficits of water and electrolytes in DKA and HHS are compared in a table (table 2). PRECIPITATING FACTORS A precipitating event can usually be identified in patients with DKA or HHS (table 3) [1,2,5,8,9,11]. The most common events are infection (often pneumonia or urinary tract infection) and discontinuation of or inadequate insulin therapy [12]. Compromised water intake due to underlying medical conditions, particularly in elderly patients, can promote the development of severe dehydration and HHS [8,13,14]. Other conditions and factors associated with DKA and HHS include: Acute major illnesses such as myocardial infarction, cerebrovascular accident, or pancreatitis. New onset type 1 diabetes, in which DKA is a common presentation. Drugs that affect carbohydrate metabolism, including glucocorticoids, higher dose thiazide diuretics, sympathomimetic agents (eg, dobutamine andterbutaline) [15], and second-generation antipsychotic agents [16]. Cocaine use, which has been associated with recurrent DKA [17,18]. Psychological problems associated with eating disorders and purposeful insulin omission, particularly in young patients with type 1 diabetes [19]. Factors that may lead to insulin omission in younger patients include fear of weight gain, fear of hypoglycemia, rebellion from authority, and the stress of chronic disease. Poor compliance with the insulin regimen. Compliance issues, with substance abuse as a contributory factor, is the main cause of decompensated diabetes in urban African Americans [20]. Malfunction of continuous subcutaneous insulin infusion devices (CSII) was reported in the early 1980s [ 21]. However, the lack of more recent reports suggests that this risk may no longer be of concern [22]. CLINICAL PRESENTATION DKA usually evolves rapidly, over a 24-hour period. In contrast, symptoms of HHS develop more insidiously with polyuria, polydipsia, and weight loss, often persisting for several days before hospital admission. The earliest symptoms of marked hyperglycemia are polyuria, polydipsia, and weight loss. As the degree or duration of hyperglycemia progresses, neurologic symptoms, including lethargy, focal signs, and obtundation, which can progress to coma in later stages, can be seen. Neurological symptoms are most common in HHS, while hyperventilation and abdominal pain are primarily limited to patients with DKA.

Initial evaluation Both DKA and HHS are medical emergencies that require prompt recognition and management. An initial history and rapid but careful physical examination should focus on: Airway, breathing, and circulation (ABC) status Mental status Possible precipitating events (eg, source of infection, myocardial infarctio n) Volume status Neurologic symptoms and plasma osmolality Neurologic deterioration primarily occurs in patients with an effective plasma osmolality above 320 to 330 mosmol/kg [5,6,10,11]. Mental obtundation and coma are more frequent in HHS than DKA because of the usually greater degree of hyperosmolality in HHS (table 1) [23]. In addition, some patients with HHS have focal neurologic signs (hemiparesis or hemianopsia) and/or seizures [23-27]. Mental obtundation may occur in patients with DKA, who have lesser degrees of hyperosmolality, when severe acidosis is also present [28]. In the calculation of effective plasma osmolality, the urea concentration is not taken into account because urea is freely permeable and its accumulation does not induce major changes in intracellular (including brain) volume or the osmotic gradient across the cell membrane [29]. The effective plasma osmolality (Posm, in mosmol/kg) can be estimated from the following equation: Effective Posm = [2 x Na (meq/L)] + [glucose (mg/dL) 18] Where Na is the serum sodium concentration, the multiple 