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A case of valproate-associated hepatotoxicity treated with l -carnitine
European Journal of Internal Medicine 14 (2003) 338–340 www.elsevier.com / locate / ejim
Brief report
A case of valproate-associated hepatotoxicity treated with L-carnitine c ´ a , Eva de la Santa-Belda,b , Rosa Garcıa-Contreras ´ Auxiliadora Romero-Falcon , Jose´ M. Varela d , * a C / Granaderos no. 4, 41010 Sevilla, Spain C / Virgen de la Antigua no. 22, 41011 Sevilla, Spain c ´ C / Vazquez de Leca no. 10, 41010 Sevilla, Spain d ´ , Av. Manuel Siurot s /n, 41013 Sevilla, Spain Department of Internal Medicine, Hospital Universitario Virgen del Rocıo b
Received 23 September 2002; accepted 10 April 2003
Abstract Valproate is a major broad-spectrum anti-epileptic drug that is effective against many different types of epileptic seizures and that is usually well tolerated. Nevertheless, serious side effects can occur, including hepatotoxicity. This side effect is rare but often fatal, and it has been hypothesized that long-term valproate therapy may induce a carnitine deficiency and cause non-specific symptoms of hepatotoxicity and hyperammonemia. These factors suggest that L-carnitine supplementation may play a role in preventing hepatotoxicity. We report a case of valproate-induced acute liver injury with a favorable evolution after L-carnitine therapy. 2003 Elsevier B.V. All rights reserved. Keywords: Valproate; Hepatotoxicity; Carnitine
1. Introduction
2. Case report
Valproate is a major broad-spectrum anti-epileptic drug that is effective against many different types of epileptic seizures. It is usually well tolerated. Nevertheless, serious side effects can occur including thrombocytopenia, polycystic ovarian disease, pancreatitis, tremor, teratogenicity with neural tube defects in offspring, and hepatotoxicity. This last side effect is rare but often fatal, and it has been hypothesized that long-term valproate therapy may induce a carnitine deficiency and cause non-specific symptoms of hepatotoxicity and hyperammonemia [1]. These factors suggest that L-carnitine supplementation may play a role in preventing hepatotoxicity [2,3]. We report a case of valproate-induced acute liver injury with a favorable evolution after L-carnitine therapy.
A 16-year-old man was admitted to the hospital because of a 16-day history of apathy, lethargy, and progressive jaundice. He had been receiving valproate therapy (1500 mg / day) for the past 8 weeks for generalized epilepsy, but it was discontinued 5 days before admission. The patient was not taking any other medications or herbal products, and he had no history of liver disease, blood transfusion, or alcohol or drug abuse. His serum valproate level was 65 mg / ml (normal: 50–100 mg / ml) 4 weeks before admission. On admission, physical examination revealed only jaundice without fever, and the midline lower border of the liver protruded 3–4 cm below the costal margin. Laboratory data showed the following values: total bilirubin 21 mg / dl (conjugated bilirubin 19 mg / dl); aspartate aminotransferase 3887 UI / l (normal: 0–30 UI / l); alkaline phosphatase 406 UI / l (normal: 98–279 UI / l); g-glutamyl transpeptidase 219 UI / l (normal: 10–50 UI / l), and partial thromboplastin time 17.5 s. His serum concentration of valproate was 10 mg / ml (normal: 50–100 mg / ml). Four days later, the laboratory revealed an impairment: a total
*Corresponding author. Apartado de Correos 7228, 41080 Sevilla, Spain. Fax: 134-955-013-473. E-mail address: [email protected] (J.M. Varela). 0953-6205 / 03 / $ – see front matter 2003 Elsevier B.V. All rights reserved. doi:10.1016 / S0953-6205(03)00104-3
´ et al. / European Journal of Internal Medicine 14 (2003) 338–340 A. Romero-Falcon
bilirubin of 29.37 mg / dl (conjugated bilirubin 27.43 mg / dl) and aspartate aminotransferase of 4538 U / l. In spite of these values, there was no encephalopathy, bleeding, or other symptoms present. Serology for hepatitis A, B, and C, and autoimmune screens (anti-nuclear, anti-mitochondrial, anti-cytoplasmic, and anti-smooth muscle antibodies) gave negative results, both at admission and 2 months later. Other infectious causes (cytomegalovirus, Epstein– Barr virus, Leptospira spp., Mycoplasma spp., Salmonella spp., Chlamydia spp., Rickettsias spp., and varicella-zoster virus) were ruled out. Tests for hemochromatosis, Wilson’s disease, and a 1 -antitrypsin deficiency gave normal results. Abdominal ultrasonography did not reveal any pathological findings. Intravenous L-carnitine therapy at a dosage of 2 g / day was initiated on the second day after admission and was administered for 7 days. The patient’s condition gradually improved and liver function tests returned to normal in 2 weeks. Valproate was replaced by lamotrigine with a good neurological response.
