Abstract
Background
Acute pancreatitis is rarely seen in children, and, in contrast to cases in adults, it is often drug induced. One possible medication is the antiepileptic drug valproic acid (VPA), which is commonly prescribed for generalized and focal epilepsy, migraine, neuropathic pain, and bipolar disorder. The common side effects associated with VPA are typically benign, but less common but more serious adverse effects may occur. These include hepatotoxicity, hyperammonemic encephalopathy, coagulation disorders, and pancreatitis. Since 1979, a few cases of pancreatitis induced by VPA have been published in the medical literature.
Methods
We mailed a questionnaire to all members of the “German Section of the International League against Epilepsy,” asking about VPA-induced side effects. We also reviewed the medical literature for VPA-induced pancreatitis.
Results
Fifty-three publications (90 patients) published from 1979 to 2005 were found. Our survey in Germany, however, yielded 16 cases of pancreatitis from 1994 to 2003 whose original files we could study in detail. None of these patients had been published previously.
Conclusions
The difference between 90 patients reported worldwide from 1979 to 2005 and the 16 new documented cases from only Germany over 10 years corroborates that the occurrence of this severe side effect is under reported.
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References
InstitutionalAuthorNameAnticonsultant drugs for acute and chronic pain D Wiffen S Collins H McQway D Carroll A Jadad A Moore (2005) ArticleTitleCochrone Database Syst Rev 20 CD001133
E Spina G Perugi (2004) ArticleTitleAntiepileptic drugs: indications other than epilepsy Epileptic Disord 6 57–75 Occurrence Handle15246950
R Hirschfeld J Baker P Wozniak K Tracy K Sommerville (2003) ArticleTitleThe safety and early efficacy of oral-loaded divalproex versus standard-titration divalproex, lithium, olanzapine, and placebo in the treatment of acute mania associated with bipolar disorder J Clin Psychiatry 64 841–6 Occurrence Handle1:CAS:528:DC%2BD3sXmsV2msr4%3D Occurrence Handle12934987
SA Koenig (1999) ArticleTitleFatal liver failure associated with valproate therapy in a patient with Friedreich’s disease: review of Valproate hepatotoxicity in adults Epilepsia 40 1036–40 10.1111/j.1528-1157.1999.tb00814.x Occurrence Handle10.1111/j.1528-1157.1999.tb00814.x
N Yehya CT Saldarini ME Koski P Davanzo (2004) ArticleTitleValproate induced hyperammonemic encephalopathy J Am Acad Adolesc Psychiatry 43 926–7 10.1097/01.chi.0000129217.79887.c8 Occurrence Handle10.1097/01.chi.0000129217.79887.c8
M Teich E Longin CE Dempfle SA Koenig (2004) ArticleTitleFactor XIII deficiency associated with valproate treatment Epilepsia 45 187–9 10.1111/j.0013-9580.2004.28302.x Occurrence Handle10.1111/j.0013-9580.2004.28302.x Occurrence Handle14738427
PB Batalden BJ Van Dyne J Cloyd (1979) ArticleTitlePancreatitis associated with valproic acid therapy Pediatrics 64 520–2 Occurrence Handle1:STN:280:DyaL3c%2Fjtl2nsA%3D%3D Occurrence Handle114966