2 accounts for the osmotic contribution of the anions accompanying sodium (primarily chloride and bicarbonate), and 18 is a conversion factors from units of mg/dL into mmol/L. Where standard units are used, the following equation applies: Effective Posm = [2 x Na (mmol/L)] + glucose (mmol/L) Importance of osmotic diuresis The rise in plasma osmolality in DKA and HHS is only in part due to the rise in serum glucose. The increase in plasma osmolality pulls water out of the cells, which reduces the plasma osmolality toward normal and lowers the serum sodium. The marked hyperosmolality seen in HHS is primarily due to the glucose osmotic diuresis that causes water loss in excess of sodium and potassium [2]. These principles and the importance of effective plasma osmolality in the development of neurologic symptoms are illustrated by observations in diabetic patients with end-stage renal disease. These patients can develop severe hyperglycemia, with serum glucose concentrations that can exceed 1000 to 1500mg/dL (56 to 83 mmol/L). However, because there is little or no osmotic diuresis, the rise in plasma osmolality is limited, hyponatremia is present, and there are few or no neurologic symptoms [30,31]. The presence of stupor or coma in diabetic patients with an effective plasma osmolality lower than 320 mosmol/kg demands immediate consideration of other causes of the mental status change. Abdominal pain in DKA Patients with DKA may present with nausea, vomiting, and abdominal pain; although more common in children, these symptoms can be seen in adults [32]. Abdominal pain is unusual in HHS. In a review of 189 consecutive episodes of DKA and 11 episodes of HHS, abdominal pain was reported in 46 percent of patients with DKA compared with none of the patients with HHS [33]. The presence of abdominal pain was associated with the severity of the metabolic acidosis (occurring in 86 and 13 percent of those with a serum bicarbonate 5 and 15 meq/L, respectively) but did not correlate with the severity of hyperglycemia or dehydration. Possible causes of abdominal pain include delayed gastric emptying and ileus induced by the metabolic acidosis and associated electrolyte abnormalities [11]. Other causes for abdominal pain should be sought when it occurs in the absence of severe metabolic acidosis and when it persists after the resolution of ketoacidosis. Physical examination Signs of volume depletion are common in both DKA and HHS, including decreased skin turgor, dry axillae and oral mucosa, low jugular venous pressure and, if severe, hypotension. Neurologic findings, noted above, also may be seen, particularly in patients with HHS. (See 'Neurologic symptoms and plasma osmolality' above and "Etiology, clinical manifestations, and diagnosis of volume depletion in adults".) Patients with DKA may have a fruity odor (due to exhaled acetone and similar to the odor of nail polish remover), and deep respirations reflecting the compensatory hyperventilation (called Kussmaul respirations). Fever is rare even in the presence of infection, because of peripheral vasoconstriction due to hypovolemia. LABORATORY FINDINGS Hyperglycemia and hyperosmolality are the two primary laboratory findings in patients with DKA or HHS; patients with DKA also have a high anion gap metabolic acidosis. Most patients also have acute elevations in the blood urea nitrogen (BUN) and serum creatinine concentration, which reflect the reduction in glomerular filtration rate induced by hypovolemia. A variety of additional laboratory tests may be affected. The impact of hyperglycemia, insulin deficiency, osmotic diuresis, and fluid intake in individual patients leads to variability in laboratory findings, depending upon the relative importance of these factors.

