| Diabetic ketoacidosis Classification and external resources |
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| ICD-10 | E10.1-E14.1 |
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| ICD-9 | 250.1 |
| DiseasesDB | 3709 |
| eMedicine | med/548 |
| MeSH | D016883 |
Diabetic ketoacidosis (DKA) is a life-threatening complication in patients with diabetes mellitus. Near complete deficiency of insulin and elevated levels of certain stress hormones increase the chance of a DKA episode. DKA is more common among Type I diabetics, but may also occur in Type II diabetics, particularly during periods of increased physiologic stress, 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, or in diabetics who fall sick due to illnesses such as pneumonia or a kidney infection. DKA was a major cause of death in Type I diabetics before insulin injections were available; untreated DKA has a high mortality rate.
| Diabetes mellitus
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| Types of Diabetes |
| Diabetes mellitus type 1 Diabetes mellitus type 2 Gestational diabetes Pre-diabetes: |
| Disease Management |
| Diabetes management: •Diabetic diet •Anti-diabetic drugs •Conventional insulinotherapy •Intensive insulinotherapy |
| Other Concerns |
| Cardiovascular disease
Diabetic comas: Diabetic myonecrosis Diabetes and pregnancy |
| Blood tests |
| Blood sugar Fructosamine Glucose tolerance test Glycosylated hemoglobin |
Contents |
DKA is characterized by high blood sugar, acidosis, and high levels of ketone bodies. The pathogenesis of DKA is mainly due to acidosis. Excessive amounts of ketone bodies lower the blood pH; a blood pH below 6.7 is incompatible with life. Onset of DKA is often within 24 hours.
A key component of DKA is that there is little to no circulating insulin. DKA occurs mainly, but not exclusively, in Type 1 diabetes because Type 1 diabetes is characterized by a lack of insulin production in the pancreas. It is much less common in Type 2 diabetes because the latter is closely related to cell insensitivity to insulin, not -- at least initially -- to a shortage or absence of insulin. Some Type 2 diabetics have lost their own insulin production and must take external insulin; they have some susceptibility to DKA.
Although glucagon plays a role as an antagonistic hormone to insulin when there are low blood glucose levels, mainly by stimulating the process of glycogenolysis in hepatocytes (liver cells), insulin has a more critical role, with more widespread effects throughout the body. The presence or absence of insulin can by itself regulate most of the pathological effects of DKA; notably, it has a short half-life in the blood of minutes (at least one suggestion is about six), so blood insulin levels decrease rapidly following cessation of insulin release by the pancreas, or by outside sources (eg, injection, though some insulins do not quickly reach the blood, extending their duration of activity).
Most cells in the body are sensitive to one or more of the effects of insulin; the main exceptions are erythrocytes, neurons, some intestinal tissue, and pancreatic beta-cells, none of which require insulin to absorb glucose from the blood. Variation in cell-type sensitivity to insulin is due to the presence of different glucose transporter (GLUT) proteins. Adipocytes and skeletal muscle cells express GLUT-4 proteins, which move to the cell surface membrane when stimulated by a secondary messenger cascade initiated by insulin docking at membrane sensor proteins, thus enabling uptake of glucose. Conversely, when insulin concentrations are low, these transporters dissociate from the cell membrane and so prevent uptake of glucose.
Other effects of insulin include the following: stimulation of the formation of glycogen from glucose and inhibition of glycogenolysis, stimulation of fatty acid (FA) production from stored lipids and inhibition of FA release into the blood, stimulation of FA uptake and storage, inhibition of protein catabolism and of gluconeogenesis, in which glucose is synthesized from non-carbohydrate substrates (such as laktate, alanine and Creb's cycle intermediates). A lack of insulin therefore has many significant effects, several of which contribute to increasing blood glucose levels, to increased fat metabolism and protein degradation. Increased fat metabolism is one of the underlying mechanisms of DKA (ketone bodies are produced during lipid metabolic processing).
