Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State in Adults Epidemiology and Pathogenesis

29/9/2020 Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Epidemiology and pathogenesis - UpToDate
Official reprint from UpToDate®

www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved.
Diabetic ketoacidosis and hyperosmolar hyperglycemic

state in adults: Epidemiology and pathogenesis
Authors: Irl B Hirsch, MD, Michael Emmett, MD
Section Editors: David M Nathan, MD, Joseph I Wolfsdorf, MD, BCh
Deputy Editor: Jean E Mulder, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2020. | This topic last updated: Mar 29, 2020.
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.
They each represent an extreme in the hyperglycemic spectrum.
The epidemiology and the factors responsible for the metabolic abnormalities 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 and
hyperosmolar hyperglycemic state in adults: Treatment".)
EPIDEMIOLOGY
Diabetic ketoacidosis (DKA) is characteristically associated with type 1 diabetes. It also occurs in type
2 diabetes under conditions of extreme stress such as serious infection, trauma, cardiovascular or
other emergencies, and, less often, as a presenting manifestation of type 2 diabetes, a disorder
called ketosis-prone diabetes mellitus. (See "Syndromes of ketosis-prone diabetes mellitus".)
DKA is more common in young (<65 years) patients, whereas hyperosmolar hyperglycemic state
(HHS) most commonly develops in individuals older than 65 years [1,2]. According to the Diabetes
Surveillance System of the Centers for Disease Control and Prevention (CDC), overall, age-adjusted
DKA hospitalization rates decreased slightly from 2000 to 2009, then reversed direction, steadily
https://www-uptodate-com.pbidi.unam.mx:2443/contents/diabetic-ketoacidosis-and-hyperosmolar-hyperglycemic-state-in-adults-epidemiology-and-pa… 1/23
increasing from 2009 to 2014 at an average annual rate of 6.3 percent. In-hospital case-fatality rates
declined consistently during the study period from 1.1 to 0.4 percent (figure 1) [3].
Population-based data are not available for HHS. The rate of hospital admissions for HHS is lower
than the rate for DKA and accounts for less than 1 percent of all primary diabetic admissions [1,4-6].
The mortality rate for patients with HHS is between 10 and 20 percent, which is approximately 10
times higher than that for DKA [7]. The mortality rate for hyperglycemic crisis declined between 1980
and 2009 [8]. Mortality in hyperglycemic crisis is primarily due to the underlying precipitating illness
and only rarely to the metabolic complications of hyperglycemia or ketoacidosis [1,9]. The prognosis
of hyperglycemic crisis is substantially worse at the extremes of age and in the presence of coma and
hypotension [9-12].
PATHOGENESIS
Normal response to hyperglycemia — 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 normal subjects and patients with diabetes mellitus".)
Summarized briefly, the extracellular concentration of glucose is primarily regulated by two hormones:
insulin and glucagon. As the serum glucose concentration rises after a glucose meal, glucose enters
the pancreatic beta cells, initiating a sequence of events leading to insulin release.
Insulin restores normoglycemia by diminishing hepatic glucose production via reductions in both
glycogenolysis and gluconeogenesis and by 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 glucagon secretion and of the
glucagon gene in the pancreatic alpha cells [13-15].
Spectrum of metabolic abnormalities — Two hormonal abnormalities are largely responsible for
the development of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) in
patients with uncontrolled diabetes [13,14,16]:
● Insulin deficiency and/or resistance.
● Glucagon excess, which may result from removal of the normal suppressive effect of insulin.
Although glucagon excess contributes to the development of DKA, it is not essential. As an

example, patients with complete pancreatectomies and who have no pancreatic glucagon will
develop DKA if insulin is withheld; however, it takes longer for DKA to develop compared with
patients with type 1 diabetes [17].
In addition to these primary factors, increased secretion of catecholamines, cortisol, and growth
hormone, which oppose the actions of insulin, also contribute to the increases in glucose and
ketoacid production (algorithm 1) [1].
The deficiency in insulin (either absolute deficiency, or a relative deficiency caused by excess
counterregulatory hormones) is more severe in DKA compared with HHS. Since suppression of
lipolysis and ketogenesis is more sensitive to insulin than the inhibition of gluconeogenesis, the
residual insulin secretion and its systemic activity in HHS is sufficient to minimize the development of
ketoacidosis but not adequate to control hyperglycemia [1]. The increase in glucagon levels and
activity is also less in HHS generating a smaller decrease in the insulin/glucagon ratio, which
generates a lesser stimulus to ketogenesis [7].
In patients with absolute or relative insulin deficiency, DKA and HHS are usually precipitated by
stresses that act in part by increasing the secretion of glucagon, catecholamines, and cortisol (table
1). (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features,
evaluation, and diagnosis", section on 'Precipitating factors'.)
DKA and HHS are two extremes in the spectrum of hyperglycemic crisis, and patients can present
anywhere along the continuum of diabetic metabolic derangement (table 2). (See "Diabetic
ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and
diagnosis", section on 'Diagnostic criteria'.)
Hyperglycemia — The serum glucose concentration in HHS frequently exceeds 1000 mg/dL (56
mmol/L), but in DKA, it is generally below 800 mg/dL (44 mmol/L) and often in the 350 to 450 mg/dL
(19.4 to 27.8 mmol/L) range [18]. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state
in adults: Clinical features, evaluation, and diagnosis", section on 'Laboratory findings'.)
At least two factors contribute to less severe hyperglycemia in DKA:
● Patients with DKA often present earlier in the course of their acute disease with symptoms of
ketoacidosis (such as shortness of breath, abdominal pain, and nausea and vomiting), rather
than late with symptoms due to hyperosmolality.
● Patients with DKA tend to be younger and to have a higher glomerular filtration rate. During the
first several years of diabetes, patients may have a supranormal glomerular filtration rate, with
levels as great as 50 percent above predicted. As a result, patients with DKA generally have a
much greater capacity to excrete glucose than the usually older patients with HHS. This severe
degree of glucosuria limits the severity of the hyperglycemia. (See "Diabetic kidney disease:
Pathogenesis and epidemiology".)
Although the glucosuria associated with DKA (and HHS) initially minimizes the rise in serum
glucose, the osmotic diuresis caused by glucosuria usually leads to volume depletion and a
reduction in glomerular filtration rate that limits further glucose excretion [18-21]. This effect is
more pronounced in HHS, which results in a higher serum glucose than seen in DKA.
Hormonal alterations in DKA and HHS generate hyperglycemia by their impact on three fundamental
processes in glucose metabolism (algorithm 1) [1,22,23]:
● Impaired glucose utilization in peripheral tissues

