The origins of bilirubin in humans as studied using labeled glycine, a substrate for the biosynthesis of heme. The studies summarized in this figure were conducted decades ago but were of fundamental importance for developing the notion of ineffective erythropoiesis. (A) Physiologic sources of bilirubin. After administration of labeled glycine (arrow), 2 peaks of labeled bile pigment (stercobilin, which derives from bilirubin in the intestine) were detected: one, corresponding to 10% to 20% of total labeled pigment, in the first few days after administration of labeled glycine and the second one at approximately 120 days, at the time of maximal disappearance of labeled hemin. This is a schematic representation of the experiments performed by London et al.⁵ (B) Components of early appearing bilirubin after administration of labeled glycine (arrow): 2 distinct peaks are visible in normal subjects. The first one after 12 to 24 hours has been related to the catabolism of porphyrins and heme-containing proteins in the liver (nonerythropoietic component of early appearing bilirubin). The second one on days 3 to 5 has been related to the catabolism of heme in bone marrow erythroid precursors (erythropoietic component of early appearing bilirubin). This is a schematic representation of the experiments performed by Yamamoto et al.⁶ (C) Potential sources of the erythropoietic component of early appearing bilirubin. Apoptosis of late-stage erythroblasts that are not reached by sufficient amounts of Epo and processing of the thin rim of cytoplasm attached to the nucleus at the time of its extrusion can be considered physiologic ineffective erythropoiesis. Professional illustration by Somersault18:24.