Transcript Pediatrics Clinical Facts_SW-Pediatrics

The Role of Levocarnitine
Therapy in Pediatrics
ST International
International Division
Division
Role of Levocarnitine in Metabolism
• Carnitine is a water-soluble amino acid
derivative involved in mitochondrial energy
metabolism and the generation of ATP
• Carnitine’s essential role is to transport fatty
acids into mitochondria and R-Acyl-CoA
compounds out
• Carnitine is not catabolized in human cells
Pons R, De Vivo D. J Child Neurol. 1995;10(suppl 2):S8-S24.
International Division
International Division
Mechanism of Action:
Levocarnitine
International Division
The Carnitine Transport System
International Division
 CoA and Acyl CoAs do not cross the inner mitochondrial
membrane
 Free CoA -critical for mitochondrial fat and protein catabolism
 Free carnitine in the mitochondrial matrix is required for:
 Generation of ATP
 Maintaining a normal intramitochondrial Acyl CoA/Free CoA
 Removal of toxic intermediates in metabolic disorders
International Division
Carnitine Sources
• Synthesized from trimethylated lysine
released from muscle protein
– final step of synthesis is in the liver
– Synthesis is low in infancy due to decreased
muscle mass
• Dietary Sources
– active placental transport
– red meat
– dairy products
International Division
Carnitine Facts
• Exists in free and acyl or etherified forms
• Normal blood free value >20 micromoles/liter
• Normal ester/free ratio is 0.4 or less
• Renal clearance
– 90% of free carnitine reabsorbed in renal tubules
– esterified carnitine excreted with loss of the
carnitine molecule
– -excessive loss is a cause secondary deficiency in
metabolic disorders
Pons R, De Vivo D. J Child Neurol. 1995;10(suppl 2):S8-S24
International Division
Carnitine Deficiency
• Tissue carnitine values 2 S.D. below the mean
• Plasma carnitine level of 20 micromoles/L or less
• Plasma acyl/free carnitine level of 0.4 or greater
suggests an increased need for carnitine
for acyl derivative excretion and is known
as relative carnitine insufficiency
Stanley CA. Adv Pediatr 1987;34:59.
Winter SC et al. Am J Dis Child 1987;141:660.
International Division
Primary Carnitine Deficiency
Membrane transporter deficiency
This is an autosomal recessive disorder
affecting carnitine transport across
membranes including the renal tubules and
muscle.
Tissue and blood levels are low
No synthetic defects have been reported
Pons R, De Vivo DC. J Child Neurol. 1995;10(suppl 2):S8-S24.
International Division
Secondary Carnitine Deficiency
• Increased loss of Acyl Carnitine
– Inborn errors of metabolism (IEM)
– Pharmacologic (Valproate, Pivalate)
– Diabetes
• Increased loss of Free Carnitine
– Renal tubular loss (Fanconi Syndrome
– Hemodialysis, peritoneal dialysis
• Decreased Supply
– Liver disease
– Malnutrition
– Soy milk based formulas unsupplemented
– TPN
– Cofactor deficiency (Iron, vitamin C)
International Division
Secondary Carnitine Deficiency due to IEMs
• Fatty acid oxidation defects
• Organic acidurias
• Amino acidurias
• Urea cycle defects
• Mitochondrial disorders of energy generation
Weiner DL. Pediatrics, inborn errors of metabolism [eMedicine Web site]. Available at:
http://www.emedicine.com/emerg/topic768.htm. Accessed August 30, 2004.