● Increased hepatic and renal gluconeogenesis
● Increased glycogenolysis
Insulin deficiency and/or resistance in diabetic patients 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 development of the often severe
fasting hyperglycemia which occurs in DKA and HHS.
Insulin deficiency and/or resistance promote and accelerate hepatic gluconeogenesis for several
reasons [13-15].
Insulin deficiency and/or resistance:
● Increase the delivery of gluconeogenic precursors (glycerol from fat and alanine and other amino
acids from muscle) to the liver
● Activate multiple enzymes in the gluconeogenic metabolic pathway
● Increase glucagon levels by removing the inhibitory effect of insulin on both glucagon synthesis
and secretion
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 [16,24,25].
The importance of glucagon in the development of hyperglycemia and ketoacidosis in uncontrolled

diabetes has been demonstrated by the following observations:
● After discontinuing insulin in a patient with type 1 diabetes, the rate of rise in serum glucose can
be markedly attenuated if glucagon release is prevented by infusing somatostatin [13].
● The magnitude of this effect is illustrated by studies in patients who have undergone total
pancreatectomy who make neither insulin nor glucagon. In one report, four such patients and six
with type 1 diabetes were fasted after having been maintained on intravenous insulin for 24
hours [17]. After withdrawal of insulin, there was a sharp increase in serum glucagon in the
patients with type 1 diabetes. Compared with the pancreatectomized patients, these patients had
significantly greater increases in blood glucose (225 versus 139 mg/dL [12.5 versus 7.7 mmol/L])
and blood ketone concentration (4.1 versus 1.8 mmol/L) at 12 hours. (See 'Ketone production'
below.)
Ketone production — Both insulin deficiency and glucagon excess contribute to the genesis of
DKA [17,24,26]. As noted above, however, glucagon is contributory, but not essential, for DKA to
occur. Insulin deficiency and resistance (eg, due to high catecholamine levels) will cause enhanced
lipolysis from peripheral fat stores, largely related to increased activity of hormone sensitive lipase,
which releases free fatty acids and glycerol. The fatty acids are transported, mainly bound to albumin,
to the splanchnic bed and are taken up by hepatocytes. Within the hepatocyte cytoplasm, they 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 the liver cells creates conditions
that accelerate the entry of the acyl-CoA into the mitochondria. This transport is mediated by a pair of
carnitine palmityl transferase reactions [16,24,26-30].
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 Krebs cycle to be oxidized to carbon dioxide (CO2) and water (H2O), thereby creating
adenosine triphosphate (ATP)
● Be indirectly exported into the cytoplasm where the acetyl-CoA is used to synthesize fatty acids
● Enter the ketogenic metabolic path to form acetoacetic acid
When fatty acid delivery to the mitochondria is high, then beta-oxidation of the fatty acid usually
occurs in a hormonal milieu characterized by low insulin and high glucagon activity. Under these
conditions, entry of acetyl-CoA into the Krebs cycle becomes rate limiting, and acetyl-CoA instead is
converted to acetoacetic acid. This true ketoacid is the first "ketone body" which forms. The
acetoacetic acid may then be reduced to beta-hydroxybutyric acid, which is also an organic acid, or
nonenzymatically decarboxylated to acetone, which is not an acid [31]. Ketones provide an alternate
water-soluble source of energy when glucose availability is reduced.
The factors responsible for the general absence of ketogenesis in HHS are incompletely understood.
However, one important issue is the differential sensitivity of fat metabolism and glucose metabolism
to the effects of insulin. Studies in humans have demonstrated that the concentration of insulin
required to suppress lipolysis is only one-tenth that required to promote glucose utilization [32]. Thus,
less severe insulin deficiency, as occurs in HHS compared with DKA, might be associated with
sufficient insulin activity to minimize lipolysis (and therefore ketoacid formation) but not enough to
block gluconeogenesis, promote glucose utilization, and thereby prevent the development of
hyperglycemia [33]. Less marked elevation of glucagon levels and therefore a higher insulin/glucagon
ratio also minimizes ketogenesis [7].
There are several observations compatible with this general hypothesis. DKA tends to occur in
patients with type 1 diabetes, who produce little or no insulin. HHS, in comparison, is found primarily
in older patients with type 2 diabetes, who have decreased, but not absent, insulin effect [16,23,34].
However, this distinction is not absolute, since DKA can occur in patients with type 2 diabetes (see
"Syndromes of ketosis-prone diabetes mellitus"). This most often occurs in obese African Americans
but has also been described in other populations in the setting of extreme stress, such as sepsis or
an acute myocardial infarction, with very elevated counterregulatory hormones [35].
Anion gap metabolic acidosis — DKA typically presents as an elevated anion gap metabolic
acidosis. This is caused by the production and accumulation of beta-hydroxybutyric and acetoacetic
acids. The anion gap is calculated by subtracting the serum concentrations of chloride and
bicarbonate from the concentration of sodium [36]:
Serum anion gap = serum sodium - (serum chloride + bicarbonate)
By convention, the measured (reported) sodium concentration (not the sodium concentration
corrected for hyperglycemia) should be used for the calculation of the anion gap.
The severity of the metabolic acidosis and the increase of the anion gap are dependent upon a
number of factors:
● The rate and duration of ketoacid production

