II. Mechanism
-
Valproate is a simple Fatty Acid
- 2-n-propylpentanoic acid
- Eight carbon branched-chain carboxylic acid
- Metabolism: Three primary mechanisms
- Hepatic Glucuronidation (50%)
- Glucuronic acid conjugation occurs in the liver
- Primary metabolism pathway
- Non-hepatic metabolism
- Mitochondrial Beta-oxidation (40%)
- Primary and preferred non-hepatic pathway
- Valproate undergoes Fatty Acid beta-oxidation in the mitochondria
- Requires acetyl-coA to enter mitichondria
- Requires carnitine to cross Mitochondrial innder-membrane
- Microsomal omega hydroxylation (<5% under normal cicumstances)
- Carnitine independent metabolism pathway
- Results in formation of Delta^4-Valproic Acid which is hepatotoxic
- Contributes to high Serum Ammonia levels
- Mitochondrial Beta-oxidation (40%)
- Hepatic Glucuronidation (50%)
- Excretion
- Urine is primary excretion pathway for the metabolized form of Valproate
III. Pathophysiology: Toxicity
- Precipitating factors
- Valproic Acid in excess or
- Carnitine deficiency (depleted when starting Valproic Acid)
- Injury mechanisms
- Microsomal omega hydroxylation replaces mitochondrial beta oxidation
- Occurs with carnitine deficiency
- Results in hepatotoxic Valproate metabolites (Delta^4-Valproic Acid)
- Results in build-up of Valproate in the cytoplasm
- Increased Valproate levels
- Direct cellular injury
- Microvesicular Steatosis
- Metabolic Acidosis
- Cerebral edema (with increased Seizure risk) due to metabolite (4-en-Valproic Acid)
- Microsomal omega hydroxylation replaces mitochondrial beta oxidation
IV. Risk factors: Carnitine deficiency
- Valproic Acid started within last few weeks (carnitine depletion uncompensated)
- Increased Fatty Acid metabolism (faster carnitine deficiency)
- Ketogenic diet or Atkins Diet
- Poor nutritional intake
V. Signs
VI. Labs
-
Serum Ammonia
- Increased levels
- Serum Ammonia may also be increased up to 80 in non-toxic chronic Valproic Acid therapy
- Serum Valproic Acid
-
Liver Function Tests
- Elevated in carnitine deficiency, with increased Valproate metabolism by microsomal omega hydroxylation
-
Venous Blood Gas (or Arterial Blood Gas)
- Metabolic Acidosis in significant Overdose (due to acidic molecule)
VII. Management
- Stop Valproic Acid
- Consider L-Carnitine (see below)
- Large ingestion management
- Multi-dose Charcoal (50g every 2-4 hours) indications
- Presentation within 1 hour of large reported Valproate ingestion AND
- No airway compromise
- Hemodialysis indications
- Very high Valproic Acid levels (e.g. >800)
- Severe Metabolic Acidosis
- Ongoing Seizures
- Multi-dose Charcoal (50g every 2-4 hours) indications
VIII. Management: L-Carnitine
- Indications
- Massive Valproic AcidOverdose
- Symptoms suggestive of Valproic Acid Toxicity
- Valproic Acid level >120
- Serum transaminase increase (AST, ALT)
- Increased Serum Ammonia
- Consider Serum Ammonia >80 as abnormal if taking Valproic Acid chronically
- Dosing
- L-Carnitine 50-100 mg/kg (up to 2 grams) IV every 8 hours
- References
IX. Prevention
- Stop Valproic Acid if symptoms suggestive of toxicity
- Consider L-Carnitine supplementation (by prescription, OTC formulation too low dose)
- L-Carnitine 50-100 mg/kg (up to 2 grams) orally three times daily
- L-Carnitine is well tolerated, but may cause GI upset or fishy odor to skin
- L-Carnitine is derived from animal proteins (as well as some plants such as avocado) with only the L-Isomer active
X. References
- Hatten and Orman in Majoewsky (2013) EM:Rap 13(7): 3-4
- Silva (2008) J Inherit Metab Dis 31(2):205-16 [PubMed]
