Measuring Ketone Bodies for the Monitoring of Pathologic and Therapeutic Ketosis

Abstract

Background
The ketone bodies β‐hydroxybutyrate and acetone are generated as a by‐product of the fat metabolism process. In healthy individuals, ketone body levels are ∼0.1 mM for blood β‐hydroxybutyrate (BOHB) and ∼1 ppm for breath acetone (BrAce). These levels can increase dramatically as a consequence of a disease process or when used therapeutically for disease treatment. For example, increased ketone body concentration during weight loss is an indication of elevated fat metabolism. Ketone body measurement is relatively inexpensive and can provide metabolic insights to help guide disease management and optimize weight loss.

Methods
This review of the literature provides metabolic mechanisms and typical concentration ranges of ketone bodies, which can give new insights for these conditions and rationale for measuring ketone bodies.

Results
Diseases such as heart failure and ketoacidosis can affect caloric intake and macronutrient management which can elevate BOHB 30‐fold and BrAce 1,000‐fold. Other diseases associated with obesity such as brain dysfunction, cancer, and diabetes may cause dysfunction because of an inability to use glucose, an excessive reliance on glucose, or poor insulin signaling. Elevating ketone body concentrations (e.g., nutritional ketosis) may improve these conditions by forcing utilization of ketone bodies, in place of glucose, for fuel. During weight loss, monitoring ketone body concentration can demonstrate program compliance and can be used to optimize the weight loss plan.

Conclusions
The role of ketone bodies in states of pathologic and therapeutic ketosis indicates that accurate measurement and monitoring of BOHB or BrAce will likely improve disease management. Bariatric surgery is examined as a case study for monitoring both types of ketosis.
This article is protected by copyright. All rights reserved.

Full text

Received: 12 February 2021
-
Revised: 29 March 2021
-
Accepted: 11 April 2021
DOI: 10.1002/osp4.516
REVIEW
Measuring ketone bodies for the monitoring of pathologic
and therapeutic ketosis
Joseph C. Anderson
1
|Samer G. Mattar
2
|Frank L. Greenway
3
|Richard J. Lindquist
4
1
Department of Bioengineering, University of
Washington, Seattle, Washington, USA
2
Department of Surgery, Baylor College of
Medicine, Houston, Texas, USA
3
Pennington Biomedical Research Center,
Baton Rouge, Louisiana, USA
4
Department of Family Medicine, Swedish
Medical Center, Seattle, Washington, USA
Correspondence
Joseph C. Anderson, Department of
Bioengineering, University of Washington,
Box 355061, Seattle, WA 98195‐5061, USA.
Email: clarkja@u.washington.edu
Funding information
Medamonitor Corp, Seattle, WA; National
Institute of General Medical Sciences, Grant/
Award Number: 1 U54 GM104940
Abstract
Background: The ketone bodies β‐hydroxybutyrate (BOHB) and acetone are
generated as a byproduct of the fat metabolism process. In healthy individuals,
ketone body levels are ∼0.1 mM for BOHB and ∼1 part per million for breath
acetone (BrAce). These levels can increase dramatically as a consequence of a
disease process or when used therapeutically for disease treatment. For example,
increased ketone body concentration during weight loss is an indication of elevated
fat metabolism. Ketone body measurement is relatively inexpensive and can provide
metabolic insights to help guide disease management and optimize weight loss.
Methods: This review of the literature provides metabolic mechanisms and typical
concentration ranges of ketone bodies, which can give new insights into these
conditions and rationale for measuring ketone bodies.
Results: Diseases such as heart failure and ketoacidosis can affect caloric intake and
macronutrient management, which can elevate BOHB 30‐fold and BrAce 1000‐fold.
Other diseases associated with obesity, such as brain dysfunction, cancer, and
diabetes, may cause dysfunction because of an inability to use glucose, excessive
reliance on glucose, or poor insulin signaling. Elevating ketone body concentrations
(e.g., nutritional ketosis) may improve these conditions by forcing utilization of
ketone bodies, in place of glucose, for fuel. During weight loss, monitoring ketone
body concentration can demonstrate program compliance and can be used to
optimize the weight‐loss plan.
Conclusions: The role of ketone bodies in states of pathologic and therapeutic
ketosis indicates that accurate measurement and monitoring of BOHB or BrAce will
likely improve disease management. Bariatric surgery is examined as a case study
for monitoring both types of ketosis.
KEYWORDS
β‐hydroxybutyrate, acetone, bariatric surgery, metabolism
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2021 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.
646
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Obes Sci Pract. 2021;7:646–656. wileyonlinelibrary.com/journal/osp4

1
|
INTRODUCTION
The recent popularity of the ketogenic diet (KD) has kindled a
renewed interest in the creation and metabolism of ketone bodies
and the state of ketosis. This diet, characterized by high‐fat and very
low‐carbohydrate (<50 g/day) intake, appears to result in improve-
ments in weight management, metabolic syndrome, and cognition.