International Division
Methylmalonic Aciduria
mutase 0 (MMA)
Isoleucine ,valine, methionine
threonine
Propionyl CoA
Methylmalonyl CoA
X
Succinyl CoA (TCA Cycle)
International Division
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
•
Rousson T, Guibaud P. Long term outcome of organic acidurias:survey of 105 French cases (1967-1983) J Inherit
Metab Dis 1984;7 Suppl 1:10-2
– 1983/1984-Carnitine treatment
•
Roe CR, Hoppel CL, Stacey TE, Chalmers RA, Tracey BM, Millington DS. Metabolic response to carnitine in
methylmalonic aciduria. An effective strategy for elimination of propionyl groups. Arch Dis Child 1983
Nov;58(11):916-20
•
Chalmers RA, Stacey TE, Tracey BM, de Sousa C, Roe CR, Millington DS, Hoppel,C. L-Carnitine insufficiency in
disorders of organic acid metabolism: response to L-carnitine by patients with methylmalonic aciduria and 3hydroxy-3-methylglutaric aciduria.J Inherit Metab Dis. 1984;7 Suppl 2:109-10
International Division
International Division
Carnitine Values
Plasma
Micromoles/L
 Total 17.4
 Normal (30-70)
 Free 7.9
 Normal (25-65)
 Ester 9.5
 Normal (0-10)
Urine
Micromoles/L
53.1
 Normal (300-360)
7.5
 Normal (140-200)
45.6
 Normal (140-200)
Metabolic Analysis Laboratory. Austin Shug, PhD
International Division
International Division
International Division
First 36 Cases of Carnitine Deficiency
(1965-1987)
• Encephalopathy (77%)
• Progressive Muscle Weakness (77%)
• Lipid Excess in Muscle (100%)
• Cardiomyopathy (23%)
• Low Serum Carnitine (89%)
• Low Muscle Carnitine (100%)
International Division
Plasma Carnitine Deficiency
51 Cases
• Hypotonia/ gross motor delay (85%)
• Recurrent infections with metabolic
decompensations (85%)
• Failure to thrive (75%)
• Mental retardation (40%)
• Cardiomyopathy (30%)
• Encephalopathy (5%)
Winter SC et al. Am J Dis Child 1987;141:660.
International Division
Medium Chain Fatty Acyl CoA
Dehydrogenase Deficiency (MCAD)
International Division
MCAD Autopsy of the Liver
International Division
Fatty Acid β-Oxidation
Pons R, De Vivo D. J Child Neurol. 1995;10(suppl 2):S8-S24.
Long-chain
fatty-acyl-CoA
Short-chain
fatty-acyl-CoA
Medium-chain
fatty-acyl-CoA
b-Oxidation cycle
R-CoA
Electron
transpor
t
chain
3 OH-R-CoA
Acetyl-CoA
Ketones
To Krebs cycle
International Division
3 Keto
R-CoA
Carnitine must be available
to remove excess R-CoA
compounds
FDA approval of Carnitine for IEM
(1987-1992)
• 1985- oral carnitine approved by FDA for
treatment of primary carnitine deficiency
• 1992-NDA for treatment for secondary carnitine
deficiency due to IEM based on retrospective
data
 Limited to disorders where Acyl CoA metabolites accumulate
International Division
Signs and Symptoms of Carnitine deficiency
These are related to altered mitochondrial energy
generation:
• Muscle hypotonia/weakness
• Cardiomyopathy
• Encephalopathy
• Hepatic dysfunction
• Failure to thrive
International Division
Summary of Data
• Significant drop in hospitalization frequency
for all groups
• Significant increase in survival
• Significant improvement in failure to thrive
• Significant change in biochemical parameters
– Improved ketosis-restoration of beta oxidation
– Increased excretion of accumulating acyl groups
– Positive effect on Acyl CoA/Free CoA ratio
International Division
RB – Age 10 Years
MMA Mut 0
International Division
RB – Effect of Carnitine PO and IV on
Plasma Carnitine Metabolites
Carnitine intake
(mg/kg/day)
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
International Division
RB – Effect of Carnitine PO and IV on Urine
Acylcarnitine Derivatives
Days
1
Oral
mg/kg/d
IV
mg/kg/d
Propionylcarnitine
(mmol/mg creatinine)
100
200
300
15.9
5.0
8.9
38.9
43.7
400
2
3
4
5
6
7
8
9
400
14
666
666
18
International Division
300
300
300
300
63.4
68.5
45.4
300
14.3
The higher the
carnitine, the higher
the excretion of toxic
R-CoA
10 years on IV carnitine therapy
6 months on IV carnitine therapy
International Division
Expanded Newborn Screening (MS/MS)
 One out of 4500 newborns has an IEM detectable by
MS/MS
 For Fatty Acid and Organic Acid disorders,the method is
based on detection of acylcarnitine derivatives in the
blood by tandem mass spectrometry (MS/MS)
 Over 30 disorders are detectable
 The expanded screen is done on the same filter paper
samples as traditional newborn screening
 Expanded newborn screening is mandated in >40 states,
National Newborn Screening and Genetics Resource Center. MS/MS Conditions Screened (by state).
Updated 8/24/04. http://genes-r-us.uthscsa.edu. Accessed August 30, 2004.
