DIABETES/METABOLISM RESEARCH AND REVIEWS
Diabetes Metab Res Rev 1999; 15: 412426.
Ketone Bodies: a Review of Physiology,
Pathophysiology and Application of Monitoring
to Diabetes
Lori Laffel*
Harvard Medical School, Joslin Clinic,
One Joslin Place, Boston, MA 02215,
USA
*Correspondence to: Harvard
Medical School, Joslin Clinic,
One Joslin Place, Boston, MA 02215,
USA
E-mail:lori.laffel@joslin.harvard.edu
Received: 3 August 1999
Revised: 22 October 1999
Accepted: 22 October 1999
Published online: 5 November 1999
CCC 1520-7552/99/06041215$17.50
Copyright # 1999 John Wiley & Sons, Ltd.
RE VI EW PA PE R
Summary
Ketone bodies are produced by the liver and used peripherally as an energy
source when glucose is not readily available. The two main ketone bodies are
acetoacetate (AcAc) and 3-b-hydroxybutyrate (3HB), while acetone is the
third, and least abundant, ketone body. Ketones are always present in the
blood and their levels increase during fasting and prolonged exercise. They
are also found in the blood of neonates and pregnant women. Diabetes is the
most common pathological cause of elevated blood ketones. In diabetic
ketoacidosis (DKA), high levels of ketones are produced in response to low
insulin levels and high levels of counterregulatory hormones. In acute DKA,
the ketone body ratio (3HB : AcAc) rises from normal (1 : 1) to as high as 10 : 1.
In response to insulin therapy, 3HB levels commonly decrease long before
AcAc levels. The frequently employed nitroprusside test only detects AcAc in
blood and urine. This test is inconvenient, does not assess the best indicator of
ketone body levels (3HB), provides only a semiquantitative assessment
of ketone levels and is associated with false-positive results. Recently,
inexpensive quantitative tests of 3HB levels have become available for use with
small blood samples (525 ml). These tests offer new options for monitoring
and treating diabetes and other states characterized by the abnormal
metabolism of ketone bodies. Copyright # 1999 John Wiley & Sons, Ltd.
Keywords acetoacetate; b-hydroxybutyrate; diabetes; diabetic ketoacidosis;
ketone bodies
Introduction
The term `ketone bodies' refers to three molecules, acetoacetate (AcAc),
3-b-hydroxybutyrate (3HB) and acetone (Figure 1). AcAc accumulates during
fatty acid metabolism under low carbohydrate conditions. 3HB is formed
from the reduction of AcAc in the mitochondria. These two predominant
ketone bodies are energy-rich compounds that transport energy from the liver
to other tissues. Acetone is generated by spontaneous decarboxylation of
AcAc [1,2] and is responsible for the sweet odor on the breath of individuals
with ketoacidosis. During periods of glucose deciency, ketone bodies play a
key role in sparing glucose utilization [3,4] and reducing proteolysis [5,6].
Unlike most other tissues, the brain cannot utilize fatty acids for energy
when blood glucose levels become compromised. In this case, ketone bodies
provide the brain with an alternative source of energy, amounting to nearly
2/3 of the brain's energy needs during periods of prolonged fasting and
starvation. Ketone bodies stimulate insulin release in vitro [79], generate
oxygen radicals and cause lipid peroxidation [1013]. Lipid peroxidation and
the generation of oxygen radicals may play a role in vascular disease in
diabetes [10].
Ketone Body Monitoring 413

Figure 1. Structures of major ketone bodies

Ketone bodies are present in small amounts in the
blood of healthy individuals during fasting or prolonged
exercise. Abnormally large quantities of ketone bodies are
found in the blood of individuals who are experiencing
diabetic ketoacidosis, alcoholic ketoacidosis, salicylate
poisoning, and other rare conditions. Ketone bodies have
been used as markers of hepatic energy metabolism
following liver transplantation [1419]. In these instan-
ces, measures of serum or urinary ketones can be useful to
assess the severity of the underlying disease and to
monitor treatment.
Ketone body metabolism
Ketone body metabolism includes both ketogenesis and
ketolysis. These biochemical activities enable fat-derived
energy to be generated in the liver and used by other
organs, such as the brain, heart, kidney cortex and skeletal
muscle when there is limited availability of carbohydrate
or when carbohydrate cannot be used effectively. For
example, after an over-night fast, ketone bodies supply
26% of the body's energy requirements, while they
supply 3040% of the energy needs after a 3-day fast.
Ketogenesis
Ketogenesis is the process by which fatty acids are
transformed into AcAc and 3HB. This process takes place
in the mitochondria of perivenous hepatocytes [2023].
The production of fatty acids and their conversion to fuel
or to ketone bodies are determined by several factors
(Figure 2). Fatty acid production in adipose tissue is
stimulated by epinephrine and glucagon and inhibited by

Figure 2. Relationship between glucose and fatty acid metabolism and the formation of ketone bodies in the hepatocyte. Glu-
cose and fatty acids are metabolized to acetyl CoA, which enters the citric acid cycle by condensing with oxaloacetate. Glycoly-
sis produces pyruvate, which is a precursor of oxaloacetate. If glycolysis falls to very low levels, then oxaloacetate is
preferentially utilized in the process of gluconeogenesis. In this case oxaloacetate is not available to condense with acetyl CoA
produced by fatty acid metabolism and acetyl CoA becomes diverted from the citric acid cycle to ketone body formation

