carnitine deficiency[1]

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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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