Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Epidemiology and pathogenesis

INTRODUCTION — 

Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS, also called hyperosmotic hyperglycemic nonketotic state [HHNK]) are two of the most serious acute complications of diabetes. Mixed presentations of DKA and HHS may also occur.

The epidemiology and pathogenesis of DKA and HHS in adults will be discussed here. The clinical features, evaluation, diagnosis, and treatment of these disorders are discussed separately. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis" and "Diabetic ketoacidosis in adults: Treatment".)

EPIDEMIOLOGY

●Predisposing factors – The combined rate of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) is far higher in adults with type 1 diabetes than in those with type 2 diabetes (44.5 to 82.5 versus 3.2 episodes per 1,000 person-years, respectively) [1-3]. Although DKA is more common with type 1 diabetes and HHS is more common with type 2 diabetes, both complications can occur in people with any type of diabetes at any age.

•DKA is usually associated with type 1 diabetes and is more common in younger adults (aged 18 to 44 years) [1]. It also occurs in type 2 diabetes under conditions of extreme stress, such as serious infection, trauma, or cardiovascular or other emergencies, in association with sodium-glucose cotransporter 2 (SGLT2) inhibitor use [4,5], or as a presenting manifestation of a ketosis-prone diabetes syndrome [6]. The increasing use of SGLT2 inhibitors has increased the risk for DKA in both type 1 and type 2 diabetes (table 1). (See "Syndromes of ketosis-prone diabetes mellitus" and "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Diabetic ketoacidosis'.)

Coronavirus disease 2019 (COVID-19) infection has also been associated with greater risk of DKA in both type 1 and type 2 diabetes. (See "COVID-19: Issues related to diabetes mellitus in adults", section on 'Clinical presentations'.)

•HHS occurs most often in middle-aged and older adults with type 2 diabetes [1].

●Hospitalization rates – In the United States and United Kingdom, the overall age-adjusted annual hospitalization rate for DKA is 30 to 35 per 1000 persons with type 1 diabetes [1]. According to the Diabetes Surveillance System of the Centers for Disease Control and Prevention (CDC), overall, age-adjusted annual DKA hospitalization rates decreased slightly from 2000 to 2009, then steadily increased from 19.5 to 30 per 1000 persons between 2009 to 2014. This increase preceded the introduction of SGLT2 inhibitors and the COVID-19 pandemic [7].

Although DKA and HHS traditionally have been considered two distinct entities, mixed DKA/HHS presentations are relatively common. For example, in a cohort study of 1211 adults admitted to a hospital with DKA or HHS, 27 percent had a mixed DKA/HHS presentation [8]. Population-based hospitalization rates are not available for HHS or mixed DKA/HHS presentations.

●Mortality rates – Inpatient mortality rates for HHS and DKA vary widely by region, but rates are consistently higher for HHS (eg, 1 to 13 percent) than for DKA (eg, 0.2 to 5 percent) [1,9]. The mortality rate for DKA and HHS declined between 1980 and 2009 [10]; however, in the United States, age-adjusted mortality rates increased from 2008 to 2015 and again from 2015 to 2019, with a further increase during the COVID-19 pandemic in 2020 and 2021 [11]. In regions with sufficient insulin availability, mortality in DKA or HHS is primarily due to the underlying precipitating illness and only rarely to the metabolic complications of hyperglycemia or ketoacidosis [12-14]. Prognosis is substantially worse at the extremes of age and in the presence of coma or hypotension [13,15-17].

PATHOGENESIS

Regulation of glucose metabolism — Circulating glucose concentration is primarily regulated by two hormones: insulin and glucagon. As the glucose concentration rises after a carbohydrate-containing meal, glucose enters the pancreatic beta cells and initiates a sequence of events leading to insulin release. Insulin restores normoglycemia by reducing hepatic glucose production and increasing glucose uptake by skeletal muscle and adipose tissue. Insulin-induced inhibition of glucagon secretion contributes to the decline in hepatic glucose production; this effect is mediated by direct inhibition of both glucagon secretion and expression of the glucagon gene in pancreatic alpha cells [18-20].

