Diabetic ketoacidosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Diabetic ketoacidosis (DKA) is a life-threatening complication in patients with untreated diabetes mellitus (chronic high blood sugar or hyperglycemia). Near-complete deficiency of insulin and elevated levels of certain stress hormones combine to cause DKA. DKA is more common among type I diabetics, but may also occur in type II diabetics generally when physiologically stressed, such as during an infection. Patients with new, undiagnosed Type I diabetes frequently present to hospitals with DKA. DKA can also occur in a known diabetic who fails to take prescribed insulin. DKA was a major cause of death in type I diabetics before insulin injections were available; untreated DKA has a high mortality rate. DKA may be classified according to severity into mild, moderate, and severe DKA. The classification system takes into account various parameters such as arterial pH, anion gap, effective serum osmolarity, mental status, serum bicarbonate levels, and serum ketone levels. The classification of DKA has important implications for the management of the disease. DKA must be differentiated from other conditions presenting with hyperglycemia, ketosis, and metabolic acidosis. The differentials include diabetes mellitus, non-ketotic hyperosmolar state, impaired glucose tolerance, ketotic hypoglycemia, alcoholic ketosis, starvation ketosis, lactic acidosis, salicylic acid ingestion, uremic acidosis, and drug-induced acidosis. These conditions may be differentiated on the basis of the patient’s history, clinical features, and laboratory abnormalities. In the Unites States, the number of hospital discharges with DKA as the first-listed diagnosis increased from about 80,000 discharges in 1988 to about 140,000 in 2009. The case-fatality rate of DKA varies according to the geographic region and ranges from a low of less than 1000 per 100,000 individuals (USA and Scotland) to a high of 30,000 per 100,000 individuals (India). If left untreated, patients with diabetic ketoacidosis (DKA) may progress to develop multi-organ failure and death. Common complications of diabetic ketoacidosis (DKA) include hypokalemia, cerebral edema, hyperglycemia, ketoacidemia, renal tubular necrosis, and pulmonary edema. The most common symptoms of DKA include extreme tiredness, vomiting, abdominal pain, fruity-smelling breath, weight loss, and polyuria. The mainstay of therapy for DKA is medical therapy including intravenous insulin, fluids, potassium replacement, and bicarbonate therapy in case of severe acidosis (pH <6.9). The basic principles guiding therapy include rapid restoration of adequate circulation and perfusion, insulin to reverse ketosis and lower glucose levels, and close monitoring to prevent and treat complications if they develop. There are minor differences in the management of DKA in U.S.A. and U.K.; these are opinion-based and depend on the healthcare setting.

Diabetic ketoacidosis (DKA) was described for the first time by Dreschfeld in 1886 and identified as one of the sudden causes of death in diabetes mellitus. In 1971, it was found that the pathogenesis of DKA involved a deficiency of insulin and an excess of glucagon. In the 20th century, major advances were made in the field of management of DKA, starting from the isolation and use of insulin in patients to the adjustment of doses of insulin to achieve optimum control of the disease.

Diabetic ketoacidosis (DKA) may be classified according to severity into mild, moderate and severe DKA. The classification takes into account various parameters for example, arterial pH, anion gap, effective serum osmolarity, mental status, serum bicarbonate levels and serum ketone levels. Classification of DKA has important implications in the management of the disease.

Development of diabetic ketoacidosis (DKA) is the result of a relative or absolute deficiency of insulin and an excess of glucagon. In diabetic patients, this leads to a shift from an anabolic state to a catabolic state. This leads to activation of various enzymes that cause an increase in blood glucose levels (via glycogenolysis and gluconeogenesis) and blood ketone levels (via lipolysis). The severe hyperglycemia results in glucosuria and osmotic diuresis leading to a state of dehydration. Muscle wasting is a consequence of proteolysis due an excess of counter-regulatory hormones (glucagon, catecholamines and cortisol).

Diabetic ketoacidosis (DKA) can be caused by a deficiency of insulin and an excess of glucagon. This process may be triggered by presence of any infection, lack of adherence to insulin treatment by diabetics, illness, prescription or illicit drugs and any condition that puts the body under physiological stress.

Diabetic ketoacidosis (DKA) must be differentiated from other conditions presenting with hyperglycemia, ketosis and metabolic acidosis. The differentials include diabetes mellitus, non-ketotic hyperosmolar state, impaired glucose tolerance, ketotic hypoglycemia, alcoholic ketosis, starvation ketosis, lactic acidosis, salicylic acid ingestion, uremic acidosis and drug-induced acidosis. All these conditions may be differentiated on the basis of history findings, clinical features and laboratory abnormalities.

