= Ketosis =

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= Ketosis =
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Introduction
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Ketosis is a metabolic state characterized by elevated levels of
ketone bodies in the blood or urine. Physiological ketosis is a normal
response to low glucose availability. In physiological ketosis,
ketones in the blood are elevated above baseline levels, but the
body's acid-base homeostasis is maintained. This contrasts with
ketoacidosis, an uncontrolled production of ketones that occurs in
pathologic states and causes a metabolic acidosis, which is a medical
emergency. Ketoacidosis is most commonly the result of complete
insulin deficiency in type 1 diabetes or late-stage type 2 diabetes.
Ketone levels can be measured in blood, urine or breath and are
generally between 0.5 and 3.0 millimolar (mM) in physiological
ketosis, while ketoacidosis may cause blood concentrations greater
than 10 mM.

Trace levels of ketones are always present in the blood and increase
when blood glucose reserves are low and the liver shifts from
primarily metabolizing carbohydrates to metabolizing fatty acids. This
occurs during states of increased fatty acid oxidation such as
fasting, carbohydrate restriction, or prolonged exercise. When the
liver rapidly metabolizes fatty acids into acetyl-CoA, some acetyl-CoA
molecules can then be converted into ketone bodies: pyruvate,
acetoacetate, beta-hydroxybutyrate, and acetone. These ketone bodies
can function as an energy source as well as signalling molecules. The
liver itself cannot utilize these molecules for energy, so the ketone
bodies are released into the blood for use by peripheral tissues
including the brain.

When ketosis is induced by carbohydrate restriction, it is sometimes
referred to as nutritional ketosis. A low-carbohydrate, moderate
protein diet that can lead to ketosis is called a ketogenic diet.
Ketosis is well-established as a treatment for epilepsy and is also
effective in treating type 2 diabetes.

Definitions
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Normal serum levels of ketone bodies are less than 0.5 mM.
'Hyperketonemia' is conventionally defined as levels in excess of 1
mM.

Physiological ketosis
=======================
Physiological ketosis is the non-pathological (normal functioning)
elevation of ketone bodies that can result from any state of increased
fatty acid oxidation including fasting, prolonged exercise, or very
low-carbohydrate diets such as the ketogenic diet. In physiological
ketosis, serum ketone levels generally remain below 3 mM.

Ketoacidosis
==============
Ketoacidosis is a pathological state of uncontrolled production of
ketones that results in a metabolic acidosis, with serum ketone levels
typically in excess of 3 mM. Ketoacidosis is most commonly caused by a
deficiency of insulin in type 1 diabetes or late stage type 2 diabetes
but can also be the result of chronic heavy alcohol use, salicylate
poisoning, or isopropyl alcohol ingestion. Ketoacidosis causes
significant metabolic derangements and is a life-threatening medical
emergency. Ketoacidosis is distinct from physiological ketosis as it
requires failure of the normal regulation of ketone body production.

Causes
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Elevated blood ketone levels are most often caused by accelerated
ketone production but may also be caused by consumption of exogenous
ketones or precursors.

When glycogen and blood glucose reserves are low, a metabolic shift
occurs in order to save glucose for the brain which is unable to use
fatty acids for energy. This shift involves increasing fatty acid
oxidation and production of ketones in the liver as an alternate
energy source for the brain as well as the skeletal muscles, heart,
and kidney. Low levels of ketones are always present in the blood and
increase under circumstances of low glucose availability. For example,
after an overnight fast, 2-6% of energy comes from ketones and this
increases to 30-40% after a 3-day fast.

The amount of carbohydrate restriction required to induce a state of
ketosis is variable and depends on activity level, insulin
sensitivity, genetics, age and other factors, but ketosis will usually
occur when consuming less than 50 grams of carbohydrates per day for
at least three days.

Neonates, pregnant women and lactating women are populations that
develop physiological ketosis especially rapidly in response to
energetic challenges such as fasting or illness. This can progress to
ketoacidosis in the setting of illness, although it occurs rarely.
Propensity for ketone production in neonates is caused by their
high-fat breast milk diet, disproportionately large central nervous
system and limited liver glycogen.