The hormonal regulation of glucose homeostasis is discussed in detail elsewhere. (See "Pancreatic beta cell function" and "Insulin action" and "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus".)

Shared pathophysiology — Two hormonal abnormalities are largely responsible for the development of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) [18,19,21]:

●Insulin deficiency (absolute or relative)

●Glucagon excess

Relative insulin deficiency can be driven by a coordinated, immune-mediated stress response and counterregulatory hormones that oppose insulin action. This acute stress response may be superimposed on underlying chronic insulin resistance or insulin deficiency. (See 'Acute stress response' below.)

Insulin deficiency — Insulin deficiency is typically absolute in DKA and relative in HHS; consequently, insulin deficiency is generally more severe in DKA. Insulin deficiency and/or resistance impair peripheral glucose utilization in skeletal muscle. However, decreased glucose utilization alone will produce only postprandial hyperglycemia; glycogenolysis and increased gluconeogenesis are also required for the development of the often severe fasting hyperglycemia that occurs in DKA and HHS.

Insulin deficiency promotes and accelerates hepatic gluconeogenesis through several mechanisms [18-20]:

●Increasing the delivery of gluconeogenic precursors (glycerol from fat and alanine and other amino acids from muscle) to the liver.

●Activating multiple enzymes in the gluconeogenic metabolic pathway.

●Increasing glucagon levels by removing the inhibitory effect of insulin on both glucagon synthesis and secretion. (See 'Glucagon excess' below.)

Oxidation of fatty acids, which are delivered in large amounts to the liver due to lipolysis of fat stores, provides the metabolic energy required to drive gluconeogenesis [21,22].

Glucagon excess — Glucagon raises serum glucose and accelerates ketogenesis. Excess glucagon, therefore, contributes to hyperglycemia in both DKA and HHS and to ketosis in DKA. Glucagon excess results in part from loss of the normal, intra-islet suppressive effect of insulin on glucagon secretion. Thus, it is more pronounced in individuals with complete insulin deficiency (eg, previously undiagnosed type 1 diabetes or type 1 diabetes with interruption in exogenous insulin delivery) than in those with relative insulin deficiency.

Nonetheless, glucagon is not an essential facet of DKA pathogenesis. For example, patients who have undergone complete pancreatectomy and lack pancreatic glucagon will develop DKA if insulin is withheld; however, DKA develops more slowly than in patients with type 1 diabetes [18,23]. (See 'Ketosis' below.)

Acute stress response — An acute stress response results from both the precipitating event(s) and the progressive metabolic derangements and volume depletion of DKA and HHS. This stress response involves hormonal and immune-mediated components that contribute to relative insulin deficiency.

●Hormonal mediators – In patients with absolute or relative insulin deficiency, DKA and HHS are usually precipitated by stressors that increase the secretion of glucagon, catecholamines, growth hormone, and cortisol (table 1). These hormones oppose the actions of insulin and thereby contribute to increases in both serum glucose levels and ketoacid production (algorithm 1) [12]. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis", section on 'Precipitating factors'.)

●Immune mediators – An immune-mediated stress response is also triggered during DKA and HHS, which may reflect responses to both the precipitating illness or event and the metabolic and oxidative stress imparted by hyperglycemia [24]. Patients with DKA or HHS exhibit elevated circulating levels of immune-derived eicosanoids and cytokines, including tumor necrosis factor-alpha and interleukin (IL)-1B, IL-6, and IL-8 [25,26]. Lipid peroxidation markers, as well as plasminogen activator inhibitor-1 and C-reactive protein (CRP), are also increased [27]. These mediators return to near-normal levels within 24 hours of insulin therapy and resolution of hyperglycemia.

METABOLIC FEATURES

Shared features — Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are both characterized by varying degrees of hyperglycemia, volume depletion, and electrolyte deficits. Patients with DKA, HHS, or mixed DKA/HHS can present anywhere along a continuum of diabetes-related metabolic derangement (table 2). (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis", section on 'Diagnostic criteria'.)