1–4
Implicitly, the diet mandates a marked reduction in carbohydrate
intake, which results in the generation and utilization of ketone
bodies, instead of carbohydrates, to fuel the brain and other neuro-
logic tissues. Many authorities assumed that ketone bodies, in states
of carbohydrate restriction, are the primary drivers for the perceived
benefits of the KD. Because of this success, an explosion in research
has taken place to identify additional interventions that may increase
ketosis (e.g., intermittent fasting and exogenous supplementation)
and to better understand the effects of ketosis in health and dis-
ease.
5–8
Ketosis is defined as the elevated concentration of ketone bodies
in the blood. Ketone bodies are comprised of three chemicals: ace-
toacetate, β‐hydroxybutyrate (BOHB), and acetone. Acetoacetate is
created in the liver from free fatty acids (FFAs) when glucose avail-
ability is limited. Acetoacetate can be enzymatically interconverted
into BOHB.
9
Additionally, acetoacetate can be decarboxylated,
spontaneously or by catalytic action, into acetone (Figure 1).
10
Ke-
tone body concentrations increase with corresponding increases in
fat metabolism.
11,12
Recent studies have also demonstrated a number of non‐diet‐
related disease conditions that can cause elevated ketosis.
13,14
These diseases cause hyperketonemia for a variety of reasons,
including poor insulin signaling in diabetes, impaired fatty acid
metabolism in heart failure (HF), and slow ketone body elimination as
a result of genetic disorders. It is logical, therefore, that monitoring
ketosis levels may provide a complete picture of the behavior and
severity of the underlying disease. Additionally, periodic ketosis
monitoring may help in the management and treatment of the
disease.
Some diseases appear to respond favorably to an increase in
ketosis. It has been demonstrated that once ketones reach “thera-
peutic” levels, they help attenuate disease severity or result in dis-
ease regression.
15–17
Examples include neurologic diseases where the
ketone bodies provide fuel to metabolically compromised brain re-
gions and treatment of type 2 diabetes to improve diabetic sequelae
and reduce medications. Thus, monitoring ketosis levels can help
maintain therapeutic concentrations of ketone bodies to optimize
disease treatment.
Additionally, weight loss creates an elevation in fat metabolism
that is reflected in elevated ketone body concentrations.
11,18
Elevated fat metabolism is correlated with increased ketone body
concentrations.
19
Thus, medical weight loss and weight loss prior to
bariatric surgery may be optimized and compliance assessed by
monitoring ketone bodies as surrogate markers of subject‐specific fat
metabolism.
Measurement of ketone bodies is becoming more common
because of an increase in the number of relatively inexpensive con-
sumer devices. These chemical sensors typically measure acetoace-
tate in urine, BOHB in blood, or acetone in breath (BrAce). While
urine samples are common, urine acetoacetate is not typically
assessed using a quantitative method causing significant measure-
ment uncertainty.
20,21
Currently, blood BOHB is the gold standard
for assessing ketosis. However, the measurement of BrAce is
becoming more widely accepted as a reliable indicator, particularly at
low ketone body levels where BrAce has greater sensitivity to change
than blood BOHB.
19
Ketone body concentrations for two reference
states are as follows (Table 1): (1) healthy individuals on a balanced
macronutrient diet typically have ketone body concentrations of
BOHB ∼0.1 mM or BrAce ∼1 part per million (ppm); and (2) subjects
in nutritional ketosis (i.e., keto‐adaptation) have ketone body con-
centrations of at least BOHB =0.5 mM
35,41,42
or BrAce ≥9 ppm.
19,22
The concentrations of ketone bodies observed for a range of
diseases haven't been summarized. This review describes diseases
that cause ketosis (ketogenic diseases), their underlying ketogenic
mechanisms, and the ranges of ketosis (as defined by blood BOHB
and BrAce concentrations) that are associated with the disease. For
diseases that can be treated with an elevation in ketosis (therapeutic
ketosis), the underlying mechanism of therapeutic ketosis and the
thresholds of ketone body concentrations associated with a thera-
peutic benefit are detailed. Measurement of ketone body concen-
trations is needed to demonstrate the achievement of a therapeutic
ketone body level. Additionally, ketone body elevation during weight
loss and how it can be used to optimize fat loss are reviewed. Finally,
a case study on bariatric surgery provides a vignette for how moni-
toring ketone bodies can be used for disease and therapeutic benefit.
2
|
KETOSIS FROM DISEASE
2.1
|
Heart failure
In health, fatty acids provide 50%–70% of the heart's energy.
