L-Carnitin in der P

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Pediatrics and L-Carnitine
ST International Division
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Indications for L-Carnitine
Sport
Renal insufficiency
Cardiovascular disease
Pregnant women/Young mothers
Immune-deficits
Newborns/ Infants
L-Carnitine
Fatigue/Chronic Fatigue Syndrome (CFS)
Muscle diseases
Nutritional deficits
Cancer
Infertility
Diabetes
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Mothers, infants and children benefits of
L-Carnitine
Childhood
Pregnancy/newborns
Primary L-Carnitine deficiency
Pregnancy
Newborn
Secondary genetic L-Carnitine deficiency
L-Carnitine Importance applications
Premature
Drugs Epilepsy/Valproic acid Cancer/Anthracycline
Mother milk
Resorption problems e.g. Mucoviscidose
Nutritional solutions
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Pediatrics and L-Carnitine

• Content of the module
• ? L-Carnitine
• Molecule
• Effects
• Distribution
• ? L-Carnitine Deficiency
• Causes
• Charachteristics
• Consequences
• ? L-Carnitine and birth
• Pregnancy
• Newborn
• Nutritional solutions

? Pediatric syndromes Primary
L-Carnitine deficiencies Genetically
determined metabolic disorders Drug
induced L-Carnitine deficiencies
Resorption problems ? The product Carnitor
Composition Use and
effects
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L-Carnitine The Molecule
Bound L- Carnitine Harmful (if too much) bad
Free L- Carnitine Not harmful good
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L-Carnitine The Effects
Fat an important energy factor
Energy content of bio-molecules
Percentage of body substance
Burning power (kcal/g)
Petrol
Fat
Carbo hydrates
Alcohol
Proteins
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L-Carnitine The Effects
The cell Center of metabolism
Mitochondrion
Mitochondrion
Mitochondrion
Mitochondrion
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L-Carnitine The Effects
The Mitochondrion Power House of the cell
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L-Carnitine The Effects
Activated long-chain fatty acids (Acyl-CoA) are
carried into mitochondria by the L-Carnitine
Carrier system
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L-Carnitine The distribution in the body
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L-Carnitine The Sources
Food 20 - 100 mg/day (75 of daily need)
Endogenous Synthesis 15 - 20 mg/day (25 of
daily need)
L-Carnitine Content in food (mg/100 g)
Where does it happens? Mainly in liver and
kidney Starting from ? The aminoacids Lysine and
Methionine Cofactors? Vitamins C, B6, B12 Folic
acid, Niacine, Iron
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L-Carnitine The Need
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L-Carnitine deficiency in infants and children
Risk factors

• Defects of the cellular L-carnitine
  transport
  system
• Risk groups infants/small children
• Increased loss of L-carnitine in certain
  metabolic
  diseases and drug therapies
  
  Risk group small children
• Maternal/Fetus low level of endogenous
  L-carnitine synthesis and reduced nutritional
  support
• Risk groups infants/prematures
• Resorption problems
  
  Risk groups infants/small children

Primary L-Carnitine deficiencies
Secondary L-Carnitine deficiencies
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L-Carnitine Deficiency
Primary L-Carnitine Deficiency Is a genetic
defect of the Carnitine transporter OCTN2 in the
cell membrane
rare
Secondary L-Carnitine Deficiency As a
consequence of mitochondrial enzymes genetic
defects, or pathologies or drugs treatment
frequent
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L-CARNITINE DEFICIENCY SYNDROMESCLASSIFICATION
CARNITINE DEFICIENCY SYNDROMES
Shannon D, 1997
PRIMARY CARNITINE DEFICIENCY
SECONDARY CARNITINE DEFICIENCY
OCTN2
Genetically determined metabolic
error Examples Organic acidurias
Beta-oxidation defects Carnitine enzymes
defects .Respiratory chain defects
Acquired medical conditions Examples Chronic
renal disease Malabsorption (cystic fibrosis
short.gut syndrome) Extreme prematurity
Carnitine-deficient diet
Iatrogenic factors Examples Chronic
valproate administration Pivalic acid
Zidovudine administration
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PRIMARY CARNITINE DEFICIENCY (PCD)
Acyl-CoA
CPT1
CPT2
CT
CARNITINE
CT
CARNITINE
?-oxidation
Respiratory Chain
OCTN2
OCTN1
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PRIMARY CARNITINE DEFICIENCY (PCD)