In 2007, the incidence of diabetic ketoacidosis (DKA) was estimated to be 13 to 26 cases per 100,000 individuals worldwide. In the Unites States, the number of hospital discharges with DKA as the first-listed diagnosis increased from about 80,000 discharges in 1988 to about 140,000 in 2009. Case-fatality rate of DKA varies according to the geographic region and ranges from a low of less than 1000 per 100,000 individuals (USA and Scotland) to a high of 30,000 per 100,000 individuals (India). The prevalence of DKA varies with age and is more common in children.

Common risk factors in the development of diabetic ketoacidosis (DKA) are young age, high mean glycosylated hemoglobin A1c, infection, low physical activity, depression, lack of health insurance, low socioeconomic status, low body mass index, improper management of diabetes, and unemployment.

There is insufficient evidence to recommend routine screening for diabetic ketoacidosis (DKA) but urine ketone dip test may be used in high-risk populations.

If left untreated, patients with diabetic ketoacidosis (DKA) may progress to develop multi-organ failure and death. Common complications of diabetic ketoacidosis (DKA) include hypokalemia, cerebral edema, hyperglycemia, ketoacidemia, renal tubular necrosis, and pulmonary edema.

There are specific cut-offs for serum glucose level, ketone levels, body pH and serum bicarbonate levels for the diagnosis for diabetic ketoacidosis as outlined by the American Association of Clinical Endocrinologists.

A positive history of type 1 diabetes mellitus, infection and history of poor compliance to insulin regimens are suggestive of diabetic ketoacidosis (DKA). The most common symptoms of DKA include extreme tiredness, vomiting, abdominal pain, fruity smell of breath, weight loss and polyuria.

Patients with diabetic ketoacidosis (DKA) may usually appear cachexic, diaphoretic or obtunded. Physical examination of patients with DKA is usually remarkable for hypothermia, hypotension, tachycardia, tachypnea, kussmaul breathing pattern, acanthosis nigricans, nausea, vomiting and abdominal pain.

Laboratory findings consistent with the diagnosis of diabetic ketoacidosis (DKA) include blood pH < 7.3, serum bicarbonate < 18 mEq/L, anion gap > 10 mEq/L and increased serum osmolarity.

Patients suffering from diabetic ketoacidosis (DKA) may exhibit electrocardiographic (EKG) changes characteristic of toxic hyperkalemia and hypocalcemia. Common abnormalities observed on EKG include tall peaking T waves, prolonged QT interval and widening of QRS complex.

There are no chest x-ray abnormalities associated with diabetic ketoacidosis (DKA).

Diabetic ketoacidosis (DKA) is associated with cerebral edema which can be visualized on CT scan of the head.

MRI in cerebral edema due to diabetic ketoacidosis (DKA) may show hyperattenuating signal on T2 FLAIR MRI.

There are no ultrasound findings associated with diabetic ketoacidosis (DKA).

There are no other imaging findings associated with diabetic ketoacidosis (DKA).

There are no other diagnostic studies associated with diabetic ketoacidosis (DKA).

Diabetic ketoacidosis (DKA) is a medical emergency. The mainstay of therapy for DKA is medical therapy including intravenous insulin, fluids, potassium replacement, and bicarbonate therapy in case of severe acidosis (pH <6.9). The basic principles guiding therapy include rapid restoration of adequate circulation and perfusion, insulin to reverse ketosis and lower glucose levels, and close monitoring to prevent and treat complications if they develop. There are minor differences in the management of DKA in U.S.A. and U.K.; these are opinion-based and depend on the healthcare setting.

Surgical intervention is not recommended for the management of diabetic ketoacidosis (DKA).

Effective measures for the primary prevention of diabetic ketoacidosis (DKA) include recognition of early signs of DKA, implementation of early and aggressive interventions (especially in patients with recurrent episodes of DKA), and administration of optimum anti-diabetic medications in diabetic patients.

Secondary prevention of diabetic ketoacidosis (DKA) is similar to primary prevention.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Diabetic ketoacidosis (DKA) was described for the first time by Dreschfeld in 1886 and labelled as one of the sudden causes of death in diabetes mellitus. In 1971, it was found that the pathogenesis of DKA involved a deficiency of insulin and an excess of glucagon. In the 20th century major advances were made in the field of management of DKA, starting from the isolation and use of insulin in patients to the adjustment of doses of insulin to achieve optimum control of the disease.