● The rate of metabolism of the ketoacids
● The rate of loss of ketoacid anions in the urine
● The volume of distribution of the ketoacid anions
● The rate of renal net acid excretion
The rate of ketoacid anion excretion depends upon the patient's volume status, renal function, and
the degree to which glomerular filtration is maintained. Patients with relatively preserved extracellular
fluid (ECF) volume and higher renal function can excrete large quantities of ketoacids (as much as 30
percent of the ketoacid load), and thereby minimize the elevation in anion gap [37]. 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 [38]. The conversion of acetoacetic acid to acetone can neutralize another 15 to 25 percent of
the acid load [38,39]. Rarely, patients excrete ketoacids so efficiently that they present with only a
small, or no, elevation in serum anion gap (they have a pure non-gap, or hyperchloremic, metabolic
acidosis) [37,40-42].
Renal excretion of ketoacid anions increases when patients are treated with intravenous isotonic
fluids to correct the hypovolemia. Excretion of ketoacid anions reduces the anion gap, but to the
extent that they are excreted as sodium and potassium salts, the severity of the systemic acidemia is
unchanged [37,40,43,44]. Sodium or potassium ketoanion salts represent both "decomposed"
bicarbonate and also "potential bicarbonate." When the ketoacids are generated, the protons mainly
combine with bicarbonate to form CO2. Thus, in essence, bicarbonate anions in the serum are
replaced with ketoacid anions ("decomposed bicarbonate"). If the ketoacids are metabolized, then 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." Furthermore,
excretion of beta-hydroxybutyrate and acetoacetate as sodium and potassium salts will reduce the
anion gap and convert the anion gap acidosis to a hyperchloremic, or non-gap, acidosis. Thus, almost
all patients with DKA who have relatively intact renal function will develop some degree of
hyperchloremic (normal anion gap) metabolic acidosis when they are treated with isotonic saline and
insulin, 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'.)
Studies have demonstrated that a portion of the anion gap acidosis in most patients with DKA is due
to yet another organic acid: D-lactic acid. A small, but clinically significant, fraction of ketoacids,
acetone, and dihydroxyacetone phosphate (a product of glycolysis) can each be converted to D-lactic
acid [45]. 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 [45]. (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'.)
Plasma osmolality and sodium — Plasma osmolality is always elevated in patients with HHS but
less so with DKA (table 2). The increase in plasma osmolality created by hyperglycemia pulls water
out of the cells, expands the ECF, and thereby reduces the plasma sodium (Na) concentration. If a
patient with normal serum electrolytes (Na = 140 mEq/L) rapidly developed a glucose concentration
of 1000 mg/100 mL and no urine was made, then that patient's serum sodium concentration would fall
to value between 119 and 126 mEq/L and the osmolality would increase to a level between 294 and
308 mosmol/L. However, the osmolality usually increases to a greater degree because a large
volume of relatively electrolyte-deficient urine is excreted during the evolution of the hyperglycemic
state. The loss of this electrolyte-free water further raises the osmolality [18]. In patients with
ketoacidosis, high plasma acetone levels also contribute to the elevated osmolality.
The measured serum sodium concentration in uncontrolled diabetes mellitus is affected by the
interaction of multiple factors, some that lower and others that raise it:
● Hyperglycemia raises the ECF osmolality (and tonicity) and shifts water from the intracellular fluid
(ICF) space to the ECF space. Expansion of the ECF dilutes serum sodium and reduces its
concentration.
● Glucosuria generates an osmotic diuresis which causes the excretion of sodium and potassium
salts, and water. The sum of the concentrations of sodium and potassium salts in the urine is
generally much lower than the sodium concentration in blood. This indicates that electrolyte-free
water is being excreted in the urine. Loss of electrolyte-free water will raise the serum sodium
concentration and plasma osmolality.
● The variable intake of water and the loss of free water in vomitus or nasogastric suction will also
impact the serum sodium concentration and plasma osmolality.
Physiologic calculations suggest that, in the absence of urine losses, 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 [46]. However, when hyperglycemia was induced in six healthy subjects by the
administration of somatostatin (to block endogenous insulin secretion) and the infusion of hypertonic
dextrose solution, the relationship between the fall in sodium concentration and the increase in
glucose concentration was not linear and the reduction in sodium was greater than had been
previously reported [47]. These authors suggested that the sodium should fall by approximately 2.4
mEq/L for each 100 mg/100 mL (5.5 mmol/L) increase in glucose concentration. A number of 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 [48]. It must be emphasized that these ratios are only very approximate
estimates of potential water deficits (or less commonly, excess). However, they do provide a rough
estimate of how much the serum sodium concentration will rise as the hyperglycemia is corrected.
Because there is so much variation in the literature and so many variables affect this relationship, we
recommend the use of a simple ratio of a 2 mEq/L decline in sodium for each 100 mg/100 mL (5.5
mmol/L) increase in glucose concentration above the normal range.
Potassium — Patients presenting with DKA or HHS have a potassium deficit that averages 300 to
600 mEq (table 3) [49-51]. A number of factors contribute to this deficit, particularly increased urinary
losses due both to the glucose osmotic diuresis and the excretion of potassium ketoacid anion salts
(the ketoacid anions are filtered primarily as sodium salts, but some of the sodium is reabsorbed in
the distal renal tubule in exchange for potassium as a result of volume contraction-related secondary
hyperaldosteronism). Gastrointestinal losses and the loss of potassium from the cells due to
glycogenolysis and proteolysis also may play a contributory role.
Despite these large total body potassium deficits, the serum potassium concentration is usually
normal or, in one-third of patients, elevated on admission [18,49,52]. This is mainly due to
hyperosmolality and insulin deficiency [22,49,53]. (See "Causes and evaluation of hyperkalemia in
adults".)
● The rise in plasma osmolality causes osmotic water movement out of the cells. Potassium also
moves into the ECF as a result of at least two mechanisms [46]:
• The contraction of the ICF space increases 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 (this process is called solvent drag)
● Insulin normally promotes potassium uptake by the cells. Therefore, insulin deficiency contributes
to elevated serum potassium levels.
Acidemia per se plays a small role in the shift of potassium from the ICF to the ECF in patients with
DKA. Although a transcellular exchange of potassium with hydrogen ions does increase serum
potassium in some forms of "inorganic" metabolic acidosis [54], it is less important in organic
metabolic acidoses such as ketoacidosis or lactic acidosis [49,54-56]. The important role of
hyperosmolality and insulin deficiency is illustrated by the observation that hyperkalemia also often
occurs in HHS, despite the absence of acidosis [18]. (See "Potassium balance in acid-base
disorders", section on 'Metabolic acidosis'.)
Inflammation — Hyperglycemic crises are proinflammatory states that lead to generation of reactive
oxygen species and oxidative stress. Studies have shown elevated proinflammatory cytokines
including tumor necrosis factor-alpha and interleukin (IL)-1B, IL-6, and IL-8. Lipid peroxidation
markers, as well as plasminogen activator inhibitor-1 and C-reactive protein (CRP), are also
increased [57]. Proinflammatory factors returned to near-normal levels within 24 hours of insulin
therapy and resolution of hyperglycemia. The proinflammatory state in DKA results in in vivo
activation of T-lymphocytes with de novo emergence of growth factor receptors [58].
A variety of eicosanoids, including prostaglandins, are involved in the pathogenesis of diabetes

