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Diabetic ketoacidosis
Specialty	Endocrinology

Diabetic ketoacidosis (DKA) is a life-threatening complication in patients with untreated diabetes mellitus. 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, 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. DKA was a major cause of death in Type I diabetics before insulin injections were available; untreated DKA has a high mortality rate.

Biochemical mechanism

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 lowers 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. Its presence or absence can by itself regulate most of DKA's pathological effects; notably, it has a short half-life in the blood of only a few minutes (typically about six), so little time is needed between cessation of insulin release and the reduction of insulin levels in the blood.

Most cells in the body are sensitive to one or more of insulin's effects; the main exceptions are erythrocytes, neurons, hepatocytes, some intestinal tissue, and pancreatic beta-cells, which do not require insulin to absorb glucose from the blood. Variation in cell-type sensitivity to insulin is due to different glucose transporter (GLUT) proteins. Most cells contain only GLUT-4 proteins which move to the cell surface membrane when stimulated by a second messenger cascade initiated by insulin, 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 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 (mostly from some amino acid types, released by protein catabolism). A lack of insulin therefore has significant effects, all of which contribute to increasing blood glucose levels, to increased fat metabolism and protein degradation. Fat metabolism is one of the underlying causes of DKA.

Muscle wasting

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 for the synthesis of ATP via partial respiration of the remaining amino acids.

In those suffering from starvation, blood glucose concentrations are low due to both low consumption of carbohydrates 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, 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.

Ketone body production

Despite possibly high circulating levels of plasma glucose, the liver acts as though the body is starving if insulin levels are low. In starvation situations, the liver produces another form of fuel: ketone bodies. that is fat metabolic processing (beginning with lipolysis), makes ketone bodies as intermediate products in the metabolic sequence as fatty acids (formerly attached to a glycerol backbone in triglycerides) are processed. The ketone bodies beta-hydroxybutyrate and acetoacetate enter the blood and are usable as fuel for 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 metabolic imbalance known as ketosis may develop, though this condition is itself not necessarily harmful. However, in HUGE quantities, UNPROCESSED ketone bodies will cause the blood ph to drop. An extreme excess of ketones causes KETOACIDOSIS. In starvation conditions, the liver also uses the glycerol produced from triglyceride metabolism to make glucose for the brain, but there is not nearly enough glycerol to meet the body's glucose needs.

Brain

Normally, ketone bodies are produced in minuscule quantities, and are used by the heart and brain as energy sources. In DKA, the body enters a starving state. Eventually, neurons (and so the brain) switch from using glucose as a primary fuel source to using ketone bodies.

In DKA, the bloodstream is filled with an increasing amount of unusable glucose (as the liver continues gluconeogenesis and exporting it to the blood). This significantly increases blood osmolality. At the same time, massive amounts of ketone bodies are produced, which, in addition to increasing the osmolar load of the blood, are acidic. As a result, the pH of the blood begins to move downward towards an acidotic state. 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. inevitably fatal). The acidic shift in the blood is significant because the proteins (i.e. body tissues, enzymes, etc.) in the body can be permanently denatured by a pH that is either too high or too low, thereby leading to widespread tissue damage and functional deficits, organ failure, and eventually 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 osmolality of the blood. Severe dehydration forces water out of cells and into the bloodstream to keep vital organs perfused. 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.

Symptoms and Signs

It is important to note that to an untrained person the symptoms of acute DKA, such as breath odor, are very similar to intoxication, and it is easy to assume that the person is drunk instead of suffering from a diabetic emergency.

• Sluggish, extreme tiredness.
• Extreme thirst, despite large fluid intake.
• Constant urination
• Fruity smell to breath, similar to nail polish remover or peardrops.
• Hyperventilation, at first rapid and shallow, then progressively deeper and less rapid.
• Extreme weight-loss.
• Oral Thrush may be present, or/ yeast infections that fail to go away, this is because the normal fungal/flora present in oral cavity/cervix in women, the balance is upset and bacterial began to feast on the high sugar from urine output/ dry mouth from extreme thirst.
• Muscle wasting.
• Agitation / Irritation / Aggression / Confusion

Labs

A high anion gap indicates that there is loss of HCO3- without increase in Cl-.

When acetoacetic acid and beta-hydroxybutyric acid dissociate, they will produce an H+ anion that will be immediately neutralized by bicarbonate. This will cause loss of bicarbonate which will increase anion gap

During treatment, a drop in HCO3- is compensated for by an increase in Cl- from IV fluids. This is also known as hyperchloremic acidosis. The effect causes anion gap to return to normal despite the persistence of the metabolic acidosis. At presentation, both types of acidosis may be present and the elevation in the anion gap will be less than expected for the degree of depression in the bicarbonate level.

Serum potassium concentration is often elevated at presentation as insulin deficiency result in potassium movement out of the cells into the extracellular fluid. Insulin therapy lowers the potassium concentration and may cause severe hypokalemia, particularly in patients with a normal or low serum potassium concentration at presentation.