PR Camfield P Bagnell CS Camfield (1979) ArticleTitlePancreatitis due to valproate acid Lancet 1 1198–9 10.1016/S0140-6736(79)91885-3 Occurrence Handle10.1016/S0140-6736(79)91885-3 Occurrence Handle1:STN:280:DyaE1M7nslelsQ%3D%3D Occurrence Handle86928
DB Sinclair M Berg R Breault (2004) ArticleTitleValproic acid-induced pancreatitis in childhood epilepsy: case series and review J Child Neurol 19 498–502 Occurrence Handle10.1177/08830738040190070401 Occurrence Handle15526953
M Berg DB Sinclair (2001) ArticleTitleValproate-associated pancreatitis in a paediatric epilepsy population: report of 10 cases Epilepsia 42 217 10.1046/j.1528-1157.2001.21101.x Occurrence Handle10.1046/j.1528-1157.2001.21101.x
A Koenig St. CE Elger F Vassella D Schmidt A Bergmann HE Boenigk (2002) Empfehlungen zur Blutuntersuchung und klinischer Überwachung zur Früherkennung des Valproinsäure-assoziierten Leberversagens G Krámer J Walden (Eds) Valproinsáure, 2nd ed Springer Heidelberg
ML Houben I Wilting H Stroink PJ van Dijken (2005) ArticleTitlePancreatitis, complicated by a pancreatic pseudocyst associated with the use of valproic acid Eur J Paediatr Neurol 9 77–80 10.1016/j.ejpn.2004.11.006 Occurrence Handle10.1016/j.ejpn.2004.11.006 Occurrence Handle15843073
SL Werlin S Kugathsan BC Frautschy (2003) ArticleTitlePancreatitis in children J Pediatr Gastroenterol Nutr 37 591–5 10.1097/00005176-200311000-00017 Occurrence Handle10.1097/00005176-200311000-00017 Occurrence Handle14581803
JJ Asconapé P Kiffin FE Dreifuss A Riela W Mirza (1993) ArticleTitleValproate-associated pancreatitis Epilepsia 34 177–83 10.1111/j.1528-1157.1993.tb02395.x Occurrence Handle10.1111/j.1528-1157.1993.tb02395.x Occurrence Handle8422855
CE Pippenger M Xianzhong AD Rothner (1991) Free radical scavenging enzyme activity profiles in risk assessment of idiosyncratic drug reactions: probable mechanism of valproate induced pancreatitis and hepatotoxicity RH Levy JK Penry (Eds) Idiosyncratic reactions to valproate: clinical risk patterns and mechanism of toxicity Raven Press New York 75–88
TB Underwood CB Freye (1993) ArticleTitleDrug induced pancreatitis Clin Pharmacol 12 440–8 Occurrence Handle1:STN:280:DyaK2c%2FgslKgsQ%3D%3D
P Meyer PA Clavien J Robert H Hauser A Rohner (1992) ArticleTitleRole of imaging techniques in the classification of acute pancreatitis Dig Dis 10 330–4 Occurrence Handle10.1159/000171373 Occurrence Handle1:STN:280:DyaK3s7htlyktQ%3D%3D Occurrence Handle1473285
B Hjelmqvist C Wattsgard A Borgstrom A Lasson U Nyman P Aspelin et al. (1989) ArticleTitleEarly diagnosis and classification in acute pancreatitis. A comparison of clinical outcome with findings at computed tomography and Ranson’s prognostic signs Digestion 44 177–83 Occurrence Handle10.1159/000199909 Occurrence Handle1:STN:280:DyaK3c3hsFSisw%3D%3D Occurrence Handle2632294
M Stojanovic D Zivanovic J Madic D Karadzic G Stanojevic M Jovanovic et al. (2004) ArticleTitleAn acute pancreatitis in a child caused by Na-valproate (case report) Acta Chir Iugosl 51 125–7 Occurrence Handle10.2298/ACI0403125S Occurrence Handle1:STN:280:DC%2BD2Mzmt1ShsA%3D%3D Occurrence Handle16018380