Copyright # 1999 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 1999; 15: 412426.
414 L. Laffel

insulin. Acetyl CoA is the link to the citric acid cycle
following glycolysis of glucose or b-oxidation of fatty
acids. To enter the citric acid cycle, acetyl CoA rst
condenses with oxaloacetate (Figure 2). Oxaloacetate is
derived from pyruvate during glycolysis. Therefore, it is
essential to have a level of glycolysis that provides
sufcient oxaloacetate to condense with acetyl CoA. If
glucose levels become too low (e.g. during fasting or low
insulin levels in diabetes), then oxaloacetate is preferen-
tially utilized in the process of gluconeogenesis, instead of
condensing with acetyl CoA. Acetyl CoA is then diverted
to ketone body formation.
In healthy adults, the liver is capable of producing up to
185 g of ketone bodies per day. The process includes the
following steps: b-oxidation of fatty acids to acetyl CoA,
formation of acetoacetyl CoA, conversion of acetoacetyl
CoA to 3-hydroxy-3-methylglutaryl CoA (HMG CoA) and
then to AcAc; and nally reduction of AcAc to 3HB
(Figure 3).
The conversion of acetyl CoA to acetoacetyl CoA is
catalyzed by 3-ketothiolase (Figure 3). HMG CoA is
formed from acetoacetyl CoA by mitochondrial HMG
CoA synthase (mHS). This step is stimulated by starva-
tion, low levels of insulin, and the consumption of a high-
fat diet [24]. HMG CoA is also produced from ketogenic
amino acids such as leucine, lysine, and tryptophan via a
separate enzymatic process. HMG CoA is then cleaved to
liberate AcAc in a step mediated by HMG CoA lyase (HL).
The reduction of AcAc to 3HB is catalyzed by 3-
hydroxybutyrate dehydrogenase (HBD), a phosphatidyl
choline-dependent enzyme. During this step, NADH is
oxidized to NAD+, and as a consequence, the ultimate
ratio of 3HB to AcAc in the blood is dependent on
the redox potential (i.e. the NADH/NAD+ ratio) within
hepatic mitochondria.
Acetoacetate and 3HB are short-chain (4-carbon)
organic acids that can freely diffuse across cell mem-
branes. Therefore, ketone bodies can serve as a source of
energy for the brain (which does not utilize fatty acids)
and the other organs mentioned above [25]. Ketone
bodies are ltered and reabsorbed in the kidney. At
physiologic pH, these organic acids dissociate completely.
The large hydrogen-ion load generated during their
pathologic production, in diabetic ketoacidosis, for
example, rapidly overwhelms the normal buffering
capacity and leads to a metabolic acidosis with an
increased anion gap.
Control of ketogenesis
The rate of ketogenesis depends upon the activity of three
enzymes: hormone-sensitive lipase (or triglyceride
lipase), which is found in peripheral adipocytes, and
acetyl CoA carboxylase and mHS, which are found in the
liver (Figure 4). The rst two of these enzymes, hormone-
sensitive lipase and acetyl CoA carboxylase, are in turn
exquisitely controlled by the level of circulating insulin
[26], which acts to inhibit ketogenesis, and epinephrine
and glucagon, which act to stimulate ketogenesis

Figure 3. Enzymes in the hepatocyte involved in ketone formation. Fatty acyl CoA is transported into mitochondria via the
carnitine shuttle, driven by carnitine palmitoyltransferase 1 (CPT 1). Acetyl CoA carboxylase catalyzes the production of malo-
nyl CoA from acetyl CoA. Since malonyl CoA inhibits CPT1, decreased activity of acetyl CoA carboxylase stimulates transport of
fatty acids into the mitochondria. The enzymes in the conversion of acetyl CoA to acetoacetate are 3-ketothiolase (3-KT), HMG
CoA synthase (mHS) and HMG CoA lyase (HL). Acetoacetate is reduced to 3HB by 3-HB dehydrogenase (HBD), and acetone is
formed by the spontaneous decarboxylation of acetoacetate

Copyright # 1999 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 1999; 15: 412426.
Ketone Body Monitoring 415

Figure 4. Relationship between hepatocytes and adipocytes in glucose and lipid metabolism. The ratio of glucagon to insulin deter-
mines the utilization and storage of glucose and fatty acids by hepatocytes and adipocytes. The rate of ketogenesis depends upon
the activity of hormone-sensitive lipase in adipocytes (right panel) and acetyl CoA carboxylase and mHS, which are found in the
liver (see Figure 3). When insulin levels are high (left panel), glucose is converted to energy (ATP) in most cells and is stored as
glycogen in hepatocytes. Fatty acids are converted to triglyceride in hepatocytes. The triglycerides are then transported by lipopro-
teins for storage in adipocytes. When insulin levels decrease (right panel), the stores of glycogen are liberated as glucose by the
hepatocytes for use as fuel by other cells. Hormone-sensitive lipase activity, regulated by insulin and glucagon, increases, and the
triglycerides stored in adipocytes are released as fatty acids. As the glucose levels drop due to depletion of the glycogen stores, the
fatty acids become the major fuel for most cells and ketone production increases in hepatocytes

[2730]. Insulin inhibits lipolysis and stimulates lipogen-
esis through deactivation of hormone-sensitive lipase and
activation of acetyl CoA carboxylase, respectively. In
other words, a low glucagon/insulin ratio inhibits keto-
genesis while a high glucagon/insulin ratio, as occurs
with fasting or diabetes, favors ketogenesis through
promotion of lipolysis in the adipocyte and stimulation
of b-oxidation of free fatty acids in the liver.
Hormone-sensitive lipase catalyzes the conversion of
triglycerides to diglycerides for further degradation to the
free fatty acids that serve as substrate for ketogenesis. On
the other hand, acetyl CoA carboxylase catalyzes the
conversion of acetyl CoA to malonyl CoA, increasing
the hepatic level of the primary substrate of fatty acid
biosynthesis. Malonyl CoA levels vary in the liver directly
according to the rate of fatty acid synthesis and inversely
with the rate of fatty acid oxidation [31]. Therefore,
malonyl CoA plays a pivotal role in the regulation of
ketogenesis. Low levels of malonyl CoA stimulate trans-
port of fatty acids into the mitochondria via the carnitine
shuttle for oxidation to ketone bodies. Malonyl CoA
normally inhibits the carnitine palmitoyltransferase 1
(CPT 1), the enzyme that transports fatty acyl CoA across
the mitochondrial membrane (Figure 3).
Insulin inhibits ketogenesis by triggering the depho-
sphorylation of hormone-sensitive lipase and activates
lipogenesis by stimulating acetyl CoA carboxylase
(Table 1; Figure 4). In the adipocytes, dephosphorylation

Table 1. Effects of insulin and glucagon on key enzymes controlling ketogenesis

Effect of insulin Effect of glucagon

Enzyme Location Action Result (ketogenesis E) (ketogenesis F)

