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Carnitine
DeficiencyPresented by:Group 3, MD I B
Miranda, Sly MaweyMorales, Christina Anne
Muldong, Frances
Munoz, Rafael
FranciscoNacpil, Ivy
Naguiat, Anjelica
Nipales, Warley
Nogoy Princess May
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Objectives:
By the end of the report, the students should be
able to:
1. Define what carnitine is.
2. Determine the structure & function of carnitine.
3. Enumerate the dietary sources of carnitine.
4. Explain the synthesis of carnitine
5. Describe the absorption & metabolism of
canitine in the body.
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Objectives:6. Explain its role in fatty acid metabolism.
7. Describe its physiologic effect on the body.
8. Explain the occurrence of carnitine deficiency.9. Enumerate diseases associated with carnitine
deficiency.
10. Determine treatments used for carnitinedeficiency.
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Case Report: 35 year old woman
admitted to hospital with acute onset confusion and
lethargy
no history of alcohol or illicit substance use
undergone several surgery and hemodialysis somnolent yet arousable; can follow simple
commands
asterixis present, with temporal wasting,
hepatomegaly, diffuse muscle weakness and bilateral
lower extremity edema
with hypoglycemia, aspartate aminotransferase
slightly elevated
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Case Report.contd:
serum ammonia level 276 ug/dL , continued to rise
and peaked at 582 ug/dL (normal: 40-80 ug/dL)
abdominal CT revealed fatty infiltration of liver
Hepa A, B and C serologies are negative
Serum total carnitine 22 mM (normal: 33.8-77.5
mM)
Free carnitine 19 umol/L (normal: 25-55 umol/L)
Acylcarnitine ester 3.0 umol/L (normal: 3.8-19
umol/L)
Mgmt: Thiamine, Lactulose, Neomycin, Levocarnitine
330 mg TID
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BRIEF REVIEW OF B-OXIDATION OF FATTY ACID
Fatty acids must firstbe activated in the
outer mitochondrial
membrane
An enzyme Acyl-
CoAsynthetase is
responsible for the
activation of fattyacids.
Acyl- CoA.
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BRIEF REVIEW OF B-OXIDATION OF FATTY ACID
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BRIEF REVIEW OF B-OXIDATION OF FATTY ACID
AcetylAcetyl--CoACoAcan then enter the Krebs cycle and
lead to the production of ATP.
Fatty acids -oxidation is a cycle composed ofthree consecutive reactions:three consecutive reactions:
1. dehydrogenation,
2. hydration of the newly formed C=C double
bond,3. and oxidation of the alcohol to a ketone
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BRIEF REVIEW OF B-OXIDATION OF FATTY ACID
Other important functions of fatty acids include:
1) serving as building blocks of phospholipids and glycolipids:
2) acting (as derivatives) as hormones and intracellular messengers:
3) modfying proteins through covalent attachment, and so affecting their
cellular targeting and functioning.
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BRIEF REVIEW OF B-OXIDATION OF FATTY ACID
Fatty acids contain a long hydrocarbon chain and a terminalcarboxylate group.
Fatty acid catabolism is initiated when triacylglycerol is
hydrolyzed by lipases.
levels of cAMP = protein kinase A =phosphorylate the lipase.
This reaction yields 3 fatty acids and glycerolThis reaction yields 3 fatty acids and glycerol.
fattyfatty acids must attached to coenzyme Aacids must attached to coenzyme A..
This reaction is driven by ATP and is catalyzed by
acylCoAsynthase, in the cytosol.
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BRIEF REVIEW OF B-OXIDATION OF FATTY ACID
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Carnitine
hydrophilic amino acid derivative,
produced endogenously in the
kidneys and liver and
biosynthesized primarily in
the liver and kidneys from the
aminoacids lysine (via trimethyllysine) or methionineand derived
from meat and dairy products in
the diet.