3. Discussion The incidence of fatal hepatotoxicity in patients receiving valproate is approximately 1 / 49 000 in adults and 1 / 800 in children younger than 2 years [1]. The principal risk factors for hepatotoxicity are anti-epileptic drug polytherapy, the presence of concomitant neurological or metabolic disorders, age younger than 2 years, and the addition of valproate therapy within 6 months of liver dysfunction [3]. Other predisposing factors are acute infections, poor nutrition, and status epilepticus. Older patients, especially those on valproate monotherapy, are considered as being at a lower risk for this complication, which makes the present case so interesting. Clinical symptoms are the most relevant indicators of the development of complications in patients treated with valproate since laboratory monitoring cannot predict acute idiosyncratic drug reactions [4]. These clinical symptoms are due to liver insufficiency. They are very similar to those in patients with carnitine deficiency and include lethargy, weakness, and hypotonia [5]. These similarities in symptomatology have led some to believe that valproate induces a carnitine deficiency by causing impairment of b-oxidation of fatty acids in the liver. In order to understand the relationship between valproate toxicity and carnitine deficiency, it is necessary to examine the metabolism of carnitine and its use by the body, as well as the mechanism by which valproate can cause hepatotoxicity. Carnitine is an essential cofactor in the b-oxidation of fatty acids. It is a nutrient that is found in meat and dairy products, and it can also be synthesized endogenously from methionine and lysine. In this final step, it is necessary to have the enzyme g-butyrobetaine hydroxylase, which is relatively deficient in newborns and young infants [6]. Approximately 98% of carnitine is
339
found in cardiac and skeletal muscle, whereas the remaining 2% is stored in the brain, liver, and kidney. The tissue concentration of carnitine is 10–20 times the plasma concentration [7]. Carnitine is necessary inside the cell to transport long-chain fatty acids from the cytoplasm into the mitochondria, resulting in mitochondrial energy metabolism through the process of b-oxidation. Another important function of carnitine is to maintain an adequate ratio of fatty acyl-CoA compounds to free CoA inside the mitochondria; therefore, a lack of carnitine results in the accumulation of acyl compounds, which may be toxic to the mitochondria. Although the exact mechanism of valproate-induced hepatotoxicity is unknown, different theories have been proposed. Valproate is a short-chain fatty acid that requires carnitine for oxidation. One theory is that valproate combines with carnitine within the mitochondria via carnitine-acyltransferases, resulting in valproylcarnitine ester, which is then transported out of the mitochondria and is eliminated in the urine, thus depleting body carnitine stores. Another mechanism involves valproate’s inhibition of mitochondrial oxidation of long-chain fatty acids by the formation of valproyl CoA, which sequesters unbound CoA and decreases its availability. Valproate may also cause hepatotoxicity by inhibiting the enzymes involved in b-oxidation by valproate metabolites, mainly 4-en-valproic acid, which may be directly hepatotoxic. In our case, plasma levels of L-carnitine were not determined because this determination is not available in our hospital laboratory. Nevertheless, monitoring serum carnitine levels is useful because some valproate-treated patients may have normal serum carnitine in spite of a tissue deficiency [1]. The first step to be taken in cases of valproate-induced hepatotoxicity is to withdraw the drug and to provide supportive care; however, the mortality rate is usually high [8]. In the present case, treatment was stopped by the patient several days before admission, but the symptoms of liver dysfunction were impaired. For this reason, L-carnitine was administered intravenously according to the recommendations made by a panel of experts [3] and because some studies have indicated that early intervention with intravenous rather than enteral L-carnitine is associated with the greatest hepatic survival [9]. Yet, L-carnitine therapy was started on day 2 after admission and liver function tests were worse on day 4. It is possible that several days of treatment with carnitine are necessary to fill the empty body stores. Although we cannot evaluate the effect of L-carnitine in this specific case, it is very important to emphasize that L-carnitine treatment is generally of value for these patients. We think that our case was compatible with acute, mixed, hepatocellular and cholestatic liver injury induced by valproate based on the causality relationship with the onset of its administration and the clinical and laboratory improvement with drug cessation. According to the Naranjo et al. scale [10], the likelihood of this adverse
340
´ et al. / European Journal of Internal Medicine 14 (2003) 338–340 A. Romero-Falcon
effect occurring is probable. Moreover, other causes and risk factors in the development of drug-induced or nondrug-related liver injury were excluded. Valproate hepatotoxicity may be suspected even in patients at a low risk for this side effect [11]. Early treatment with L-carnitine is recommended in order to obtain the best results.