• The known history of diabetes dates back to the Egyptian era, and the first documented evidence was found in an Egyptian papyrus dating back to 1552 BC.
• In 1886, Dreschfeld provided the first description of diabetic ketoacidosis (DKA) in the modern medical literature. He described it in one of his lectures on diabetic coma and labelled it as one of the sudden causes of death in diabetes.^[1]
• In 1971, DKA was referred to as a disorder involving insulin deficiency and glucagon excess.^[2]

• In 1922 insulin was discovered and isolated by Banting and Best, after which they used it to treat patients with diabetic ketoacidosis.
• In 1945, a study was conducted and it was found that the mortality rate of diabetic ketoacidosis was reduced from to 12% in 1940 and to 1.6% by 1945, after the use of high doses of insulin.
• In Birmingham, UK, high-dose insulin was also being used, leading to a decrease in overall mortality, with doses varying depending on the degree of consciousness, with those on admission given doses ranging between 500 to 1400 units per 24 hours.^[3]
• In early 1970’s the concept of low dose insulin for the management of diabetic ketoacidosis was introduced.
• The UK favored the use of insulin infusions of between 1.2 and 9.6 units per hour at a fixed rate during the management of diabetic ketoacidosis.^[4]
• In the USA, Kitabchi et al. employed a variety of regimens, based on body weight.^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Diabetic ketoacidosis (DKA) may be classified according to severity into mild, moderate and severe DKA. The classification takes into account various parameters for example, arterial pH, anion gap, effective serum osmolarity, mental status, serum bicarbonate levels and serum ketone levels. Classification of DKA has important implications in the management of the disease.

Diabetic ketoacidosis (DKA) may be classified according to severity into the following types:^[1][2]

• Mild DKA
• Moderate DKA
• Severe DKA

Shown below is a table summarizing the diagnosis of Diabetic ketoacidosis according the the American Diabetes Association (ADA) guidelines. ^{[3] [4]}

VARIABLE	DIABETIC KETOACIDOSIS
	MILD (Plasma Glucose > 250mg/dL or 13.88 mmol/L)	MODERATE (Plasma Glucose > 250mg/dL or 13.88 mmol/L)	SEVERE (Plasma Glucose > 250mg/dL or 13.88 mmol/L)
Arterial pH	7.25 to 7.30	7.00 to < 7.24	< 7.00
Serum bicarbonate	15 to 18 mEq/L	10 to < 15 mEq/L	< 10 mEq/L
Urine ketone (Nitroprusside reaction method)	Positive	Positive	Positive
Serum ketone (Nitroprusside reaction method)	Positive	Positive	Positive
Effective serum osmolality	Variable	Variable	Variable
Anion gap	> 10 mEq/L (10 mmol/L)	> 12 mEq/L (12 mmol/L)	> 12 mEq/L (12 mmol/L)
Mental status	Alert	Alert/drowsy	Stupor/coma

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Development of diabetic ketoacidosis (DKA) is the result of a relative or absolute deficiency of insulin and an excess of glucagon. In diabetic patients, this leads to a shift from an anabolic state to a catabolic state. This leads to activation of various enzymes that cause an increase in blood glucose levels (via glycogenolysis and gluconeogenesis) and blood ketone levels (via lipolysis). The severe hyperglycemia results in glucosuria and osmotic diuresis leading to a state of dehydration. Muscle wasting is a consequence of proteolysis due an excess of counter-regulatory hormones (glucagon, catecholamines and cortisol).

Diabetic ketoacidosis (DKA) is the result of insulin deficiency from new-onset diabetes (usually type 1 diabetes), insulin noncompliance, prescription or illicit drug use, and increased insulin need because of any condition. DKA features hyperglycemia, acidosis, and high levels of circulating ketone bodies. When there is no or minute amounts of circulating insulin, for example in type 1 diabetes or less commonly in type 2 diabetes, the consequence is an elevation of counter-regulatory hormones/stress hormones (glucagon, catecholamines, cortisol, and growth hormone). This process eventually leads to the development of DKA.^[1]

• In type 1 diabetics there is immune-associated destruction of insulin-producing pancreatic β cells, which leads to no or decreased levels of insulin in the body. This leads to a major pre-disposition to the development of DKA in this patient population.^[2]
• In type 2 diabetics, although the major mechanism of hyperglycemia is peripheral insulin resistance and there is some basal production of insulin; patients may develop a failure of pancreatic β cells at late stages of the disease. This is rare but may lead to development of DKA in these patients.^[3]
• The major effect of insulin deficiency is decreased intra-cellular glucose utilization and mobilization of body sources of glucose by counter-regulatory or stress hormones namely, glucagon, catecholamines, cortisol and growth hormone. This eventually leads to a large increase in blood glucose levels and ketonemia.^[4]

