The AHPs and hepatic heme regulation. The 4 AHPs are AIP, VP, HCP, and ADP, which result from pathogenic variants in HMBS, PPOX, CPOX, and ALAD, respectively. ALAS1 is the first and rate-limiting step of heme synthesis. The induction of ALAS1 is responsible for the acute neurovisceral attacks of AHP and the accumulation of the neurotoxic intermediates ALA and PBG. Givosiran is an RNA interference medication that targets hepatic ALAS1, decreasing the levels of the ALAS1 enzyme. Hemin is intravenous heme that exerts its effect by negative feedback on ALAS1. Additionally, glucose increases insulin, which has an inhibitory effect on ALAS1 by both decreasing transcription and inhibiting the activity of PGC1α, a transcriptional coactivator that increases transcription of ALAS1. Professional illustration by Somersault18:24.