[5] [6] [7] [8]
References [9] [1] Raskind JY, El-Chaar GM. The role of supplementation during valproic acid therapy. Ann Pharmacother 2000;34:630–8. [2] Murakami K, Sugimoto T, Woo M, Nishida N, Huro H. Effect of L-carnitine supplementation on acute valproate intoxication. Epilepsia 1996;37:687–9. [3] De Vivo DC, Bohan TP, Coulter DL, Dreifuss FE, Greenwood RS, Nordli DR et al. L-Carnitine supplementation in childhood epilepsy: currents perspectives. Epilepsia 1998;39:1216–25. [4] Wyllie E, Wyllie R. Routine laboratory monitoring for serious
[10]
[11]
adverse effects of antiepileptic medication: the controversy. Epilepsia 1991;32(Suppl. 5):S74–79. Coulter DL. Carnitine, valproate and toxicity. J Child Neurol 1991;6:7–14. Carter AL, Aney TO, Lapp DF. Biosynthesis and metabolism of carnitine. J Child Neurol 1995;10(Suppl. 2):S3–7. Pons R, De Vivo DC. Primary and secondary carnitine deficiency syndromes. J Child Neurol 1995;10(Suppl. 2):S8–24. Konig SA, Siemes H, Blaker F, Boenigk E, Gross SG, Hanefeld F et al. Severe hepatotoxicity during valproate therapy: an update and report of eight new fatalities. Epilepsia 1994;35:1005–15. Bohan TP, Helton E, McDonald I, Konig S, Gazitt S, Sugimoto T et al. Effect of L-carnitine treatment for valproic induced hepatotoxicity. Neurology 2001;56:1405–9. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239–45. Konig SA, Schenk M, Sick C, Holm E, Heubner C, Weiss A et al. Fatal liver failure associated with valproate therapy in a patient with Friedreich’s disease: review of valproate hepatotoxicity in adults. Epilepsia 1999;40:1036–40.
Brief report
A case of valproate-associated hepatotoxicity treated with L-carnitine c ´ a , Eva de la Santa-Belda,b , Rosa Garcıa-Contreras ´ Auxiliadora Romero-Falcon , Jose´ M. Varela d , * a C / Granaderos no. 4, 41010 Sevilla, Spain C / Virgen de la Antigua no. 22, 41011 Sevilla, Spain c ´ C / Vazquez de Leca no. 10, 41010 Sevilla, Spain d ´ , Av. Manuel Siurot s /n, 41013 Sevilla, Spain Department of Internal Medicine, Hospital Universitario Virgen del Rocıo b
Received 23 September 2002; accepted 10 April 2003
Abstract Valproate is a major broad-spectrum anti-epileptic drug that is effective against many different types of epileptic seizures and that is usually well tolerated. Nevertheless, serious side effects can occur, including hepatotoxicity. This side effect is rare but often fatal, and it has been hypothesized that long-term valproate therapy may induce a carnitine deficiency and cause non-specific symptoms of hepatotoxicity and hyperammonemia. These factors suggest that L-carnitine supplementation may play a role in preventing hepatotoxicity. We report a case of valproate-induced acute liver injury with a favorable evolution after L-carnitine therapy. 2003 Elsevier B.V. All rights reserved. Keywords: Valproate; Hepatotoxicity; Carnitine
1. Introduction
2. Case report
Valproate is a major broad-spectrum anti-epileptic drug that is effective against many different types of epileptic seizures. It is usually well tolerated. Nevertheless, serious side effects can occur including thrombocytopenia, polycystic ovarian disease, pancreatitis, tremor, teratogenicity with neural tube defects in offspring, and hepatotoxicity. This last side effect is rare but often fatal, and it has been hypothesized that long-term valproate therapy may induce a carnitine deficiency and cause non-specific symptoms of hepatotoxicity and hyperammonemia [1]. These factors suggest that L-carnitine supplementation may play a role in preventing hepatotoxicity [2,3]. We report a case of valproate-induced acute liver injury with a favorable evolution after L-carnitine therapy.
