As noted in Chapter 1, nutritional ketosis is defined by serum ketones ranging from 0.5 up to 5 mM, depending on the amounts of dietary carbohydrate and protein consumed. In most people, the combined intake of 100 grams of carbohydrate and 100 grams of protein will drive serum ketones well below 0.5 mM. While there is nothing magical about having circulating ketones above this threshold level, it does have the practical value of providing the brain with a virtually limitless, fat-derived fuel source. This alternative fuel is eminently more sustainable, particularly in the insulin resistant or carbohydrate intolerant individual.
Within a few days of starting on carbohydrate restriction, most people begin excreting ketones in their urine. This occurs before serum ketones have risen to their stable adapted level because un-adapted renal tubules actively secrete beta-hydroxybutyrate and acetoacetate into the urine. This is the same pathway that clears other organic acids like uric acid, vitamin C, and penicillin from the serum.
Meanwhile, the body is undergoing a complex set of adaptations in ketone metabolism[99]. Beta-hydroxybutyrate and acetoacetate are made in the liver in about equal proportions, and both are initially promptly oxidized by muscle. But over a matter of weeks, the muscles stop using these ketones for fuel. Instead, muscle cells take up acetoacetate, reduce it to beta-hydroxybutyrate, and return it back into the circulation. Thus after a few weeks, the predominant form in the circulation is beta-hydroxybutyrate, which also happens to be the ketone preferred by brain cells (as an aside, the strips that test for ketones in the urine detect the presence of acetoacetate, not beta-hydroxybutyrate). The result of this process of keto-adaptation is an elegantly choreographed shuttle of fuel from fat cells to liver to muscle to brain.
In the kidney, this process of keto-adaptation is also complex. Over time, urine ketone excretion drops off, perhaps to conserve a valuable energy substrate (although urine ketone excretion never amounts to very many wasted calories). This decline in urine ketones happens over the same time-course that renal uric acid clearance returns to normal (discussed below) and thus may represent an adaptation in kidney organic acid metabolism in response to sustained carbohydrate restriction.
These temporal changes in how the kidneys handle ketones make urine ketone testing a rather uncertain if not undependable way of monitoring dietary response/adherence. Testing serum for beta-hydroxybutyrate is much more accurate but requires drawing blood, and it is expensive be¬cause it is not a routine test that doctors normally order.
A non-invasive alternative is to measure breath acetone concentration. Acetone is produced by the spontaneous (i.e., non-enzymatic) breakdown of acetoacetate. Because it is volatile, acetone comes out in expired air, and its content is linearly correlated with blood ketone levels. A number of busi-nesses have developed prototype handheld devices to measure breath ac-etone, but at the time of this writing, nothing practical is on the market.
But whatever test is used, the key question is why do it? Many people are able to initiate and follow a low carbohydrate diet just fine without ever measuring ketones. Others, however, find an objective measure of nutri-tional ketosis to be reassuring. in some clinical settings, ketone testing is used as a measure of 'diet compliance. While this may be useful in the short term to keep patients on track in a strictly regimented dietary pro¬gram, it begs the question of how that individual's diet will be managed long term. For this purpose, the handheld breath acetone monitors under development hold some promise as a guidance tool put into the hands of the individual striving to find the right level of carbohydrate intake for long-term maintenance.