• Ethnic Incidence About one in every 40,000
  babies in USA is born with PCD
• Symptom Onset Neonatal onset between 3-30
  months of age
• Late onset from 7 years of age
• Symptoms Encephalopathy, coma, hypoketotic
  hypoglycemia, hyperammonemia, cardiomyopathy,
  muscle weakness, muscle and/or liver steatosis
• Carnitine levels Plasma FC plasma (lt5-10
  ?moli/L)
• Tissue FC (lt5 ?moli/g)
• Treatment Carnitine supplementation (100-150
  mg/Kg/day) is lifesaving and curative

Angelini et al., 1992 Tein 2003
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PRIMARY CARNITINE DEFICIENCY (PCD)
WINTER S, AHJ, 2000
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SECONDARY CARNITINE DEFICIENCIES (SCD)
genetic causes
Acyl-CoA
CPT1
CPT2
CT
CARNITINE
CT
CARNITINE
?-oxidation
Respiratory Chain
OCTN2
OCTN1
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SECONDARY CARNITINE DEFICIENCIES (SCD)
Genetic causes Inborn errors of metabolism
Organic acidurias, Fatty acid oxidation
defects Clinically characterized by Reye-like
syndrome with hyperammonemic encephalopathy,
Muscle weakness, Myoglobinuria,
Cardiomyopathy, Sudden death Biochemically
characterized by Hypoglycemia, Hypoketonemia,
Dicarbossilic aciduria, Hyperuricemia Carniti
ne levels Normal or slightly decreased plasma
free carnitine concentrations (lt 20 ?mol/L),
increased AC/FC ratio (normal values are lt
0.4) Treatment L-Carnitine (25-200 mg/Kg/day)
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Methylmalonic Aciduria mutase 0 (MMA)
Isoleucine, valine, methionine threonine
Propionyl CoA
Methylmalonyl CoA
X
Succinyl CoA (TCA Cycle)
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Initial Patient Experience

• 1982- MMA mut0-neonatal onset
• Results in increased excretion of propionyl
  carnitine (not understood in 1982)
• Only treatment in 1982 was dietary and supportive
• Long term prognosis fatal

• Plasma (?mol/L)
• TC 17.4 - Normal (30-70)
• FC 7.9 - Normal (25-65)
• AC 9.5 - Normal (0-10)

• Urine (?mol/L)
• TC 53.1 - Normal (300-360)
• FC 7.5 - Normal (140-200)
• AC 45.6 - Normal (140-200)

Roe CR, Arch Dis Child 1983 Chalmers RA, J
Inherit Metab Dis. 1984
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• 1983- L-Carnitine treatment
• (25 up to 200 mg/Kg/day)
• Once the plasma free carnitine level reached a
  normal value at 12 months he showed a rapid
  improvement in weight gain.
• By 18 months, he was well again and thriving

Roe CR, Arch Dis Child 1983 Chalmers RA, J
Inherit Metab Dis. 1984
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• From age 18 months to 10 years L-Carnitine
  treatment was not increased during that time and
  he showed severe failure to thrive, muscle
  weakness, cardiomyopathy, and recurrent
  infections with acidosis
• Starts iv L-Carnitine treatment

Carnitine intake (mg/kg/day) Carnitine intake (mg/kg/day) Plasma carnitine (mmol/L) Plasma carnitine (mmol/L) Plasma carnitine (mmol/L)
Date Oral IV Total Free Ester
6/13 400 0 87.6 7.2 80.4
6/16 0 200 170.0 63.4 106.6
6/21 400 300 396.7 304.0 92.7
6/26 666 300 523.5 338.8 134.7
6/30 666 0 186.5 94.6 91.9
Roe CR, Arch Dis Child 1983 Chalmers RA, J
Inherit Metab Dis. 1984
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• Direct relationship between the dose of carnitine
  administered and the excretion of propionyl
  carnitine
• The higher the carnitine, the higher the
  excretion of toxic Acyl-CoA
• The clinical response after 10 years on this IV
  therapy is evident above.