A 16-year-old man was admitted to the hospital because of a 16-day history of apathy, lethargy, and progressive jaundice. He had been receiving valproate therapy (1500 mg / day) for the past 8 weeks for generalized epilepsy, but it was discontinued 5 days before admission. The patient was not taking any other medications or herbal products, and he had no history of liver disease, blood transfusion, or alcohol or drug abuse. His serum valproate level was 65 mg / ml (normal: 50–100 mg / ml) 4 weeks before admission. On admission, physical examination revealed only jaundice without fever, and the midline lower border of the liver protruded 3–4 cm below the costal margin. Laboratory data showed the following values: total bilirubin 21 mg / dl (conjugated bilirubin 19 mg / dl); aspartate aminotransferase 3887 UI / l (normal: 0–30 UI / l); alkaline phosphatase 406 UI / l (normal: 98–279 UI / l); g-glutamyl transpeptidase 219 UI / l (normal: 10–50 UI / l), and partial thromboplastin time 17.5 s. His serum concentration of valproate was 10 mg / ml (normal: 50–100 mg / ml). Four days later, the laboratory revealed an impairment: a total
*Corresponding author. Apartado de Correos 7228, 41080 Sevilla, Spain. Fax: 134-955-013-473. E-mail address: [email protected] (J.M. Varela). 0953-6205 / 03 / $ – see front matter 2003 Elsevier B.V. All rights reserved. doi:10.1016 / S0953-6205(03)00104-3
´ et al. / European Journal of Internal Medicine 14 (2003) 338–340 A. Romero-Falcon
bilirubin of 29.37 mg / dl (conjugated bilirubin 27.43 mg / dl) and aspartate aminotransferase of 4538 U / l. In spite of these values, there was no encephalopathy, bleeding, or other symptoms present. Serology for hepatitis A, B, and C, and autoimmune screens (anti-nuclear, anti-mitochondrial, anti-cytoplasmic, and anti-smooth muscle antibodies) gave negative results, both at admission and 2 months later. Other infectious causes (cytomegalovirus, Epstein– Barr virus, Leptospira spp., Mycoplasma spp., Salmonella spp., Chlamydia spp., Rickettsias spp., and varicella-zoster virus) were ruled out. Tests for hemochromatosis, Wilson’s disease, and a 1 -antitrypsin deficiency gave normal results. Abdominal ultrasonography did not reveal any pathological findings. Intravenous L-carnitine therapy at a dosage of 2 g / day was initiated on the second day after admission and was administered for 7 days. The patient’s condition gradually improved and liver function tests returned to normal in 2 weeks. Valproate was replaced by lamotrigine with a good neurological response.
3. Discussion The incidence of fatal hepatotoxicity in patients receiving valproate is approximately 1 / 49 000 in adults and 1 / 800 in children younger than 2 years [1]. The principal risk factors for hepatotoxicity are anti-epileptic drug polytherapy, the presence of concomitant neurological or metabolic disorders, age younger than 2 years, and the addition of valproate therapy within 6 months of liver dysfunction [3]. Other predisposing factors are acute infections, poor nutrition, and status epilepticus. Older patients, especially those on valproate monotherapy, are considered as being at a lower risk for this complication, which makes the present case so interesting. Clinical symptoms are the most relevant indicators of the development of complications in patients treated with valproate since laboratory monitoring cannot predict acute idiosyncratic drug reactions [4]. These clinical symptoms are due to liver insufficiency. They are very similar to those in patients with carnitine deficiency and include lethargy, weakness, and hypotonia [5]. These similarities in symptomatology have led some to believe that valproate induces a carnitine deficiency by causing impairment of b-oxidation of fatty acids in the liver. In order to understand the relationship between valproate toxicity and carnitine deficiency, it is necessary to examine the metabolism of carnitine and its use by the body, as well as the mechanism by which valproate can cause hepatotoxicity. Carnitine is an essential cofactor in the b-oxidation of fatty acids. It is a nutrient that is found in meat and dairy products, and it can also be synthesized endogenously from methionine and lysine. In this final step, it is necessary to have the enzyme g-butyrobetaine hydroxylase, which is relatively deficient in newborns and young infants [6]. Approximately 98% of carnitine is
339