Hormone-sensitive lipase peripheral adipocytes breaks down triglycerides elevated serum fatty acids inhibited stimulated
(see Figure 4) into fatty acids
Acetyl CoA carboxylase hepatocytes converts acetyl CoA to malonyl CoA blocks fatty stimulated inhibited
(see Figure 3) malonyl CoA acid transport into mitochondria
HMG CoA synthase hepatic mitochondria converts acetoacetyl CoA rate limiting step in producing inhibited stimulated
(see Figure 3) into acetoacetate the rst of the series of ketone
bodies

Copyright # 1999 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 1999; 15: 412426.
416
of hormone-sensitive lipase inhibits the breakdown of
triglycerides to fatty acids and glycerol, the rate-limiting
step in the release of free fatty acids from the adipocyte.
This thereby reduces the amount of substrate that is
available for ketogenesis. In addition, insulin-mediated
dephosphorylation of inhibitory sites on hepatic acetyl
CoA carboxylase increases the production of malonyl CoA
and simultaneously reduces the rate at which fatty acids
can enter hepatic mitochondria for oxidation and ketone
body production.
Glucagon stimulates ketogenesis by triggering the
phosphorylation of both lipase and acetyl CoA carboxy-
lase by cyclic AMP-dependent protein kinase. In the
adipocytes, phosphorylation of lipase by cyclic AMP-
dependent protein kinase stimulates the release of fatty
acids from triglycerides (Figure 4). Glycerol freely
diffuses out of the adipose tissue into the circulation for
transport to the liver. Free fatty acids enter the circulation
and travel bound to albumin for uptake and metabolism
in other tissues such as the heart, skeletal muscle, kidney,
and the liver. In hepatocytes, phosphorylation of acetyl
CoA carboxylase by cyclic AMP-dependent protein kinase
reduces the production of malonyl CoA which, in turn,
stimulates fatty acid uptake by the mitochondria, and
thus increases the amount of substrate available for
ketogenesis.
Hepatic mitochondrial HMG CoA synthase (mHS) is the
third key enzyme involved in the control of ketogenesis.
The activity of this enzyme is increased by starvation and
a high-fat diet, and it is decreased by insulin. These
factors modulate the activity of mHS by altering the
production of mRNA and the post-translational phase of
Figure 5. Entry of ketone bodies into the citric acid cycle. Ketone bodies are used as fuel by the brain during prolonged starva-
tion. They enter the citric acid cycle after being converted to acetyl CoA by succinyl CoA-oxoacid transferase (SCOT) and
methylacetoacetyl CoA thiolase (MAT)
Copyright # 1999 John Wiley & Sons, Ltd.
L. Laffel
protein synthesis via reversible succinylation of the
enzyme itself [32]. Increasing the activity of mHS leads
to the production of ketone bodies (Figures 3 and 4).
Ketolysis
Ketolysis is the process by which ketone bodies are
converted into energy that can be used to fuel various
intracellular metabolic activities. Ketolysis occurs in the
mitochondria of many extrahepatic organs. The central
nervous system is particularly dependent on the delivery
of ketone bodies produced in the liver for the process of
ketolysis, since ketogenesis occurs very slowly if at all in
the central nervous system. Ketolysis involves two key
steps (Figure 5), the reconstitution of acetoacetyl CoA
from AcAc by the enzyme succinyl CoA-oxoacid transfer-
ase (SCOT), and the subsequent cleavage of an acetyl
group from acetoacetyl CoA to form acetyl CoA by the
enzyme methylacetoacetyl CoA thiolase (MAT).
SCOT is the rate-determining step in ketolysis. SCOT
activity is highest in the heart and kidney, followed by the
central nervous system and skeletal muscle [33]. SCOT
activity is also present, but at very low levels, in the liver.
Due to the sheer mass of skeletal muscle, this tissue
accounts for the highest fraction of total ketone body
metabolism in the resting state [34]. SCOT activity is
down-regulated by high (>5 mM) intracellular levels of
AcAc [35]. This phenomenon is responsible for the
observed increase in circulating levels of ketone bodies
during the early phases (3 days to 2 weeks) of starvation,
despite relatively constant rates of hepatic ketogenesis
during this period.
Diabetes Metab Res Rev 1999; 15: 412426.
Ketone Body Monitoring
MAT, the enzyme responsible for the second key step in
ketolysis, is present in the liver the primary locus of
ketogenesis as well. In extrahepatic tissues, this enzyme
tends to enhance the production of acetyl CoA from
acetoacetyl CoA as mentioned above. In the liver,
however, MAT plays a key role in ketogenesis [36]; in
this case, MAT helps create acetoacetyl CoA, the substrate
for mitochondrial HMG CoA synthase (mHS).
Ketone body levels
The levels of circulating ketone bodies vary across
populations of normal individuals even after controlling
for age and duration of fasting. This variation is
presumably caused by variations in basal metabolic
rate, hepatic glycogen stores and differences in the
mobilization of amino acids from muscle proteins [2].
Marked elevations in circulating levels of ketone bodies
are seen in certain pathophysiological states, such as
diabetic ketoacidosis. The levels of circulating ketone
bodies range from <50 mM in certain postprandial
subjects to >25 mM in subjects with diabetic ketoacidosis
[21,3742]. Most investigators agree that normal serum
levels of ketone bodies can be dened as <0.5 mM;
hyperketonemia can be dened as levels in excess of
1.0 mM, and ketoacidosis can be dened as levels in
excess of 3.0 mM [2,29].
The ketone body ratio, dened as the ratio of
circulating 3HB to AcAc, is approximately 1 following a
meal, but this rises to nearly 6 after prolonged fasting
[2,41,4345]. The ketone body ratio can also be markedly
elevated in diabetic ketoacidosis, alcoholic ketoacidosis,
severe hypoxia, end-stage liver disease, hepatic ischemia,
various metabolic disorders, and multiple organ failure.
All of these pathological states are characterized by
changes in the redox potential within hepatocellular
mitochondria such that there are low levels of the reduced
form of nicotinamide adenine dinucleotide (NADH) and
high levels of the oxidized form of nicotinamide adenine
dinucleotide (NAD+).
Ketosis
Ketosis is nearly always a transient condition that is
characterized by elevated serum levels of ketone bodies.
Both hyperketonemia and ketoacidosis are considered to
be forms of ketosis. The most common causes of ketosis
are `physiological', in which mildly to moderately elevated
levels of circulating ketone bodies are present in response
to fasting (especially during infancy or pregnancy),
prolonged exercise, or a ketogenic (high-fat) diet. Ketosis
can also be caused by pathological processes such as those
precipitated by endocrine diseases including diabetes
mellitus, cortisol deciency, and growth hormone de-
ciency; toxic ingestions of ethanol or salicylates; and
certain rare inborn errors of metabolism. The most
common pathological causes of ketosis are diabetic
ketoacidosis and toxic ketoacidoses, especially those
Copyright # 1999 John Wiley & Sons, Ltd.
417
associated with withdrawal following binge drinking
(alcoholic ketoacidosis), salicylate overdose and isopropyl
alcohol ingestion.
Physiological ketosis
Physiological ketosis occurs quite readily in the neonatal
period and during pregnancy. In newborn infants, ketone
production is activated by the high-fat content of milk.
The resulting mild hyperketonemia is not associated
with ketonuria. Ketonuria in neonates is abnormal and
suggestive of an inborn error of metabolism. In toddlers
and young children, hyperketonemia becomes apparent
within 24 h of the onset of a fast. Mild infections in this
age group, especially those associated with vomiting and
diarrhea, commonly cause ketone body levels to rise
above 1.0 mM and occasionally into the range of frank
