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Epidemiology and pathogenesis of diabetic ketoacidosis and hyperosmolar hyperglycemic state Author

Abbas E Kitabchi, PhD, MD, FACP, FACE

Section Editors

David M Nathan, MD

Joseph I Wolfsdorf, MB, BCh

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: Feb 2012. | This topic last updated: Mar 4, 2011.

INTRODUCTION — Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state

(HHS, also called 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 epidemiology and pathogenesis of DKA and HHS will be discussed here. The clinical

features, diagnosis, and treatment of these disorders are discussed separately. (See

"Clinical features and diagnosis of diabetic ketoacidosis and hyperosmolar hyperglycemic

state in adults" and "Treatment of diabetic ketoacidosis and hyperosmolar hyperglycemic

state in adults".)

EPIDEMIOLOGY — Diabetic ketoacidosis 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) diabetic patients and in women compared to

men [1-3]. The National Diabetes Surveillance Program of the Centers for Disease Control

(CDC) estimated that there were 120,000 hospital discharges for DKA in 2005 in the United

States, compared to 62,000 in 1980 (figure 1) [4]. On the other hand, DKA mortality per

100,000 diabetic patients declined between 1985 and 2005 with the greatest reduction in

mortality among those 65 years of age and older (figure 2) [5]. Mortality in DKA is primarily

due to the underlying precipitating illness and only rarely to the metabolic complications of

hyperglycemia or ketoacidosis [1]. The prognosis of DKA is substantially worse at the

extremes of age and in the presence of coma and hypotension [6-9].

Population-based data are not available for HHS. It is estimated that 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 [1,10-12]. HHS is most commonly seen in individuals older

than 65 years with type 2 diabetes [1,10]. Mortality attributed to HHS is higher than that of

DKA, with rates ranging from 5 to 20 percent; as in DKA, mortality is most often due to the

underlying illness or comorbidity [1,3,10,11,13,14].

PATHOGENESIS — Two hormonal abnormalities are largely responsible for the

development of hyperglycemia and ketoacidosis in patients with uncontrolled diabetes [15]:

Insulin deficiency and/or resistance.

Glucagon excess, which may result from removal of the normal suppressive effect of

insulin [16,17]. There is no evidence for defective pancreatic alpha cell function in

diabetes, since there is a normal glucagon response to nonhypoglycemic stimuli,

such as arginine [18,19].

Although glucagon excess contributes to the development of DKA, it is not required. 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.

In addition to these primary factors, increased secretion of catecholamines and cortisol can

contribute to the increases in glucose and ketoacid production.

Normal response to hyperglycemia — The hormonal regulation of glucose homeostasis

is discussed in detail elsewhere. (See "Insulin secretion and pancreatic beta-cell

function" and "Insulin action" and "Physiologic response to hypoglycemia in normal subjects

and patients with diabetes mellitus".)

Summarized briefly, the extracellular supply 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 acts to 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

[16,17,20].

Precipitating factors — Both DKA and HHS are usually precipitated by stresses that act in

part by increasing the secretion of glucagon, catecholamines, and cortisol. Infection, such as

pneumonia, gastroenteritis, and urinary tract infection, can be found in 40 to 50 percent of

patients with hyperglycemic crisis; other stresses include pancreatitis, myocardial infarction,

stroke, trauma, and alcohol and drug abuse [21-23].

The mistaken omission of insulin in the setting of an acute illness, especially with

gastroenteritis; failure to appropriately augment insulin; and dehydration with inability to

replenish water intake, are common precipitants of a hyperglycemic crisis (table 1). (See

"Clinical features and diagnosis of diabetic ketoacidosis and hyperosmolar hyperglycemic

state in adults", section on 'Precipitating factors'.)

Spectrum of hyperglycemic crises — The basic mechanism underlying both DKA and

HHS is reduction in the net effective action of circulating insulin, with concomitant elevation

of counterregulatory hormones, primarily glucagon, but also catecholamines, cortisol, and

growth hormone (figure 3) [1,7-9,13,15,17-19,24-27].

The deficiency in insulin (absolute deficiency, or relative to excess counterregulatory

hormones) is more severe in DKA compared to HHS. The residual insulin secretion in HHS is

sufficient to minimize ketosis but does not control hyperglycemia [28].

DKA and HHS are two extremes in the spectrum of hyperglycemic crisis and patients can fall

anywhere along the disease continuum of diabetic metabolic derangement (table 2). (See

"Clinical features and diagnosis of diabetic ketoacidosis and hyperosmolar hyperglycemic

state in adults", section on 'Definitions'.)