Prominent features of DKA also include ketosis and metabolic acidosis, whereas elevated plasma osmolality is typically more pronounced in HHS. (See 'Prominent features of DKA' below and 'Prominent features of HHS' below.)

Variable hyperglycemia

●Severity of hyperglycemia

•DKA – In DKA, serum glucose is generally <800 mg/dL (44 mmol/L) and often between 350 to 450 mg/dL (19.4 to 27.8 mmol/L) [28]. However, serum glucose may be minimally elevated or even normal in some patients, a presentation called normoglycemic or euglycemic DKA. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis", section on 'Laboratory findings'.)

•HHS – Marked hyperglycemia is present in HHS, and serum glucose frequently exceeds 1000 mg/dL (56 mmol/L). (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis", section on 'Laboratory findings'.)

●Underlying mechanisms – Hormonal alterations in DKA and HHS generate hyperglycemia through three fundamental changes in glucose metabolism (algorithm 1) [12,29,30]:

•Impaired glucose utilization in peripheral tissues

•Increased hepatic and renal gluconeogenesis

•Increased glycogenolysis

Glucosuria occurs with both DKA and HHS and initially minimizes the rise in serum glucose. However, glucosuria causes an osmotic diuresis that usually leads to volume depletion and a reduction in glomerular filtration rate, limiting further glucose excretion [28,31-33]. This effect is more pronounced in HHS, which results in higher serum glucose levels than does DKA. Further, patients with DKA tend to be younger and to have a higher glomerular filtration rate, facilitating glucose excretion. Early after diagnosis, patients with type 1 diabetes may have a supranormal glomerular filtration rate, as high as 50 percent above predicted. As a result, compared with patients with HHS, those with DKA generally have a greater capacity to excrete glucose, and pronounced glucosuria limits the severity of hyperglycemia. (See "Diabetic kidney disease: Pathogenesis and epidemiology".)

The lower glucose levels in DKA compared with HHS may also be evident because DKA often progresses rapidly, and patients present earlier in the course of illness with symptoms of ketoacidosis (eg, shortness of breath, abdominal pain, and nausea and vomiting). In contrast, patients with HHS may present later with more insidious symptoms, including changes in mentation, due to hyperosmolality. (See 'Hyperosmolality and hyponatremia' below.)

Volume and electrolyte deficits

Volume depletion — Volume depletion occurs in both DKA and HHS, although it is typically more severe in HHS (table 3). Fluid losses result from a glucosuria-induced osmotic diuresis and may be exacerbated by fever, gastrointestinal losses (vomiting, diarrhea), and/or diminished fluid intake due to nausea or altered mental status. Volume depletion leads to secondary hyperaldosteronism, which causes renal potassium loss and contributes to a total body potassium deficit, discussed immediately below.

Potassium depletion — Patients presenting with DKA or HHS have a potassium deficit that averages 300 to 600 mEq (table 3) [34-36].

●Total body potassium deficit – Several factors contribute to this total body potassium deficit, particularly increased urinary losses due to both the glucosuria-induced osmotic diuresis and the excretion of potassium ketoacid anion salts (ie, potassium salts of beta-hydroxybutyrate and acetoacetate). Although ketoacid anions are filtered primarily as sodium salts, secondary hyperaldosteronism causes sodium reabsorption in the distal renal tubule in exchange for potassium. Gastrointestinal losses and cellular potassium loss due to glycogenolysis and proteolysis also may play a contributory role; when accelerated glycogenolysis or proteolysis occurs in the setting of prolonged fasting and/or severe infection, potassium is released from the stored glycogen or protein and subsequently undergoes renal excretion.

●Preserved serum potassium – Despite these large total body potassium deficits, the serum potassium concentration is usually normal or, in approximately one-third of patients, elevated on admission [28,34,37]. Hyperosmolality and insulin deficiency contribute to this preserved serum potassium concentration [29,34,38]. (See "Causes and evaluation of hyperkalemia in adults".)