43
In HF,
myocardial fatty acid metabolism is impaired which may be due to a
downregulation of myocardial proteins used to metabolize fatty
acids. However, lipolysis and FFAs are elevated in HF because of
increases in stress hormones (e.g., cortisol), cytokines, malnutrition,
FIGURE 1 Acetoacetate, formed primarily from β‐oxidation of
fatty acids, can be reduced to β‐hydroxybutyrate (BOHB) or
decarboxylated to acetone. Beta‐hydroxybutyrate dehydrogenase
(BDH) interconverts acetoacetate and BOHB depending on
intercellular conditions (e.g., NADH). Acetone is produced via
spontaneous or catalytic decarboxylation of acetoacetate. NADH,
nicotinamide adenine dinucleotide
ANDERSON ET AL.
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647

or cardiac cachexia.
23,24,44,45
Unable to metabolize FFA, the failing
heart shifts to other fuels including ketone bodies which are elevated
in HF.
46
Greater concentrations of ketone bodies are observed
because (1) the abundance of serum FFA causes a rise in liver
ketogenesis, the source of ketone bodies; and (2) skeletal muscles
have lower consumption of BOHB.
44,46
BOHB can be rapidly utilized
by the metabolically compromised myocardium because the enzymes
required for ketone body metabolism are more abundant in HF.
43,44
In scientific studies, subjects with HF have 2–20‐fold greater
levels of the ketone body acetone in breath (BrAce, Table 1) as
compared to healthy controls (BrAce ∼1 ppm) or to cardiac patients
without HF.
23,25,26
Increases (decreases) in BrAce correspond to
increased (decreased) HF severity.
23,24,47
Thus, monitoring BrAC may
provide a marker of HF deterioration or improvement.
24,48
2.2
|
Ketoacidosis
In healthy individuals, insulin in the blood interacts with the cell
membrane to facilitate the uptake of blood glucose by the cell.
Additionally, the interaction of insulin with adipose tissue suppresses
lipolysis. In individuals with diabetes, cells are unable to receive the
insulin signal because either insulin is not present (type 1 diabetes) or
the cell is insensitive to insulin and doesn't respond to its presence
(type 2 diabetes). Thus, glucose is not taken up by the cell, and the
concentration of glucose in the blood rises. Without the insulin signal,
lipolysis is no longer inhibited, plasma FFA rises, and hepatic ketone
body production increases.
49
In lieu of glucose as a primary fuel
source, cells can use fatty acids and ketone bodies to meet their
energy requirements. Without the insulin signal to reduce blood
sugar and suppress fat breakdown, glucose (hyperglycemia), ketone
bodies (hyperketonemia), and hydrogen ions (acidosis) can increase
dramatically in the blood and, without intervention, lead to diabetic
ketoacidosis (DKA).
27,50
Because ketone bodies are a precursor and marker of DKA,
measurement of ketone bodies can help identify the development,
assess the severity, and assist in monitoring the resolution of DKA.
As ketoacidosis develops, BOHB and BrAce increase from healthy
levels (BOHB ∼0.1 mM or BrAce ∼1 ppm) to those associated with
the onset of ketoacidosis (BOHB >3 mM or BrAce >75 ppm) (Ta-
ble 1). Because of the large concentration range between healthy
ketone body levels and ketoacidosis, ketone body monitoring can
provide a critical tool to alert providers and patients that a healthy
ketosis state is developing into ketoacidosis, allowing expedient
treatment before it reaches a critical level.
28,51
When DKA is present,
measurement of BOHB and BrAce may help to assess the severity of
ketoacidosis. BOHB (3–20 mM) and BrAce (75–1250 ppm) range
considerably in people with DKA, and the magnitude of these ketone
bodies may be associated with increased severity of DKA.
19,52
After
the intervention, scientific studies have demonstrated that ketone
body measurement can improve the course of DKA resolution.
53,54
Four diabetes associations recommend ketone body monitoring,
TABLE 1Ketone body (BOHB in mM or BrAce in ppm) concentration ranges observed in health, for disease states and for therapeutic
benefit (minimum concentration thresholds)
Ketosis Condition
Range or threshold
ReferencesBOHB (mM) BrAce (ppm)
Health Balanced macronutrient diet 0.1 1
19
Nutritional ketosis 0.5 9
19,22
Disease Heart failure >0.2 2–20
23–26
Ketoacidosis >3.0 >75
9,13,14,19,27,28
Genetic disorders ― ― See text
Therapy Brain function: Alzheimer’s 0.5 9
a 29,30
Brain function: Parkinson’s 1.0 ―
31
Brain function: Dementia 0.5 9
a 32
Brain function: Migraine 4.0 ―See text
Cancer 0.5 9
a 33,34
Type 2 diabetes 0.5 9
a 35,36
Epilepsy 4.0 ―
37–40
Weight loss ―2
11
Bariatric surgery Ketoacidosis >3.0 >75 See text and references above
Weight loss ―2
Abbreviations: BOHB, β‐hydroxybutyrate; BrAce, breath acetone.
a
Nutritional ketosis. BrAce ≥9 ppm when BOHB =0.5 mM.
19,22
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typically BOHB, during DKA resolution.
55
During DKA, the concen-
tration of BOHB is much greater than acetoacetate.