ketoacidosis. Children of this age are thus more sus-
ceptible to physiological ketosis because of their dimin-
ished hepatic stores of glycogen and their proportionately
larger central nervous system than adults, in whom
ketone body levels rise above 1.0 mM only after a fast of
approximately 3 days, rising further to a plateau of
68 mM after 4 weeks of starvation [37].
Pregnancy is associated with two- to three-fold eleva-
tions in maternal ketone body levels at baseline [46] and
a rapid, exaggerated rise in these levels in response to a
fast [47]. Ketone bodies can be detected in the urine of
normal individuals who are fasting and in approximately
30% of the rst morning specimens of pregnant women
[48]. Ketone bodies have been found to cross the placenta
freely [49]. In rodent models, prolonged periods of
maternal ketosis have been associated with fetal mal-
formations including neural tube defects [50].
Ketogenic diets and prolonged exercise are also
associated with physiological ketosis. Ketogenic diets,
which are used in certain weight-reduction programs [51]
and which have been used to treat patients with
refractory epilepsy, contain at least 50% of their calories
as fat. This degree of fat content is nearly twice as high as
that found in the typical diet of individuals in developed
nations. Prolonged exercise is also associated with mild
hyperketonemia, with ketone body levels not uncom-
monly rising to the range of 12 mM [52].
Diabetic ketoacidosis
Diabetic ketoacidosis (DKA) and the hyperglycemic
hyperosmolar nonketotic state (HHNS) are two serious,
acute metabolic complications of diabetes [53,54]. Of
these two complications, only DKA is associated with
elevated levels of ketone bodies in the blood. Several
comprehensive reviews of DKA have been published in
recent years [5562]. This paper provides a brief overview
of DKA and a detailed summary of ketone metabolism in
this pathological setting. The hyperglycemic hyperosmolar
nonketotic state is not discussed further.
DKA is an acute pathological process that is character-
ized by elevated blood glucose, elevated levels of ketone
Diabetes Metab Res Rev 1999; 15: 412426.
418
Table 2. Comparison of typical changes in selected laboratory results associated with DKA and other states altering ketone meta-
bolism
Total plasma ketones
Diabetic ketoacidosis large increase
Starvation or high fat intake slight increase
Alcohol ketosis (starvation) slight to moderate increase
Salicylate intoxication normal
Methanol or ethylene glycol normal
intoxication
a
Respiratory alkalosis and metabolic acidosis.
This table was adapted from Kitabchi A, Fisher J, Murphy M, Rumbak M. Diabetic ketoacidosis and the hyperglycemic, hyperosmolar nonketotic state. In Joslin's
Diabetes Mellitus, Kahn C, Weir G (eds). Philadelphia: Lea & Febiger, 1994; 738770. Reproduced with permisson of the author, Dr Abbas E. Kitabchi, and the
publisher, Lippincott Williams & Wilkins.
bodies in the blood, and metabolic acidosis [63]. These
metabolic derangements are caused by an effective lack of
insulin and simultaneous elevations of the counter-
regulatory hormones glucagon, catecholamines, cortisol,
and growth hormone. DKA occurs most often in patients
with Type 1 diabetes, although it can occur in patients
with Type 2 diabetes. DKA is precipitated by infections,
omission of or inadequate use of insulin, new-onset
diabetes, and other events, such as the stress associated
with surgery. In the case of Type 2 diabetes, obese African
Americans represent a subset with a higher probability of
ketoacidosis than other Type 2 subsets [64,65]. The
development of DKA was most likely due to impairment
of insulin secretion [64,65]. In contrast with patients
having Type 1 diabetes, two-thirds of the obese patients
with Type 2 diabetes and DKA were able to maintain
good metabolic control during follow-up when insulin
treatment was withdrawn [64]. The treatment of DKA
usually involves hospitalization, continuous infusions of
insulin, rehydration, careful replacement of electrolytes,
restoration of acid/base balance [66,67], and manage-
ment of any underlying infection or other precipitating
event.
From the time of Dreschfeld's original description of
DKA in 1886 [68] until the discovery of insulin nearly 40
years later, mortality from this condition approached
100%. By the early 1930s, however, mortality had
decreased to 30%, and by 1960 the National Institutes
of Health reported a 10% mortality from DKA [69]. Even
in the 1990s, however, DKA is associated with mortality
rates in the range of 45% [53]. Mortality from DKA is
usually caused by complications such as cerebral edema
[70], adult respiratory distress syndrome, and throm-
boembolic phenomena.
Ketone body metabolism in DKA
In diabetic ketoacidosis, the effective lack of insulin and
concomitant elevations of counter-regulatory hormones
combine to stimulate lipolysis in the adipose tissue and
ketogenesis in the liver [71,72]. Indeed, insulin deciency
is the most important regulator of ketogenesis. Lipolysis
the breakdown of triglycerides is mediated by hormone-
sensitive lipase in adipose tissue. Hormone-sensitive
lipase is activated by both insulin deciency and the
Copyright # 1999 John Wiley & Sons, Ltd.
L. Laffel
Plasma glucose Glycosuria Plasma pH
increase positive decrease
normal negative normal
normal or decrease negative decrease or increase
normal or decrease negative decrease or increasea
normal negative, false positive, decrease
or false negative
rise in counter-regulatory hormones, the precise hormo-
nal milieu that characterizes DKA. This same hormonal
milieu inhibits lipid synthesis and re-esterication in the
adipocytes. The net impact of these events on adipose
tissue is the release into the circulation of large quantities
of free fatty acids (FFA).
Circulating FFA are both the principal substrate for
ketogenesis and the major stimulant for this process to
occur. In the liver of patients with active DKA, the
effective lack of insulin and the high levels of counter-
regulatory hormones combine to impair the re-
esterication of FFA (that is, to impair hepatic lipid
synthesis) and to catalyze the processes by which FFA are
transported into mitochondria [73,74] and subsequently
converted into ketone bodies. FFA transport into hepatic
mitochondria is enhanced by glucagon-mediated reduc-
tions in the cytosolic malonyl-CoA, which removes
inhibition of carnitine palmitoyltransferase 1 (CPT1).
Malonyl-CoA competitively inhibits CPT1, the enzyme
that transports fatty acyl CoA across hepatic mitochon-
drial membranes (Figure 3) [54,75]. Within the mito-
chondria, fatty acyl CoA normally undergoes b-oxidation
to acetyl CoA, and acetyl CoA is in turn shunted into
the tricarboxylic acid cycle. In DKA, however, the
enormous supply of fatty acyl CoA and deciency in
oxaloacetate overwhelm these normal biochemical path-
ways. When this occurs, excessive amounts of fatty acyl
CoA derivatives are oxidized to form ketone bodies, and
large quantities of 3HB and AcAc are released into the
blood.
In addition to the generation of abnormally high levels
of ketone bodies in the blood, DKA is also associated with
an alteration in the ratio of these two ketone bodies. This
ratio rises to 3 : 1 or higher (to as high as 10 : 1) in DKA,
with relatively high levels of 3HB being generated as a
result of the highly reduced state of hepatic mitochondria
in the patient with DKA [76] (Figure 6).
The increased level of ketone bodies in the blood of
patients with DKA is offset to some extent by increased
utilization in the brain, skeletal muscle, and kidneys.
Ketone bodies are also ltered in large quantities by the
kidneys, and the fraction that is not re-absorbed is
excreted in the urine. In DKA, hypoinsulinemia acts to
decrease renal clearance of ketone bodies via unclear
Diabetes Metab Res Rev 1999; 15: 412426.
Ketone Body Monitoring 419