D Mileusnic ER Donoghue BD Lifschultz (2002) ArticleTitlePathological case of the month: sudden death in a child as a result of pancreatitis during valproic acid therapy Pediatr Pathol Mol Med 21 477–84 10.1080/15227950290104805 Occurrence Handle10.1080/15227950290104805 Occurrence Handle12396903
RP Munhoz ML dos Santos OJ Hernandez-Fustes (2001) ArticleTitleFatal necro-hemorrhagic pancreatitis related to sodium valproate: case report Arq Neuropsiquiatr 59 821–3 Occurrence Handle1:STN:280:DC%2BD3Mrks1Shsg%3D%3D Occurrence Handle11593293
MA Cooper A Groll (2001) ArticleTitleA case of chronic pancreatic insufficiency due to valproic acid in a child Can J Gastroenterol 15 127–30 Occurrence Handle1:STN:280:DC%2BD3M3jsFKmsA%3D%3D Occurrence Handle11240383
MD Engelmann SD Henriksen LK Tingsgaard (1995) ArticleTitleFatal pancreatitis associated with valproate therapy Ugeskr Laeger 31 4357–8
D Talwar (1994) ArticleTitleValproate-associated acute pancreatitis in a child with neuronal ceroid lipofuscinosis J Child Neurol 9 36–7 10.1177/088307389400900107 Occurrence Handle10.1177/088307389400900107 Occurrence Handle1:STN:280:DyaK2c3gtFGisQ%3D%3D Occurrence Handle8151078
N Taira H Nishi M Mano N Waki Y Tsugita S Takashima et al. (2001) ArticleTitlePancreatitis induced by valproic acid: report of a case Surg Today 31 1027–31 10.1007/s005950170018 Occurrence Handle10.1007/s005950170018 Occurrence Handle1:CAS:528:DC%2BD38XlvFKqtA%3D%3D Occurrence Handle11766076
A Bahamonde Carrasco A Moran Blanco JL Olcoz Goni (1996) ArticleTitleAcute pancreatitis caused by valproic acid: apropos a case Gastroenterol Hepatol 19 253–4 Occurrence Handle1:STN:280:DyaK283psVeksQ%3D%3D Occurrence Handle8752568
RJ Evans RN Miranda J Jordan FJ Krolikowski (1995) ArticleTitleFatal acute pancreatitis caused by valproic acid Am J Forensic Med Pathol 16 62–5 Occurrence Handle1:STN:280:DyaK2M3ovFaquw%3D%3D Occurrence Handle7771387 Occurrence Handle10.1097/00000433-199503000-00014
T Momota S Ito K Kobayashi S Mimasu T Kuniya (1993) ArticleTitleA case of acute pancreatitis during administration of valproic acid No To Hattatsu 25 453–8 Occurrence Handle1:STN:280:DyaK2c%2FgtV2gtw%3D%3D Occurrence Handle8398236
J Binek A Hany M Heer (1991) ArticleTitleValproic-acid-induced pancreatitis. Case report and review of the literature J Clin Gastroenterol 13 690–3 10.1097/00004836-199112000-00016 Occurrence Handle10.1097/00004836-199112000-00016 Occurrence Handle1:STN:280:DyaK387gsFKktw%3D%3D Occurrence Handle1761843
JA Lott LW Bond RC Bobo HJ McClung RD Murray (1990) ArticleTitleValproic acid-associated pancreatitis: report of three cases and a brief review Clin Chem 36 395–7 Occurrence Handle1:STN:280:DyaK3c7ltVGlsg%3D%3D Occurrence Handle2105864
PH Parker GL Helinek FK Ghishan HL Greene (1981) ArticleTitleRecurrent pancreatitis induced by valproic acid. A case report and review of the literature Gastroenterology 80 826–8 Occurrence Handle1:STN:280:DyaL3M7jvFGitg%3D%3D Occurrence Handle6162706
M Sasaki S Tonoda Y Aoki (1980) ArticleTitlePancreatitis due to Valproic acid Lancet 1 1196 10.1016/S0140-6736(80)91660-8 Occurrence Handle10.1016/S0140-6736(80)91660-8 Occurrence Handle1:STN:280:DyaL3c3gvVKmtg%3D%3D Occurrence Handle6104020
