Diabetic Ketoacidosis (DKA) and Hyperglycemic Hyperosmolar State (HHS)

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Hyperglycemic Crises in Diabetes Mellitus,

Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State

Abbas E. Kitabchi, Ph.D., M.D.

Monday, December 14, 2009, 8:00-8:50am


Diabetic Ketoacidosis (DKA) and Hyperglycemic Hyperosmolar State (HHS)

1. Be able to define the diagnostic criteria and typical total body deficit of water and electrolytes in DKA and HHS.

2. Know the precipitating factors of development of DKA and HHS.

3. Be able to calculate serum osmolality on the basis of serum glucose, sodium and BUN. 4. Understand the pathophysiology of DKA and HHS, which leads to abnormality of

proteins, fat and CHO metabolism.

5. Understand how the above leads to polyuria, polydipsia, polyphagia, loss of electrolytes, dehydration, weight loss and coma.

6. Understand which metabolic pathways are altered in DKA and HHS (i.e., gluconeogenesis, glycolysis, lipolysis, lipogenesis, protein synthesis, ketogenesis, etc.) based on the state of insulin deficiency.

7. Be able to differentiate, biochemically, the pathogenesis of DKA versus HHS. HYPERGLYCEMIC CRISES IN DIABETES MELLITUS (DM)

Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) are the two most serious acute complications of diabetes mellitus and continue to be important causes of morbidity and mortality among patients with diabetes mellitus. Diabetic ketoacidosis accounts for 8 - 29% of all admission with primary diagnosis of diabetes to the hospital. The annual incidence of DKA is about 3 - 8 episodes per 1,000 patients admitted with diabetes, which may be increasing. The rate of hospital admissions for HHS is lower than DKA and is less than 1% of all diabetic-related admissions.

Although DKA and HHS are often discussed as separate entities, they represent points along a spectrum of emergencies caused by poorly controlled diabetes. Both DKA and HHS are characterized by effective insulinopenia, and clinically, they differ only by the magnitude of dehydration and the severity of metabolic acidosis. Diabetic ketoacidosis most often occurs in patients with Type 1 DM, but patients with Type 2 DM are also susceptible to DKA under certain conditions. Similarly, whereas HHS occurs most commonly in patients with Type 2 DM it also can be seen with Type 1 DM in conjunction with DKA. Table 1 summarizes biochemical criteria for DKA and HHS as well as water and electrolyte deficits in these two conditions. It also provides a simple method for


calculating serum osmolality from serum Na, BUN and glucose data.Table 2 provides data on water and electrolyte deficits in DKA and HHS.

TABLE 1. Diagnostic Criteria for Diabetic Ketoacidosis (DKA) and Hyperglycemic Hyperosmolar Syndrome (HHS)

Diagnostic Criteria and Classification


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 - < 15 < 10 > 15

Urine ketone * Positive Positive Positive Small

Serum ketone* Positive Positive Positive Small

Anion gap†† >12 >12 >12 Variable

Effective Serum

Osmolality (mOsm/kg)** Variable Variable Variable > 320

Alteration in sensorium

or mental obtundation Alert Alert/Drowsy Stupor/Coma Stupor/Coma

* Nitroprusside reaction method

** Calculation: Effective serum osmolality: 2[measured Na (mEq/L)] + glucose (mg/dl)/18 = mOsm/kg H20

Calculation: Total serum osmolality:

Serum Na (mEq/L) x 2 + Serum glucose (mg/dl) + BUN (mg/dl) = mOsm/kg H20

18 2.8



TABLE 2. Typical Total Body Deficits of Water & Electrolytes in DKA & HHS DKA HHS Water (L) 6 9 Water (ml/kg)# 100 100 - 200 Na+ (mEq/kg) 7 - 10 5 - 13 K+ (mEq/kg) 3 - 5 4 - 6 PO4 (mmol/kg) 1.0 1.0 #

Per kilogram of body weight

Pathophysiology of DKA and HHS

DKA is a syndrome complex consisting of hyperglycemia, ketosis, and acidosis, each of which is independently associated with other conditions as depicted in Figure 1. Table 3 provides information on precipitating factors for DKA and HHS.