Muscle wasting occurs primarily due to the lack of inhibition of protein catabolism; insulin inhibits the breakdown of proteins and, since muscle tissue is made of proteins, a lack of insulin encourages muscle wasting, releasing amino acids both to produce glucose (by gluconeogenesis) and to provide materials for the synthesis of ATP via partial respiration of the remaining amino acids.
In individuals suffering from starvation, blood glucose concentrations are low due to both low carbohydrate consumption and because most of the glucose available is being used as a source of energy by tissues unable to use most other sources of energy, such as neurons in the brain. Since insulin lowers blood sugar levels by enabling many cells' glucose uptake, the normal bodily mechanism here is to prevent insulin secretion, thus leading to similar fat and protein catabolic effects as in type 1 diabetes. Thus, the muscle wastage visible in those suffering from starvation also occurs in type 1 diabetics, normally resulting in weight loss.
Under low-insulin conditions, regardless of circulating plasma glucose concentration, the liver acts as though the body is starving and produces another form of fuel, known as ketone bodies. This is an aspect of fat metabolism (beginning with lipolysis) that makes ketone bodies as intermediate products in the fatty acid-processing metabolic sequence. Two of the ketone bodies beta-hydroxybutyrate and acetoacetate enter the blood and can be used as fuel by some organs such as the brain, though the brain still requires a large amount of glucose to function. If large amounts of ketone bodies are produced, the metabolism is in the state termed ketosis; this condition is itself not necessarily harmful, and is normal during times of relatively low carbohydrate availablility (as, for instance, between meals). However, if produced in very large quantities, unprocessed ketone bodies will cause the blood pH to drop, leading to ketoacidosis.
Normally, ketone bodies are produced in minute quantities, and are used by the heart and brain as a supplementary energy source. In starvation conditions and DKA, neurons (and therefore the brain) adapt to use ketone bodies as a major energy source since glucose is in short supply.
In non-starvation DKA, a lack of insulin leads to high blood glucose levels (from both diet and unregulated gluconeogenesis in the liver). This often significantly increases blood osmolality. At the same time, and also due to low insulin permitted ketosis, large quantities of ketone bodies are produced, two of which -- in addition to increasing the osmolar load of the blood -- are acidic. As a result, the pH of the blood begins to move toward increasing acidity. The normal pH of human blood is 7.35-7.45; in acidosis, the pH dips below 7.35. Very severe acidosis may be as low as 6.9-7.1. (A pH of 6.8 or lower is generally considered to be incompatible with life; i.e., fatal). The acidic shift in the blood is significant because proteins (eg, body tissues, enzymes, etc.) can be significantly (even permanently) denatured (ie, distorted and so non-functional) by a pH that is either too high or too low, leading to widespread tissue damage, functional deficits, organ failure, and ultimately death.
Glucose begins to spill into the urine as the proteins responsible for reclaiming it from urine (the SGLT family) reach maximum capacity (the renal threshold for glucose). As glucose is excreted in the urine, it takes a great deal of body water with it, resulting in dehydration. Dehydration further concentrates the blood and worsens the increased serum osmolality. Severe dehydration forces water out of cells and into the bloodstream, with further functional derangement, changing organs behavior. This shift of intracellular water into the bloodstream occurs at a cost as the cells themselves need the water to complete chemical reactions that allow the cells to function as required.
It is important to note that to an untrained person the symptoms of acute DKA, such as breath odor, are very similar to alcohol intoxication, and it is easy to assume that the person is drunk instead of suffering from a diabetic emergency.
A high anion gap indicates that there is loss of bicarbonate (HCO3-) without increase in Chloride (Cl-).
When acetoacetic acid and beta-hydroxybutyric acid dissociate, they produce an H+ anion that will be immediately neutralized by bicarbonate if available. This causes loss of bicarbonate which increases the anion gap
During treatment, a drop in HCO3- (bicarbonate) is compensated for by an increase in Cl- from IV fluids. This is also known as hyperchloremic acidosis. The effect causes the anion gap to move toward a normal value despite persistence of metabolic acidosis. At patient presentation for treatment, both types of acidosis may be present, and the elevation in the anion gap may be less than expected for the degree of bicarbonate level reduction.