PG Lankisch CP Criee K Winkler (1980) ArticleTitleAcute pancreatitis under anticonvulsive therapy with sodium valproate (ergenyl) Leser Zuschriften 25 905–6
DL Coulter RJ Allen (1980) ArticleTitlePancreatitis associated with valproic acid therapy for epilepsy Ann Neurol 7 92 10.1002/ana.410070118 Occurrence Handle10.1002/ana.410070118 Occurrence Handle1:STN:280:DyaL3c7lt1SqtA%3D%3D Occurrence Handle6767434
MJ Murphy LW Lyon JW Taylor (1981) ArticleTitleValproic acid associated pancreatitis in an adult Lancet 1 41–2 10.1016/S0140-6736(81)90143-4 Occurrence Handle10.1016/S0140-6736(81)90143-4 Occurrence Handle1:STN:280:DyaL3M%2FpslynsA%3D%3D Occurrence Handle6109073
JYK Ng APS Disney TE Jones (1982) ArticleTitleAcute pancreatitis and sodium valproate Med J Aust 2 362 Occurrence Handle1:STN:280:DyaL3s%2Fmt1aktg%3D%3D Occurrence Handle6815441
N Callaghan J O’Hara D O’Driscoll P O’Neil (1982) ArticleTitleComparative study of ethosuximide and sodium valproate treatment of typical absence seizures (petit mal) Dev Med Child Neurol 24 830–6 Occurrence Handle1:STN:280:DyaL3s7gs1Wlsw%3D%3D Occurrence Handle6818076 Occurrence Handle10.1111/j.1469-8749.1982.tb13703.x
LHP Williams RP Reynolds JL Emery (1980) ArticleTitlePancreatitis during sodium valproate treatment J Bone Joint Surg 62 166–7
E Wyllie R Wyllie RP Cruse (1984) ArticleTitlePancreatitis associated with valproic acid therapy Am J Dis Child 138 912–4 Occurrence Handle1:STN:280:DyaL2czgsVSntA%3D%3D Occurrence Handle6206716
HK Rosenberg W Ortega (1987) ArticleTitleHemorrhagic pancreatitis in a young child following valproic acid therapy Clin Pediatr 26 98–101 Occurrence Handle10.1177/000992288702600208 Occurrence Handle1:STN:280:DyaL2s7gtl2nug%3D%3D
MD Ford GJ Portman GM Lum (1990) ArticleTitlePancreatitis in children on chronic dialysis treated with valproic acid Pediatr Nephrol 4 259–61 10.1007/BF00857671 Occurrence Handle10.1007/BF00857671 Occurrence Handle1:STN:280:DyaK3czotFSqtw%3D%3D Occurrence Handle2119213
JM Pellock BJ Wilder R Deaton KW Sommerville (2002) ArticleTitleAcute pancreatitis coincident with valproate use: a critical review Epilepsia 43 1421–4 10.1046/j.1528-1157.2002.18502.x Occurrence Handle10.1046/j.1528-1157.2002.18502.x Occurrence Handle12423394
F Eyer N Felgenbauer K Gempel W Steimer KD Gerbitz T Zilker (2005) ArticleTitleAcute valproate poisoning—pharmacokinetics, alteration in fatty acid metabolism and changes during therapy J Clin Psychopharmacol 25 376–80 10.1097/01.jcp.0000168485.76397.5c Occurrence Handle10.1097/01.jcp.0000168485.76397.5c Occurrence Handle1:CAS:528:DC%2BD2MXmtVahs7w%3D Occurrence Handle16012283
VD Laghate SB Gupta (2004) ArticleTitleAcute pancreatitis and diabetic ketoacidosis in non-diabetic person while on treatment with sodium valproate, chlorpromazine and haloperidol J Assoc Physicians India 52 257–8 Occurrence Handle1:STN:280:DC%2BD2M%2FhtVKkug%3D%3D Occurrence Handle15636323
S Kayemba Kay’s Kabangu M Bovier Lapierre E Jalaguier (1991) ArticleTitleAcute pancreatitis and valproic acid Pediatrie 46 839–43 Occurrence Handle1667041
P Grosse L Rusch B Schmitz (2002) ArticleTitlePancreatitis complicating treatment with intravenous valproic acid J Neurol 249 484–5 10.1007/s004150200045 Occurrence Handle10.1007/s004150200045 Occurrence Handle11967659
