Ketoacidosis

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Ketoacidosis is a type of metabolic acidosis which is caused by high concentrations of keto acids, formed by the deamination of amino acids. This is most common in untreated type 1 diabetes mellitus, when the liver breaks down fat and proteins in response to a perceived need for respiratory substrate. It can also occur with people undergoing hunger strikes, fasting over 3 days, or people starving to death as the body is forced to break down fat for sustenance due to their lack of outside nutrition.

Ketoacidosis should not be confused with ketosis, which is one of the body's normal processes for the metabolism of body fat. In ketoacidosis, the accumulation of keto acids is so severe that the pH of the blood is substantially decreased.

In diabetic patients, ketoacidosis is usually accompanied by dehydration, hyperglycemia, and insulin deficiency. Since insulin is required to use glucose, lack of insulin means the body cannot use glucose and causes an energy crisis. The body then goes to extremes to produce more glucose and provide ketone bodies for energy. Glucose accumulates to the point that the kidney must use water to spill it into the urine, losing that water and causing dehydration in the process. The dehydration exacerbates the acidosis in a vicious cycle.

Alcoholic ketoacidosis is also an energy crisis but of different origin. Because alcohol causes dehydration and blocks the first step of gluconeogenesis, the body is unable to synthesize enough glucose to meet its needs, thus the energy crisis begins.

The acidity results from the dissociation of the H⁺ ion at physiological pH of metabolic ketone bodies such as acetoacetate, and β-hydroxybutyrate, produced from ketogenesis and its concentration is increased by dehydration.

Some diets (such as the Atkins diet) are reported to induce a mild-to-moderate state of ketosis, but this does not result in ketoacidosis if the dieter drinks an appropriate amount of water. Any diet which burns fat molecules at a significant rate results in an increased production of ketone bodies.

Generally, ketosis is well-regulated by the milieu of hormones governing the fasting and fed states, predominantly glucagon and insulin, and dieting (in an otherwise healthy person) is too mild to lead to acidosis. Before the recent abundant and sedentary lifestyles, it was probably normal for most humans to spend some of each year in ketosis, due to seasonal or temporary carbohydrate and/or calorie shortages. Unlike ketoacidosis, for most of human history, ketosis has been a normal condition and an essential capability.

Ketoacidosis occurs in two very different situations — in type 1 diabetes (diabetic ketoacidosis) and in alcohol withdrawal (alcoholic ketoacidosis). The ultimate reason for ketoacidosis in both cases is the same: The cell does not have enough glucose (in the case of diabetes because lack of insulin prevents the cell from taking up glucose, in the case of starvation because there is less glucose around), so it begins metabolizing fat molecules instead of simple sugars. As a result of this metabolic change, acetyl-CoA is mainly produced from the breakdown of fatty acids and fed into the citric acid cycle. The intermediates of the citric acid cycle are used for other anabolic purposes as well and have to be replenished. Normally, this is done by converting pyruvate into oxaloacetate or L-malate (the so-called anaplerotic pathways). But pyruvate is the end product of glycolysis, the breakdown of glucose, and glucose levels are lower in the cases we consider. This means that the citric acid cycle intermediates cannot be replenished, the cycle slows down, acetyl-CoA accumulates and ketogenesis becomes more important.