•Hyperosmolality – The rise in plasma osmolality causes osmotic water movement out of the cells. Potassium also moves into the extracellular fluid as a result of at least two mechanisms [39]:

-The contraction of the intracellular fluid space increases the intracellular potassium concentration and favors passive potassium exit through potassium channels in the cell membrane.

-The frictional forces between solvent (water) and solute result in potassium being carried across the cell membrane with water, a process called solvent drag.

•Insulin deficiency – Insulin normally promotes potassium uptake by the cells. Thus, insulin deficiency reduces cellular potassium uptake and thereby contributes to elevated serum potassium levels.

•Acidemia (minor role in DKA) – Acidemia plays a small role in the shift of potassium from the intracellular fluid to the extracellular fluid in patients with DKA. Although a transcellular exchange of potassium with hydrogen ions increases serum potassium in some forms of "inorganic" metabolic acidosis [40], this exchange is less important in organic metabolic acidoses such as ketoacidosis or lactic acidosis [34,40-42]. Thus, hyperkalemia often occurs in HHS, despite the absence of acidosis [28]. (See "Potassium balance in acid-base disorders", section on 'Metabolic acidosis'.)

Prominent features of DKA — The hallmark features of DKA are ketosis and metabolic acidosis. Although hyperglycemia is also a common feature of DKA, glucose may be minimally elevated or even normal in some patients. (See 'Variable hyperglycemia' above.)

Hyperglycemia leads to increased plasma osmolality in patients with DKA; however, severe hyperosmolality is not typically a feature of DKA, whereas it is a hallmark feature of HHS due to the presence of more profound hyperglycemia and volume depletion. (See 'Hyperosmolality and hyponatremia' below.)

Ketosis — Ketosis results from lipolysis, with synthesis of ketones from free fatty acids in the liver mitochondria. Ketones provide an alternate water-soluble source of energy when glucose availability is reduced, as occurs with absolute insulin deficiency. Insulin deficiency causes enhanced lipolysis from peripheral fat stores, largely through loss of inhibition of hormone-sensitive lipase activity. Lipolysis releases free fatty acids and glycerol. Circulating fatty acids are primarily bound to albumin and transported to the splanchnic bed and are subsequently taken up by hepatocytes. Within the hepatocyte cytoplasm, the fatty acids are "activated" by linkage of the fatty acid to coenzyme A (CoA), forming acyl-CoA (ie, fatty acid-CoA). The combination of low insulin and increased glucagon activity in hepatocytes accelerates the entry of acyl-CoA into the mitochondria. This transport is mediated by a pair of carnitine palmitoyl transferase reactions [21,43-48].

Within the mitochondria, beta-oxidation splits the fatty acids into multiple two-carbon units of acetyl-CoA. This molecule can have one of three fates:

●Enter the cytoplasm where the acetyl-CoA is used to synthesize fatty acids. Lipogenesis requires insulin sufficiency.

●Enter the Krebs cycle to be oxidized to carbon dioxide and water, thereby generating adenosine triphosphate (ATP). When insulin levels are low and glucagon activity is increased, high fatty acid delivery to the mitochondria leads to beta-oxidation. The rate-limiting step in beta-oxidation is the entry of acetyl-CoA into the Krebs cycle.

●Enter the ketogenic metabolic path to form acetoacetic acid. If acetyl-CoA accumulation exceeds its rate of entry into the Krebs cycle, it is instead converted to acetoacetic acid, the first ketoacid or "ketone body" that forms. The acetoacetic acid may then be reduced to beta-hydroxybutyric acid, which is also an organic acid, or undergo nonenzymatic decarboxylation to form acetone, which is not an acid [49].

Anion gap metabolic acidosis — DKA typically presents as an elevated anion gap metabolic acidosis, which is caused by the production and accumulation of beta-hydroxybutyric and acetoacetic acids. Rarely, patients excrete ketoacids so efficiently that they present with only a small elevation in anion gap or a non-gap, hyperchloremic metabolic acidosis [50-53].