Figure 6. Plasma and urine levels of acetoacetic acid, b-hydroxybutyrate and ketone bodies (determined by nitroprusside reac-
tion) in 37 patients with diabetic ketoacidosis before (time 0) and during low-dose infusion (IV) of insulin for 48 h. Panels A
through C indicate levels determined in plasma specimens and Panel D indicates levels determined in urine specimens.
Adapted from Kitabchi A, Fisher J, Murphy M, Rumbak M. Diabetic ketoacidosis and the hyperglycemic, hyperosmolar non-
ketotic state. In Joslin's Diabetes Mellitus, Kahn C, Weir G (eds). Philadelphia: Lea & Febiger, 1994; 738770. Reproduced with
permission of the author, Dr Abbas E. Kitabchi, and the publisher, Lippincott Williams & Wilkins

mechanisms [7779]. The utilization of ketone bodies by
skeletal muscle is reduced as the uptake mechanisms
become saturated [34]. The uptake capacity for 3HB in
muscle is reduced in diabetes [8082] and insulin does
not further increase the rate of 3HB uptake [80].
However, it is the rate of production of ketones, not an
impaired uptake, that appears to be the major factor in
hyperketonemia [34]. In any case, as a rule, the rate of
ketone body generation always exceeds the combined
rates of ketone body utilization and excretion in DKA.
Plasma ketone body concentrations in excess of 200300
times higher than those seen in the normal fasting state
are possible [83]. 3HB and AcAc are strong organic acids
that dissociate fully at physiological pH. The associated
rapid and progressive rise in serum hydrogen ion
concentration far outstrips the buffering capacity of the
serum and tissues, and the result is the development of
metabolic acidosis [84].
A third ketone body, acetone, is formed via the
spontaneous decarboxylation of AcAc in patients with
DKA [85]. Acetone, while present in abnormally high
concentrations during DKA, does not contribute to
metabolic acidosis since it does not dissociate to yield
hydrogen ions. Acetone is highly fat soluble and is
excreted slowly via the lungs. It generates the distinctive,
aromatic smell on the breath of patients in DKA.
Toxic ketoacidosis
Ketoacidosis can also be precipitated following binge
drinking and withdrawal in chronic alcoholics [8689],
isopropyl alcohol [90,91] and salicylates [92,93]. After
DKA, alcoholic ketoacidosis is the most common cause
of ketoacidosis in adults. It is a relatively common
syndrome in chronic alcohol abusers and binge drinkers.
Alcoholic ketoacidosis (AKA) is generally associated with