International Division
Disorders Detected by MS/MS in California
Total Births 2,204,032 (7/05-7/09)
• Phenylketonuria- Classical 1/40,073
• Other Amino Acid Disorders 1/40,073
• Fatty Acid Oxidation Disorders 1/8,816
• Organic Acid Disorders 1/12,594
International Division
Causes of Carnitine Deficiency in
Hemodialysis Patients
• Dietary Restrictions
– Red meat and dairy products are primary exogenous sources
(75% of body’s need)
• Impaired Synthesis
– Kidney, along with liver, is a primary site of endogenous
carnitine synthesis (25% of body’s need)
• Excessive Loss from HD
– Reasons for carnitine loss
• Small molecular weight (162 Daltons)
• Highly water soluble
• Poorly protein bound
International Division
Free Carnitine Plasma
Concentrations (uM)
More than 70% of the total plasma carnitine
is removed during each dialysis session
20
15
10
5
0
0
0,5
1
1,5
2
2,5
3
3,5
Dialysis Tim e (hours)
Evans et al; 2000
International Division
Frequency of low carnitine levels in children
on dialysis.
• 100 study patients, 70 were on PD
• Median age was 13 years, and the median time on
dialysis, 10.5 months
• Carnitine levels were lower than normal in 75 and
deficienct in 29
• No difference was found between the dialysis
modality types, time on dialysis , or carnitine intake
• Frequency of low serum carnitine among pediatric
patients on dialysis is high
Ibarra-Cazares P, etal. Adv Perit Dial. 2006;22:208-10
International Division
Protective effect of intravenous carnitine on subsequentmonth hospitalization among hemodialysis patients
1998 to 2003.
• Effect of 1 g L-carnitine for 10 or more sessions during
a month on subsequent hospitalization days
– 10.8% decrease in subsequent-month hospitalization days.
– 21.7% decrease in hospitalization days
• The association of monthly intravenous L-carnitine
therapy with lower hospitalization rate is clinically
significant.
,
Rao M et al. Am J Kidney Dis. 2007 Nov;50(5):803-12
International Division
Prematurity and Risks of Secondary
Carnitine Deficiency
• Premature infants are susceptible to carnitine deficiency
– Decreased carnitine placental transfer
– Renal tubular loss of free carnitine
– Immature, dysfunctional muscle and liver synthesis
• Consequences of carnitine deficiency
– Limited b-oxidation of fatty acids; low ATP production
– Decreased ketogenesis
– Poor growth
Borum PR. J Child Neurol. 1995;10(suppl 2):S25-S31.
International Division
Acquired Carnitine Deficiency: HIV/AIDS
• Causes of carnitine deficiency in HIV/AIDS
– Antiretroviral medications
– Nutritional deficiencies
– Gastrointestinal disturbances
– Renal losses
– Shifts in metabolic pathways
– Drug toxicities, particularly zidovudine
Mintz M. J Child Neurol. 1995;10(suppl 2):S40-S44.
International Division
Valproic Acid,
Hepatic Failure
and Carnitine
Deficiency
International Division
Iatrogenic Carnitine Deficiency: Valproate
• Valproate-induced hepatotoxicity results in a direct disruption of
mitochondrial processes
• Valproate is transported as a valproyl-carnitine derivative into the
mitochondria, undergoes partial b-oxidation, and some metabolites
are removed as carnitine derivatives
• Symptoms of valproate-induced carnitine deficiency
– Hepatotoxicity
– Encephalopathy: lethargy to coma
– Increased seizure frequency
– Progressive muscle weakness
– Hyperammonemia
Bohan TP, et al. Neurology. 2001;56:1405-1409.
International Division
Iatrogenic Carnitine Deficiency:
Valproate cont.
• Hypothesis to explain the potential benefit of levocarnitine
– Patients taking valproate have an ongoing loss of
valproylcarnitine and valproylcarnitine metabolite derivatives
– When stress-induced catabolism (eg, seizures) occurs,
carnitine deficiency will aggravate any underlying mitochondrial
dysfunction
• Early intervention with IV levocarnitine has been associated
with decreased mortality
• Prophylactic carnitine recommended for children under age 2
Bohan TP, et al. Neurology. 2001;56:1405-1409.
International Division
Iatrogenic Carnitine Deficiency:
Valproate (cont.)
Survival (%)
The survival of patients with VPA hepatotoxicity gets worse the longer
the valproate is continued: comparison of L-carnitine–treated patients
with untreated patients
100
L-Carnitine treated
80
Untreated controls
60
40
20
0
Hepatotoxic episode duration before valproate stopped
Reproduced with permission from Lippincott, Williams & Wilkins. Bohan TP.
Neurology. 2001;56:1405-1409.