56
As DKA is
treated, BOHB decreases by conversion to acetoacetate, which
causes an elevation of acetoacetate. Because DKA is not resolved
until both BOHB and acetoacetate concentrations return to baseline,
monitoring BrAce, a product of acetoacetate decarboxylation, at 30‐
min intervals, can demonstrate the full resolution of DKA.
27,53
Additionally, monitoring ketone bodies during resolution should
reduce the duration and cost of medical treatment.
57
Prevention of DKA may be the best use of ketone body mea-
surement. DKA requires immediate medical attention (e.g., emer-
gency room visit), with an average cost for hospitalization of $26,566
in 2014.
58
To reduce DKA events and hospitalization, scientific
studies recommend self‐monitoring of ketone bodies in patients with
type 1 diabetes, insulin‐dependent type 2 diabetes, sustained blood
glucose concentration >300 mg/dl, acute illness, or stress.
20,27,56
Patients have indicated that measurements of elevated BOHB were
useful in determining subsequent insulin dose and food intake.
59
During sick days, particularly those involving nausea, vomiting, or
infections, scientific studies recommend monitoring BOHB
throughout the day, specifically for young children because of the
frequency of illness in this population.
59
Studies indicate that chil-
dren and adults who measure BOHB during “sick days” can prevent
the onset of DKA, reduce the time to DKA resolution, reduce mon-
etary costs, and decrease the rate of hospitalizations.
55,59,60
2.3
|
Euglycemic ketoacidosis
In addition to ketoacidosis associated with poorly controlled dia-
betes, ketoacidosis can occur in patients with diabetes who control
their blood sugar with a sodium–glucose cotransporter‐2 (SGLT2)
inhibitor. The SGLT2 inhibitor eliminates excess blood glucose
through excretion by the kidneys and may lead to ketoacidosis, in a
subset of individuals with diabetes, even though blood glucose is well
controlled (i.e., euglycemic ketoacidosis).
61–64
This condition appears to be driven by low insulin levels in in-
dividuals with impaired insulin secretion, poor fluid intake, low car-
bohydrate intake, and/or fasting.
51,62,65
Because the SGLT2 inhibitor
maintains blood glucose within a “healthy range”, blood glucose
monitoring will not alert individuals or clinicians to the developing
ketoacidosis. Thus, measurement of ketone bodies is important for
these subjects, perhaps even more so on sick days. The monitoring
guidelines outlined for ketoacidosis (above) could be applied. The
large concentration differential between healthy ketone body levels
and ketoacidosis can be exploited to monitor elevations in ketosis.
Significant elevations can be addressed before a crisis develops.
28,51
Interestingly, pregnant women with diabetes (<3% of all diabetic
gestations) can have euglycemic ketoacidosis which may progress
more rapidly as compared to nonpregnancy states.
66
Thus, ketone
body measurement may identify the early stages of hyperketonemia
before it escalates to DKA.
2.4
|
Genetic disorders
Genetic disorders can elevate ketosis through the overproduction
of ketone bodies or impairment of ketone body utilization. Hepatic
ketone body production elevates when low blood glucose causes a
reduction in insulin and an increase in circulating fatty acids.
Normal glucose levels, maintained via glycogen metabolism
or gluconeogenesis, are dependent on key enzymes such
as glycogen synthase, glycogen phosphorylase kinase, fructose‐
1,6‐diphosphatase, or glucose‐6‐phosphatase. Genetic disorders
can prevent the expression of these enzymes, which would cause
fasting hypoglycemia and accelerated ketogenesis leading to
hyperketonemia.
14
A lack of peripheral tissue utilization will cause ketone body
elevation. The pathway for ketolysis is controlled by two enzymes
(Figure 2): succinyl‐CoA:3‐oxoacid‐CoA transferase (SCOT) and
acetyl‐CoA acetyltransferase1 (ACAT1), which early literature iden-
tified as 2‐methylacetoacetyl‐CoA thiolase (MAT). A lack of these
enzymes causes hyperketonemia and ketoacidosis, particularly in a
fasting state.
68,69
Monitoring ketonemia via BOHB or BrAce measurement can
provide a quantitative check on dietary compliance, particularly on
sick days, and a method to minimize the conversion of hyper-
ketonemia to ketoacidosis. Ketone body thresholds have not been
described but would likely be similar to those for ketoacidosis
(BOHB >3 mM or BrAce >75 ppm—see Section 2.2).
FIGURE 2 Pathway for utilization of ketone bodies (ketolysis) where deficiencies in SCOT or ACAT1 cause significant ketonemia (adapted
from Aubert et al.
67
). β‐oxidation is output from β‐oxidation of fatty acids. ACAT1, acetyl‐CoA acetyltransferase1; BDH, β‐hydroxybutyrate
dehydrogenase; MCT, monocarboxylate transporter; SCOT, succinyl‐CoA:3‐oxoacid‐CoA transferase
ANDERSON ET AL.