mellitus and its complications [59]. Some are protective and others accelerate organ dysfunction,
including pancreatic beta-cell destruction. Prostaglandins accumulate during DKA, increase in the
circulation before elevation of epinephrine, and return promptly to normal levels with insulin therapy
[60,61].
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 5th to 6th 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 10th to 12th 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 topic (see "Patient education: Hyperosmolar nonketotic coma (The Basics)")
SUMMARY
● Diabetic ketoacidosis (DKA) is more common in younger patients with type 1 diabetes, though it
can occur in type 2 diabetes. HHS occurs less frequently and is associated with higher mortality,
at least in part due to underlying comorbidity. (See 'Epidemiology' above.)
● DKA and hyperosmolar hyperglycemic state (HHS) are part of a spectrum, representing the
metabolic consequences of insulin deficiency, glucagon excess, and counterregulatory hormonal
responses to stressful triggers in patients with diabetes (table 2). (See 'Spectrum of metabolic
abnormalities' above.)
● Glucose concentrations are typically lower (usually <800 mg/dL [44 mmol/L]) in DKA compared
with HHS (usually >1000 mg/dL [56 mmol/L]). Patients with DKA present earlier because of
symptoms and generally can excrete glucose more effectively than older patients with HHS. (See
'Hyperglycemia' above.)
● Hyperglycemia results from impaired glucose utilization, increased gluconeogenesis, and

increased glycogenolysis (algorithm 1). Gluconeogenesis results from delivery of precursors to
the liver from breakdown of fat and muscle and is promoted by insulin deficiency and glucagon
https://www-uptodate-com.pbidi.unam.mx:2443/contents/diabetic-ketoacidosis-and-hyperosmolar-hyperglycemic-state-in-adults-epidemiology-and-p… 10/23
excess. Glycogenolysis is stimulated by catecholamines and a high glucagon-to-insulin ratio.

