Valproic acid and secondary hyperammonemia

Rawat, Sumant; Borkowski, Winslow J.; Swick, Herbert M.

doi:10.1212/wnl.31.9.1173

Cited by 60 publications

(24 citation statements)

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“…[32][33][34] In most such cases with hyperammonemia, the biochemical metabolism of ammonia is impaired in various ways and the blood concentration of ammonia is elevated to toxic levels. In addition, hyperammonemia has also been reported to be associated with urinary tract infections, 59,60 valproic acid treatment, 61,62 portacaval shunts in cases with gastric cancer 63 and high-dose cytoreductive chemotherapies for cases with hematological malignancies. 64 Recently, there have been several reports of cases with myeloma associated with hyperammonemia, [21][22][23][24][25][26][27][28][29][30] most of whom have been Japanese.…”

Section: Discussionmentioning

confidence: 99%

In vitro excess ammonia production in human myeloma cell lines

et al. 1998

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It is well known that cases with multiple myeloma reveal various clinical manifestations such as pancytopenia, hyperproteinemia, renal dysfunction, bone lesions, hypercalcemia and immunodeficiency. Recently, a few more clinical features associated with myeloma, such as salivary type hyperamylasemia and elevated serum C-reactive protein (CRP) concentration, have been reported. The elevation of CRP is thought to be related to interleukin-6 (IL-6) production by myeloma cells, because of identification of IL-6 as an autocrine and/or paracrine growth factor for myeloma cells. More recently, there have been several reports of cases with myeloma associated with hyperammonemia. This hyperammonemia is not considered to be due to liver dysfunction, because in most of these cases tests revealed normal hepatic function, and some cases showed different patterns of serum amino acid distribution than that associated with hepatic failure. However, there have been no apparent observations of ammonia production by myeloma cells. In this study, we used six human myeloma cell lines including KMS-18, which was recently established from a myeloma case associated with hyperammonemia. These lines were treated with MRA (mycoplasma removal agent) to observe ammonia production in vitro. They produced and released significantly higher levels of ammonia into culture medium than non-myeloma hematological cell lines or the HepG2 human hepatic carcinoma cell line. Although attempts to analyze the relative expression levels of the enzymes related to ammonia biosynthesis using the reverse transcriptase-polymerase chain reaction assay failed to detect any differences between these myeloma lines and other cell lines, in vitro excess ammonia production by the myeloma cells was confirmed and the relevance to clinical manifestations is discussed.

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Section: Discussionmentioning

confidence: 99%

In vitro excess ammonia production in human myeloma cell lines

et al. 1998

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“…[14] The fact that the basic mechanism caused to hyperammonemia via drug's direct effects on neurotransmitters has also been emphasized. [15][16][17] Encephalopathy connected to valproate has been identified four subtypes: 1) It ranges between liver enzymes and serious highness of serum ammonia. Hyperammoniemia leads to the development of neuronal damage, brain edema, seizures and encephalopathy by inhibiting the uptake of glutamate via astrocytes.…”

Section: Discussionmentioning

confidence: 99%

Primum non nocere: A case of valproate encephalopathy

Kozak¹,

Uca²

2014

Epilepsi

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Valproik asit (VPA) bazı tip epileptik nöbetlerin tedavisinde kullanılan geleneksel bir antiepileptiktir. Ensefalopati, VPA'nın nadir ancak ciddi sonuçlara yol açan yan etkilerinden biri olup hiperamonemi bu tabloya eşlik edebilir. VPA'nın ortaya çıkardığı asemptomatik hiperamonemi insidansı %20, semptomlu hiperamoniemi insidansı %5 olarak belirtilmektedir. VPA'ya bağlı hiperamoniemi patogenezi tam olarak anlaşıla-mamıştır. Bu makalede, VPA'ya bağlı ensefalopati tanısı konulan 60 yaşındaki bir erkek hasta sunuldu. Sunulan olgu, daha önce VPA kullanan ve ensefalopati tablosu izlenmeyen bir hastada tekrar ortaya çıkan nöbetlerin ardından başlanan VPA tedavisi sonrası ensefalopati ortaya çıkması yönüyle literatürde ilktir.Anahtar sözcükler: Ensefalopati; hiperamoniemi; valproik asit. SummaryValproic acid (VPA) is a traditional antiepileptic which is used in the treatment of some types of epileptic seizures. Encephalopathy is a side effect of VPA which leads to rare but serious results and hyperammoniemia may be accompanied by one of these statements. It is specified that asymptomatic hyperammoniemia which VPA revealed is 20% and the incidence of symptomatic hyperammoniemia is 5%. The reason why VPA induced hyperammoniemia pathogenesis is not fully understood. In this article we present a 60-year-old male patient who was diagnosed VPA induced encephalopathy. The case presented is the first in the literature, in that, the patient previously taking valproate and whose encephalopathy unmonitored, valproate has been used after repeated seizures; and, after that encephalopathy has emerged.