Conditions Associated with Hyperglycemic, Metabolic Acidosis, and Ketosis in Addition to Diabetic Ketoacidosis

Other Hyperglycemic States

Diabetes Mellitus

Hyperglycemic Hyperosmolar State Impaired Glucose Tolerance Stress Hyperglycemia

Other Metabolic Acidotic States

Lactic Acidosis

Hyperchloremic Acidosis Drug-induced Acidosis Uremia

Other Ketotic States

Alcoholic Ketoacidosis Starvation Ketosis Ketotic Hypoglycemia


Hyperglycemia Acidosis Ketosis


Precipitating factors in DKA and HHS

Although both conditions occur as the result of ineffective insulin concentrations, precipitating events leading to DKA and HHS may be different, as summarized in Table 3.


Precipitating Factors for Development of Diabetic Ketoacidosis (DKA) and Hyperglycemic Hyperosmolar State (HHS)

% of Admissions

Precipitating Factor DKA HHS

Infection 35 60 Pneumonia 18 35 Septicemia 9 5 Urosepsis 5 5 Abscess 3 10 Gastroenteritis ... 5 New-onset diabetes 30 33 Discontinued insulin 20 ... Unknown/miscellaneous 15 7

The basic underlying defect leading to DKA or HHS is an absolute or relative deficiency of insulin. This “lack” of insulin results in the failure of glucose to enter insulin-sensitive tissues (e.g., muscle, liver, adipose tissue) and failure of gluconeogenesis to be suppressed in liver. Since the insulin-sensitive tissues are in fact “starved” of glucose (in spite of plenty of glucose in the circulation), the organism recognizes this alteration as “hypoglycemia’ and responds hormonally similarly to that of stress of hypoglycemia [i.e., elevation of counterregulatory hormones (catecholamines, glucagon) and other hormones such as ACTH, GH, and cortisol]. The patterns of these hormonal responses were depicted in Figures 8 & 9 (Chapter 13) for insulin-induced hypoglycemia and fasted state, which were presented in previous section under pancreatic hormones (Figures 8 & 9, Chapter 13). Of note is suppression of endogenous insulin secretion (as demonstrated by decreased C-peptide) in response to exogenous insulin injection in normal subjects with an intact pancreas (Figure 8, Chapter 13). In DKA, of course, C peptide is nil and responses of counterregulatory hormones are more severe.


Intermediary Metabolism in DKA

DKA is characterized by severe alterations in the metabolism of carbohydrate, protein, and lipid, mainly as a result of lack, ineffectiveness or deficiency of insulin with concomitant elevations of counterregulatory hormones (glucagon, catecholamines, GH and cortisol). As such, hyperglycemia and lipolysis play central roles in the genesis of this metabolic decomposition.

Figure 2 depicts the metabolism of glucose, fatty acids, and amino acids in the major insulin sensitive tissues, liver, muscle, and fat, in the fed state (2a). The major hormone of the fed state is insulin, which facilitates utilization of glucose, FFA and amino acids in these tissues to high energy compounds after feeding. The metabolic pathways, however, are altered in the fasted state or super fasted state, which resemble DKA (2b). In this situation, the hormones of fasted state (i.e. stress hormones – cortisol, catecholamines, glucagon, and growth hormone) are increased while concentration of insulin in blood is minimal. This in effect is the state of alarm reaction when the body produces more glucose to ensure adequate fuel for the brain, which is insulin insensitive tissue and does not require insulin for its glucose utilization.

Figure 2 Glucose Amino Acids Proteins CO2

Free Fatty Acids

Triglycerides Epinephrine Ketone Bodies Glucagon Alpha Cell Ketogenesis Glycogenolysis Gluconeogenesis Brain Cell Liver Cell Glucose Pancreatic Islet Cells Glycogen Protein Amino Acids Insulin Beta Cell Protein Glycogen

Glucose Muscle Cell Free Fatty Acids

Fat Cell Triglycerides 2a. Fed State 2b. Fasting State or DKA

Normal mechanisms of glucose regulation can maintain supply to the brain when the body has been deprived of caloric intake for days, even weeks. In the fed state (left), assimilation of metabolic fuels and substrates is promoted by insulin in tissues sensitive to the hormone. In the DKA state (right), counterregulatory hormones (notably glucagon and epinephrine) reverse these processes, promoting proteolysis, lipolysis and glycogenolysis,


thus creating substrates for ketogenesis and gluconeogenesis. Shunting of glucose from insulin-sensitive tissues preserves it for the brain.