Copyright # 1999 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 1999; 15: 412426.
420
a period of excessive alcohol consumption, followed by
withdrawal and minimal food intake. The decreased food
intake is often due to gastroenteric problems, including
gastritis, hepatitis, pancreatitis, or related to the with-
drawal itself. AKA presents as a syndrome of abdominal
pain, nausea, vomiting, and dehydration [94,95]. It is
frequently associated with (and sometimes confused
with) acute gastritis, hepatitis or pancreatitis. Patients
often develop supervening pneumonias, strokes, rhabdo-
myolysis and alcohol withdrawal syndrome. In this
condition, blood glucose levels are often normal, but
they can be elevated [96] (Table 2).
While ethanol can directly antagonize ketogenesis
[97,98], the pathophysiology of AKA is triggered by an
alcohol-induced change in the redox potential within the
hepatocytes, and a reduction in oxaloacetate. These
biochemical effects are triggered when ethyl alcohol is
metabolized in the liver to acetoacetate and then to
acetate. Excess amounts of NADH are produced in
association with this process. To reoxidize NADH,
chemical processes are activated in the hepatocytes, in
which pyruvate is converted to lactate and oxaloacetate is
converted to malate [94,99,100]. Since pyruvate and
oxaloacetate are substrates for gluconeogenesis, this
latter process is diminished.
As with DKA, a cascade of biochemical processes is
triggered in AKA. Diminished intracellular oxaloacetate
concentrations decrease entry of acetyl CoA into the Krebs
cycle. The low ratio of insulin to glucagon decreases
the activity of acetyl CoA carboxylase and consequently
reduces intracellular levels of malonyl CoA. The reduced
levels of malonyl CoA in turn trigger an increase in the
transmitochondrial transport of fatty acyl CoA in
hepatocytes. Thus, fatty acyl CoA, the substrate of hepatic
ketogenesis, is in abundant supply in the mitochondria of
patients with AKA.
In AKA, ketogenesis itself is stimulated by increased
levels of glucagon, cortisol and catecholamines. These
counter-regulatory hormones are elevated in AKA in
response to volume depletion and intercurrent illnesses.
The ketone bodies that are created in AKA exhibit a high
3HB/AcAc ratio as a result of the above-mentioned
reduced environment in hepatocyte mitochondria. As
discussed below, this phenomenon may create clinically
misleading false-negative urine and blood tests for
ketones, since the routine tests for ketones do not
detect 3HB.
Ingestion of isopropyl alcohol is associated with
ketonemia and a clinical syndrome that resembles alcohol
intoxication. Isopropyl alcohol, which is found in anti-
freeze and rubbing alcohol, is metabolized directly to
acetone. In patients that have ingested isopropyl alcohol,
acetone levels are exceedingly high, but levels of the
ketoacids 3HB and AcAc are normal.
Unlike isopropyl alcohol ingestion, salicylate poisoning
stimulates `true' ketogenesis and causes frank ketoacido-
sis. Salicylate poisoning should always be considered in
the differential diagnosis of ketoacidosis of undetermined
origin.
Copyright # 1999 John Wiley & Sons, Ltd.
L. Laffel
Measurement of ketone bodies in
clinical practice
In the 1970s, patient monitoring for diabetes generally
included routine home urine tests for glucose and ketone
bodies combined with occasional laboratory determina-
tions of blood glucose. Urinary ketones were used
primarily in patients with Type 1 insulin-dependent
diabetes to screen for impending DKA. Physicians
reserved venous blood glucose testing to manage acute
metabolic complications and intercurrent illnesses, and to
investigate new or worsening symptoms [101104].
Blood testing for ketones, usually qualitative in nature,
was reserved for the domain of emergency rooms and
medical wards, where it was used for the differential
diagnoses of metabolic acidosis, and as an adjunct in the
management of DKA.
Technical advances in blood glucose self-monitoring,
combined with proof that aggressive control of blood
glucose levels reduces the incidence of complications
[105], has fostered dramatic changes in both the methods
for glucose measurement and the goals of glucose
monitoring. In the 1990s, patient self-monitoring of
blood glucose (SMBG) levels by ngerstick has replaced
urine glucose testing as the recommended approach to
home monitoring of diabetes, and glycated hemoglobin
testing in the clinic has become an accepted approach to
assess diabetes control in the long-term.
Traditional ketone-testing methods
In contrast to these striking advances in the approach to
glucose monitoring, the process by which ketone bodies
are measured in urine and blood, and the clinical
indications for doing so, have not changed signicantly
in 25 years. Urine ketone testing remains a time-honored
part of patient monitoring, especially for those with Type 1
diabetes [106,107], and blood ketone testing remains
focussed on diagnosis and management of acute acid-
base disturbances such as DKA. The American Diabetes
Association recommends that all people with diabetes
should test their urine for ketones during periods of acute
illness or stress, when blood glucose levels are consistently
in excess of 300 mg/dl, during pregnancy, or when
symptoms suggestive of ketoacidosis are present [108].
Commercial ketone tests for urine and blood rely on the
Legal reaction, in which AcAc in a specimen of urine or
blood reacts in the presence of alkali with nitroprusside
(nitroferricyanide) to produce a purple-colored complex
on a test strip or a test tablet. If glycine is added to the test
reagent, the Legal test can also detect acetone in the
specimen, although to a lesser degree. However, none of
the commercial tests for ketone bodies reacts to the
presence of 3HB in the specimen. The Legal test is
semiquantitative; it does not measure the exact amount of
ketones in urine or blood.
Some commercial tests for ketone bodies contain
glycine and hence can detect both acetone and AcAc,
Diabetes Metab Res Rev 1999; 15: 412426.
Ketone Body Monitoring
while others only detect AcAc. There is no evidence that
any of these commercial tests offer advantages over the
others. Multitest urine strips used in the professional ofce
or hospital setting utilize the methodology noted above.
Problems with traditional approaches
Conventional ketone testing with the nitroprusside test is
associated with several problems. Perhaps the most basic
one is that patients perceive urinary ketone testing to be
an unpleasant and time-consuming experience, particu-
larly in this era of promoting blood glucose monitoring.
As a result, the rates of noncompliance are exceedingly
high. In addition, commercial ketone tests can provide
misleading information in the diagnosis and manage-
ment of DKA or impending DKA, and they are associated
with a signicant risk of false-positive and false-negative
ndings.
Commercial ketone tests are associated with well-
known difculties in their role as DKA diagnostic and
management tools [85,109]. For example, ketones can be
found in signicant quantities in the urine of individuals
who are not in DKA. In DKA management, urinary ketone