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Carnitine
L-Carnitine is naturally occurring in all
mammalian species and is found in almost all
cells
L-Carnitine was shown to be an essential
nutrient for a meal worm (Tenebriomolitor)
and was therefore called vitamin BT
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Carnitine
the essential role of L-
Carnitine in the
utilization of long chain
fatty acids for energy
was confirmed
found that L-Carnitinecan actually increase
fatty acid oxidation in
healthy adults
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Functions of L-Carnitine
In Exercise:
L-Carnitine supplementation may foster
exercise performance. Both anincrease in maximal oxygen
consumption and a lowering of the
respiratory quotient indicate that L-Carnitine has the potential to stimulate
lipid metabolism
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Functions of L-Carnitine
Exercise:
high intensity exercise - significantlyeffective in assisting recovery.
decrease in the production of freeradicals, less tissue damage, reducedmuscle soreness after exercise and
better utilization of fat as an energysource during recovery.
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Functions of L-Carnitine
Cardiovascular health: L-Carnitine supplementation can positively
support healthy heart muscle
significantly increase heart muscle viability
beneficial in supporting a healthy heartbeat
have a favourable effect on blood lipid
levels helpful for people with angina, arrhythmias
and heart failure
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Functions of L-Carnitine
Infants:
an essential nutrient for infants
unlike adults, infants are unable to
synthesize sufficient L-Carnitine in
their bodies to meet theirrequirements
present in breast milk
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Functions of L-Carnitine
Vegetarians (and people with reduced
meat intake):
get very little L-Carnitine in their diet
Since intake of dietary L-Carnitine is
directly linked to meat intake
& meat is the richest source of this
nutrient
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Functions of L-Carnitine
Vegetarians (and people with reduced
meat intake):
also low in some of the nutrients that areessential for L-Carnitine biosynthesis in the
body
strict vegetarian diet over years = decreasedplasma L-Carnitine concentrations and may
benefit from supplementary L-Carnitine
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Functions of L-Carnitine
Male Fertility:
High concentrations of L-Carnitine and its
metabolite acetyl-L- Carnitine are found insperm, and both have a crucial role to play
in sperm energy metabolism
The concentration of L-Carnitine in semen is
closely linked to sperm quality
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Functions of L-Carnitine
Healthy aging:
after supplementation with L-Carnitine
= improved mental status and learningability, improved immune function or
an increase in muscle mass
has beneficial effects in seniors for themaintenance of fitness and health
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Importance of Carnitine
Is required for the transport ofIs required for the transport oflonglong--chain fattychain fatty
acids into the mitochondria, the site of betaacids into the mitochondria, the site of beta--
oxidation of fatty acids.oxidation of fatty acids.
Plays aPlays a critical role in energy productioncritical role in energy production..
Essential for a variety ofEssential for a variety ofimportant physiologicalimportant physiological
functions in energy metabolismfunctions in energy metabolism..
It also transports theIt also transports the toxic compoundstoxic compounds generatedgenerated
out of this cellular organelle to prevent theirout of this cellular organelle to prevent their
accumulation.accumulation.
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Other importance are:Other importance are:
Clears the bloodstream of ammonia and aids in creatingClears the bloodstream of ammonia and aids in creatingglycogen, the form in which theglycogen, the form in which the body stores glucose.body stores glucose.
CarnitineCarnitine is a key nutrient for helping to prevent muscleis a key nutrient for helping to prevent muscle
atrophy. Anyone suffering from a severe degenerativeatrophy. Anyone suffering from a severe degenerative
disease, such as cancer or AIDS, stands to gain fromdisease, such as cancer or AIDS, stands to gain from carnitinecarnitinesupplementation.supplementation.
Taking 2 grams ofTaking 2 grams of carnitinecarnitine per day for four weeks, hospitalper day for four weeks, hospital--
based studies show, can cut the number of complicationsbased studies show, can cut the number of complications
from heart attack in half.from heart attack in half.
This amino acid protects the heart from damage when aThis amino acid protects the heart from damage when a
heart attack or a spasm cuts off the oxygen supply.heart attack or a spasm cuts off the oxygen supply.
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CarnitineCarnitine is considered indispensable for infants.is considered indispensable for infants.
Babies usually getBabies usually get carnitinecarnitine through breast milk orthrough breast milk or
fortified formulas.fortified formulas.
Low thyroid functionLow thyroid function indicates a need forindicates a need for carnitinecarnitine
to help overcome lowto help overcome low energy levels and thelevels and the
tendency to gain weight.tendency to gain weight.