Basic enzymes involved

• The rate of lipolysis and ketogenesis depends upon the action of three enzymes:^{[5] [6][7][8][9]}
  • Hormone-sensitive lipase (or triglyceride lipase), which is found in peripheral adipocytes
  • Acetyl CoA carboxylase, which is found in the liver
  • Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHS), which is also found in the liver

• Insulin and glucagon play the key roles in regulating lipolysis and ketogenesis by acting in opposition to each other.^[10][11][12]
• Insulin inhibits ketogenesis by causing the dephosphorylation of hormone-sensitive lipase (HSL) and leads to lipogenesis by stimulating acetyl CoA carboxylase.^[6]
• In the adipose tissue, dephosphorylation of hormone-sensitive lipase (HSL) decreases the degradation of triglycerides into fatty acids and glycerol, the rate-limiting step in the release of free fatty acids from the adipocyte. This subsequently reduces the amount of substrate that is available for ketogenesis.^[13]
• Insulin also dephosphorylates the inhibitory sites on acetyl CoA carboxylase leading to enzyme activation and increased production of malonyl CoA. Malonyl CoA inhibits beta oxidation of fatty acids thereby decreasing ketogenesis.^[13]
• Glucagon stimulates ketogenesis by causing the phosphorylation of both hormone-sensitive lipase (HSL) and acetyl CoA carboxylase via cyclic AMP-dependent protein kinase. in the adipocytes, phosphorylation of lipase by cyclic AMP-dependent protein kinase causes degradation of triglycerides into fatty acids.^[11][14]
• In hepatocytes, phosphorylation of acetyl CoA carboxylase by cyclic AMP-dependent protein kinase decreases the production of malonyl CoA which subsequently stimulates fatty acid uptake by the mitochondria of the cells for oxidation, and thus increases the amount of substrate available for ketogenesis.
• The activity of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHS) is increased by starvation and a high-fat diet, and it is decreased by insulin.^[15]

Ketosis and acedemia in DKA

• Insulin deficiency is the most important regulator of ketogenesis.
• Lipolysis is mediated by hormone-sensitive lipase in adipose tissue. Hormone-sensitive lipase is activated by both insulin deficiency and the rise in counter-regulatory hormones in DKA.^[16]
• In the liver of patients with active DKA, the deficiency of insulin and the high levels of counter-regulatory hormones (mainly glucagon) act synergistically to decrease the re-esterification of free fatty acids (FFA) and to increase the processes by which FFAs are transported into mitochondria where they are converted into ketone bodies. FFA transport into hepatic mitochondria is enhanced by glucagon-mediated decrease in the cytosolic malonyl-CoA, which removes inhibition of carnitine palmitoyltransferase 1 (CPT1).^[17][18]
• Excessive amounts of fatty acyl CoA derivatives are oxidized to form ketone bodies, and large quantities of 3-hydroxybutyrate and acetoacetate are released into the blood.
• Ketone bodies are acidic in nature and lead to a decrease in pH of the body (acedemia).
• In DKA the ratio of 3-hydroxybutyrate to acetoacetate rises to 3:1 or higher (to as high as 10:1).^[19]
• Insulin deficiency also acts to reduce renal clearance of ketone bodies via unclear mechanisms.^[20][21]

Basic enzymes involved

• Glycogen and proteins are catabolized to form glucose.^[19]
• Increased lipolysis, proteolysis, glycogenolysis and decreased glucose utilization lead to an increased glucose concentration in blood.
• The following enzymes are involved in these processes:
  • Glycogenolysis: Glycogen phosphorylase.
  • Gluconeogenesis: Phosphofructokinase-2 (PFK-2) and fructose bisposphatase-2 (FB-2) which control the production of fructose 2,6-bisphosphate (an allosteric modifier of the activity of phosphofructokinase-1 (PFK-1) and fructose 1,6-bisphosphatase (FBPase-1), which control gluconeogenesis and glycolysis).
• Insulin inhibits glycogen phosphorylase, leading to decreased blood glucose and dephosphorylates PFK-2 leading to its activation and inhibiting the FBPase-2 activity. With increased fructose 2,6-bisphosphate present, activation of PFK-1 occurs to stimulate glycolysis while inhibiting gluconeogenesis.^[22]
• Glucagon triggers production of cyclic adenosine monophosphate (cAMP), which activates a cAMP-dependent protein kinase. This kinase phosphorylates the PFK-2and FBPase-2 enzymes. This causes activation of FBPase-2 activity and inhibition of PFK-2 activity, thereby decreasing the levels of fructose 2,6-bisphosphate in the cell. With decreasing amounts of fructose 2,6-bisphosphate, glycolysis is inhibited while gluconeogenesis is activated.^[23]