Biochemistry
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The precursors of ketone bodies include fatty acids from adipose
tissue or the diet and ketogenic amino acids. The formation of ketone
bodies occurs via ketogenesis in the mitochondrial matrix of liver
cells.

Fatty acids can be released from adipose tissue by adipokine signaling
of high glucagon and epinephrine levels and low insulin levels. High
glucagon and low insulin correspond to times of low glucose
availability such as fasting. Fatty acids bound to coenzyme A allow
penetration into mitochondria. Once inside the mitochondrion, the
bound fatty acids are used as fuel in cells predominantly through beta
oxidation, which cleaves two carbons from the acyl-CoA molecule in
every cycle to form acetyl-CoA. Acetyl-CoA enters the citric acid
cycle, where it undergoes an aldol condensation with oxaloacetate to
form citric acid; citric acid then enters the tricarboxylic acid cycle
(TCA), which harvests a very high energy yield per carbon in the
original fatty acid.
Acetyl-CoA can be metabolized through the TCA cycle in any cell, but
it can also undergo ketogenesis in the mitochondria of liver cells.
When glucose availability is low, oxaloacetate is diverted away from
the TCA cycle and is instead used to produce glucose via
gluconeogenesis. This utilization of oxaloacetate in gluconeogenesis
can make it unavailable to condense with acetyl-CoA, preventing
entrance into the TCA cycle. In this scenario, energy can be harvested
from acetyl-CoA through ketone production.

In ketogenesis, two acetyl-CoA molecules condense to form
acetoacetyl-CoA via thiolase. Acetoacetyl-CoA briefly combines with
another acetyl-CoA via HMG-CoA synthase to form
hydroxy-β-methylglutaryl-CoA. Hydroxy-β-methylglutaryl-CoA form the
ketone body acetoacetate via HMG-CoA lyase. Acetoacetate can then
reversibly convert to another ketone body--D-β-hydroxybutyrate--via
D-β-hydroxybutyrate dehydrogenase. Alternatively, acetoacetate can
spontaneously degrade to a third ketone body (acetone) and carbon
dioxide, which generates much greater concentrations of acetoacetate
and D-β-hydroxybutyrate. The resulting ketone bodies cannot be used
for energy by the liver so are exported from the liver to supply
energy to the brain and peripheral tissues.

In addition to fatty acids, deaminated ketogenic amino acids can also
be converted into intermediates in the citric acid cycle and produce
ketone bodies.

Measurement
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Ketone levels can be measured by testing urine, blood or breath. There
are limitations in directly comparing these methods as they measure
different ketone bodies.

Urine testing
===============
Urine testing is the most common method of testing for ketones. Urine
test strips utilize a nitroprusside reaction with acetoacetate to give
a semi-quantitative measure based on color change of the strip.
Although beta-hydroxybutyrate is the predominant circulating ketone,
urine test strips only measure acetoacetate. Urinary ketones often
correlate poorly with serum levels because of variability in excretion
of ketones by the kidney, influence of hydration status, and renal
function.

Serum testing
===============
Finger-stick ketone meters allow instant testing of
beta-hydroxybutyrate levels in the blood, similar to glucometers.
Beta-hydroxybutrate levels in blood can also be measured in a
laboratory.

Epilepsy
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Ketosis induced by a ketogenic diet is a long-accepted treatment for
refractory epilepsy.

Obesity and metabolic syndrome
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Ketosis can improve markers of metabolic syndrome through reduction in
serum triglycerides, elevation in high-density lipoprotein (HDL) as
well as increased size and volume of low-density lipoprotein (LDL)
particles. These changes are consistent with an improved lipid profile
despite potential increases in total cholesterol level.