The process of fasted state (DKA) involves greater amount of glucose production (hyperglycemia) through increased gluconeogenesis, glycogenolysis, and decreased glucose utilization by liver, muscle and fat. Increased FFA production through lipolytic action of catecholamines leads to increased ketogenesis and acidosis. Decreased insulin and increased cortisol result in decreased protein synthesis and increased proteolysis with increased production of amino acids, which serve as substrates for gluconeogenesis. These events are depicted in Figure 3. In HHS there is enough residual insulin in the body to prevent ketogenesis but not enough to promote glucose utilization in fasted or DKA. Figure 3

Substrate Utilization in Fed, Fasted, and Diabetic Ketoacidosis (DKA)

Catecholamines, in the absence of effective insulin concentration, promote triglyceride breakdown (lipolysis) to free fatty acids (FFA) and glycerol, the latter providing carbon skeletons and the former providing reduced equivalence for gluconeogenesis. Gluconeogenesis (glucose production from noncarbohydrate precursors) is specifically stimulated as a result of increased glucagon and decreased insulin levels, which results in stimulation of the rate-limiting enzyme of gluconeogenesis, phosphoenol pyruvate carboxykinase (PEPCK) and the other three enzymes depicted in Figure 4. Hyperglycemia, therefore, is brought about primarily by increased gluconeogenesis, but also by accelerated conversion of glycogen to glucose (glycogenolysis) and by inadequate


utilization of glucose by peripheral tissues as a result of insulinopenia. The latter is further exaggerated by increased levels of circulating catecholamines and FFA.

The beta oxidation of the accumulated FFA leads to increased ketone body formation, as well as to conversion of FFA to very low-density lipoprotein (VLDL) by the liver. Severe hypertriglyceridemia may be evident clinically as lipemia retinalis. Ketogenesis is further enhanced by decreased concentrations of malonyl Coenzyme A (CoA), which occurs as a result of the increased ratio of glucagon to insulin levels in DKA. Malonyl CoA inhibits carnitine palmitoyl acyl transferase (CPT1), the rate-limiting enzyme of ketogenesis; therefore, reduction in malonyl CoA leads to stimulation of CPT1 and effective increase in ketogenesis. The insulin-sensitive tissues, therefore, alter their normal intermediary metabolism from a carbohydrate metabolizing mode to a fat metabolizing mode (which is characterized in the DKA system) (see Figures 2 and 3).

Biochemical alterations in these three pathways (fat, protein, carbohydrate) for DKA are depicted in Figure 4. As stated previously, hyperglycemia results from increased glycogen breakdown (glycogenolysis) and gluconeogenesis in the liver, as well as decreased glucose utilization by muscle and fat tissues. However, the major cause of hyperglycemia in DKA is increased gluconeogenesis. Hyperglycemia results in glycosuria and subsequent polyuria (osmotic diuresis), polydipsia, and polyphagia (as a result of glucose loss and therefore calorie loss in the urine) with progressive loss of fluid and electrolytes. These events lead to weight loss and severe dehydration and death, if not corrected promptly.

Increased lipolysis (conversion of triglycerides to FFA) results in increased FFA. Increased provision of this substrate further stimulates its beta oxidation and conversion to ketone bodies (ketogenesis). These ketoacids are buffered by extracellular and cellular buffers, resulting in their loss and development of metabolic acidosis. Increased proteolysis and decreased protein synthesis (as a result of excessive cortisol and decreased insulin) also bring about increased amino acids release, which serve as major substrates for gluconeogenesis.