Osmotic diuresis further contributes to elevated blood glucose. (See 'Hyperglycemia' above.)
● Ketoacidosis results from lipolysis, with synthesis of ketones from free fatty acids in the liver
mitochondria. Insulin levels in HHS are insufficient to allow appropriate glucose utilization but are
adequate to prevent lipolysis and subsequent ketogenesis. (See 'Ketone production' above.)
● The elevated anion gap metabolic acidosis characteristic of DKA is caused by the production and
accumulation of beta-hydroxybutyric and acetoacetic acids. The severity of the metabolic
acidosis is dependent upon a number of factors, including the rate and duration of ketoacid
production, the rate of metabolism of the ketoacids, and the rate of acid excretion in the urine.
(See 'Anion gap metabolic acidosis' above.)
● Plasma osmolality is always elevated in patients with HHS but less so with DKA (table 2). The
marked hyperosmolality seen in HHS is only in part due to the rise in serum glucose. It is also
due to the glucose osmotic diuresis that causes urine electrolyte-free water loss. These factors
also influence the measured serum sodium concentration, which is variable because of the
interaction of multiple factors, some that lower and others that raise it. (See 'Plasma osmolality
and sodium' above.)
ACKNOWLEDGMENT
The editorial staff at UpToDate would like to acknowledge Abbas Kitabchi, PhD, MD, FACP, MACE,
now deceased, who contributed to an earlier version of this topic review.
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES
1. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with
diabetes. Diabetes Care 2009; 32:1335.
2. Centers for Disease Control and Prevention, Diabetes Public Health Resource http://www.cdc.g
ov/diabetes/statistics/hospitalization_national.htm (Accessed on March 26, 2014).
3. Benoit SR, Zhang Y, Geiss LS, et al. Trends in Diabetic Ketoacidosis Hospitalizations and In-
Hospital Mortality - United States, 2000-2014. MMWR Morb Mortal Wkly Rep 2018; 67:362.
4. Fishbein HA, Palumbo PJ. Acute metabolic complications in diabetes. In: Diabetes in America,
2nd ed, National Diabetes Data Group, National Institutes of Health, Bethesda, MD Vol (NIH pu
bl. no: 95-1468), p.283.
5. Umpierrez GE, Kelly JP, Navarrete JE, et al. Hyperglycemic crises in urban blacks. Arch Intern
Med 1997; 157:669.
6. Kitabchi AE, Fisher JN, Murphy MB, Rumbak MJ. Diabetic ketoacidosis and the hyperglycemic
hyperosmolar nonketotic state. In: Joslin's Diabetes Mellitus, 13th, Kahn CR, Weir GC (Eds), Le
a & Febiger, Philadelphia 1994. p.738.
7. Pasquel FJ, Umpierrez GE. Hyperosmolar hyperglycemic state: a historic review of the clinical
presentation, diagnosis, and treatment. Diabetes Care 2014; 37:3124.
8. Wang J, Williams DE, Narayan KM, Geiss LS. Declining death rates from hyperglycemic crisis
among adults with diabetes, U.S., 1985-2002. Diabetes Care 2006; 29:2018.
9. Gaglia JL, Wyckoff J, Abrahamson MJ. Acute hyperglycemic crisis in the elderly. Med Clin North
Am 2004; 88:1063.
10. Kitabchi AE, Umpierrez GE, Murphy MB. Diabetic ketoacidosis and hyperglycemic hypersmolar
state. In: International Textbook of Diabetes Mellitus, 3rd, DeFronzo RA, Ferrannini E, Keen H,
Zimmet P (Eds), John Wiley & Sons, Chichester, UK 2004. p.1101.
11. Wachtel TJ, Silliman RA, Lamberton P. Prognostic factors in the diabetic hyperosmolar state. J
Am Geriatr Soc 1987; 35:737.
12. MacIsaac RJ, Lee LY, McNeil KJ, et al. Influence of age on the presentation and outcome of
acidotic and hyperosmolar diabetic emergencies. Intern Med J 2002; 32:379.
13. Unger RH, Orci L. Glucagon and the A cell: physiology and pathophysiology (first two parts). N
Engl J Med 1981; 304:1518.
14. Diamond MP, Hallarman L, Starick-Zych K, et al. Suppression of counterregulatory hormone

response to hypoglycemia by insulin per se. J Clin Endocrinol Metab 1991; 72:1388.
15. Philippe J. Insulin regulation of the glucagon gene is mediated by an insulin-responsive DNA
element. Proc Natl Acad Sci U S A 1991; 88:7224.
16. Rose BD, Post TW. Clinical physiology of acid-base and electrolyte disorders, 5th, McGraw-Hill,
New York 2001. p.794.
17. Barnes AJ, Bloom SR, Goerge K, et al. Ketoacidosis in pancreatectomized man. N Engl J Med
1977; 296:1250.
18. Arieff AI, Carroll HJ. Nonketotic hyperosmolar coma with hyperglycemia: clinical features,
pathophysiology, renal function, acid-base balance, plasma-cerebrospinal fluid equilibria and
the effects of therapy in 37 cases. Medicine (Baltimore) 1972; 51:73.
19. Lorber D. Nonketotic hypertonicity in diabetes mellitus. Med Clin North Am 1995; 79:39.
20. Hillman K. Fluid resuscitation in diabetic emergencies--a reappraisal. Intensive Care Med 1987;
13:4.
21. Delaney MF, Zisman A, Kettyle WM. Diabetic ketoacidosis and hyperglycemic hyperosmolar
nonketotic syndrome. Endocrinol Metab Clin North Am 2000; 29:683.
22. DeFronzo RA, Matzuda M, Barret E. Diabetic ketoacidosis: a combined metabolic-nephrologic

approach to therapy. Diabetes Rev 1994; 2:209.
23. Chupin M, Charbonnel B, Chupin F. C-peptide blood levels in keto-acidosis and in hyperosmolar
non-ketotic diabetic coma. Acta Diabetol Lat 1981; 18:123.
24. Foster DW. Banting lecture 1984. From glycogen to ketones--and back. Diabetes 1984;
33:1188.
25. Saccà L, Orofino G, Petrone A, Vigorito C. Differential roles of splanchnic and peripheral tissues
in the pathogenesis of impaired glucose tolerance. J Clin Invest 1984; 73:1683.
26. Miles JM, Haymond MW, Nissen SL, Gerich JE. Effects of free fatty acid availability, glucagon
excess, and insulin deficiency on ketone body production in postabsorptive man. J Clin Invest
1983; 71:1554.
27. McGarry JD, Woeltje KF, Kuwajima M, Foster DW. Regulation of ketogenesis and the
renaissance of carnitine palmitoyltransferase. Diabetes Metab Rev 1989; 5:271.
28. Cook GA, Nielsen RC, Hawkins RA, et al. Effect of glucagon on hepatic malonyl coenzyme A
concentration and on lipid synthesis. J Biol Chem 1977; 252:4421.
29. McGarry JD, Robles-Valdes C, Foster DW. Role of carnitine in hepatic ketogenesis. Proc Natl
Acad Sci U S A 1975; 72:4385.
30. Edgerton DS, Ramnanan CJ, Grueter CA, et al. Effects of insulin on the metabolic control of
hepatic gluconeogenesis in vivo. Diabetes 2009; 58:2766.
31. Owen OE, Trapp VE, Skutches CL, et al. Acetone metabolism during diabetic ketoacidosis.
Diabetes 1982; 31:242.
32. ZIERLER KL, RABINOWITZ D. EFFECT OF VERY SMALL CONCENTRATIONS OF INSULIN