Hyperglycemia in DKA

• In DKA, due to a profound insulin deficiency, here is an excess of counter-regulatory hormones/stress hormones, for example, glucagon, cortisol, catecholamines and growth hormone which all lead to an increase production of glucose in the body.
• The serum glucose level in DKA is usually > 250 mg/dl but usually < 1000 mg/dl. Values exceeding 1000 mg/dl are usually found in hyperosmolar non-ketotic state, which is found in type 2 diabetics.^[24]
• The increased serum glucose may lead to osmotic diuresis in patient leading to dehydration and weakness.^[25]

• Muscle wasting occurs primarily due to the lack of inhibition of protein catabolism.
• Insulin inhibits the breakdown of proteins and, since muscle tissue is protein, a lack of insulin encourages muscle wasting, releasing amino acids both to produce glucose (by gluconeogenesis).

Pathophysiology of diabetic ketoacidosis at a glance

Profound insulin deficiency/stress/infection

Increased levels of counter-regulatory hormones (glucagon, catecholamines, cortisol)

Increased lipolysis

Increased proteolysis, decreased protein synthesis (increased availability of gluconeogenic substrates)

Increased glycogenolysis

Increased ketogenesis (acidosis)

Increased gluconeogenesis (hyperglycemia)

Hyperglycemia

Glucosuria and dehydration

Glucosuria and dehydration

The following conditions are associated with diabetic ketoacidosis (DKA):

• Type 1 diabetes mellitus
• Type 2 diabetes mellitus

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Diabetic ketoacidosis (DKA) can be caused by a deficiency of insulin and an excess of glucagon. This process may be triggered by presence of any infection, lack of adherence to insulin treatment in diabetics, illness, prescription or illicit drugs and any condition that puts the body under physiological stress.

The following are the causes of diabetic ketoacidosis (DKA):

• Drugs:^[1][2]
  • Antipsychotic agents (clozapine, olanzapine, risperidone)
  • Illicit drugs (cocaine and alcohol)
  • Corticosteroids^[3]
  • Glucagon^[4]
  • Interferon^[5]
  • Pentamidine^[6][7]
  • Sympathomimetic agents (albuterol, dopamine, dobutamine, terbutaline, ritodrine, thiazide diuretics)^[8][9]

• Infections:
  • Pneumonia^[10]
  • Sepsis^[11][12][13]
  • Urinary tract infection^[14]

• Lack of insulin^[13]

• Unrecognized symptoms of new-onset diabetes mellitus^[15]

Nonadherence to insulin treatment plans:^[16][17]

• Body image issues
• Financial problems
• Psychological factors

Physiological stressors:

• Acromegaly^[18]
• Thrombosis^[19]
• Cerebrovascular accident^[20]
• Cushing’s disease^[21]
• Hemochromatosis^[22]
• Myocardial infarction^[23]
• Pancreatitis^[24]
• Pregnancy^[25]
• Psychological stress
• Shock/hypovolemia^[26]
• Trauma^[27]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Diabetic ketoacidosis (DKA) must be differentiated from other conditions presenting with hyperglycemia, ketosis and metabolic acidosis. The differentials include diabetes mellitus, non-ketotic hyperosmolar state, impaired glucose tolerance, ketotic hypoglycemia, alcoholic ketosis, starvation ketosis, lactic acidosis, salicylic acid ingestion, uremic acidosis and drug-induced acidosis. All these conditions may be differentiated on the basis of history findings, clinical features and laboratory abnormalities.

Diabetic ketoacidosis must be differentiated from other diseases causing the following conditions:^{[1][2][3][4][5][6][7][8]}

• Hyperglycemia
  • Diabetes mellitus
  • Non-ketotic hyperosmolar state
  • Impaired glucose tolerance
  • Stress hyperglycemia
• Ketosis
  • Ketotic hypoglycemia
  • Alcoholic ketosis
  • Starvation ketosis
• Metabolic acidosis
  • Lactic acidosis
  • Salicylic acid ingestion
  • Uremic acidosis
  • Drug-induced acidosis