The initial laboratory evaluation of a patient with suspected DKA or HHS should include determination of: Serum glucose Serum electrolytes (with calculation of the anion gap), BUN, and serum creatinine Complete blood count with differential Urinalysis, and urine ketones by dipstick Plasma osmolality Serum ketones (if urine ketones are present) Arterial blood gas (if urine ketones or anion gap are present) Electrocardiogram Additional testing, such as cultures of urine, sputum, and blood, serum lipase and amylase, and chest x-ray, should be performed on a case-by-case basis. Measurement of A1C may be useful in determining whether the acute episode is the culmination of an evolutionary process in previously undiagnosed or poorly controlled diabetes or a truly acute episode in an otherwise wellcontrolled patient. Serum glucose The serum glucose concentration frequently exceeds 1000 mg/dL (56 mmol/L) in HHS [2,5], but is generally below 800 mg/dL (44mmol/L) in DKA [2,6]. Euglycemic DKA, in which the serum glucose is normal or near normal but the patient requires insulin therapy for the clearance of ketoacidosis, has been described, particularly in the presence of poor oral intake or pregnancy [34-36]. At least two factors contribute to the lesser degree of hyperglycemia in DKA compared with HHS: Patients with DKA often present early with symptoms of ketoacidosis (such as shortness of breath and abdominal pain), rather than late with those of hyperosmolality. Patients with DKA tend to be young and to have a glomerular filtration rate that, at least in the first five years, may be as much as 50 percent above normal. As a result, they have a much greater capacity to excrete glucose than the usually older patients with HHS, thereby limiting the degree of hyperglycemia. (See "Overview of diabetic nephropathy", section on 'Glomerular filtration rate'.) Patients with end-stage renal disease can develop severe hyperglycemia, but develop few if any neurologic symptoms, because there is no osmotic diuresis that is largely responsible for the marked rise in plasma osmolality [30,31]. (See 'Importance of osmotic diuresis' above.) Serum ketones Three ketone bodies are produced in DKA: acetoacetic acid, which is the only true ketoacid; betahydroxybutyric acid, a hydroxyacid formed from the reduction of acetoacetic acid; and acetone, which is derived from the decarboxylation of acetic acid. Acetone is a true ketone but is chemically neutral and therefore not an acid. Urine ketone bodies are detected by a dipstick. Testing for serum ketones is performed if urine testing is positive, using nitroprusside (Acetest) tablets or reagent sticks. A 4+ reaction with serum diluted 1:1 is strongly suggestive of ketoacidosis. False negative tests Nitroprusside reacts with acetoacetate and acetone, but not with beta-hydroxybutyrate [3,37]. This is important because beta-hydroxybutyrate is the predominant ketone, particularly in severe DKA. It is therefore possible, although unusual, to have a negative serum nitroprusside reaction in the presence of severe ketosis [11,36]. An indirect method to circumvent the masking of ketoacidosis is to add a few drops of hydrogen peroxide to a urine specimen. This will nonenzymatically convert beta-hydroxybutyrate to acetoacetate, which will then be detectable by nitroprusside [38]. An alternative is to directly measure beta-hydroxybutyrate in the blood; monitors are available to measure beta-hydroxybutyrate at the bedside, but this assay may not be available in many hospitals [39,40]. False positive tests Sulfhydryl drugs, such as captopril, penicillamine, and mesna, interact with the nitroprusside reagent and can lead to a false positive ketone test [41]. Thus, a positive nitroprusside test cannot be reliably interpreted in patients treated with these drugs and direct measurement of beta-hydroxybutyrate is recommended. If it is not available, the diagnosis of DKA in this setting should be made on the basis of clinical presentation and an otherwise unexplained high anion gap metabolic acidosis in association with hyperglycemia. Anion gap metabolic acidosis The serum bicarbonate concentration in DKA is reduced to a variable degree, ranging from mild to severe. In contrast, the serum bicarbonate concentration is normal or only mildly reduced in HHS. The sine qua non of DKA is an elevated anion gap metabolic acidosis, due to the production and accumulation of beta-hydroxybutyrate and acetoacetate. Compensatory hyperventilation results in a fall in the partial pressure of CO2 that minimizes the fall in arterial pH. The arterial pH in DKA is less than 7.30 and can be lower than 6.90. The severity of the metabolic acidosis is dependent upon a number of factors: The rate of ketoacid production. The duration of increased ketoacid production. The acidosis will be less severe in patients who present early due, as an example, to abdominal pain or an underlying infection that precipitated the ketoacidosis.