The serum glucose concentration in HHS frequently exceeds 1000 mg/dL (56 mmol/L), but

in DKA is generally below 800 mg/dL (44 mmol/L) [29].

At least two factors contribute to the lesser degree of hyperglycemia in DKA:

Patients with DKA often present early with symptoms of ketoacidosis (such as

shortness of breath and abdominal pain), rather than late with symptoms due to

hyperosmolality.

Patients with DKA tend to be young and to have a glomerular filtration rate that, at

least in the first five years of diabetes, 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".)

Hyperglycemia — Hormonal alterations in DKA and HHS result in hyperglycemia by their

impact on three fundamental processes in glucose metabolism (figure 3) [1,8,9,24,26-

28,30-32]:

Impaired glucose utilization in peripheral tissues

Increased gluconeogenesis (both hepatic and renal)

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; increased gluconeogenesis is required for the often severe

fasting hyperglycemia seen in DKA and HHS.

Insulin deficiency and/or resistance promote hepatic gluconeogenesis by two mechanisms:

increased delivery of gluconeogenetic precursors (glycerol and alanine) to the liver due to

increased fat and muscle breakdown [15,33,34]; and increased secretion of glucagon by

removal of the inhibitory effect of insulin on glucagon secretion and the glucagon gene

[16,17,20,35].

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 [16].

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 [36]. After withdrawal of insulin, there was a

sharp increase in serum glucagon in the patients with type 1 diabetes. Compared to

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 meq/L) at 12 hours. (See 'Ketoacidosis' below.)

The glucosuria associated with DKA and HHS initially minimizes the rise in serum glucose.

However, the osmotic diuresis caused by glucosuria leads to volume depletion and a

reduction in glomerular filtration rate that limits further glucose excretion [14,29,31,32].

This effect is more pronounced in HHS which, as noted above, is usually associated with a

higher serum glucose than seen in DKA [29]. (See 'Spectrum of hyperglycemic crises' above

and "Clinical features and diagnosis of diabetic ketoacidosis and hyperosmolar

hyperglycemic state in adults", section on 'Importance of osmotic diuresis'.)

Ketoacidosis — Both insulin deficiency and glucagon excess contribute to the genesis of

DKA [33,36,37]. As noted above, however, glucagon is not required for DKA to occur.

Acetoacetic acid is the initial ketone formed; it may then be reduced to beta-hydroxybutyric

acid, which is also an organic acid, or nonenzymatically decarboxylated to acetone, which is

chemically neutral [38]. Ketones provide an alternate source of energy when glucose

utilization is impaired.

Insulin deficiency and increased catecholamine lead to enhanced lipolysis, thereby

increasing free fatty acid delivery to the liver [15,33,37]. Normal subjects will convert these

free fatty acids primarily into triglycerides. The development of ketoacidosis requires a

specific alteration in hepatic metabolism so that free fatty acyl CoA can enter the

mitochondria, where conversion to ketones occurs [15,33].

Mitochondrial entry is regulated by the cytosolic enzyme carnitine palmitoyltransferase I

(CPT I), the activity of which varies inversely with malonyl CoA [33,39-41]. Glucagon

decreases the production of malonyl CoA, thereby increasing CPT I activity and ketogenesis

[33,42]. A concurrent increase in hepatic carnitine content contributes to this process [43].

Insulin does not appear to directly affect hepatic ketogenesis [37].

In states of insulin deficiency, the combination of increased free fatty acid delivery and

glucagon excess promotes ketogenesis [37]. In the study comparing pancreatectomized and

type 1 diabetic patients cited above, there was a marked increase in serum glucagon after

insulin withdrawal in the patients with type 1 diabetes, associated with a significantly

increased blood ketone concentration at twelve hours [36].

The factors responsible for the general absence of ketoacidosis in HHS are incompletely

understood. One important factor may be the differential sensitivity of fat and glucose 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 [44]. Thus, moderate insulin deficiency, as seen in HHS, might be associated with

sufficient insulin to block lipolysis (and therefore ketoacid formation) but not enough to

promote glucose utilization and prevent the development of hyperglycemia [30]. More

severe insulin deficiency will also be associated with ketoacidosis.

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 [15,28,45].

However, this distinction is not absolute since DKA can occur in patients with type 2

diabetes. This most often occurs in obese African Americans, but has also been described in

Caucasians, Hispanics, and other populations [46]. (See "Syndromes of ketosis-prone

diabetes mellitus".)