Characteristic Common to DKA	Condition	History Findings	Clinical Features	Lab abnormalities
Hyperglycemia	Diabetes mellitus	Family history of diabetes Obesity (BMI >25 kg/m2) Stress Sedentary lifestyle History of gestational diabetes Polycystic ovarian syndrome Acanthosis nigricans Hypertension (Blood pressure >140/90 mmHg)	Polyuria Polydipsia Polyphagia Weight loss Central obesity Autonomic and peripheral neuropathy Vascular occlusion secondary to atherosclerosis (Stroke, myocardial infarction) Renal impairment (microalbuminuria leading to renal failure) Decreased visual acuity (diabetic retinopathy) Increased susceptibility to infections Charcot’s joints	Hyperglycemia: Fasting blood glucose level: >126 mg/dl Random blood glucose level: >200 mg/dl HbA1C: >6.5 % Urinanalysis may show: Proteinuria Glucosuria Positive antibodies(Type 1 diabetes): Anti-glutamic acid decarboxylase Anti-islet cell Anti-insulin
	Non-ketotic hyperosmolar state	Elderly with type 2 diabetes mellitus Undiagnosed type 2 diabetes Prolonged hyperglycemia	May have all clinical features of diabetes mellitus plus: Hypotension Dehydration Tachycardia Decreased mentation Focal neurological abnormalities	Hyperglycemia (600-2000 mg/dl) Increased serum osmolarity (330-380 mOsm/kg) Arterial pH >7.3 Anion gap normal No ketosis
	Impaired glucose tolerance	Family history of diabetes Obesity (BMI >25 kg/m2) Stress Sedentary lifestyle History of gestational diabetes Acanthosis nigricans	May have all clinical features of diabetes mellitus	Hyperglycemia: Fasting blood glucose level: 100-125 mg/dl Oral glucose tolerance test: 140-200 mg/dl
Ketosis	Alcoholic ketosis	Non-diabetic chronic alcohol user Binge drinking history Fasting for 1-2 days after binge drinking	Nausea Vomiting Diffuse abdominal pain Dehydration Stress Anorexia	Serum glucose normal (only 10% with serum glucose >250 mg/dl) Serum bicarbonate < 18 mEq/L Arterial pH may show acidosis or may be alkalotic due to respiratory alkalosis Increased anion gap Acetoacetate and beta hydroxybutyrate elevated
	Starvation ketosis	Several weeks of low caloric intake Malnourishment	Halitosis Dehydration Dry coated tongue Confusion Drowsiness Cold extremities Hypotension (postural or supine) Leg cramps	Serum glucose normal or hypoglycemia Serum bicarbonate > 18 mEq/L Arterial pH may show acidosis Increased anion gap
Metabolic acidosis	Lactic acidosis	Hypermetabolic states: Trauma Burns Sepsis Hypoxia Short bowel syndrome Jejuno-ileal bypass surgery Chronic pancreatic insufficiency Chronic renal insufficiency Large carbohydrate intake Carbon monoxide poisoning Drug intake: Cyanide Salicylates Biaguanides INH Anti-retroviral agents Valproic acid COPD Asthma Mesenteric ischemia	Neurological: Confusion Stupor Slurred speech Nausea Vomiting Warm extremities Dyspnea Cough Tachycardia Weakness Fatigue	Arterial pH <7.3 Increased anion gap Increased blood lactate
	Salicylic acid ingestion	Acute overdose: Young individuals or infants Intentional Suicidal Rapid progression of signs and symptoms Chronic overdose: Therapeutic misadventures Chronic pain disorders Acute lung injury	Early symptoms: Nausea Vomiting Anorexia Diaphoresis Tinnitus Hyperventilation Tachycardia Late symptoms: Drowsiness Fatigue Dizziness Confusion Delirium Hallucinations Seizures Hyperthermia	Mixed respiratory alkalosis and metabolic acidosis Increased anion gap Hyperkalemia Increased bleeding time, normal prothrombin time (PT) and activated partial thromboplastin time (aPTT)
	Uremic acidosis	Renal failure Pre-renal: Dehydration due to gastroenteritis, diarrhea, hemorrhage, hypovolemia, cardiac failure Renal: Hemolytic uremic syndrome, acute glomerulonephritis, renal necrosis, drugs, sepsis, shock Post-renal: Renal stones, renal tumors, posterior ureteric valves, renal trauma, renal vein thrombosis	Neurological: Delayed tendon reflexes Confusion Headache Seizures Peripheral neuropathy Uremic frost Uremic fetor Hypertension Osteomalacia Muscular weakness Cardiac arrythmias Gout (podagra) Kussmaul breathing Nausea Vomiting	Arterial pH < 7.3 Increased anion gap Hyperkalemia Hypocalcemia Hyperphosphatemia Secondary hyperparathyroidism Hyperuricemia Hypermagnesemia
	Drug-induced acidosis	Drug intake: Potassium sparing diuretics (amiloride, triamterene, spironolactone Trimethoprim Pentamidine ACE inhibitors ARBs NSAIDs Cyclosporine Tacrolimus Aspirin Amphotericin B Opiates Anaesthetics Phenobarbital	Neurological: Confusion Seizures Nausea Vomiting Chest discomfort Cardiac arrythmias Abdominal pain	Arterial pH < 7.3 Normal anion gap Increased hepatic transaminases (aspartate aminotrasnferase, alanine aminotransferase) Hyperkalemia (ACE inhibitors, ARBs, NSAIDs, trimethoprim, potassium sparing diuretics) Increased BUN, creatinine