ON FOREARM METABOLISM. PERSISTENCE OF ITS ACTION ON POTASSIUM AND FREE
FATTY ACIDS WITHOUT ITS EFFECT ON GLUCOSE. J Clin Invest 1964; 43:950.
33. Kitabchi AE, Fisher JN. Insulin therapy of diabetic ketoacidosis: Physiologic versus pharmacolo
gic doses of insulin and their routes of administration. In: Handbook of Diabetes Mellitus, Brownl
ee M (Ed), Garland ATPM, New York 1981. p.95.
34. Khardori R, Soler NG. Hyperosmolar hyperglycemic nonketotic syndrome. Report of 22 cases
and brief review. Am J Med 1984; 77:899.
35. Umpierrez GE, Smiley D, Kitabchi AE. Narrative review: ketosis-prone type 2 diabetes mellitus.
Ann Intern Med 2006; 144:350.
36. Emmett M, Narins RG. Clinical use of the anion gap. Medicine (Baltimore) 1977; 56:38.
37. Adrogué HJ, Eknoyan G, Suki WK. Diabetic ketoacidosis: role of the kidney in the acid-base
homeostasis re-evaluated. Kidney Int 1984; 25:591.
38. Owen OE, Licht JH, Sapir DG. Renal function and effects of partial rehydration during diabetic
ketoacidosis. Diabetes 1981; 30:510.
39. Fulop M. The treatment of severely uncontrolled diabetes mellitus. Adv Intern Med 1984;
29:327.
40. Adrogué HJ, Wilson H, Boyd AE 3rd, et al. Plasma acid-base patterns in diabetic ketoacidosis.
N Engl J Med 1982; 307:1603.
41. Oh MS, Carroll HJ, Goldstein DA, Fein IA. Hyperchloremic acidosis during the recovery phase
of diabetic ketosis. Ann Intern Med 1978; 89:925.
42. Oh MS, Carroll HJ, Uribarri J. Mechanism of normochloremic and hyperchloremic acidosis in
diabetic ketoacidosis. Nephron 1990; 54:1.
43. Viallon A, Zeni F, Lafond P, et al. Does bicarbonate therapy improve the management of severe
diabetic ketoacidosis? Crit Care Med 1999; 27:2690.
44. Latif KA, Freire AX, Kitabchi AE, et al. The use of alkali therapy in severe diabetic ketoacidosis.
Diabetes Care 2002; 25:2113.
45. Lu J, Zello GA, Randell E, et al. Closing the anion gap: contribution of D-lactate to diabetic
ketoacidosis. Clin Chim Acta 2011; 412:286.
46. Katz MA. Hyperglycemia-induced hyponatremia--calculation of expected serum sodium

depression. N Engl J Med 1973; 289:843.
47. Hillier TA, Abbott RD, Barrett EJ. Hyponatremia: evaluating the correction factor for
hyperglycemia. Am J Med 1999; 106:399.
48. Emmett M. Case 6: Diabetes and Acidosis. In: NephSAP: Nephrology Self-Assessment Progra
m: Fluid, Electrolyte, and Acid-Base Disturbances, Sterns RH, Emmett M (Eds), The American
Society of Nephrology 2013. Vol 12, No 3, p.191.
49. Adrogué HJ, Lederer ED, Suki WN, Eknoyan G. Determinants of plasma potassium levels in
diabetic ketoacidosis. Medicine (Baltimore) 1986; 65:163.
50. Kreisberg RA. Diabetic ketoacidosis: new concepts and trends in pathogenesis and treatment.
Ann Intern Med 1978; 88:681.
51. Abramson E, Arky R. Diabetic acidosis with initial hypokalemia. Therapeutic implications. JAMA
1966; 196:401.
52. Atchley DW, Loeb RF, Richards DW, et al. ON DIABETIC ACIDOSIS: A Detailed Study of
Electrolyte Balances Following the Withdrawal and Reestablishment of Insulin Therapy. J Clin
Invest 1933; 12:297.
53. Kitabchi AE, Murphy MB. Consequences of insulin deficiency. In: Atlas of Diabetes, 4th, Skyler
J (Ed), Springer US, New York 2012. p.39.
54. Adrogué HJ, Madias NE. Changes in plasma potassium concentration during acute acid-base
disturbances. Am J Med 1981; 71:456.
55. Fulop M. Serum potassium in lactic acidosis and ketoacidosis. N Engl J Med 1979; 300:1087.
56. Adrogué HJ, Chap Z, Ishida T, Field JB. Role of the endocrine pancreas in the kalemic
response to acute metabolic acidosis in conscious dogs. J Clin Invest 1985; 75:798.
57. Stentz FB, Umpierrez GE, Cuervo R, Kitabchi AE. Proinflammatory cytokines, markers of
cardiovascular risks, oxidative stress, and lipid peroxidation in patients with hyperglycemic
crises. Diabetes 2004; 53:2079.
58. Kitabchi AE, Stentz FB, Umpierrez GE. Diabetic ketoacidosis induces in vivo activation of
human T-lymphocytes. Biochem Biophys Res Commun 2004; 315:404.
59. Luo P, Wang MH. Eicosanoids, β-cell function, and diabetes. Prostaglandins Other Lipid Mediat
2011; 95:1.
60. McRae JR, Day RP, Metz SA, et al. Prostaglandin E2 metabolite levels during diabetic
ketoacidosis. Diabetes 1985; 34:761.
61. Li J, Huang M, Shen X. The association of oxidative stress and pro-inflammatory cytokines in
diabetic patients with hyperglycemic crisis. J Diabetes Complications 2014; 28:662.
Topic 1794 Version 15.0
GRAPHICS
Age-adjusted diabetic ketoacidosis hospitalization rate per 1000 persons