The rate of acid excretion in the urine [42]. Patients with relatively normal renal function can markedly increase acid excretion, thereby minimizing the severity of the acidosis. The magnitude of this effect was illustrated in a study of patients with DKA: ketone production averaged 51 meq/hour, while net acid excretion with the ketoacid anions averaged 15 meq/hour or 30 percent of the ketoacid load [43]. The conversion of acetoacetic acid to acetone can neutralize another 15 to 25 percent of the acid load [43,44]. The serum anion gap provides an estimate of the quantity of unmeasured anions in the serum, such as albumin and, in DKA, ketoacids. It is calculated by subtracting the major measured anions (chloride and bicarbonate) from the major measured cation (sodium): Serum anion gap = Serum sodium - (serum chloride + bicarbonate) (See "Approach to the adult with metabolic acidosis", section on 'Serum anion gap and differential diagnosis'.) Patients with DKA usually present with a serum anion gap greater than 20 meq/L. However, the increase in anion gap is variable, being determined by two factors: the rate and duration of ketoacid production, and the rate of loss of ketoacid anions in the urine. With respect to ketonuria, excretion of the sodium and potassium salts of betahydroxybutyrate and acetoacetate lowers the serum anion gap without affecting the serum bicarbonate concentration and therefore the degree of acidosis [42,45]. The amount of ketoacid anions excreted depends upon the degree to which glomerular filtration is maintained. Patients with relatively normal renal function can lose large quantities of ketoacids (as much as 30 percent of the ketoacid load [43]), which minimizes the elevation in anion gap. Rarely, patients excrete so much ketoacids that they present with only a small elevation in serum anion gap [45]. In addition, all patients, except those with end-stage renal disease, will develop a normal anion gap during the treatment phase of DKA because of the urinary ketoacid anion losses [46]. These principles are discussed in detail elsewhere. (See "The anion gap/HCO3 ratio in patients with a high anion gap metabolic acidosis", section on 'Urinary loss of unmeasured anions'.) Serum sodium The measured serum sodium concentration in uncontrolled diabetes mellitus is variable, as factors are present that can both lower and raise the measured value. The final serum sodium concentration will reflect the balance between dilution of sodium due to osmotic water movement out of the cells, and concentration of sodium due to glucosuria-induced osmotic diuresis resulting in water loss in excess of sodium. Physiologic calculations suggest that the serum sodium concentration should fall by 1 meq/L for every 62 mg/dL (3.5 mmol/L) rise in the serum concentration of glucose [47]. However, this standard correction factor was not verified experimentally. In an experimental model, hyperglycemia was induced in six healthy subjects by the administration of somatostatin (to block endogenous insulin secretion) and a hypertonic dextrose solution [48]. A nonlinear relationship was observed between the changes in the glucose and sodium concentrations: The 1:62 ratio applied when the serum glucose concentration was less than 400 mg/dL (22.2 mmol/L). At higher glucose concentrations, there was a greater reduction in the serum sodium concentration (1:25 ratio, a 4 meq/L reduction in serum sodium per 100 mg/dL further increase in serum glucose). An overall ratio of 1:42 (a 2.4 meq/L reduction in the serum sodium concentration for every 100 mg/dL [5.5 mmol/L] elevation in the serum glucose) provided a better estimate of this association than the usual 1:62 ratio. The direct effect of hyperglycemia on the serum sodium concentration is counteracted to a variable degree by the glucosuria-induced osmotic diuresis. The diuresis results in water loss in excess of sodium and potassium, which will tend to raise the serum sodium concentration and plasma osmolality unless there is a comparable increase in water intake. Some patients with uncontrolled diabetes have such a marked osmotic diuresis that, at presentation, the serum sodium concentration is increased and the serum osmolality is markedly elevated. Inadequate water intake prevents partial correction of the hyperosmolality and is a particular problem in hot weather and in elderly patients who may have an impaired thirst mechanism [49]. The above calculations are best used to estimate how much the serum sodium concentration will rise as the hyperglycemia is corrected. The administration of insulin drives glucose and water into the cells, reversing the initial direction of water movement and raising the serum sodium concentration. Most patients with DKA and HHS are mildly hyponatremic [50]. However, patients with HHS [51] who have a marked osmotic diuresis may have a normal or even elevated serum sodium concentration despite a serum glucose concentration that can exceed 1000 mg/dL (56 mmol/L). These patients are extremely hyperosmolar and often have neurologic symptoms that can include seizures and coma. (See 'Neurologic symptoms and plasma osmolality' above.) In contrast, the osmotic diuresis is attenuated in patients with advanced underlying renal disease (usually due to diabetic nephropathy) and does not occur in patients already on maintenance dialysis. In this setting, there is hyperglycemia-induced hyponatremia (with the serum sodium concentration falling below 125 meq/L in many cases), only a modest elevation in the plasma osmolality (due to the counterbalancing effects of hyperglycemia and hyponatremia), and usually no neurologic symptoms despite marked hyperglycemia [30,31].