Kidney dialysis rinses away amino acidsKidney dialysis rinses away amino acids, causing a, causing a
weak, tired condition, which is threatened by highweak, tired condition, which is threatened by high
triglycerides.triglycerides.
CarnitineCarnitine may be of some value inmay be of some value in treatingtreating
diabetes, studies suggest, hypertension, liver disease,diabetes, studies suggest, hypertension, liver disease,
and immune problems.and immune problems.
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Carnitine
exists in two stereoisomers:
Its biologically active form is L-carnitine,
whereas
its enantiomer, D-carnitine, is
biologically inactive
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Structure of L-Carnitine
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Molecular Model
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Dietary: 75%
The highest concentrations of carnitine are found in redmeat and breast milk, dairy products.
Other natural sources of carnitine include
nuts and seeds (e.g. pumpkin, sunflower, sesame)legumes or pulses (beans, peas, lentils, peanuts)
vegetables (artichokes, asparagus, beet greens,broccoli, brussel sprouts, collard greens, garlic,mustard greens, okra, parsley)
fruits (apricots, bananas, avocados)
cereals (buckwheat, corn, millet, oatmeal, rice bran,rye, whole wheat, wheat bran, wheat germ)
and other 'health' foods (bee pollen, brewer's yeast,
carob, and kale)
Sources of Carnitine
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Sources of L-Carnitine
Endogenous synthesis The human body synthesizes about 20 mg
of L-Carnitine every day (Liver & Kidneys)
Dietary sources
Daily L-Carnitine requirement is met by
food intake. Animal products containreasonable amounts of this nutrient
whereas foods of plant origin contain only
very little, if any, L-Carnitine
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Table 1: L-Carnitine content in selected foods
[mg/100g]
Food of animalorigin
(uncooked)
Lamb
Beef
Pork
Poultry
Fish Egg
L-Carnitine[
mg/100g]
2.6
0.4
0.4
0.3 0.1
0.1
L-Carnitine[mg/100g]
190
143
25
13
3-10
0.8
Food ofplant origin
(uncooked)
Mushroom
Carrot
Bread
Rice
Banana
Tomato
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The pathway thatCarnitine can be synthesize
in our body
Concentrated in tissues like skeletal
and cardiac muscle that utilize fatty acids
as a dietary fuel.
Predominantly in the liver and kidney,
via a biochemical pathway involving theamino acids L -lysine and methionine,
vitamin C, and iron.
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Drugs that contain Carnitine and its indications
Acetyl L-Carnitine
-is a dietary supplementused to improve memory,
such as in Alzheimer's
disease.
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Carnitor
-For the acute and
chronic treatment of
patients with an
inborn error of
metabolism that
results in secondary
carnitine deficiency
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Biosynthesis of L-Carnitine
Carnitine can be synthesized via an
enzymatic pathway in the liver and
kidney by utilizing the amino acids: L-
lysine and L-methionine
L-lysine provides the four-carbon chain ofcarnitine (C3-C6), as well as provides the
amino group from the (epsilon) amino
group of lysine
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Biosynthesis of L-Carnitine
The methyl groups in carnitine are provided by
L-methionine.
These residues are methylated as aposttranslational modification of peptide-
bound lysine residues, and are catalyzed by
protein-lysine methyltransferase & methyl
groups from S-adenosylmethionine, thenremoved from the protein via hydrolysis
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Biosynthesis of L-Carnitine
The next step of formation of L-carnitineoccurs when -N-Trimethyllysine is
hydroxylated to -hydroxy-N-
trimethyllysine via the mitochondrialenzyme trimethyllysinedioxygenase.
It is then cleaved in an aldolase-type
reaction to -trimethylaminobutyraldehyde and glycine.
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Biosynthesis of L-Carnitine
Next, -trimethylaminobutyraldehyde isoxidized by -
trimethylaminobutyraldehydedehydroge
nase into -butyrobetaine (also known as-trimethylammoniobutanoic acid).
Finally, -butyrobetaine is transformed
into L-carnitine via the enzyme -butyrobetainedioxygenase.