International Division
Glutaric Aciduria II-ETF
International Division
GA II patient when
diagnosed and
started on IV
carnitine, riboflavin,
and protein/fat
restricted diet
Same patient
after 10 days
of carnitine,
riboflavin and
diet
International Division
Patient at Age 14 Remaining well on
L-Carnitine treatment
International Division
Cardiomyopathy: A Potential
Manifestation of Carnitine Deficiency
• During first year of life, estimated incidence is one
in 10,000 live births
– ~5000 cases reported annually in the pediatric population
• Cardiomyopathy can occur in many inborn errors
of metabolism, especially those resulting in
secondary carnitine deficiency
Helton E, et al. Pediatrics. 2000;105:1260-1270.
International Division
Pediatric Cardiomyopathy
Retrospective Study
10-year retrospective chart review from
7 centers (221 patients)
• 76 treated with levocarnitine
– 29 metabolic diagnoses
• 3 LCHAD
• 145 controls
– 15 metabolic diagnoses
• 3 LCHAD
LCHAD, long-chain hydroxyacyl-CoA dehydrogenase deficiency.
Helton E, et al. Pediatrics. 2000;105:1260-1270.
International Division
Cardiomyopathy and L-Carnitine
Baseline
Endpoint
Ejection fraction
Baseline vs endpoint in L-carnitine–
treated patients vs control subjects
0.5
0.4
0.3
0.2
0.1
5
4
3
2
1
0
L-Carnitine
Control
Treatment group
Clinical severity score
Clinical functioning score
0
14
12
10
8
6
4
2
0
L-Carnitine
Control
Treatment group
L-Carnitine
Control
Treatment group
Reproduced with permission from Pediatrics. 2000;105:1260-1270.
International Division
Results
• Significant improvement in ejection fraction, clinical
severity scores, and clinical functioning in levocarnitinetreated versus placebo group
• Improved survival for first 100 days in the levocarnitinetreated versus untreated metabolic patients
• Long-term survival in both groups was the same,
despite carnitine-deficient patients having worse scores
at treatment onset
Helton E, et al. Pediatrics. 2000;105:1260-1270.
International Division
L-Carnitine Treatment
• Oral Liquid-100 mg/ml
• Tablet-330 mg
• Intravenous-1g/5 ml.
• Dose and length of treatment
– Depends on cause of deficiency
– Depends on age
– Emergency treatment versus maintenance
treatment
International Division
L-Carnitine Treatment
• Dietary deficiency
• 100 mg/kg/day oral
• 50 mg/kg/day IV
• Preventative dose-TPN - 15 mg/kg/day
• Renal dialysis
• 1 gram IV after each dialysis session
• Valproate/Pivalic acid/diabetes
• 50-100 mg/kg/day oral treatment
International Division
L-Carnitine Treatment
Inborn errors of metabolism
•
Life long treatment
•
Emergency management-up to 300 mg/kg/day
Intravenous carnitine
•
High Dose oral therapy up to 600mg/kg/day
•
Indwelling venous port for delivery of intravenous
carnitine at home
International Division
Adverse Events (26 patient cohort)
• Vomiting -
9/26 (37%)
• Diarrhea -
6/26 (23%)
• Abdominal pain -
3/26 (12%)
• Fishy odor (TMA)-
3/26 (12%)
• Alopecia/rash-
1/26 ( 4%)
• Death in one patient with propionic acidemia
International Division
Treatment of Trimethylaminuria Secondary
to Oral Carnitine Therapy
• 7% of patients in FDA safety trials.
• Due to carnitine conversion by bowel bacteria to
trimethylamine
• FMO3 mutations are common [~7%]
• Treatment with Metranidazole in low doses rapidly
resolves odor.
• Doses used are 125-250 mg. per day for 10 days with
repeated courses as necessary.
International Division
Conclusion 1
• L-Carnitine is a natural substance vital to energy
metabolism for:
– Transporting long-chain fatty acids across
mitochondrial membrane for generating ATP
– Modulating mitochondrial Free CoA/acyl-CoA ratio
– Scavenging potentially toxic acyl compounds
International Division
Conclusion 2
• Secondary Carnitine Deficiency is common in
children
– Increased loss of acyl carnitine: inborn errors,
pivalic acid, valproic acid
– Increased loss of free and acyl carnitine: Renal
Tubular Fanconi syndrome, Dialysis
– Decreased intake or absorption: gastrointestinal
malabsorption, diet low in carnitine
International Division
Conclusion 3
• Dose and duration of carnitine therapy depends
on the cause of the deficiency
• Oral and IV carnitine treatment is safe with few
side effects
• Treatment results in improvement of symptoms
associated with carnitine deficiency
International Division