Serum potassium concentration is often elevated at presentation as insulin deficiency results in potassium movement out of the cells into the extracellular fluid. Insulin therapy lowers the potassium concentration by forcing it into the cells and may cause severe hypokalemia, particularly in patients with a normal or low serum potassium concentration at presentation.
At this point, DKA is life-threatening and medical attention should be sought immediately.
People with diabetic ketoacidosis need close and frequent monitoring for complications. Surprisingly, some of the most common complications of DKA are related to the treatment:
Treatment consists of hydration to lower the osmolality of the blood, replacement of lost electrolytes, insulin to force glucose and potassium into cells, and eventually glucose simultaneously with insulin in order to correct other metabolic abnormalities, such as elevated ketone levels. Many patients require admission to a step-down unit or an intensive care unit (ICU) due to IV administration of fluids, glucose, and insulin and so that vital signs, urine output, and blood tests can be monitored frequently. Brain edema is not rare during the treatment phase, is quite dangerous, and so this may suggest intensive monitoring as well. In patients with severe alteration of mental status, intubation and mechanical ventilation may be required. Survival is largely dependent on how badly deranged the metabolism is at presentation to a hospital, but today properly treated DKA is only occasionally fatal.
DKA occurs more commonly in type 1 diabetes because insulin deficiency is most severe, though it can occur in type 2 diabetes. In about a quarter of young people who develop type 1 diabetes, insulin deficiency and hyperglycemia lead to ketoacidosis before the disease is recognized and treated. This can occur at the onset of type 2 diabetes as well, especially in young people. In a person known to have diabetes and being adequately treated, DKA usually results from omission of insulin, mismanagement of acute gastroenteritis, the flu, or the development of a serious new health problem (e.g., bacterial infection, myocardial infarction).
Insulin deficiency switches many aspects of metabolic balance in a catabolic direction. The liver becomes a net producer of glucose by way of gluconeogenesis (from a few of the amino acids in protein) and glycogenolysis (from glycogen, though this source is usually exhausted within hours). Fat in adipose tissue is reduced to triglycerides and fatty acids by lipolysis. Muscle is degraded to release protein for gluconeogenesis. The rise of fatty acid levels is accompanied by increasing levels of ketone bodies (acetone, acetoacetate and beta-hydroxybutyrate; only one, acetone, is chemically a ketone -- the name is an historical accident). As ketosis worsens, it produces a metabolic acidosis, with anorexia, abdominal distress, and often eventual vomiting. The rising level of blood glucose increases the volume of urine produced by the kidneys as it passes the renal threshold (an osmolar diuresis). The high volume of urination (polyuria) also produces increased losses of electrolytes, especially sodium, potassium, chloride, phosphate, and magnesium. Reduced fluid intake from vomiting combined with amplified urination produce dehydration. As the metabolic acidosis worsens, it induces obvious hyperventilation (termed Kussmaul respiration). Kussmaul's respirations are essentially an involuntary attempt to remove carbon dioxide from the blood that would otherwise form carbonic acid and further worsen the ketoacidosis. See also arterial blood gas.
On presentation to hospital, patients in DKA are typically suffering dehydration and breathing both fast and deeply. Abdominal pain and vomiting is also common and may be severe. Consciousness level is typically normal until late in the process, when obtundation (dulled or reduced level of alertness or consciousness) may progress to coma. Dehydration can become severe enough to cause shock. Laboratory tests typically show hyperglycemia, metabolic acidosis, normal or elevated potassium, and severe ketosis. Many other tests can be affected.
At this point the patient is urgently in need of intravenous fluids. The basic principles of DKA treatment are:
Treatment usually results in full recovery, though death can result from inadequate treatment or a variety of complications, such as cerebral edema (occurs mainly in children).
Management: refer to DKA flowchart in [1]
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