with diabetes and in-hospital case-fatality rate: United States, 2000-2014
Symbols indicate observed points; lines indicate modeled trends. All modeled trends were significant at
a p-value of <0.05.
DKA: diabetic ketoacidosis.
Reproduced from: Benoit SR, Zhang Y, Geiss LS, et al. Trends in diabetic ketoacidosis hospitalizations and in-
hospital mortality — United States, 2000–2014. MMWR Morb Mortal Wkly Rep 2018; 67:362.
Graphic 117707 Version 1.0
Pathogenesis of diabetic ketoacidosis and hyperosmolar

hyperglycemic state
DKA: diabetic ketoacidosis; HHS: hyperosmolar hyperglycemic state.

++: Accelerated pathway.
Copyright © 2006 American Diabetes Association From Diabetes Care Vol 29, Issue 12, 2006.
Reprinted with permission from The American Diabetes Association.
Predisposing or precipitating factors for diabetic ketoacidosis and hyperosmolar

hyperglycemic state
DKA HHS
Inadequate insulin treatment or Inadequate insulin treatment or noncompliance (21 to 41
noncompliance percent)
New-onset diabetes (20 to 25 percent) Acute illness
Acute illness Infection (32 to 60 percent)
Infection (30 to 40 percent) Pneumonia

Urinary tract infection
Cerebral vascular accident
Sepsis
Myocardial infarction
Cerebral vascular accident
Acute pancreatitis
Myocardial infarction
Drugs
Acute pancreatitis
Clozapine or olanzapine
Acute pulmonary embolus
Cocaine
Intestinal obstruction
Lithium
Dialysis, peritoneal
SGLT2 inhibitors
Mesenteric thrombosis
Terbutaline
Renal failure
Heat stroke
Hypothermia
Subdural hematoma
Severe burns
Endocrine
Acromegaly
Thyrotoxicosis
Cushing's syndrome
Drugs/therapy
Beta-adrenergic blockers
Calcium-channel blockers
Chlorpromazine
Chlorthalidone
Cimetidine
Clozepine
Diazoxide
Ethacrynic acid
Immunosuppressive agents
L-asparaginase
Loxapine
Olanzapine
Phenytoin
Propranolol
Steroids
Thiazide diuretics
Total parenteral nutrition
Previously undiagnosed diabetes
DKA: diabetic ketoacidosis; HHS: hyperosmolar hyperglycemic state; SGLT2: sodium-glucose co-transporter 2.
Data from: Kitabchi AE, Umpierrez GE, Murphy MB, et al. Management of hyperglycemic crises in patients with diabetes
mellitus (Technical Review). Diabetes Care 2001; 24:131.
Typical laboratory characteristics of DKA and HHS*
DKA
HHS
Mild Moderate Severe
Plasma glucose (mg/dL) >250 >250 >250 >600
Plasma glucose (mmol/L) >13.9 >13.9 >13.9 >33.3
Arterial pH 7.25 to 7.30 7.00 to 7.24 <7.00 >7.30
Serum bicarbonate (mEq/L) 15 to 18 10 to <15 <10 >18
Urine ketones ¶ Positive Positive Positive Small
Serum ketones - Nitroprusside reaction Positive Positive Positive ≤ Small
Serum ketones - Enzymatic assay of beta 3 to 4 4 to 8 >8 mmol/L <0.6 mmol/L

hydroxybutyrate (normal range <0.6 mmol/L) Δ mmol/L mmol/L
Effective serum osmolality (mOsm/kg) ◊ Variable Variable Variable >320
Anion gap § >10 >12 >12 Variable
Alteration in sensoria or mental obtundation Alert Alert/drowsy Stupor/coma Stupor/coma
DKA: diabetic ketoacidosis; HHS: hyperosmolar hyperglycemic state.