tests are unreliable for monitoring recovery due to un-
predictable degrees of ketone-body reabsorption in the
kidneys, and the fact that ketone bodies may be detected
in urine long after blood concentrations have returned to
normal levels.
Ketone test results can actually cause a false impression
that DKA is failing to respond to therapy, when in fact an
adequate response is underway. The nitroprusside
reagent only detects AcAc, not 3HB. The ketone body
ratio in the setting of DKA is initially 3 : 1 (3HB : AcAc), or
greater. As DKA improves with insulin therapy, there is an
overall reduction in the levels of ketone bodies and a
coincident conversion of 3HB to AcAc, which is driven by
an increasingly oxidized state in the hepatocytes. The net
effect of these two changes is that AcAc levels tend
to plateau for a period of time even as 3HB levels and
overall ketone body levels are dropping precipitously
[110]. In such a circumstance, the nitroprusside test,
whether it is performed on urine or blood, fails to detect
the overall improvement and may lead to unnecessary
and potentially dangerous increases in insulin therapy
[111].
Furthermore, ketone tests based on the nitroprus-
side reaction have been reported to give false-positive
results in the presence of drugs containing sulfhydryl
groups such as the antihypertensive drug Captopril1,
mesna, N-acetylcysteine, dimercaprol and penicillamine
[112116]. An overwhelming majority of laboratories fail
to follow procedures to eliminate or recognize these false-
positive results [117,118]. Cases in which patients
received or nearly received inappropriate therapy with
insulin due to false-positive ketone recordings have been
reported [114,115].
False-negative readings also have been reported when
nitroprusside test strips or tablets have been exposed to
air for an extended period of time or when urine
Copyright # 1999 John Wiley & Sons, Ltd.
421
specimens are highly acidic, such as after the ingestion
of large quantities of ascorbic acid. Potentially prevent-
able DKA has been reported in children with Type 1
diabetes due to falsely negative home urine ketone test
results [119].
Quantitative tests for 3HB in the blood
The inability of the nitroprusside test to detect 3HB and
an increasing belief that blood levels of 3HB might prove
useful in the management of DKA, as well as provide the
potential to avert DKA, have recently stimulated the
development of assays for 3HB in the blood [45,120].
Rapid enzymatic methods have now been developed for
the quantication of 3HB levels in small-volume samples
[121,122], and at least two manufacturers offer a blood
ketone test based on these methods.
The rst of these systems is marketed by GDS
Diagnostics (Elkart, IN, USA), which is a bench-top
analyzer for use in clinical laboratories and physicians'
ofces. The GDS System determines 3HB levels on a drop
of blood (25 ml) in about 2 min. The detection range of
3HB for the GDS System is 02 mM. Adhering to
recommended procedures, the performance of the GDS
Diagnostics System compared favorably to that of an
automated Hitachi 717 analyzer that is normally reserved
for laboratory use [120]. The need to dilute sample with
serum and the need to assay at room temperature are,
however, both deterrents to rapid and routine use.
A second system for the precise quantication of 3HB
levels in the blood has recently been introduced by Abbott
Laboratories, MediSense Products Inc. (Bedford, MA,
USA). The Precision XtraTM Advanced Diabetes Manage-
ment Systems is a simple-to-use hand-held device that is
currently available as a tool for self-monitoring of blood
3HB levels in the home. This system can measure 3HB
levels on a ngerstick blood specimen (5 ml) within 30 s
and is accurate for 3HB levels from 0 mM to as high as
6 mM. The Precision XtraTM System utilizes a specic re-
agent card for 3HB and one for glucose. This allows users
to assess serum glucose levels during the same procedure.
Applications of quantitative blood 3HB
tests
Quantitative determinations of 3HB levels in the blood
would appear to have certain advantages in Type 1
diabetes, DKA, pregnancy complicated by diabetes, and
managing toxic ketoacidoses and other medical condi-
tions when compared with the nitroprusside test for
ketone bodies. At a minimum, the new test eliminates the
problem of false-positive test results caused by sulfhydryl-
containing drugs.
Can ngerstick determinations of 3HB levels
increase patient compliance with
recommendations for ketone testing?
While there are no data to support the hypothesis that a
ngerstick test for 3HB would increase patient compli-
Diabetes Metab Res Rev 1999; 15: 412426.
422
ance for ketone testing, the shift from urine glucose
testing to SMBG should provide a reasonable predictive
model. The American Diabetes Association recommends
that most patients with diabetes perform SMBG 34 times
daily in order to lower blood glucose levels to normal or
near-normal levels [106]. Nevertheless, national survey
data from 1989 indicate that only 33% of people with
diabetes (including 40% of those with Type 1) perform
SMBG even once daily [123]. Barriers to increasing the
use of SMBG, and presumably blood 3HB testing, include
`high costs . . . inadequate education of both health care
providers and patients about the health benets . . .
patient psychological and physical discomfort associated
with nger-prick blood sampling, and patient-perceived
inconvenience of testing in terms of time requirements
and complexity of the technique' [101,124]. Thus, while
the ngerstick approach is likely to be more palatable to
some than the nitroprusside test on urinary specimens,
this approach may not represent a `magic bullet' for
patient compliance. However, studies specic to ketone
testing are needed.
Can quantication of 3HB levels in the blood of
patients with Type 1 diabetes be used to help
monitor diabetes control and guide insulin
therapy?
Available evidence suggests that this test could indeed be
helpful to physicians who treat patients with Type 1
diabetes. For example, 3HB levels were found to be
more sensitive than the nitroprusside test in the detec-
tion of under-insulinization and avoidance of DKA
[125,126]. Also, there was a dissociation between
serum glucose levels and serum 3HB levels in several
patients. Based on these observations, 3HB levels,
especially those determined before breakfast, can be a
sensitive metabolic marker to estimate the adequacy of
insulin therapy [127].
Serum 3HB levels were found to be elevated in several
Type 2 patients despite normal fasting blood glucose
levels if they were treated with diet and/or oral
antidiabetic medications and no insulin [125]. The role
of 3HB testing in Type 2 patients certainly requires
further investigation [128].
Serum 3HB levels are useful in designing new insulin
regimens aimed at optimizing glycemic control for
Type 1 patients with a history of nocturnal hypo-
glycemia [129]. A separate, larger issue is whether
home use of the 3HB blood test can prove useful
in daily management of Type 1, much as SMBG has
become a central part of diabetes daily management.
While there are no published studies that focus on this
key issue, experiences with SMBG again can be applied