Pseudohyponatremia Some patients with uncontrolled diabetes have marked hyperlipidemia and lactescent serum. In this setting, each liter of serum contains less water and therefore less sodium. As a result, the measured serum sodium concentration will fall, even though the physiologically important serum water sodium concentration and plasma osmolality are not affected [52,53]. Ion-selective electrodes will reveal a normal serum sodium concentration if an instrument employing direct potentiometry is used. (See "Evaluation of adults with hyponatremia".) The effect of therapy on the serum sodium concentration in DKA is discussed separately. (See "Treatment of diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults".) Serum potassium Patients with DKA or HHS, at presentation, have a potassium deficit that averages 300 to 600 mEq [50,54,55]. A number of factors contribute to this deficit, particularly increased urinary losses due both to the glucose osmotic diuresis and to the need to maintain electroneutrality as ketoacid anions are excreted. Gastrointestinal losses and the loss of potassium from the cells due to glycogenolysis and proteolysis also may play a contributory role. Despite these potassium losses, the serum potassium concentration is usually normal or, in one-third of patients, elevated on admission [2,50,56,57]. It is thought that hyperosmolality and insulin deficiency are primarily responsible for the relative rise in the serum potassium concentration in this setting [15,29,50]. (See "Causes and evaluation of hyperkalemia in adults".) The rise in plasma osmolality leads to osmotic water movement out of the cells. This can promote the para llel movement of potassium into the extracellular fluid by two mechanisms: the rise in cell potassium concentration induced by water loss favors passive potassium exit through potassium channels in the cell membrane, and the frictional forces between solvent (water) and solute can result in potassium being carried out through the water pores in the cell membrane (a process that is called solvent drag) [47]. Since insulin normally promotes potassium uptake by the cells, insulin deficiency also contributes to elevated serum potassium levels. Acidemia probably does not play a major role in the elevated serum potassium associated with DKA. Although a transcellular exchange of potassium with hydrogen ions resulting in a rise in serum potassium occurs in most forms of metabolic acidosis [58], it does not appear to play a major role in ketoacidosis (or lactic acidosis) [50,58-60]. The greater importance of hyperosmolality and insulin deficiency is illustrated by the observation that hyperkalemia also occurs in HHS despite the absence of acidosis [2]. (See "Potassium balance in acid-base disorders", section on 'Metabolic acidosis'.) Insulin therapy lowers the potassium concentration and may cause severe hypokalemia, particularly in patients with a normal or low serum potassium concentration at presentation [55]. Thus, careful monitoring and timely administration of potassium supplementation are essential. (See "Treatment of diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults", section on 'Potassium depletion'.) Serum phosphate Patients with uncontrolled hyperglycemia are typically in negative phosphate balance because of decreased phosphate intake and phosphaturia caused by osmotic diuresis. Despite phosphate depletion, the serum phosphate concentration at presentation is usually normal or even high because both insulin deficiency and metabolic acidosis cause a shift of phosphate out of the cells [61]. This transcellular shift is reversed and the true state of phosphate balance is unmasked after treatment with insulin. In a review of 69 episodes of DKA, the mean serum phosphate concentration fell from 9.2 mg/dL (3 mmol/L) at presentation to 2.8 mg/dL (0.9 mmol/L) at 12 hours, and some patients had values as low as 1.0 mg/dL (0.32 mmol/L) [61]. (See "Treatment of diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults", section on 'Phosphate depletion'.) Serum amylase and lipase Serum amylase and lipase are the standard tests to diagnose acute pancreatitis, which