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“…Although these latter metabolites have a minor role, they can be highly toxic in patients on chronic therapeutic dosing or after an acute overdose. 4-en-VPA has been incriminated in the development of cerebral edema, hepatotoxicty, and hyperammonemia [8,19,29,[31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48].…”

Section: How Is Valproic Acid Metabolized?mentioning

confidence: 99%

“…Although the incidence of hyperammonemia associated with hepatic encephalopathy is over 90% in the United States, elevated serum ammonia can be seen in patients therapeutically taking VPA or after a VPA overdose without any evidence of hepatic injury or failure [30,42,64,65]. Duarte et al reported a case of a 46-year-old woman who developed isolated hyperammonemia without any evidence of hepatic failure after being started on the drug [33].…”

Section: What Occurs With Valproic Acid Toxicity?mentioning

confidence: 99%

“…There are reports of patients presenting in a coma with normal serum VPA concentrations; this is possibly due to the presence of unmeasured metabolites such as 2-en-VPA and 4-en-VPA or due to hyperammonemia [28,33,42]. Ammonia levels, therefore, should be obtained in all cases of suspected VPA toxicity.…”

Section: How Do You Manage Patients With Valproic Acid Toxicity?mentioning

confidence: 99%

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Case files of the Children’s Hospital of Michigan Regional Poison Control Center: The use of carnitine for the management of acute valproic acid toxicity

Katiyar

Aaron

2007

J. Med. Toxicol.

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A 28-year-old African-American male was found unresponsive outside of his girlfriend's house around 7 o'clock in the morning. He spent the night at the girlfriend's house and was last witnessed to be awake about 12 hours earlier. The girlfriend and her family were unable to awaken the patient and called emergency medical services (EMS). There was no history of headache, dizziness, fever, chills, nausea, vomiting, seizures, trauma, depressive thoughts, or suicidal ideation. When EMS arrived, they administered 6 mg of naloxone intramuscularly without effect, and the patient was transported to the emergency department (ED).After arriving in the ED, the cardiac monitor displayed a narrow-complex rhythm with a rate of 85-90 per minute. His initial vital signs were: heart rate 91/min; blood pressure 148/80 mmHg; respiratory rate 24/min; temperature 35.1°C (95.1°F) rectally; and pulse oximetry 100% on non-rebreather face mask oxygen. A fingerstick glucose determination was 106 mg/dL.Physical examination revealed a well developed, well nourished individual who was obtunded and unresponsive. His pupils were 2 mm, unreactive to light, and without nystagmus. He had diffuse bilateral wheezing, regular heart rate without any murmurs, and decreased bowel sounds. The patient had warm skin with good distal pulses in all extremities and no cyanosis, erythema, or edema. There was no clonus or hyperreflexia, and the gag reflex was intact.His past medical history was only pertinent for an old gunshot wound to the head. He developed a seizure disorder and was taking divalproex, 500 mg BID. Reportedly, he was allergic to carbamazepine and phenytoin. The patient smoked cigarettes, but the family stated that he had no history of alcohol or illicit drug use.A 12-lead electrocardiogram showed a sinus rhythm with a rate of 92 bpm, a PR interval of 134 msec, a QRS duration of 90 msec, and a QTc of 601 msec. A head CT and chest radiograph were unremarkable. Laboratory tests were obtained.

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Valproic acid and secondary hyperammonemia

Cited by 60 publications

References 0 publications

In vitro excess ammonia production in human myeloma cell lines

In vitro excess ammonia production in human myeloma cell lines

Primum non nocere: A case of valproate encephalopathy

Case files of the Children’s Hospital of Michigan Regional Poison Control Center: The use of carnitine for the management of acute valproic acid toxicity

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