Acute intermittent porphyria (AIP) is an autosomal dominant metabolic disease caused by hepatic deficiency of hydroxymethylbilane synthase (HMBS), the third enzyme of the heme synthesis pathway. The dominant clinical feature is acute neurovisceral attack associated with high production of potentially neurotoxic porphyrin precursors due to increased hepatic heme consumption. Current Standard of Care is based on a down-regulation of hepatic heme synthesis using heme therapy. Recurrent hyper-activation of the hepatic heme synthesis pathway affects about 5% of patients and can be associated with neurological and metabolic manifestations and long-term complications including chronic kidney disease and increased risk of hepatocellular carcinoma. Prophylactic heme infusion is an effective strategy in some of these patients, but it induces tolerance and its frequent application may be associated with thromboembolic disease and hepatic siderosis. Orthotopic liver transplantation is the only curative treatment in patients with recurrent acute attacks. Emerging therapies including replacement enzyme therapy or gene therapies (HMBS-gene transfer and ALAS1-gene expression inhibition) are being developed to improve quality of life, reduce the significant morbidity associated with current therapies and prevent late complications such as hepatocellular cancer or kidney failure in HMBS mutation carriers with long-standing high production of noxious heme precursors. Herein, we provide a critical digest of the recent literature on the topic and a summary of recently developed approaches to AIP treatment and their clinical implications.

中文翻译：

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急性间歇性卟啉症的新兴疗法

急性间歇性卟啉症 (AIP) 是一种常染色体显性遗传代谢疾病，由血红素合成途径的第三种酶羟甲基胆烷合成酶 (HMBS) 肝缺乏引起。主要的临床特征是急性神经内脏发作，由于肝脏血红素消耗增加，导致潜在神经毒性卟啉前体的大量产生。当前的护理标准基于使用血红素疗法下调肝血红素合成。肝血红素合成途径的反复过度激活影响约 5% 的患者，并且可能与神经和代谢表现以及包括慢性肾病和肝细胞癌风险增加在内的长期并发症有关。在这些患者中，预防性血红素输注是一种有效的策略，但它会诱导耐受性，其频繁应用可能与血栓栓塞性疾病和肝铁质沉着症有关。原位肝移植是复发性急性发作患者的唯一治疗方法。新兴疗法包括替代酶疗法或基因疗法（HMBS-基因转移和阿拉斯1基因表达抑制）正在开发中，以提高生活质量，降低与当前疗法相关的显着发病率，并预防长期高产有害血红素前体的 HMBS 突变携带者的晚期并发症，如肝细胞癌或肾衰竭。在此，我们提供了有关该主题的最新文献的批判性摘要，并总结了最近开发的 AIP 治疗方法及其临床意义。