may precipitate DKA, but both are often elevated in patients with DKA who do not have pancreatitis [62-66]. As a result, the diagnosis of pancreatitis in patients with DKA should be based upon clinical findings and imaging. (See "Clinical manifestations and diagnosis of acute pancreatitis", section on 'Imaging'.) The mechanisms for hyperamylasemia and hyperlipasemia in DKA are not well defined, but the following observations have been made: In 100 consecutive cases of DKA, 11 had acute pancreatitis as confirmed by CT scan; the most common causes were hypertriglyceridemia and alcohol intake [67]. Two of the 10 evaluable patients (one was comatose) did not have abdominal pain. In a review of 134 consecutive episodes of DKA in patients with no CT evidence of acute pancreatitis, elevations of serum amylase and lipase (threefold or higher in some patients) were seen in 17 and 24 percent, respectively [62]. Abdominal pain was present in 19 percent of the patients in this series. The source of these nonspecific amylase elevations is most often salivary, though may also be pancreatic [63,64,66]. The source of nonspecific lipase elevations is not known. The rise in amylase correlates with pH and plasma osmolality, while the rise in lipase correlates only with plasma osmolality [62]. Peak values are seen within 24 hours of presentation [66].

Leukocytosis The majority of patients with hyperglycemic emergencies present with leukocytosis, which is proportional to the degree of ketonemia [15,68]. Leukocytosis unrelated to infection may occur as a result of hypercortisolemia and increased catecholamine secretion [69]. However, a white blood cell count greater than 25,000/microL or a band count greater than 10 percent may designate infection and indicates a need for further work up [70]. Lipids Patients with DKA or HHS may present with marked hyperlipidemia and lactescent serum. In a study of 13 patients with DKA, the mean plasma triglyceride and cholesterol levels on admission were 574 mg/dL (6.5 mmol/L) and 212 mg/dL (5.5 mmol/L), respectively [71]. Triglycerides fell below 150mg/dL (1.7 mmol/L) in 24 hours with insulin therapy. Insulin is the most anti-lipolytic hormone. Insulin deficiency, combined with elevated levels of lipolytic hormones (catecholamines, growth hormone, ACTH, and glucagon) in DKA and HHS result in accumulation of free fatty acids. The increase in serum fatty acids leads to inhibition of glycolysis, production of triacylglycerol, and increased ketones by fatty acid entry into mitochondria where they serve as a substrate for ketogenesis. DIFFERENTIAL DIAGNOSIS The differential diagnosis of metabolic causes of acidosis and coma are depicted in a table (table 4). Alcoholic and fasting ketoacidosis Alcoholic ketoacidosis (AKA) and starvation ketosis are other causes of ketoacidosis. The acidosis can be relatively severe in alcoholic ketoacidosis. In comparison, ketoacid levels in fasting ketoacidosis do not exceed 10 meq/L with prolonged fasting alone, which means that the serum bicarbonate concentration is typically above 14 meq/L [72]. (See "Fasting ketosis and alcoholic ketoacidosis".) The presence of ketoacidosis without hyperglycemia in an alcoholic patient is virtually diagnostic of AKA. However, modest elevations in serum glucose have been reported in alcoholic ketoacidosis [73]. This may reflect underlying unrecognized diabetes or a catecholamine-mediated stress response. Measurement of A1C may be helpful to detect chronic hyperglycemia. In addition to fasting, a case report suggested a relationship between low carbohydrate diet and ketoacidosis [74]. Anion gap acidosis DKA must also be distinguished from other causes of high anion gap metabolic acidosis including lactic acidosis (which can be induced by metformin, particularly in patients with impaired renal function); ingestion of drugs such as aspirin, methanol, and ethylene glycol; and advanced chronic kidney disease. None of these disorders causes ketoacidosis. (See "Approach to the adult with metabolic acidosis".