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3
|
KETOSIS FOR THERAPY
In addition to weight loss, multiple obesity‐associated diseases
respond favorably to elevated ketosis. These diseases appear to have
impaired glucose metabolism (e.g., brain dysfunction) or an inability
to manage elevated insulin and glucose (e.g., cancer, diabetes).
Elevated BOHB may provide relief by replacing glucose as a primary
source of energy and removing oxidant species.
15,16
For these
obesity‐associated diseases, carbohydrate restriction may be the
optimal modality for elevating ketone bodies while decreasing insulin
and blood glucose concentration. Therapeutic BOHB concentrations
are primarily disease dependent and modulated by a multitude of
factors including age, gender, weight, diet, and disease severity. Thus,
sequential ketone body measurements over time can demonstrate
that the threshold for therapeutic ketosis has been achieved and
maintained.
3.1
|
Brain function
In health, glucose fuels the brain. During starvation, glucose is scarce
and FFAs are abundant. Because the brain cannot use fat for fuel, the
body converts fat into ketone bodies to fuel the brain.
52,70
Scientific
studies have demonstrated that elevated ketone bodies (via KD,
supplementation with medium chain triglyceride, fasting, etc.) can
improve brain function in subjects with Alzheimer's, dementia, and
Parkinson's disease.
It appears that these diseases are characterized by the
inability of specific brain regions to use glucose for fuel, which
causes regional dysfunction in the brain. When available, ketone
bodies can fuel diseased brain regions resulting in improvement of
neurologic function. At BOHB concentrations >4 mM, ketone
bodies are estimated to supply more than 50% of the brain's en-
ergy requirement.
71
3.1.1
|
Alzheimer's
Many factors drive Alzheimer's disease including insulin resistance,
genetic defects, and a regional reduction in glucose metabolism
which is correlated to decrements in cognitive scores.
7,72
Elevation in
BOHB to ∼0.5 mM (BrAce ≥9 ppm) via consumption of ketogenic
foods appears to improve cognitive function.
29,30,73,74
Additionally,
improvement in cognitive function is associated with increased
BOHB concentrations.
29,30,75
3.1.2
|
Parkinson's
The benefits of elevated ketone bodies on mitochondrial activity
have been proposed for Parkinson's disease. While similar to the
mechanisms for other brain maladies, it is hypothesized that
BOHB increases energy production because BOHB may bypass a
defect in complex I of the electron transport chain.
76
In one
study, subjects with Parkinson's on a 4‐week KD showed
improvement on the Unified Parkinson's Disease Rating Scale. A
pilot study showed some symptom resolution when BOHB =1.0
mM.
31
While additional studies are needed, it is expected that
BOHB must range between 2 and 7 mM to provide a therapeutic
effect.
7,77
3.1.3
|
Dementia
Older subjects with mild cognitive impairment may experience
improved verbal memory performance using a very low carbohydrate
diet (<35 g/day on average). Improved memory performance corre-
lated with increases in ketone levels and reductions in insulin
levels.
32
Healthy geriatric individuals will also likely benefit from the
best improvement found in subjects with strong dietary compli-
ance.
78
Based on the dietary criteria, subjects with cognitive
impairment may need BOHB concentrations >0.5 mM (BrAce ≥9
ppm) to achieve a benefit.
32
3.1.4
|
Migraine
Migraine can be characterized as a neurologic inflammation and a
reduction in brain metabolism.
79
To prevent or protect against
migraines, elevated ketone bodies may reduce neuroinflammation,
inhibit oxidative stress, and modulate mitochondrial function.
80
Ketotherapeutic benefits for migraines have been known for
almost 100 years.
81
In recent studies, consumption of a very low
carbohydrate (<30 g/day) and low‐calorie KD was associated with
significant reductions in the number of migraine attacks per
month (76% drop) and the number of days with headaches (82%
drop).
80,82
One subject had complete remission of migraine
headaches.
83
Relief was observed within a few days of diet
initiation.
79
Because the diets used are similar to those used for
epilepsy therapy, a BOHB greater than 4 mM may be required
(Table 1).
3.1.5
|
Epilepsy
Some subjects with epilepsy have intractable seizures, which are
unresponsive to antiepileptic drugs.
84,85
The frequency of these sei-
zures can, in many cases, be reduced with a KD. In children,
approximately 50% of subjects experienced an improvement in
seizure frequency when adhering to this diet for a few months.
86
For
children adhering to the diet for 1 year, almost 50% of subjects re-
ported a nearly complete (≥90%) reduction in seizures; similar out-
comes persisted for years after study termination.
87
Adults with
epilepsy also experienced a reduction in seizure frequency when
placed on KDs. It is clear that elevations in ketone bodies correspond
to successful ketogenic therapy.
19
Scientific studies have shown a
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relationship between elevated BOHB and improved seizure control
in children.