Days Oral mg/kg/d IV mg/kg/d Propionylcarnitine (mmol/mg creatinine)
1 400 15.9
2 5.0
3 100 8.9
4 200 38.9
5 300 43.7
6 300 63.4
7 300 68.5
8 300 45.4
9 400 300
14 666 300
18 666 14.3
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L-Carnitine improves the clinical picture of
patients with inborn errors of metabolism and
L-Carnitine deficiency
Winter, 2003
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SECONDARY CARNITINE DEFICIENCIES (SCD)
Acquired causes Increased utilization
cachexia, surgery, trauma, burns, stress, sport,
pregnancy, lactation, extreme prematurity,
anthracycline, statins, clofibrate,
sulfonylureas, amiodarone, sepsis, cancer,
diabetes, heart failure, thyroid
disease Increased loss drugs (pivalic acid,
valproic acid, zidovudine, cephalosporins,
pyrimethamine, sulfadiazine, benzoic acid,
ifosfamide, cisplatin) cystinosis,
haemodialysis, scurvy Decreased synthesis
Cirrhosis, homocystinuria, chronic renal failure,
extreme prematurity, scurvy Reduced intake
Long-term total parenteral nutrition, vegetarian
and lactoovo-vegetarian diets, fasting, celiac
disease, cystic fibrosis, malnutrition, heart
failure
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Increased L-Carnitine utilization
during Pregnancy
L-Carnitine Plasma levels of pregnant women
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Increased L-Carnitine Loss
due to cytostatics


Enquiry of Marthaler et al., Cancer Chemotherapy
and Pharmacology, 1999 Objective and Methods
5 Patients with advanced Sarcoma under
5 days of Ifosfamide-Treatment
determination of daily urine excretion of Free
and Total carnitinie Results Before
Ifosfamide Administration L-Carnitine-Excretion
within normal range After Ifosfamide
(2,8 3,2 g/m2) 30-fold increase of
L-Carnitine-Excretion ? During one cycle of
chemotherapy up to 10 of depletion of
L-Carnitine- storage
L-Carnitine in Urine
Marthaler et al., 1999
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Hemodialysisreduced LC intake and synthesis,
increased loss
Plasma Concentrations of Endogenous L-carnitine
During Hemodialysis
Evans A et al., 2000
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Reduced L-Carnitine intake
Mucoviscidose/ Cystic fibrosis (CF)
Coeliac disease
Lerner et al., 1993
Lloyd-Still et al., 1993
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Reduced L-Carnitine utilization
during Heart failure
L-Carnitin-Deficit in the Heart ? Not enough
Free L-Carnitine ? Excess of Acyl-L-Carnitine ?
Longterm L-Carnitine-deficit
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Drug-induced carnitine deficiency
Metabolic disfunctions under therapy with
valproic acid ? Inhibition of cellular
L-Carnitine transport mechanism ? Free-CoA
is sequestered by valproyl-moyeties
? Increased L-Carnitine loss ?
Increased risk for patients with inborn metabolic
errors
Positive effects when giving L-Carnitine,
expecially if early and as i.v. administration
Bohan et al., 2001
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Drug-induced carnitine deficiency
Disfunction under therapy with anthraciclyne