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and th th Beyond the Basics. The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics th patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10 to th 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (see "Patient information: Diabetic ketoacidosis (The Basics)" and "Patient information: Hyperosmolar nonketotic coma (The Basics)") SUMMARY AND RECOMMENDATIONS Although part of a spectrum of diabetic complications, diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) primarily differ according to the presence of ketoacidosis and the degree of hyperglycemia. Neurologic complications, related to higher glucose levels and serum osmolality, are more common in HHS. The triad of DKA consists of hyperglycemia, anion gap metabolic acidosis, and ketonemia. (See 'Definitions'above.) A precipitating event can usually be identified in patients with DKA or HHS. The most common are infection (most often pneumonia or urinary tract infection) and discontinuation of or inadequate insulin therapy. (See 'Precipitating factors' above.) The initial evaluation of patients with hyperglycemic crises should include assessment of cardiorespiratory status, volume status, and mental status. Abdominal pain is common in DKA but not in HHS, and requires evaluation if it does not resolve with treatment of the acidosis. Neurologic symptoms, which may include focal findings, are more often seen in HHS and primarily occur when the effective serum osmolality is greater than 320 to 330mosmol/kg. The presence of stupor or coma in diabetic patients with an effective serum osmolality below 320 mosmol/kg demands immediate consideration of other causes of the mental status change. Infection can occur without fever. (See 'Clinical presentation' above.) Glucose concentrations in DKA are usually less than 800 mg/dL (44 mmol/L), but often exceed 1000 mg/dL (56 mmol/L) in HHS. (See 'Serum glucose'above.)

Three ketone bodies are produced in DKA: one ketoacid (acetoacetic acid), one hydroxyacid (beta hydroxybutyric acid), and one neutral ketone (acetone). The nitroprusside test (Acetest) may give false negative readings since it does not detect beta-hydroxybutyrate which may be the major ketone body present. (See 'Serum ketones' above.) Patients with DKA usually present with a serum anion gap greater than 20 meq/L. However, the increase in anion gap is variable, being determined by two factors: the rate and duration of ketoacid production, and the rate of loss of ketoacid anions in the urine. (See 'Anion gap metabolic acidosis' above.) The serum sodium concentration in DKA and HHS reflects the balance between the dilutional effect of water moving out of cells in response to the hyperglycemia-induced increase in serum osmolality and the increase in water excretion due to the glucosuria-induced osmotic diuresis. Most patients are mildly hyponatremic, but patients who have a marked osmotic diuresis may have a normal or even elevated serum sodium concentration. Hypertriglyceridemia can interfere with measurement of serum sodium with certain assays, resulting in falsely low values. (See 'Serum sodium' above.) Patients with DKA or HHS have a potassium deficit that averages 300 to 600 mEq. Despite this deficit, the serum potassium concentration is often elevated at presentation as both insulin deficiency and hyperosmolality result in potassium movement out of the cells into the extracellular fluid. Insulin therapy lowers the potassium concentration and may cause severe hypokalemia, particularly in patients with a normal or low serum potassium concentration at presentation. Thus, careful monitoring and timely administration of potassium supplementation are essential. (See 'Serum potassium'above.) Serum amylase and lipase levels are elevated in 15 to 25 percent of patients with DKA and, in most cases, do not reflect acute pancreatitis. The diagnosis of pancreatitis should be based upon clinical findings and confirmed by imaging. (See 'Serum amylase and lipase' above.) Ketoacidosis may also be caused by alcohol abuse or fasting. Other causes of an anion gap acidosis include lactic acidosis, ingestion of drugs such asaspirin, methanol, and ethylene glycol, and advanced chronic kidney disease. (See 'Differential diagnosis' above.)