A small, but clinically significant, fraction of ketoacids, acetone, and dihydroxyacetone phosphate (a product of glycolysis) can each be converted to D-lactic acid, a non-ketone organic acid [54]. D-lactic acid can account for as much as 8 to 10 mEq/L of the anion gap elevation and bicarbonate reduction in patients with severe DKA [54]. Patients with severe dehydration may also have L-lactic acidosis due to tissue underperfusion and anaerobic glycolysis. (See "The delta anion gap/delta HCO3 ratio in patients with a high anion gap metabolic acidosis", section on 'D-lactic acidosis and toluene inhalation'.)

●Calculating the anion gap – The anion gap is calculated by subtracting the serum concentrations of chloride and bicarbonate from the concentration of sodium [55]:

By convention, the measured (reported) sodium concentration, rather than the sodium concentration corrected for hyperglycemia, should be used to calculate the anion gap. (See 'Hyperosmolality and hyponatremia' below.)

●Severity of acidosis – The severity of the metabolic acidosis and the increase in the anion gap depend on several factors:

•The rate and duration of ketoacid production.

•The rate of metabolism of the ketoacids. The conversion of acetoacetic acid to acetone can neutralize 15 to 25 percent of the acid load [56,57].

•The volume of distribution of the ketoacid anions and the rate of renal net acid excretion. The rate of ketoacid anion excretion depends on the patient's volume status and kidney function. Patients with relatively preserved extracellular fluid volume and higher kidney function can excrete large quantities of ketoacids (as much as 30 percent of the ketoacid load) and thereby minimize the elevation in anion gap [50]. 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 [56].

●Resolution of acidosis – Administration of intravenous isotonic fluids corrects hypovolemia and increases renal excretion of ketoacid anions. Ketoacid anion excretion reduces the anion gap, but to the extent that ketoacids are excreted as sodium and potassium salts, the severity of the systemic acidemia is unchanged [50,51,58,59]. When ketoacids are generated, the protons mainly combine with bicarbonate to form carbon dioxide. Thus, circulating bicarbonate anions are replaced with ketoacid anions ("decomposed bicarbonate"). If the ketoacids are metabolized, a bicarbonate anion is regenerated ("potential bicarbonate"). Therefore, the urinary loss of ketoacid anions as sodium or potassium salts represents the loss of "potential bicarbonate."

Excretion of beta-hydroxybutyrate and acetoacetate as sodium and potassium salts reduces the anion gap and converts the anion gap acidosis to a hyperchloremic, or non-gap, acidosis. Thus, almost all patients with DKA who are treated with isotonic saline and insulin will develop some degree of hyperchloremic (normal anion gap) metabolic acidosis due to the urinary loss of potential bicarbonate. These principles are discussed in detail elsewhere. (See "The delta anion gap/delta HCO3 ratio in patients with a high anion gap metabolic acidosis", section on 'The delta AG/delta HCO3 in ketoacidosis'.)

Prominent features of HHS — Unlike DKA, metabolic acidosis and ketosis are not prominent features of hyperosmolar hyperglycemic state (HHS). Rather, marked plasma hyperosmolality, in addition to severe hyperglycemia, is a hallmark finding in HHS. Ketosis is typically minimal or absent. (See 'Variable hyperglycemia' above.)

Hyperosmolality and hyponatremia — Plasma osmolality is always elevated in patients with HHS but is variably present with DKA (table 2). Hyperglycemia increases plasma osmolality, which pulls water out of the cells, expands the extracellular fluid, and thereby reduces the serum sodium concentration.

If a patient with normal serum electrolytes (serum sodium 140 mEq/L) rapidly developed a glucose concentration of 1000 mg/100 mL in the theoretical absence of urine production, the serum sodium concentration would fall to a value between 119 and 126 mEq/L, and osmolality would increase to between 294 and 308 mOsmol/L. However, osmolality usually increases to a greater degree because a large volume of electrolyte-poor urine is excreted once serum glucose rises above the threshold for renal glucose excretion and causes an osmotic diuresis. The loss of electrolyte-poor urine further raises the osmolality [28]. In patients with ketoacidosis, high plasma levels of acetone, beta-hydroxybutyrate, and acetoacetate also contribute to the elevated osmolality.