Figure 4: Mitochondria TCA Cycle Citrate PEPCK Oxaloacetate PC Pyruvate PEP Pyruvate Kinase

Liver and Kidney

Insulin Deficiency


GH Glucagon Catecholamines Cortisol Protein Kinase Lipase Triacylglycerol (Hyperlipidemia)

Fatty Acyl CoA

+ CoA + ATP TG Adipocytes


HK PFK PK Glycolysis Citrate Synthetase F-6-P PFK Triose PO4 F 1, 6, biphosphate F 1, 6, biphosphatase G–6-Phosphatase Glucose Ketogenesis CAT1 Fatty acyl carnitine

Mal CoA Phosphorylase HMP Shunt Glycogen G – 1 – P G – 6 – P

Proposed biochemical changes that occur during diabetic ketoacidosis. These alterations lead to increased gluconeogenesis and lipolysis and decreased glycolysis. ATP = adenosine triphosphate. CoA = coenzyme A; FFA = free fatty acids; F-6-P = fructose-6-phosphate; G-(X)-P = glucose-(X)-fructose-6-phosphate; HK = hexokinase; HMP = hexose monophosphate; PC = pyruvate carboxylase; PFK = phosphofructokinase; PEP = phosphoenolpyruvate; PEPCK = PEP carboxykinase; PK = pyruvate kinase; TCA = tricarboxylic acid; TG = triglycerides. NOTE: Lipolysis occurs mainly in adipose tissue. Other events occur primarily in the liver (except some gluconeogenesis in the kidney).


There are important biochemical differences between DKA and HHS which are summarized in Table 4. Figure 5 also differentiates between pathogenesis of DKA and HHS.

TABLE 4. Admission Biochemical Data in Patients with Hyperglycemic Hyperosmolar State (HHS) or

Diabetic Ketoacidosis (DKA) †

Mean ± SEM

Parameters Measured HHS (n=12) DKA (n=22)

Glucose (mg/dL) 930 ± 83 616 ± 36 Na+ (mEq/L) 149 ± 3.2 134 ± 1.0 K+ (mEq/L) 3.9 ± 0.2 4.5 ± 0.13 BUN (mg/dL) 61 ± 11 32 ± 3 Creatinine (mg/dL) 1.4 ± 0.1 1.1 ± 0.1 PH 7.3 ± 0.03 7.12 ± 0.04 Bicarbonate (mEq/L) 18 ± 1.1 9.4 ± 1.4 3- -hydroxybutyrate (mM) 1.0 ± 0.2 9.1 ± 0.85 Total Osmolality* 380 ± 5.7 323 ± 2.5 IRI (nM) 0.08 ± 0.01 0.07 ± 0.01 C-peptide (nM) 1.14 ± 0.1 0.21 ± 0.03 FFA (nM) 1.5 ± 0.19 1.6 ± 0.16

Human growth hormone (ng/ml) 1.9 ± 0.2 6.1 ± 1.2

Cortisol (ng/ml) 570 ± 49 500 ± 61

IRI (nM)** 0.27 ± 0.05 0.09 ± 0.01

C-peptide (nM)** 1.75 ± 0.23 0.25 ± 0.05

† Data are from Chupin et al (99). IRI = immunoreactive insulin. * According to the formula: 2(Na + K) + urea (mM) + glucose (mM). ** Values following intravenous administration of tolbutamide.

As stated earlier, the pathophysiology of DKA and HHS are very closely parallel to that of alarm reactions such as stress, starvation, injury and burns, in which the body marshals all of its defenses to provide adequate glucose in order to protect the brain against hypoglycemia. But the major differences between DKA and HHS are that in HHS: 1) there is more pancreatic reserve [(i.e. insulin), which is enough to prevent lipolysis (as it takes 1/10 as much insulin to suppress lipolysis but not enough to stimulate utilization of glucose)] than in DKA; 2) greater dehydration in HHS than in DKA and 3) possible smaller increases in counterregulatory hormones in HHS than in DKA. Table 4 summarizes laboratory characteristics of these two conditions. NOTE: Comparative level of pancreatic reserve for insulin (as defined by C-peptide) in DKA and HHS (which is much higher in HHS than in DKA). These events are depicted in Figure 5.


