Eadie M J, Hooper W D, Dickinson R G
Department of Medicine, University of Queensland, Brisbane.
Med Toxicol Adverse Drug Exp. 1988 Mar-Apr;3(2):85-106. doi: 10.1007/BF03259935.
Intake of the anticonvulsant drug valproic acid, or its sodium salt, has been associated with occasional instances of severe and sometimes fatal hepatotoxicity. Probably at least 80 cases have occurred worldwide. The syndrome affects perhaps 1 in 10,000 persons taking the drug, and usually develops in the early weeks or months of therapy. Most instances have involved children, usually those receiving more than 1 anticonvulsant. Multiple cases have occurred in 2 families. The typical presentation is of worsening epilepsy, increasing depression of consciousness, and progressive clinical and biochemical evidence of liver failure. The liver has sometimes shown hepatocyte necrosis, and on other occasions widespread microvesicular steatosis, while cholestatic changes have also occurred. The appearances are interpreted as consistent with a drug toxicity reaction. During the hepatotoxicity increased amounts of unsaturated metabolites of valproate, notably 4-en-valproate, have been found in blood and urine. In 4 cases there has been evidence of impaired beta-oxidation of valproate with, in 1 case, accumulation of isomers of valproate glucuronide caused by intramolecular rearrangement of the conjugate. There are molecular structural similarities between 4-en-valproate and 2 known hepatotoxins (4-en-pentanoate and methylenecyclopropylacetic acid, the latter being responsible for hypoglycin poisoning). There are also clinical and histopathological similarities between valproate hepatotoxicity and both hypoglycin poisoning and certain spontaneous disorders of isoleucine metabolism (one pathway of valproate metabolism is analogous to oxidative degradation of isoleucine). Unsaturated metabolites of valproate, in particular 4-en-valproate, may contribute to the hepatotoxicity of the drug. However, since the hepatotoxicity appears to involve an element of idiosyncrasy, the primary defect in some cases may be an inherited or acquired deficiency in the drug's beta-oxidation. This defect may divert valproate metabolism towards omega-oxidation, with increased formation of the toxin 4-en-valproate, but may also allow increased formation of a toxic metabolite derived from isoleucine, since beta-oxidation of isoleucine derivatives will also be impaired.
服用抗惊厥药物丙戊酸或其钠盐偶尔会引发严重的、有时甚至是致命的肝毒性。全球可能至少已发生80例。该综合征在服用此药的人群中发生率约为万分之一，通常在治疗的最初几周或几个月内出现。多数病例涉及儿童，通常是那些同时服用不止一种抗惊厥药物的儿童。在两个家庭中出现了多例病例。典型表现为癫痫病情恶化、意识障碍加重，以及出现肝功能衰竭的进行性临床和生化证据。肝脏有时表现为肝细胞坏死，其他时候则出现广泛的微泡性脂肪变性，同时也会发生胆汁淤积性改变。这些表现被认为与药物毒性反应一致。在肝毒性发作期间，血液和尿液中发现丙戊酸盐的不饱和代谢产物，尤其是4 - 烯丙戊酸的含量增加。有4例证据显示丙戊酸的β - 氧化受损，其中1例中，由于共轭物的分子内重排导致丙戊酸葡萄糖醛酸异构体蓄积。4 - 烯丙戊酸与2种已知的肝毒素（4 - 烯戊酸和亚甲基环丙基乙酸，后者是导致低血糖素中毒的原因）在分子结构上有相似之处。丙戊酸肝毒性与低血糖素中毒以及某些异亮氨酸代谢的自发性疾病在临床和组织病理学上也有相似之处（丙戊酸代谢的一条途径类似于异亮氨酸的氧化降解）。丙戊酸的不饱和代谢产物，特别是4 - 烯丙戊酸，可能是该药物肝毒性的原因。然而，由于肝毒性似乎涉及个体特异反应因素，某些病例中的主要缺陷可能是药物β - 氧化的遗传性或获得性缺乏。这种缺陷可能使丙戊酸代谢转向ω - 氧化，导致毒素4 - 烯丙戊酸形成增加，但也可能使源自异亮氨酸的有毒代谢产物形成增加，因为异亮氨酸衍生物的β - 氧化也会受损。