WT Anderson FJ Ritter MD Frost JR Gates (2003) ArticleTitleIV Valproate induced pancreatitis during prolonged administration in dose exceeding 130 mg/kg/day Epilepsia 44 274
B Battillocchi M Diana R Dandolo S Stefanini L D’Amore I Negro (2002) ArticleTitleDrug-induced acute pancreatitis: a personal contribution Chir Ital 54 605–12 Occurrence Handle12469456
RD Buzan (1996) ArticleTitleValproate-associated pancreatitis and cholecystitis in six mentally retarded adults JAMA 275 563
S Otsubo T Huruzone H Kobae S Yoshimi K Miyata (1995) ArticleTitlePancreatitis with normal serum amylase associated with sodium valproate: a case report Brain Dev 17 219–21 10.1016/0387-7604(95)00025-7 Occurrence Handle10.1016/0387-7604(95)00025-7
AM Baskies (1984) ArticleTitleCase report: pancreatic pseudocyst associated with valproic acid therapy J Med Soc NJ 81 399–400 Occurrence Handle1:STN:280:DyaL2c3pt1arsg%3D%3D
M Zenker M Metzker E Wegener PH Heidemann (1995) ArticleTitleValproat-inuzierte Pankreatitis Monatsschr Kinderheilkd 143 843–6
R Pezzilli P Billi R Melandri PL Broccoli G Fontana (1992) ArticleTitleAnticonvulsant-induced chronic pancreatitis. A case report J Gastroenterol 24 245–6 Occurrence Handle1:STN:280:DyaK38zitlSgtw%3D%3D
Werth B, Kuhn M, Hartmann K, Reinhart WH. Medikamentös induzierte Pankreatitiden: Erfahrungen der Schweizer Arzneimittel-Nebenwirkungszentrale (SANZ) 1981–1993. Poster Präsentation an der 59. Jahresversammlung der Schweizerischen Gesellschaft für Gastroenterologie und Hepatologie, Bern September 1994
JD Tobias C Chapers P Sims GW Holcomb (1995) ArticleTitleNecrotizing pancreatitis after 10 years of therapy with valproic acid Clin Pediatr 8 446–8 Occurrence Handle10.1177/000992289503400810
HM Tannhauser Barros EJ Guardão Barros (1986) ArticleTitlePancreatite aguda assosiada ao uso de valproida sodio Rev Assoc Med Brasil 32 33–4
E Braun B Spannagel HD Bundschu (1987) ArticleTitleInapparent verlaufende Pankreatitis mit Pseudozystenbildung und cholestatischem Ikterus unter antikonvulsiver Therapie mit Valproinsáure Klein Wochenschr 65 433–6 10.1007/BF01715767 Occurrence Handle10.1007/BF01715767 Occurrence Handle1:STN:280:DyaL2s3lsFKitg%3D%3D
SE Fecik SC Stoner J Raphael C Lindsey (1999) ArticleTitleRecurrent acute pancreatitis associated with valproic acid use for mood stabilization J Clin Psychopharmacol 19 483–4 10.1097/00004714-199910000-00021 Occurrence Handle10.1097/00004714-199910000-00021 Occurrence Handle1:STN:280:DyaK1MvjtlCitQ%3D%3D Occurrence Handle10505598
E Rose G de Miscault M Thome N Boussard (1991) ArticleTitle[Acute pancreatitis caused by sodium valproate. Review of the literature apropos of a case in a child] Pediatrie 46 831–7 Occurrence Handle1:STN:280:DyaK383ivVKntg%3D%3D Occurrence Handle1667040
T Sugimoto N Nishida A Yasuhara A Ono Y Sakane T Matsumura (1983) ArticleTitleReye-like syndrome associated with valproic acid Brain Dev 5 334–7 Occurrence Handle1:STN:280:DyaL3szgs1CisQ%3D%3D Occurrence Handle6412580