●Calculating "corrected" serum sodium – Although published findings have varied considerably for the relationship between serum sodium and glucose levels, we use a ratio of a 2 mEq/L decline in sodium for each 100 mg/dL (5.5 mmol/L) increase in glucose concentration above 100 mg/dL (5.5 mmol/L). In the absence of urine production, physiologic calculations suggest that the serum sodium concentration should fall by approximately 1.6 mEq/L for each 100 mg/100 mL (5.5 mmol/L) increase in glucose concentration [39]. However, when hyperglycemia was induced in six healthy participants by administering somatostatin (to block endogenous insulin secretion) and infusing hypertonic dextrose, the relationship between the fall in sodium concentration and the increase in glucose concentration was not linear; rather, the fall in sodium was greater than predicted, and the authors concluded that serum sodium falls by approximately 2.4 mEq/L for each 100 mg/100 mL (5.5 mmol/L) increase in glucose concentration [60]. Several prior and subsequent studies reported a fall in sodium between 1.6 and 2.4 mEq/L for each 100 mg/100 mL increase in glucose [61]. These ratios are only rough estimates of potential water deficits or, uncommonly, excess. However, they do provide a general guide for the expected rise in serum sodium concentration as hyperglycemia is corrected.

●Factors affecting plasma osmolality and serum sodium – In the presence of marked hyperglycemia, osmolality and the measured serum sodium concentration are affected by multiple factors:

•Hyperglycemia – Hyperglycemia raises the osmolality (and tonicity) of the extracellular fluid and shifts water from the intracellular fluid to the extracellular fluid space. Expansion of extracellular fluid dilutes serum sodium and reduces its concentration.

•Glucosuria – Glucosuria generates an osmotic diuresis, which causes the excretion of water and sodium and potassium salts. The sum of the concentrations of sodium and potassium salts in urine is generally much lower than the sodium concentration in blood, indicating that electrolyte-free water is being excreted in the urine. Loss of free water raises the serum sodium concentration and plasma osmolality.

•Fluid intake and loss – Variable water intake and the loss of free water (eg, from vomiting, nasogastric suction) also affect serum sodium concentration and plasma osmolality.

Minimal or absent ketosis — In HHS, ketosis is typically minimal or absent unless patients have a mixed HHS/DKA presentation. The factors underlying this general absence of ketogenesis in HHS are incompletely understood. Although ketoacidosis is generally absent, severe dehydration and poor tissue perfusion may lead to lactic acidosis.

●Relative versus absolute insulin deficiency – One possible contributing factor is that HHS is a state of relative rather than absolute insulin deficiency [21,30,62]. Thus, low circulating insulin levels may be adequate to suppress lipolysis and ketogenesis but not to normalize peripheral glucose uptake or suppress hepatic glucose production [12,63]. For example, physiologic studies in humans show that the concentration of insulin required to suppress lipolysis is only one-tenth of that required to promote glucose utilization [64]. However, these concentration-dependent effects of insulin were observed in healthy, unstressed men, and their physiologic relevance to HHS is uncertain.

●Lesser increase in glucagon – In HHS, the elevation in glucagon levels is less pronounced than in DKA. This lesser increase in glucagon activity may also contribute to a relative preservation of insulin activity and thereby minimize ketogenesis [9].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hyperglycemic emergencies".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th 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 patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th 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 education: Diabetic ketoacidosis (The Basics)" and "Patient education: Diabetic ketoacidosis – Discharge instructions (The Basics)" and "Patient education: Hyperosmolar hyperglycemic state (The Basics)")

SUMMARY

●Epidemiology – In the United States and United Kingdom, the overall age-adjusted annual hospitalization rate for diabetic ketoacidosis (DKA) is 30 to 35 per 1000 persons with type 1 diabetes. DKA is usually associated with type 1 diabetes but can also occur in type 2 diabetes under conditions of extreme stress, such as serious infection, trauma, or cardiovascular or other emergencies, in association with sodium-glucose cotransporter 2 (SGLT2) inhibitor use, or as a presenting manifestation of a ketosis-prone diabetes syndrome (table 1).

