毒理性
前瞻性研究表明，长期服用丙戊酸治疗期间，5%至10%的人会出现丙氨酸转氨酶（ALT）升高，但这些异常通常无症状，即使继续用药也可能恢复正常。与苯妥英钠和卡马西平不同，丙戊酸不会诱导血清γ-谷氨酰转移酶（GGT）水平升高。更重要的，也是常见的是，丙戊酸可能引起多种临床明显的肝毒性。确实，文献中已报告了超过100例由于丙戊酸导致的急性或慢性肝损伤的致命病例。丙戊酸可引起三种临床上可区分的肝毒性形式（除了简单的转氨酶升高）。
第一种综合征是高氨血症，几乎没有或没有肝损伤的证据。这种综合征通常表现为进行性和发作性混乱，随后是昏睡和昏迷。发病时间通常在开始服用丙戊酸或增加剂量的几周内，但可能在开始用药后的几个月甚至几年才出现（案例1）。诊断依据是血清氨升高，而血清转氨酶和胆红素水平正常（或接近正常）。丙戊酸水平通常正常或略高。停止服用丙戊酸后几天内综合征会缓解，但补充肉碱或进行肾脏血液透析可能会更快逆转。
丙戊酸引起的第二种损伤是急性肝细胞损伤伴黄疸，通常伴有肝细胞或混合模式的酶升高（案例2）。这种急性肝损伤模式通常在开始服用丙戊酸的1到6个月内发病。血清酶升高的模式可以是肝细胞型或混合型；有时尽管损伤严重，血清转氨酶水平并没有显著升高。
免疫过敏特征（发热、皮疹、嗜酸性粒细胞增多）通常不存在，但已有报告极少数病例具有明显的超敏反应特征（案例3）。已发表的由于丙戊酸导致的致命性急性肝衰竭的多个案例，丙戊酸经常被列为药物诱导急性肝衰竭的原因。肝脏组织学特点是微囊泡性脂肪变性，伴有中央小叶坏死、轻至中度炎症和胆汁淤积。在病程延长的病例中，可能会出现纤维化、胆管增生和再生结节。使用历史对照的前瞻性研究表明，如果及时给予肉碱（尤其是静脉注射），可能有益。
丙戊酸引起的第三种肝损伤形式是在服用丙戊酸的儿童中描述的类似雷耶综合征，这些儿童在出现发热和乏力（提示病毒感染）后，接着出现混乱、昏睡和昏迷，伴有血氨水平升高和明显的ALT升高，但胆红素水平正常或仅轻微升高。代谢性酸中毒也很常见，且综合征可能会迅速致命。如果儿童在患流感或水痘感染时正在服用丙戊酸，丙戊酸可能只是一个像阿司匹林一样的诱因，能够触发雷耶综合征。
所有三种丙戊酸肝毒性的形式都具有线粒体损伤的特征，肝脏组织学通常显示微囊泡性脂肪变性，伴有不同程度的炎症和胆汁淤积。年轻的年龄（
可能性评分：A（是几种临床明显肝损伤的已知原因）。
Prospective studies suggest that 5% to 10% of persons develop ALT elevations during long term valproate therapy, but these abnormalities are usually asymptomatic and can resolve even with continuation of drug. Unlike phenytoin and carbamazepine, valproate does not induce elevations in serum GGT levels. More importantly and not uncommonly, valproate can cause several forms of clinically apparent hepatotoxicity. Indeed, more than 100 fatal cases of acute or chronic liver injury due to valproate have been reported in the literature. Three clinically distinguishable forms of hepatotoxicity (besides simple aminotransferase elevations) can occur with valproate.
The first syndrome is hyperammonemia with minimal or no evidence of hepatic injury. This syndrome typically presents with progressive and episodic confusion followed by obtundation and coma. The time to onset is often within a few weeks of starting valproate or increasing the dose, but it can present months or even years after starting the medication (Case 1). The diagnosis is made by the finding of elevations in serum ammonia with normal (or near normal) serum aminotransferase and bilirubin levels. Valproate levels are usually normal or minimally high. The syndrome resolves within a few days of stopping valproate, but may reverse more rapidly with carnitine supplementation or renal hemodialysis.
The second form of injury from valproate is an acute hepatocellular injury with jaundice, typically accompanied by hepatocellular or mixed pattern of enzyme elevations (Case 2). This acute liver injury pattern usually has its onset within 1 to 6 months of starting valproate. The pattern of serum enzyme elevations can be hepatocellular or mixed; sometimes the serum aminotransferase levels are not markedly elevated, despite the severity of injury.
Immunoallergic features (fever, rash, eosinophilia) are usually absent, but rare cases with prominent features of hypersensitivity have been reported (Case 3). Multiple instances of fatal acute hepatic failure due to valproate have been published and valproate is regularly listed as a cause of drug induced acute liver failure. Liver histology is distinctive and reveals a microvesicular steatosis with central lobular necrosis, mild to moderate inflammation and cholestasis. In cases with a prolonged course, fibrosis, bile duct proliferation and regenerative nodules may be present. Prospective studies using historical controls suggest that carnitine (particularly intravenously) may be beneficial if given soon after presentation.
The third form of hepatic injury due to valproate is a Reye-like syndrome described in children on valproate who develop fever and lethargy (suggestive of a viral infection) followed by confusion, stupor and coma, with raised ammonia levels and marked ALT elevations but normal or minimally elevated bilirubin levels. Metabolic acidosis is also common and the syndrome can be rapidly fatal. Valproate may simply be an aspirin-like agent capable of triggering Reye syndrome if it is being taken when the child develops either influenza or varicella infection.
All three forms of valproate hepatotoxicity have features of mitochondrial injury, and liver histology usually demonstrates microvesicular steatosis with variable amounts of inflammation and cholestasis. Young age (
Likelihood score: A (well known cause of several forms of clinically apparent liver injury).
来源:LiverTox
