毒理性
典型的口服铁剂替代剂量并未被确凿地与治疗期间血清酶水平升高或特异质、急性临床明显的肝损伤相关联。相比之下，无论是故意还是意外过量服用口服铁剂，都可能导致肝损伤，这主要是铁中毒的一个组成部分。铁中毒最常见于幼儿（1至3岁），他们摄入了成人处方的铁片。在摄入3克或更多的硫酸亚铁（大约10片，或约650毫克元素铁）后，会发生毒性反应，有毒水平是每公斤体重超过60毫克元素铁，致命水平是每公斤体重超过180毫克元素铁。典型的症状序列是在摄入后1到3小时内出现恶心、呕吐和腹痛，随后是腹泻、虚弱、烦躁、嗜睡和昏迷。呕吐物可能带有血丝或明显的呕血。腹泻通常是液体状且颜色深（由于铁而不是血液）。在更高剂量下，这一初始阶段迅速发展为苍白、低血压和休克。上消化道和下消化道都可能出血，早期变化包括代谢性酸中毒和凝血病。在某些情况下，症状出现几小时后可能会有所改善，但随后可能会突然出现血流动力学崩溃、心源性休克和严重酸中毒，这可能是致命的。早期干预（包括洗胃、补液和铁螯合）似乎可以改善损伤过程。肝毒性通常在24小时后出现，成人可能比儿童更常见。严重的肝毒性，伴有黄疸和明显的转氨酶升高（ALT和AST超过正常上限25倍），通常仅在大量过量和初始血清铁水平较高时发生（>1000微克/分升）。黄疸最初较轻，而凝血酶原时间（或INR）延长和酸中毒出现较早（案例1）。铁中毒导致死亡的通常原因是心脏骤停，但也有因肝衰竭死亡以及紧急肝移植治疗铁中毒的报道。有趣的是，急性铁肝毒性的肝脏组织学发现是出血性、亚大块坏死，主要位于门周区（区域1），这是直接肝毒素的特征，这些毒素不需要肝脏代谢就能产生毒性。在更严重的毒性情况下，损伤是广泛和全小叶的。
Typical replacement doses of oral iron have not been linked convincingly to serum enzyme elevations during therapy or to idiosyncratic, acute clinically apparent liver injury. In contrast, overdoses of oral iron, whether intentional or accidental, can cause liver injury, largely as a component of iron poisoning. Iron poisoning occurs most common in toddlers (1 to 3 years old) who ingest iron tablets prescribed for adults. Toxicity occurs after ingestion of 3 grams or more of ferrous sulfate (approximately 10 tablets, or ~650 mg of elemental iron), with toxic levels being more than 60 mg/kg of elemental iron and fatal levels more than 180 mg/kg. The typical sequence of events is appearance of nausea, vomiting and abdominal pain within 1 to 3 hours of the ingestion, followed by diarrhea, weakness, irritability, lethargy and stupor. Vomitus may be blood streaked or frank hematemesis. The diarrhea is generally fluid and dark (as a result of iron rather than blood). With higher doses, this initial phase is rapidly followed by pallor, hypotension and shock. Both upper and lower gastrointestinal bleeding can occur and early changes include metabolic acidosis and coagulopathy. In some instances, there is an improvement after a few hours of symptoms which can then be followed by sudden hemodynamic collapse, cardiogenic shock and severe acidosis that may be fatal. Early intervention (with gastric lavage, fluid replacement and iron chelation) appears to ameliorate the course of injury. Liver toxicity generally arises after 24 hours and may be more common in adults than children. Severe liver toxicity, with jaundice and marked aminotransferase elevations (ALT and AST greater than 25 times ULN), generally occurs only with larger overdoses and high initial serum iron levels (>1000 μg/dL). Jaundice is initially mild, while prolongation of the prothrombin time (or INR) and acidosis arise early (Case 1). The usual cause of death from iron poisoning is cardiac arrest, but deaths from hepatic failure as well as emergency liver transplantation for iron poisoning have been reported. Interestingly, the hepatic histological findings of acute iron hepatotoxicity are those of hemorrhagic, submassive necrosis which is predominantly peri-portal (zone 1), a finding typical of direct hepatotoxins that do not require hepatic metabolism for their toxicity. With more severe toxicity, the injury is massive and pan-lobular.
来源:LiverTox