Parameters	Diabetic ketoacidosis (DKA)	Hyperosmolar hyperglycemic state (HHS)
Plasma glucose	> 250 mg/dl	> 600 mg/dl
Serum osmolality	Variable	> 320 mOsm/kg
Plasma and urine ketones	Positive	None or trace
Serum bicarbonate	< 18 mEq/L	> 15 mEq/ L
Arterial ph	< 7.30	> 7.30
Anion gap	> 12	< 12

• Causes of increased anion gap metabolic acidosis can be differetiated from each other with the help of following alogrhythm:^{[9][10][11][12][13]}

↑ anion gap metabolic acidosis

↑ Lactate

Yes

No

Lactic acidosis

Check for hyperglycemia and ketonuria

Present

Not Present

Diabetic ketoacidosis

↑ BUN, ↑ creatinine and history of hemodyalysis

Yes

No

Uremic acidosis

Physical findings include odor of alcohol

Yes

No

↑ Ethanol level in serum or expired air

Auditory symptoms present

Ethanol overdose

Salicylic acid overdose

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

In 2007, the incidence of diabetic ketoacidosis (DKA) was estimated to be 13 to 26 cases per 100,000 individuals worldwide. In the Unites States, the number of hospital discharges with DKA as the first-listed diagnosis increased from about 80,000 discharges in 1988 to about 140,000 in 2009. Case-fatality rate of DKA varies according to the geographic region and ranges from a low of less than 1000 per 100,000 individuals (USA and Scotland) to a high of 30,000 per 100,000 individuals (India). The prevalence of DKA varies with age and is more common in children.

• In the United States, the overall prevalence of diabetic ketoacidosis (DKA) among patients with type 1 diabetes mellitus during 2013-2014 was 3000 individuals per 100,000 patients.

• The following table outlines the temporal variation in the prevalence of diabetic ketoacidosis (DKA) at diagnosis of type 1 or type 2 diabetes in children and adolescents from 2002 to 2010 in the United States:^[1]

Year of study	Age group								All
	0–4 Years		5–9 Years		10–14 Years		15–19 Years
	Prevalence per 100,000 cases	95% CI	Prevalence per 100,000 cases	95% CI	Prevalence per 100,000 cases	95% CI	Prevalence per 100,000 cases	95% CI	Prevalence per 100,000 cases	95% CI
Type 1 diabetes
2002–2003	40100	34500–45600	27900	23800–32000	28900	25100–32800	22900	16800–29100	30200	27800–32500
2004–2005	36200	30400–41900	25200	21400–29000	31500	27800–35300	22400	16700–28200	29100	26900–31400
2008–2010	41100	36400–45800	29800	26700–32900	30900	27900–33900	23500	19400–27700	31100	29300–32900
Type 2 diabetes
2002–2003	—	—	—	—	14700	9000–20300	9200	4900–13500	11700	8200–15200
2004–2005	—	—	—	—	9500	5100–14000	3100	400–5700	6300	3700–8900
2008–2010	—	—	—	—	7300	4700–9900	4200	2200–6200	5700	4100–7400

• The following table outlines the temporal variation in the prevalence of diabetic ketoacidosis (DKA) in type 1 diabetics:^[2][3][3]

Year of study	Age group
	18-25 Years	26-30 Years	31-49 Years	50-64 Years	>65 years
	Prevalence per 100,000 cases	Prevalence per 100,000 cases	Prevalence per 100,000 cases	Prevalence per 100,000 cases	Prevalence per 100,000 cases
2010-2012	12000	7000	5000	6000	6000
2013-2014	6000

• The annual incidence of diabetic ketoacidosis varies in different reports and is related to the geographic location.
• Worldwide, the annual incidence of diabetic ketoacidosis varies from a low of 13 persons per 100,000 persons (Denmark) to a high of 26 per 100,000 persons (Malaysia).^[4][5]
• In the Unites States, the number of hospital discharges with DKA as the first-listed diagnosis increased from about 80,000 discharges in 1988 to about 140,000 in 2009.^[6]

• Case-fatality rate of DKA varies from a low of less than 1000 per 100,000 individuals (USA and Scotland) to a high of 30,000 per 100,000 individuals (India).^[7]
• Case-fatality rates of DKA differ according to the level of care provided and healthcare setting.^[3]
• DKA is the most common cause of death in children and adolescents with type 1 diabetes and accounts for half of all deaths in diabetic patients younger than 24 years of age.^[3][8]