37–39
Ketone body measurement can demonstrate dietary compliance
required for therapeutic benefit.
38,88,89
The therapeutic benefit ap-
pears to be around 4 mM for BOHB
37–40
(Table 1). When adverse
effects of the diet occur (e.g., constipation, bloating, or irregular
menstrual cycles), ketone body measurement can provide positive
reinforcement, provide information to optimize dietary composition,
and hasten return to therapeutic ketosis after a “cheat” day.
3.2
|
Cancer
Rapid and uncontrolled cell growth in cancer is fueled by glucose, an
observation named the Warberg effect.
90
Thus, restricting circulating
glucose (e.g., by consumption of a very low‐carbohydrate and high‐fat
diet) should cause tumor cells to starve and die.
90
In healthy cells,
energy is produced via aerobic respiration of glucose, fats, or ketone
bodies which requires healthy mitochondria, an intact tricarboxylic
acid cycle, and a functional electron transport chain. In cancer cells,
compromised aerobic respiration forces cancer cells to rely solely on
anaerobic glycolysis and aerobic fermentation of glucose for en-
ergy.
91
High corresponding insulin levels signal the expression of
glucose transporters (e.g., GLUT3) and glycolytic enzymes.
Carbohydrate restriction will slow cancer growth in three ways.
Without fuel, these cells starve and become more susceptible to
chemotherapeutics.
91,92
A decrease in circulating insulin inhibits the
signal to upregulate the glucose transporters (e.g., GLUT3) and
glycolytic enzymes required for metabolism. Increased BOHB re-
duces oxidative stress and inflammation, induces apoptosis, and is
associated with regression of cancer growth.
33,92–94
Meanwhile,
healthy cells thrive via aerobic metabolization of fats and ketone
bodies.
90,91
The few studies using ketotherapy have shown potential benefits
(e.g., tumor stability or regression) to the brain (i.e., glioblastoma),
breast, lung, and colon cancer.
33,34,93,95
This regimen likely requires
carbohydrate restriction combined with one or more of the following:
high‐fat consumption, caloric restriction, fasting, or exogenous ke-
tone supplementation. Measurement of ketosis in cancer patients
may help monitor compliance, facilitate dietary modifications, and
achieve therapeutic levels of ketone bodies. The minimum threshold
for therapeutic benefit appears to be 0.5 mM (BrAce ≥9 ppm) and
likely depends on the cancer type.
33,34,95
3.3
|
Type 2 diabetes
One hallmark of diabetes is elevated blood glucose. In people with
type 2 diabetes, tissues are insensitive to insulin, resulting in the rise
of blood glucose due to increased liver production and a lack of up-
take. To achieve normal levels of blood glucose, clinical investigators
have proposed “prescribing” a KD to restrict dietary carbohydrates
to <50 g/day.
4,96
After adaption to KD, subjects, on average,
experience an improvement in diabetic sequelae and medications,
including weight reduction, reduced exogenous insulin, improved
insulin sensitivity, and reduced HbA1c.
35,36,96,97
To achieve these results, clinical studies have measured BOHB
levels to verify carbohydrate restriction, to guide the reduction of
diabetes medication, and to adjust dietary therapy.
35,36
Subjects
strive to maintain a state of nutritional ketosis, defined as BOHB ≥
0.5 mM.
35,36
As an alternative to BOHB, a BrAce ≥9 ppm, which
corresponded to BOHB ≥0.5 mM for 95% of measurements, could
be used to demonstrate nutritional ketosis.
19,22
Daily ketone body
measurements demonstrate dietary and lifestyle compliance and may
provide a rationale for weaning patients from diabetic medica-
tions.
35,36,98
As lifestyle and dietary factors change with time, ketone
body measurements will reflect changes in carbohydrate restriction
and, thus, can be used to help compensate for these changes.
3.4
|
Weight loss
During calorie restriction, energy needs are met by mobilizing fat
from adipose cells. A portion of the circulating fatty acids is con-
verted into ketone bodies within the liver. The amount of ketone
bodies produced is proportional to the rate of fatty acid metabolism
within the liver. For subjects on a calorie‐restricted diet, the BrAce
concentration has been shown to be proportional to the rate of fat
loss.
19
While BrAce is ∼1 ppm for a typical subject, individuals who
lost one‐half pound of fat mass per week on a calorie‐restricted diet
had BrAce =2 ppm. Further elevations in BrAce correlated linearly
with increases in fat mass loss.
11
As a result of the relationship between BrAce and fat mass loss,
frequent monitoring of BrAce can be used as a tool by individuals and
clinicians to optimize fat loss. During calorie restriction, BrAce ≥2
ppm indicates an elevated state of fat metabolism and predicts fat
loss if these levels can be maintained. Frequent monitoring provides
individuals with immediate feedback to understand how their well-
ness choices (e.g., diet, exercise, sleep, stress, etc.) affect their state of
fat metabolism. Using this feedback, individuals can adjust their
choices, daily if needed, to optimize and maintain fat loss and in-
crease compliance (unpublished observations). Coaches and clinicians
can utilize longitudinal BrAce measurements to understand individual
fat metabolism, to customize the program for each individual, and to
counsel patients on how to overcome weight‐loss obstacles. Addi-
tionally, BrAce can be used in weight‐loss strategies when preparing
for bariatric surgery (discussed below).