D Scheffner S Koenig I Rauterberg-Ruland W Kochen WJ Hofmann S Unkelbach (1988) ArticleTitleFatal liver failure in 16 children with valproate therapy Epilepsia 29 530–42 Occurrence Handle10.1111/j.1528-1157.1988.tb03757.x Occurrence Handle1:STN:280:DyaL1czht1CqtA%3D%3D Occurrence Handle3137017
RG Dickinson ML Bassett J Searle JH Tyrer MJ Eadie (1985) ArticleTitleValproate hepatotoxicity: a review and report of two instances in adults Clin Exp Neurol 21 79–91 Occurrence Handle1:STN:280:DyaL2s7ovVChsA%3D%3D Occurrence Handle3939614
TL Levin WE Berdon RR Seigle MA Nash (1997) ArticleTitleValproic-acid-associated pancreatitis and hepatic toxicity in children with endstage renal disease Pediatr Radiol 27 192–3 10.1007/s002470050100 Occurrence Handle10.1007/s002470050100 Occurrence Handle1:STN:280:DyaK2s7otFSisw%3D%3D Occurrence Handle9028861
B Boudailliez JL Andre M Broyer JC Davin G Landthaler JB Palcoux (1988) ArticleTitleAcute pancreatitis in six nontransplanted uraemic children: a co-operative study from the French Society of Pediatric Nephrology Pediatr Nephrol 2 431–5 10.1007/BF00853437 Occurrence Handle10.1007/BF00853437 Occurrence Handle1:STN:280:DyaK3M%2Fgt1SktQ%3D%3D Occurrence Handle2484654
NL Grauso-Eby O Goldfarb LB Feldman-Winter GN McAbee (2003) ArticleTitleAcute pancreatitis in children from valproic acid: case series and review Pediatr Neurol 28 145–8 10.1016/S0887-8994(02)00517-9 Occurrence Handle10.1016/S0887-8994(02)00517-9 Occurrence Handle12699868
F Apple P Benson L Preese S Eastep L Bilodeau G Heiler (1991) ArticleTitleLipase and pancreatic amylase activities in tissues and in patients with hyperamylasemia Am J Clin Pathol 96 610–4 Occurrence Handle1:STN:280:DyaK38%2FlvVygug%3D%3D Occurrence Handle1719798
E Longin M Teich W Koelfen SA Koenig (2002) ArticleTitleTopiramate enhances the risk of valproate-associated side effects in three children Epilepsia 43 451–4 10.1046/j.1528-1157.2002.42401.x Occurrence Handle10.1046/j.1528-1157.2002.42401.x Occurrence Handle11952778
M Norgaard J Jacobsen C Ratanajamit P Jepsen JK McLaughlin L Pedersen et al. (2006) ArticleTitleValproic acid and risk of acute pancreatitis: a population-based case–control study Am J Ther 13 113–7 10.1097/00045391-200603000-00005 Occurrence Handle10.1097/00045391-200603000-00005 Occurrence Handle16645426
SA König H Siemes F Bláker E Boenigk G Groß-Selbeck D Scheffner et al. (1994) ArticleTitleSevere hepatotoxicity during valproate therapy: an update and report of eight new fatalities Epilepsia 35 1005–15 10.1111/j.1528-1157.1994.tb02546.x Occurrence Handle10.1111/j.1528-1157.1994.tb02546.x Occurrence Handle7925143
B Begaud K Martin F Haramburu N Moore (2002) ArticleTitleRates of spontaneous reporting of adverse drug reactions in France JAMA 288 1588 10.1001/jama.288.13.1588 Occurrence Handle10.1001/jama.288.13.1588 Occurrence Handle12350188
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Gerstner, T., Büsing, D., Bell, N. et al. Valproic acid-induced pancreatitis: 16 new cases and a review of the literature. J Gastroenterol 42, 39–48 (2007). https://doi.org/10.1007/s00535-006-1961-4
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DOI: https://doi.org/10.1007/s00535-006-1961-4