Schematic of the heme biosynthetic pathway with clinical correlates of three autosomal dominant AHPs: AIP, HCP, and VP; and autosomal recessive EPP. The 8 enzymatic steps (represented by arrows) and the key enzymes (protein abbreviations under arrows) highlight the pathobiological consequences of enzyme insufficiency. In patients with an AHP, induction of ALAS1 activity leads to buildup of the neurotoxic porphyrin precursors ALA and PBG, which distribute into tissues and cause neurovisceral signs and symptoms. The bar charts above the pathway depict the relative elevations of proximal and distal porphyrin precursors that are excreted into urine and feces with AIP, HCP, or VP during an acute symptomatic attack (dotted line represents relative 4-fold elevations above the upper ranges of normal). Relative fecal levels of coproporphyrin and protoporphyrin differentiate HCP from VP. Physiological inhibitors of ALAS1 include glucose and intracellular heme. Pharmacologic inhibitors include exogenous hemin and a hepatocyte-directed, small interfering RNA drug, givosiran, which targets the ALAS1 transcript. A fourth, extremely rare AHP is caused by ALAD deficiency. FECH mutations lead to erythrocyte buildup and leakage of PPIX. Lipophilic PPIX deposits in the skin, where it causes painful photosensitivity. Afamelanotide, which stimulates melanin production, can protect against photoactivation for patients with EPP. Biliary excretion of PPIX can lead to chronic cholestatic liver injury.