Safety
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The safety of ketosis from low-carbohydrate diets is often called into
question by clinicians, researchers and the media. A common safety
concern stems from the misunderstanding of the difference between
physiological ketosis and pathologic ketoacidosis. There is also
continued debate whether chronic ketosis is a healthy state or a
stressor to be avoided. Some argue that humans evolved to avoid
ketosis and should not be in ketosis long-term. The counter-argument
is that there is no physiological requirement for dietary
carbohydrates, as adequate energy can be made via gluconeogenesis and
ketogenesis indefinitely. Alternatively, the switching between a
ketotic and fed state has been proposed to have beneficial effects on
metabolic and neurologic health. The effects of sustaining ketosis for
up to two years are known from studies of people following a strict
ketogenic diet for epilepsy or type 2 diabetes; these include
short-term adverse effects leading to potential long-term ones.
However, literature on longer term effects of intermittent ketosis is
lacking.

Medication considerations
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Some medications require attention when in a state of ketosis,
especially several classes of diabetes medication. SGLT2 inhibitor
medications have been associated with cases of euglycemic ketoacidosis
- a rare state of high ketones causing a metabolic acidosis with
normal blood glucose levels. This usually occurs with missed insulin
doses, illness, dehydration or adherence to a low-carbohydrate diet
while taking the medication. Additionally, medications used to
directly lower blood glucose including insulin and sulfonylureas may
cause hypoglycemia if they are not titrated prior to starting a diet
that results in ketosis.

Adverse effects
=================
There may be side effects when changing over from glucose metabolism
to fat metabolism. These may include headache, fatigue, dizziness,
insomnia, difficulty in exercise tolerance, constipation, and nausea,
especially in the first days and weeks after starting a ketogenic
diet. Breath may develop a sweet, fruity flavor via production of
acetone that is exhaled because of its high volatility.

Most adverse effects of long-term ketosis reported are in children
because of its longstanding acceptance as a treatment for pediatric
epilepsy. These include compromised bone health, stunted growth,
hyperlipidemia, and kidney stones.

Contraindications
===================
Ketosis induced by a ketogenic diet should not be pursued by people
with pancreatitis because of the high dietary fat content. Ketosis is
also contraindicated in pyruvate carboxylase deficiency, porphyria,
and other rare genetic disorders of fat metabolism.

Veterinary medicine
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In dairy cattle, ketosis commonly occurs during the first weeks after
giving birth to a calf and is sometimes referred to as 'acetonemia'.
This is the result of an energy deficit when intake is inadequate to
compensate for the increased metabolic demand of lactating. The
elevated β-hydroxybutyrate concentrations can depress gluconeogenesis,
feed intake and the immune system, as well as have an impact on milk
composition. Point of care diagnostic tests can be useful to screen
for ketosis in cattle.

In sheep, ketosis, evidenced by hyperketonemia with
beta-hydroxybutyrate in blood over 0.7 mmol/L, is referred to as
'pregnancy toxemia'. This may develop in late pregnancy in ewes
bearing multiple fetuses and is associated with the considerable
metabolic demands of the pregnancy. In ruminants, because most glucose
in the digestive tract is metabolized by rumen organisms, glucose must
be supplied by gluconeogenesis. Pregnancy toxemia is most likely to
occur in late pregnancy due to metabolic demand from rapid fetal
growth and may be triggered by insufficient feed energy intake due to
weather conditions, stress or other causes. Prompt recovery may occur
with natural parturition, Caesarean section or induced abortion.
Prevention through appropriate feeding and other management is more
effective than treatment of advanced stages of pregnancy toxemia.

See also
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*Bioenergetics
*Ketonuria
*Ketogenic diet
*Very-low-calorie diet
*Inuit cuisine

External links
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*
*[http://www.nhs.uk/conditions/ketosis/Pages/Introduction.aspx NHS
Direct: Ketosis]
* The Merck Manual --
**[http://www.merckmanuals.com/professional/sec13/ch169/ch169b.html
Diabetic Ketoacidosis]
**[http://www.merckmanuals.com/professional/sec13/ch169/ch169d.html
Alcoholic Ketoacidosis]

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=========
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Original Article: http://en.wikipedia.org/wiki/Ketosis