Inflammation — Hyperglycemic crises are proinflammatory states that lead to generation

of reactive oxygen species, which are indicators of oxidative stress. Studies have shown

elevation of the pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin (IL)-1B,

IL-6, and IL-8 and lipid peroxidation markers, as well as plasminogen activator inhibitor-1

and C-reactive protein (CRP) [47]. Proinflammatory factors returned to near normal levels

within 24 hours of insulin therapy and remission of hyperglycemia. The proinflammatory

state in DKA results in in vivo activation of T-lymphocytes with de novo emergence of

growth factor receptors [48].

SUMMARY

Diabetic ketoacidosis (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. (See 'Introduction' above.)

DKA is more common in younger patients with type 1 diabetes, though can occur in

type 2 diabetes. HHS occurs less frequently, and is associated with higher mortality,

representing underlying comorbidity. (See 'Epidemiology' above.)

Hyperglycemia results from impaired glucose utilization, increased gluconeogenesis

and increased glycogenolysis (figure 3). Gluconeogenesis results from delivery of

precursors to the liver from breakdown of fat and muscle, and is promoted by insulin

deficiency and glucagon excess. Glycogenolysis is stimulated by catecholamines and

a high glucagon to insulin ratio. Osmotic diuresis further contributes to elevated

blood glucose. (See 'Hyperglycemia' above.)

Glucose concentrations are most often lower (usually <800 mg/dL [44 mmol/L]) in

DKA compared to HHS. Patients with DKA present earlier, because of symptoms, and

generally can excrete glucose more effectively than older patients with HHS. (See

'Spectrum of hyperglycemic crises' 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 'Ketoacidosis' above.)

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Topic 1794 Version 2.0

GRAPHICS

Number (in thousands) of hospital discharges with diabetic ketoacidosis as first-listed diagnosis, United States, 1980-2005

The number of hospital discharges with diabetic ketoacidosis (DKA) as the first-listed

diagnosis increased between 1980 and 2005, with about 62,000 discharges in 1980 with

DKA as the first-listed diagnosis and about 120,000 in 2005. Reproduced from: Centers for

Disease Control and Prevention: Diabetes Data & Trends. Retreived from http://www.cdc.gov/diabetes/statistics/dkafirst/fig1.htm on March 1, 2011.

Age-adjusted death rates for diabetic hyperglycemic crises as underlying cause per 100,000 general population, United States, 1980-

2005

Between 1980 and 2005, the age-adjusted death rate for hyperglycemic crises in the

general population declined. In 2005, the age-adjusted death rate for hyperglycemic crises

was 0.8 per 100,000 general population, almost half the rate in 1980 (1.5 per 100,000). Reproduced from: Centers for Disease Control and Prevention: Diabetes Data & Trends. Retreived from http://www.cdc.gov/diabetes/statistics/mortalitydka/ fRateDKAGenAgeAdjusted.htm on February 23, 2011.

Predisposing or precipitating factors for DKA and HHS

DKA

Inadequate insulin treatment or

noncompliance

New onset diabetes (20-25 percent)

Acute illness

Infection (30-40 percent)

Cerebral vascular accident

Myocardial infarction

Acute pancreatitis

Drugs

Clozapine or olanzapine

Cocaine

Lithium

Terbutaline

HHS

Inadequate insulin treatment or noncompliance (21-41 percent)

Acute illness

Infection (32-60 percent)

Pneumonia

Urinary tract infection

Sepsis

Cerebral vascular accident

Myocardial infarction

Acute pancreatitis

Acute pulmonary embolus

Intestinal obstruction

Dialysis, peritoneal

Mesenteric thrombosis

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

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.

Pathogenesis of DKA and HHS

++: Accelerated pathway. Copyright © 2006 American Diabetes Association From Diabetes Care Vol 29, Issue 12, 2006. Reprinted with permission from The American Diabetes Association.

Diagnostic criteria for diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS)

DKA

HHS Mild Moderate Severe

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

Arterial pH 7.25-7.30

7.00-7.24 <7.00 >7.30

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

Urine ketones* Positive Positive Positive Small

Serum ketones* Positive Positive Positive Small

Effective serum osmolality (mOsm/kg)•

Variable Variable Variable >320

Anion gapΔ >10 >12 >12 Variable

Alteration in sensoria or mental

obtundation

Alert Alert/drowsy Stupor/coma Stupor/coma

* Nitroprusside reaction method.

• Calculation: 2[measured Na (mEq/L)] + glucose (mg/dL)/18.

Δ Calculation: (Na+) - (Cl- + HCO3-) (mEq/L). See text for details. 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.

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