• The prevalence of DKA decreases with increasing age.^[9]
• In children and adolescents with type 1 diabetes, DKA is the most common cause of death.
• In adult patients, DKA has an overall mortality is <1%.^[10]
• In the elderly and in patients with concomitant life-threatening illnesses, the mortality rate is greater than 5%.^[11]
• DKA and severe DKA at the time of type 1 diabetes diagnosis have been known to be more common among religious ultra-orthodox than among secular Jewish children, indicating that patient education and awareness of symptoms plays an important role in affecting incidence and prevalence.^[12]

• The prevalence and incidence of DKA is higher in men as compared to women.^[9]

• The prevalence and incidence of DKA is higher in non-caucasians than caucasians.^[9]

• There is marked variability in the incidence of DKA in different parts of the world.
• The frequency of DKA at the time of diagnosis of type 1 diabetes varies across different countries, for example, in United Arab Emirates where it has been reported to be 80% and in Sweden it is 12.8%.^[5][13]
• In Canada and Europe, hospitalization rates for DKA in established and new patients with type 1 diabetes mellitus is 10 per 100 000 children.^[14]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Common risk factors in the development of diabetic ketoacidosis (DKA) are young age, high mean glycosylated hemoglobin A1c, infection, low physical activity, depression, lack of health insurance, poor socioeconomic status, low body mass index, improper management of diabetes and unemployment.

The following factors are associated with an increased risk of diabetic ketoacidosis (DKA):^{[1][2][3][4][5]}

• Young age
• High mean glycosylated hemoglobin A1c (HbA1c)
• Infection
• Low physical activity
• Depression
• Lack of health insurance
• Low body mass index (BMI)
• Delayed or improper management of diabetes
• Low socioeconomic status
• Unemployment

The following factors are associated with a reduced risk of diabetic ketoacidosis (DKA):^[6]

• Family history of type 1 diabetes
• Higher education level of both patient and parents
• Higher background incidence of type 1 diabetes (associated with increased awareness of DKA)
• Adequate and optimum management of diabetes

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

There is insufficient evidence to recommend routine screening for diabetic ketoacidosis (DKA) but urine ketone dip test may be used in high risk population.

• The urine ketone dip test has high sensitivity for detecting DKA and a high negative predictive value for excluding DKA in hyperglycemic patients with diabetes.
• It is considered that urine dip test is a better tool for screening of DKA than serum ketone levels or serum bicarbonate levels.^[1][2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

If left untreated, patients with diabetic ketoacidosis (DKA) may progress to develop multi-organ failure and death. Common complications of diabetic ketoacidosis (DKA) include hypokalemia, cerebral edema, hyperglycemia, ketoacidemia, renal tubular necrosis and pulmonary edema.

• If left untreated, diabetic ketoacidosis may progress to multi-organ failure and death
• Early in the course of the ketoacidotic process, hyperventilation results in a decrease in pCO2. The metabolic acidosis is compensated, and pH may be normal or only slightly reduced (e.g., in mild or moderate DKA)
• As DKA progresses into the severe stage, more significant acidosis occurs and pH falls
• If compensatory hyperventilation does not occur for the acidosis, such as, in pulmonary disease (pneumonia, asthma, or adult respiratory distress syndrome) or CNS depression (e.g., cerebral edema), the acidosis becomes more severe and results in a poor prognosis
• Although acidosis impairs myocardial contractility, heart failure and cardiogenic shock are rare in children with DKA
• Hypotension or shock during DKA is nearly always the result of hypovolemia or cerebral edema in children
• Heart failure, myocardial infarction, and arrhythmias during DKA are seen commonly in untreated diabetic ketoacidosis

People with diabetic ketoacidosis need close and frequent monitoring for complications. Surprisingly, the most common complications of DKA are related to the treatment:^{[1][2][3][4][5]}

• Hypokalemia and often, potassium depletion
• Cerebral edema
• Hyperglycemia
• Ketoacidemia
• Fluid and electrolyte depletion
• Aspiration
• Unrecognized renal tubular necrosis
• Pulmonary edema

• The following are the signs of poor prognosis in diabetic ketoacidosis at the time of diagnosis:^[6][7][8]
  • Hypothermia
  • Coma
  • Oliguria
  • Extremes of age (young and elderly)
  • Intercurrent comorbidity, for example, myocardial infaction, sepsis
  • Positive tropinins without evident acute coronary syndrome
  • High platelet to lymphocyte ratio

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