Reduction of heart function and performances in
patients
L- Carnitine deficiency in the blood
Hauser et al., 2001
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Drug-induced carnitine deficiency
Cancer patients Protection of the cardiac
muscle and less cardiac complications using
L-Carnitine
Anselmi et al., 1993
Neri et al., 1983
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L-Carnitine Deficiency overall consequences
Clinical ? Heart and muscle weakening?
Quick physical fatigue? Heart and muscle
damages? Immune deficits? Anemia ?
Growth problems in children? Risk of
Arteriosclerosis? Liver dysfunction?
Lethargy/Fatigue
Physiological ? Fat burning ? ? Glucose
consumption ? ? Lactate acidosis ? ?
Cell and tissue damage ? ? Blood lipids
? ? Liver function ?
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L-Carnitine Deficiency in Pregnancy

• Plasma carnitine concentrations markedly decline
  (50) during gestation, secondary to
• Placental L-Carnitine passage from the mother to
  the fetus
• Removal of toxic metabolites
• Maternal reduced L-Carnitine biosynthesis
• Maternal reduced protein breakdown

Keller U, EJ Clin Nutr (2009)
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L-Carnitine Deficiency in Pregnancy

Reduction of L-carnitine concentration
Koutmantakis et al., 1997
Genger et al., 1988
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L-Carnitine Deficiency in Pregnancy
L-Carnitine deficiency is prevented by
L-Carnitine treatment (500 mg/day) from the 13th
week of pregnancy until delivery
Plt0.05
Plt0.05
Keller U, EJ Clin Nutr (2009)
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L-Carnitine importance for the fetus

• Maternal L-Carnitine supplementation
  significantly improves fetal growth

L-Carnitine n15 placebo n15
BW (Kg) 2.722 (0.4) 2643 (0.5)
Lenght (cm) 47.9 (1.9) 47.2 (2.5)
Percentile 33.8 (19.8) 32.2 (17.7)
Apgar 8.6 (0.7) 8.2 (1.4)
Genger H. 1988
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L-Carnitine importance in the newborn
? In the fetus energy is provided mainly
through carbohydrates oxydation ? At birth
energy requirements increase rapidly due to
respiration,

movements, body temperature,general growth
and development ? The use of previous
energy reserve and the nutritional offer is
mandatory ? Exhaustion of carbohydrate
stock in a few hours ? Activation of fat
reservoir ? Energy supply of the central
nervous system via keton bodies of lipid
metabolism ? Need to have sufficient
L-carnitine to guarantee the lipid metabolism
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L-Carnitine importance in the newborn

Less endogenous L-Carnitine synthesis
L-Carnitine in the muscle Impact of timing and
weight at birth
Rebouche Engel, 1980
Shenai Borum, 1980
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L-Carnitine importance in the newborn
Increased use of lipids after birth
Effective use of L-Carnitine rich nutrition
Increased free fatty acids in
the blood
Warshaw et al, 1980
Novak, 1992
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L-Carnitine importance in the prematures
If not supplemented, the prematures is
carnitine-deficient
L-Carnitine deficiency in the blood
Loss in organs
Penn et al., 1980
Penn et al., 1985
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L-Carnitine importance in the prematures
Prematures L-Carnitine supplementation
Correction of the L-Carnitine
deficiency
Trend to a more rapid weight increase
Better fat utilization
Bonner et al., 1995
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L-Carnitine supplementation in infant nutrition
L-Carnitine supplementation with mother milk
L-Carnitine content of the different milk sources
Sandor et al., 1982
Ferreira, 2003
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L-Carnitine supplementation in infant nutrition
1985
Carnitine was added to soy baby formulae to
prevent "floppy baby syndrome" as it was realised
that carnitine is present in breast and cow's
milk but not other milk substitutes.
European Carnitine Development Dept
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L-Carnitine treatment of newborns children

• Newborns who receive TPN 2-10 mg/Kg as
  continuous infusion or divided into four daily
  doses
• Newborns with primary or secondary carnitine
  deficiency
• starting dose is 50-100 mg/Kg/d (to be
  adjusted based on plasma levels)

Scaglia 1999 Crill 2007
European Carnitine Development Dept
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