Late signs

At this point, DKA is life-threatening and medical attention should be sought immediately.

• Emesis (vomiting), although this is not always a sign of late-stage ketoacidosis, and can occur both in early-stage ketoacidosis and in non-ketoacidic hyperglycaemia.
• Confusion.
• Abdominal pain.
• Loss of appetite.
• Flu-like symptoms.
• Lethargy and apathy.
• Extreme weakness.
• Kussmaul breathing ("air hunger"). A type of hyperventilation where patients breathe very deeply at a normal or reduced rate. This is a sign of severe acidosis.
• Unconsciousness (diabetic coma) after prolonged DKA. At this stage, speedy medical attention is imperative.

Complications

People with diabetic ketoacidosis need close and frequent monitoring for complications. Surprisingly, the most common complications of DKA are related to the treatment:

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

Treatment

Treatment consists of hydration to lower the osmolality of the blood, replacement of lost electrolytes, insulin to force glucose and potassium into the cells, and eventually glucose simultaneously with insulin in order to correct other metabolic abnormalities, such as lowered blood potassium (hypokalemia) and elevated ketone levels. Many patients require admission to a step-down unit or an intensive care unit (ICU) so that vital signs, urine output, and blood tests can be monitored frequently. Brain edema is not rare, 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 dependent on how badly-deranged the metabolism is at presentation to a hospital, but the process 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 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 amino acids 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 eventually vomiting. The rising level of glucose increases the volume of urine produced by the kidneys (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 the body's 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 is 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:

• Rapid restoration of adequate circulation and perfusion with isotonic intravenous fluids
• Gradual rehydration and restoration of depleted electrolytes (especially sodium and potassium), even if serum levels appear adequate
• Insulin to reverse ketosis and lower glucose levels
• Careful monitoring to detect and treat complications

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

Diabetic ketoaddosis (DKA) is a result of severe insulin insufficiency. It occurs in type I diabetics and may be the presenting manifestation. Precipitating factors of DKA include insufficient or interrupted insulin therapy, infection, emotional stress, and excessive alcohol ingestion. presentation preceded by polyuria and polydipsia dehydration and sweating, anorexia, nausea, vomiting, fatigue, abdominal pain(especially in children), Kussmaul’s respirations (fruity rapid deep breathing) Pathophysiology in DKA. Lack of insulin causes the liver to turn fat into ketone bodies, a fuel mainly used by the brain. Elevated levels of ketone bodies in the blood decrease the blood's pH, leading to most of the symptoms of DKA. Elevated levels of ketone bodies cause severe Abdominal pain & decrease the blood's pH. electrolyte disturbance

       with hyperkalemia 
       decreased  level of consciousness that  may progress to coma. 

Ketoacidosis with electrolyt disturbance ,dyhydration & sever abdominal pain are severe enough to cause hypotension, shock, and death. Diagnosis of DKA 1-Elevated blood glucose, increased serum levels of keton bodies, & metabolic acidosis (low serum bicarbonate and low blood pH), 2- increased anion gap . Mangment Prompt proper treatment of DKA is managed with insulin, fluids, and electrolyte replacement. insulin• initial bolus of 5-10 U (or 0.1 U/kg) IV in adults • followed by continuous infusion at 5-10 U (or 0.1 U/kg) per hour Hyperosmolar nonketotic coma (HONK) is a syndrome that occurs predominantly in patients with type II diabetes and is characterized by severe hyperglycemia in the absence of significant ketosis. CAUSES Elderly diabetics. With Infections, strokes, use of phenytoin, steroids, immunosuppressant agents, and diuretics are other precipitating factors. HONK can occur after therapeutic procedures such as peritoneal or hemodialysis, tube-feeding of high-protein formulas, and high-carbohydrate infusion. The pathophysiology profound dehydration resulting from a sustained hyperglycemic diuresis. Theclinical findings are weakness, polyuria, polydipsia, lethargy, confusion, convulsions, and coma. The diagnosis of HONK is suggested by elevated blood glucose (1,000 mg/dl), extremely high serum osmolality BUN (prerenal azotemia) and mild metabolic acidosis (bicarbonate around 20 mEq/L) is also seen without ketosis. management of HONK involves fluid and electrolyte replacement as well as insulin.

cerebral edema may result if osmolality is treated aggressively ,,overall mortality high >50%

References

1. "Diabetic ketoacidosis". Diabetic ketoacidosis. Mayo Foundation for Medical Education and Research. 2006. Retrieved 2007-06-15. {{cite web}}: Text "By Mayo Clinic Staff" ignored (help)
2. "Diabetic Coma > Diabetic ketoacidosis". Diabetic ketoacidosis. Armenian Medical Network. 2006. Retrieved 2007-06-15. {{cite web}}: Text "Umesh Masharani, MB, BS, MRCP" ignored (help)
3. "Diabetic ketoacidosis complications". Diabetic ketoacidosis. The Diabetes Monitor. 2007. Retrieved 2007-06-15.

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