One case for measuring BrAce could be tailoring the macronu-
trient composition to optimize weight loss. In general, customization
is difficult because the optimal macronutrient composition for weight
loss is not clear. Scientific debates between proponents of a high
carbohydrate diet
99
and supporters of a low carbohydrate diet
100
have not provided resolution. Optimal diet composition is likely
subject dependent. A recent study
101
suggests a high carbohydrate
diet (60% carbohydrate, 20% fat, and 20% protein) is preferred for
women with obesity who were insulin sensitive (fasting insulin <10
ANDERSON ET AL.
-
651

µU/ml) while a lower carbohydrate diet (40% carbohydrate, 40% fat
and 20% protein) is preferred for women with obesity who were
insulin resistant. For all subjects, the preferred macronutrient
composition gave a ∼twofold increase in body weight loss as
compared to the alternative. These findings would indicate that the
ability (inability) to efficiently metabolize carbohydrates, as predicted
by insulin sensitivity (resistance), may predict the best macronutrient
composition for weight loss.
As weight is lost, the body becomes more insulin sensitive. Thus,
at some point during weight loss, the best diet may change from a low
to a high carbohydrate diet. This change could be monitored with
measurements of fasting insulin. However, the cost and invasive
nature make this measurement impractical. A different inflection
point occurs for others during the first 6 months of dieting. Often
when people reach a plateau in their weight loss, they give up dieting
and regain the weight.
Measuring BrAce over days and weeks can give feedback on
metabolic changes within the patient. A reduction in BrAce from
above 2 ppm to near 1 ppm indicates a loss of fat oxidation and, when
combined with a weight‐loss plateau, may suggest the need for a
dietary change. One cause of this plateau could be the increase in
insulin sensitivity which can be quantified via measurement of fasting
insulin. If insulin sensitivity has improved, an increase in the carbo-
hydrate content could restart weight loss. Thus, regular monitoring of
BrAce during a weight‐loss program could potentially enable
personalization of dietary carbohydrates and optimize weight loss
over the weight‐loss journey.
3.5
|
Bariatric surgery
Bariatric surgery serves as a case study for monitoring ketone bodies
for both pathologic (i.e., ketoacidosis) and therapeutic (i.e., weight
loss) ketosis. Over the past half‐century, bariatric surgery has
emerged as a valid and effective treatment for significant weight loss
and improvement, if not resolution, of associated comorbidities,
including diabetes, hypertension, and sleep apnea.
102
Most of these
operations, typically indicated for patients with a BMI >35, result in
the correction of the metabolic dysfunction at the center of the
metabolic syndrome and morbid obesity. The dramatic reduction in
hunger and the normalization of disturbed metabolic processes result
in significant weight loss that is derived from a reduction in both fat
and fat‐free mass.
103,104
Prior to bariatric surgery, weight loss can reduce surgical com-
plications, surgery time, and length of hospital stay.
105
Very low‐
calorie diets (VLCD) are commonly used prior to bariatric surgery
as a means to both reduce initial weight and to reduce liver fat
mass.
106
Although VLCDs vary somewhat in calorie and nutrient
composition (typically <800 calories/day), they are as a group
effective in weight loss and metabolic improvement
41
while typically
maintaining fat‐free mass.
107–109
VLCD with carbohydrate levels of
<50 g/day result in nutritional ketosis. To demonstrate compliance
with the dietary plan and optimize weight loss, BrAce can be moni-
tored. In fact, measurement of BrAce has been shown to correlate
with weight loss and adherence to the prescribed VLCD
intervention.
110
After bariatric surgery, patients are monitored by a multidisci-
plinary team of physicians, nurses, and dietitians, whose main
objective is to ensure that patients maintain optimal benefits with
minimal harm, including that weight loss be predominantly from fat
mass components, and the sparing of fat‐free mass. While many
patients do achieve these healthy weight‐loss objectives, there is a
minority who, for a variety of reasons, may be unable to adhere to
nutritional recommendations and suffer the consequences of poor
oral intake if not rescued in a timely manner. It is imperative,
therefore, that patients at risk should have their fluid status, elec-
trolyte levels, acid–base balance, and nutritional parameters closely
monitored. Comprehensive monitoring may benefit from quantita-
tive measurement of ketone bodies (e.g., BrAce), which could be
used to enhance post‐bariatric diabetes management and distin-
guish between types and degrees of ketoacidosis such as SGLT2‐
associated euglycemic ketoacidosis and post‐surgery starvation
ketoacidosis.