found in cardiac and skeletal muscle, whereas the remaining 2% is stored in the brain, liver, and kidney. The tissue concentration of carnitine is 10–20 times the plasma concentration [7]. Carnitine is necessary inside the cell to transport long-chain fatty acids from the cytoplasm into the mitochondria, resulting in mitochondrial energy metabolism through the process of b-oxidation. Another important function of carnitine is to maintain an adequate ratio of fatty acyl-CoA compounds to free CoA inside the mitochondria; therefore, a lack of carnitine results in the accumulation of acyl compounds, which may be toxic to the mitochondria. Although the exact mechanism of valproate-induced hepatotoxicity is unknown, different theories have been proposed. Valproate is a short-chain fatty acid that requires carnitine for oxidation. One theory is that valproate combines with carnitine within the mitochondria via carnitine-acyltransferases, resulting in valproylcarnitine ester, which is then transported out of the mitochondria and is eliminated in the urine, thus depleting body carnitine stores. Another mechanism involves valproate’s inhibition of mitochondrial oxidation of long-chain fatty acids by the formation of valproyl CoA, which sequesters unbound CoA and decreases its availability. Valproate may also cause hepatotoxicity by inhibiting the enzymes involved in b-oxidation by valproate metabolites, mainly 4-en-valproic acid, which may be directly hepatotoxic. In our case, plasma levels of L-carnitine were not determined because this determination is not available in our hospital laboratory. Nevertheless, monitoring serum carnitine levels is useful because some valproate-treated patients may have normal serum carnitine in spite of a tissue deficiency [1]. The first step to be taken in cases of valproate-induced hepatotoxicity is to withdraw the drug and to provide supportive care; however, the mortality rate is usually high [8]. In the present case, treatment was stopped by the patient several days before admission, but the symptoms of liver dysfunction were impaired. For this reason, L-carnitine was administered intravenously according to the recommendations made by a panel of experts [3] and because some studies have indicated that early intervention with intravenous rather than enteral L-carnitine is associated with the greatest hepatic survival [9]. Yet, L-carnitine therapy was started on day 2 after admission and liver function tests were worse on day 4. It is possible that several days of treatment with carnitine are necessary to fill the empty body stores. Although we cannot evaluate the effect of L-carnitine in this specific case, it is very important to emphasize that L-carnitine treatment is generally of value for these patients. We think that our case was compatible with acute, mixed, hepatocellular and cholestatic liver injury induced by valproate based on the causality relationship with the onset of its administration and the clinical and laboratory improvement with drug cessation. According to the Naranjo et al. scale [10], the likelihood of this adverse
340
´ et al. / European Journal of Internal Medicine 14 (2003) 338–340 A. Romero-Falcon
effect occurring is probable. Moreover, other causes and risk factors in the development of drug-induced or nondrug-related liver injury were excluded. Valproate hepatotoxicity may be suspected even in patients at a low risk for this side effect [11]. Early treatment with L-carnitine is recommended in order to obtain the best results.
[5] [6] [7] [8]
References [9] [1] Raskind JY, El-Chaar GM. The role of supplementation during valproic acid therapy. Ann Pharmacother 2000;34:630–8. [2] Murakami K, Sugimoto T, Woo M, Nishida N, Huro H. Effect of L-carnitine supplementation on acute valproate intoxication. Epilepsia 1996;37:687–9. [3] De Vivo DC, Bohan TP, Coulter DL, Dreifuss FE, Greenwood RS, Nordli DR et al. L-Carnitine supplementation in childhood epilepsy: currents perspectives. Epilepsia 1998;39:1216–25. [4] Wyllie E, Wyllie R. Routine laboratory monitoring for serious
[10]
[11]
adverse effects of antiepileptic medication: the controversy. Epilepsia 1991;32(Suppl. 5):S74–79. Coulter DL. Carnitine, valproate and toxicity. J Child Neurol 1991;6:7–14. Carter AL, Aney TO, Lapp DF. Biosynthesis and metabolism of carnitine. J Child Neurol 1995;10(Suppl. 2):S3–7. Pons R, De Vivo DC. Primary and secondary carnitine deficiency syndromes. J Child Neurol 1995;10(Suppl. 2):S8–24. Konig SA, Siemes H, Blaker F, Boenigk E, Gross SG, Hanefeld F et al. Severe hepatotoxicity during valproate therapy: an update and report of eight new fatalities. Epilepsia 1994;35:1005–15. Bohan TP, Helton E, McDonald I, Konig S, Gazitt S, Sugimoto T et al. Effect of L-carnitine treatment for valproic induced hepatotoxicity. Neurology 2001;56:1405–9. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239–45. Konig SA, Schenk M, Sick C, Holm E, Heubner C, Weiss A et al. Fatal liver failure associated with valproate therapy in a patient with Friedreich’s disease: review of valproate hepatotoxicity in adults. Epilepsia 1999;40:1036–40.