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Biosynthesis of L-Carnitine
The synthetic pathway of carnitine occursubiquitously in the human body.
However the last step only occurs in the
liver and kidney, as well as in the brain toa lesser extent, due to the presence of -
butyrobetainedioxygenase enzyme in
only those organs. A number of transport systems then
carry the produced carnitine to other
tissues of the body
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Metabolism of L-Carnitine
Carnitine transports long-chain acyl groups from fatty
acids
mitochondrial matrix broken down through -oxidation to Acetyl
CoA to obtain usable energy via the citric acid
cycle.
Fungi - acetate is used in the glyoxylate cycle
for gluconeogenesis and formation of
carbohydrates.
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Metabolism of L-Carnitine
Fatty acids must be activated before
binding to the carnitine molecule to form
acylcarnitine.
The free fatty acid in the cytosol is attached
with a thioester bond to coenzyme A (CoA).
This reaction is catalyzed by the enzyme
fatty acyl-CoA synthetase and driven to
completion by inorganic pyrophosphatase.
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Metabolism of L-Carnitine
The acyl group on CoA can now be
transferred to carnitine and the
resulting acylcarnitine transportedinto the mitochondrial matrix
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This occurs via a series of steps:
1. Conjugation of AcylCoA to carnitine
carnitine acyltransferase I (palmitoyltransferase)located on the outer mitochondrial membrane
2. Shuttling of Acylcarnitine carnitine-acylcarnitinetranslocase
3. Conversion of Acylcarnitine to acylCoA
carnitine acyltransferase II (palmitoyltransferase)located on the inner mitochondrial membrane.*The liberated carnitine returns to the cytosol.
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Physiological effects of L-Carnitine
It helps increase lean body mass and
maintains bone mass.
It exhibits antioxidant effects and destroys
free radicals in the body
It protects against the risks of oxidative stress
at the myocardial level and lipid peroxidation
of phospholipid membranes.
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Carnitine Deficiency
Long chain fatty acids are the major source of
metabolic energy in humans, in particular forthe heart and skeletal muscles.
Persons with carnitine or
carnitinepalmitoyltransferase (CPT) deficiencyare unable to metabolize long-chain fatty
acids
Biochemical Background
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Carnitine Deficiency
Carnitine is an amino acid that is required for
the transport of long-chain fatty acids into themitochondria, the site of beta-oxidation of
fatty acids.
About 25 percent of the carnitine required bythe body is produced by the liver and kidneys
Biochemical Background
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Carnitine Deficiency
While the rest is derived from dietary intake,
primarily from red meat, poultry, fish, anddairy products.
Most of the carnitine in the body is located in
the voluntary and cardiac muscles.
Biochemical Background
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Two Types of Carnitine Deficiency
Primary
Secondary
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Primary carnitine deficiency
A person with primary carnitine deficiency has
very low levels of carnitine in the blood due to
a faulty carnitine transporter which prevents
carnitine from getting into the cells where it is
needed.
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Primary carnitine deficiency
systemic carnitine deficiency
affects many organ systems including the heart
and the brain
muscle carnitine deficiency
restricted to voluntary muscles
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Secondary carnitine deficiency
The secondary form of carntine deficiency can
arise secondary to metalobic disorders in the
mitochondria.
Blockage of metabolic pathways in the
mitochondria leads to a build-up of acyl
compounds. These compounds then bind tocarnitine and the bound complex is then excreted
by the kidney, causing carnitine levels to drop.
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Secondary carnitine deficiency
Some of these mitochondrial disorders include
cytochrome c oxidase deficiency,
mitochondrial ATPase deficiency, and fatty
acyl-CoA dehydrogenase deficiencies.
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Carnitine Deficiency: Pathophysiology
Causes/Risk Factors: Poor Intake (Fad diets, long-term IV feeding)
Enzyme Deficiency (CPT-I, CPT-II)
Carnitine Leak (Renal loss, inherited)
Surgery or Medical Procedure (Hemodialysis)
Medication (Valproate, Zidovudine)
Prematurity among newborn
Illness (2, e.g., liver disease, ketosis, majorburns, diuresis, severe diarrhea,intermittent claudication, angina and sepsis
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