Bilirubin

Abstract

Bilirubin is the end product of the degradation of heme and heme proteins [1, 2]. The majority of the circulating bilirubin (80%–85%) is derived from the breakdown of hemoglobin, originating in senescent red blood cells, in the reticuloendothelial system. The remaining proportion derives from the destruction of maturing erythroid cells in the bone marrow (ineffective erythropoiesis) and from nonerythroid components involving the turnover of heme and heme proteins; these components constitute the “early-labeled” fraction of bilirubin. In adults up to 400 mg (4–5 mg/kg per day) of unconjugated bilirubin (UCB) is formed each day through enzymatic degradation of heme derived from hemoglobin (35 mg hemoglobin yields 350 mg UCB). UCB is metabolized by the liver to conjugated bilirubin (CB) via a multistep process, which can be divided into three distinct phases:

• Uptake by the hepatocyte, which involves the dissociation of the UCB-albumin complex, followed by internalization and binding to the cytoplasmic anionic binding protein Ligandin, which prevents the reflux of UCB back into the circulation.

• Conjugation, predominantly with glucuronic acid, which converts the bilirubin molecule into the water-soluble form (CB). The conjugation reaction occurs in the endoplasmic reticulum, catalyzed by specific isoforms of a group of membrane-bound enzymes known as uridine diphosphogluconurate glucuronosyltransferase (UGT), also called UDP glucuronyl transferase. This is a two-step process. producing bilirubin monoglucuronide (BMG) and then bilirubin diglucuronide (BDG), both of which are then excreted by the hepatocyte. The normal proportion of these conjugates in bile is 85% BDG and 15% BMG.

• Excretion into bile, an energy-dependent step, is rate limiting in bilirubin metabolism. Only CB can be excreted in the bile, primarily as BMG and BDG. Photoisomers of the naturally occurring Z-Z isomeric form of bilirubin are water soluble and thus can be excreted in the bile; this constitutes the rationale for phototherapy in the treatment of unconjugated hyperbilirubinemia. Any alteration in the excretion process results in a regurgitation of bilirubin back into the circulation, manifested as jaundice.