* There may be considerable diagnostic overlap between DKA and HHS.
¶ Nitroprusside reaction method.
Δ Many assays for beta hydroxybutyrate can only report markedly elevated values as >6.0 mmol/L.
◊ Calculation: 2[measured Na (mEq/L)] + glucose (mg/dL)/18.
§ Calculation: (Na+) – (Cl– + HCO3–) (mEq/L).
Copyright © 2006 American Diabetes Association. From Diabetes Care Vol 29, Issue 12, 2006. Information updated from
Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care 2009;
32:1335. Reprinted with permission from the American Diabetes Association.
Typical total body deficits of water and electrolytes in diabetic ketoacidosis and
hyperosmolar hyperglycemic state*
DKA HHS
Total water (L) 6 9
Water (mL/kg ¶) 100 100 to 200
Na + (mEq/kg) 7 to 10 5 to 13
Cl - (mEq/kg) 3 to 5 5 to 15
K + (mEq/kg) 3 to 5 4 to 6
PO 4 (mmol/kg) 5 to 7 3 to 7
Mg ++ (mEq/kg) 1 to 2 1 to 2
Ca ++ (mEq/kg) 1 to 2 1 to 2
DKA: diabetic ketoacidosis; HHS: hyperosmolar hyperglycemic state; Na +: sodium; Cl -: chloride; K +: potassium; PO 4 :
phosphate; Mg ++: magnesium; Ca ++: calcium.
* Data are from Ennis et al (1994) and Kreisberg (1978).
¶ Per kilogram of body weight.
Copyright © 2006 American Diabetes Association From Diabetes Care Vol 29, Issue 12, 2006. Reprinted with permission from
the American Diabetes Association.
Contributor Disclosures
Irl B Hirsch, MD Grant/Research/Clinical Trial Support: Medtronic [Diabetes]. Consultant/Advisory Boards:
Abbott [Diabetes]; Roche [Diabetes]; Bigfoot Biomedical [Diabetes]. Michael Emmett, MD Consultant/Advisory
Boards: AstraZeneca (Zirconium silicate). David M Nathan, MD Grant/Research/Clinical Trial Support: Abbott
[Diabetes]. Joseph I Wolfsdorf, MD, BCh Consultant/Advisory Boards: Ultragenyx DSMB [Glycogen storage
disease type 1a]. Jean E Mulder, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform to
UpToDate standards of evidence.
Conflict of interest policy

Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State in Adults Epidemiology and Pathogenesis

Încărcat de

Informații document

Titlu original

Drepturi de autor

Formate disponibile

Partajați acest document

Partajați sau inserați document

Opțiuni de partajare

Vi se pare util acest document?

Este necorespunzător acest conținut?

Drepturi de autor:

Formate disponibile

Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State in Adults Epidemiology and Pathogenesis

Încărcat de

Drepturi de autor:

Formate disponibile

29/9/2020 Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Epidemiology and pathogenesis - UpToDate

Official reprint from UpToDate®

Diabetic ketoacidosis and hyperosmolar hyperglycemic

Normal response to hyperglycemia — The hormonal regulation of glucose homeostasis is

● Insulin deficiency and/or resistance.

Although glucagon excess contributes to the development of DKA, it is not essential. As an

At least two factors contribute to less severe hyperglycemia in DKA:

● Impaired glucose utilization in peripheral tissues

Insulin deficiency and/or resistance:

The importance of glucagon in the development of hyperglycemia and ketoacidosis in uncontrolled

● Enter the ketogenic metabolic path to form acetoacetic acid

Serum anion gap = serum sodium - (serum chloride + bicarbonate)

● The rate and duration of ketoacid production

A variety of eicosanoids, including prostaglandins, are involved in the pathogenesis of diabetes

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

● Hyperglycemia results from impaired glucose utilization, increased gluconeogenesis, and

excess. Glycogenolysis is stimulated by catecholamines and a high glucagon-to-insulin ratio.

Use of UpToDate is subject to the Subscription and License Agreement.

14. Diamond MP, Hallarman L, Starick-Zych K, et al. Suppression of counterregulatory hormone

22. DeFronzo RA, Matzuda M, Barret E. Diabetic ketoacidosis: a combined metabolic-nephrologic

32. ZIERLER KL, RABINOWITZ D. EFFECT OF VERY SMALL CONCENTRATIONS OF INSULIN

46. Katz MA. Hyperglycemia-induced hyponatremia--calculation of expected serum sodium

Topic 1794 Version 15.0

Age-adjusted diabetic ketoacidosis hospitalization rate per 1000 persons

DKA: diabetic ketoacidosis.

Graphic 117707 Version 1.0

Pathogenesis of diabetic ketoacidosis and hyperosmolar

DKA: diabetic ketoacidosis; HHS: hyperosmolar hyperglycemic state.

Graphic 78145 Version 4.0

Predisposing or precipitating factors for diabetic ketoacidosis and hyperosmolar

New-onset diabetes (20 to 25 percent) Acute illness

Acute illness Infection (32 to 60 percent)

Infection (30 to 40 percent) Pneumonia

Total parenteral nutrition

Previously undiagnosed diabetes

Graphic 64374 Version 5.0

Typical laboratory characteristics of DKA and HHS*

Plasma glucose (mg/dL) >250 >250 >250 >600

Plasma glucose (mmol/L) >13.9 >13.9 >13.9 >33.3

Arterial pH 7.25 to 7.30 7.00 to 7.24 <7.00 >7.30

Serum bicarbonate (mEq/L) 15 to 18 10 to <15 <10 >18

Urine ketones ¶ Positive Positive Positive Small

Serum ketones - Nitroprusside reaction Positive Positive Positive ≤ Small

Serum ketones - Enzymatic assay of beta 3 to 4 4 to 8 >8 mmol/L <0.6 mmol/L

Effective serum osmolality (mOsm/kg) ◊ Variable Variable Variable >320

Anion gap § >10 >12 >12 Variable

Alteration in sensoria or mental obtundation Alert Alert/drowsy Stupor/coma Stupor/coma

DKA: diabetic ketoacidosis; HHS: hyperosmolar hyperglycemic state.

Graphic 72111 Version 8.0

Total water (L) 6 9

Water (mL/kg ¶) 100 100 to 200

Graphic 76060 Version 6.0

Conflict of interest policy

S-ar putea să vă placă și