Hyperosmolar hyperglycemic state (HHS) is associated with higher mortality than DKA. In regions with sufficient insulin availability, mortality in DKA or HHS is primarily due to the underlying, precipitating illness. Although DKA and HHS traditionally have been considered two distinct entities, mixed DKA/HHS presentations are common. (See 'Epidemiology' above.)

●Shared pathophysiology – Two hormonal abnormalities are largely responsible for the development of DKA and HHS:

•Insulin deficiency (absolute or relative)

•Glucagon excess

Relative insulin deficiency can be driven by an immune-mediated stress response and counterregulatory hormones that oppose insulin action.

●Shared metabolic features – DKA and HHS are both characterized by varying degrees of hyperglycemia, volume depletion, and electrolyte deficits. Patients with DKA, HHS, or mixed DKA/HHS can present anywhere along a continuum of diabetes-related metabolic derangement (table 2). (See 'Shared features' above.)

•Variable hyperglycemia – Hyperglycemia results from impaired glucose utilization, increased gluconeogenesis, and increased glycogenolysis (algorithm 1). Volume contraction from osmotic diuresis and reduced glomerular filtration further contribute to elevated blood glucose. (See 'Variable hyperglycemia' above.)

-DKA – In DKA, serum glucose is generally <800 mg/dL (44 mmol/L) and often between 350 to 450 mg/dL (19.4 to 27.8 mmol/L). However, serum glucose may be minimally elevated or even normal in some patients, a presentation called normoglycemic or euglycemic DKA.

-HHS – Marked hyperglycemia is present in HHS, and serum glucose frequently exceeds 1000 mg/dL (56 mmol/L).

•Volume and electrolyte deficits – Volume depletion occurs in both DKA and HHS, although it is typically more severe in HHS (table 3). Volume depletion leads to secondary hyperaldosteronism, which causes renal potassium loss and contributes to a total body potassium deficit. (See 'Volume and electrolyte deficits' above.)

●Metabolic features of DKA – In addition to variable hyperglycemia, the hallmark features of DKA are ketosis and metabolic acidosis. (See 'Prominent features of DKA' above.)

•Ketone production – Ketosis results from lipolysis, with synthesis of ketones from free fatty acids in the liver mitochondria. Ketones provide an alternate water-soluble source of energy when glucose availability is reduced, as occurs with absolute insulin deficiency. (See 'Ketosis' above.)

•Anion gap metabolic acidosis – The elevated anion gap metabolic acidosis characteristic of DKA is caused by the production and accumulation of beta-hydroxybutyric and acetoacetic acids. (See 'Anion gap metabolic acidosis' above.)

●Metabolic features of HHS – Unlike DKA, metabolic acidosis and ketosis are not prominent features of HHS. Rather, marked plasma hyperosmolality, in addition to severe hyperglycemia, is a hallmark finding in HHS. (See 'Prominent features of HHS' above.)

•Hyperosmolality and hyponatremia – Plasma osmolality is always elevated in patients with HHS but is variably present with DKA (table 2). Hyperglycemia increases plasma osmolality, which pulls water out of the cells, expands the extracellular fluid, and thereby reduces the serum sodium concentration. (See 'Hyperosmolality and hyponatremia' above.)

•Minimal or absent ketosis – In HHS, ketosis is typically minimal or absent unless patients have a mixed HHS/DKA presentation. The factors underlying this general absence of ketogenesis in HHS are incompletely understood. (See 'Minimal or absent ketosis' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Abbas Kitabchi, PhD, MD, FACP, MACE, who contributed to earlier versions of this topic review.