111,112
Starvation ketoacidosis can result secondary to poor oral intake
following bariatric surgery.
113
Poor oral intake rapidly depletes
hepatic and muscular glycogen stores. Aggravating this situation is
the vomiting and dehydration that are occasionally present and
stimulate the sympathetic system resulting in released cortisol,
adrenaline, glucagon, and growth hormone, which in turn suppress
insulin secretion. The cumulative effects of these changes are
lipolysis and FFA production from adipose tissue and hepatic ke-
tone formation, the basis for starvation ketoacidosis.
114
Therefore,
all patients who present with severe acid–base imbalance should
undergo ketone body measurement since their elevation is a key
determinant that ketoacidosis is the underlying mechanism for
metabolic acidosis.
In clinical settings, it is important to differentiate starvation
ketoacidosis from DKA, since the treatment for each condition can
have a critical impact on the outcome of these emergency conditions.
DKA is a potentially lethal condition that is more common in patients
with type 1 diabetes who exhibit poor compliance or inadequate
insulin replacement therapy. It is usually associated with hypergly-
cemia and dehydration, and is typically managed with dedicated
protocols that call for aggressive rehydration and insulin adminis-
tration in an attempt to correct the acid–base imbalance. It is
important to distinguish diabetic from starvation ketoacidosis since
glucose administration can be a life‐saving measure in the latter
situation. Although DKA after bariatric surgery is an uncommon
event, it has been documented in patients with type 1 diabetes who
have undergone gastric bypass.
112
Anesthesia and surgical stress,
abrupt discontinuation of insulin or inadequate treatment in the
perioperative period, postoperative infection, prolonged poor oral
intake, and severe dehydration can be the precipitating causes for
postoperative DKA.
115
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4
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SUMMARY
The measurement of ketone body concentration (BOHB or acetone)
can provide valuable information. Diseases such as congestive heart
failure, ketoacidosis, and genetic disorders create an elevated
ketosis which, in many cases, correlates to disease severity. Because
the magnitude of the increased ketosis is typically related to dis-
ease severity, early detection can aid in modifying behaviors before
disease symptoms clinically manifest. The intentional induction of
elevated BOHB concentrations can be used to treat obesity and
obesity‐associated diseases such as brain disorders and type 2
diabetes. Elevated BOHB levels provide a benefit through modifi-
cation of mitochondrial energy production and through reduction of
insulin and blood glucose when achieved via glucose restriction.
Measurement of ketosis is critical to verify that a therapeutic level
of ketosis has been achieved and maintained. Frequent measure-
ment of ketosis can allow users to adjust and personalize their diet
and behaviors to maintain therapeutic levels of ketosis. A case
study of bariatric surgery demonstrates that monitoring ketone
bodies before and after surgery may optimize surgical outcomes
and reduce complications.
To date, monitoring ketone concentrations has been shown to
address three conditions: ketoacidosis (prevention, acidosis severity,
and resolution monitoring), improvement of type 2 diabetes (achieve
nutritional ketosis and dietary adherence), and epilepsy (optimize
seizure control). These methods of ketone monitoring can be used as
starting points for the other conditions reviewed. Additional studies
are needed to demonstrate the value of ketone body monitoring for
the other diseases that generate elevated ketosis. For therapeutic
ketosis, ketone monitoring is necessary, at a minimum, to demon-
strate a therapeutic dose has been achieved. Additional research is
needed to better quantify the therapeutic dose as a function of
subject‐specific factors, which include disease severity, de-
mographics, and genetics.
ACKNOWLEDGMENTS
All authors were involved in literature search, writing the manuscript
and final approval of the submitted and published versions.
This work was supported, in part, by Medamonitor Corp, Seattle,
WA and by the National Institute of General Medical Sciences Grant
1 U54 GM104940 which funds the Louisiana Clinical and Trans-
lational Science Center. The content is solely the responsibility of the
authors and does not necessarily represent the official views of the
National Institutes of Health.
CONFLICTS OF INTEREST
Joseph C. Anderson consults for and holds stock in Medamonitor.
Samer G. Mattar has no conflicts to report. Frank L. Greenway re-
ports serving on science advisory boards for JC USA, Regeneron
Pharmaceuticals, and Pfizer; consulting for Jazz Pharmaceuticals,
Basic Research, Dr. Reddy's Laboratories, General Nutrition Corpo-
ration, Melior Discovery Inc., Novmeta Pharma, Novo Nordisk; grants
from Melior Discoveries, Novmeta Pharma; and stock/stock options
from Ketogenic Health Systems, Inc., Plensat Inc., UR Labs. Richard J.
Lindquist consults for Medamonitor.
ORCID
Joseph C. Anderson
https://orcid.org/0000-0003-4030-8897
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How to cite this article: Anderson JC, Mattar SG, Greenway
FL, Lindquist RJ. Measuring ketone bodies for the monitoring
of pathologic and therapeutic ketosis. Obes Sci Pract.
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