as a model. For example, accurate results with home
3HB testing are likely to be technique dependent
[130132]. Some effort will be required to assure that
patients' techniques are acceptable, both initially and
with time. Further, any device approved for home
blood ketone testing should, therefore, be technique
independent.
Copyright # 1999 John Wiley & Sons, Ltd.
L. Laffel
As another example, patients must be taught how to
deal with the new volume of information that they will be
collecting. In cases where serum glucose levels and
ketone levels are both elevated or both normal, it will be
reasonably clear what is required. But what should
patients do when there is some degree of discordance
in the ndings, e.g. if 3HB levels are found to be elevated
in the setting of normal or near-normal glucose values?
Clearly more studies are necessary, and perhaps guide-
lines for patient self-management of 3HB levels need to be
drafted before there can be a clear path forward.
Can the direct measurement of 3HB enhance
the management of DKA in any way
[133,134]?
b-Hydroxybutyrate levels correlate better than AcAc with
changes in acid-base status during the course of treatment
for DKA [64]. For example, acidosis had resolved in all
patients in whom 3HB levels were <0.5 mM but in none
of the patients in whom 3HB levels exceeded 1.1 mM. In
contrast, more than half of the patients had positive
nitroprusside tests for up to 24 h after acidosis had
resolved. Rapid determinations of 3HB levels were `useful
in establishing the diagnosis of DKA and in the manage-
ment of patients with prolonged metabolic acidosis,
combined diabetic and lactic acidosis, and other mixed
acid-base disorders'. Direct measurements of 3HB
improved laboratory turnaround time and replaced a
subjective, qualitative result with one that is quantitative
and less subject to observer bias [135].
A new insulin regimen for the acute treatment of DKA
used normalization of serum 3HB levels, rather than
normalization of serum glucose levels, as the primary
endpoint for reducing insulin therapy from continuous
infusion (5 U/h) to a lower dose [136]. This `extended
insulin regimen' was safe and produced resolution of
ketosis approximately 14 h earlier than the conventional
regimen. The authors speculated that more effective
resolution of ketosis may lead to a more rapid improve-
ment in insulin sensitivity during the early recovery
period from DKA, and that this may, in turn, potentially
shorten the length of hospital stay [137].
Other investigators [120] recently concluded that
frequent monitoring of serum ketone bodies adds little
if any useful information in the management of DKA
to that provided by a routine chemistry panel that
included measurements of serum glucose and total
carbon dioxide levels, even when 3HB specically was
determined. In this study, the investigators found no
clear relation between 3HB levels on admission and the
course of the DKA and development of DKA complica-
tions. These investigators speculated that quantitative
determinations of 3HB were probably not necessary even
in DKA patients that had multiple causes of acidosis. In
such cases, the investigators suggested that `selective use
of the nitroprusside test along with measurement of
lactate may help differentiate mixed acidosis'. These
conclusions have recently been supported by another
group [53].
Diabetes Metab Res Rev 1999; 15: 412426.
Ketone Body Monitoring
Thus, this small cohort of recent studies has provided
conicting results on the benets of 3HB testing in the
management of DKA. In this setting, the American
Diabetes Association has adopted this position on such
tests:
Healthcare professionals should be aware . . . that
currently available urine ketone tests are not reliable
for diagnosing or monitoring treatment of ketoacidosis.
Blood ketone testing methods that quantify 3-
hydroxybutyric acid, the predominant ketone body,
are now available. These may offer a useful alternative
to urine ketone testing because 3-hydroxybutyric acid
determinations are reliable for diagnosing and mon-
itoring treatment of ketoacidosis [101].
Do quantitative assays for 3HB have value in
predicting certain fetal outcomes in the
offspring of pregnant women with diabetes
and gestational diabetes?
A few studies have provided support for the role of 3HB
testing in pregnant women with diabetes. For example, it
has been known for many years that prolonged maternal
ketonemic states, be they physiological or pathological,
adversely impact fetal brain development [49,138]. A
subsequent study [139] found that after correction for
socioeconomic status, race and ethnic origin, fasting,
third-trimester maternal 3HB levels in 188 women with
diabetes or gestational diabetes were associated with
impaired intellectual development in their offspring.
These correlations were demonstrated in the setting of
reasonably good diabetes control and benign obstetrical
courses in the cohort. It is important to note that the mean
3HB levels during the third trimester were 0.17 mM t
0.08 in the women with diabetes and 0.14 mM t 0.05 in
the non-diabetic women.
However, in all likelihood, not all fetal outcomes are
correlated with serum 3HB levels. In the recently
published Diabetes in Early Pregnancy Study [140], for
example, rst-trimester serum 3HB elevations were not
found to be associated with fetal malformations in the
offspring of women with Type 1 diabetes, and were also
not associated with an increase in the risk of pregnancy
loss.
Can assays for 3HB help in the diagnosis and
management of patients with other medical
conditions?
Quantitative assays for 3HB may provide useful informa-
tion for diagnosing and managing alcoholic ketoacidosis
[89] and assessing the mitochondrial redox state in
patients with hepatic allografts [44,141] and those who
are critically ill from other acute disease states [142,143].
Other potential applications for home or bedside 3HB
testing lie in the realm of inborn errors of metabolism.
Finally, additional research questions may include the
relationship of 3HB levels and the development of
diabetes complications. The levels of 3HB may alter
renal hemodynamics, with an increase in ltration
fraction arising from elevations in 3HB levels [144].
Copyright # 1999 John Wiley & Sons, Ltd.
423
Conclusion
Ketones are normally present in the blood during fasting
and prolonged exercise. They are also found in the blood
of neonates and pregnant women. Diabetes is the most
common pathological cause of elevated blood ketones.
SMBG has become the standard of practice for optimizing
metabolic control in patients with both Type 1 and Type 2
diabetes. Recently, a similar technology has become
available for self-monitoring of blood ketones. To date,
the proper role for such a technology has yet to be
established. For those who are already comfortable with
SMBG, the new technology offers the opportunity to
obtain additional information without having to resort to
the time consuming and sometimes unpleasant task of
urine testing for ketones.
Acknowledgements
Supported by an unrestricted educational grant from Abbott
Laboratories, Medisense Products Inc.
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