Figure 5

Pathogenesis of DKA and HHS

Stress, Infection and / or insufficient insulin intake

Glucagon Catecholamines Cortisol Growth Hormone




Relative Insulin


Lipolysis FFA to liver Ketogenesis Alkali Reserve Ketoacidosis



Absent or minimal ketogenesis Proteolysis Protein Synthesis GluconeogenicSubstrates Gluconeogenesis Glycogenolysis Hyperglycemia

Glycosuria (Osmotic Diuresis) Loss of Water and electrolytes Dehydration

Impaired Renal Function


Decreased Fluid ntake



Glucose Utilization



Liver Peripheral Adipose Liver

Tissue Tissue

Increased Decreased Released Increased

Hepatic Glucose FFA Ketogenesis

Glucose Utilization



Osmotic Diuresis Decreased Alkali Reserve

Volume Depletion Metabolic Acidosis

Figure 6 provides a simplified diagram to differentiate the two different mechanisms, one leading to hyperglycemia and one to ketoacidosis.

Hyperglycemic hyperosmolar state (HHS) most commonly occurs in older individuals with type 2 diabetes mellitus. It is life-threatening, as the mortality rate exceeds 50% in most series compared to 5 - 10% for DKA. There are many precipitating factors for HHS, including the use of therapeutic agents or procedures that may induce hyperglycemia, and a variety of acute and chronic diseases and conditions, in particular infections. Common features include severe hyperglycemia (blood glucose > 600 mg/dl and often much higher), absent or minimal ketosis, extreme dehydration, and plasma or serum hyperosmolality greater than 330 mOsm per kg of water.

DIFFERENTIAL DIAGNOSIS: Patients may present with metabolic conditions resembling DKA or HHS, which emphasizes the need for laboratory and physical evaluation to assess the metabolic causes of various acidoses and comas. Therefore, in alcoholic ketoacidosis (AKA), total ketone bodies are much greater than in DKA with a higher beta-hydroxybutyrate to acetoacetate ratio of 7:1 versus a ratio of 3:1 in DKA. The AKA patients seldom present with hyperglycemia. It is also possible that patients with a low intake of food will present with mild ketoacidosis (starvation ketosis). However, this may not occur in individuals on prolonged fasting unless they have a problem with ketone metabolism. Thus, patients with starvation ketosis rarely present with serum bicarbonate concentration less than 18, and do not exhibit hyperglycemia. Additionally, DKA has to be distinguished from high anion gap acidoses including lactic acidosis, advanced chronic renal failure as well as ingestion of drugs such as salicylate, methanol and ethylene glycol. These conditions have been reviewed and the laboratory findings are presented in Table 5.


Myoglo bin-Uria Hemoglo bin-Uria + serum levels Salycilate serum levels + Serum BUN>200 mg/dl lactate >7 mmol/l F alse + Miscella neous Ne gativ e Negative Ne gativ e ++ Negative Negative † Negative Negative Negative ++ Negative Glycosuria^ Normal Normal Normal Normal Normal Normal Normal Mild Uric Acid Normal or slight Normal >330 mOsm/k g Normal Normal Normal Normal Osmolality Normal Normal or Slight Normal Slight Slight Anion gap Normal Normal or slight Normal or slight Normal Normal Slight to Moderate Normal Normal Slight Total plasma Ketones * Normal <30 mg/dl >500 mg/dl Normal Normal or Or Normal Normal Normal Normal Plasma glucose Normal Mild Maybe Normal Normal Mild Normal pH

Iso pro pyl alcoho l Rha bdo mylysis

Hypo-Glycemic coma Hyper-osmolar coma Methanol or ethyleneglycol intoxication Salicylate intoxication Alchoholi c Ketosis Uremic acidosis Lactic acidosis DKA Starvation or high fat intake

+, positive; *Acetest and Ketostix measure acetoacetic acid only: thus, misleading low values may be obtained because the majority of "ketone bodies” are -hydroxybutyrate:

†respiratory alkalosis/metabolic acidosis; ^may get false-positive or false-negative urinary glucose caused by the presence of salicylate or its metabolites; Adapted from Morris and Kitabchi, 1982


Figure 7:

Mortality Rates for Hyperglycemic Crises as Underlying Cause, United States

Number of Deaths per annum

DKA Death Rates by Age

Overall 2006 mortality rate for DKA: 0.41%

Figure 8: Hospitalization Cost of DKA

Hospitalization Charges – US estimated at $2.4 billion in 2006 -500,000 1,000,000 1,500,000 2,000,000 2,500,000 3,000,000 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006

DKA Total Annual

Hospitalization Charges, $ ('000s)

Key Statistics (Source: HCUP) - 2006

- Number of DKA episodes 136,510

- Mean Length of Stay 3.5 days

- Mean charges per episode $17,559 - Total DKA-related


Case #1

A 50-year-old male minister brought his daughter (age 14) for care and study to the Clinical Research Center. A maternal and paternal grandparent had diabetes and obesity. Her father volunteered to have an oral glucose tolerance test (OGTT) after three days of high carbohydrate (150 - 300gm) intake. His medical history was negative except he was sedentary and consumed a diet high in saturated fats and refined sugars.

P.E.: Wt. 210 lbs. (95.5 Kg); Ht. 5'10" (1.78m); B.P. 148/94. A baseline random blood glucose was 142 mg/dl. The OGTT results were: Fasting - 110 mg/dl; 30 minutes - 150; 60 minutes - 180; 90 minutes - 220 and 120 minutes - 240 mg/dl.


1. How much overweight is this man compared to his ideal body weight (%IBW)? 2. What is his BMI?

3. Comment on the proper preparation of a patient for OGTT. What is your diagnosis of this man's condition based on his OGTT?

4. What would your diagnosis have been if his two-hour blood glucose were 180 mg/dl, with all other blood glucoses as stated above?

5. How would you classify his FBG?

6. Do you expect this man to respond to diet and weight reduction?

7. Do you expect this man to have insulin resistance, and if so, what type?

8. What would be the incidence of diabetes in an identical twin of this man (25%, 50%, 75% or 98%)?

9. What are other causes of insulin resistance?

10. What is the most common complication in this man's type of diabetes (macroangiopathy or microangiopathy), and why?

11. What would be the mechanism of diabetes or glucose intolerance with the following endocrinopathies:

(a) Cushing's syndrome (b) Acromegaly

(c) Pheochromocytoma (d) Hyperaldosteronism


Case #2

LAP, who has had the diagnosis of DM since the age of 20 and has been on an insulin pump for 10 years, was admitted to the hospital because his insulin pump was accidentally disconnected. Since the patient was blind and his wife was not at home, he was not aware of this problem for 6 hours. Therefore, he developed nausea, polyuria, polydipsia, dry mouth and irregular breathing. Once the pump problem was discovered he restarted his pump, but his blood glucose by self-monitoring (SGM) was reading "high" on his glucose meter. Upon admission to the ER, he was found to be blind, tachypneic and sleepy, but oriented x3, with the following vital signs: B.P. - supine 140/88, sitting 120/65; pulse - 88; temperature - 97.6 and respiratory rate - 35 and irregular. Lab tests: Blood glucose - 900; Na - 140; K - 5.4; Cl - 90; HCO3 - 6; BUN - 28; Cr - 2.5.


1. What is the clinical and laboratory diagnosis of this man? 2. What is the actual level of serum sodium in this man? 3. Calculate total and effective osmolality.

4. What is his anion gap?

5. Differentiate between DKA and HHS.

6. What do you expect this person's pancreatic insulin to be measured by C-peptide (high, normal, low or very low)?

7. What are the chances of this individual's identical twin developing diabetes (90%, 70%, 30% or 10%)?

8. What intermediatory metabolic steps (ketogenesis, glycogenolysis, glycogen synthesis, proteolysis, lipolysis, gluconeogenesis) are decreased in this man?

9. What intermediatory metabolic steps are increased in this man? 10. What are the precipitating causes of this problem in this patient?





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