急性肝卟啉症（AHPs）是遗传性血红素合成障碍，其特征为由因子引起肝脏5-氨基戊酸合酶1（ALAS1）活性上调的急性神经内脏攻击。诱导肝脏ALAS1会导致卟啉前体物质的积累，尤其是5-氨基戊酸（ALA），被认为是导致急性攻击症状如剧烈腹痛和自主神经功能障碍的神经毒素介质。患者可能还会发展令人严重的慢性症状和长期医学并发症，包括肾脏疾病和肝细胞癌的增加风险。外源性血红素是历史上用于治疗攻击的治疗方法，通过抑制肝脏ALAS1活性发挥其治疗效果。急性攻击的病理生理提供了开发RNA干扰（RNAi）治疗的理论基础，该治疗可以抑制肝脏ALAS1表达。Givosiran是一种皮下给药的N-乙酰半乳糖胺（GalNAc）共价小干扰RNA，针对ALAS1，通过雌三醇糖蛋白受体几乎完全被肝细胞吸收。临床试验确认，通过每月给予givosiran来持续抑制肝脏ALAS1 mRNA，可以有效降低尿量中的ALA和卟胆原（PBG）含量，降低急性发作率，提高生活质量。常见的副作用包括注射部位反应和肝酶和肌酐水平升高。Givosiran分别在2019年和2020年被美国食品药品监督管理局和欧洲药品管理局批准用于治疗AHP患者。虽然givosiran有可能降低慢性并发症的风险，但缺乏关于长期阻断AHP患者ALAS1抑制的安全性和影响的长期数据。版权所有 © 2023美国血液学会。

The acute hepatic porphyrias (AHPs) are inherited disorders of heme biosynthesis characterized by life-threatening acute neurovisceral attacks precipitated by factors that upregulate hepatic 5-aminolevulinic acid synthase 1 (ALAS1) activity. Induction of hepatic ALAS1 leads to accumulation of porphyrin precursors, in particular 5-aminolevulinic acid (ALA), which is thought to be the neurotoxic mediator leading to acute attack symptoms such as severe abdominal pain and autonomic dysfunction. Patients may also develop debilitating chronic symptoms and long-term medical complications including kidney disease and increased risk of hepatocellular carcinoma. Exogenous heme is the historical treatment for attacks and exerts its therapeutic effect by inhibiting hepatic ALAS1 activity. The pathophysiology of acute attacks provided the rationale to develop an RNA interference (RNAi) therapeutic that suppresses hepatic ALAS1 expression. Givosiran is a subcutaneously administered N-acetyl galactosamine (GalNAc)-conjugated small interfering RNA against ALAS1 that is taken up nearly exclusively by hepatocytes via the asialoglycoprotein receptor. Clinical trials established that continuous suppression of hepatic ALAS1 mRNA via monthly givosiran administration effectively reduces urinary ALA and porphobilinogen (PBG) levels and acute attack rates and improves quality of life. Common side effects include injection site reactions and increases in liver enzymes and creatinine. Givosiran was approved by the U.S. Food and Drug Administration and European Medicines Agency in 2019 and 2020, respectively, for treatment of AHP patients. While givosiran has the potential to decrease the risk of chronic complications, long-term data on the safety and effects of sustained ALAS1 suppression in AHP patients are lacking.Copyright © 2023 American Society of Hematology.